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2022v1.0
Gastrointestinal
and Liver Pathology
Gastrointestinal
and Liver Pathology
THIRD EDITION
A Volume in the SeriesFoundations in Diagnostic Pathology
Edited By
Amitabh Srivastava, MD
Member, Memorial Hospital
Attending, Memorial Hospital for Cancer and Allied Diseases
Memorial Sloan Kettering Cancer Center
New York, New York
Daniela S. Allende, MD, MBA

Co-Section Head, Gastrointestinal and Hepatobiliary Pathology
Vice Chair of Research
The Cleveland Clinic
Associate Professor of Pathology
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University
Cleveland, Ohio
Series Editor
John R. Goldblum, MD, FCAP, FASCP, FACG
Chairman
Department of Pathology
The Cleveland Clinic;
Professor of Pathology
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University
Cleveland, Ohio
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
GASTROINTESTINAL AND LIVER PATHOLOGY, ISBN: 978-0-323-52794-1

THIRD EDITION
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2019v1.0
To my mentors and my family
—AS
To my wonderful sons and husband for their love and support
—DA
Contributors
Daniela S.Allende, MD, MBA Ilyssa O.Gordon, MD, PhD

Co-Section Head, Gastrointestinal and Hepatobiliary Associate Professor of Pathology
Pathology Co-Section Head, Gastrointestinal and Hepatobiliary
Vice Chair of Research Pathology
The Cleveland Clinic; Cleveland Clinic
Associate Professor of Pathology Cleveland, Ohio
Cleveland Clinic Lerner College of Medicine at Case Non-Neoplastic Disorders of the Esophagus
Western Reserve University
Cleveland, Ohio Catherine Hagen, MD
Non-Neoplastic Disorders of the Liver; Liver Neoplasms, Consultant, Division of Anatomic Pathology
and Pathology of the Liver; and Small Bowel and Assistant Professor of Laboratory Medicine and
Pancreas Transplantation Pathology
Mayo Clinic
Lodewjk A.A.Brosens, MD, PhD Rochester, Minnesota
Associate Professor of Pathology Tumors of the Esophagus
Gastrointestinal and Endocrine Pathology
UMC Utrecht, Netherlands BenceKövari, MD, PhD
Non-Neoplastic and Neoplastic Pathology of the Assistant Professor
Pancreas Department of Pathology
University of Szeged
MichaelCruise, MD, PhD Albert Szent-Györgyi Medical School,
Associate Professor of Pathology Hungary Department of Pathology
Gastrointestinal and Hepatobiliary Pathology Staff H. Lee Moffitt Cancer Center & Research Institute
Informatic Systems Medical Director Tampa, FL
Department of Pathology Epithelial Polyps and Neoplasms of the Stomach
Cleveland Clinic
Cleveland, Ohio Gregory Y.Lauwers, MD, PhD
Gastrointestinal Lymphoma Professor of Pathology
Moffit Cancer Center
JamesConner, MD, PhD
Tampa, Florida
Assistant Professor
Non-Neoplastic Disorders of the Stomach and Epithelial
Department of Laboratory Medicine & Pathobiology
Polyps and Neoplasms of the Stomach
University of Toronto
Toronto, Canada Mikhail Lisovsky, MD
Pathology of the Gallbladder and Extrahepatic Bile Associate Professor of Pathology and Laboratory
Ducts Medicine
Leona Doyle, MD Geisel School of Medicine, Dartmouth
Associate Professor of Pathology Department of Pathology
Harvard Medical School Dartmouth Hitchcock Medical Center
Department of Pathology Lebanon, New Hampshire
Brigham and Women’s Hospital Pathology of the Anal Canal
Boston, Massachusetts
Gastrointestinal Mesenchymal Tumors
vii
viii Contributors
Mari Mino-Kenudson, MD Safia NawazishSalaria, MD, MMHC

Professor of Pathology Section Chief and Fellowship Director
Pulmonary Pathology Director Division of GI, Liver and Pancreas Pathology
Gastrointestinal Pathology Staff Diversity, Equity, and Inclusion Officer
Massachusetts General Hospital Associate Professor, Pathology, Microbiology and
Boston, Massachusetts Immunology
Non-Neoplastic and Neoplastic Pathology of the Pancreas Vanderbilt University Medical Center
Nashville, Tennessee
Reetesh K.Pai, MD
Liver Neoplasms
Professor of Pathology
Anatomic Pathology Director Amitabh Srivastava, MD
UPMC Presbyterian Member, Memorial Hospital
Gastrointestinal Pathology Center of Excellence Director Attending, Memorial Hospital for Cancer and Allied
Pittsburgh, PA, USA Diseases
Neoplasms of the Small Bowel Memorial Sloan Kettering Cancer Center
New York, New York
RishK. Pai, MD, PhD
Tumors of the Esophagus, Gastrointestinal Polyposis
Professor of Laboratory Medicine and Pathology
Syndromes, Pathology of the Gallbladder and
Department of Laboratory Medicine and Pathology
Extrahepatic Bile Ducts, and Liver Neoplasms
Consultant
Mayo Clinic Arizona Sarah E.Umetsu, MD
Phoenix, Arizona Assistant Professor
Non-Neoplastic Disorders of the Colon Department of Pathology
University of California San Francisco
Nicole C.Panarelli, MD
San Francisco, California
Non-Neoplastic Disorders of the Stomach
Albert Einstein College of Medicine
Section Head, Gastrointestinal Pathology Kwun WahWen, MD, PhD
Director of Anatomic Pathology Research Associate Professor
Montefiore Medical Center Department of Pathology
New York, N
ew York University of California San Francisco
Infectious Diseases of the Gastrointestinal Tract San Francisco, California
Epithelial Polyps and Neoplasms of the Stomach
DavidPapke, MD, PhD
Instructor in Pathology Laura D.Wood, MD, PhD
Department of Pathology Associate Professor of Pathology & Oncology
Brigham and Women’s Hospital Department of Pathology
Boston, Massachusetts Johns Hopkins University School of Medicine
Gastrointestinal Mesenchymal Tumors Baltimore, Maryland
Non-Neoplastic and Neoplastic Pathology of the
Deepa T.Patil, MBBS, MD
Pancreas
Harvard Medical School Lisa M.Yerian, MD
Pathologist Chief Improvement Officer
Brigham and Women’s Hospital Associate Professor of Pathology
Boston, Massachusetts Gastrointestinal and Hepatobiliary Pathology Staff
Non-Neoplastic and Inflammatory Disorders of the Cleveland Clinic
Small Bowel; Non-Neoplastic and Neoplastic Disorders Cleveland, Ohio
of the Appendix; Epithelial Neoplasms of the Colorectum, Non-Neoplastic Disorders of the Liver and Pathology of
Molecular Testing of Colorectal Carcinoma; and Pathology the Liver, Small Bowel, and Pancreas Transplantation
of the Liver, Small Bowel, and Pancreas Transplantation
ScottRobertson, MD, PhD
Assistant Professor of Pathology
Research Analytics Medical Director
Gastrointestinal Pathology Staff
Cleveland Clinic
Cleveland, Ohio
Non-Neoplastic and Inflammatory Disorders of the
Small Bowel
Foreword
The study and practice of anatomic pathology are both pancreas, and liver. The list of contributors is impressive
exciting and overwhelming. Surgical pathology, with all and includes nationally and internationally renowned
of the subspecialties it encompasses, and cytopathology pathologists who excel in their areas of expertise. The
have become increasingly complex and sophisticated, content in each chapter is practical, well organized, and
particularly with the incorporation of molecular pathol- well written, focusing on the thorough evaluation of
ogy. It is simply not possible for any single individual to biopsy and resection specimens and culminating in an
master all of the skills and knowledge required to per- accurate diagnosis using traditional morphology sup-
form these tasks at the highest level. Simply being able ported by immunohistochemical and molecular genetic
to make a correct diagnosis is challenging enough, but techniques.
the standard of care has far surpassed merely providing This edition of Gastrointestinal and Liver Pathology
a diagnosis. Pathologists are now asked to provide large is organized into 20 chapters, covering all of the major
amounts of ancillary information, both diagnostic and problems encountered in gastrointestinal pathology.
prognostic, often on small amounts of tissue, a task that There are separate chapters that describe the non-neo-
can be daunting even to the most experienced surgical plastic and neoplastic conditions of the esophagus, stom-
pathologist. ach, small intestine, appendix, colon, and anus. Superb
Although large general surgical pathology textbooks separate chapters on mesenchymal tumors of the gas-
are useful resources, by necessity, they could not pos- trointestinal tract, infectious diseases of the colon, and
sibly cover many of the aspects that pathologists need polyps and polyposis syndromes allow for the necessary
to know and include in their diagnostic reports. As depth to cover these broad topics. In addition, pathology
such, the concept behind the F oundations in Diagnostic of the gallbladder, extrahepatic bile ducts, and pancreas
Pathology series was born. F oundations in Diagnostic are covered in separate chapters, each of which provides
Pathology is designed to cover the major areas of sur- the essential information and nuances of the organ that
gical and cytopathology, and each edition is focused on is covered. The last four chapters of the book cover
one major topic. The goal of every book in this series is non-neoplastic liver pathology, transplantation, liver
to provide the essential information that any patholo- neoplasms, and gastrointestinal lymphomas. I know of
gist, whether general or subspecialized, in training or in no other book in the literature that covers all of these
practice, would find useful in the evaluation of virtually aspects of gastrointestinal pathology in such a concise
any type of specimen encountered. manner. Moreover, many of the photomicrographs are
I am pleased that Drs. Daniela S. Allende and Amitabh new to this edition.
Srivastava agreed to edit this edition of their book. Both I wish to extend my sincere appreciation to Drs.
of these individuals are superb gastrointestinal pathol- Allende and Srivastava, as well as all of the authors
ogists from major academic centers (Cleveland Clinic who contributed to this outstanding edition in the
and Memorial Sloan Kettering Cancer Center, respec- Foundations in Diagnostic Pathology series. I sincerely
tively), and they have edited an outstanding, state-of- hope you enjoy this volume in the F oundations in
the-art book on gastrointestinal pathology, which cuts Diagnostic Pathology series.
to the essentials of what all pathologists want and need
to know about diseases of the tubular gut, biliary tree, John R. Goldblum, MD
ix
Preface
The practice of gastrointestinal, hepatobiliary, and pan- by numerous tables and illustrations. This should allow
creatic pathology has undergone significant changes rapid skimming through any chapter or section to gather
since the publication of the second edition of this book. the most relevant information that may be of interest to
To keep up with the ever-expanding pool of knowledge, a particular reader. We are deeply grateful to the editors
addition of multiple new entities and the increasing inte- of the previous editions for giving us a wonderful tem-
gration of molecular pathology into anatomic pathology plate to work with and even more to all the authors who
can be incredibly challenging. This is more so in an envi- contributed time, effort, and expertise while submitting
ronment of increasing daily workloads, physician stress, chapters for this third edition. We would not have been
and burnout that applies not just to pathologists in prac- able to bring this book to fruition without their invalu-
tice but also those in residency or fellowship training. We able support. Our hope is that this book will provide a
are delighted to have this opportunity to put together the concise yet valuable sign out resource for all those inter-
third edition of G astrointestinal and Liver Pathology for ested in gastrointestinal pathology.
the Foundations in Diagnostic Pathology series for all of
you. Each chapter in this edition retains the novel struc- Amitabh Srivastava, MD
tured format of the prior editions that is complemented Daniela S. Allende, MD, MBA
xi
Acknowledgments
The editors acknowledge the tireless support and patience

at Elsevier of Michael Houston, who has kept us on track,
and Rishi Arora and Haritha Dharamrajan, who went
through each and every page of the text with great care.
Amitabh Srivastava, MBBS

xiii
Contents
1 Non-Neoplastic Disorders of the 12 Epithelial Neoplasms of the

Esophagus 1 Colorectum 363
Ilyssa O. Gordon, MD, PhD Deepa T. Patil, MD
2 Tumors of the Esophagus 29 13 Molecular Testing of Gastrointestinal

Catherine Hagen, MD and Amitabh Srivastava, MD
Neoplasms 395
Daniela S. Allende, MD, MBA and
3 Non-Neoplastic Disorders of the Amitabh Srivastava, MD
Stomach 53
Sarah E. Umetsu, MD and Gregory Y. 14 Pathology of the Anal Canal 407
Lauwers, MD Mikhail Lisovsky, MD
4 Epithelial Polyps and Neoplasms of the 15 Pathology of the Gallbladder and
Stomach 91 Extrahepatic Bile Ducts 435
Bence Kövari, MD, PhD, Kwun Wah Wen, MD, PhD, James Conner, MD, PhD and Amitabh Srivastava, MD
and Gregory Y. Lauwers, MD, PhD
16 Non-Neoplastic and Neoplastic
5 Non-Neoplastic and Inflammatory Pathology of the Pancreas 455
Disorders of the Small Bowel 119 Lodewijk A.A. Brosens, MD, PhD, Mari Mino-
Scott Robertson, MD, PhD and Deepa T. Patil, MD Kenudson, MD, and Laura D. Wood, MD, PhD
6 Neoplasms of the Small Intestine 151 17 Non-Neoplastic Disorders of the

Reetesh K. Pai, MD
Liver 489
Daniela S. Allende, MD, MBA and Lisa M. Yerian, MD
7 Gastrointestinal Mesenchymal
Tumors 169 18 Liver Neoplasms 557
David Papke, MD, PhD and Leona Doyle, MD Safia N. Salaria, MD, Amitabh Srivastava, MD, and
8 Non-Neoplastic and Neoplastic
Disorders of the Appendix 211 19 Gastrointestinal Lymphoma 613
Michael Cruise, MD, PhD
Deepa T. Patil, MD
9 Infectious Diseases of the 20 Pathology of Liver, Small Bowel, and

Gastrointestinal Tract 243 Pancreas Transplantation 657
Daniela S. Allende, MD, MBA, Lisa M. Yerian, MD, and
Nicole C. Panarelli, MD
Deepa T. Patil, MD
10 Non-Neoplastic Disorders of the Index 691

Colon 299
Rish K. Pai, MD, PhD
11 Gastrointestinal Polyposis

Syndromes 337
Amitabh Srivastava, MD
xv
1
Non-Neoplastic Disorders of the Esophagus
■ Ilyssa O. Gordon, MD, PhD
The esophagus is designed to simply serve as a conduit ■ ESOPHAGITIS

to carry food into the stomach. It does not have any
digestive, endocrine, or metabolic role. As a result, most
non-neoplastic disorders affecting the esophagus are a Inflammatory Disorders
result of mechanical, chemical, or immune-mediated
injury to the relatively resilient nonkeratinizing squa- Reflux Esophagitis
mous mucosa. These disorders can be broadly catego-
rized into inflammatory, infectious, congenital and Reflux esophagitis, also known as gastroesophageal
acquired structural abnormalities; motility, traumatic, reflux disease (GERD), is one of the most common
and vascular disorders; and those associated with sys- non-neoplastic disorders of the esophagus. Its preva-
temic diseases. Inflammatory disorders and infections lence ranges between 5% and 22% and depends on
are by far the most common disorders encountered in the geographic location. The reported prevalence of
daily practice. The remainder of the disorders usually GERD is 22% in the United States. Pregnant women
require a combination of clinical, radiographic, and have a higher incidence. The pathophysiologic hallmark
endoscopic examinations for accurate diagnosis, and of reflux is the presence of lower esophageal sphincter
histologic examination often does not yield specific diag- (LES) dysfunction. Nonerosive reflux disease (NERD)
nostic findings. is defined as patients with classic GERD symptoms but
This chapter is organized based on broad categories no evidence of mucosal injury on endoscopy.
of non-neoplastic esophageal disorders. It is, however,
essential to note that inflammatory disorders are a man- Clinical Features
ifestation of several common types of stimuli, such as
reflux, infections, drugs, and systemic disorders, among Reflux occurs at all ages and in both genders. Typical
others. Therefore, based on the predominant inflamma- symptoms include heartburn and regurgitation. Other
tory cell, these disorders can also be categorized into uncommon or atypical symptoms include dysphagia,
neutrophil-rich esophagitis, eosinophil-rich, lympho- angina-like chest pain, chronic hoarseness or cough,
cyte-rich, and paucicellular esophagitis. Neutrophil-rich asthmatic episodes, and protracted hiccups. If left
disorders are most commonly caused by reflux disease untreated, reflux may lead to complications such as ero-
and infections (see Chapter 9 for details). Eosinophil- sive esophagitis, strictures, Barrett’s esophagus (BE),
rich disorders include eosinophilic esophagitis (EoE), and malignancy. Importantly, a number of individuals
reflux, parasitic infections, Crohn’s disease, drug hyper- with reflux do not manifest symptoms, although the risk
sensitivity, hypereosinophilic syndrome, celiac disease, for adenocarcinoma arising from BE remains. GERD
vasculitis, and collagen vascular disorders. Lymphocytes may be a secondary complication of other disorders
are a predominant component of inflammation in affecting the esophagus, such as systemic sclerosis.
patients with chronic reflux, drugs or medications, Gastroesophageal reflux disease is a clinical diagno-
Crohn’s disease (pediatric), achalasia or motility disor- sis and is often classified as erosive or nonerosive based on
ders, autoimmune diseases, immunodeficiency (human endoscopic or pathologic findings. The current recommen-
immunodeficiency virus [HIV], common variable immu- dations from the American Society of Gastrointestinal
nodeficiency [CVID]), celiac disease, and dermatologic Endoscopy do not support using endoscopy and biopsy to
conditions. Last, some conditions, such as corrosive diagnose typical GERD but rather to exclude other pathol-
injury, sloughing esophagitis, graft-versus-host disease ogies in complicated or refractory cases. Furthermore, the
(GVHD), CVID, and certain medications may not show degree of histologic damage may not correlate with clin-
a significant inflammatory component and thus manifest ical symptoms, and histologic findings alone have a low
as paucicellular esophagitis. sensitivity and specificity for diagnosing GERD.
1
2 Gastrointestinal and Liver Pathology
Pathologic Features
Gross Findings
Endoscopic examination in cases of reflux is variable,
depending on the severity and the chronicity of the
symptoms. Some patients may have erythema, erosions,
or ulceration. Deep ulcerations, bleeding, and peptic
strictures are seen in severe cases (Fig. 1.1). Patients
with NERD by definition have normal white-light
endoscopy, although high-definition endoscopy or nar-
row-band imaging may reveal subtle changes, including
prominent vascularity and irregularity of the gastro-
esophageal junction (GEJ), creating a group of patients
with so-called minimal change esophagitis.
Microscopic Findings
FIGURE 1.2
Histologic findings are usually localized to the lower Reflux esophagitis. Basal cell hyperplasia, elongation of papillae, and
esophagus and taper off or are virtually absent in the spongiosis.
proximal segment of esophagus. The typical histo-

logic features include basal cell hyperplasia (thicken-
ing of the basal layer to >15% of the total epithelial
thickness or more than four to six basal cell layers
in well-oriented sections), elongation of the papillae
(>60% of the total epithelial thickness), and spongio-
sis (Fig. 1.2). Inflammatory changes include increased
numbers of lymphocytes (Fig. 1.3), neutrophils, and
eosinophils (Fig. 1.4). Erosions or ulcers are typically
associated with severe GERD. Intraepithelial lympho-
cytes are predominantly T cells, which tend to acquire
an elongated shape (“squiggly lymphocytes”) while
traversing between the intercellular spaces. Additional
findings including balloon cell change (Fig. 1.5) and
hyperkeratosis.
The presence of dilated intercellular spaces (spongio- FIGURE 1.3
sis; see Fig. 1.3) was once considered to be a promising Reflux esophagitis. Increased numbers of intraepithelial lymphocytes are
histologic marker of early GERD. It may be the predom- present among dilated intercellular spaces (spongiosis).
inant histologic finding in a patient with GERD; how-
ever, given the low interobserver agreement in assessing
this feature, it remains less helpful compared with other
FIGURE 1.1 FIGURE 1.4

Esophagitis. Severe, with hemorrhagic erosions. (Courtesy of Dr. P. Vasallo.) Reflux esophagitis. Intraepithelial eosinophils (arrows).
CHAPTER 1 Non-Neoplastic Disorders of the Esophagus 3
A B
FIGURE 1.5
Reflux esophagitis. Balloon cells can be present along the luminal aspect (A) or within (B) the squamous epithelium.
typical features of GERD described already. It should esophagitis reveals yeast and pseudohyphal forms that
be noted that many patients undergoing endoscopic invade the mucosa and are accompanied by severe acute
biopsy have been on a trial of proton pump inhibitors inflammation. Squamous epithelial cells infected with
(PPIs) and may have been asked to discontinue the med- HSV show multinucleation, nuclear molding, and mar-
ications 1 or 2 weeks or before endoscopy. In this set- gination of chromatin. Viral cytopathic effect of CMV
ting, the most common histologic features are increased is best appreciated in stromal and endothelial cells
intraepithelial lymphocytes, basal layer hyperplasia, and within granulation tissue where large, infected cells
elongation of the papillae. The finding of basal layer show intranuclear and intracytoplasmic eosinophilic
hyperplasia, elongation of the papillae, and a few eosin- inclusions.
ophils within 1 to 2 cm of the GEJ may also represent Pill esophagitis can be associated with prominent
physiologic reflux. This finding is of no clinical signifi- eosinophilia, spongiosis, and ulceration. These changes
cance. In a recent prospective evaluation of 336 patients are nonspecific and need to be analyzed in light of the
with clinical symptoms of GERD, Vieth et al. (2016) clinical presentation. Polarizable crystalline mate-
found that total epithelial thickness of 400 µm or greater rial may be seen in alendronate-related injury, and
at 0.5 cm and 430 µm or greater at 2.0 cm above the Z crystalline stainable iron can be found in ferrous sul-
line was the best histologic feature to reliably identify fate-induced esophagitis. Lymphocytic esophagitis (LE),
patients with GERD. skin disorders such as lichen planus, and esophageal
Although endoscopically normal, patients with dysmotility states, such as achalasia and strictures, are
NERD may have dilated intercellular spaces (spongio- in the differential diagnosis when increased intraepi-
sis), as well as basal layer hyperplasia and elongation of thelial lymphocytes are present. Esophagitis can also be
the papillae of the squamous epithelium, often grouped seen in Crohn’s disease, sarcoidosis, GVHD, collagen
together as reactive epithelial change, without signif- vascular disease, or Stevens-Johnson syndrome.
icant inflammation. Reporting these findings may be
helpful to distinguish patients with NERD from those Prognosis and Therapy
with functional heartburn.
Prognosis depends on the degree of LES pressures.
Differential Diagnosis Extremely low pressures (6 mm Hg) predict a more
severe degree of reflux and worse prognosis. Early
Eosinophilic esophagitis, infectious esophagitis, and diagnosis, before the onset of extensive ulcers and
pill esophagitis are in the differential diagnosis. In strictures, is essential for best patient outcome.
EoE, there is an increased density of eosinophils per Conservative therapy includes significant lifestyle
high-power field (hpf) along with eosinophil microab- modifications, such as elevation of the head of the
scess formation and superficial layering of eosinophils. bed, avoiding recumbence after meals, weight loss in
More importantly, EoE affects both the distal as well as obese patients, avoiding dietary triggers, and avoid-
proximal segments of the esophagus, is associated with ing tobacco and alcohol consumption. PPIs, histamine
characteristic rings and furrows on endoscopy, and is 2 receptor antagonists, and antacids are the mainstay
resistant to PPI therapy. medical therapy for GERD. Nissen fundoplication
Infectious esophagitis, such as that caused by and laparoscopic sphincter augmentation are surgical
Candida, herpes simplex virus (HSV), and cytomeg- options for those who have failed medical or endoscopic
alovirus (CMV) shows specific features. Candida therapy,
■ EOSINOPHILIC ESOPHAGITIS
REFLUX ESOPHAGITIS—FACT SHEET
Definition Clinical Features

n Inflammation of the lower esophagus resulting from damage
caused by acid reflux from the stomach

Eosinophilic esophagitis is a primary clinicopathologic
Incidence and Location disorder of the esophagus that has been associated with
n The most common form of esophagitis, with prevalence of about an increasing prevalence and has gained significant rec-
22% in the United States ognition over the past few years. It is defined as a chronic
n Localized to the distal esophagus
immune and antigen-mediated esophageal disease char-
acterized clinically by symptoms related to esophageal
Gender and Age Distribution
dysfunction and histologically by eosinophil-predomi-
n Affects both sexes and all age groups
nant inflammation. Three specific criteria are required
Clinical Features to diagnose EoE: symptoms related to esophageal dys-
n Heartburn and regurgitation are the typical symptoms; dysphagia
function, a peak eosinophil count of at least 15 eosino-
also occurs phils/hpf on esophageal biopsy, and eosinophilia limited
n Atypical presentation includes angina-like pain, hoarseness, to the esophagus with other causes of esophageal eosin-
cough, asthma, and hiccups ophilia excluded. Although one of the clinical features
n Some individuals are asymptomatic
of EoE is the lack of response to PPIs, recent studies
Prognosis and Therapy
have shown that one-third or more patients with esoph-
n Prognosis depends on the degree of lower esophageal sphincter
ageal eosinophilia can show response to PPIs. This phe-
pressure nomenon has been termed PPI-responsive esophageal
n Early detection prevents complications eosinophilia. A recent transcriptome analysis study by
n If left untreated, severe ulcerations, strictures, Barrett’s esophagus, Wen et al. (2015) found significant molecular overlap
and adenocarcinoma may develop between PPI-responsive esophageal eosinophilia and
n Treatment includes lifestyle modifications, proton pump inhibitors,
and surgical procedures (Nissen fundoplication) in severe cases

EoE, suggesting these two entities represent a diagnos-
tic continuum or that PPI-responsiveness is a subpheno-
type of EoE. However, this relationship is yet to be fully
characterized.
Eosinophilic esophagitis occurs in all age groups but
Reflux Esophagitis—Pathologic Features is seen more frequently in young children with atopic
symptoms such as eczema, asthma, and food allergies.
Gross Findings Symptoms manifest differently in different age groups:
n Half of symptomatic patients have normal endoscopic whereas infants and children often present with feed-
examinations ing difficulties, regurgitation, dyspepsia, abdominal
n Erythema, erosions, or ulceration can be seen
n Deep ulcers are followed by strictures in severe disease

pain, and vomiting, adults usually describe dysphagia
n Barrett’s esophagus (salmon-colored mucosal tongues) may be
and food impaction with or without chest or abdominal
present in long-standing cases pain. If not recognized early, EoE can progress to odyno-
phagia and stenosis.
n Architectural changes of basal cell layer hyperplasia, elongation of
papillae, and spongiosis

n Increased numbers of intraepithelial eosinophils, lymphocytes,
and/or neutrophils EOSINOPHILIC ESOPHAGITIS—FACT SHEET

n Erosion or ulceration
n Balloon cell change, hyperkeratosis, and increased total epithelial Definition

thickness may be seen n A form of allergic esophagitis associated with atopic symptoms
n Can present alone or as part of eosinophilic gastroenteritis

Differential Diagnosis
n Eosinophilic esophagitis has proximal esophageal involvement Incidence and Location
and often has more severe eosinophilic infiltrates, superficial n 1% to 2% of patients undergoing esophageal biopsy
eosinophil layering, and eosinophilic microabscesses n The entire esophagus is involved; proximal eosinophil count may
n Infectious esophagitis (Candida, herpes simplex virus, and
be higher than distal; eosinophils may be patchy in distribution
cytomegalovirus) can be assessed on hematoxylin and eosin and
confirmed by special stains and immunohistochemical stains
n Lymphocytic esophagitis and lymphocyte-rich skin disorders
n Occurs in all age groups but is more common in the children and
typically have only lymphocytes without neutrophils or
eosinophils but require clinical correlation young adults
n Men are more frequently affected than women
n Pill esophagitis and Crohn’s disease require clinical correlation
Clinical Features
n Symptoms in children include vomiting, abdominal pain,
dyspepsia, and solid food impaction

n Symptoms in adults include dysphagia, food impaction, and chest
and abdominal pain

n Associated with food allergies and atopic symptoms

n Best outcome if diagnosed and treated early
n May lead to severe esophageal strictures if untreated
n Elimination of food allergens and topical corticosteroids are the
treatments of choice
n When strictures occur, dilation is indicated
Pathologic Features
FIGURE 1.7
Eosinophilic esophagitis—endoscopy. Typical furrows and rings. (Courtesy of
Gross Findings Dr. J. Gramling.)
Classic endoscopic findings include mucosal rings, fur-

rows (also known as “trachealization” of the esoph-
agus), granularity, exudates, and mucosal fragility
(Figs. 1.6 and 1.7). However, in some patients, the
endoscopic findings can be completely normal. In long-
standing cases, stricture formation may be seen.
Biopsies show increased intraepithelial eosinophils

(≥15 eosinophils/hpf) with concentration of eosinophils
toward the luminal aspect of the epithelium (superficial
layering). Eosinophilic microabscesses and degranula-
tion of eosinophils (Fig. 1.8) are frequently present. The
density of eosinophils can vary with anatomic location
of biopsy and within biopsy fragments. In general, biop-
sies from the proximal segment reveal more eosinophilia
than the distal segment. It is therefore recommended
that the total number of eosinophils per high-power field
FIGURE 1.8
Eosinophilic esophagitis. Intense eosinophilic infiltrate.
be generated by examining the fragments at low magni-

fication and selecting the high-power field with maxi-
mum number of eosinophils (Fig. 1.9). Care should be
taken to avoid counting eosinophils within the papillae.
Other findings include basal cell hyperplasia, elongation
of the papillae to greater than 50% the thickness of the
squamous epithelium, spongiosis, lamina propria, and
submucosal fibrosis. In patients who have received diet
FIGURE 1.6 elimination or steroid therapy, follow-up biopsies may
Eosinophilic esophagitis—endoscopy. Mucosal granularity. (Courtesy of Dr. J. be performed to evaluate response to therapy, in which
Gramling.) case, giving the exact eosinophil count may be helpful.
be seen in patients with reflux esophagitis. Distal esopha

Eosinophilic Esophagitis—Pathologic Features gus-predominant mucosal changes with unremarkable
proximal esophageal biopsy favors a diagnosis of reflux
Gross Findings
esophagitis. Pill-induced esophagitis is often accompa-
n Endoscopic examination reveals mucosal rings, furrows
(“trachealization” of esophagus), erythema, and granularity nied by ulcer and granulation tissue. Some medications
n In long-standing cases, strictures are seen (alendronate, iron supplements) can be visualized on
light microscopy. However, confirmation of drug-induced
Microscopic Findings injury requires clinicopathologic correlation. Eosinophilic
n Marked increase in intraepithelial eosinophils (≥15/hpf)
gastroenteritis is usually associated with peripheral blood
n Eosinophil infiltrates may be more prominent in the proximal than
eosinophilia and affects the rest of the gastrointestinal
in the distal esophagus
n Superficial layering of eosinophils, eosinophilic microabscesses,
(GI) tract. Parasitic infections tend to be a localized
and degranulation phenomenon, and deeper levels may reveal the organism.
n Additional findings include basal cell hyperplasia, elongation of
the papillae, spongiosis, and fibrosis of the lamina propria and

submucosa
n Reflux esophagitis changes are mostly seen in biopsy samples
from the distal esophagus or gastroesophageal junction The prognosis is excellent when treatment is given
n In eosinophilic gastroenteritis, eosinophils are also present in promptly. Dietary elimination of the six common
other segments of the gastrointestinal tract offending foods (milk, egg, wheat, soy, peanuts and
n Drug-induced injury to the esophagus requires clinicopathologic
tree nuts, and seafood) and topical steroids leads to dra-
correlation
n Parasitic infections do not typically affect the entire esophagus.
matic improvement in symptoms and histology. Rarely,
Biopsy specimens may show parasitic organisms patients refractory to steroid therapy may show disease
progression in the form of esophageal strictures that
require repeated dilation procedures.
■ LYMPHOCYTIC ESOPHAGITIS
Lymphocytic esophagitis is a poorly defined clinico-

pathologic entity. A variety of clinical diagnoses may be
associated with increased intraepithelial lymphocytes
on biopsy; therefore, lymphocytic esophagitis pattern of
injury is the preferred diagnostic terminology used by
many pathologists. Some studies have demonstrated
that the increased intraepithelial lymphocytes of LE
in patients with dysmotility are predominantly CD4+
T cells, in contrast to the normally present scattered
intraepithelial lymphocytes, which are CD8+ T cells. In
patients with LE and normal motility, both CD4+ and
CD8+ T cells are increased.
Clinical Features
FIGURE 1.9 Symptoms include dysphagia, chest pain, heartburn,

Eosinophilic esophagitis. Intraepithelial eosinophils (>20/hpf). nausea, and odynophagia. Symptoms can lead to a clin-
ical impression of EoE. Adults and children both can be
affected, and most patients are diagnosed in the fifth or
sixth decade of life. Men and women are equally affected.
Many patients diagnosed with LE also have potentially
Eosinophilic esophagitis must be distinguished from confounding diagnoses, including GERD, inflamma-
reflux esophagitis, pill-induced esophagitis, eosinophilic tory bowel disease (IBD), hypothyroidism, allergies
gastroenteritis, and parasitic infections. It is important to or asthma, history of radiation or chemotherapy, and
note that any of the histologic features of EoE can also connective tissue disease.
Pathologic Features neutrophils and eosinophils. Esophageal Crohn’s disease

is characterized by increased intraepithelial lympho-
cytes, especially in the pediatric population. Granulomas
Gross Findings may be seen in some cases. However, involvement of the
In about a quarter of patients, the endoscopic impres- rest of the GI tract is helpful in confirming a diagnosis
sion of the mucosa is normal. Endoscopic findings can of Crohn’s disease. Achalasia and other motility disor-
mimic those seen in EoE and include esophageal rings, ders can have increased intraepithelial lymphocytes on
esophagitis, and strictures. Findings suggestive of motil- biopsy but usually show radiographic and endoscopic
ity disorder may be identified. Erythema, nodularity, evidence of dysmotility. Inflammatory disorders of the
plaques, furrows, and webs have also been reported. skin, including lichen planus, can affect the esophagus
resulting in increased intraepithelial lymphocytes. The
presence of interface activity, hyperkeratosis, parakera-
tosis, dyskeratotic keratinocytes, or a history of inflam-
matory skin disease can be helpful.
The esophageal biopsy shows increased intraepithelial

lymphocytes, predominantly in a peripapillary distri-
bution, with spongiosis of the associated peripapillary
squamous epithelium (Fig. 1.10). Similar to EoE, the dis-
tribution of intraepithelial lymphocytes is usually patchy More than half of patients have symptomatic improve-
and can vary between different biopsy fragments, with ment with treatment, which most often includes a PPI.
some papillae being unaffected. Neutrophils or eosino- Patients with IBD may benefit from immunomodula-
phils are rare or even absent. There may be accompany- tory therapy. Dilation is often helpful in patients with
ing basal cell hyperplasia and spongiosis. Unfortunately, strictures. Follow-up endoscopic biopsies with the LE
there is no standard number of intraepithelial lym- pattern of injury have shown persistence of LE, progres-
phocytes to diagnosis LE, and studies have included sion to reflux or Crohn’s disease, or complete resolution
various minimum cut-offs of 20 lymphocytes, 30 lym- of histologic findings.
phocytes, or 50 lymphocytes per high-power field. It is
therefore appropriate to render a descriptive diagnosis
of “LE pattern of injury” with a comment consisting of
the various conditions that may result in this pattern
of injury. LYMPHOCYTIC ESOPHAGITIS—FACT SHEET
Definition
n Increased number of intraepithelial lymphocytes, predominantly
Differential Diagnosis peripapillary, within the squamous esophageal mucosa, with
associated spongiosis, and rare to no neutrophils or eosinophils
Increased intraepithelial lymphocytes can be seen
Incidence and Location
in reflux esophagitis, which typically shows more
n Incidence has been increasing over time
n Can be seen anywhere along the esophagus

n Men and women are equally affected
n Any age can be affected; most patients are diagnosed in the fifth
to sixth decade of life
Clinical Features
n Symptoms include dysphagia, odynophagia, chest pain, and
heartburn
n Patients may also carry a diagnosis of gastroesophageal reflux
disease, inflammatory bowel disease, or allergy

n Most patients have symptomatic improvement with proton pump
inhibitors
n Dysphagia is likely to resolve
n Gastrointestinal symptoms and histologic findings persist in some
FIGURE 1.10 patients

Lymphocytic esophagitis. Peripapillary lymphocytosis with spongiosis.
cell types are not prominent. Direct immunofluores-

Lymphocytic Esophagitis—Pathologic Features cence demonstrates globular immunoglobulin M (IgM)
deposits at the squamous–subsquamous interface in
Gross (Endoscopic) Findings
lichen planus and cases with negative direct immuno-
n Normal mucosa, esophageal rings, esophagitis, strictures,
features of motility disorder, erythema, nodularity, plaques,

fluorescence but with the other histologic features of
furrows, and webs lichen planus have been termed lichenoid esophagitis
pattern of injury.
n Increased peripapillary lymphocytes associated with
spongiosis and rare to no neutrophils or eosinophils on

biopsy of esophageal squamous mucosa Differential Diagnosis
n The lymphocytosis is patchy, with some unaffected papillae
Differential Diagnosis Graft-versus-host disease, achalasia and other motility

n Gastroesophageal reflux disease has more than rare disorders, Crohn’s disease, and reflux esophagitis with
granulocytes increased intraepithelial lymphocytes are prominent. LE
n Crohn’s disease may have granulomas and almost always has has a peripapillary lymphocytosis, rather than bandlike,
involvement of other gastrointestinal sites and lacks Civatte bodies.
n Motility disorders have radiographic and endoscopic evidence
of dysmotility
n Inflammatory disorders of skin may have interface activity,
hyperkeratosis, and dyskeratotic keratinocytes

Lichen planus is a chronic progressive disease that can

■ LICHEN PLANUS AND LICHENOID result in esophageal stricture or even squamous cell car-
ESOPHAGITIS cinoma (SCC). Immunomodulatory medications are the
mainstay of treatment.
Clinical Features
■ CROHN’S DISEASE
Lichen planus of the esophagus, or lichen planus esoph-
agitis, can occur with or without concurrent cutaneous
lichen planus. For both lichen planus and lichenoid Clinical Features
esophagitis pattern of injury, girls and women are
affected about three times more often than boys and Esophageal involvement in Crohn’s disease is uncom-
men. Adults and children can be affected, with a median mon, affecting about 6% of patients with Crohn’s
age of about 64 years. Clinical symptoms include dys- disease.
phagia and stricture and less commonly, esophagi-
tis, heartburn, chest pain, and hiatal hernia. Whereas
comorbidities including viral infections (HIV, hepatitis
Pathologic Features
B, and hepatitis C) have been reported in patients with
lichenoid esophagitis, hypothyroidism and rheumato-
logic diseases have been reported in patients with lichen Esophageal biopsies may show increased intraepithelial
planus esophagitis. Polypharmacy is associated with lymphocytes, especially in pediatric patients (Fig. 1.11).
both conditions. Well-formed, non-necrotizing epithelioid granulomas
may also be present. Active inflammation consisting of
intraepithelial neutrophils, erosion, or ulceration can be
seen.
Pathologic Features
The squamous epithelium and lamina propria are

involved by a dense band of predominantly T-cell lym-
phocytic infiltrates. Lymphocytic inflammation can be
patchy or diffuse and affect the upper and lower esopha- Knowledge of a patient’s diagnosis of Crohn’s dis-
gus. Apoptotic or otherwise degenerating squamous cells ease, by demonstrated involvement in other organs,
(Civatte bodies) in a lichenoid background are diagnosis useful when considering the differential diagnosis.
tic of lichen planus esophagitis. The background squa- Granulomatous esophagitis and LE are the main consid-
mous epithelium can be atrophic. Other inflammatory erations if there is no other evidence of Crohn’s disease
and rarely sloughing, can be seen. Chronic GVHD

may affect the esophagus with lamina propria fibrosis,
although this may be difficult to detect on biopsy.
Infectious esophagitis, pill esophagitis, sloughing esoph-

agitis, LE, cutaneous lichenoid disorders affecting the
esophagus, and mycophenolate injury are all in the dif-
ferential diagnosis and can be excluded by clinical his-
tory and special stains.
FIGURE 1.11
Crohn’s disease. Inflammation is predominantly lymphocytic with a few ■ IGG4-RELATED ESOPHAGEAL DISEASE
eosinophils and dyskeratotic keratinocytes.
Similar to other organ systems, a rare subset of patients

in other organs. Granulomatous esophagitis can be with IgG4-related disease can show esophageal involve-
caused by infections, such as mycobacteria and fungus, ment. The clinical presentation can be quite variable and
sarcoidosis, Wegener’s granulomatous, chronic granulo- includes strictures, posttreatment achalasia, erosive esoph-
matous disease, or some medications. agitis, and submucosal esophageal nodule. The diagnostic
criteria for IgG4-esophagitis include the presence of IgG4-
positive plasma cells (≥50 IgG4-positive plasma cells per
high-power field or a ratio of IgG4 to IgG-positive plasma
cells ≥50%) and two of the three major histologic features:
prominent lymphoplasmacytic inflammation, storiform
Patients with Crohn’s disease who have esophageal pattern of fibrosis, and obliterative phlebitis. Needless
involvement are treated similar to those with disease to say, these changes are best appreciated on esophageal
elsewhere in the GI tract, including antiinflammatory resection specimens. The biopsy findings tend to be quite
agents and immunomodulators. There is no reported variable and nonspecific. Whereas some cases may show
difference in prognosis for patients with Crohn’s disease ulceration with a marked increase in intraepithelial lym-
who have esophageal involvement. phocytes and plasma cells, others show an esophagitis dis-
secans superficialis–like pattern. Immunohistochemical
stain is helpful in highlighting a dominant population of
IgG4-positive plasma cells. A study by Clayton et al. (2014)
■ GRAFT-VERSUS-HOST DISEASE
found IgG4-positive plasma cells to be prominent in adults
with EoE, raising the possibility for a role of the IgG4 path-
Clinical Features
way in the pathophysiology of EoE. At this time, there is
no standard recommendation as to when to perform an
Esophageal involvement is uncommon in patients with IgG4 immunohistochemical stain, especially on biopsy
GVHD and usually accompanies involvement of other specimens.
parts of the GI tract. Symptoms of esophageal involve-
ment include dysphagia and chest pain. On endos-
copy, the mucosa appears friable and may be ulcerated.
Rarely, severe cases may show prominent sloughing of ■ THERAPY OR TOXIN-RELATED INJURY
the esophageal mucosa. RADIATION OR CHEMOTHERAPY
ESOPHAGITIS
Pathologic Features Clinical Features
A lichenoid pattern of intraepithelial lymphocytosis Esophageal symptoms in radiation injury depend on

along with scattered apoptosis manifested as dysker- factors such as total dose, time period, and previous sur-
atotic keratinocytes is characteristic. In acute GVHD, gery. At doses of 60 Gy (6000 rads), the esophagus suf-
neutrophilic inflammation, including erosions or ulcers fers irreversible damage. Acute radiation injury develops
after 2 weeks of therapy and consists of dysphagia, ody-

nophagia, and sometimes hematemesis and chest pain.
These symptoms subside after radiation stops. Sequelae
of radiation include strictures with dysmotility and
dysphagia.
Symptoms are similar with different chemotherapeu-
tic agents. When chemotherapy and radiation therapy
are given, their synergistic effect results in more severe
damage and more serious symptoms. The incidence of
severe acute esophagitis in patients with lung cancer
receiving chemoradiotherapy is 14%.
Pathologic Features FIGURE 1.13

Radiation esophagitis. Cytomegaly with pale nuclei, abundant cytoplasm, and
multinucleation.
Gross Findings
In acute cases, endoscopic examination reveals friable
mucosa with edema and coalescent ulcers (mucositis). pattern. Multinucleation as well as abundant vacu-
In chronic cases, strictures develop 13 to 21 months olated cytoplasm is common (Fig. 1.13). The nucle-
after therapy (Fig. 1.12). ar-to-cytoplasmic ratio is usually preserved. More
superficial biopsies show active esophagitis, granula-
tion tissue, or both.
Resection specimens of posttreatment esophageal car-
cinomas often show atrophic mucous glands, squamous
metaplasia of esophageal ducts, submucosal and mural
Biopsies are not often procured in the acute stage, fibrosis, and hyalinized vessels. These atrophic glands
but when examined, they show mucosal necrosis and should not be misinterpreted as residual tumor and can
edema. Histologic examination in chronic radiation be identified by their location and lobular configuration.
or chemotherapy esophagitis shows significant atypia The mural fibrosis may alter the wall architecture suf-
in epithelial and stromal cells. The cells are enlarged ficiently to make staging of residual tumor difficult. A
with hyperchromatic nuclei and a smudged chromatin localized ulcer may also be present.
The most important entities in the differential diagnosis

are malignancy and viral esophagitis. Malignant epithe-
lial cells and radiation- or chemotherapy-induced dam-
age can mimic each other and sometimes coexist in the
same patient. Malignant cells show an increased nucle-
ar-to-cytoplasmic ratio, hyperchromatic nuclei, irregu-
lar nuclear membranes, and mitotic activity. Malignant
glands may be simplified but are often angulated and do
not form a lobule as an atrophic gland would. Atypical
stromal cells are usually single cells with ill-defined cell
borders, smudged nuclear chromatin, and elongated cell
processes. It can mimic therapy-related changes in an
isolated malignant cell, which usually has a well-defined
cell border and denser eosinophilic cytoplasm. A cyto-
keratin immunostain can be helpful to confirm the pres-
ence of a malignant cell versus an atypical stromal cell.
Multinucleation can be confused with herpes infection,
FIGURE 1.12
but there is no molding or margination of chromatin.
Esophageal stricture. (From Turk JL, ed. Royal College of Surgeons of
England. Slide Atlas of Pathology. Alimentary Tract System. London, Gower Special immunostains for HSV are indicated to help in
Medical, 1986, with permission.) this differential diagnosis.
Prognosis and Therapy Differential Diagnosis

n Malignancy can coexist with radiation- or chemotherapy-induced
damage or can be missed if the clinical history is not known

Reversible damage occurs in doses lower than 6000 n Multinucleation or atypia of viral esophagitis can be confused
rads. There prognosis is more severe when the damage is with radiation- or chemotherapy-induced damage and atypia.
a result of both radiation and chemotherapy. Esophageal Immunohistochemical stains for viral entities should be used
dilation is indicated when stricture develops.
■ PILL ESOPHAGITIS
RADIATION OR CHEMOTHERAPY ESOPHAGITIS—FACT
SHEET Clinical Features
Definition
n Damage to the esophagus as a result of radiation, chemotherapy, Pill esophagitis is a result of esophageal injury that
or both occurs because of prolonged direct mucosal contact
with tablets or capsules taken in therapeutic doses.
Commonly implicated agents include antibiotics (partic-
The incidence of severe acute esophagitis in patients with lung
ularly doxycycline), potassium chloride, ferrous sulfate,
n
cancer receiving chemoradiotherapy is 14%

n Any part of the esophagus exposed to the therapy may be quinidine, and alendronate, among others.
affected Although the older adult population is more often
affected, pill esophagitis can occur at any age. The main
Clinical Features symptoms are sudden retrosternal pain and painful swal-
n Acute radiation injury occurs after 2 weeks of therapy, and lowing. The patient often gives a history of having taken
symptoms include dysphagia, odynophagia, hematemesis, and
the medication with little or no fluid just before going to
chest pain
n Chronic radiation injury resulting in stricture leads to dysmotility
bed and was aware that the pill had “stuck” in the chest.
and dysphagia Some patients present with atypical symptoms, suggest-
n Symptoms from chemotherapy are similar ing a myocardial infarction or reflux disease. Some med-
ications such as sodium valproate, ferrous sulfate, and
Prognosis and Therapy aspirin–caffeine compounds have been associated with
n Damage is reversible if exposure is less than 6000 rads
esophageal perforation and mediastinitis.
n The prognosis is worse when damage is from a combination of
radiation and chemotherapy

n Dilation is indicated for therapy of esophageal stricture
Pathologic Features
Gross Findings
Endoscopic examination reveals the presence of one or
Radiation or Chemotherapy Esophagitis—Pathologic
Features
more discrete ulcers, often containing residual pill frag-
ments. The lesions are more commonly seen at the level
Gross (Endoscopic) Findings of the aortic arch.
n Acute injury includes friable mucosa with edema and ulceration
n Chronic injury is characterized by stricture Microscopic Findings

Microscopic Findings Histologic findings are nonspecific and include superfi-
n Mucosal necrosis and edema are seen in the acute stage on cial erosions or ulcerations with marked acute inflamma-
biopsy
tion and florid granulation tissue (Figs. 1.14 and 1.15).
n Atypia of stromal cells and epithelial cells are seen in the chronic
stage However, many patients have prominent eosinophilia,

n Enlarged, hyperchromatic nuclei with smudged chromatin and spongiosis, and necrosis of the squamous epithelium.
multinucleation Polarizable crystalline material (alendronate) or stainable
n Vacuolated cytoplasm and preserved nuclear-to-cytoplasmic ratio crystalline iron can be demonstrated in the ulcer bed.
n In posttreatment resection specimens, there are atrophic mucous
glands, squamous metaplasia of esophageal ducts, fibrosis within

the wall (sometimes distorting the normal wall organization and Differential Diagnosis
architecture), and hyalinized vessels. Localized ulceration can also
be seen Severe GERD, infections, and EoE can mimic pill
esophagitis. Fungal or viral infection can be excluded
Pill Esophagitis—Pathologic Features
Gross Findings
n One or more discreet ulcers, which may contain pill fragments,
most commonly at the level of the aortic arch
n Nonspecific erosions or ulcerations
n Prominent eosinophilia, spongiosis, and necrosis of the
squamous epithelium
n Pill fragments or polarizable or stainable crystalline material can
sometimes be seen
FIGURE 1.14
n Severe gastroesophageal reflux disease and eosinophilic
Pill esophagitis. Esophageal mucosa with ulceration.
esophagitis have basal cell hyperplasia, spongiosis, and prior
typical clinical symptoms
n Fungal or viral infections can be excluded by special stains and
immunohistochemistry
by special stains. GERD and EoE are typically associ-

ated with other salient histologic findings of basal cell
hyperplasia, spongiosis, and history of prior clinical
symptoms.
Most patients have an uneventful recovery after discon-

tinuing use of the medication. Antireflux medication
and topical anesthetics may also be helpful to relieve
symptoms.
FIGURE 1.15
Pill esophagitis. Refractile brown iron pill material (arrows) is present among
inflamed squamous epithelium.
PILL ESOPHAGITIS—FACT SHEET
Definition
n Esophageal injury that occurs because of prolonged direct ■ ESOPHAGITIS DISSECANS SUPERFICIALIS
mucosal contact with tablets or capsules taken in therapeutic OR SLOUGHING ESOPHAGITIS
doses
Gender and Age Distribution Clinical Features

n Any age can be affected but more common in older adults
Clinical Features Sloughing esophagitis is a recently described entity that

n Antibiotics are among the common medications that cause pill
has also been reported in the literature as esophagitis
esophagitis superficialis dissecans. It is unclear whether these are
n Feeling of a pill being stuck in the esophagus after taking the pill two distinct entities or represent a spectrum of the same
with little or no fluid, especially just before lying down disease process. Patients are typically middle aged, debil-
n Atypical symptoms can mimic myocardial infarction or reflux
itated, and taking multiple (five or more) medications
(especially bisphosphonates, potassium chloride, nonste-
n Recovery occurs after stopping the medication
roidal antiinflammatory drugs [NSAIDs]), often includ-
n Antireflux medication or topical anesthetic may help alleviate ing a central nervous system depressant. Consumption
symptoms of hot beverages, chemical irritants, smoking, and colla-
gen vascular diseases have also been associated with this
condition. Clinical symptoms include upper GI bleed,

dysphagia, and nausea and vomiting.
Pathologic Features
Gross Findings
Endoscopically, necrosis of the superficial squamous

epithelium is seen as white plaques or membranes, the
edges of which may be detached from the underlying tis-
sue, creating the appearance of linear ulcers (Fig. 1.16).
The distal esophagus is most often affected. Involvement
of the mid and proximal esophagus can be seen when
the process is more diffuse.
FIGURE 1.17
Sloughing esophagitis. Superficial necrosis is seen as an eosinophilic luminal
Microscopic Findings aspect and a basophilic basal aspect. This case has degenerative nuclei in
between the layers.
The most striking feature is a two-toned appearance of
the squamous mucosa at low power, with the superfi-
cial necrotic aspect being markedly eosinophilic com- Bullous skin lesions affecting the esophagus should also
pared with the viable basal aspect (Fig. 1.17). A distinct be considered and can be distinguished by their char-
demarcation between the two layers is present, and neu- acteristic histologic features and immunofluorescence.
trophils and apoptotic debris may be present along this Acute esophageal necrosis may have a similar endoscopic
line of demarcation. In some cases, the superficial layer appearance, but histologically, the characteristic features
shows parakeratosis and sloughing of the necrotic squa- include diffuse and deep ulceration with fibrinopurulent
mous epithelium. exudate and full-thickness mucosal necrosis.
Differential Diagnosis Prognosis and Therapy
Fungal esophagitis, pill esophagitis, and caustic esopha- The lesion tends to heal with acid suppressants, topical
geal injury can all result in necrosis of the esophageal epi- anesthetics, and discontinuation of the offending agents.
thelium. Clinical history of ingestion and special stains A high death rate of patients with sloughing esophagitis
for fungal elements can help distinguish these entities. is attributed to the comorbid conditions.
ESOPHAGITIS DISSECANS SUPERFICIALIS OR

SLOUGHING ESOPHAGITIS—FACT SHEET
Definition
n A recently described entity that may be a spectrum of the same
disease process, characterized by detachment of the superficial

squamous epithelium
Clinical Features
n Affects middle-aged debilitated patients taking five or more
medications, which often include a central nervous system

depressant, bisphosphonates, potassium chloride, and
nonsteroidal antiinflammatory drugs
n Also can occur in the setting of hot beverage consumption,
chemical irritant exposure, smoking, and collagen vascular disease

n Symptoms include upper gastrointestinal tract bleeding,
dysphagia, nausea, and vomiting

n Lesions heal with acid suppressants, topical anesthetics, and
FIGURE 1.16 discontinuation of the offending agents

Sloughing esophagitis. Endoscopically, white plaques with detached edges n High death rate attributed to comorbid conditions
characterize the superficial epithelial necrosis.

Esophagitis Dissecans Superficialis or Sloughing

Esophagitis—Pathologic Features

n White plaques or membranes, the edges of which are detached
from the underlying tissue, creating the appearance of a linear ulcer

n Distal esophagus most often affected, but diffuse cases can
involve the mid and proximal esophagus
n Two-toned appearance of the squamous mucosa at low
power: superficial aspect is markedly eosinophilic and sharply

demarcated from the viable basal aspect
n Neutrophils and apoptotic debris may be present along the line
of demarcation
n Fungal esophagitis can have acute inflammation and some
sloughing; fungal elements can be highlighted by special stains

n Pill esophagitis often has more an ulcer and a typical clinical
history
n Caustic esophageal injury can be considered based on the clinical
history
n Bullous skin lesions affecting the esophagus have characteristic
histologic features and immunofluorescence

n Acute esophageal necrosis has diffuse and deep ulceration with FIGURE 1.18
fibrinopurulent exudates Esophageal mucosal cast. (From Turk JL, ed. Royal College of Surgeons of
England. Slide Atlas of Pathology. Alimentary Tract System. London, Gower
Medical, 1986, with permission.)
■ CAUSTIC ESOPHAGEAL INJURY
edema and erythema. Second-degree cases have mus-

Clinical Features
cular involvement with ulceration and necrosis. Third-
degree cases have transmural lesions with possible
Caustic injuries in children are a public health problem, extraesophageal extension (Fig. 1.19).
with more than 5000 cases reported yearly in the United
States. It is less common in adults, with an incidence
of 1 in 100,000; the majority are the result of suicidal
attempts. Children younger than 3 years are the most
frequent victims of accidents involving common house-
hold products such as bleaches, detergents, and alkalis. Variable degrees of injury occur depending on the offen-
The symptoms are quite variable, and there is little cor- sive agent. Lesions caused by alkali are more severe than
relation between the severity of symptoms and the degree those caused by acids. Areas of coagulative necrosis,
of esophageal damage. Dysphagia and odynophagia are diffuse ulceration, and hemorrhage are characteristic.
the main symptoms, with chest and back pain presenting Transmural ulceration and necrosis are seen in third-
to a lesser extent. In severe cases, the entire esophageal degree lesions.
mucosal cast is extruded (Fig. 1.18). In the most extreme
cases, esophageal and gastric perforation with mediasti-
nitis and peritonitis occur. Alkali ingestions are less com-
mon but more severe than those caused by acids.
When the clinical history is not available, other entities

Pathologic Features enter into the differential diagnosis, including reflux and
infectious esophagitis. Extensive and diffuse coagulative
Gross Findings necrosis is uncommon in reflux esophagitis. Infectious
processes are usually associated with discrete esoph-
Endoscopic findings vary depending on the severity of ageal ulcers or esophageal plaques with characteristic
mucosal injury. A grading system exists similar to the viral cytopathic effect (CMV or HSV) or fungal forms
one in skin burns. First-degree cases have superficial (Candida), respectively.
the upper esophageal sphincter, found in 1% to 18%

of endoscopic studies. Cervical inlet patch consists of
benign gastric cardiac, antral, or fundic mucosa sur-
rounded by esophageal squamous mucosa (Fig. 1.20).
Complications of cervical inlet patch include involve-
ment by Helicobacter pylori infection, ulceration, stric-
ture, IM, and dysplasia.
■ HETEROTOPIC SEBACEOUS GLANDS
Heterotopic sebaceous glands are found in the mid to

distal esophagus. They are seen endoscopically as single
or multiple small 1- to 2-mm yellow to white mucosal
plaques or nodules. Heterotopic sebaceous glands are
mature clusters of sebaceous glands interspersed among
the esophageal squamous mucosa (Fig. 1.21). Heterotopic
sebaceous glands have no clinical significance.
FIGURE 1.19
Caustic esophagitis. Necrosis and perforation. (From Turk JL, ed. Royal
College of Surgeons of England. Slide Atlas of Pathology. Alimentary Tract
System. London, Gower Medical, 1986, with permission.)
Cases are always fatal when more than 6 mL of concen-

trated alkaline material is ingested. Intravenous (IV)
fluids, total parenteral nutrition (if patients are unable
to swallow), steroid therapy, and antibiotics are used
for conservative management. Esophageal dilation is
required if strictures develop. Because patients with
FIGURE 1.20
corrosive strictures have an increased risk of develop-
Gastric heterotopia inlet patch. Cardiac-type mucosa with inflammation.
ing SCC, patients should be evaluated, especially if they
develop dysphagia or poor response to dilation after a
latent period of negligible symptoms.
■ MISCELLANEOUS LESIONS
Miscellaneous lesions include lesions discovered inci-

dentally during upper GI endoscopy. The differential
diagnosis includes fungal esophagitis, esophageal neo-
plasm, or metastatic malignancy.
■ INLET PATCH
Heterotopic gastric mucosa of the proximal esophagus, FIGURE 1.21

also called a gastric or cervical inlet patch, is an asymp- Heterotopic sebaceous glands. A mature sebaceous gland is present
tomatic salmon-colored mucosal patch just distal to surrounded by esophageal squamous mucosa.
■ GLYCOGENIC ACANTHOSIS Taggart et al. (2013) reported an incidence on esopha-

geal biopsy of 2%. In 62% of these patients, hyperker-
Glycogenic acanthosis is seen as multiple, slightly ele- atosis was found within squamous mucosa associated
vated, rounded nodules less than 1 cm in diameter. with BE or adenocarcinoma. In the remaining 38%
Eighty percent of patients with Cowden syndrome (a of patients, hyperkeratosis was more often multifocal,
PTEN hamartoma tumor syndrome) have a characteris- involved the midesophagus, was associated with endo-
tic diffuse glycogenic acanthosis. Biopsy of incidentally scopic leukoplakia 24% of the time, and was seen more
identified esophageal lesions is performed to confirm the often in patients with current or former alcohol use.
benign nature of the lesion and to exclude a neoplastic The presence of hyperkeratosis outside of BE or ade-
process. Glycogenic acanthosis may be seen as a subtle nocarcinoma was associated with squamous neoplasia
hyperplasia of the esophageal squamous mucosa at low of the esophagus and with squamous carcinoma of the
power. At higher magnification, squamous cells in the oropharynx.
involved area have abundant glycogen-filled cytoplasm, Epidermoid metaplasia is a rare entity, seen endo-
which can be confirmed by periodic acid–Schiff stain scopically as a white to tan well-demarcated and slightly
(Fig. 1.22). Sporadic glycogenic acanthosis may be related elevated mucosal patch or scaly plaque of variable size
to GERD. The presence of diffuse glycogenic acanthosis (from 1 cm to 24 cm, with a median of 8.5 cm), within
should prompt further work-up for Cowden syndrome. the proximal to middle third of the esophagus. On
biopsy, there are thickening of the basal layer, acan-
thosis, and a prominent granular cell layer, not usually
found in the esophageal squamous mucosa. The luminal
■ ESOPHAGEAL HYPERKERATOSIS AND
aspect shows hyperorthokeratosis. Epidermoid meta-
EPIDERMOID METAPLASIA
plasia is associated with synchronous or metachronous
esophageal SCC. Targeted next-generation sequencing
In esophageal hyperkeratosis, a white plaque, which has revealed epidermoid hyperplasia to be a precur-
may be circumferential, is seen on endoscopy. Biopsy sor to esophageal dysplasia and carcinoma, harboring
of the plaque reveals hyperkeratosis with a prominent gene mutations in TP53, PIK3CA, EGFR, and others.
granular layer, with or without a few neutrophils or Similar to esophageal squamous carcinoma, epidermoid
eosinophils. This lesion has been reported in associa- metaplasia is seen in patients with history of signifi-
tion with gastroesophageal reflux and vitamin A defi- cant tobacco smoking and alcohol intake. Interestingly,
ciency and has been reported in adults and children. although inflammation is not a characteristic of epider-
Although the findings may persist with antireflux moid metaplasia of the esophagus, patients can have
therapy, there are no reported long-term sequelae. concurrent histologic features of lichenoid esophagitis
In patients being seen at a specialty cancer center, or esophageal lichen planus.
A B
FIGURE 1.22
Glycogenic acanthosis. Multiple small round nodules are seen on endoscopy (A). Squamous cells in involved areas have abundant glycogen-filled
cytoplasm (B).
■ INFLAMMATION AND INTESTINAL One of every 3500 live births is affected. The affected
METAPLASIA OF THE GASTROESOPHAGEAL babies have food regurgitation, salivation, cyanosis,
JUNCTION and aspiration. Sometimes they are associated with a
trisomy (21, 18, and partial 13) or with the VACTERL
The GEJ mucosa usually shows some degree of chronic (vertebral abnormalities, anal atresia, cardiac abnor-
inflammation within the lamina propria. This can either malities, tracheoesophageal fistula and/or esophageal
be attributed to physiologic or pathologic GERD. In the atresia, renal agenesis and dysplasia, and limb defects)
setting of inflamed GEJ, the main differential diagnoses association.
are H. pylori–induced gastritis versus reflux disease. On Esophageal duplications and developmental cysts
its own and without other more specific findings, such are not always easy to differentiate from one another.
as accompanying antral Helicobacter gastritis or reflux Esophageal duplication accounts for 10% to 20% of
squamous esophagitis, the cause of inflammation of gas- all GI duplications and is the result of a morphogenetic
tric-type mucosa in this region cannot be ascertained. abnormality occurring around the fifth to eighth week
Intestinal metaplasia (IM) at the GEJ similarly has of gestation. Cysts can be classified as bronchogenic,
been a subject of an ongoing debate as to whether met- enteric, or neuroenteric. Patients experience feeding
aplastic columnar epithelium in biopsy samples taken difficulties or respiratory distress during childhood. In
from the GEJ is caused by reflux disease–induced BE or some cases, the anomaly remains asymptomatic and is
H. pylori–induced intestinalized pangastritis. To date, discovered during a routine chest x-ray examination.
the clinical significance of these distinctions is unknown
because long-term prospective follow-up data are lacking.
As a practical matter, at present, if the biopsy shows the
Pathologic Features
presence of submucosal or mucosal esophageal glands,
squamous-lined ducts, multilayered epithelium, or hybrid
glands, the biopsy is derived from the tubular esopha- Gross Findings
gus rather than gastric cardia (see Chapter 2 for details).
Fortunately, given that the current American College Esophageal atresias, with or without tracheoesoph-
of Gastroenterology guideline defines BE when there ageal fistulas, are of five different types (Fig. 1.23).
is extension of salmon-colored mucosa into the tubular Type C is the most common, accounting for 85%
esophagus extending 1 cm or more proximal to the GEJ of the cases (Figs. 1.24 and 1.25). The E type (also
with biopsy confirmation of IM, the problem of IM at GEJ known as H because of its shape) may be overlooked
perhaps is less relevant to daily practice. and diagnosed in older children with repeated bouts of
pneumonia.
Duplications occur in the lower esophagus in 60% of
cases; they are usually intramural and do not commu-
STRUCTURAL ABNORMALITIES nicate with the esophageal lumen. Bronchogenic cysts
present anteriorly and contain a rim of cartilage. Enteric
■ CONGENITAL (ESOPHAGEAL ATRESIA, or neuroenteric cysts sometimes have an hourglass
TRACHEOESOPHAGEAL FISTULA, shape, with one portion in the posterior mediastinum
DUPLICATION, AND DEVELOPMENTAL CYSTS) and the other inside the vertebral canal.
Clinical Features
Esophageal atresia and tracheoesophageal fistula typi-
cally occur together and result from failure of the fore- Duplications are located within the esophageal wall
gut to completely divide into the esophagus and trachea. and have distinct layers of muscularis propria con-
This separation occurs in the fourth week of gestation. taining nerve plexuses (Fig. 1.26). In contrast, other
A B C D E
FIGURE 1.23
The five types (A–E) of esophageal atresias.
FIGURE 1.26
Esophageal duplication. Intact muscularis propria and cuboidal epithelium.
FIGURE 1.24
Esophageal atresia with tracheoesophageal (TE) fistula (posterior view).
Blind pouch in the upper esophagus and distal TE fistula at the tracheal
bifurcation. (From Turk JL, ed. Royal College of Surgeons of England. Slide
Atlas of Pathology. Alimentary Tract System. London, Gower Medical, 1986,
with permission.)
FIGURE 1.27
Esophageal cyst with columnar epithelium, luminal secretions, and attenu-
ated muscle layer.
developmental cysts show an attenuated single layer of

smooth muscle. The epithelial lining of either duplica-
tions or cysts may have squamous, cuboidal, or ciliated
epithelium (Fig. 1.27). Most bronchogenic cysts contain
cartilage in their walls.
Esophageal atresia and tracheoesophageal fistula should

be differentiated from the less common congenital
esophageal stenosis (Fig. 1.28), which demonstrates a
significant narrowing of the midesophagus resulting
from a web or muscular hypertrophy. Congenital pyloric
stenosis presents with projectile vomiting, and radio-
graphs show esophageal integrity with air trapped in
FIGURE 1.25 the stomach. Acquired diverticula occur in adults and
Esophageal atresia with tracheoesophageal fistula. The stomach and dis- always communicate with the esophageal lumen. The
tal esophagus connect with the fistula at the tracheal bifurcation. (From
Turk JL, ed. Royal College of Surgeons of England. Slide Atlas of Pathology. squamous epithelial lining may show erosions and
Alimentary Tract System. London, Gower Medical, 1986, with permission.) ulcerations.
n Located in lower third of esophagus, duplications protrude into

the posterior mediastinum
n Bronchogenic cysts protrude into the anterior mediastinum
n Enteric or neuroenteric cysts occupy the posterior mediastinum
n Neuroenteric cysts can have an hourglass configuration

n Newborn through early childhood
n Some cases remain asymptomatic and are discovered on routine
chest radiography
Clinical Features
n Food regurgitation, drooling, and aspiration in newborns
n Older children with repeated bouts of pneumonia

n Excellent prognosis with early diagnosis and surgical correction
n Patients with associated anomalies have poorer outcomes
Congenital Structural Abnormalities—Pathologic Features
Gross Findings
n There are five types of atresia, most occur with
tracheoesophageal fistula (see Fig. 1.23)

n The most common is type C, which occurs in 85% of cases
FIGURE 1.28 n Duplication appears as an intramural mass in the lower
Esophagus with congenital esophageal stenosis. Note the narrowing of the esophagus
middle segment. (From Turk JL, ed. Royal College of Surgeons of England. n Bronchogenic cysts may show a rim of cartilage on gross
Slide Atlas of Pathology. Alimentary Tract System. London, Gower Medical, examination
1986, with permission.) n Neuroenteric cysts may have an hourglass appearance with one
component in the posterior mediastinum and the other inside

the vertebral canal
Prognosis and Therapy n Duplications have a complete muscle layer with neural plexuses
n Developmental cysts usually contain an attenuated single muscle
layer
Early diagnosis with prompt surgical repair confers an n Bronchogenic cysts contain cartilage in their walls
excellent prognosis. Additional anatomic anomalies and n Duplications as well as developmental cysts can be lined by
chromosomal alterations are associated with poor out- squamous, cuboidal, or ciliated epithelium
comes in patients with esophageal atresia and tracheo- n Neuroenteric cysts are lined with intestinal epithelium or gastric
esophageal fistula. mucosa
n Congenital esophageal stenosis and congenital pyloric stenosis
CONGENITAL STRUCTURAL ABNORMALITIES—FACT may mimic atresia and can be distinguished by radiologic
SHEET examination
n Acquired diverticula communicate with the esophageal lumen
Definition and are lined by squamous epithelium
n Esophageal atresia and tracheoesophageal fistula are congenital
anomalies resulting from failure of the foregut to divide into

trachea and esophagus during the fourth week of embryonic
development
n Duplications and developmental cysts are congenital anomalies ■ ACQUIRED (DIVERTICULA, WEBS,
caused by failure of normal development around the fifth to AND RINGS)
eighth week of gestation
Incidence and Location Clinical Features

n Esophageal atresia and tracheoesophageal fistula occur in 1 of
every 3500 live births

n Duplications are seen in 1 in 8000 autopsies Diverticula are outpouchings of the esophagus con-
taining one or more layers of the esophageal wall.
Three major types are recognized based on location: Pathologic Features

upper esophagus (Zenker’s and Killian-Jamieson),
level of tracheal bifurcation (midesophageal), and
lower esophagus (epiphrenic). Zenker’s diverticulum Gross Findings
is associated with symptoms of dysphagia, regurgita-
tion, halitosis, and aspiration in middle-aged and older Zenker’s diverticulum is a pouch located at the level
adults. A gurgling sound upon swallowing and a neck of the pharyngoesophageal junction, a weak point in
mass may be present. Midesophageal diverticula may the wall between the inferior constrictor muscle of the
be asymptomatic and are often associated with medi- pharynx and the fibers of the cricopharyngeal muscle.
astinal inflammation. The epiphrenic diverticulum This triangular area is known as the triangle of Killian
is symptomatic because of its coexistence with hiatal (Fig. 1.30). The diverticula vary in size and may be filled
hernia. with necrotic debris. The midesophageal diverticulum
Esophageal webs and rings are common and are (also called traction diverticulum) is located at the level
mostly acquired, except for the rare cases of congenital of the tracheal bifurcation (Figs. 1.31 and 1.32). The
esophageal stenosis. They are concentric or eccentric epiphrenic diverticulum lies close to the diaphragm and
narrowings of the esophageal lumen. Webs are found in is seen in association with a hiatal hernia. Endoscopic
4% to 10% of autopsies. Clinically, they are observed examination reveals rings and webs as mucosal folds or
in 5% to 15% of patients presenting with dysphagia indentations. Ulceration may be present. Webs are usu-
and choking sensation. The now rare Plummer-Vinson ally noncircumferential.
syndrome consists of iron-deficiency anemia, glossi-
tis, cheilosis, and an upper esophageal web (Fig. 1.29).
Rings are found in 0.7% to 16% of autopsies. Their
Microscopic Features
pathogenesis is unclear. Rings are usually localized to
the lower esophagus, and the most common type of
ring associated with reflux disease and hiatal hernia Esophageal diverticula are true diverticula because they
is Schatzki’s ring. are lined by squamous epithelium and contain a mus-
cular wall that can be attenuated (Fig. 1.33). SCC has
been reported in 0.3% of Zenker’s diverticula cases.
Webs are lined by squamous mucosa with edematous

Upper esophageal web with glossitis. (From Turk JL, ed. Royal College of Zenker’s diverticulum. Thin wall and luminal debris. (From Turk JL, ed. Royal
Surgeons of England. Slide Atlas of Pathology. Alimentary Tract System. College of Surgeons of England. Slide Atlas of Pathology. Alimentary Tract
London, Gower Medical, 1986, with permission.) System. London, Gower Medical, 1986, with permission.)
FIGURE 1.33
Zenker’s diverticulum. Muscularis propria and squamous epithelial lining.
FIGURE 1.31 Diverticula should be differentiated from pseudodi-

Midesophageal diverticulum (traction diverticulum; inside view). (From verticula, which are cystic dilations of submucosal
Turk JL, ed. Royal College of Surgeons of England. Slide Atlas of Pathology. glands, lack involvement of the entire esophageal wall.
Alimentary Tract System. London, Gower Medical, 1986, with permission.) A unique entity called diffuse esophageal intramural
pseudodiverticulosis is also in the differential diagnosis.
The radiologic examination with contrast media shows
multiple minute outpouchings within the esophageal
wall. This entity is associated with diabetes, alcohol-
ism, candidiasis, and chronic granulomatous disease.
Esophageal rings and webs must be distinguished from
postinflammatory stenosis, which can be consequence
of long-standing reflux disease or exposure to corrosive
agents. Stenosis resulting from these conditions is char-
acterized by marked submucosal fibrosis.
Prognosis depends on the size of the diverticulum and

on whether it is complicated by ulceration, hemor-
rhage, or superimposed infection. Large diverticula are
treated with diverticulectomy and esophagomyotomy.
Esophageal rings and webs can be treated with dietary
modifications, dilation, or surgery in refractory cases.
FIGURE 1.32
Midesophageal diverticulum (traction diverticulum; outside view). Adhesions
between the lymph nodes and diverticulum. (From Turk JL, ed. Royal College
of Surgeons of England. Slide Atlas of Pathology. Alimentary Tract System. ACQUIRED STRUCTURAL ABNORMALITIES—FACT SHEET
London, Gower Medical, 1986, with permission.)
Definition
n Diverticula are acquired outpouchings in the upper, middle, and
and inflamed submucosa. Lower esophageal rings and lower esophagus
webs have squamous epithelium on the proximal side n Rings and webs are folds causing concentric or eccentric
and columnar epithelium on the distal side. Some rings narrowing of the esophageal lumen
are a result of localized annular muscular thickening.
Incidence and Location Microscopic Findings

n Zenker’s diverticulum is the most common (70%) n Diverticula contain all layers of the esophagus, but the muscle
n Zenker’s diverticulum is located on the posterior wall at the layer is attenuated

junction between the pharynx and esophagus in an area called n Diverticula and webs are lined by stratified squamous epithelium
the Killian triangle which may be inflamed or ulcerated

n Killian-Jamieson diverticulum is located in the upper esophagus n Squamous cell carcinoma rarely develops in Zenker’s diverticulum
on the anterolateral wall n Rings have squamous mucosa on the proximal side and
n Midesophageal diverticulum is less common and occurs at the columnar epithelium on the distal side
level of tracheal bifurcation
n Epiphrenic diverticulum is located in the lower esophagus and
commonly associated with hiatal hernia

n Rings and webs are common; Schatzki ring is most common
n Webs are more common in the upper esophagus; rings are

■ MOTILITY DISORDERS
common in the lower esophagus

Normal esophageal motility is a complex mechanism
n Middle-aged and older adults
requiring intact, coordinated autonomic innervation.
n No gender preference
Inadequate function leads to motility disorders, which
can be divided into the spastic variety and achalasia.
Clinical Features Motility disorders are relatively uncommon. The preva-
n Small diverticula may be asymptomatic lence of achalasia is 10 cases per 105 population. Spastic
n In large Zenker’s diverticulum, dysphagia, a gurgling sound, and a motility disorders include diffuse esophageal spasm
neck mass may develop
n Regurgitation of food eaten several hours before is quite
(DES) and hypercontraction and are reported to occur
characteristic in 4% to 12% of patients tested for typical symptoms.
n Inflammatory diseases of the mediastinum accompany the
midesophageal diverticulum
n Hiatal hernia is seen in association with epiphrenic diverticulum
n Motility abnormalities are the most likely causes of upper and Clinical Features
epiphrenic diverticula
n Rings and webs are mostly asymptomatic but may have
dysphagia and odynophagia Dysphagia for liquids and solids occurs in DES, which is
n Upper esophageal webs are associated with the now rare associated with impaired inhibitory innervation affect-
Plummer-Vinson syndrome ing the distal esophagus. Unexplained chest pain and
psychiatric conditions are associated with hypercon-
n Prognosis depends on the size of the lesion and associated
traction, which includes hypertensive peristalsis (also
conditions referred to as nutcracker esophagus) and hypertensive
n Large diverticula are treated with surgical resection and LES. Diagnosis is based on esophageal manometry and
myomectomy esophageal pressure topography after excluding other
n Rings and webs are treated with dietary modifications, dilation, or
esophageal disorders by endoscopic biopsy.
surgery in refractory cases
In achalasia, the abnormality consists of aperistalsis,
Differential Diagnosis lack of LES relaxation, and increased intraesophageal
n Pseudodiverticula, either single or multiple (diffuse esophageal
pressure. Patients are 25 to 60 years of age and have
intramural pseudodiverticulosis), are dilations of submucosal symptoms of progressive dysphagia, regurgitation, and
glands and lack involvement of the entire esophageal wall aspiration. Systemic disorders such as systemic sclerosis,
n Postinflammatory stenosis, occurring after long-standing reflux, or
muscular dystrophies, amyloidosis, chronic idiopathic
stenosis secondary to corrosive agents, such as lye
intestinal pseudo-obstruction, chronic gastroesophageal
reflux, eosinophilic gastroenteritis, and Chagas disease
also affect the normal peristaltic mechanism. The inci-
dence of SCC is increased in patients with achalasia.
Acquired Structural Abnormalities—Pathologic Features
Gross Findings
n Zenker’s diverticulum is a sac located at the pharyngoesophageal
junction Pathologic Features
n Mid-diverticulum occurs at the level of bifurcation of the
trachea
n Epiphrenic diverticulum occurs in the lower 10 cm of the
Gross Findings
esophagus
n Rings are seen as stenosis of the distal esophagus on
Endoscopic examination in patients with achalasia shows
endoscopy dilation of the lumen, prominent vascularity, and pooled
n Webs are seen as thin mucosal folds on endoscopy debris adherent to the wall (Figs. 1.34 and 1.35). In some
cases, reflux changes and strictures are present.
Microscopic Changes
Mucosal biopsies may appear normal or involved

by inflammation and ulceration secondary to stasis.
Although resection is not a standard therapy for acha-
lasia, autopsy examination reveals characteristic find-
ings of loss of myenteric plexus associated with chronic
inflammation of the ganglion cells (Fig. 1.36). Similar
morphologic changes can be seen in esophagomyotomy
specimens from patients with achalasia. The LES also
shows a decrease in the number of these cells but to a
lesser degree and hypertrophic muscle. Mucosal changes
are nonspecific and appear to be related to stasis. They
consist of hyperplasia, papillomatosis, and increased
intraepithelial lymphocytes. P53 immunoreactivity and
increased CD3+ T cells have been demonstrated and
may be related to SCC risk.
FIGURE 1.34
Spastic disorders can mimic angina pectoris. Idiopathic
Achalasia. Marked lumen dilation. (From Turk JL, ed. Royal College of
Surgeons of England. Slide Atlas of Pathology. Alimentary Tract System. achalasia should be differentiated from secondary acha-
London, Gower Medical, 1986, with permission.) lasia resulting from systemic sclerosis (Fig. 1.37), amyloi-
dosis, muscular dystrophy, chronic idiopathic intestinal
pseudo-obstruction, chronic gastroesophageal reflux,
eosinophilic gastroenteritis, and Chagas disease (Fig.
1.38). In systemic sclerosis, marked intimal fibrosis
of blood vessels is associated with atrophy and fibrosis
of the muscularis propria. Amyloidosis reveals depos-
its of congophilic amyloid deposits in arterioles of the
lamina propria. In the chronic phase of Chagas disease,
there is complete destruction of myenteric plexuses,
resulting in megaesophagus. The trypomastigotes and
amastigote forms, however, are seldom present during
this stage.
FIGURE 1.35
Achalasia. Tortuous esophagus and narrow distal segment. (From Turk JL, ed.
Royal College of Surgeons of England. Slide Atlas of Pathology. Alimentary FIGURE 1.36
Tract System. London, Gower Medical, 1986, with permission.) Achalasia. Myenteric plexus with chronic inflammation (ganglionitis).

n Patients with achalasia are 25 to 60 years of age
n Men and women are equally affected
Clinical Features
n Severe episodic dysphagia and angina-type chest pain are typical
of spastic disorders
n Achalasia presents with progressive dysphagia, regurgitation,
aspiration, and weight loss

n Prognosis depends on early diagnosis and treatment
n Treatment modalities for achalasia include botulinum toxin
injections, pneumatic dilation, and Heller’s myotomy

n Treatment for spastic disorders includes nitrates, sedatives,
botulinum toxin, and pneumatic dilation

n Patients with achalasia have increased risk of developing
squamous cell carcinoma
Motility Disorders—Pathologic Features
Gross Findings
n In achalasia, endoscopic examination reveals a dilated lumen,
pooled debris, prominent vascularity, and a lack of normal

relaxation of the lower esophageal sphincter (LES)
n Spastic disorders reveal abnormal motility on endoscopic
examination
FIGURE 1.37
n Chronic ganglionitis with myenteric plexus destruction in the
Scleroderma. Luminal dilation and thinning of muscle wall. (From Turk JL, ed. dilated portion of the esophagus is seen in achalasia
Royal College of Surgeons of England. Slide Atlas of Pathology. Alimentary
n Thickened LES is common
Tract System. London, Gower Medical, 1986, with permission.)
n Mucosal biopsies may show hyperplasia, papillomatosis, and
lymphocytic esophagitis
n Primary achalasia should be differentiated from secondary
The treatment options for patients with achalasia achalasia caused by systemic sclerosis, Chagas disease, and
include botulinum toxin injections and pneumatic dila- amyloidosis, among others
tion. Heller myotomy is an effective surgical therapy
for those who do not respond to nonsurgical options.
Achalasia is associated with increased risk for develop-
ing esophageal SCC. Treatment modalities for spastic ■ SYSTEMIC SCLEROSIS
disorders include calcium channel blockers, sedatives,
nitrates, and pneumatic dilation. Clinical Features
Systemic sclerosis, or scleroderma, commonly involves

the GI tract, though not all patients are symptomatic.
MOTILITY DISORDERS—FACT SHEET Symptoms include dysphagia, heartburn, choking sen-
sation, and hoarseness. Most symptoms are caused by
Definition chronic gastroesophageal reflux associated with esopha-
n Disease entities affecting the normal coordination of swallowing geal hypomotility and LES incompetence.
and peristalsis
Incidence and Location Pathologic Features

n Motility disorders affect the entire esophageal length
n Spastic disorders are recognized with the use of manometric Gross Findings
studies in patients with noncardiac chest pain
n Achalasia is an uncommon disorder with a prevalence of 10 Endoscopic findings can include reflux esophagitis,
cases per 105 population infection such as fungal or viral esophagitis, BE, and
stricture. Biopsy can show corresponding findings.
Specific histologic features of systemic sclerosis are usu-

ally seen on esophageal resection specimen or at autopsy
and include atrophy of the distal esophageal muscu-
laris propria fibers and intimal proliferation of arteri-
oles, without evidence of ischemic injury or significant
myenteric plexus inflammation. Smooth muscle atrophy
affects the circular layer more so than the longitudinal
layer (Fig. 1.39) and the central fiber bundles more so
than the peripheral fiber bundles. Fibrosis is not a signif-
icant finding, although this was once thought to be the
mechanism of esophageal involvement. In patients with
known systemic sclerosis, biopsies of the esophagus
show proliferative and inflammatory gene expression
profiles consistent with involvement by systemic scle-
rosis despite the lack of significant or specific histologic
features and resulting in molecular subsets independent
of skin subtype or serum autoantibodies.
Prognosis
The major complication from esophageal involvement

is microaspiration, which can result in and exacerbate
interstitial lung disease in these patients.
■ ESOPHAGEAL VARICES, PERFORATIONS,

AND TEARS
Clinical Features
FIGURE 1.38
Esophageal varices can be subdivided radiographically
Chagas disease. Moderate luminal dilation. (From Turk JL, ed. Royal College
of Surgeons of England. Slide Atlas of Pathology. Alimentary Tract System.
into uphill or downhill types. Uphill esophageal varices
London, Gower Medical, 1986, with permission.) are a manifestation of portal hypertension. Downhill
A B
FIGURE 1.39
Scleroderma. A, Smooth muscle atrophy affects the inner circular layer (asterisk) of esophageal muscularis propria more so than the outer longitudinal layer.
B, Fibrosis is not a significant finding, as seen on the accompanying trichrome stain.
esophageal varices are a result of superior vena cava occasional thrombosis. In fatal perforations, there is
obstruction caused by bronchogenic carcinoma with extensive intramural hemorrhage with or without sero-
mediastinal metastasis. Patients with esophageal varices sal or adventitial fibroinflammatory reaction.
may be completely asymptomatic. However, rupture of
varices results in massive hematemesis, melena, shock,
and subsequent hepatic coma.
Esophageal perforations can be subdivided into sponta-
neous (Boerhaave’s syndrome), iatrogenic, and posttrau-
matic. A sudden increase in intraesophageal pressure can
cause “spontaneous” perforation. Boerhaave’s syndrome
typically occurs in middle-aged men after alcohol and food
overindulgence. Esophageal tears are commonly iatrogenic
in origin, resulting from surgical trauma. Endoscopic dila-
tions and blunt trauma are other causes of perforation.
Penetrating injuries result from knife or gunshot wounds
(11%–17%) or from trauma related to foreign bodies
(7%–14%). Symptoms and signs include severe chest
and upper abdominal pain, nausea, subcutaneous emphy-
sema, and shock. Esophageal (Mallory-Weiss) tears occur
spontaneously or as a result of repeated episodes of vomit-
ing in patients with alcoholism. Hematemesis and melena
are the most common symptoms.
Pathologic Features
Gross Findings
Endoscopic examination reveals tortuous bluish muco- FIGURE 1.41

sal elevations secondary to dilated submucosal veins Esophageal varices. Prominent tortuous veins. (Courtesy of Dr. P. Vasallo.)
(Figs. 1.40 and 1.41). Mallory-Weiss tears appear as
longitudinal mucosal tears surrounded by hemorrhage
extending across the Z line.
Specimens from postmortem examination show

ectatic submucosal veins and venules (Fig. 1.42) with
FIGURE 1.40
Esophageal varices—endoscopy. Varices with impending bleed. (Courtesy of FIGURE 1.42
Dr. E. Frizzell.) Esophageal varices. Dilated vessel beneath hyperplastic mucosa.
Differential Diagnosis Clinical Features

n A patient with esophageal varices may be asymptomatic
n Ruptured varices are associated with massive hematemesis and a

Mallory-Weiss tears need to be distinguished from
high mortality rate
severe GERD. Clinically, a large number of diseases can n Symptoms and signs of perforation include severe chest pain,
be confused with rupture, including perforated peptic vomiting, and subcutaneous emphysema
ulcer, myocardial infarct, pancreatitis, and mesenteric n Hematemesis and melena are characteristic of Mallory-Weiss
thrombosis. syndrome

n The prognosis of esophageal varices is poor if it is associated with
Prognosis and Therapy cirrhosis and better if it is associated with portal vein thrombosis
n Sclerotherapy is the treatment of choice for varices
n There is a high mortality rate (15%–29%) in spontaneous or
In 60% of cases, the first episode of ruptured varices iatrogenic perforations if the diagnosis is delayed
n Treatment in most cases of perforation is surgical repair
is fatal. Sclerotherapy is the treatment of choice for
n Endoscopic hemostasis and thermal therapy are treatments of
patients awaiting liver transplant for cirrhosis. In cases choice in Mallory-Weiss syndrome
with delayed diagnosis, spontaneous and iatrogenic
perforations are associated with a high mortality rate
(15%–24%). Most patients are treated with surgery
within 24 hours of diagnosis. Some, however, are treated
conservatively with IV fluids and antibiotics if the per- Esophageal Varices, Perforations, and Tears—Pathologic
Features
foration is contained. Patients with Mallory-Weiss tears
are treated conservatively with thermal therapy and
have a good prognosis.
n Varices appear as bluish veins protruding into the esophageal
lumen; red spots on the mucosal surface are associated with a

high risk for rupture
n Perforations average 2 cm with surrounding hematoma or
abscess
n Endoscopic findings in Mallory-Weiss syndrome show longitudinal
mucosal tears extending across the Z line

ESOPHAGEAL VARICES, PERFORATIONS, AND TEARS—
FACT SHEET Microscopic Findings
n Postmortem histology shows markedly ectatic veins and venules
Definition in the submucosa in cases of varices
n Varicose veins in the lower esophagus are the result of portal n In fatal cases of Mallory-Weiss syndrome, the tears demonstrate
hypertension caused by cirrhosis (uphill varices) mucosal dehiscence, edema, and mural hemorrhage
n Varicose veins in the upper esophagus are the result of superior
vena cava obstruction (downhill varices) Differential Diagnosis

n Spontaneous, iatrogenic, or traumatic lesions that result in
n No other entity looks like esophageal varices, but radiologically,
perforation or tears in the esophagus they may be confused with submucosally infiltrating esophageal
carcinomas
Incidence and Location n Endoscopically, Mallory-Weiss syndrome may be confused with
n Varices are a frequent complication of alcoholic cirrhosis in the severe reflux. Reflux shows basal cell hyperplasia, elongation
United States of papillae, and intramucosal neutrophil, eosinophils, and
n Iatrogenic cases account for almost half of all perforations lymphocytes
n Tears (Mallory-Weiss syndrome) probably have a higher incidence n Clinically, the differential diagnosis of a perforation includes
than perforations perforated peptic ulcer, myocardial infarct, pancreatitis, and
n Varices, perforations, and tears occur most commonly in the mesenteric thrombosis
lower esophagus

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2
Tumors of the Esophagus
■ Catherine Hagen, MD and Amitabh Srivastava, MD
■ SQUAMOUS PAPILLOMAS HPV-related squamous papillomatosis of the esophagus

(Fig. 2.2).
Clinical Features
These are uncommon, incidental findings at endoscopy
that usually occur in women in the fifth decade of life.
The vast majority are solitary; some may present as a The differential diagnosis includes squamous dysplasia,
papillomatosis. They are thought to be a reactive pro- but squamous papillomas show no epithelial atypia, and
liferation secondary to gastroesophageal reflux disease the diagnosis is usually straightforward.
(GERD). In the Western population, most lesions arise
in the distal esophagus, whereas mid-esophagus is the
most common site of involvement reported in Japan.
Squamous papillomas have no risk of recurrence or

Pathologic Features
malignant transformation.
Gross Findings
The lesions are typically seen as tiny well-demarcated

polyps at endoscopy. Mucosal biopsy samples appear as
small whitish nodules.
SQUAMOUS PAPILLOMA OF THE ESOPHAGUS—FACT
SHEET
Definition
These lesions are composed of bland polypoid squamous
n Small, incidental nodules of the esophagus composed of
mucosa with fibrovascular cores (Fig. 2.1). Exceptional proliferative benign squamous epithelium
cases may display viral cytopathic effect, and these
appear to be more prevalent in the upper esophagus. Incidence and Location
n Uncommon (<0.5%); usually involve the distal esophagus
Morbidity and Mortality

Ancillary Studies n None; other than rare examples associated with laryngeal
papillomatosis, which may cause obstruction

Immunohistochemistry
Gender, Race, and Age Distribution
n Squamous papillomas are more common in white women,
The majority of squamous papilloma are negative usually in their early 40 s
for human papillomavirus (HPV) by both immu-
nohistochemistry and in situ hybridization. A sub- Clinical Features
set of patients with HPV-associated laryngeal n Incidental smooth nodular lesions on endoscopy
papillomatosis are reported to also have concurrent
29
■ ATYPICAL LIPOMATOUS TUMOR (“GIANT

Squamous Papilloma of the Esophagus—Pathologic Features
FIBROVASCULAR POLYP” OF THE
Gross Findings
ESOPHAGUS)
n Small nodule with a smooth surface seen at endoscopy
Clinical Features
n Small nodular squamous proliferation aligned in a papillary
configuration with fibrovascular cores Fibrovascular polyps are extremely rare submucosal
tumors of the esophagus that have been variably clas-
Immunohistochemistry sified as lipomas, fibromas, and fibrolipomatous polyps.
n Results from immunohistochemical, polymerase chain reaction, Most patients described in literature are middle-aged
and in situ hybridization studies for human papillomavirus are or older men, although children, infants, and women
negative in most series
may also be affected. Presenting complaints include dys-
Differential Diagnosis phagia, substernal discomfort, and sensation of a mass.
n Papillary squamous neoplasia (low or high grade)
Recent data suggest these lesions are almost universally
positive for MDM2 and CDK4 and show MDM2 ampli-
fication on fluorescence in situ hybridization, suggesting
that the so-called “giant fibrovascular polyp” is actually
a unique macroscopic appearance of atypical lipomatous
tumor involving the esophagus.
Pathologic Features
Gross Findings
On gross examination, these are sausage-like peduncu-

lated polyps arising in the upper third of the esophagus
and attached to the wall with a narrow stalk. Their sur-
face is covered by squamous mucosa, and their cores
consist of an admixture of grossly identifiable adipose
tissue and firm white connective tissue.
FIGURE 2.1 Microscopic Findings

Squamous papilloma of the esophagus. Most such tumors are incidental and
not associated with human papillomavirus infection. The lesions are composed of variable amount of mature
adipose tissue, often separated by thick fibrous bands
FIGURE 2.2
Esophageal papillomatosis in a young patient with tracheal papillomatosis associated with human papillomavirus.
CHAPTER 2 Tumors of the Esophagus 31
12q have been described in these lesions, similar to

atypical lipomatous tumors of somatic soft tissue.
The main differential diagnosis is secondary esophageal

involvement of the esophagus by contiguous extension of
a primary mediastinal liposarcoma. The latter typically
A
presents as a large mural mass while primary esophageal
atypical lipomatous tumors presents as a slender elon-
gated polyp with a narrow base. Inflammatory polyps of
the esophagus usually occur in the distal third and show
a fibromuscular stroma without an adipocytic compo-
nent. The diagnosis of a “giant fibrovascular polyp”
should not be made unless careful microscopic evalu-
ation and ancillary work-up have completely excluded
the possibility of an atypical lipomatous tumor.

B
FIGURE 2.3 Complete excision is curative in most cases, although

Giant fibrovascular polyp, low magnification. It consists of fat, fibrous local recurrences have also been described. Excision can
tissue, and vessels (A). Almost all such lesions reported in literature be accomplished by endoscopic ligation or surgical exci-
represent atypical lipomatous tumors involving the esophagus. Careful
evaluation for nuclear atypia in adipocytic and stromal components (B), sion when the base of the lesion is poorly visualized by
and immunohistochemistry for MDM2 and CDK4 is helpful in making the endoscopy. Metastasis has not yet been reported from
diagnosis. these lesions.
or sometimes a myxoid stroma and prominent vascu- ATYPICAL LIPOMATOUS TUMOR (“GIANT
FIBROVASCULAR POLYP”) OF THE
lature, all surrounded by mature squamous epithelium
ESOPHAGUS—FACT SHEET
(Fig. 2.3A). Scattered, large, atypical cells with hyper-
chromatic nuclei and classic atypical multivacuolated Definition
lipoblasts may also be seen (Fig. 2.3B). Rarely, dediffer- n Submucosal-based esophageal tumor composed of adipocytes
entiated foci may also occur, similar to atypical lipoma- and atypical stromal cells, thick-walled blood vessels and a
tous tumors of soft tissue. fibrocollagenous or myxoid stroma similar to atypical lipomatous
tumor of soft tissue

n Very rare; usually in the upper third of the esophagus
■ ANCILLARY STUDIES
n May cause morbidity and rare mortality based on obstruction of
the esophagus or aspiration
MDM2 and CDK4 show positive staining in the adipo- Gender, Race, and Age Distribution
cytic component and the atypical stromal cells in almost n Male predominance
n Typically middle aged to older

all cases.
Clinical Features
n Present with dysphagia, mass sensation, retrosternal discomfort,
Molecular Findings or regurgitation of the mass

Fluorescence in situ hybridization shows MDM2 ampli- n Local excision is curative
fication and ring chromosome involving chromosome

histologic definition of the entity. The requirement for

Atypical Lipomatous Tumor (“Giant Fibrovascular Polyp”) goblet cells is still used in the United States because pop-
of the Esophagus —Pathologic Features ulation-based studies have shown a much higher risk of
esophageal adenocarcinoma in patients with intestinal
Gross Findings
metaplasia than in those without intestinal metaplasia.
n Long, slender, finger-like lesion with a narrow stalk arising from
Including patients without goblet cells into the peri-
the esophageal wall and protruding into the lumen
odic surveillance pool has major implications for cost
Microscopic Findings of care and cannot be justified unless the risk in non-
n Mature squamous mucosa with underlying adipose tissue with goblet metaplastic columnar epithelium is shown to be
adipocytes of variable size, atypical stromal cells, multivacuolated significant and comparable to those with goblet cells in
atypical lipoblasts in a fibrocollagenous or myxoid stroma rich in longitudinal outcome studies. Detection of goblet cells
blood vessels is susceptible to sampling error. At least eight random
biopsies or four biopsies per centimeter of columnar
Ancillary studies
epithelium are recommended to obtain the maximum
n Positive for CDK4 and MDM2
n MDM2 amplification on FISH

yield of intestinal metaplasia on histologic examination.
n Ring chromosomes involving chromosone 12q According to the recently published 2016 American
College of Gastroenterology guidelines, BE should only
Differential Diagnosis be diagnosed if there is extension of metaplastic colum-
n Inflammatory polyps nar epithelium 1 cm or greater proximal to the GEJ.
n Secondary involvement by mediastinal liposarcoma
This change was recommended because patients with
less than 1 cm of metaplastic columnar epithelium have
a very low risk of esophageal adenocarcinoma in long-
term follow-up studies, which does not justify routine
surveillance. However, the AGA criteria do not have a
■ BARRETT’S ESOPHAGUS length requirement and only require definite columnar
mucosa lining the distal esophagus with intestinal meta-
Clinical Features plasia detected on biopsies from this segment.
Barrett’s esophagus (BE) arises as a complication of

Pathologic Features
chronic GERD. Its incidence is rising in the Western
Hemisphere and parallels the increase in esophageal
adenocarcinoma. Other risk factors for BE include male Gross Findings
sex, white race, advanced age, and truncal obesity; cig-
arette smoking is a minor contributor. The presence of Barrett’s esophagus appears as tongues and patches of
Barrett’s mucosa in the esophagus does not cause symp- red salmon-colored mucosa that extend up from the gas-
toms, which makes it hard to screen the population for troesophageal junction (GEJ) for variable distance into
this precursor lesion of significant clinical consequence. the tubular esophagus and contrasts with the pearly
The major importance of BE is the marked predisposi- gray-pink color of the normal squamous epithelium
tion it confers on patients for subsequent development (Figs. 2.4 and 2.5). Traditionally, short-segment BE is
of esophageal adenocarcinoma through inflammation defined as less than 3 cm of metaplastic columnar epi-
to metaplasia to dysplasia to adenocarcinoma sequence. thelium, and long-segment BE is defined as greater than
However, most patients with esophageal adenocarci- 3 cm of metaplastic columnar epithelium. This distinc-
noma present with cancer and do not carry a prior diag- tion is important because although short-segment BE is
nosis of BE. Periodic surveillance and biopsy for early more common, it is less likely than long-segment BE to
detection of neoplasia is the current standard of care for give rise to esophageal adenocarcinoma.
BE patients, but only a small minority of those under
surveillance develop adenocarcinoma. Microscopic Findings
The 2011 American Gastroenterology Association
(AGA) guidelines defined BE as intestinal-type met- A majority of patients with BE have a concurrent hia-
aplastic epithelium that replaces stratified squamous tal hernia, and biopsies from the columnar segment
mucosa in the esophagus and predisposes to cancer in the distal esophagus may show a cardia- or oxynto-
development, requiring both endoscopic evidence of cardiac-type glandular epithelium or an intestinalized
columnar metaplasia and histologic demonstration of epithelium with goblet cells. Goblet cells are readily iden-
goblet cells. However, in Japan and much of Europe and tifiable on hematoxylin and eosin–stained slides, and
the United Kingdom, goblet cells are not required to ancillary stains are unnecessary (Fig. 2.6). Typically,
diagnose BE. The term columnar lined esophagus is used these goblet cells are admixed with gastric-type lining
instead of BE, emphasizing the endoscopic rather than cells, and this type of metaplasia is termed incomplete.
FIGURE 2.4
Barrett’s esophagus, endoscopic appearance. Note the tongues of salm-
on-colored epithelium extending into the gray squamous mucosa to a vari-
able extent.
B
FIGURE 2.6
Barrett’s esophagus. This biopsy specimen came from the tubular esophagus
and shows intestinal metaplasia (A). Periodic acid–Schiff (PAS) and Alcian
Blue (AB) stains can be used to highlight goblet cells but are not necessary
in routine practice. Note the blue goblet cells with interposed cells displaying
neutral mucin, imparting a magenta color on the PAS AB stain. This pattern
is similar to gastric foveolar cells rather than intestinal absorptive cells. This
combination of cell types is termed incomplete intestinal metaplasia (B).
FIGURE 2.5
Long-segment Barrett’s esophagus, resection specimen, showing velvetlike
mucosa above the anatomic gastroesophageal junction which is defined by
the proximal limit of the gastric rugal folds. This esophagus was excised in
1996 because of extensive high-grade columnar epithelial dysplasia. Today,
such patients are managed endoscopically by radiofrequency ablation.
Multilayered epithelium is a hybrid epithelium con-

sisting of mucin-containing glandular cells and basally
located squamous cells, frequently seen in patients with
GERD and may be a precursor of BE (Fig. 2.7). Its pres-
ence is not routinely reported in GEJ or esophageal biop-
FIGURE 2.7
sies, and it should not be considered to represent BE.
Multilayered epithelium (hematoxylin and eosin) is a hybrid epithelium
The metaplastic intestinalized mucosa often lays down demonstrating features of both squamous and columnar differentiation and
a new muscularis mucosae, resulting in two distinct suggested by may be a precursor of Barrett’s esophagus.
layers: a delicate, frayed, superficial layer and a deep,

thick, compact, native muscularis mucosae. The latter BARRETT’S ESOPHAGUS—FACT SHEET
can be mistaken for muscularis propria because of its
Definition
thickness.
n Columnar epithelium in the tubal esophagus with intestinal
metaplasia on biopsy (US definition). In addition, some

gastroenterology societies in the United States have also included
a length (>1 cm) requirement. Goblet cells are not part of the
Differential Diagnosis definition in many parts of Europe and Japan (columnar-lined
esophagus used as a synonym for Barrett’s esophagus [BE])
The differential diagnosis of BE includes gastric carditis
with intestinal metaplasia (CIM), seen in approximately
n 5% of individuals with gastroesophageal reflux disease
30% of patients with an abnormal squamocolumnar
junction. CIM is most often associated with Helicobacter Morbidity and Mortality
pylori infection and has a lower incidence of dyspla- n Strong risk factor for esophageal adenocarcinoma, with an
sia compared with BE. Autoimmune gastritis may also estimated annual rate of progression of approximately 0.5%
cause CIM and should be considered in the differential
diagnosis when only GEJ biopsies are available. Certain Gender, Race, and Age Distribution
n White male predominance with a median age in the early 50 s
histologic features have been described to help distin-
guish BE from CIM. These include metaplastic crypts
Clinical Features
buried underneath squamous mucosa, hybrid glands
n Usually asymptomatic; reflux symptoms may lead to screening for
consisting of cardia-type and intestinalized glands, and BE
esophageal glands and ducts. The presence of esopha- n Well-defined criteria for screening patients for BE are lacking
geal glands or ducts adjacent to foci of intestinal meta-
plasia is diagnostic of BE (Fig. 2.8); other features are
suggestive but not definitive.
Prognosis and Therapy Barrett’s Esophagus—Pathologic Features
Barrett’s esophagus is a preneoplastic precursor lesion Gross Findings

with the risk of adenocarcinoma being approximately n Salmon-colored mucosa in the esophagus
0.5% per year. Patients with nondysplastic BE are there- n May appear as a markedly irregular Z-line, a visible tongue of
fore recommended periodic endoscopic surveillance columnar epithelium, or a discrete island of columnar epithelium
surrounded on all sides by squamous mucosa
at 3- to 5-year intervals. Therapy is largely based on
treating GERD, typically with proton pump inhibitor Microscopic Findings
therapy. n Admixture of cardia-type, oxyntocardiac-type, and intestinalized
glands
n Intestinal metaplasia is typically of incomplete type, which shows
goblet cells interspersed gastric foveolar-type cells

n Double muscularis mucosae may be present
Ancillary Studies
n PAS-AB stain highlights goblet cells but is not recommended for
routine diagnosis
n Intestinal metaplasia of the gastric cardia secondary of
Helicobacter pylori or autoimmune gastritis

n Esophageal glands or ducts, when present, are helpful in
establishing a diagnosis of Barrett’s esophagus. Endoscopic

correlation needed in the remaining cases
■ RISK FACTORS FOR ESOPHAGEAL

CARCINOMA
FIGURE 2.8
In biopsies obtained from the gastroesophageal junction, the presence of
esophageal gland ducts (bottom of field) within the focus of intestinal meta- Barrett’s esophagus arises as a complication of chronic
plasia is diagnostic of Barrett’s esophagus. reflux disease and is the major predisposing risk
factor for esophageal adenocarcinoma. Other risk fac- evaluation of BE biopsies include the presence of archi-
tors include obesity, older age, and to a lesser extent, tectural complexity, cytologic atypia involving the surface
smoking and alcohol intake. Any condition that causes epithelium, and the presence of lamina propria inflam-
chronic local irritation and inflammation of the esopha- mation, erosions, or ulcers. Surface maturation is key to
geal mucosa appears to predispose to squamous cell car- diagnosis of nondysplastic BE. The proliferating nuclei
cinoma (SCC). Significant alcohol intake, especially in in the basal part of the intestinalized crypts are larger,
combination with smoking, greatly increases the risk of more hyperchromatic, and more stratified than those at
SCC. Other predisposing factors include achalasia and the surface, which are generally arranged in a monolayer
esophageal diverticula in which food retention leads to with polarized basal nuclei. Architectural abnormalities
local release of chemical irritants, frequent consumption include gland crowding, crypt branching and budding,
of extremely hot beverages, and ingestion of lye or other and villiform change. Cytologic features of dysplasia
caustic liquids. SCC is also linked to low socioeconomic include nuclear enlargement and hyperchromasia, irreg-
status and to nutritional deficiency syndromes, such as ular nuclear contours, coarse chromatin with prominent
the Plummer-Vinson syndrome (dysphagia, iron-defi- nucleoli, and loss of polarity. In “normal polarity,” the
ciency anemia, and esophageal webs). long axis of the nucleus remains perpendicular to the
Nonepidermolytic palmoplantar keratoderma (tylo- basement membrane and the nuclei are aligned parallel
sis), a rare autosomal dominant disorder defined by a one to another, whereas “loss of nuclear polarity” refers
genetic abnormality at chromosome 17q25, is a familial to loss of this perpendicular and parallel orientation.
syndrome that predisposes patients to SCC. It is char- Inflammation with consequent reparative changes can
acterized by hyperkeratosis of the palms and soles and impart worrisome cytologic alterations that can be mis-
thickening of the oral mucosa. It confers up to a 95% taken for dysplasia. An abrupt morphologic change from
risk for SCC of the esophagus by the age of 70 years. adjacent mucosa favors a diagnosis of dysplasia.
A polymorphism that increases the risk for esophageal
squamous carcinoma has also been identified in individ- Barrett’s Esophagus, Negative for Dysplasia
uals with inactive aldehyde dehydrogenase.
In BE without dysplasia, the glands tend to be straight
with smooth contours, crypt budding or branching is
minimal, and abundant lamina propria is present
■ DYSPLASIA IN BARRETT’S ESOPHAGUS between glands. The cytologic atypia, if any, is confined
to the basal aspect of the crypts, while the surface epi-
thelium shows maturation with small basally located
Grading Dysplasia in Barrett’s Esophagus nuclei and abundant cytoplasm (Fig. 2.9). Mitoses may
be present but are localized to the basal crypt epithe-
Surveillance biopsies from patients with BE are classified lium. Nuclei have smooth nuclear membranes with fine
as negative for dysplasia, indefinite for dysplasia (IND), chromatin and inconspicuous nucleoli. In the setting of
low-grade dysplasia (LGD), and high-grade dysplasia reactive changes, epithelial cells in the zone of inflam-
(HGD) (Table 2.1). Histologic features that are helpful in mation may display nuclear enlargement, and nucleoli
TABLE 2.1
Features for Classifying Dysplasia in Barrett’s Esophagus
Surface Nuclear
Dysplasia Maturation Architecture Cytology Inflammation Polarity
Negative + Normal; abundant Nuclear stratification and −/+ Maintained

lamina propria mitoses limited to gland base;
between glands smooth nuclear contours and
inconspicuous nucleoli
Indefinite +/− Normal to slight Nuclear irregularity and +/− Maintained
crowding of glands hyperchromasia or mitoses
typically limited to gland base
Low grade − Mild to marked Pencillate, stratified, hyperchromatic −/+ Maintained
crowding of glands nuclei extending to surface
epithelium (resemble colonic
tubular adenoma)
High grade − Marked crowding of Enlarged hyperchromatic nuclei, −/+ Lost
glands; villiform coarse clumped chromatin,
architecture nucleoli may be prominent; loss of
polarity, frequent mitoses
FIGURE 2.10
A Barrett’s esophagus, indefinite for dysplasia. The crypts show both pen-
cillate and round nuclei with some hyperchromasia and gland crowding,
but the lamina propria is densely inflamed, and multiple foci of crypti-
tis are present. Although the cytologic alterations are worrisome, these
changes are best classified as indefinite for dysplasia in the setting of
marked inflammation.
precludes an unequivocal diagnosis of dysplasia (Fig.

2.10). Cases in the IND category may have normal archi-
tecture or show some degree of glandular crowding. On
cytologic evaluation, nuclei may be irregular and hyper-
chromatic, small nucleoli may be present, but surface
maturation is usually preserved. Architectural abnor-
malities can be striking if the atypical focus is next to an
ulcer. The presence of an abrupt “clonal” demarcation
of the atypical from adjacent epithelium can be helpful
B in favoring a diagnosis of dysplasia. “Mutant” pattern of
p53 expression (diffuse strong staining or complete loss
FIGURE 2.9
of staining) on immunohistochemistry may be useful in
Barrett’s esophagus, negative for dysplasia (A). The basal aspect of the
crypts often appears regenerative and may be mistaken for dysplasia. The
this setting to suggest close surveillance but should not
presence of surface maturation, as illustrated in this case, argues against a be used to upgrade the morphological diagnosis to low-
diagnosis of dysplasia. A “wild-type” pattern of p53 immunoreactivity shows or high-grade dysplasia.
scattered nuclei with weak positive staining (B) and can sometimes be use-
ful in confirming the morphologic impression. Routine use of p53 immunos-
tain in all surveillance biopsies is not recommended. Barrett’s Esophagus, Low-Grade Dysplasia
may become more prominent, but nuclear contours Barrett’s esophagus with low-grade dysplasia resembles
are generally smooth with a vesicular chromatin, small a colonic adenoma (Fig. 2.11). The architecture shows
nucleoli and the overall nuclear-to-cytoplasmic ratio is mild distortion with glandular crowding, but lamina
preserved. There may be loss of cytoplasmic mucin, but propria is still identifiable between glands. The nuclei
surface maturation is preserved. are pencillate and hyperchromatic, stratified, and per-
pendicular to the basement membrane, and the changes
Barrett’s Esophagus, Indefinite for Dysplasia extend to the surface epithelium. Nucleoli are not prom-
inent, and the cells still retain their nuclear polarity.
The indefinite for dysplasia (IND) category is a provi- Both “wild-type” and mutant patterns of p53 staining
sional category that should only be used in specific sit- can be seen in LGD. Therefore, p53 immunohistochem-
uations. Most often, these are either cases that show istry should not be performed upfront or routinely to
cytologic changes suggestive of dysplasia in deeper determine the presence or grade of dysplasia without
aspects of the crypt but also show surface maturation taking into account the histologic findings, which are
or those that show epithelial changes worrisome for still considered to be the gold standard for dysplasia
dysplasia but significant inflammation is present and diagnosis.
A
FIGURE 2.11
Low-grade dysplasia in Barrett’s esophagus. Pencillate, stratified hyperchro-
matic nuclei uniformly involve the entire crypt from the base to the surface
epithelium.
Barrett’s Esophagus, High-Grade Dysplasia
In high-grade dysplasia (HGD), the metaplastic glands

show significant glandular crowding with back-to-back
arrangement and scant lamina propria between the
glands. The nuclei are large and hyperchromatic with
irregular nuclear membranes, clumped chromatin and
prominent nucleoli and show loss of polarity (Fig. 2.12). B
The nuclei may become monolayered and lose stratifi- FIGURE 2.12
cation, which often leads to a paradoxical bland appear- High-grade dysplasia in Barrett’s esophagus. Abrupt transition to two crypts
ance and underdiagnosis of HGD as LGD. Mitoses are on the right that show marked nuclear pleomorphism with loss of polarity
readily identifiable and can also be present in the sur- (A). The p53 immunostain shows a diffuse strong “mutant pattern” of stain-
ing restricted to the focus of dysplasia (B).
face epithelium. HGD may be present endoscopically
as nodules of variable size and may surface trauma
and erosion may lead to varying degrees of inflamma-
tion in the lamina propria and even in the neoplastic
epithelium.
Variants of Dysplasia
Basal “Crypt” Dysplasia. As mentioned earlier,

some cases may show significant atypia involving the
crypt bases with a mature surface epithelium (Fig. 2.13).
Aberrant p53 expression and high Ki-67 proliferation
may be present in these foci, supporting a neoplastic pro-
liferation. Whether this represents tangential sectioning
of a focus of dysplasia or early neoplastic change is un-
clear. More than half of such cases have been reported
to be associated with concurrent dysplasia or carcino-
ma. The natural history of these lesions in the absence
of concurrent conventional dysplasia is unknown. Un-
less definitive features of HGD are present, preferably
FIGURE 2.13
supported by a mutant pattern of p53 expression, these
Basal atypia with surface maturation. Occasional examples show the epithe-
lesions are best classified as IND which leads to repeat lial changes restricted to deeper glands, sometimes as a result of tangential
surveillance biopsies within 6 to 12 months. embedding. These biopsies are best classified as indefinite for dysplasia.

Foveolar type dysplasia in Barrett’s esophagus is characterized by abundant Intramucosal adenocarcinoma in Barrett’s esophagus can be distinguished
pale cytoplasm that stains positively for MUC5. Nuclei are often round and from high-grade dysplasia by the presence of anastomosing glands, sheets
monolayered, often leading to an underdiagnosis of LGD. This phenotype of of neoplastic cells, single cell infiltration, intraglandular necrosis, or neoplastic
dysplasia has been described variously as foveolar, gastric, and nonadeno- glands invading into the muscularis mucosae.
matous in literature.
Ancillary Studies
Foveolar, Nonadenomatous or Gastric-Type
Dysplasia. A peculiar form of dysplasia that is rich in
gastric foveolar type mucin has been described variously Immunohistochemistry
as foveolar, nonadenomatous or gastric-type dysplasia in
BE (Fig. 2.14). This accounts for approximately 6% to Various biomarkers have been examined to aid in the
8% of all dysplasia cases. It is characterized by back-to- diagnosis of BE-related dysplasia, of which p53 is the
back glands lined by a monolayer epithelium with round most well-studied. Aberrant immunohistochemical stain-
basally located nuclei, abundant apical cytoplasm, high ing for p53 is a useful surrogate marker of p53 mutations,
nuclear-to-cytoplasmic ratio, and prominent nucleoli. but reported concordance between aberrant staining and
Some cases may show eosinophilic instead of clear cyto- p53 mutations is about 90%. This highlights the risk of
plasm. There are no validated grading schemes for this misdiagnosis in a significant subset of cases if too much
pattern of dysplasia, but patients develop adenocarcino- reliance is placed on p53 pattern of expression only.
ma at rates similar to patients with high-grade conven- Whereas “wild-type” p53 staining shows scattered, weak
tional adenomatous dysplasia. Therefore, these lesions nuclear positivity (see Fig. 2.9B), a “mutant” pattern
are best regarded as high risk and managed similar to shows confluent, “clonal” diffuse strong expression (see
HGD. Fig. 2.12B) or complete loss of nuclear staining caused by
truncating p53 mutations. Caution must be used when
using p53 staining because a lack of a mutant pattern
■ INTRAMUCOSAL ADENOCARCINOMA does not rule out dysplasia, and the presence of a mutant
pattern may be seen both in LGD and HGD. Similarly,
Intramucosal adenocarcinoma is characterized by inva- the significance of a mutant p53 staining in biopsies neg-
sion of neoplastic cells into the lamina propria. This may ative for dysplasia is uncertain and should not change the
occur more obviously but less commonly in the form recommended surveillance interval. None of the other
of single cells infiltration or neoplastic cells floating ancillary biomarkers reported in BE have been validated
in pools of extracellular mucin or in a more subtle but for use in clinical practice, and even routine use of p53
common pattern of confluent sheet-like or anastomos- immunostain in classification of BE-associated dysplasia
ing glandular growth pattern, or expansile invasion by is not recommended for reasons discussed above.
cystically dilated glands with intraluminal papillary or
cribriform architecture. Intraglandular necrosis is also a
helpful sign of intramucosal adenocarcinoma (Fig. 2.15).
Deep infiltration into the submucosa or beyond is often
associated with desmoplasia, and a clearly infiltrative Guidelines for surveillance intervals have been devel-
growth pattern is more readily apparent in deeply inva- oped by the American College of Gastroenterologists as
sive tumors. in Table 2.2. The grade of dysplasia correlates well with
at a late stage. As mentioned earlier, more than 90% of

TABLE 2.2 all patients with adenocarcinoma are diagnosed at the
time of their first endoscopy (prevalent carcinomas) and
American College of Gastroenterology
Guidelines for Follow-up of Barrett’s Esophagus only 5% to 10% are diagnosed during surveillance for
BE (incident carcinomas). The majority of adenocarci-
Dysplasia Documentation Follow-up nomas occurring in association with BE occur in white,
middle-aged men, with a median age in the late fifties.
None If adequate biopsies Endoscopy every 3–5
were obtained at years The predisposing risk factors for adenocarcinoma are
index examination the same as for BE and include male gender, white race,
when diagnosis and obesity.
of BE was
established, repeat
endoscopy within
1 year not required
Low Highest grade on Endoscopic eradication Pathologic Features
grade repeat EGD with therapy or1-year
biopsies within 6 interval until two
Gross Findings
months. Expert negative EGDs with
review biopsy
High Repeat EGD with Endoscopic mucosal Esophageal adenocarcinomas are most often seen
grade biopsies within 3 resection or at esophagectomy as firm white mass lesions, usu-
months to exclude other endoscopic ally involving the distal third of the esophagus (Figs.
carcinoma. Expert eradication 2.16A–C). Residual Barrett’s mucosa can be recognized
review therapy, such as
in the background by its salmon color and “velvety
radiofrequency
ablation. Surveillance appearance.”
every 3 months
EGD, Esophagogastroduodenoscopy.
risk of progression to invasive carcinoma, and it remains Esophageal adenocarcinomas are composed of malignant
an imperfect but current gold standard for clinical decision cells with glandular differentiation. Well-recognized
making. Consensus diagnosis and review by an expert GI patterns of adenocarcinoma include tubular, papillary,
pathologist is recommended by gastroenterology society mucinous, and signet-ring cell types (Figs. 2.16D–F).
guidelines to help minimize interobserver variability and Some tumors may also show endocrine cells or Paneth
improve patient management. In the past, esophagectomy cells or an admixed malignant squamous component.
was the treatment of choice for patients with HGD and Although poorly differentiated adenocarcinomas behave
intramucosal adenocarcinoma, but this is no longer the more aggressively than well-differentiated ones, stage is
case. In the absence of a deep invasive component (pT1b the most important prognostic parameter. The muscu-
or higher) on endoscopic ultrasound, visible neoplas- laris mucosae of the esophagus tend to either thicken
tic lesions are removed by EMR or ESD, depending on or duplicate, and invasion between the two muscularis
size, followed by ablation of the remaining BE segment. mucosae should not be misinterpreted as submucosal
Radiofrequency ablation (RFA) is the most common abla- invasion (Figs. 2.16G and H). Similarly, the thick deep
tion technique currently used for eradication of early BE muscularis mucosae should not be mistaken for muscu-
neoplasia. Endoscopically invisible HGD and even LGD, at laris propria, which has major implications for patient
some centers, is now usually treated by RFA. Interestingly, management.
after ablation from any technique, there is a regrowth of In patients treated with preoperative chemoradiation,
squamous mucosa in the esophagus previously lined by the residual tumor cells may be rare, consisting of single or
metaplastic BE segment. Postablation neoplastic recurrence small clusters of cells associated with dense fibrosis and
typically occurs at the original site of neoplasia, commonly large pools of mucin. In some cases, acellular pools of
in the distal esophagus, and may be buried underneath the mucin may be the only residual indication of a preex-
neosquamous mucosa in many cases. isting tumor, and this is considered complete treatment
response. Grading schemes for tumor regression exist
and are typically included as part of tumor synoptic
■ ADENOCARCINOMA reporting. The modified Ryan scheme is most commonly
used and has four different tumor regression scores: 0,
no viable cancer cells; 1, single or small groups of cancer
Clinical Features cells; 2, residual cancer with evident tumor regression
but more than single or small groups of cancer cells;
Esophageal adenocarcinoma is rapidly increasing in and 3, extensive residual cancer with no evident tumor
incidence in the United States and is often diagnosed regression.
A B
D E
C
F H
FIGURE 2.16
Esophagectomy from a patient with an early invasive G
adenocarcinoma (A). Note the columnar mucosa in the distal esophagus. A subtle nodule in the distal
esophagus in another case (B) corresponded to an early invasive adenocarcinoma. Large bulky tumors with extensive ulceration (C) can be seen in patients
with poor response to neoadjuvant therapy. Microscopically, esophageal adenocarcinomas show variable grades of differentiation (D and E) and may show
mucinous (F) or signet ring cell phenotype. The phenomenon of double muscularis mucosae in Barrett’s esophagus is a pitfall that may lead to misdiagnosis
of submucosal invasion in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection specimens. EMR specimen showing duplication of the
muscularis mucosae. There are large submucosal glands at the bottom of the field, proving that the deepest portion of the sample is submucosal (G). EMR for
T1a adenocarcinoma with invasion into (but not beyond) muscularis mucosae (H).
instability, most often caused by sporadic methylation of

Ancillary Studies MLH1, is rare in esophageal adenocarcinomas.
Molecular Findings
Reported molecular genetic alterations include p53 muta-
Immunohistochemical staining is not typically necessary tion and deletion; deletion of Rb, p16, and APC; over-
to establish the diagnosis of esophageal adenocarcinoma expression of epidermal growth factor receptor (EGFR)
but can be helpful in poorly differentiated cases to rule and transforming growth factor-α; and clonal DNA aneu-
out squamous and neuroendocrine differentiation and ploidy and tetraploidy. There is no important role for Ras
to exclude metastases. Positivity for broad-spectrum gene mutations. Mutations in chromatin modifier genes,
cytokeratin and CK7 is typically seen, whereas positiv- such as ARID1A, are also reported in a small subset of
ity for CDX-2 is variable and CK20 is usually negative. tumors. Promoter methylation for numerous genes has
Special stains for mucin are positive but may be focal in been reported, but is of little clinical significance.
poorly differentiated cases. A subset of tumors, usually of
intestinal type, demonstrate HER2 amplification, which
can be targeted for therapy. Similarly, a minority of high
stage adenocarcinomas with metastatic disease are posi-
tive for PDL1, which is useful to identify patients likely The differential diagnosis is the same as with other ade-
to respond to anti-PD1 immunotherapy. Microsatellite nocarcinomas, including metastases and direct extension
from other primary sites. The presence of adjacent BE chemotherapy and radiotherapy followed by esophagec-
and associated dysplasia is strong evidence of primary tomy is the preferred treatment. The overall 5-year sur-
esophageal origin. Immunohistochemical staining may be vival rate is poor (∼15%–20%). The few patients with a
helpful in excluding metastases. When esophageal carcino- good outcome tend to be those with early lesions detected
mas appear poorly differentiated or undifferentiated, the
usual differential diagnosis is SCC or adenocarcinoma or
a high-grade neuroendocrine carcinoma. A panel of p40/ ESOPHAGEAL ADENOCARCINOMA—FACT SHEET
p63 in combination with CDX2, chromogranin, synapto-
physin, and INSM1 can help in determining the dominant Definition
line of differentiation in most cases. Poorly differentiated n A carcinoma displaying varying degrees of glandular differentiation
neuroendocrine carcinomas may show loss of Rb pro- arising in the esophagus, usually in the setting of Barrett’s
esophagus
tein and aberrant p53 but this finding is not lineage spe-
cific since a subset of SCC may show a similar phenotype. Incidence and Location
Undifferentiated SMARCA4 deficient carcinomas can also n The overall incidence of esophageal cancer in the United States is
occur in the esophagus in a background of BE. This possi- 2.58 cases per 100,000 persons (4.87 per 100,000 in men)
bility should be considered in poorly differentiated tumors n The incidence of adenocarcinoma has increased approximately
with limited keratin positivity and features reminiscent 6% per year over the past several decades
n The distal esophagus is most common site
more of a lymphoma rather than carcinoma or when
tumors show a rhabdoid or plasmacytoid morphology. Morbidity and Mortality
The esophagus can also be the site of primary malignant n The overall 5-year survival rate is poor (∼15%–20%) because of
melanoma, which can be easily diagnosed using immunos- the high stage at presentation
tains when the diagnosis is suspected. Lymphomas involv- n Low-stage lesions have an excellent prognosis
ing the esophagus are very rare but primary esophageal

plasmablastic lymphomas have been described in HIV pos- Gender, Race, and Age Distribution
n The mean age at diagnosis is in the mid-60s with a strong white
itive patients. Carcinomas involving the GEJ are defined as
male prevalence
tumors with epicenters within 2 cm from GEJ and extend-
ing into the esophagus and are staged similar to distal Clinical Features
esophagus cancers. Tumors with epicenters in the stomach n Dysphagia, odynophagia, and weight loss are common symptoms
greater than 2 cm from the GEJ or those within 2 cm of the at presentation
esophagogastric junction but without involvement of the n Some patients have symptomatic reflux
GEJ are classified and staged as proximal gastric cancers.
Prognosis and Therapy Esophageal Adenocarcinoma—Pathologic Features
Gross Findings
Patients with early-stage adenocarcinoma treated with n Mass lesion typically involving the lower one-third of the
EMR or ESD undergo a completion esophagectomy in the esophagus

n Background Barrett’s mucosa seen in most cases
presence of deep submucosal invasion, positive deep mar-
gin of resection, or lymphovascular invasion (Fig. 2.17).
For deeply invasive tumors, preoperative neoadjuvant
n Malignant invasive tumor with glandular differentiation
n Tubular and papillary patterns most common; signet ring cell and
mucinous types less common

n Tumors show a wide spectrum of differentiation (well to poorly
differentiated)
n Adjacent mucosa often shows residual Barrett’s esophagus with
dysplasia
n Not specific; often CK7+, variable CDX2
n HER2 and PDL1 expression or loss of DNA mismatch repair
proteins useful in metastatic tumors to guide adjuvant therapy
n When poorly differentiated, squamous cell carcinoma,
neuroendocrine carcinoma, SMARCA4 deficient undifferentiated

FIGURE 2.17 carcinoma, melanoma, and lymphoma should be considered
n Can be easily differentiated by immunohistochemistry in most
The presence of lymphovascular invasion in early-stage adenocarcinomas
treated by endoscopic therapy is an indication for completion esophagec- cases
tomy to rule out the possibility of nodal metastasis.
on surveillance or those with complete response to neo-

adjuvant therapy. Positive lymph nodes in posttreat- ESOPHAGEAL SQUAMOUS CARCINOMA—FACT SHEET
ment resections are the worst prognostic factor in these
Definition
patients. Residual or recurrent neoplastic glands may be
n Malignant neoplasm of the esophagus showing squamous
completely buried underneath squamous mucosa after differentiation, often with keratinization
treatment with RFA (Fig. 2.18). Surveillance biopsies
from the entire segment involved by BE before ablation Incidence and Location
are therefore performed routinely in these patients. n The incidence in US men is approximately 1.8 per 100,000
persons; it is 0.7 per 100,000 in women

n The incidence of squamous cell carcinoma is declining in the
United States
■ SQUAMOUS DYSPLASIA AND SQUAMOUS n Mid- or upper esophagus involved preferentially; in contrast
CELL CARCINOMA to adenocarcinomas that more commonly involve the distal

esophagus
Clinical Features Morbidity and Mortality

n The overall prognosis for these tumors is poor

The prevalence of esophageal squamous dysplasia varies
n More common in African American men in sixth to seventh
worldwide and is much more common in the East, in
decades of life
China and Iran. The incidence is declining in the United n High tobacco and alcohol use are strong risk factors
States. Estimates regarding the prevalence of squamous
dysplasia are from higher-risk countries and range Clinical Features
from 3% to 38%. Esophageal squamous dysplasia is a n Presenting symptoms are similar to adenocarcinoma—dysphagia,
odynophagia, and weight loss
precursor to SCC and is seen adjacent to SCC in up to

90% of cases. As with adenocarcinomas, most patients
with squamous carcinomas are men in their 50s. Unlike
adenocarcinomas, which typically affect white men,
SCC is more common among African American men.
Pathologic Features
A Gross Findings
Squamous dysplasia appears as foci of mucosal erythema

that tends to be irregular and friable. Lugol iodine stain-
ing can be used to detect lesions that are endoscopically
invisible, leaving dysplastic areas “unstained” because
of decreased glycogen content. Enhanced endoscopic
techniques, such as narrow-band imaging, are helpful in
detecting and delineating dysplastic areas. At esophagec-
tomy, carcinomas are firm white mass lesions of variable
size that may appear exophytic or endophytic (Fig. 2.19)
or present as a diffuse stricture, typically involving the
middle third of the esophagus.
B
FIGURE 2.18 Dysplasia involving esophageal squamous mucosa is
In patients with high-grade dysplasia or intramucosal adenocarcinoma who morphologically similar to oropharyngeal and laryn-
are treated with radiofrequency ablation, non-neoplastic metaplastic crypts geal squamous neoplasia and may be seen without a
or neoplastic glands may remain buried underneath squamous mucosa and
are an important cause for neoplastic recurrence. (A). At higher magnifica- concurrent invasive tumor in high-risk patients under-
tion, the dysplastic nature of buried gland is apparent (B). going screening or surveillance endoscopy. Low-grade
FIGURE 2.19
Squamous cell carcinoma of the esophagus. This lesion is prox-
imal and involves the cervical esophagus. Most examples are seen in the
mid-esophagus.
squamous dysplasia (Fig. 2.20A) is composed of basa-

loid cells with high nuclear-to-cytoplasmic ratio and typ- B
ically involves the lower third of the mucosa. A greater FIGURE 2.20
degree of involvement by cells with similar morphologic Squamous dysplasia may be low grade when basaloid cells with scant
features is diagnostic of high-grade squamous dysplasia cytoplasm involve the lower third of the mucosa (A) or high grade when
neoplastic cells with similar features occupy a greater thickness of the
(Fig. 2.20B). SCC of the esophagus shows a spectrum mucosa (B).
of differentiation from well-differentiated keratiniz-
ing carcinomas (Fig. 2.21A) to poorly differentiated or
undifferentiated tumors (Fig. 2.21B) that can only be
classified as squamous based on immunophenotypic Esophageal Squamous Carcinoma—Pathologic Features
positivity for p40/63 or the presence of adjacent high-
grade squamous dysplasia. Several histologic variants of Gross Findings
n Exophytic or endophytic mass or stricture involving the middle
SCC exist. A prominent spindle cell component may be
third of the esophagus
present, and these tumors have been variably designated
as polypoid carcinoma, carcinosarcoma, and sarcomatoid Microscopic Findings
carcinoma in the past (Fig. 2.22). Spindle cell SCC is the n Carcinoma with variable grades of squamous differentiation
preferred designation for these tumors. Short-term sur- n Associated high-grade dysplasia or in situ carcinoma often seen
vival in patients with such tumors is better than that n Variants include spindle cell, basaloid, and verrucous carcinomas
for those with flat typical carcinomas, owing to their

exophytic growth, but deeply invasive tumors have a Immunohistochemistry
n Positivity for CK5/6, P63, and/or P40 helpful in establishing
dismal prognosis. Basaloid SCCs are characterized by
diagnosis in poorly differentiated tumors
solid or cribriform nests of round cells with open chro-
matin and scant cytoplasm (Fig. 2.23). Areas of cen- Differential Diagnosis
tral necrosis and peripheral palisading of nuclei may n Majority easily diagnosed on morphology; poorly differentiated
be present. Verrucous SCCs are a rare variant with an tumors need confirmation by immunohistochemistry
exophytic growth pattern. Histologically, these tumors
are composed of well-differentiated squamous cells with

prominent acanthosis and a pushing boarder of invasion.
These tumors typically grow very large before coming to
clinical attention and are usually difficult to diagnose on
biopsy because of their well-differentiated appearance.
n Spindle cell squamous cell carcinomas can be challenging

because positivity for keratins can be focal; sampling to detect
a typical invasive component or adjacent dysplasia is helpful in
making the diagnosis.
FIGURE 2.22
Spindle cell squamous cell carcinoma (SCC), also known in the literature
as polypoid carcinoma or sarcomatoid carcinoma, is a SCC variant that can
show undifferentiated spindle cell morphology admixed with sarcomatoid
differentiation. Note the presence of malignant cartilaginous foci in this
example. The presence of in situ squamous neoplasia and foci of conven-
tional invasive SCC are helpful in establishing the diagnosis.
A
FIGURE 2.23
Basaloid squamous cell carcinoma of the esophagus may be mistaken for ade-
noid cystic carcinoma because of cribriform architecture and basement mem-
brane–like material but is composed of a single population of round cells with
scant cytoplasm. The tumor is present in broad nests that may show peripheral
palisading and central necrosis. A myoepithelial component, as seen in adenoid
cystic carcinoma, is lacking in basaloid squamous cell carcinoma.
Ancillary Studies
Squamous cell carcinomas are positive for CK5/6, p40,

p63, and broad- spectrum keratins.
B
FIGURE 2.21 Other Studies
Typical keratinizing squamous cell carcinoma of the esophagus (A). Other
examples may show a poorly differentiated or undifferentiated appearance Reported molecular genetic abnormalities include p53
(B) and may be recognizable as squamous only by virtue of immunohisto-
chemical positivity for p40/63 or the presence of squamous dysplasia in the mutations and deletion; deletion of Rb and p16; ampli-
adjacent mucosa. fication of EGFR; and c-myc, int-2/hst-1, and cyclin D1;
overexpression of EGFR and insulin-like growth factor ■ MICROSCOPIC FINDINGS

receptor-1 has also been reported.
By definition, these tumors lack squamous, glandular, and

neuroendocrine differentiation. Tumors have a nested,
syncytial, or sheet-like growth pattern (Fig. 2.24). The
As with adenocarcinomas, the diagnosis is challenging neoplastic cells reveal amphophilic to slightly eosino-
only in poorly differentiated or undifferentiated tumors. philic cytoplasm and oval nuclei with vesicular chromatin.
Careful evaluation of background mucosa for BE or squa- Admixed pleomorphic and rhabdoid cells are often seen.
mous dysplasia and a basic panel of immunostains can Lymphoepithelioma-like carcinoma is considered a
resolve the differential diagnosis in most cases. Primary subtype of undifferentiated carcinoma. As opposed to
sarcomas of the esophagus are extremely rare, and the those in the head and neck region, positivity for Epstein-
possibility of a spindle cell SCC must be excluded before Barr virus is not frequent.
rendering such a diagnosis. Basaloid SCCs can mimic mel-
anoma or high-grade neuroendocrine carcinomasbut this
is easily resolved on immunohistochemical stains. Reactive ■ ANCILLARY STUDIES
epithelial changes are in the differential diagnosis of verru-
cous SCC and challenging to distinguish in a biopsy but the
overall clinical context and presence of a mass lesion on Immunohistochemistry
endoscopy is helpful in rendering the right diagnosis.
The goal of using immunostains is to exclude primary
tumors with distinct differentiation (adenocarcinoma,
squamous, or neuroendocrine) or involvement by other
nonepithelial neoplasms such as lymphomas, melano-
mas, among others. SMARCA4 or INI-1 deficient undif-
Squamous cell carcinomas are also high stage at initial ferentiated carcinomas can also occur in the esophagus
presentation, and extension into periesophageal soft and easily diagnosed using the appropriate immunos-
tissue is already present. Esophageal obstruction, exten- tains. SALL4 expressing undifferentiated carcinoma
sion of carcinoma into mediastinal and intrathoracic carry a worse prognosis compared to those which are
structures (tracheobronchial tree, aorta, and lung), and negative.
mediastinal lymph node metastases are frequent, but dis-
tant metastases are rare. Radiotherapy or chemotherapy
is the usual treatment, sometimes with esophagectomy,
which may be palliative rather than curative. Esophageal
SCC has a dismal prognosis with an overall 5-year sur- The prognosis is poor with a 1-year survival rate of
vival rate of 5% to 10%. Patients with squamous dyspla- approximately 25%.
sia in the absence of invasive carcinoma can be treated
with endoscopic techniques such as radiofrequency abla-
tion or mucosal resection or submucosal dissection.
■ UNDIFFERENTIATED CARCINOMA
Clinical Features
This tumor is rare, representing fewer than 4% of all

esophageal carcinomas. It presents more commonly in men
in the sixth decade of life and involves the distal esophagus
and GEJ. Patients present with dysphagia and weight loss.
■ PATHOLOGIC FINDINGS
Gross Findings FIGURE 2.24

Undifferentiated carcinoma of the esophagus characterized by sheets of
Tumors are exophytic with a central depression or ulcer- atypical cells that do not display glandular, squamous, or neuroendocrine
ation and involve the distal esophagus or GEJ. differentiation.
■ PATHOLOGIC FEATURES
Undifferentiated Carcinoma—Fact Sheet
Definition Gross Features

n Tumors that lack glandular, squamous, or neuroendocrine
differentiation
Mucoepidermoid carcinomas appear grossly similar
Incidence and Location to SCCs, presenting as ulcerated or infiltrative mass
n Uncommon (<4%); usually involves the distal esophagus lesions in the midesophagus. Adenoid cystic carcinoma
can present as a discrete submucosal mass or as large,
Gender and Age Distribution polypoid or fungating mass lesions, also predominantly
n More common in men in their 60 s involving the midesophagus.
Clinical Features
n Dysphagia and weight loss

Mucoepidermoid carcinomas are characterized by an inti-

Undifferentiated Carcinoma—Pathologic Features mate mixture of squamous cells, mucus secreting cells,
and intermediate cells (Fig. 2.25). Squamous areas resem-
Gross Findings ble SCC with intercellular bridges and keratinization. A
n Mass forming with central depression or ulceration on endoscopy limited in situ SCC component is present in some cases.
Adenoid cystic carcinomas are composed of two cell popu-
Microscopic Findings lations: ductal epithelium and basaloid myoepithelial cells.
n Nests, syncytial, or sheet-like growth pattern The tumor may show cribriform, tubular, or solid growth
n Cell with amphophilic to eosinophilic cytoplasm and oval nuclei;
patterns (Fig. 2.26). Areas of cribriform growth character-
rhabdoid or pleomorphic cells
istically contain abundant eosinophilic basement mem-
n Lymphoepithelioma-like carcinoma is a subtype
brane material. The tumor cells are very monomorphic
Immunohistochemistry and only show mild nuclear atypia. The tumor nests are
n Lacks a characteristic staining pattern sharply circumscribed unlike the streaming appearance of
n Stains can help exclude tumors such as squamous cell myoepithelial cells in benign mixed tumors.
carcinoma, adenocarcinoma, or neuroendocrine neoplasms,
among others; SMARCA4 and INI-1 deficient carcinomas also fall
within this category ■ ANCILLARY STUDIES
n Squamous cell carcinoma
n Adenocarcinoma
n Neuroendocrine carcinoma Like SCC, mucoepidermoid carcinoma is positive for most

n Melanomas
cytokeratins and markers of squamous differentiation
n Lymphomas
n Others
■ SALIVARY GLAND TYPE TUMORS
Clinical Features
Primary tumors of the salivary glands originating from

esophageal submucosal glands or ducts have also been
described. These tumors are relatively rare, repre-
senting fewer than 1% of all esophageal carcinomas.
Mucoepidermoid and adenoid cystic carcinomas are the
most common variants and predominantly present in
the seventh decade of life with a male predominance. FIGURE 2.25
Presenting symptoms are similar to other esopha- An example of mucoepidermoid carcinoma involving the esophagus. The tumor
geal carcinomas and include dysphagia and weight shows an infiltrative growth pattern in the esophageal wall and displays the typical
loss. mucoid cells admixed with intermediate and squamous cells.
SALIVARY GLAND TYPE TUMORS OF THE ESOPHAGUS—

FACT SHEET
Definition
n Primary esophageal carcinomas arising from submucosal glands
or ductal epithelium of the esophagus and resembling salivary

gland counterparts

n Extremely rare, representing fewer than 1% of all esophageal
carcinomas
n Predominantly in the midesophagus
FIGURE 2.26
Adenoid cystic carcinoma in the esophagus. In this example, the two-cell
n Mucoepidermoid carcinomas have poor prognosis
population characteristic of this tumor (ductal and basal myoepithelial cells)
n Adenoid cystic carcinomas tend to do slightly better than
can be appreciated on hematoxylin and eosin stain. The tumor reveals cribri-
form (left) and tubular (right) predominant growth patterns. squamous cell carcinomas because of the earlier stage at
presentation
Gender, Age, and Race Distribution

(p63, p40). In addition, mucin stains (mucicarmine,
n Middle-aged to older patients with peak incidence in the seventh
Alcian blue) highlight the mucin-secreting cells. Ductal decade of life
cells of adenoid cystic carcinoma are strongly positive n Male predominance
for cytokeratins, CEA and KIT. The basal cells may

show weak keratin staining but are strongly positive Clinical Features
for p63, S100, actin, and calponin. MYB expression can n Dysphagia and weight loss
also be a helpful adjunct to diagnosis and correlates with

MYB translocations seen in the majority of adenoid cys-
tic carcinomas.
Salivary Gland Type Tumors of the Esophagus—Pathologic

Features
■ DIFFERENTIAL DIAGNOSIS
Gross Findings
Mucoepidermoid carcinoma and adenosquamous car- n Mucoepidermoid carcinomas present as ulcerated or infiltrative
cinoma show extensive histologic overlap and may be mass lesions in the midesophagus
n Adenoid cystic carcinomas present as submucosal lesions at early
difficult to distinguish. Adenosquamous carcinoma has
stages and progress to polypoid or fungating mass lesions
clearly distinguishable components of adenocarcinoma
and SCC, whereas in mucoepidermoid carcinoma the Microscopic Findings
components are intimately admixed. Mucoepidermoid n Mucoepidermoid carcinomas are characterized by intimate
carcinoma must also be differentiated from pure SCC by mixture of squamous cells, mucus cells, and intermediate cells
identification of the mucus-secreting cells. This distinc- n Adenoid cystic carcinomas are characterized by two cell populations
tion may be difficult on biopsy samples. The main differ- consisting of ductal cells and myoepithelial cells; typically, there
are tubular and cribriform areas containing basement membrane
ential diagnosis for adenoid cystic carcinoma is basaloid material; solid areas mimic basaloid carcinoma
SCC, especially if a solid growth component and base-
ment membrane-like material is prominent. Presence of Immunohistochemistry
an in situ squamous component strongly favors basaloid n Mucin stains, keratin, p63, p40 positive in mucoepidermoid
SCC. In contrast, identification of two cell populations, carcinoma

histologically or immunohistochemically, supports the n Keratin, KIT, and CEA positive in ductal cells of adenoid cystic
carcinoma; basal myoepithelial cells are positive for p63, S100,

diagnosis of adenoid cystic carcinoma. Adenoid cystic
actin, calponin; MYB positivity also helpful in diagnosis
carcinoma also typically has minimal pleomorphism and
limited mitotic activity. Differential Diagnosis
n Adenosquamous carcinoma has discrete areas of
adenocarcinoma and squamous cell carcinoma (SCC) rather

than an intimate admixture of both components typically seen
Prognosis and Therapy in mucoepidermoid carcinoma; intermediate cells are absent in
typical adenosquamous carcinoma
n Basaloid SCC has more cytologic atypia and lacks the two cell
Treatment usually consists of surgical resection with populations of adenoid cystic carcinoma; presence of squamous
or without chemoradiation therapy. The prognosis for dysplasia also is absent in adenoid cystic carcinoma
patients with mucoepidermoid carcinoma is poor with
a 5-year survival rate of approximately 20 % to 25%.

Follow-up data for patients with adenoid cystic carci-
noma are limited. In general, patients with adenoid cys-
tic carcinoma tend to do better than patients with SCC,
presenting with lower-stage disease and a lower fre-
quency of lymph node metastases. The estimated 5-year
survival rate is approximately 35%.
■ NEUROENDOCRINE NEOPLASMS
Clinical Features
Well-differentiated neuroendocrine tumors are FIGURE 2.27

extremely uncommon lesions in the esophagus and are Small cell carcinomas of the esophagus are rare but may arise in association
typically found incidentally at the time of esophagec- with both squamous cell or adenocarcinomas. The latter are often associated
tomy for other diagnoses. Poorly differentiated (small with a background of Barrett’s esophagus, as seen in this example, with met-
aplastic crypts on the left and a poorly differentiated small cell neuroendo-
cell and large cell) neuroendocrine carcinomas are the crine carcinoma on the right.
most common variant of neuroendocrine tumors in the
esophagus but are still rare and make up fewer than 1%
of all esophageal malignancies. Like other esophageal and are considered when at least 30% of each tumor com-
malignancies, patients with neuroendocrine carcinomas ponent is present. These tumors have been designated
may present with dysphagia, chest pain, weight loss, or mixed neuroendocrine non-neuroendocrine neoplasms in
symptoms of reflux. There is a male predominance, and the recent World Health Organization classification.
the age at presentation varies greatly with most cases
occurring in the sixth or seventh decade of life.
■ PATHOLOGIC FEATURES Immunohistochemistry
Gross Findings Immunohistochemical stains for keratins and neuro-

endocrine markers, chromogranin, synaptophysin,
INSM1, and CD56, and synaptophysin are positive in
Neuroendocrine neoplasms are primarily found in variable intensity and extent.
the distal esophagus. Well-differentiated neuroendo-
crine tumors are usually incidental polypoid lesions.
Neuroendocrine carcinomas, on the other hand, present
as large ulcerated and fungating masses.
The main differential diagnosis for esophageal neu-
roendocrine carcinomas is other poorly differentiated
malignancies or metastasis from another site. Positive
immunohistochemical staining for neuroendocrine mark-
ers helps differentiate these tumors from other carcinomas.
Esophageal neuroendocrine tumors show identical histo- Discriminating metastatic neuroendocrine carcinoma is
logic features, and grading is based on mitotic count and not possible on histologic grounds alone. Immunostaining
Ki-67 proliferative index, similar to other sites in the GI for TTF-1 is not helpful in differentiating lung metastases
tract. Poorly differentiated neuroendocrine carcinomas because the majority of small cell carcinomas show posi-
are subclassified as small cell or large cell neuroendocrine tive staining regardless of primary site of origin.
carcinoma. Small cell variants are composed of cells with
hyperchromatic, irregular nuclei, nuclear molding, and
scant cytoplasm (Fig. 2.27). In contrast, large cell variants
are composed of cells with moderate cytoplasm, coarse
chromatin, and prominent nucleoli often growing in a
nested or acinar pattern. Mixed neuroendocrine carcino- Follow-up data on well-differentiated neuroendo-
mas with adenocarcinoma or SCC components do exist crine tumors are limited given the rarity of occurrence.
Well-differentiated neuroendocrine tumors appear benign

Admixed adenocarcinoma or squamous cell carcinoma
in nature with most reported patients alive and disease n
component may be present

free on follow-up. Poorly differentiated neuroendocrine
carcinomas are aggressive tumors with nearly half of Immunohistochemistry
patients presenting with distant metastases at diagnosis. n Positive for cytokeratins, synaptophysin, chromogranin, CD56, and
Treatment typically consists of neoadjuvant chemother- INSM1
apy followed by esophagectomy in cases amenable to
resection. However, these tumors in general show poor Differential Diagnosis
n Immunohistochemistry can help differentiate from poorly
response to preoperative chemoradiation. The overall
differentiated squamous or adenocarcinoma; distinguishing
median survival period is approximately 14 months;
metastatic neuroendocrine carcinoma from another site can only
patients with small cell carcinoma tend to have worse be done based on correlation with clinical or imaging findings
survival than those with large cell carcinoma (median,
16 months vs 22 months). Patients with localized disease
have a slightly better survival (median, 28 months). ■ SECONDARY TUMORS OF THE ESOPHAGUS
NEUROENDOCRINE NEOPLASMS OF THE ESOPHAGUS— Clinical Features

FACT SHEET
Metastases to the esophagus do occur, but are rare. They
Definition
are also seldom the only site of metastatic disease and
n Neoplasms of esophagus with neuroendocrine differentiation
hence may not be biopsied if the diagnosis is already
Incidence and Location clear based on clinical presentation. Direct extension is
n Well-differentiated neuroendocrine tumors are exceedingly rare in
most common pattern of spread and typically occurs sec-
the esophagus; poorly differentiated neuroendocrine carcinomas ondary to tumors arising from the larynx, hypopharynx,
are more common but still account for only approximately 1% of trachea, and stomach. The most common primary sites
esophageal malignancies for secondary tumors involving the esophagus include
n Most cases are found in the distal esophagus
carcinomas of the lung and breast. Metastatic malignant
Morbidity and Mortality melanoma can also occur in the esophagus (Fig. 2.28A).
n Well-differentiated tumors are rare but appear largely benign in
nature
n Neuroendocrine carcinomas are aggressive tumors with a median
survival of approximately 14 months

n Most cases occur in the sixth decade of life
n Neuroendocrine carcinomas are more common in men; there is an
equal distribution in men and women for well-differentiated tumors
Clinical Features
n Well-differentiated tumors are typically incidental
n Dysphagia and weight loss
Neuroendocrine Neoplasms of the Esophagus—Pathologic

Features
Gross Findings
n Well-differentiated tumors present as incidental polypoid lesions
n Poorly differentiated neuroendocrine carcinomas appear as large,
ulcerated mass lesions
n Grading is based on mitotic count and Ki-67 proliferative index
n Well-differentiated tumors show organoid or trabecular growth
and nuclei with finely granular chromatin B

n Small cell neuroendocrine carcinomas show scanty cytoplasm
FIGURE 2.28
with nuclear hyperchromasia and molding; large cell
Malignant melanomas involving the esophagus are most often secondary
neuroendocrine carcinomas show more abundant cytoplasm and
tumors that display features akin to those of primary skin lesions (A). The
prominent nucleoli
presence of a junctional component (B) or background melanocytosis is a
helpful feature that favors a primary esophageal malignant melanoma.
It should be noted that primary melanoma of the esoph-

agus can also occur (Fig. 2.28B) but is quite rare, with
n TTF-1 positivity in lung metastases
fewer than 300 cases reported.
n ER/PR positivity in breast metastases
Metastases to the esophagus typically present several
years after diagnosis of the primary tumor. If lesions are Differential Diagnosis
large and obstructive, patients may present with dys- n Primary esophageal cancer; presence of in situ component
phagia, but the submucosal location of metastases often
makes these lesions less likely to cause clinical symp-
toms. Most patients are older, presenting in the seventh
or eighth decades of life. Ancillary Studies
SECONDARY TUMORS OF THE ESOPHAGUS—FACT SHEET
Definition Immunohistochemistry can be useful in determin-

n Tumor metastasizing to the esophagus from another primary
ing metastatic origin, and an appropriate panel can be
selected based on tumor morphology and clinical his-
Incidence and Location tory. TTF-1 positivity suggests lung origin and positiv-
n Relatively uncommon; one autopsy series reported an incidence ity of hormone receptors (ER/PR) can suggest breast
of 6% origin. SMAD4 loss can be seen metastatic pancreatic
cancer but has also been reported in primary esophageal
adenocarcinomas.
n Varies based on underlying disease

n Older individuals Differential Diagnosis
Clinical Features
n Most are submucosal in location and do not cause clinical The main differential diagnosis is primary esophageal
symptoms; obstructive lesions may cause dysphagia cancer. The presence of an in situ squamous carcinoma
component or BE with dysplasia in the case of adeno-
carcinoma strongly favors a primary esophageal tumor.
Pathologic Features

Gross Findings
Lesions are typically submucosal with associated stric- The prognosis in these patients is variable owing to the
ture but can present as large obstructive lesions. The heterogeneity of the underlying diseases. Reported sur-
midesophagus is the most common site of involvement. vival has ranged from months to years after the diagno-
sis of esophageal metastases. Treatment is also variable
Microscopic Findings with reports of resection, chemotherapy, and palliative
dilation of stricturing lesions.
Histologic features vary based on the primary site of
tumor origin. Submucosal tumor involvement with lack
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3
Non-Neoplastic Disorders of the Stomach
■ Sarah E. Umetsu, MD and Gregory Y. Lauwers, MD
The recognition of the central role of Helicobacter pylori

in the development of what was once the most com- ACUTE EROSIVE/HEMORRHAGIC GASTRITIS (STRESS
mon form of chronic gastritis has elicited a significant GASTRITIS)—FACT SHEET
interest in non-neoplastic gastric pathology. This has
been paralleled by easier access to upper endoscopic Definition
n Direct irritant action of chemical agents such as
examinations, which has allowed the characterization
ferrous sulfate, NSAIDs, and alcohol
of various patterns of gastritis with defined etiologic n Hydrochloric acid, pepsin, and bile salts that gain entry, resulting
associations. from the disrupted mucosal barrier
The prevalence of H. pylori gastritis has significantly n NSAIDs with their cyclo-oxygenase–inhibiting action inhibit
decreased over time because of effective antibiotic prostaglandins, which in turn reduces bicarbonate and mucin
therapy and improved sanitary conditions, and reac- secretions that have mucosal protective roles
n In cases of hypoperfusion-related stress ulcers, the pathogenesis
tive gastropathy has become the most common histo- is related to reduced mucosal blood flow, vasoconstriction, and
logic diagnosis rendered in gastric biopsies in Western reperfusion injury with release of free oxygen radicals
countries. n Abrupt onset of abdominal pain and bleeding associated
Numerous attempts at classifying the different types with alcohol, nonsteroidal antiinflammatory drugs, or low
of gastritides have been made, mostly based on the hemodynamic state after major trauma
n Present with multiple erosions in the gastric mucosa
acuteness or chronicity of gastric mucosal injury. This
chapter does not offer a new classification but presents Morbidity and Mortality
a review of the major clinicopathological entities, based n Bleeding can be minimal and self-resolving or life threatening.
either on the salient morphologic features or the under- n Patients with comorbid conditions such as liver disease have
lying etiologies. higher morbidity and mortality rates
Clinical Features
n Abrupt onset of abdominal pain, vomiting, and gastrointestinal
■ ACUTE EROSIVE/HEMORRHAGIC bleeding
GASTRITIS (“STRESS” GASTRITIS)
n Most patients have an uneventful course with full recovery within
Acute erosive/hemorrhagic gastritis is the result of a short period
severe and often acute mucosal injury. It is commonly n Intravenous fluids and blood transfusion
n Stop the offending agent

associated with abrupt onset of abdominal pain and
n H blockers, proton pump inhibitors, prostaglandin analogues
mucosal bleeding. Common causes include alcohol, ste- 2
n Life-threatening hematemesis may require surgical intervention
roids, nonsteroidal antiinflammatory drugs (NSAIDs),
various iatrogenic injuries, and low hemodynamic state
after major trauma.
■ CLINICAL FEATURES
The pathogenesis of acute hemorrhagic gastri-
tis reflects an imbalance between mucosal irritants
such as acid, pepsin, bile salts, NSAIDs, and other Patients commonly present with abrupt onset of burn-
chemicals and mucoprotective mechanisms such ing epigastric pain, nausea, vomiting, and gastrointestinal
as mucin, bicarbonates, prostaglandins, epidermal (GI) bleeding. The bleeding can be minimal occult bleed-
growth factors, mucosal blood flow, and the remark- ing, self-resolving melena, or life-threatening hematemesis.
able ability of gastric mucosa to reepithelialize. Patients with aspirin- or alcohol-induced injury usually
Various mechanisms can be at play to damage the make a quick recovery, whereas hypoperfusion-related gas-
mucosa (Box 3.1): tritis (stress ulcers) is associated with greater morbidity and
53
mortality. Acute erosive gastropathy is a common cause of

upper GI bleeding and accounts for 6% to 34% of cases.
Acute Erosive/Hemorrhagic Gastritis (Stress

Gastritis)—Pathologic Features
Gross Findings
n Superficial, round, dark erosions, few millimeters in size;
frequently multiple
n The intervening mucosa is edematous and hyperemic
n Stress-related ulcers are present in the fundus and body
n Nonsteroidal antiinflammatory drug–related erosions are usually
present in the antrum
n Superficial lamina propria hemorrhage, mucosal sloughing,
fibrinous exudate with neutrophils, and mucosal necrosis

n Changes limited to the mucosa
n Lack of significant lymphoplasmacytic infiltrate in lamina propria
n The healing phase is associated with regenerative epithelium with FIGURE 3.1
dark enlarged nuclei with prominent nucleoli Endoscopic appearance of acute erosive gastritis with mucosal necrosis and
hemorrhage.
n Mallory-Weiss tear, peptic ulcers
n Nasogastric tube trauma
n Dysplasia in cases with marked regenerative changes
Pathologic Features
Gross Findings
The gastric erosions are multiple, 2 to 5 mm in diameter,

superficial, round, and dark. The intervening mucosa is
edematous and hyperemic with petechial hemorrhage.
Stress-related ulcers are mostly located in the fundus
and body, whereas NSAID-related erosions are present
in the antrum.
Acute damage presents as mucosal denudation and

sloughing, surface hemorrhage, or fibrin exudate with FIGURE 3.2
neutrophils, epithelial necrosis, and lack of significant Acute erosive gastritis involving the gastric antrum with denuded surface
lymphoplasmacytic infiltration in the lamina propria mucosa covered by a band of fibrin and acute inflammatory cells. Necrotic
(Fig. 3.1). Mucosal damage ranges from gastric erosions debris is present within remnants of glandular epithelium toward the base
limited to the mucosa to deep ulcers that extend beyond
the submucosa. Etiologically specific changes may some-
times be seen (Figs. 3.2 to 3.4). Mucosal healing is asso-
ciated with regenerative epithelial changes with enlarged
hyperchromatic nuclei with prominentf nucleoli, amph-
ophilic cytoplasm, and sometimes syncytial glandular • Trauma related to nasogastric tubes presents as a very
architecture with increased mitotic activity (Figs. 3.5 and focal erosion and hemorrhage with unremarkable sur-
3.6). These changes can be alarming and may be mis- rounding mucosa. The clinical scenario makes the diag-
taken for dysplasia or adenocarcinoma. The presence of nosis obvious, and these lesions are seldom biopsied.
an overlying ulcer or erosion with active fibrin and neu- • Severe chronic active H. pylori gastritis: Ulcers are
trophilic exudate should caution against making a diag- associated with diffuse lymphoplasmacytic inflam-
nosis of malignancy. mation in lamina propria with variable neutrophilic
CHAPTER 3 Non-Neoplastic Disorders of the Stomach 55

Erosive gastritis secondary to an alcoholic binge involving gastric corpus Erosive gastritis secondary to radiation injury may be associated with marked
mucosa characterized by superficial necrosis with marked vascular conges- reactive glandular changes mimicking neoplasia and often shows vascular
tion and fibrinopurulent exudate. thrombi (inset).
A
FIGURE 3.6
Healing erosive gastritis with marked regenerative epithelial changes with amph-
ophilic cytoplasm and enlarged nuclei. There appears to be surface maturation.
infiltrate in gastric epithelium. Organisms are seen

on hematoxylin and eosin (H&E) or ancillary stains.
• Dysplasia or malignancy: Regenerative epithelial
change in a setting of erosion or ulcers can mimic
neoplasia caused by hyperchromatic nuclei with
prominent nucleoli, increased mitotic activity, and
amphophilic cytoplasm. The changes are limited to
epithelium adjacent to the erosion or ulcer, which
cautions against a diagnosis of neoplasia.
B • Chemical gastropathy: Usually associated with bile reflux,
FIGURE 3.4 alcohol, and NSAIDs. This is histologically characterized
Brown-yellow refractile deposits (A) in erosive gastritis secondary to iron by surface mucin depletion, foveolar hyperplasia, and
pills; special stain for iron (Prussian blue) is positive (B). smooth muscle hyperplasia in the lamina propria.
Prognosis and Therapy Morbidity and Mortality

n Often an incidental finding with no clinical implications; some cases
may be associated with gastrointestinal (GI) bleeding caused by

Most patients make an uneventful recovery within a short concurrent erosions or ulcers
time period. Depending on the hemodynamic state, man- Gender, Race, and Age
agement consists of supportive measures such as intrave- n Seen at any age but more prevalent in older adults; mean age,
nous fluids and blood transfusion, stopping the offending 66 years (range, 22–88 years)
n No gender predilection
agent, H2 blockers, proton pump inhibitors (PPIs), and
Clinical Features
prostaglandin analogues. In cases of life-threatening
n Frequently asymptomatic; vague upper abdominal pain, nausea,
bleeding, surgical intervention may be necessary.
vomiting, gastroduodenal ulcers, and GI bleeding can be
reported
n Causes include long-term aspirin use, nonsteroidal
antiinflammatory drug (NSAID) use, various iatrogenic injuries,

REACTIVE (CHEMICAL) GASTROPATHY and bile reflux after gastroenterostomies
n Treatment involves proton pump inhibitors and discontinuing
offending agents such as NSAIDs

Reactive gastropathy is the result of surface muco-
sal damage induced by bile, medications, or chemical
agents. It is a histologic diagnosis characterized by
surface mucin depletion, foveolar hyperplasia, regen-
erative epithelial changes, smooth muscle proliferation
in the lamina propria, and vascular congestion of the
gastric mucosa. The lamina propria does not typically
show an increase in lymphoplasmacytic infiltrate.
Reactive gastropathy is synonymous with type C gas-
tritis, chemical gastropathy, and alkaline or bile reflux
gastritis.
Reactive gastropathy is one of the most common diagno-

sis rendered in gastric biopsies. It is commonly asymp-
tomatic; however, some patients report vague upper A
abdominal pain, nausea, and vomiting. The mean age
at presentation is 66 years (range, 22–88 years), with-
out any gender predilection. Common causes include
chronic aspirin or other NSAID use and various medi-
cations (e.g., ferrous sulfate), bile reflux after gastroen-
terostomies, vagotomy, and pyloroplasty. In nonsurgical
patients, bile reflux may be caused by an incompetent
pyloric sphincter or gastric dysmotility. Other putative
causes include alcohol intake and smoking.
REACTIVE (CHEMICAL) GASTROPATHY—FACT SHEET
Definition
n Surface mucosal damage characterized by mucin depletion, B
foveolar hyperplasia, regenerative epithelial changes, smooth FIGURE 3.7
muscle proliferation in the lamina propria, and vascular
Reactive gastropathy involving antral mucosa and showing foveolar hyperpla-
congestion in the absence of significant lymphoplasmacytic
sia and corkscrew appearance of gastric pits (A). Note the mucin-depleted
infiltration in the lamina propria surface and lamina propria with smooth muscle proliferation and paucity of
inflammatory cells (B).
■ Pathologic Features Differential Diagnosis
Gross and Endoscopic Findings

The marked foveolar hyperplasia in chemical gastropathy
The endoscopy may be normal or display nonspecific may resemble hyperplastic polyps and the endoscopic appear-
findings, including erythema and localized erosions. ance of a polyp or nodule is important in making this distinc-
Visible gastric bile staining on endoscopic examination tion. Changes similar to reactive gastropathy are also present
can be helpful in the diagnosis. in gastric antral vascular ectasia (GAVE), but the typical
endoscopic appearance is that of a “watermelon stomach,”
Microscopic Findings and vascular ectasia with fibrin thrombi in lamina propria
capillaries are helpful in establishing a diagnosis of GAVE.
The mucosa shows marked surface mucin deple-
tion accompanied by foveolar hyperplasia, which is
characterized villiform change, elongation, and tor-
tuosity of gastric pits with a corkscrew appearance
(Fig. 3.7). The lamina propria shows smooth muscle Management involves discontinuing the offending agents,
proliferation and vascular congestion. There is typically such as NSAIDs, and medical management with PPIs.
a paucity of inflammatory cells in the lamina propria,
hence the term gastropathy instead of gastritis. Focal ero-
sions may be associated with small clusters of neutrophils
and eosinophils but are restricted to the foci of injured HELICOBACTER PYLORI GASTRITIS
mucosa, and diffuse lamina propria infiltrate is not
seen. The changes are commonly limited to the antrum,
whereas the oxyntic mucosa occasionally may occasion- H. pylori gastritis is a chronic infectious form of gastri-
ally show subtle reactive changes limited to the surface tis caused by spiral, flagellated gram-negative rods and
with separation of the surface foveolar epithelium from characterized by a diffuse chronic active gastritis.
the glandular compartment. Reactive gastropathy may
also be, at times, associated with intestinal metaplasia in
cases with recurrent injury over a long period. Bile reflux
gastropathy after Billroth I to II surgery with antrectomy
is present in the body. Findings of histochemical or immu-
nostains for H. pylori are negative. The prevalence of infection varies worldwide, and most
people acquire infection during childhood. Transmission
of infection is human to human, with poor sanitary con-
Reactive (Chemical) Gastropathy—Pathologic Features ditions and overcrowding being risk factors. It is more
prevalent in developing countries, where up to 75% of
Endoscopic Findings the population older than 25 years of age is infected. In
n Can be normal or show erythema, typically in the gastric antrum developed countries, the overall prevalence is 25% to
n Visible bile reflux on endoscopic examination or erosions may 30%, and the seroprevalence ranges from 5% to 27%
also be seen in early childhood to 50% to 60% in adults older than
60 years of age. Currently, despite a decrease of infec-
tion worldwide, at least 50% of the world’s popula-
n Changes are commonly in the antrum and prepyloric area
n Marked foveolar hyperplasia characterized by villiform change of

tion is actively infected. In the United States, African
the surface foveolae and elongation and corkscrew tortuosity of Americans, Asian Americans, and Hispanics have a
the gastric pits higher prevalence (70%) than whites (35%).
n Surface mucin depletion leads to high nuclear-to-cytoplasmic H. pylori is a 3.5-µm-long, microaerophilic gram-
ratio that may be mistaken for dysplasia negative rod with S-shaped or seagull wing appearance
n Smooth muscle proliferation and vascular congestion in the
lamina propria
that appears comma or spiral shaped on routine or special
n Paucity of inflammatory cells; focal erosions may be
stains. This organism has a tropism for gastric mucosa or
associated with neutrophils and eosinophils limited to the gastric metaplasia in the duodenum. The pathogenesis
injured focus depends on its ability to colonize gastric epithelium via
adhesins such as BabA, SabA, urease and virulence factors
Ancillary Studies
such as Cag A, Vac A, and urease, which in turn generates
n Stains for H. pylori are negative
cytokines such as interleukin-8 to attract neutrophils.
The majority of infected patients carry and transmit H.
n Hyperplastic polyp
pylori without any symptoms or are mildly symptomatic.
n Gastric antral vascular ectasia
Other patients may develop moderate to severe symptoms
of abdominal pain, nausea, vomiting, dyspepsia, weight
TABLE 3.1
Helicobacter pylori Tests
INVASIVE TESTS
Biopsy, special Modified Giemsa, Diff-Quik, silver Diff-Quik and modified Giemsa are preferred
stains stains—Warthin-Starry, Genta stain. over silver stains (cost).
Sensitivity is 84%–99%, and specificity
is 90%–99%.
Immunostain Especially useful in demonstrating variant forms of Costly compared with special stains such as Diff-
for H. pylori, such as the coccoid forms (see Fig. 3.13D) Quik; performed when the findings of special
Helicobacter that can occur in partially treated cases, patients stains are questionable. Immunostain is also
pylori taking antibiotics or PPIs, and resistant forms. positive in H. heilmannii gastritis.
PPI therapy can drive the organisms into the parietal
cells when they become visible by immunostains.
Biopsy-based Biopsy tissue is placed on urea medium, and positive CLOtest, Hpfast, PyloriTek
rapid urease test result is indicated by color change caused by Sensitivity is 89%–98%, and specificity
tests an increase in pH as a result of urea breakdown into is up to 93%–98%.
ammonia catalyzed by urease produced by all strains Sensitivity depends on organism load in the biopsy
of Helicobacter organisms. tissue and number of biopsy samples used.
Less sensitive in pediatric population.
Culture Incubation in nonselective mediums such as chocolate Sensitivity is 77%–92%, and specificity is 100%.
or blood agar for 5–7 days. Not used routinely but may gain importance
in the future owing to the emergence of
resistant strains.
Molecular PCR-based detection of H. pylori using various Rarely used in clinical practice.
tests genetic targets such as 23 S ribosome, vac A,
ure A, and cag A gene.
NONINVASIVE TESTS
Serology Detect IgG antibodies in serum or even whole Screening test used to detect current or past infec-
blood to H. pylori antigens using ELISA. tion. Performance varies with the different commer-
cial kits with an overall sensitivity and specificity of
88%92% and 86%–95%, respectively.
Reduced sensitivity in HIV-infected individuals.
Patients with H. heilmannii may have a negative test
result to anti–H. pylori IgG assays.
Serologic results can stay positive for a very long
time, making them less useful for follow-up.
Follow-up serology to test for eradication
should be done only after 1 year.
Urea breath Patient is given radioactively labeled urea to drink. Sensitivity is 90%–100%, and specificity
test (UBT) The urease produced by Helicobacter organisms is 98%–100%.
breaks down urea, and the labeled CO 2 is detected UBT is used as a follow-up for patients who
in the exhaled breath. continue to be symptomatic.
Stool antigen H. pylori antigen is detected from fecal sample by Sensitivity is 89%, and specificity is 94%.
test enzyme immunoassay. Like UBT, this test can also be used to confirm erad-
ication.
ELISA, Enzyme-linked immunosorbent assay; IgG, immunoglobulin G; PCR, polymerase chain reaction; PPI, proton pump inhibitor.
loss, and iron-deficiency anemia. The recognition of the

Helicobacter organism and its association with peptic Pathologic Features
ulcer disease, gastric mucosa–associated lymphoid tissue
(MALT) lymphoma, and carcinoma has revolutionized Gross Findings
modern understanding of disease processes and influenced
patient management. The World Health Organization has Endoscopic findings are variable and include mucosal ery-
classified H. pylori as a group I human carcinogen of gastric thema, erosions, granularity, and nodularity. Gastric and
cancer. Infected persons have a three- to sixfold greater risk duodenal ulcers may be present in severe cases. Mucosal nod-
of developing gastric cancer over that of uninfected per- ularity may be prominent in cases associated with marked
sons. Australian researchers Robin Warren, a pathologist, lymphoid hyperplasia or MALT lymphoma. In rare instances,
and Barry Marshall, a gastroenterologist, became the recip- the mucosa may appear completely normal. For optimal eval-
ients of the Nobel Prize in 2005 for this significant discov- uation, at least two mucosal biopsy specimens, one each from
ery. Noninvasive and invasive tissue-based, serologic, and the antrum and body, are recommended. Sampling of a single
stool tests for diagnosis of H. pylori infection have been site may reduce the test sensitivity. The Sydney system and
developed and are summarized in Table 3.1. the Operative Link for Gastritis Assessment (OLGA) staging
HELICOBACTER PYLORI GASTRITIS—FACT SHEET
Definition
n Chronic infectious form of gastritis caused by curved, flagellated
gram-negative rods—Helicobacter pylori—and characterized by a

chronic active gastritis of variable severity

n Variable prevalence across the globe
n In developing countries, up to 75% of the population older
than 25 years is infected, with the prevalence reaching

80% to 90%
n In developed countries, the overall prevalence is 25%–30%;
the seroprevalence ranges from 5% to 27% in early childhood

and exceeds 50% in adults older than 60 years of age A
n In the United States, African Americans and Hispanics have a
higher prevalence than whites

n Epidemiologic association with peptic ulcer disease, gastric
lymphoma, and carcinoma

n Group I human carcinogen (World Health Organization)
Clinical Features
n Abdominal pain, nausea, vomiting, dyspepsia, weight loss,
iron-deficiency anemia, and possibly ulcer-related bleeding in

symptomatic patients
Prognosis and Therapy B

n Triple therapy for 14 days consisting of either bismuth or FIGURE 3.8
proton pump inhibitors combined with two antibiotics such as Chronic gastritis secondary to Helicobacter pylori is associated with a diffuse
metronidazole, clarithromycin, tetracycline, or amoxicillin bandlike infiltrate of lymphocytes and plasma cells separating the surface
n Cure rate is greater than 95% epithelium from the glandular compartment (A). Lymphoid follicles with
n Short treatment courses of 1 to 5 days may be effective with a active germinal centers are often present (B).
slightly lower eradication rate
system have been proposed for systematic reporting of gastri-

tis but are seldom followed in the West.
H. pylori typically presents as a chronic active gastri-

tis of variable severity. The infection can be antrum
predominant or a pangastritis at initial presentation.
Posttreatment cases may show persistence of infec-
tion in the gastric corpus or cardia with resolution
of inflammation and lack of organisms in the distal
stomach.
In involved regions, the superficial lamina propria
shows a diffuse bandlike mononuclear infiltrate of
lymphocytes and plasma cells along with activated lym-
phoid follicles with germinal centers (Fig. 3.8). The
term follicular gastritis has been used in the past for
cases with prominent lymphoid aggregates (Fig. 3.9).
Various degrees of neutrophilic infiltrate, reported as
FIGURE 3.9
evidence of activity, may be seen in the surface epithe-
Gastric mucosal nodularity simulating lymphoma or carcinoma. Such a nodularity
lium and gastric pits and crypt abscesses (Fig. 3.10). A as this is often present in Helicobacter gastritis, caused by the florid lymphoid
pattern of lymphocytic gastritis can also be seen with hyperplasia. (Courtesy of Shriram Jakate, MD, Rush Medical College, Chicago).
H. pylori infection. Severe cases with ulcers may show

regenerative foveolar hyperplasia, and intestinal meta-
plasia is already present in a subset of patients at first
diagnosis.
The organisms appear as slightly curved seagull wing–
shaped rods, clustered in the gastric mucus, adherent to
the gastric surface foveolar epithelium, or deep in the gas-
tric pits. When abundant, the organisms are easily visible
on H&E, but special stains (e.g., Giemsa, silver stains)
and immunohistochemistry can aid in their detection
(Fig. 3.11) when the density is low or posttreatment
change has transformed the typical spiral shape of the
organisms into a more coccoid appearance. Table 3.2
highlights other manifestations that may be attributed
to H. pylori infection. A pattern of chronic inactive
gastritis with residual mononuclear cell infiltration in
the lamina propria but without any foci of neutrophilic
infiltration may be seen in biopsies obtained soon after
treatment with antibiotics (Fig. 3.12). The pattern is not
etiologically specific, and organisms are usually absent
FIGURE 3.10
in posttreatment biopsies. The only way to establish the
High-power view of Helicobacter pylori gastritis showing active neutrophilic
diagnosis is by correlating findings with patient history.
inflammation infiltrating gastric pit and glandular epithelium.
A B
C D
FIGURE 3.11
A, Helicobacter pylori organisms seen on hematoxylin and eosin stain, admixed in surface mucin. Notice the curved shapes. B, Helicobacter gastritis. Diff-Quik stain high-
lights the slightly curved seagull wing–shaped H. pylori organisms in the gastric pits lining the foveolar epithelium. C, Immunostain for H. pylori shows the organisms lining
the gastric foveolae. D, Coccoid, deep, intracellular location of H. pylori is common after treatment and best visualized on immunostains.
TABLE 3.2
Histologic Manifestations Indicative of Present or Past Helicobacter pylori Infection
Acute Helicobacter Acute manifestation at the time of initial acquisition of the infection. It almost never comes to
gastritis medical attention and therefore is not biopsied. Best evidence came from Dr. Marshall himself,
who drank from a Petri dish containing the organisms from the culture of a patient with H. pylori
infection and had acute gastritis with nausea, vomiting, and halitosis.
Chronic active gastritis Neutrophilic inflammation within the epithelium, most prominent in gastric pits accompanied by
diffuse lymphoplasmacytic infiltrate in the lamina propria.
Chronic inactive gastritis Characterized by clusters of plasma cells in the lamina propria (see Fig. 3.14); lacks active
inflammation and may reflect past Helicobacter infection.
Lymphocytic gastritis Lymphocytic gastritis contains prominent intraepithelial lymphocytosis.
Hyperplastic polyp May be a marker of H. pylori infection in the nonpolypoid gastric mucosa in a subset of cases.
Environmental atrophic H. pylori is an important cause of EMAG, a precursor to gastric dysplasia and carcinoma.
metaplastic gastritis Characterized by gradual loss of normal glands and multifocal intestinal metaplasia, predominantly
(EMAG), multifocal in the gastric antrum but may also present in the body and cardia. Unlike autoimmune gastritis, the
atrophic gastritis, or gastrin level in EMAG is either low or normal. The antrum is normal in autoimmune gastritis, which
type B gastritis is not the case in EMAG.
n The organisms can be visible on hematoxylin and eosin stain,

especially when numerous, but ancillary stains can be used in
selected situations discussed next
Ancillary Studies
n Histochemical stains: modified Giemsa, Diff-Quik, Warthin-Starry,
Genta stain, and Alcian yellow have all been used in the past
n Immunohistochemistry for Helicobacter is often used in current
practice when:
n Organisms are not seen on hematoxylin and eosin despite
the presence of a chronic gastritis reminiscent of H. pylori

infection
n In posttreatment biopsies when the density of organisms is
low and they have transformed into a coccoid appearance
FIGURE 3.12 n Helicobacter heilmannii gastritis
n Gastric marginal zone B-cell lymphoma

Chronic inactive gastritis in a patient recently treated for Helicobacter pylori
n Focally enhanced gastritis
infection. Note the lamina propria with plasma cells but without active
inflammation. n Autoimmune gastritis
n Non–H. pylori infectious gastritis
Helicobacter Pylori Gastritis—Pathologic Features
Gross Findings Differential Diagnosis

n Gastric mucosal erythema, erosions, granularity, and nodularity
Microscopic Findings Helicobacter heilmannii gastritis (Gastrospirillum homi-

n For optimal evaluation, two mucosal biopsies from both the nis) is responsible for approximately 0.3% of the cases
antrum and body are recommended of Helicobacter gastritis. It is caused by a tight spiral
n Chronic active gastritis with marked lymphoplasmacytic bacterium that is 5 to 6 μm in length, which is longer
inflammation and variable neutrophilic infiltration and prominent than H. pylori (Fig. 3.13A and 3.13B). It is also seen in
lymphoid aggregates
n The inflammation is predominantly in the superficial mucosa
cats and dogs, and the disease in humans may be a zoo-
n Active (or neutrophilic) inflammation, a marker for the presence of notic infection. They can be seen on H&E examination
Helicobacter organisms, is prominent in the gastric pits, causing pititis easily because of their large size and are present in the
n Foveolar hyperplasia, erosion, hemorrhage, reactive epithelial gastric mucus and lumen of gastric pits without coming
changes, and in severe cases, mucosal erosion and ulceration in close contact with the epithelium. Immunostain for
n Mucosal atrophy and intestinal metaplasia may be present
n Helicobacter pylori appear as slightly curved seagull wing–shaped

H. pylori also stains H. heilmannii (Fig. 3.13C). H. heil-
rods, most prominent in the gastric mucus and the lining surface mannii infection has been associated with the develop-
foveolar epithelium and also in gastric pits ment of marginal zone B-cell lymphoma but not with
gastric cancer.
of CD20 and CD43 and light chain restriction. The

intraepithelial lymphocytes in Helicobacter gastritis are
mostly CD3-positive T lymphocytes, unlike the CD20-
positive neoplastic B-cells in gastric marginal zone B-cell
lymphoma. A clonal population of lymphoid cells may
be seen in Helicobacter gastritis, and a diagnosis of lym-
phoma should not be based on molecular studies alone
(see details in Chapter 19).
Focally enhanced gastritis is typically associated with
Crohn’s disease, medication-induced mucosal injury,
and the resolving phase of gastric erosions. The biopsy
shows a localized increase in lymphoplasmacytic inflam-
mation with neutrophilic infiltration into the epithe-
A lium and a cuff of loose histiocytic aggregates around
damaged gastric pits.
Autoimmune gastritis typically involves the oxyntic
mucosa and shows atrophy with marked reduction in
oxyntic glands, pyloric gland and intestinal metaplasia,
and enterochromaffin-like (ECL) hyperplasia. The latter
feature shows a spectrum of linear to micronodular to
adenomatoid hyperplasia culminating in well-differenti-
ated neuroendocrine tumors. The presence of micronod-
ular hyperplasia is helpful in differentiating autoimmune
gastritis from H. pylori gastritis. Antibodies to intrinsic
factor and parietal cells are diagnostic and lead to hypoch-
lorhydria, vitamin B12 deficiency, and hypergastrinemia.
Hypergastrinemia can also occur in H. pylori gastritis but
not to the extent seen in autoimmune gastritis.
B A variety of other bacterial, viral, fungal, and parasitic
infections may rarely involve the stomach and must be
excluded when the mucosa is inflamed and Helicobacter
organisms are not identified.
In most untreated cases, the gastritis progresses to glan-

dular atrophy (loss of specialized glandular epithelium)
and intestinal metaplasia. Patients with gastric atrophy
have up to a 16-fold increased risk of developing gastric
neoplasia. The OLGA system arranges histologic pheno-
C types of gastritis along a scale of progressively increas-
ing gastric cancer risk by scoring the extent and location
FIGURE 3.13 of atrophy. However, this system is not typically used
A, Unlike Helicobacter pylori, Helicobacter heilmannii organisms are longer, in daily practice. These patients are also at risk for the
tightly spiraled, present in the lumen, and less tightly adherent to surface
foveolar cells (hematoxylin and eosin). B, H. heilmannii in (GMS). C, The development of MALT extranodal marginal zone B-cell
antibody for H. pylori cross reacts with H. heilmannii and can be useful in lymphoma. Antral restricted and pangastritis both
cases with low density of the organisms. increase the risk of gastric cancer, whereas antral domi-
nant gastritis also increases risk of duodenal ulcers.
The florid lymphoid hyperplasia in Helicobacter gas- Triple therapy for 14 days consisting of either bis-
tritis can be mistaken for low-grade extranodal marginal muth or a PPI combined with two antibiotics has been
zone B-cell lymphoma. However, marginal zone B-cell the most popular regimen, achieving up to a 95% cure
lymphoma is characterized by aggregates or sheets of rate. The recommended antibiotics are metronidazole,
monomorphic B cells with destructive lymphoepithe- clarithromycin, and tetracycline or amoxicillin.
lial lesions. The neoplastic lymphoid cells in marginal However, recent studies have shown that short treat-
zone B-cell lymphoma may show aberrant coexpression ment courses of 1 to 5 days may be equally effective with
an eradication rate of 89% to 95% with better compli-

ance, reduced cost, and fewer adverse effects.
GASTRIC PEPTIC ULCER DISEASE
Peptic ulcer disease is a clinical term used for patients

with discrete ulcers in the stomach or duodenum, most
often in association with H. pylori gastritis or NSAID use.
FIGURE 3.14
Benign gastric ulcer with a smooth base and regular borders.
The incidence of gastric peptic ulcer disease has been
decreasing since the 1980s. Common locations are stom-
ach and proximal duodenum, with a mean age of 40 years
and 20 years, respectively. Symptoms include severe epi-
gastric pain exacerbated by food intake, in contrast to
duodenal ulcer pain, which is relieved by food intake. In
addition, vomiting, weight loss, hematemesis, melena,
and gastric outlet obstruction can be caused by scarring
and pyloric stenosis. Peritonitis can develop after perfora-
tion. NSAID ulcers are on the rise as the prevalence of H.
pylori infection is declining. Certain medications, such as
steroids, can also contribute to ulcer development. Other
rare causes of peptic ulcers include ZES and multiple
endocrine neoplasia type I (MEN-I).
A
Pathologic Features
Gross Findings
Gastric ulcers are variably sized and usually present in the

lesser curvature, round to oval in shape with a smooth base
and regular, perpendicular edges (Fig. 3.14), unlike the
irregular heaped-up borders of malignant ulcers.
Histologically, mucosal defects are seen extending below

the muscularis mucosae with extension into the submu- B
cosa and muscularis propria in severe cases. Early ulcers FIGURE 3.15
are associated with fibrin, necrosis, inflammation, and Gastric ulcers can be with extension below the muscularis mucosae (A).
granulation tissue reaction. Chronic ulcers are associ- Chronic ulcers are characterized by fibrosis and stricture (B).
ated with scarring and stenosis (Fig. 3.15).
Eradication of H. pylori infection is the key to successful
The histologic changes seen in gastric peptic ulcer dis- healing and reduces the risk of recurrence or rebleeding.
ease are nonspecific. The possibility of an associated Acid suppressors, especially PPIs, are used in addition to
malignancy should be ruled out. stopping intake of NSAIDs and prostaglandin analogues
such as misoprostol. Discontinuing smoking and alco- iron to ferrous state for absorption. Pernicious anemia is
hol use may be helpful. Endoscopic treatment modalities present in 15% to 25% of patients and is characterized by
such as epinephrine injection, coagulation, or clipping of macrocytosis, megaloblastic anemia, pancytopenia, atrophic
bleeding sites, or in cases of perforation or severe hemor- glossitis, low serum B12 concentration, and normal folate
rhage, surgical management can be used in selected cases. level. This is a late manifestation of autoimmune gastritis,
taking 20 to 30 years to develop, and is caused by progres-
sive loss of parietal cells, which are necessary for intrinsic
factor production. Concomitant autoimmune disorders such
AUTOIMMUNE GASTRITIS as insulin-dependent diabetes mellitus, Hashimoto’s thyroid-
itis, adrenal insufficiency, Graves’ disease, vitiligo, or myas-
thenia gravis can also be seen in patients with autoimmune
Autoimmune gastritis is an immune-mediated destruc- gastritis.
tion of the oxyntic glands caused by antiparietal cell
antibodies. Patients also have antibodies to intrinsic fac-
tor, and loss of oxyntic glands leads to hypochlorhydria, AUTOIMMUNE GASTRITIS —FACT SHEET
vitamin B12 deficiency, and endocrine ECL cell hyper-
plasia. Type A gastritis, diffuse corporal atrophic gastri- Definition
n Immune-mediated chronic gastritis and loss of oxyntic glands
tis, and autoimmune metaplastic atrophic gastritis are all
caused by antiparietal cell and anti-intrinsic factor antibodies
terms used for autoimmune gastritis in the past.
leading to hypochlorhydria, achlorhydria, and vitamin B12 deficiency

n Affects nearly 2% of people older than 60 years
n No racial predilection
Autoimmune gastritis affects nearly 2% of the population Gender, Race, and Age
n Patients are usually older white women in the fifth or sixth
older than 60 years old and is responsible for approximately
decades of life
4% of cases of chronic gastritis. It was classically described
n Male-to-female ratio of 1 to 3
in individuals of northern European or Scandinavian
descent but is now known to be equally represented in Clinical Features
African Americans and Latin Americans. White women n Frequently asymptomatic, but abdominal pain and discomfort,
in the fifth to sixth decade of life are affected three times weight loss, pernicious anemia, and rarely subacute combined
more commonly than men. Patients may be asymptomatic degeneration of spinal cord are reported
n Patients may have other immune-related disorders such as
or present with abdominal pain, weight loss, diarrhea, mal-
insulin-mediated diabetes mellitus, Hashimoto’s thyroiditis, or
absorption, and neurologic complications, such as periph- adrenal insufficiency
eral neuropathy and subacute combined degeneration of n Serum analysis positive for antiparietal cell antibodies (∼80% of
the spinal cord, related to severe vitamin B12 deficiency. The patients) and anti-intrinsic factor antibodies (∼30% of patients)
antiparietal cell antibodies that target H+/K+-ATPase pro- n Elevated serum gastrin
n Reduced B ; positive Schilling test result corrected by

ton pump are present in 60% to 85%, and anti-intrinsic 12
administering intrinsic factor but is seldom performed nowadays
factor antibodies are identified in 30% to 50% of patients n Helicobacter serology is usually negative
(Table 3.3). Reduced gastric acid plays a role in iron defi-
ciency in 20% to 40% of cases because gastric acid is nec- Prognosis and Therapy
essary to release iron bound to proteins and to reduce ferric n 2% to 9% prevalence of gastric well-differentiated
neuroendocrine tumors and a two- to threefold increase in gastric

carcinomas
n Medical management includes vitamin B injections
TABLE 3.3 12
n Management for multiple well-differentiated neuroendocrine
Pertinent Laboratory Findings in Autoimmune tumors includes endoscopic polypectomies or mucosal resection,
Gastritis antrectomy, or rarely total gastrectomy
Antiparietal cell Positive (target H +/K +ATPase):

antibodies 60%–85%
Intrinsic factor antibodies Positive: 30%–50%
Serum gastrin Elevated
Gastric pH Alkaline or neutral Pathologic Features
Vitamin B 12 level Reduced
Serum pepsinogen I Reduced (loss of chief cells)
Gross Findings
Schilling test Positive and corrected by
vitamin B 12 injection
Helicobacter pylori Usually negative Autoimmune gastritis affects the oxyntic mucosa and
serology spares the antrum in the vast majority of cases. On
HLA haplotypes HLA-B8, DR-3
endoscopic examination, the body or fundic mucosa
appears flat and congested with a prominent submuco- The gastric atrophy leads to hypergastrinemia, which
sal vascular pattern caused by mucosal atrophy. Multiple acts as a trophic signal to the ECL cells in the gastric corpus.
small mucosal elevations or pseudopolyps, represent- This results in a unique hyperplasia to neoplasia contin-
ing preserved islands of oxyntic mucosa surrounded by uum culminating in the development of well-differentiated
flattened atrophic mucosa, may be seen. Other polypoid neuroendocrine tumors. Linear, micronodular, adeno-
lesions in autoimmune gastritis include hyperplastic pol- matoid hyperplasia and dysplastic nodular lesions have
yps (most common), pyloric adenomas, well-differenti- been described, but this subclassification is seldom used in
ated neuroendocrine tumors, and dysplastic lesions or daily practice other than using the presence of neuroendo-
adenocarcinoma. crine cell hyperplasia to render a diagnosis of autoimmune
gastritis. Expansile nodules greater than 0.5 mm or lesions
Microscopic Findings infiltrative into the muscularis mucosa or submucosa are
designated as well-differentiated neuroendocrine tumor.
The histologic findings are limited to the oxyntic mucosa An atrophic corpus in the late stages of the disease
lining the gastric corpus. The antrum is normal in the vast can resemble the antrum and the diagnosis can be easily
majority of cases. The corpus mucosa shows a chronic missed when antrum and corpus biopsies are submitted
gastritis with prominent lymphocytic and plasma cell in the same container, a common practice in many parts
infiltration that is more prominent in the deep aspect of of the world. Immunostains for gastrin and chromogr-
lamina propria. There is a variable loss of oxyntic glands anin can aid in establishing the diagnosis. Therefore,
depending on stage of the disease and manifests as atro- the presence of a patchy chronic gastritis or intestinal
phy, pyloric gland metaplasia, and intestinal metaplasia metaplasia restricted to corpus biopsies in the setting of
with goblet and Paneth cells (Fig. 3.16A). Pancreatic aci- a negative H. pylori immunostain should always lead to
nar metaplasia may also be present. work-up for autoimmune gastritis in gastric biopsies.
A B
C D
FIGURE 3.16
A, Autoimmune gastritis. Gastric body biopsy sample showing loss of oxyntic glands, chronic lymphoplasmacytic infiltrate more in the deeper aspect, and pyloric
gland metaplasia. B, Body biopsy with marked atrophy and intestinal metaplasia. C, Chromogranin immunostain highlighting linear and nodular enterochromaf-
fin-like cell hyperplasia in the body mucosa. D, Gastrin immunostain in the body is negative. Based on this, some observers refer to the presence of metaplastic
antral type glands as pseudopyloric metaplasia because the glands do not produce gastrin.
The antral mucosa may show only limited changes

including foveolar hyperplasia or mild chronic inflam-
mation. Furthermore, the low-acid state created by the
loss of parietal cells stimulates antral gastrin cell hyper-
plasia presenting as increased density of gastrin-positive
G cells in the gastric pits. Extremely rare cases of an
autoimmune pangastritis with antral involvement have
also been reported.
Other associated findings in autoimmune gas-
tritis include gastric hyperplastic polyps, pyloric
gland adenomas, well-differentiated neuroendocrine
tumors of variable size, and gastric dysplasia and
adenocarcinoma.
A
Autoimmune Gastritis—Pathologic Features
Gross Findings
n Involves the gastric body and fundus and spares the antrum
n Effacement of rugal folds and prominent submucosal vascular
pattern in gastric corpus caused by glandular atrophy
n Chronic gastritis with prominent lamina propria lymphocytic and
plasma cell infiltration, often prominent within the deep lamina

propria
n Loss of specialized glandular epithelium (atrophy) in the gastric
corpus
B
n Pyloric gland metaplasia, intestinal metaplasia, and linear
or micronodular enterochromaffin-like (ECL) hyperplasia is FIGURE 3.17

characteristic A, Antral biopsy specimen from an autoimmune gastritis case showing mild
reactive gastropathy and lack of chronic gastritis and metaplasia. B, Gastrin
Immunohistochemical Features immunostain of the antrum highlights G cells.
n Gastrin and chromogranin A can be used to demonstrate ECL-
cell hyperplasia when antrum and corpus biopsies are submitted

together in the same container Differential Diagnosis
n Helicobacter pylori gastritis Chronic H. pylori gastritis, when associated with
n Lymphocytic and collagenous gastritis gastric atrophy, can mimic autoimmune gastritis
n Infectious gastritis, other than H. pylori (Table 3.4). Involvement of the antrum, demonstration
n Pernicious anemia associated with autoimmune polyglandular
of H. pylori on H&E or ancillary stains, and the lack of
syndrome
ECL cell hyperplasia and antiparietal and anti-intrinsic
factor antibodies can help rule out the diagnosis of auto-
immune gastritis.
Immunohistochemistry Lymphocytic and collagenous gastritis can resemble
autoimmune gastritis when restricted or predominantly
Gastrin and chromogranin immunohistochemical involving the gastric corpus or when associated with atro-
stains are helpful, especially when the gastroenterol- phy. However, neither is associated with endocrine cell
ogist places multiple biopsies in the same container or hyperplasia, and autoimmune gastritis is not associated with
if the specimen site is unspecified (Fig. 3.16B–D). The marked intraepithelial lymphocytosis or abnormality of sub-
neuroendocrine ECL cell hyperplasia stains positive epithelial collagen. Infections other than H. pylori, such as
with chromogranin but is negative for gastrin, con- Epstein-Barr virus, may cause a destructive gastritis with
firming the corpus-restricted nature of the disease. The loss of parietal cells that mimics autoimmune gastritis. The
gastrin immunostain highlights normal G cells in the corpus-restricted nature and the associated endocrine cell
gastric antral fragments (Fig. 3.17). H. pylori immu- hyperplasia and lack of EBER CISH positivity in the mono-
nostain is usually negative. nuclear cells are helpful in establishing the correct diagnosis.
Pernicious anemia related to autoimmune polyglan- management includes endoscopic polypectomy or muco-
dular syndrome type I is a rare childhood disorder char- sal resection with continued surveillance. Antrectomy
acterized by antibodies directed against endocrine cells is reserved for selected patients with numerous lesions
that leads to a generalized loss of GI endocrine cells, or rapidly enlarging lesions and causes resolution of
including gastrin-secreting G cells. Patients have a low the hypergastrinemic state and reduction in the size of
serum gastrin, unlike typical autoimmune gastritis, and tumors.
variably present with antiparietal cell antibodies. The
loss of parietal cells in the gastric corpus is a result of the
low serum gastrin.
■ GRANULOMATOUS GASTRITIS
Granulomatous gastritis is an uncommon form of gas-

tritis, comprising 0.27% to 0.35% of all gastritides. It
encompasses a wide spectrum of diseases that lead to
Autoimmune gastritis carries a 2% to 9% prevalence of the development of mucosal or submucosal granulo-
gastric well-differentiated neuroendocrine tumors that mas as the defining histologic feature. The types of
are often multiple, usually less than 1 cm in diameter, granulomas vary widely from discrete nodular circum-
and typically have a better prognosis than their sporadic scribed collection of epithelioid histiocytes, reminis-
counterparts. There is also a two- to threefold increase cent of sarcoidosis, to those admixed with lymphocytes,
in the risk of gastric adenocarcinoma in patients with eosinophils, and even neutrophils, with or without
autoimmune gastritis. giant cells, to others with prominent central necrosis
Medical therapy includes vitamin B12 injections and and a lymphoid cuff similar to necrotizing granulomas
iron supplementation for those with pernicious anemia seen in Mycobacterium tuberculosis infection. Notably,
or iron-deficiency anemia, respectively. In patients with determining the underlying cause usually requires cor-
multiple well-differentiated neuroendocrine tumors, relation with the clinical, radiologic, endoscopic, and
microbiological findings and sometimes the response
to treatment (Table 3.5). When a granuloma is seen on
H&E examination, additional studies such as the use
TABLE 3.4 of polarized light to rule out presence of foreign body
Features of Autoimmune versus Environmental and special stains such as acid-fast bacilli, Gomori meth-
Atrophic Gastritis enamine silver, and periodic acid–Schiff (PAS) are oblig-
atory parts of the diagnostic assessment. A controversial
Environmental
diagnosis of idiopathic granulomatous gastritis has been
Autoimmune Metaplastic Atrophic
Gastritis Gastritis reported in the literature to define patients with large
and compact granulomas limited to the stomach and
Synonyms Type A gastritis Type B gastritis after exclusion of known entities such as Crohn’s dis-
Diffuse corporal Diffuse antral
gastritis gastritis
ease and sarcoidosis. Some authors have linked these
Multifocal atrophic granulomas to an inflammatory response to H. pylori
gastritis
Population Northern European Worldwide
affected and Scandinavian
descent TABLE 3.5
Sex Female No sex predilection
Differential Diagnoses of Granulomatous
predominance
Gastritis
Etiology Immune mediated Helicobacter pylori
infection Gastric Crohn’s disease—52%
H. pylori <20% 90%–100% Sarcoidosis-1—21%
colonization Foreign body granuloma-food, suture material, barium,
Affected Oxyntic mucosa Antrum mucin—10%
mucosa predominantly Isolated granulomatous gastritis—25%
with extension to Tumor-associated granulomas—7%
body, multifocal Infections (tuberculosis, histoplasmosis, schistosomiasis
Antiparietal cell Positive Negative Whipple’s disease, leprosy, syphilis)
antibody Vasculitis-associated granulomas (Churg Strauss disease)
Anti-intrinsic Positive Negative Helicobacter pylori gastritis
factor
antibody Data from Ectors NL, Dixon MF, Geboes KJ, et al. Granulomatous gastritis: a
Vitamin B 12 Low Normal morphological and diagnostic approach. Histopathology. 1993;23:55–61; and
level Shapiro JL, Goldblum JR, Petras RE. A clinicopathologic study of 42 patients
with granulomatous gastritis: is there really an “idiopathic” granulomatous
Serum gastrin Very high Normal or low
gastritis? Am J Surg Pathol. 1996;20:462–470.
infection after reporting the disappearance of the gran-

ulomas following successful eradication of the bacteria.
Other authors have found an association with vasculitis.
■ GASTRIC CROHN’S DISEASE
Approximately 30% to 50% of patients with Crohn’s

disease have upper GI manifestations. Patients with
both small and large bowel involvement are more likely
to have upper GI involvement. Patients are usually
younger and often belong to the pediatric age group.
Patients may present with symptoms of abdominal pain, A
nausea, and vomiting, often combined with lower GI
symptoms such as chronic diarrhea and weight loss. In
the West, Crohn’s disease accounts for 17% to 55% of
all cases with granulomatous gastritis.
Endoscopically, the mucosal appearance is quite vari-
able and ranges from completely normal mucosa to find-
ings that include erythema, erosions or ulcers, nodules,
thickened folds (so-called bamboo stomach), and even
gastric outlet stenosis. Findings are usually predomi-
nant in the antrum.
The finding of granulomas is helpful in establish-
ing the diagnosis of Crohn’s disease in the appropriate
clinical setting. However, granulomas are present in
only 7% to 34% of cases. Crohn’s granulomas usu-
ally consist of small clusters of epithelioid histiocytes. B
Notably, granulomas can also be detected in appar- FIGURE 3.18
ently normal mucosa, thus emphasizing the impor- Gastric Crohn’s showing lymphoplasmacytic infiltrate and crypt abscess (A)
tance of sampling. and giant cell (B). Immunostain for Helicobacter pylori was negative.
More commonly, the gastric involvement in
patients with Crohn’s disease may show a spectrum
of inflammatory changes that range from focally
enhanced gastritis to a patchy or diffuse chronic
active gastritis of variable severity (Fig. 3.18). Focally
enhanced gastritis is a patchy inflammatory process
composed of inflamed gastric pits surrounded by a
cuff of loose lymphohistiocytic aggregates (Fig. 3.19).
Focally enhanced gastritis, particularly in adults, can
also be associated with drug-induced mucosal injury,
graft-versus-host disease, or incompletely treated
H. pylori gastritis.
■ GASTRIC SARCOIDOSIS
Sarcoidosis is a systemic granulomatous disorder that FIGURE 3.19

commonly affects the lungs and hilar lymph nodes. It Focal enhancing gastritis can be a manifestation of Crohn’s disease and is
characterized by active inflammation surrounded by a loose cuff of lympho-
usually affects young adults and is more common in cytes and histiocytes.
African Americans. Gastric antral involvement can be
seen in 10% of patients with systemic disease.
The gastric mucosa may be macroscopically nodular Compact noncaseating granulomas (Figs. 3.21) are seen
(Fig. 3.20) with ulcers, thickening, and a segmental lin- in gastric sarcoidosis, which is a diagnosis of exclusion and
itis plastica–like appearance. Gastric outlet obstruction confirmed by correlation with clinical and imaging find-
and bleeding have been reported. ings. Patients often respond to steroid therapy.
celiac disease and 29% having H. pylori gastritis. Other less

common associations consist of Crohn’s disease, human
immunodeficiency virus (HIV) infection, esophageal car-
cinoma, and gastric lymphoma. Lymphocytic gastritis is
found in 33% of patients with celiac disease who undergo
gastric biopsies, and 4% of patients with H. pylori gastri-
tis have lymphocytic gastritis. Patients with celiac disease
with lymphocytic gastritis may also have lymphocytic coli-
tis (38%). More recently, a lymphocytic gastritis pattern
has also been shown in patients with an immune check-
point inhibitor therapy–associated gastritis.
LYMPHOCYTIC GASTRITIS—FACT SHEET
Definition
FIGURE 3.20 n Chronic gastritis characterized by marked intraepithelial
Gastric sarcoidosis with a nodular mucosal appearance on endoscopy. lymphocytosis, similar to the pattern seen in lymphocytic colitis

n 1% to 4% of all upper endoscopies
n May show diffuse involvement or be restricted to antrum or
corpus mucosa
Gender, Race, and Age

n Seen across all age groups; more common in older adults
n Slight female predominance
Clinical Features
n May be asymptomatic or present with dyspepsia, iron-deficiency
anemia, or diarrhea
n Common etiological associations include celiac disease (38%)
and Helicobacter pylori infection (29%)

FIGURE 3.21 n Other causes include Crohn’s disease, immune deficiency
Antral mucosa showing noncaseating granulomas in the lamina propria in a disorders, and drug-induced gastritis
patient with sarcoidosis.
n Treatment of H. pylori infection leads to resolution in cases
LYMPHOCYTIC GASTRITIS associated with this organism

n Similarly, treatment of the underlying cause, such as gluten
withdrawal, leads to histologic resolution
Lymphocytic gastritis is an uncommon form of chronic

gastritis characterized by marked intraepithelial lym-
phocytosis in the gastric surface and pit epithelium; the
glandular compartment is often spared. Lymphocytic Pathologic Features
gastritis is synonymous with varioliform gastritis, which
refers to the endoscopic appearance and with chronic Gross Findings
erosive verrucous gastritis.
The endoscopic appearance may either be normal or con-
sist of mucosal nodules, erosions, and enlarged gastric folds
resembling Ménétrier-like protein-losing gastropathy. The
latter appearance can mimic neoplastic processes. The
Lymphocytic gastritis has a prevalence of 1% to 4% in nodules may contain a central depression or erosion and
upper GI endoscopies. Symptoms include dyspepsia, are described as varioliform or aphthoid erosions.
iron-deficiency anemia, and diarrhea. It has been seen in
adults and children (age range, 1–89 years) but is more Microscopic Findings
common in older adults. A slight female predominance
is present. Etiologic associations are broad with approxi- Histologic findings include marked intraepithelial lym-
mately 38% of patients with lymphocytic gastritis having phocytosis predominantly involving the surface foveolar
and pit epithelium; the deeper glandular compartment Lymphocytic gastritis can involve the entire gastric
is frequently spared. Lymphocytic gastritis is typically mucosa or may predominantly involve the antrum or
characterized by the presence of greater than 25 lym- the body and fundic region. The antrum-predominant
phocytes per 100 epithelial cells. It has been shown distribution is more often associated with celiac dis-
that normal gastric epithelium usually harbors around ease, whereas H. pylori–associated lymphocytic gastri-
3.5 lymphocytes per 100 cells, and diseased control tis is more likely to involve the body or fundus. The
participants s such as patients with Helicobacter gastri- intraepithelial lymphocytes are CD3- and CD8-positive
tis have 5 lymphocytes per 100 cells. The lamina pro- cytotoxic/suppressor T-lymphocytes and thus easily dis-
pria is also expanded by lymphocytes and plasma cells tinguishable from CD20-positive B cells seen in lympho-
(Fig. 3.22). The intraepithelial lymphocytes are recog- epithelial lesions of extranodal marginal zone lymphoma
nized by their condensed, dark nuclei surrounded by a (MALT lymphoma). Stains for Helicobacter organisms
clear halo (Fig. 3.23). The foveolar pits are slightly tor- may be positive in a subset of cases.
tuous and elongated. Patchy foci of active neutrophilic
infiltration may also be present in some cases, usually
close to foci of erosion, and are acceptable within the
spectrum of lymphocytic gastritis. Lymphocytic Gastritis—Pathologic Features
Gross Findings
n May be normal or show a nodular appearance with or without
erosions or diffuse enlargement of gastric rugal folds
n Chronic gastritis with prominent intraepithelial lymphocytes
n The lymphocytes preferentially infiltrate the surface foveolar
epithelium and the superficial gastric pit epithelium while sparing

the deep glandular compartment
n Patchy foci of neutrophilic infiltration may also be present
in some cases, usually close to mucosal erosions, and are

compatible with this diagnosis
n Helicobacter pylori may be present in a subset of cases
Immunohistochemical Features
n The intraepithelial lymphocytes show a CD3/CD8-positive
cytotoxic/suppressor T-cell phenotype, unlike the CD20-positive

FIGURE 3.22 B cells present in lymphoepithelial lesions of extranodal marginal
Lymphocytic gastritis. Oxyntic mucosa with marked increase in intraepithelial zone B-cell lymphoma
lymphocytes in the surface epithelium and gastric pits. The lamina propria is
expanded by plasma cells and lymphocytes. Differential Diagnosis
n H. pylori gastritis
n Collagenous gastritis
n Extranodal marginal zone B-cell lymphoma
H. pylori gastritis can show foci of intraepithelial lym-

phocytosis, but in its typical form, it shows a chronic
active gastritis with diffuse lymphoplasmacytic infil-
trate and prominent neutrophilic activity. The intraep-
ithelial lymphocytes are minimal and patchy and do
not approach the 25 lymphocytes per 100 epithelial
cells cut-off commonly seen in lymphocytic gastritis.
Similar to colonic biopsies, whenever a diagnosis of
lymphocytic gastritis is entertained, a close look at the
subepithelial collagen is warranted to rule out the pos-
sibility of a collagenous gastritis.
FIGURE 3.23 Extranodal marginal zone lymphoma (MALT lym-
Lymphocytic gastritis. High-power view showing the condensed dark nuclei phoma) is characterized by significant expansion of the
of intraepithelial lymphocytes surrounded by a clear halo. lamina propria by a monotonous lymphoid infiltrate
composed of small- to medium-sized lymphocytes that is

associated with characteristic lymphoepithelial lesions.
The lymphoid population is composed of CD20 positive
B cells that often show aberrant CD43 coexpression. In
contrast, the lymphocytes in lymphocytic gastritis are
CD3-positive mature T lymphocytes.
Treatment is directed at the underlying conditions such as a

gluten-free diet in patients with celiac disease or eradication
of Helicobacter gastritis or discontinuation of the offending
medication in patients with drug-induced gastritis.
A
■ INFECTIOUS GASTRITIS
The most common form of infectious gastritis is

Helicobacter infection, which has been discussed already.
Various other infectious causes, such as cytomegalo-
virus (CMV) and adenovirus (Figs. 3.24 and 3.25) in
B
FIGURE 3.25
Smudgy nuclear inclusions in adenovirus gastritis can be easily missed (A).
The mucosa may not be significantly inflamed because the infection typi-
cally occurs in immunocompromised patients. Immunostain for adenovirus
is essential for establishing the diagnosis (B).
immunocompromised patients and a wide array of other

B bacterial, viral, fungal, and parasitic infections in the
stomach have been described. The diagnostic findings
FIGURE 3.24 in these infections are not site specific and are discussed
Gastric foveolar epithelial cells with cytomegalovirus (CMV) inclusions. Note in detail in Chapter 9 on infectious disorders of the
both nuclear and cytoplasmic inclusions (A). Similar CMV inclusions may be
seen in endothelial and stromal cells (B). GI tract.
EOSINOPHILIC GASTRITIS ■ CLINICAL FEATURES
The diagnostic criteria for eosinophilic gastroenteri-

Eosinophilic gastritis is a morphologic pattern of injury
tis include (1) GI symptoms; (2) histologic evidence of
characterized by a dense eosinophilic infiltrate in the
eosinophilic infiltration of the GI tract; (3) absence of
lamina propria accompanied by foci of epithelial destruc-
eosinophilic infiltration in extraintestinal organs; and
tion by eosinophils. The common underlying etiologic
(4) exclusion of known causes of eosinophilia, such as
conditions associated with eosinophilic gastritis include
healing ulcer site, parasitic infestation, and drug hyper-
primary eosinophilic gastroenteritis, drug-induced hyper-
sensitivity reaction.
sensitivity or other allergic reactions, and parasitic infec-
Eosinophilic gastroenteritis may affect all races and
tions. The discussion here is limited to gastric involvement
any age group but usually affects adults between 20 and
in eosinophilic gastroenteritis, which is defined by the
50 years of age. There is no sex predominance. Pediatric
presence of GI symptoms, dense tissue infiltration by
presentation is common with 15% to 20% of cases diag-
eosinophils, lack of extraintestinal eosinophilia, and
nosed in children. Any part of the GI tract from the esoph-
exclusion of all other known causes of eosinophilic
agus to the rectum can be involved, and the gastric antrum
infiltration.
is the most common site of involvement. The esophagus
and small bowel are also commonly affected. Eosinophilic
proctocolitis is seen most often in infants (an important
cause of bloody stool) and is usually attributed to cow’s
EOSINOPHILIC GASTRITIS—FACT SHEET milk allergy. The estimated prevalence of eosinophilic
gastritis and gastroenteritis is 6.3 and 8.4 per 100,000,
Definition respectively, in some recent studies.
n Eosinophilic gastritis is a rare inflammatory condition characterized Eosinophilic gastroenteritis can show preferential
by dense eosinophilic infiltration in the lamina propria with involvement of the mucosa, muscle layer, or serosa, but
epithelial injury
this subclassification is seldom used in daily practice.
Symptoms depend on the site and extent of eosinophilic
n Patients may present with acute abdominal emergency and
infiltration. Mucosal disease can present as abdominal
perforation pain, nausea, vomiting, diarrhea, weight loss, malabsorp-
n Gastrointestinal bleeding tion, protein-losing enteropathy, and anemia caused by
bleeding. Patients with involvement of the submucosa and
Gender, Race, and Age muscularis propria present with obstructive symptoms
n Patients are usually 20 to 50 years old and symptoms mimicking pyloric stenosis. Thickening
n Pediatric involvement in 15% to 20% of cases
of the stomach may also be noted on imaging studies in
n Male-to-female ratio is 1 to 1
cases with dominant mural involvement. Serosal involve-
Clinical Features ment is characterized by eosinophilic ascites, peripheral
n History of allergy, asthma, food intolerance, eczema, drug
eosinophilia, and dramatic response to steroids. Rarely,
sensitivities, peripheral blood eosinophilia, and increased patients may present with an acute abdominal emergency
immunoglobulin E levels and perforation necessitating emergency laparotomy.
n Symptoms depend on the site and extent of eosinophilic
The patients commonly present with a history
infiltration
n Mucosal disease can present as abdominal pain, nausea,
of allergy (25%–50%), asthma, food intolerance
vomiting, diarrhea, weight loss, malabsorption, protein-losing (52%), eczema, drug sensitivities, peripheral blood
enteropathy, and gastrointestinal bleeding eosinophilia (80%), and elevated serum immuno-
n Submucosal and muscularis propria involvement present in cases globulin E levels. Connective tissue diseases (sclero-
with obstructive symptoms derma, polymyositis) are also commonly described
n Eosinophilic ascites with serosal involvement
n Other causes of tissue eosinophilia such as parasitic infestation,

associations.
drug reaction, and hypereosinophilic syndrome should be
excluded
Endoscopic and Radiologic Features Pathologic Features

n Marked edema and thickening of the gastric folds and wall
Gross Findings
n Dramatic improvement with steroids in cases with primary
eosinophilic gastroenteritis
Gastric mucosa may be normal on endoscopic exam-
n Surgery in obstructive or refractory cases
ination or reveal erosions, ulcerations, erythema, and
nodularity.
Gastric involvement in eosinophilic gastroenteritis is

characterized by intense eosinophilic infiltration of the
lamina propria (>20 per high-power field [hpf]), intraep-
ithelial eosinophils, and eosinophilic crypt abscesses
(Fig. 3.26). The finding of greater than 30 eosinophils/
hpf in at least 5 hpf has also been proposed as diagnos-
tic criteria. The eosinophilic infiltration is accompanied
by epithelial damage, regenerative change, and marked
edema. Eosinophils are the dominant cell type, and
other inflammatory cells are not prominent, with the
exception of an increase in mast cells. The eosinophilic
infiltrate can be patchy or diffuse, and mucosal biopsies
can be nondiagnostic in up to 10% of cases. The pres-
ence of clusters of eosinophils deep in the submucosa,
FIGURE 3.26
muscularis propria, or serosa should prompt careful
Intense eosinophilic infiltration in a case of eosinophilic gastritis. Notice the
evaluation of clinical and histologic findings to ensure surface regenerative changes and glandular infiltration by eosinophils.
prompt diagnosis of eosinophilic gastroenteritis.
Eosinophilic Gastritis—Pathologic Features

degrees. This is seldom to a degree typical for eosino-
Gross Findings
philic gastroenteritis, and the localization adjacent to
n Gastric mucosa may be normal or display erosions, ulcerations,
foci of ulceration is a clue to the right diagnosis.
erythema, and nodules • Parasitic infestation is associated often with intense
eosinophilic infiltration surrounding parasitic ova, lar-
Microscopic Findings vae, or nematode such as anisakiasis, Strongyloides, and
n Gastric antral mucosa commonly involved Ascaris. Careful histologic examination for ova and par-
n Intense eosinophilic infiltration with prominent lamina propria asites (Fig. 3.27) and stool examination are important.
eosinophils, eosinophilic crypt abscesses, and epithelial
• Drugs such as gold, azathioprine, carbamazepine,
damage
n >20/HPF or >30/HPF in at least five fields have been proposed
enalapril, and cotrimoxazole can also cause a hyper-
criteria for diagnosis sensitivity reactive, leading to tissue eosinophilia in
n Eosinophilic infiltrate can be patchy or diffuse, and mucosal the GI tract.
biopsies can be nondiagnostic in up to 10% • Hypereosinophilic syndrome is a fatal disease charac-
n Involvement of deep submucosa, muscularis propria, or serosa
terized by peripheral eosinophilia (>1500/mm3) and
should raise suspicion for diagnosis
diffuse infiltration of eosinophils in various organs
Differential Diagnosis such as the myocardium, lungs, and GI tract.
n Infiltrate secondary to mucosal ulcers
• Eosinophilic infiltration is also prominent in cases of
n Parasitic infestation Langerhans cell histiocytosis and systemic mastocyto-
n Hypereosinophilic syndrome sis, where it is recruited secondarily by the neoplastic
n Langerhans cell histiocytosis
cells. The diagnosis can easily be made by using the
n Systemic mastocytosis
n Drugs such as nonsteroidal antiinflammatory drugs, gold,

appropriate immunostains for Langerhans cells (CD1a
azathioprine, carbamazepine, enalapril, and cotrimoxazole and S-100) and abnormal mast cells (KIT and CD25).
n Eosinophils can be focally prominent in gastric Crohn’s disease, • Eosinophils can be focally prominent in gastric
gastric carcinomas, lymphomas, connective tissue disorder, and Crohn’s disease, gastric carcinomas, lymphomas,
peptic ulcer disease connective tissue disorder, vasculitis such as Churg-
Strauss disease, and peptic ulcer disease.
• Eosinophils can be present in the stroma whenever Patients with eosinophilic gastroenteritis show an excel-
there is a breach of surface epithelium, allowing lumi- lent response to steroids and relapse can occur after dis-
nal contents to come in contract with connective tis- continuation. Patients have also shown good response to
sue in the lamina propria. Healing erosions and ulcers oral sodium cromoglycate. Surgical resection may be nec-
often show lamina propria eosinophilia to varying essary in patients with obstruction or in refractory cases.
is associated with other inflammatory conditions, including

collagenous colitis, lymphocytic colitis, celiac or collagenous
sprue, inflammatory bowel disease, or autoimmune disor-
ders, or it may be a manifestation of drug-induced gastritis,
including immunotherapy-associated gastritis. The patho-
genesis is unknown. Proposed mechanisms are excessive
collagen deposition caused by a reparative process after
chronic inflammation, collagen deposition by abnormal
pericryptal fibroblasts, and leakage of plasma proteins and
fibrinogen with subsequent replacement by collagen
COLLAGENOUS GASTRITIS—FACT SHEET

A
Definition
n Chronic gastritis characterized by subepithelial collagen
deposition of more than 10 μm, surface epithelial damage,

lymphoplasmacytic inflammation of the lamina propria, and
variable intraepithelial lymphocytosis
Incidence
n Rare entity

n Can cause chronic morbidity, including anemia, chronic diarrhea,
and significant weight loss

B n Seen both in children and adults over a wide age range
FIGURE 3.27 Clinical Features

Eosinophilic infiltrate can be striking in parasitic infections involving the stomach. n Symptoms include chronic watery diarrhea, weight loss, anorexia,
Gastric antral mucosa with cross sections of Strongyloides stercoralis larvae in nausea, vomiting, abdominal pain, anemia, and bleeding
gastric pits (A) and numerous schistosome eggs; some are calcified (B). n Can be associated with collagenous colitis, lymphocytic
colitis, celiac sprue, collagenous sprue, lymphocytic gastritis,

inflammatory bowel disease, autoimmune disorders, and drug-
COLLAGENOUS GASTRITIS induced mucosal injury

n Prednisone, budesonide, azathioprine, and a gluten-free diet have
Collagenous gastritis is a rare entity characterized by sub- been shown to improve symptoms and cause weight gain
epithelial collagen deposition in superficial gastric mucosa n It is important to biopsy the duodenum and colon to exclude
exceeding 10 μm in thickness accompanied by surface epithe- concurrent celiac and collagenous sprue, as well as collagenous
lial damage, increased lymphoplasmacytic inflammation of and lymphocytic colitis
the lamina propria, and variable intraepithelial lymphocytosis.
Pathologic Features
Gross Findings
The disease presents over a wide age range, including chil-
dren and older adults, with a slight female predominance. The disease can be patchy or manifest as a pangastritis
Clinical manifestations are broad include chronic diarrhea, involving both the gastric antrum and body. The endo-
anorexia, nausea, vomiting, abdominal pain, weight loss, scopic appearance consists of diffuse nodularity, ery-
anemia, and bleeding. According to several series, patients thema, and erosions.
with collagenous gastritis generally fall into two clinical
groups, (1) children and young adults presenting with ane- Microscopic Findings
mia and disease limited to the stomach with a nodular gastric
mucosa on endoscopy and (2) older adult patients present- Histologic findings resemble those seen in collagenous
ing with chronic watery diarrhea, often associated with colitis. The lamina propria is expanded by a prominent
collagenous colitis. In some patients, collagenous gastritis lymphoplasmacytic infiltrate accompanied by a variable
Collagenous Gastritis—Pathologic Features
Gross Findings
n The gastric antrum and/or corpus can be affected
n Endoscopy shows diffuse nodularity (common), diffuse or patchy
erythema, or erosions
n The lamina propria is expanded by lymphoplasmacytic infiltrate,
and the subepithelial collagen layer is thick and frayed

n Subepithelial collagen band abnormality can be patchy, and
surface epithelium can strip off

n Variable degrees of intraepithelial lymphocytosis may be present
n A prominent eosinophilic infiltrate may be present in the lamina propria
n Masson’s trichrome may help to highlight the subepithelial
collagen layer
A
n Autoimmune gastritis
n Lymphocytic gastritis
n Gastric amyloidosis
n Radiation gastritis
hallmark of autoimmune gastritis, subepithelial collagen

layer abnormalities are diagnosis of collagenous gastritis.
• Lymphocytic gastritis is in the differential diagnosis
because of increased intraepithelial lymphocytosis that
B may be present in collagenous gastritis cases. However,
FIGURE 3.28
similar to interpretation of small intestine and colon biop-
Collagenous gastritis with increased subepithelial deposition of collagen.
sies, the presence of a thick or abnormal collagen layer is
The thick collagen band entraps capillaries and inflammatory cells (A). The diagnostic of collagenous gastritis. Special stains for colla-
subepithelial collagen thickness and irregularity can be highlighted by a gen are helpful in cases with subtle abnormalities.
trichrome stain that stains collagen blue (B).
• Gastric amyloidosis may mimic collagenous gastritis
because the amyloid deposition may in some cases be
intraepithelial lymphocytosis, and the subepithelial col- superficial and resemble a collagen band. However, the
lagen is increased in thickness and frayed in nature, often deposit is not just limited to the superficial mucosa as in
entrapping capillaries and mononuclear cells within it collagenous gastritis but often involves the blood vessels
(Fig. 3.28A). The collagen thickness is typically greater than and may be present as stromal deposits in severe cases.
10 μm, ranging from 20 to 120 μm, and the surface epithe- Amyloid is more homogeneous in appearance compared
lium may strip off. The lamina propria may also show prom- with the fibrillary character of collagen in collagenous
inent eosinophils and contain foci of active gastritis. Most gastritis. The distinction is easily achieved using special
patients with collagenous gastritis are negative for H. pylori stains for amyloid such as Congo red that show charac-
infection. Collagenous gastritis is a chronic gastritis and can teristic apple-green birefringence upon polarization.
show atrophy and intestinal metaplasia in some cases, mim- • Lamina propria fibrosis in radiation and ischemic
icking autoimmune gastritis. The lack of neuroendocrine gastritis or scleroderma is not restricted to the subep-
cell hyperplasia and presence of collagen abnormalities ithelial zone. Furthermore, scleroderma can involve
are key to making this distinction. Trichrome or Sirius red the submucosa and muscularis propria and even
stains can help in highlighting the abnormalities of subepi- subserosa. Radiation gastritis also shows hyalinized
thelial collagen in subtle cases (Fig. 3.28B). blood vessels and atypical stromal fibroblasts.
• Atrophy and intestinal metaplasia can be present in col- Treatment is empirical and includes budesonide, predni-
lagenous gastritis involving the gastric corpus, raising sone, azathioprine, 5-aminosalicylates, nutritional sup-
the possibility of autoimmune gastritis. Whereas the plements, and even a gluten-free diet. In most instances,
presence of linear and micronodular hyperplasia is a despite symptomatic improvement, follow-up biopsies show
a persistence of collagen. Considering the frequent associa- Pathologic Features

tion with other collagenous enterocolitides, it is important
to biopsy the duodenum and colon in all cases of collagenous
gastritis. Endoscopic Findings
Gastric mucosal calcinosis appears as small white

GASTRIC MUCOSAL CALCINOSIS plaques or nodules and may involve the antrum or cor-
pus mucosa.
Gastric mucosal calcinosis (GMC) is infrequently Microscopic Findings

encountered in biopsies and is associated with calcium
deposition in the gastric mucosa. The gastric biopsies show basophilic extracellular
deposits in the superficial aspect of the mucosa, usu-
ally beneath the foveolar epithelium, but can also be
present deep in the mucosa as well (Fig. 3.29). The
deposits are 50 to 500 μm in size, slightly refractile, and
do not polarize. They may occasionally be rimmed by
Gastric mucosal calcinosis is mostly seen in chronic renal histiocytes and giant cells. Background stomach may
failure, organ transplant patients, and patients taking alu- show foveolar hyperplasia with mucin depletion and
minum-containing antacids or sucralfate. It is also seen and reactive epithelial changes. Despite the nomenclature
been classified as dystrophic when encountered in inflamed
or necrotic gastric mucosa and as “metastatic” when devel-
oping in normal gastric mucosa of patients with hypercal-
cemia and hyperphosphatemia. Other associations include
hyperparathyroidism, sarcoidosis, multiple myeloma, tumor
lysis syndrome, hypervitaminosis D, hypervitaminosis A,
milk-alkali syndrome, and isotretinoin use. The overall inci-
dence of mucosal calcinosis is fewer than 0.1% of all gas-
tric biopsies but can be as high as 14% to 60% in selected
patients with transplants and chronic renal disease. A report
quoted an incidence of 5% in nontransplant patients with
gastric ulcers. An underlying etiology may not be apparent
in some patients. Patients may present with nausea, vomit-
ing, dyspepsia, abdominal pain, anemia, or GI bleeding.
GASTRIC MUCOSAL CALCINOSIS—FACT SHEET
Definition
A
n Condition characterized by gastric mucosal deposits of calcium
beneath the foveolar epithelium

n Rare condition; more likely to occur in selected clinical settings
n 14% to 60% of gastric biopsies from transplant patients
n 5% of gastric biopsies from nontransplant patients with gastric
ulcers

n Usually seen in patients with end-stage renal failure, organ
transplant recipients, patients on dialysis, and patients using

aluminum-containing antacids and sucralfate
Clinical Features
n Asymptomatic or associated with nausea, vomiting, dyspepsia,
abdominal pain, anemia, or bleeding B

FIGURE 3.29
Prognosis and Treatment
Gastric mucosal calcium deposits beneath the foveolar tips appear baso-
n Benign outcome
philic and refractile, and the surface epithelium is stripping off (A). Basophilic
calcium deposits slightly deep in the lamina propria (B).
the deposits are actually composed of an admixture of

calcium, aluminum, phosphorus, and chlorine, which
has been demonstrated on x-ray microanalysis.
Gastric Mucosal Calcinosis—Pathologic Features
Endoscopic Findings
n Appear as white plaques or nodules
n Basophilic, extracellular deposits located beneath the foveolar tips
or deep in lamina propria

n May be rimmed by macrophages
n Slightly refractile but do not polarize
n Deposits shown to contain calcium, aluminum, phosphorus, and FIGURE 3.30

chlorine on x-ray microanalysis Lanthanum deposits in the lamina propria appear as brown-purple amor-
phous grungy material engulfed within large histiocytes. Deposits may be
Immunohistochemical Findings refractile and can stain positive with calcium stains. The localization within
histiocytes is different from mucosal calcinosis, and the patient history is key
n Variably positive with calcium stains such as Von Kossa and
to making the right diagnosis.
Alizarin red
n Deposit of lanthanum carbonate Iron Pill Gastritis
n Gastric siderosis
Patients prescribed oral iron therapy for anemia may

develop gastric mucosal injury secondary to the medi-
cation. It is seen in about 15% of patients taking iron
supplements. The changes are more frequently detected
in older adult patients and particularly women.
The basophilic deposit of Lanthanum carbonate pre-

scribed to lower hyperphosphatemia can vaguely
Clinical Features
mimic GMC. Furthermore, the same population is
at risk. In patients with lanthanum deposition, the
gastric mucosa shows a histiocyte-rich inflammatory Many patients are asymptomatic, but others present
infiltrate that is usually subepithelial in distribu- with abdominal pain, nausea, and vomiting. Melena can
tion. The histiocytes are filled with pale to ampho- also develop, and in extremely rare instances, recurrent
philic material that is fine or coarse in appearance. ulcers may lead to stricture.
The lanthanum accumulation within the histiocytes
has been found to stain positively for PAS; PAS after
diastase digestion; and, in some cases, Prussian blue
Pathologic Features
(Fig. 3.30). In contrast, mucosal calcinosis consists of
large, extracellular, basophilic deposits that are PAS
negative but Prussian blue positive. The mucosa is normal in most cases, but mucosal ery-
thema and erosions and ulcerations can be detected.
Brown-green discoloration of the mucosa may be seen
in severe cases.
Microscopically, the gastric biopsy shows golden
brown refractile crystalline material that is either embed-
The significance of GMC is unclear. However, it is ded in the superficial lamina propria within macrophages
important to report the findings, given their frequent and stromal elements or as a layer of encrustation on the
association with underlying medical conditions, such as damaged epithelium (see Fig. 3.31). It may even be seen
chronic renal failure, and with history of transplanta- within in vessel walls. The epithelium shows regenera-
tion. Calcium deposits in the stomach may also be an tive foveolar hyperplasia, but infarct-like necrosis can be
indicator of generalized deposition of calcium within observed as well. Prussian blue stain is confirmatory and
other organs. highlights deposits that were not detected on H&E.
DOXYCYCLINE GASTRITIS
Exogenous deposits form the differential diagnosis, includ-
ing mucosal calcinosis (see earlier), kayexalate resin crys-
tals (nonpolarizing refractile crystals with a fish-scale Esophageal and gastric mucosal alterations can also
appearance staining with acid fast stain), cholestyramine be seen in patients taking tetracycline. The antibiotic
(PAS positive) angulated crystals, sevelamer (tree bark– is ulcerogenic and can sometimes produce distinctive
shaped yellowish crystals), and colesevelam (red-brown changes in the gastric mucosa.
angulated crystals). Gastric glandular siderosis (Fig. 3.31)
also consists of iron deposition in gastric mucosa in patients
with primary or secondary iron overload. In contrast to pill
gastritis, the iron in gastric siderosis is present as granular
intracytoplasmic deposits within macrophages or glandu-
lar epithelium deep in the mucosa. Some patients maybe asymptomatic, but most present
with epigastric pain. The endoscopy may reveal either
Prognosis and Therapy white-yellow plaque-like lesions or nonbleeding ulcers
The symptoms decrease, and mucosal changes heal after

ferrous sulfate medication is discontinued and less corro-
Pathologic Features
sive supplements, such as ferrous gluconate, are substituted.
The gastric biopsy shows superficial mucosal necrosis

and erosion, with variable neutrophilic infiltrate and
regenerative epithelial changes. Characteristic vascular
degeneration of the capillaries in the superficial lamina
propria is seen, consisting of eosinophilia of the vessel
wall creating a ring-like deeply eosinophilic structures
(Fig. 3.32). Microthrombi are noted in some of the ves-
sels. Regenerative foveolar hyperplasia may be seen in
cases associated with erosions and ulcers.
The differential diagnosis includes exogenous deposits

such as calcium and iron discussed earlier or GAVE in
cases associated with prominent foveolar hyperplasia.
However, endoscopically, GAVE shows a characteristic
A
B
FIGURE 3.32
FIGURE 3.31 Acute erosive gastritis secondary to doxycycline involving antrum. The sur-
Iron pill gastritis with reactive epithelial changes and ill defined granular face is completely denuded and replaced by a fibrinous exudate. The striking
material on the mucosal surface and the lamina propria (A). The Iron stain eosinophilic necrosis of the walls of superficial capillaries in the mucosa (top
highlights the deposition of ferrous sulfate (B). left) is typical of this entity.
“watermelon stomach” pattern. Reactive gastropathy, such as foveolar hyperplasia, increased mucin content,
such as that caused by NSAIDs, might also be a consid- decreased parietal cell mass, and reduced acid production.
eration in cases with foveolar hyperplasia but lacks the
characteristic vascular degenerative changes seen with
doxycycline. Small vessel vasculitis is rare in the stom-
Pathologic Features
ach, and changes in doxycycline injury are restricted to
the areas of mucosal erosion and necrosis and clinical
features suggestive of vasculitis are lacking. Gross Findings
Prognosis and Therapy Gross findings consist of massively thickened irregular

“cerebriform” gastric folds (1–3 cm in thickness) with
The symptoms decrease and mucosal changes heal after large amounts of viscous mucus and superficial erosions
discontinuation of doxycycline. (Fig. 3.33). These changes are seen in the proximal
stomach, although localized or diffuse cases have been
reported. Localized disease of the gastric antrum, with
sparing of the fundus and body, mainly manifested by
MÉNÉTRIER’S DISEASE polyposis has also been observed.
Ménétrier’s disease is a rare acquired disorder involving
the gastric body characterized by diffuse gastric rugal Ménétrier’s disease is characterized by markedly
hypertrophy, hypoproteinemia, and hypochlorhydria elongated and tortuous foveolae lined by mucous
secondary to excessive mucosal protein loss. Synonyms cells that may show cystic dilatation of the pits and
include giant hypertrophic gastritis, hypoproteinemic massive overproliferation of the surface mucus-pro-
hypertrophic gastropathy, and giant mucosal rugae. ducing cells. The glands may also extend into the
submucosa and present as gastritis cystica profunda
(Fig. 3.34). A reduction or even absence of oxyn-
tic glandular component (parietal and chief cells) is
frequent. Inflammation is usually scarce or absent,
although prominent eosinophilia can be observed.
Ménétrier’s disease has been described in both adults In a subset of cases, lymphocytic gastritis showing
and children (average age, fourth to sixth decades of marked intraepithelial lymphocytosis may be seen.
life). It is more common in men with a male-to-female Other changes include a thickened and disorganized
ratio of 3 to 1. CMV is associated in 70% of affected chil- muscularis mucosae, with strands of smooth muscles
dren. In contrast, H. pylori has been reported in 90% of extending into the lamina propria. Immunostains for
affected adults in some series and rarely in association CMV and H. pylori may be helpful.
with herpes simplex virus infection. From a practical point of view, histologic examina-
The disease course is usually chronic, with an unfa- tion on conventional endoscopic biopsies usually fails to
vorable prognosis. Patients present with hypoproteinemia
resulting from nonselective protein loss across the gas-
tric mucosal barrier and peripheral edema. Studies have
shown loss of immunoglobulins, albumin, and transfer-
rin, and acid output may be low or normal. Symptoms
appear insidiously and become progressive, consisting of
vomiting, abdominal pain and dyspepsia, anorexia, and
peripheral edema. A thickened gastric wall with marked
enlargement of gastric mucosal folds is seen on endos-
copy along with a fine reticulated barium pattern result-
ing from mucus hypersecretion. The risk for developing
carcinoma with Ménétrier’s disease is debatable. It is
reported that the patients have a 2% to 15% lifetime risk,
but the exact risk is unknown, and there is no consensus
on the appropriate surveillance in these patients.
The pathogenesis remains uncertain, but overexpres-
FIGURE 3.33
sion of transforming growth factor-α (TGF-α) has a pos-
Ménétrier’s disease. The giant mucosal hypertrophy of gastric body in
sible role. Transgenic mice that overproduce TGF-α in Ménétrier’s disease, with a cerebriform appearance. The antrum is spared.
the stomach have many features of Ménétrier’s disease, (A, Courtesy of Shriram Jakate, MD, Rush Medical College, Chicago).
However, none of these diagnoses is associated with such a

severe foveolar hyperplasia restricted to the gastric corpus.
Zollinger-Ellison syndrome shows hyperplasia of pari-
etal and chief cells with increased acid production as a
result of increased gastrin secretion caused by gastrinomas
and is often associated with multiple gastric and duodenal
ulcers but not with protein loss or foveolar hyperplasia.
Hyperplastic hypersecretory gastropathy is also asso-
ciated with features similar to ZES, but the gastrin level is
normal. Hyperplastic polyps are composed of prominent fov-
eolae but are localized polypoid lesions and do not show the
diffuse thick and enlarged gastric folds seen in Ménétrier’s
disease. Cronkhite-Canada syndrome involving the stom-
ach may mimic Ménétrier’s disease but is also associated
with abnormalities in the colon and the gastric mucosa in
Cronkhite-Canada syndrome is nodular and can also involve
the antrum in contrast to the diffuse enlargement restricted
to the gastric corpus seen in Ménétrier’s disease.
A
In adults, the disease course is chronic with an unfavor-

able prognosis. It seems reasonable to test and treat for
CMV and H. pylori when these organisms are identified.
Symptoms may improve with antibiotics, histamine H2
blockers, anticholinergic agents that reduce gastric protein
loss, corticosteroids, and octreotide (somatostatin ana-
logue). One study reported marked improvement in symp-
B
toms such as vomiting and increased serum albumin after
FIGURE 3.34 an experimental treatment with cetuximab, a monoclonal
Low- and medium-power view of Ménétrier’s disease: Marked tortuosity and antibody against directed epidermal growth factor recep-
elongation of gastric foveolar epithelium and cystic dilation of the deeper
mucous glands (A). The oxyntic glands are replaced by mucous glands (B). tor. Partial or total gastrectomy is reserved for patients with
severe complications such as massive bleeding and those
with refractory protein loss or obstructive symptoms.
demonstrate the massive foveolar hyperplasia, and some
recommend obtaining full-thickness biopsies. Because
marked foveolar hyperplasia can be seen in a variety of
conditions such as chemical gastropathy, hyperplastic pol- ZOLLINGER-ELLISON SYNDROME
yps, and gastric ulcers and at the postgastroenterostomy
stomal site, a diagnosis of Ménétrier’s disease requires
typical histologic findings in a full-thickness mucosal Zollinger-Ellison syndrome is a triad consisting of
biopsy in conjunction with other clinical features. hypergastrinemia caused by gastrin-secreting tumors
(gastrinomas), increased acid production, and severe
peptic ulcer disease.
The appearance of thick enlarged gastric folds is not spe-
cific to Ménétrier’s disease and can be seen in a number of
other conditions such as Zollinger-Ellison syndrome (ZES), Zollinger-Ellison syndrome has an incidence rate of 0.1
gastric lymphoma, diffuse-type gastric cancer, H. pylori and to 3 per million people in the United States and com-
CMV gastritis, granulomatous gastritis, eosinophilic gastri- prises 0.1% of all duodenal ulcer patients. It affects
tis, and gastric polyposis in Cronkhite-Canada syndrome. adults and children (age range, 7–90 years; average age,
50 years). Male and female patients show an equal dis-

ease distribution. ZES is characterized by gastrinomas
located usually in the duodenum, pancreas, or area
adjacent to the common bile duct (gastrinoma triangle).
The secondary hypergastrinemia leads to persistent
and massive secretion of acid and pepsin, giving rise to
multiple and recurrent peptic ulcers, severe esophagi-
tis, enteritis, epigastric pain, diarrhea, malabsorption,
and weight loss. The massive acid output causes inacti-
vation of pancreatic enzymes and bile salts, leading to
malabsorption and diarrhea. An elevated fasting serum
gastrin level of greater than 1000 pg/mL is virtually
diagnostic of ZES.
Other clinical features include a positive secretin test FIGURE 3.35
result (secretin injection followed by elevation of gas- Zollinger-Ellison syndrome. Note the massive hypertrophy of gastric rugal
trin >200 pg/mL above basal level) and basal acid output folds with polypoid appearance. (Courtesy of Shriram Jakate, MD, Rush
Medical College, Chicago).
greater than 10 mEq/hr but is seldom needed now for
diagnosis.
Eighty percent of patients with ZES have sporadic
gastrinomas. In the remaining 20% of patients with
ZES, gastrinomas are part of MEN-I syndrome. MEN-I
is an autosomal dominant disorder resulting from
mutations in the MEN-I gene on chromosome 11q13,
which encodes for a 610–amino acid protein, menin.
MEN-I is characterized by parathyroid hyperplasia,
pancreatic endocrine tumors, pituitary adenomas, and
adrenal adenomas.
Imaging studies such as computed tomography (CT)
and magnetic resonance imaging (MRI) demonstrate
FIGURE 3.36
markedly thickened gastric folds. Imaging studies such
Low-power view shows the diffuse hyperplasia of gastric oxyntic mucosa in
as somatostatin receptor scintigraphy (gastrinomas have Zollinger-Ellison syndrome.
somatostatin type 2 receptors) and endoscopic ultraso-
nography are sensitive modalities to localize gastrino-
mas and are often used along with abdominal CT and linear and nodular ECL hyperplasia. Well-differentiated
MRI for staging. neuroendocrine tumors may be seen in up to 37% of
patients with MEN-I–associated ZES. However, this is
almost never seen in patients with sporadic ZES.
Gastrinomas stain for gastrin, chromogranin, and syn-
Pathologic Features
aptophysin. ECL hyperplasia and neuroendocrine tumors
stain for chromogranin and vesicular monoamine trans-
Gross Findings porter, isoform 2 (VMAT-2), which regulates the intra-
vesicular accumulation of histamine. The ECL cells are
Zollinger-Ellison syndrome causes massive hypertrophy negative for gastrin, somatostatin, and serotonin.
of gastric rugae in the body and fundus that can range
from 0.6 to 4.5 cm in thickness (Fig. 3.35). The antral
mucosa is often reduced in thickness.
Ménétrier’s disease is associated with gastric rugal hyper-
The trophic effect of gastrin causes increased thickness trophy, protein-losing gastropathy, and hypochlorhydria.
of oxyntic mucosa in ZES (Fig. 3.36). Parietal cells show In contrast to ZES, acid secretion is generally reduced.
hypertrophy and hyperplasia and extend up to the foveolar Microscopically, Ménétrier’s disease is associated with giant
neck region (Fig. 3.37). Parietal cells can also extend into foveolar hyperplasia, and the oxyntic cells are replaced by
the gastric antrum. Excess gastrin also causes physiologic mucous cells, whereas ZES is associated with hypergas-
hyperplasia of ECL cells in the gastric corpus, leading to trinemia, leading to hyperplasia of oxyntic mucosa and ECL
with localized well-differentiated gastrinomas without

metastases are ideal candidates for surgical removal of
the tumor. Patients with hepatic or distant metastases are
managed with chemotherapy, hormonal therapy, or sur-
gical debulking. Achieving surgical cure in ZES patients
with MEN-I is more difficult, and patients need to be on
lifelong acid suppressors. The need for family screen-
ing and screening for endocrine tumor elsewhere also is
important. ZES patients who have had successful tumor
resection show a 60% to 100% survival rate at 10 years.
Patients with unresectable tumors have a 40% survival
A rate at 5 years. Patients with MEN-I have better 5- and
10-year survival rates than do those with sporadic ZES
GASTRIC AMYLOIDOSIS
Amyloidosis is a group of disorders thought to be sec-

ondary to misfolding of extracellular proteins. Similar to
other organs, the stomach can also be affected by amyloi-
dosis. Gastric involvement almost always represents the
systemic form of amyloidosis and is characterized by the
B deposition of extracellular, insoluble, β-pleated fibrillary
protein sheets anywhere within the wall of the stomach.
FIGURE 3.37
Localized form of amyloidosis is extremely rare.
Zollinger-Ellison syndrome, medium-power view shows striking parietal cell
hyperplasia and hypertrophy of parietal cells extending up to foveolar neck.
cells in the gastric body and fundus. Autoimmune gastritis
is another important cause of hypergastrinemia. However, Amyloidosis is classified based on the fibril precur-
unlike ZES, the gastric body shows atrophy rather than sor protein (AL, amyloid light chain; AA, amyloid;
hypertrophy of oxyntic glands along with hypochlorhydria ATTR, amyloid transthyretin; Aβ2M, β2 microglob-
or achlorhydria. The majority of patients with autoimmune ulin related) and can be present as following clini-
gastritis have antibodies against the intrinsic factor and pari- cal syndromes: systemic AL amyloidosis (associated
etal cells. In addition, most patients present with symptoms with plasma cell neoplasia), systemic AA amyloido-
associated with megaloblastic and iron-deficiency anemia sis (associated with infectious or inflammatory or
caused by reduced vitamin B12 concentration and concur- neoplastic disorders), β2-microglobulin amyloidosis
rent reduced iron absorption. (associated with long-term renal dialysis), heredi-
Chronic active H. pylori gastritis often results in tary systemic amyloidosis (associated with autosomal
antral G-cell hyperplasia, acid hypersecretion, and pep- dominant deposition of ATTR), and senile systemic
tic ulcer disease. However, the nature of inflammatory amyloidosis (associated with wild-type transthyretin
infiltrate (superficial predominant lymphoplasmacytic deposition). In general, the GI tract, including the
inflammation with or without activity) and the presence stomach, is most commonly affected by systemic AL
of curved bacilli help in distinguishing it from ZES. form of amyloidosis.
Patients present with nausea and vomiting, weight
Prognosis and Therapy loss, malabsorption, gastric outlet obstruction, gastropa-
resis, and stasis-related change such as bacterial over-
Patients with ZES require long-term medical therapy growth and diarrhea. Amyloid deposits in the blood
for adequate control of gastric hypersecretion with PPIs vessels make the vessels fragile and leaky, leading to
such as omeprazole or lansoprazole. Partial or total gas- hemorrhage. Rarely, gastric amyloidosis may present as
trectomy may be required for intractable cases. Patients a tumoral mass and can be mistaken for a carcinoma.
acellular, eosinophilic extracellular deposits within the lam-

GASTRIC AMYLOIDOSIS—FACT SHEET ina propria, submucosa, muscularis propria, nerve trunks,
and vessel walls (Fig. 3.39). Amyloid deposits often show
Definition “cracking” with slit-like spaces as a result of tissue processing
n Extracellular deposition of insoluble, fibrillary β-pleated amyloid artifact. In biopsy specimens, amyloid is often present within
protein sheets in the gastric mucosa the lamina propria as irregularly distributed deposits, which
may have a globular appearance. If the specimen contains
superficial submucosa, these deposits are visible in the peri-
n May be associated with fatal bleeding
vascular region as well as within the vessel wall.
n Patients are usually old adults, except in hereditary cases
Clinical Features
n Hemorrhage, nausea and vomiting, weight loss, malabsorption,
and diarrhea
n Gastric outlet obstruction, gastroparesis, and stasis-related changes

n Depends on the type and extent of deposits as well involvement
of other organs
n AL amyloidosis has the worst prognosis
n Therapy is directed at reducing the supply of precursor proteins
n Bortezomib (a proteasome inhibitor) as a single agent or in
combination with dexamethasone is now considered first-line

therapy for patients with AL amyloidosis
Pathologic Features
Gross Findings
Endoscopic appearance consists of mucosal erosions,

ulcers, thickened folds, and less commonly, a localized mass
(Fig. 3.38). Resection specimens with massive amyloid depo-
sition have thick and rigid walls with a waxy appearance.
The distribution of amyloid can be patchy or diffuse. On

H&E section, amyloid deposits appear as dense, homogenous,
B
C
FIGURE 3.39
FIGURE 3.38 A, Gastric amyloid, consisting of eosinophilic, acellular deposits with cracking
Endoscopic appearance of gastric amyloidosis with thick, vaguely nodular artifact appearing as a tumoral mass. B, Notice the globular amyloid deposits
mucosa. (Courtesy of Shriram Jakate, MD, Rush Medical College, Chicago). beneath the foveolar epithelium. C, Vascular amyloid deposits.
Arteriosclerosis of vessels with hyalinization may be

mistaken for amyloid deposits. Masson’s trichrome
stains the sclerosis blue, and Congo red stain is negative.
Connective tissue disorder such as scleroderma, result-
ing in fibrosis of muscularis and submucosa, which
may be mistaken for amyloid but are seldom biopsied.
Masson’s trichrome stains the collagen blue, and Congo
red is negative. Ischemic gastritis is associated with
hemorrhage, unlike amyloidosis, and radiation gastritis
and other causes of lamina propria fibrosis are associ-
A ated with increased collagen in the lamina propria that
is easily distinguished from amyloid deposits
Prognosis depends on the type, extent, and severity of

amyloid deposit; organs involved; and severity of the
underlying disease. Microscopic focal deposits in older
adults may be of no clinical significance, but widespread
deposition can be a progressive and even fatal disease.
Therapy is mostly directed at reducing the supply of
precursor proteins, correcting bleeding problems, and
enhancing motility. Liver transplantation is curative
B in hereditary transthyretin amyloidosis because the
FIGURE 3.40 mutated transthyretin is produced by the liver.
The amyloid appears brick red using standard illumination light (A) and, with
polarization (B), showing bright-green birefringence.
A Congo red stain shows bright orange positivity in

areas of amyloid deposition with a characteristic apple- GASTRIC ANTRAL VASCULAR ECTASIA
green birefringence on polarized microscopy (Fig. (“WATERMELON STOMACH”)
3.40). Immunostains may be used to classify the type
of amyloid, which is helpful with patient management.
Gastric antral vascular ectasia is an uncommon cause of
acute or chronic occult GI bleeding that is characterized
Gastric Amyloid—Pathologic Features
endoscopically by linear vascular stripes in the gastric
Gross Findings antrum.
n Mucosal erosions, ulcers, thickened folds, tumoral mass
n Thick and rigid walls with waxy appearance
Microscopic Findings ■ CLINICAL FEATURES

n Dense, homogenous, acellular, eosinophilic extracellular deposits
in the lamina propria, submucosa, muscularis propria, nerve

Gastric antral vascular ectasia is an uncommon condi-
trunks, and vascular wall
n Nonbranching fibrils 7.5 to 10 nm in diameter on ultrastructural
tion that is increasingly recognized as a cause of acute or
examination chronic GI blood loss leading to iron-deficiency anemia.
n Congo red—characteristic apple-green birefringence on polarized light The anemia can be severe and refractory to iron replace-
n Thioflavin T—fluorescent dye
ment therapy and may require blood transfusions. GAVE
n Immunostains can be used to subclassify type of amyloid
primarily affects women (76%), with a mean age of 69
Differential Diagnosis years (range, 42–89 years). Clinical presentations include
n Vascular arteriosclerosis
iron-deficiency anemia (88%), heme-positive stool (42%),
n Systemic sclerosis melena (15%), and rarely hematemesis (3%) and hemato-
n Ischemic gastritis, radiation gastritis, and other causes of lamina chezia (1%). GAVE is commonly associated with autoim-
propria fibrosis mune and connective tissue disorders such as Raynaud’s
phenomenon, sclerodactyly, autoimmune gastritis, hypo-

thyroidism, primary biliary cirrhosis, autoimmune liver
disease, and diabetes mellitus. Other associations include
cirrhosis, chronic renal failure, and cardiovascular dis-
ease. The pathogenesis is unknown. It has been proposed
that traumatic gastric peristalsis and subsequent prolapse
of antral mucosa through the pylorus may cause vascu-
lar ectasia. Humoral factors such as hypergastrinemia,
proliferation of neuroendocrine cells secreting vasoactive
intestinal polypeptide (VIP), and 5-hydroxy tryptamine
(serotonin) have also been speculated.
GASTRIC ANTRAL VASCULAR ECTASIA (“WATERMELON

STOMACH”)—FACT SHEET
Definition A
n Uncommon cause of acute or chronic gastric bleeding
characterized endoscopically by linear vascular stripes in the
gastric antrum

n Related mainly to gastrointestinal blood loss
n May give rise to severe anemia refractory to iron replacement
therapy, requiring blood transfusions

n Female predominance (76% are women)
n Mean age 69 years (range, 42–89 years)
Clinical Features
n Iron-deficiency anemia (88%), heme-positive stool (42%),
melena (15%), and rarely hematemesis (3%) and hematochezia

(1%)
n Commonly associated with autoimmune and connective tissue
disorders such as Raynaud’s phenomenon, sclerodactyly,

autoimmune gastritis, hypothyroidism, primary biliary cirrhosis,
autoimmune liver disease, and diabetes mellitus
n Other associations include cirrhosis, chronic renal failure, after
bone marrow transplantation, and cardiovascular disease

B
FIGURE 3.41
n Treatment is dictated by the rate of blood loss
Characteristic endoscopic appearance of gastric antral vascular ectasia. Note the par-
n Conservative management includes iron supplement or blood
allel, intensely red vascular stripes resembling watermelon, in two separate patients
transfusion, which may be insufficient (A and B). (A, Courtesy of Shriram Jakate, MD, Rush Medical College, Chicago).
n Various endoscopic treatment modalities include laser, heater
probe therapy, bipolar electrocautery, and injection

sclerotherapy
n Surgical antrectomy offers definitive therapy but carries a mortality resection specimen can show a thickened antral wall
rate of 7.4% with prominent submucosal vessels running in a longi-
tudinal direction toward the pylorus.
Pathologic Features Microscopic Findings
The histologic appearance consists of foveolar hyperplasia,

Gross Findings dilated mucosal capillaries with fibrin thrombi, and fibro-
muscular hyperplasia of lamina propria with minimal or
The phrase “watermelon stomach” describes the char- absent inflammation. The presence of fibrin thrombi is
acteristic endoscopic appearance of GAVE consisting important for diagnosis (Fig. 3.42). In subtle cases, CD61
of parallel, intensely red vascular stripes situated at the stain can highlight thrombi within capillaries to support
crests of mucosal folds traversing the gastric antrum the diagnosis. The submucosal vessels are also dilated
and converging on the pylorus (Fig. 3.41). A surgical and tortuous. The foveolar epithelium may show reactive
Gastric Antral Vascular Ectasia (“Watermelon Stomach”)—

Pathologic Features
Gross Findings
n Predominantly located in the antrum; may also involve the
cardia
n Endoscopic appearance consisting of intense red, linear, vascular
stripes situated at the crests of mucosal folds traversing the

gastric antrum and converging on the pylorus
n Resection specimen shows thickened antral wall with dilated and
tortuous submucosal vessels
n Dilated mucosal capillaries with characteristic fibrin thrombi
FIGURE 3.42 (CD61 positive) and fibromuscular hyperplasia of lamina propria
Gastric antral vascular ectasia. Antral biopsy shows foveolar hyperplasia, with minimal or absent inflammation
dilated mucosal capillaries with fibrin thrombi, the fibrin thrombi (arrows), n The submucosal vessels may also be dilated and tortuous
which are helpful for diagnosis. n Minimal or no inflammation in the lamina propria
n Portal hypertensive gastropathy
epithelial changes consisting of mucin loss and preserved

nuclear-to-cytoplasmic ratio. The gastric body may show
atrophic gastritis with intestinal metaplasia. The gastric
cardia can also be involved in a subset of cases.
TABLE 3.6
Comparison of Distinction between Gastric
Differential Diagnosis Antral Vascular Ectasia and Portal Hypertensive
Gastropathy
The distinction between GAVE and portal hypertensive Gastric Antral Portal Hypertensive
gastropathy (PHG) is summarized in Table 3.6. PHG Vascular Ectasia Gastropathy
involves the gastric corpus, usually spares the antrum,
Location Predominantly Predominantly body
and is seen in patients with cirrhosis and portal hyper- antrum
tension. The gastric corpus mucosa shows distended Endoscopic Linear red stripes Diffuse mosaic
capillaries but may be completely normal because the appearance resembling a vascular pattern,
shunts may involve the larger submucosal vessels. watermelon cherry-red spots,
scarlatina rash
Endoscopy in PHG shows a characteristic “snake-skin”
Endoscopic Thin atrophic Diffusely thickened
appearance unlike the watermelon appearance seen in ultrasound gastric wall gastric wall with
GAVE. It is important to emphasize that GAVE may with thickening dilated veins
be present in a subset of patients with cirrhosis, and limited to antral
severe PHG may also involve the antrum. The distinc- region
Characteristic Dilated mucosal Vascular ectasia,
tion is important because GAVE is a localized disorder
histology capillaries with perivascular stromal
that can be treated with endoscopic therapy, but PHG thrombi thickening
is a systemic condition that requires medical or surgi- Associated AutoiDmmune Cirrhosis with portal
cal intervention to lower portal pressures in patients conditions and connective hypertension
with varices. tissue diseases,
also cirrhosis
Management Endoscopic Portal
laser therapy, decompression,
antrectomy shunting
Treatment is based mainly on the rate of blood loss. probe therapy, bipolar electrocautery, and injection
Conservative management with iron supplement or sclerotherapy. Excellent results have been shown with
blood transfusion may be insufficient. Various endo- laser therapy. Surgical antrectomy offers definitive ther-
scopic modalities are available and include laser, heater apy but carries a mortality rate of 7.4%.
PORTAL HYPERTENSIVE GASTROPATHY

PORTAL HYPERTENSIVE GASTROPATHY—FACT SHEET
Definition
The term portal hypertensive gastropathy is used to describe
n Vascular manifestations of portal hypertension in the stomach
the vascular manifestations of portal hypertension in the consisting of a mosaic mucosal pattern (“snake-skin” appearance)
stomach characterized by a mosaic mucosal appearance with or without red spots on endoscopy
(“snake skin”) with or without red spots on endoscopy.
n Morbidity is related to the low-volume blood loss
n Not a significant cause of mortality

n Male predominance
Portal hypertensive gastropathy is seen in patients with
cirrhotic or noncirrhotic portal hypertension. Patients Clinical Features
usually present with mild bleeding, and unlike GAVE, n Seen in patients with cirrhotic or noncirrhotic portal
anemia or transfusion requirement is less common. hypertension
The stomach is most often involved, but the small n Mild bleeding
n Patients who have undergone sclerotherapy or banding for

intestine and colon can also show manifestations of
their esophageal varices are at higher risk of developing portal
portal hypertension (portal hypertensive intestinal hypertensive gastropathy
vasculopathy, portal colopathy). PHG can affect adults
and children, and a male predominance is present. The Prognosis and Therapy
pathogenesis of PHG is thought to be hemodynamic n Transjugular intrahepatic portosystemic shunt and shunt surgery
alterations and increased splenic circulation resulting n Nonselective β-blockers such as propranolol
in increased gastric mucosal blood flow caused by por-

tal hypertension. Patients who have undergone sclero-
therapy or banding for their esophageal varices are at
higher risk of developing PHG.
Pathologic Features
Gross Findings
Portal hypertensive gastropathy typically involves

the proximal stomach (an important distinction from
GAVE). The endoscopic appearance ranges from diffuse
fine pink speckling or “scarlatina” rash with a mosaic
pattern resembling snake skin (Fig. 3.43) to severe gas-
tropathy with cherry-red spots and diffuse hemorrhagic
gastropathy.
The histologic findings consist of marked congestive vas-

culopathy with dilated mucosal capillaries and venules
(Figs. 3.44 and 3.45), but the mucosa may also be com-
FIGURE 3.43
pletely normal and changes confined to larger submucosal
“Mosaic” or snake-skin appearance of the gastric body mucosa in a patient
vessels. The submucosal veins show marked congestion, with portal hypertensive gastropathy.
intimal thickening, and tortuosity. The ectatic vessels
are accompanied by perivascular stromal fibrosis, lamina
propria edema, and scant or absent inflammation. Fibrin
thrombi are absent. abnormalities, and endoscopists are reluctant to get
For these reasons, mucosal biopsies often have low deeper biopsies given the coagulation abnormalities in
yield given the predominantly submucosal vascular these cirrhotic patients.
Portal Hypertensive Gastropathy—Pathologic Features
Gross Findings
n Portal hypertensive gastropathy involves the fundus and body;
may also involve the antrum in some cases

n Endoscopic appearance ranges from diffuse fine pink speckling or
“scarlatina” rash with a mosaic pattern resembling “snake-skin” to

severe gastropathy with cherry-red spots and diffuse hemorrhagic
gastropathy
n Marked congestive vasculopathy with dilated mucosal capillaries
and venules
n Changes are more prominent in submucosal veins, which show
marked congestion, intimal thickening, and tortuosity

n Fibrin thrombi are absent
n Mucosal biopsies often have low yield

FIGURE 3.44
Gastric mucosal biopsy in a portal hypertensive gastropathy with dilated Differential Diagnosis
mucosal capillaries and congestion. Note the absence of fibrin thrombi.
n Gastric antral vascular ectasia
DIEULAFOY’S LESION (CALIBER

PERSISTENT ARTERY)
Dieulafoy’s lesion is an uncommon cause of recurrent

and often massive upper GI bleeding. It presents as a
small mucosal defect overlying an artery of persistent
large caliber in the mucosa.
Dieulafoy’s lesion typically presents as recurrent, often

massive upper GI bleeding without preceding symp-
toms. Patients develop hematemesis, melena, and ane-
FIGURE 3.45
mia frequently needing red cell transfusions. Symptoms
High-power view showing prominent and dilated mucosal capillaries in por-
tal hypertensive gastropathy. such as abdominal pain, anorexia, and dyspepsia are not
common. History of NSAID use, peptic ulcer, and alco-
hol abuse is notably absent.
The lesion is usually found in the proximal fundus
within 6 cm of the gastroesophageal junction, along the
Differential Diagnosis lesser curvature. Apart from stomach, other sites such
as the duodenum, jejunum, large intestine, and rectum
can be involved. It is slightly more common in boys and
The differential diagnosis is typically with GAVE which is men (male-to-female ratio, 2 to 1), with a median age of
discussed in the section earlier and summarized in Table 3.6. 54 years (range, 16–91 years).

Pathologic Features
Portal decompression procedures such as transjugular
intrahepatic portosystemic shunt and shunt surgery Gross Findings
are effective in resolving the gastropathy and bleeding.
Nonselective β-blockers such as propranolol have shown The endoscopic appearance consists of a 2- to 5-mm
promise in preventing bleeding. mucosal defect with a protruding vessel. The mucosa may
aneurysmal dilation, and vasculitis are absent, and the

DIEULAFOY’S LESION (CALIBER PERSISTENT ARTERY)— surrounding gastric mucosa is essentially normal.
FACT SHEET
Definition Dieulafoy’s Lesion (Caliber Persistent Artery)—Pathologic

n Dieulafoy’s lesion is an uncommon cause of upper
Features
gastrointestinal (GI) bleeding consisting of a small mucosal defect
overlying an artery of persistent large caliber in the mucosa Gross Findings
n The endoscopic appearance consists of a 2- to 5-mm mucosal
Incidence and Location defect with a protruding vessel
n The incidence as a cause of GI bleeding varies from 0.3% to 6.7%
n Typically located in the proximal fundus within 6 cm of the Microscopic Findings

gastroesophageal junction, along the lesser curvature n Histology consists of a large-caliber muscular artery with a
n Extra gastric lesions are uncommon, but rarely, the duodenum, tortuous course through the submucosa focally extending to the
jejunum, large intestine, and rectum can also be involved mucosa and into the gastric lumen
n The large-caliber vessel may show partial disruption with the
Morbidity and Mortality overlying mucosa showing erosion, hemorrhage, and blood clots;
n Modern endoscopic therapeutic modalities have reduced arteriosclerosis, calcification, aneurysmal dilation, and vasculitis
morbidity and mortality rates are not observed. The surrounding gastric mucosa is essentially
normal
n Slightly more common in males, with a male-to-female ratio of 2 to 1
n Median age, 54 years; range, 16 to 91 years n Other causes of bleeding, such as Mallory Weiss tear, peptic ulcer
disease, angiodysplasia, chemical gastropathy, and gastric antral

Clinical Features vascular ectasia, need to be ruled out
n Presents as recurrent, often massive upper GI bleeding without
preceding symptoms
n Symptoms include hematemesis, melena, and anemia frequently
needing red cell transfusions

n Abdominal pain, anorexia, and dyspepsia are uncommon Differential Diagnosis
n History of nonsteroidal antiinflammatory drug use, peptic ulcer, or
alcohol abuse is notably absent

n Almost 80% of the lesions are identified by endoscopy, Other causes of bleeding such as Mallory-Weiss tear,
sometimes requiring multiple endoscopies peptic ulcer disease, angiodysplasia, chemical gastrop-
n Angiography and endoscopic ultrasonography are useful to
athy, and GAVE need to be ruled out, at least clinically.
identify lesions not detected by white-light endoscopy

n Endoscopic therapeutic modalities are the first line of treatment, Prognosis and Therapy
including electrocoagulation, hemoclipping, banding, epinephrine
injection, and injection sclerotherapy
n Recurrent bleeding may warrant surgical therapy, which includes Once associated with a high mortality rate, endoscopic
gastrotomy with ligation of the responsible vessel and proximal therapeutic modalities have reduced mortality rates
gastric resection
considerably provided that the lesion is identified and
treated early. Therapeutic interventions consist of
electrocoagulation, hemoclipping, banding, epineph-
look normal between bleeding episodes. This diagnosis rine injection, and injection sclerotherapy. Recurrent
should be seriously considered when a patient presents bleeding may warrant surgical therapy, which includes
with massive GI bleeding without an endoscopically iden- gastrotomy with ligation of the responsible vessel or
tifiable source of bleeding because this lesion may be dif- proximal gastric resection.
ficult to visualize because of its proximal fundic location.
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4
Epithelial Polyps and Neoplasms
of the Stomach
■ Bence Kővari, MD, PhD, Kwun Wah Wen, MD, PhD and
Gregory Y. Lauwers, MD, PhD
Gastric carcinoma is the second most common gas- Clinical Features

trointestinal (GI) cancer worldwide, only behind
colorectal carcinoma, with more than 1 million cases
diagnosed annually. With the increasing use of endos- Fundic gland polyps occur in two common settings, spo-
copy, the diagnosis of early gastric cancer is more radic and syndromic. In the sporadic setting, the polyps
frequent, and previously rare or unrecognized preneo- are most commonly detected in the fourth to sixth decade
plastic lesions have been described and better character- of life. However, in syndromic cases, the polyps occur in
ized. Diagnosis of gastric neoplasms and preneoplastic younger individuals in the second or third decade. They
conditions has clinical management implications that can be seen even in children and show an equal sex distri-
impact surveillance or resection and sometimes screen- bution. Patients are mostly asymptomatic or may present
ing of other organs and family members for inheritable with mild abdominal pain, dyspepsia, or reflux.
syndromes. The increased prevalence noted over the past 2
decades is attributed to the decreasing Helicobacter
pylori infection and widespread use of PPIs. In fact,
FGPs have an inverse correlation with H. pylori infec-
■ GASTRIC POLYPS tion and atrophy. Long-term PPI use is associated with
a fourfold risk of developing FGPs. Moreover, complete
Gastric polyps have many subtypes, all with character- regression of some FGPs has been shown on cessation
istic endoscopic appearance, topography, and predis- of the PPI therapy.
posing conditions, such as proton pump inhibitor (PPI) Fundic gland polyps are present in 0.8% to 1.9% of
therapy, autoimmune gastritis, or polyposis syndromes. all patients undergoing gastroscopy. Among the syn-
Assessment of the background antral and oxyntic dromic conditions, they are most commonly found in
mucosa is essential for the accurate evaluation of gastric patients with familial adenomatous polyposis (FAP)
polyps. followed by gastric adenocarcinoma and proximal poly
posis of stomach (GAPPS) and rarely in those with
MUTYH-associated polyposis (MAP). FGP is diagnosed
in 26% to 84% of patients with FAP.
FUNDIC GLAND POLYPS
Fundic gland polyps (FGPs) are the most commonly
diagnosed gastric polyps, comprising 77% of all pol- Pathologic Features
yps. These benign epithelial lesions are found in
the gastric body and fundus and are characterized Gross Findings
oxyntic gland proliferation with luminal dilation
and various degrees of parietal cell hyperplasia and Fundic gland polyps are present exclusively in the
hypertrophy. body or fundus. In the syndromic setting, these polyps
91
FIGURE 4.1
Endoscopic appearance of fundic gland polyps. In this patient with familial
adenomatous polyposis, the fundic mucosa is studded by hundreds of small
sessile polyps.
often carpet the oxyntic mucosa. They are soft, sessile,

and hemispherical, with a smooth and translucent
appearance (Fig. 4.1). FGPs are small, ranging from 1
to 7 mm in size. Because of their small size, these pol-
yps are often hidden by gastric rugal folds and become
visible when the stomach is fully distended. They are
usually identical in color to the surrounding gastric B
mucosa. The nonpolypoid gastric mucosa is typically FIGURE 4.2
normal. Fundic gland polyps with cystically dilated fundic glands (A) lined by parietal
and chief cells (B).
be slight hyperplasia of the surface foveolar epithe-
lium with shallow to absent pits.
Fundic gland polyps consist of proliferation of oxyntic In 25% to 46% of FGPs in FAP and fewer than
glands with cystic dilation. The proliferating glands are 1% of sporadic FGPs, low-grade epithelial dysplasia
formed predominantly by parietal cells, but chief cells characterized by nuclear hyperchromasia, enlarge-
and mucous neck cells may also be present (Fig. 4.2). ment, mild pseudostratification, and loss of mucin
The morphology of FGPs is slightly different accord- (Fig. 4.3) may be present. The dysplasia in FGPs is
ing to the etiologic background of the polyp. PPI usually of the foveolar type. High-grade dysplasia
therapy–induced lesions are characterized by the or adenocarcinoma are uncommon in patients with
presence of more prominent parietal cell hyperpla- FAP. In contrast, low- and high-grade dysplasia as
sia, increased diameter of dilated oxyntic glands, well as adenocarcinoma can be seen in patients with
and elongation of surface foveolar epithelium. FAP- GAPPS.
associated lesions tend to show smaller microcysts
lined by pure fundic epithelium with limited pari-
etal cell and surface foveolar hyperplasia. FGPs in
Molecular Studies
patients with GAPPS tend to be generally large, but
the microcysts are smaller than PPI-related lesions
and are lined by a mixture of fundic and foveolar Studies have revealed molecular abnormalities in FGPs,
type cells. The characteristic inverted foveolar epi- suggesting they are neoplastic lesions. FGPs associ-
thelium in this setting is designated as hyperpro- ated with FAP and even sporadic FGPs with dysplasia
liferative aberrant pits. The lamina propria lacks harbor somatic APC gene alterations in 50% of cases.
inflammation and is mildly edematous. There may Sporadic FGPs show activating β-catenin mutations in
CHAPTER 4 Epithelial Polyps and Neoplasms of the Stomach 93
Sporadic- and FAP-associated low-grade dysplastic FGPs

have a low progression rate to high-grade dysplasia or
adenocarcinoma. Conversely, GAPPS-associated FGPs
have a higher risk of progression. The diagnosis of FGPs
virtually never requires surgical resection, but endo-
scopic mucosal resection may be considered in large dys-
plastic FGPs. Upper endoscopic surveillance in patients
with FAP is warranted to monitor the 300-fold risk for
duodenal adenocarcinoma, but the question whether
dysplastic FGPs deserve follow-up surveillance remains
controversial.
FIGURE 4.3
Low-grade surface epithelial dysplasia with hyperchromatic and pseudostrati-
fied nuclei in a sporadic fundic gland polyp. FUNDIC GLAND POLYPS—FACT SHEET
Definition
up to 90% of cases. In the setting of MAP, the changes n Benign epithelial polyps developing in oxyntic mucosa and
are driven by biallelic mutations in MUTYH. Recently, composed of disordered proliferation and dilation of fundic
point mutations in the YY1 binding site of the APC glands with variable degrees of foveolar hyperplasia
promoter 1B were reported in several patients with
Incidence
GAPPS.
n Commonest gastric polyps (0.8%–1.9% of patients undergoing
gastroscopy)
n Prevalence ranges from 26% to 84% in patients with familial
adenomatous polyposis, the most common causative syndrome

n Patients with gastric adenocarcinoma and proximal polyposis
(GAPPS), a recently described autosomal dominant inherited

syndrome, present with multiple (30–100), usually small, fundic
Biopsies of oxyntic mucosa from patients on PPI ther-
gland polyps (FGPs). Dysplasia and early adenocarcinoma may
apy can show hypertrophic parietal cells with api- be present in these patients
cal cytoplasmic protrusions and dilated glands. The n FGPs can also be detected in about 10% of patients with
low-acid environment created by the H+/K+-ATPase MUTYH-associated polyposis, frequently in association with
inhibiting action of the PPIs causes gastrin stimula- adenomas
tion, which in turn has a trophic effect on parietal
cells, resulting in dilated intracytoplasmic canaliculi
n Benign with limited malignant potential in the sporadic setting
caused by the inspissated hydrogen ion. FGPs, on the n Dysplasia and carcinoma develop more commonly in the
other hand, show fundic gland cysts with flattened syndromic setting
oxyntic lining. Compensatory hyperplastic parietal
cells in remnant oxyntic mucosal islands of patients Gender, Race, and Age
with autoimmune gastritis may mimic hyperplas- n Patients are 40 to 69 years of age (average, 57 years)
tic features reminiscent to the effect of PPI therapy. n FGPs in FAP occur in younger individuals in their 20 s and 30 s
n FGPs in children are extremely rare and warrant a search for FAP
This phenomenon can lead to the development of
endoscopic pseudopolyposis when the remnant nona- Clinical Features
trophic mucosal patches appear polypoid between the n Most are asymptomatic
depressed atrophic areas.
Oxyntic gland adenomas (OGAs) are also composed Prognosis and Therapy
of proliferating fundic or oxyntic gland but display n Malignant potential is limited in sporadic cases (incidence of
unmistakable neoplastic features, including an irregu- dysplasia, ~1%)

lar tubular growth pattern and usually mild but obvious n In FAP, dysplasia occurs with a reported prevalence of 25%
to 46% and correlates with increased severity of duodenal

cytologic atypia. Hyperplastic polyps are also common
polyposis, larger polyp size, and the presence of antral
polypoid lesions involving the stomach but are com- gastritis
posed entirely of mucous neck cells. Parietal cells and n Low- and high-grade dysplasia and early adenocarcinoma are
chief cells are not part of the polyp lining epithelium in detected in GAPPS-associated FGPs
hyperplastic polyps
greater than 50 hyperplastic polyps in the stomach. A

Fundic Gland Polyps—Pathologic Features slight female predominance may be seen (male-to-female
ratio, 1 to 2.4), and adults in the sixth and seventh
Gross Findings decades of life are commonly affected. Hyperplastic pol-
n Present exclusively in the body or fundus yps are the most common polyps in pediatric patients,
n Often multiple, occurring in clusters
accounting for 42% of gastric polyps in children.
n Soft, sessile, hemispherical, with a smooth and translucent
appearance
Most (especially small) polyps are incidental findings
n Small (1–7 mm in size), identical in color to the surrounding during endoscopy performed for other reasons. Symptoms
gastric mucosa sometimes associated with large hyperplastic polyps include
n Normal surrounding gastric mucosa bleeding, abdominal pain, anemia, nausea, and vomiting.
Large pedunculated polyps in the pyloric region may produce
gastric outlet obstruction. Gastric hyperplastic polyps are
n Disarrayed proliferation of oxyntic mucosa with cystically dilated
frequently associated with abnormalities in the surrounding
fundic glands lined mostly by parietal cells; less often by chief
cells and mucous neck cells nonpolypoid mucosa in up to 85% of cases. These changes
n Minimal or absent inflammation include H. pylori gastritis (25%), chemical gastropathy
n Fundic gland polyps (FGPs) may contain foveolar low-grade (21%), autoimmune gastritis (12%), intestinal metaplasia
dysplasia characterized by hyperchromasia, nuclear enlargement, (37%), dysplasia (2%), and synchronous or metachronous
pseudostratification, and loss of mucin
carcinoma (6%). Other common etiological associations
Molecular Features
include partial gastrectomies for ulcers, postlaser ther-
n Sporadic FGPs: β-catenin mutations, 90%
apy for gastric antral vascular ectasia, and cytomegalovirus
n Familial adenomatous polyposis: somatic APC gene mutation gastritis. An increased prevalence of hyperplastic polyps has
n Gastric adenocarcinoma and proximal polyposis of stomach: point also been reported in the transplant setting.
mutation in the binding site of the APC promoter 1B Finally, a rare family pedigree with hyperplastic pol-
n In MUTYH-associated polyposis, the alteration is a biallelic
yposis and increased incidence of poorly cohesive gas-
mutation of the MUTYH gene
tric carcinoma has been reported and associated with
Differential Diagnosis KRAS point mutation at codon 12. In recent studies on
n Proton pump inhibitor effect with prominent parietal cell
small cohorts, no pathogenic mutations were detected
hyperplasia in small hyperplastic polyps without dysplasia; however,
n Oxyntic gland pseudopolyps in autoimmune gastritis TP53 gene mutations were the most common alteration
n Oxyntic gland (chief cell) adenoma
in hyperplastic polyps with dysplasia. Large hyperplas-
n Hyperplastic polyps
tic polyps may show loss of MGMT expression or APC,
CTNNB1 (beta-catenin), KRAS, or BRAF mutations.
GASTRIC HYPERPLASTIC POLYPS

Pathologic Features
Hyperplastic polyps are the second most common
type of gastric epithelial polyps and are composed of
elongated and tortuous foveolar epithelium. Given the Gross Findings
strong association with background gastritis, hyper-
plastic polyps are believed to represent a regenerative Most hyperplastic polyps are smaller than 1 cm, but they
response to mucosal injuries. In the past, these polyps can sometimes grow up to 12 cm in size and be mistaken
were often referred to as regenerative polyps or hyper- for a carcinoma. They are usually broad based or sessile
plasiogenous polyps. but can also be pedunculated. The polyps have a smooth,
lobulated, and glistening surface, often containing areas
of erosion (Fig. 4.4).
Clinical Features
Hyperplastic polyps have a prevalence rate of approx-
imately 1% to 2% at endoscopic examination in the
adult population and represent about 20% of all gastric The polyps are composed of hyperplastic, elongated, and
polyps. The prevalence of hyperplastic polyps has sig- tortuous gastric foveolae (Fig. 4.5) with outpouchings,
nificantly decreased over the past 20 years because of papillary infoldings, or cystic dilation. The foveolar cells
the declining rate of H. pylori infection. may become hypertrophic and reminiscent of goblet cells
Hyperplastic polyps are antral predominant (60%). because of accumulation of abundant cytoplasmic mucin.
They are usually single but can be multiple in 20% of Scattered single hyperplastic foveolar cells created by the
cases. The term hyperplastic polyposis is used to denote damage and disintegration of such foveolar epithelium
A subset of larger polyps contain prominent vessels and

wisps of smooth muscle bundles extending from muscu-
laris mucosae into the lamina propria of the polyp, a phe-
nomenon most likely caused by mucosal prolapse. Areas
with erosion may show regenerative changes with depleted
mucin, hyperchromatic nuclei, and visible nucleoli that
should not be mistaken for dysplasia.
Hyperplastic polyps may contain foci of intestinal
metaplasia (16%), dysplasia (4%), and rarely malig-
nant transformation (0.6%). Dysplastic foci are charac-
terized by lack of surface maturation, pseudostratified
epithelium with enlarged hyperchromatic nuclei, and
increased mitotic figures. High-grade dysplasia is char-
acterized by loss of polarity, marked cytologic atypia,
and architectural abnormalities such as cribriform
glands. Size appears to be the biggest risk factor with
FIGURE 4.4 most lesions harboring dysplasia or carcinoma measur-
Single smooth and hyperemic pedunculated gastric hyperplastic polyp. ing 2 cm or more.
(Courtesy of Shriram Jakate, MD, Rush Medical College, Chicago.)
Focal foveolar hyperplasia or polypoid foveolar hyperplasia

is often seen adjacent to ulcers, and small sessile excres-
cences with elongated superficial gastric foveolae occur as
part of chemical gastropathy. Gastritis cystica glandularis
usually develops in patients after Billroth gastrectomies
or near stomal sites and shows marked foveolar hyperpla-
sia. The hallmark of these lesions is the cystically dilated
glands misplaced in the submucosa and muscularis propria.
Mucosal prolapse polyps can show foveolar hyperplasia but
also contain a prominent glandular component and smooth
muscle proliferation in the lamina propria. Hyperplastic and
hamartomatous polyps are both composed of proliferating
A
foveolar epithelium and can be indistinguishable, especially
when only superficial pinch biopsies are available. Some his-
tologic features are suggestive of hamartomas, but the correct
diagnosis often cannot be reached without proper clinical
correlation. Peutz-Jeghers polyps may present with char-
acteristic arborizing bundles of smooth muscle that cause
mucosal splitting, along with other clinical stigmata charac-
teristic of the syndrome. Juvenile polyps contain prominent
cystic glands, often filled with neutrophils in a distinctive
abundant, edematous, and inflamed stroma. These polyps
are more common in children and have a smooth rounded
surface that is frequently eroded. Gastric polyps in PTEN
hamartoma tumor syndrome (e.g., Cowden’s disease) show
great phenotypic diversity and may resemble hyperplastic or
juvenile polyps. However, peculiar stromal changes (fibrosis,
B lipomatosis, ganglion cells) and the presence of multiple dif-
FIGURE 4.5 ferent histologic types of polyps (e.g., intramucosal lipomas
Dilated, tortuous gastric foveolar epithelium (A) in a gastric hyperplastic and ganglioneuromas), simultaneous esophageal glycogenic
polyp with frequent outpouchings and edematous and inflamed stroma (B). acanthosis, or extra-GI manifestations help in establishing
the diagnosis. Endoscopically, diffuse mucosal hyperplasia is
should not be mistaken for signet ring cells. The stroma is encountered in diseases that may clinically present with pro-
edematous, causing separation of glands, and contains vari- tein-losing gastropathy. Ménétrier’s disease involves the gas-
able numbers of inflammatory cells such as lymphocytes, tric body with dramatic foveolar hyperplasia and concurrent
plasma cells, eosinophils, and even lymphoid aggregates. oxyntic gland atrophy. Cronkhite-Canada syndrome also
causes diffuse mucosal involvement by confluent polyposis

containing marked lamina propria edema. Abnormal skin Gastric Hyperplastic Polyps—Pathologic Features
pigmentation and nail dystrophy are helpful in establishing
the diagnosis. Gross Findings
n Range in size from a few millimeters up to 12 cm (average, 1 cm)
n Have a smooth, lobulated, and glistening surface, often with areas

Prognosis and Therapy of erosion
n Usually sessile; can be pedunculated
Hyperplastic polyps are benign lesions, and although small n Multiple in 20% of cases
lesions seem to be truly regenerative, large polyps that har-
bor clonal mutations and could be regarded as neoplastic. Microscopic Findings
On follow-up, approximately 70% of polyps are stable, and n Dilated, elongated, branched, and tortuous foveolar epithelium
n Edematous and inflamed stroma

30% polyps increase or decrease in size. Complete regres-
n Regenerative foci can mimic dysplasia because of depleted
sion has been noted after H. pylori eradication. Polyps
mucin, hyperchromatic nuclei, and prominent nucleoli
larger than 1 cm in size may recur after endoscopic resec- n May contain foci of intestinal metaplasia, dysplasia, or invasive
tion in roughly half of the cases, and neoplastic transfor- carcinoma. Risk of neoplasia is greater in large lesions
mation may occur in 10.4%. Polyps larger than 25 mm n Often associated with mucosal pathology in the surrounding
and harboring intestinal metaplasia are associated with mucosa

an increased risk of neoplastic transformation. The risk of
Histochemistry and Immunohistochemistry
adenocarcinoma is about 0.7% to 2.2%. These carcinomas
n Stains for highlighting Helicobacter pylori useful in polyps with
are mostly intramucosal and carry a good prognosis; com- inflamed epithelium or stroma
plete removal of the lesion is recommended. The risk of n Increased and surface Ki-67 staining and overexpression of p53
metachronous or synchronous epithelial dysplasia or ade- staining may aid in confirming a hematoxylin and eosin–based
nocarcinoma elsewhere in the stomach is also increased. impression of dysplasia in difficult cases
n Focal foveolar hyperplasia or polypoid foveolar hyperplasia
GASTRIC HYPERPLASTIC POLYPS—FACT SHEET
n Mucosal prolapse polyps
n Gastritis cystica glandularis

Definition n Peutz-Jeghers polyp
n Epithelial polyps composed of elongated, dilated, branched, and n Juvenile polyp
tortuous foveolar epithelium and edematous stroma containing n Cronkhite-Canada syndrome
inflammatory cells n Ménétrier’s disease

n Represent approximately 20% of stomach polyps
n Most are located in the antrum (60%)

GASTRITIS CYSTICA POLYPOSA
Morbidity and Mortality Gastritis cystica polyposa is characterized by cystically
n Large polyps may cause bleeding and gastric outlet obstruction dilated glands misplaced within the submucosa, forming
n Dysplasia and adenocarcinoma develop in 10% of large
polypoid lesions near postgastroenterostomy anastomo-
hyperplastic polyps (particularly those >2.5 cm in size)
ses and stomas. Gastritis cystica polyposa is synonymous
Gender, Race, and Age with gastritis cystica profunda, gastritis cystica superfi-
n Slight female predominance (male-to-female ratio, 1 to 2.4)
cialis, gastric cystic polyposis, polypoid mucosal prolapse,
n Adults in their sixth to seventh decades of life are commonly affected stromal polypoid hypertrophic gastritis, and polypoid
cystic gastritis. Although a non-neoplastic lesion, it is
Clinical Features discussed in this section because it can mimic an inva-
n Smaller polyps are often incidental findings during surveillance sive adenocarcinoma on endoscopy, and a subset may
n Patients can present with bleeding, iron-deficiency anemia,
undergo neoplastic transformation.
abdominal pain, and dyspepsia
n Patients with large prepyloric polyps can present with gastric
outlet obstruction
Clinical Features
n The majority of hyperplastic polyps (especially small ones) are benign
n Treatment includes snare polypectomy, endoscopic mucosal resection, This rare entity is similar to mucosal prolapse lesions else-
and treating associated conditions such as Helicobacter gastritis where in the GI tract, such as solitary rectal ulcer, colitis cys-
n Large polyps (>1 cm) may recur after endoscopic resection in
50% of the cases tica profunda, and prolapse at colostomy and ileostomy sites.
n Associated carcinomas are mostly intramucosal and carry a good Gastritis cystica polyposa presents near gastroenterostomy
prognosis stomal sites 3 to 40 years after surgery, typically in men in
their 70 s who have history of Billroth I and II procedures.
Clinically, the patients are frequently suspected of having Differential Diagnosis

stump carcinoma or an adenoma. Computed tomography
examination can demonstrate multiple exophytic masses The presence of epithelial elements deep in the sub-
around gastric stomal or anastomotic sites. Anastomotic site mucosa or even muscularis propria in gastritis cystica
changes, including mechanical or ischemic injury, mucosal profunda can be mistaken for invasive adenocarcinoma.
prolapse, and bile reflux, are thought to play a role in the Unlike in carcinomas, these cystic glands lack pleo-
pathogenesis. Unlike the benign rectal mucosal prolapse morphism and desmoplastic stroma and are often sur-
lesions, gastritis cystica polyposa can be associated with dys- rounded by lamina propria or smooth muscle bundles.
plasia and gastric stump carcinoma.
Although benign, gastritis cystica polyposa can be asso-

Gross Findings ciated with dysplasia and stump carcinoma. Thus, regu-
lar follow-up is important.
Gastritis cystica polyposa presents as single or multiple, soft,
sessile 1- to 3-cm polyps or confluent, circumferential masses
around gastric stomal or anastomotic sites. The mucosa Gastritis Cystica Polyposa—Pathologic Features
overlying the polyp is usually smooth and resembles the sur-
Gross Findings
rounding gastric mucosa or may be red. Cut sections show
n Single or multiple, soft, sessile 1- to 3-cm polyps around gastric
thickened gastric wall containing numerous cystic structures. stomal or anastomotic sites
n Cut sections show thickened gastric wall containing numerous
cystic glands
Microscopic Findings Microscopic Findings

n Foveolar hyperplasia, regenerative surface epithelial changes,
cystically dilated pyloric-type glands surrounded by lamina propria

Histologic features include foveolar hyperplasia, regen-
in the mucosa, submucosa, and even muscularis propria
erative surface epithelial changes, and cystically dilated n Lamina propria and submucosa display scarring, fibrosis, and
pyloric-type glands in the mucosa, the submucosa, thickened and splayed muscle bundles
and even the muscularis propria (Fig. 4.6). Depending n Gastric remnant shows reduced oxyntic glands, edema, and
on the location of the cystic glands, these lesions can chronic inflammation
also be termed gastritis cystica superficialis or gastritis
cystica profunda. The lamina propria and submucosa
n Invasive adenocarcinoma
contain increased chronic inflammation, fibrosis, and
scarring and often display thickened and splayed muscle
bundles. Biopsy of the gastric remnant shows reduced
oxyntic glands owing to the lack of gastrin caused by PANCREATIC HETEROTOPIA
antrectomy, lamina propria edema, and chronic inflam-
mation. There may be intestinal metaplasia or dysplasia. Pancreatic heterotopia is the presence of pancreatic tis-
sue outside the normal pancreas with no vascular or
ductal continuity with the organ. It is synonymous with
pancreatic rest and ectopic pancreas. It is believed to orig-
inate during embryologic development from duodenal
invaginations that persist in the GI wall.
Clinical Features
Pancreatic heterotopia is an uncommon lesion, detected

in 0.5% to 13% of autopsies, the majority of which are
seen in the stomach (30%) followed by the duodenum,
jejunum, and Meckel’s diverticulum. Less common sites
include the lungs, gallbladder, mediastinum, mesentery,
esophagus, bile ducts, and umbilical cord. It can affect
adult and pediatric patients, and the average age is 45
FIGURE 4.6
years with a slight male predominance. Most patients
Gastritis cystica profunda showing cystically dilated glands extending into the
submucosa. The overlying mucosa shows atrophic changes. (Courtesy of are not symptomatic, but abdominal pain, epigastric dis-
Richard Lash, MD, Caris Diagnostics, Irving) comfort, nausea, vomiting, and bleeding can develop.
Large prepyloric lesions may present with gastric outlet and can be divided into four types: type I, total hetero-
obstruction. Rarely, the heterotopic tissue may develop topia (all cell types, most common variant); type II,
pancreatitis, pancreatic cysts, neuroendocrine (islet cell) canalicular heterotopia (ducts only); type III, exocrine
tumor, or even ductal adenocarcinoma. heterotopia (acinar cells only); and type IV, endocrine
heterotopia (islets only, rare).
Because the usually submucosal location, superficial
biopsies may not be diagnostic. Thus, deeper biopsies or
Pathologic Features
endoscopic removal are important for a definite diagnosis.

Pancreatic Heterotopia—Pathologic Features
Pancreatic heterotopias present as usually solitary, 0.2- to
Gross Findings
5-cm nodules of the antrum or prepyloric area. Endoscopic
n Usually solitary, antral or prepyloric, dome-shaped polypoid
appearance consists of a smooth surfaced, hemispher- nodules
ical, intramural nodule with normal or eroded overlying n Covered by smooth normal or ulcerated mucosa with a central
mucosa and a central dimple that represents the draining umbilication
pancreatic duct. On cut section, the lesion is well demar- n Cut sections show a well-demarcated tan-yellow and often
cated, located in the submucosa or muscularis propria, yel- lobulated intramural mass, resembling normal pancreatic
parenchyma
lowish, and lobulated, resembling normal pancreas.
Microscopic Findings n The heterotopic tissue contains admixture of pancreatic acini,
ducts, and islets in varying proportions

The heterotopic pancreas (Fig. 4.7) may contain varying n Superficial biopsies may not be diagnostic because of the
proportions of acinar, ductal, and islet cell components submucosal location, thus necessitating deeper sampling
n Most cases are easily diagnosed based on the hematoxylin and
eosin stain
n Endocrine or islet cell stain with chromogranin A and
synaptophysin
n Pancreas exocrine markers mark the acinar cells
n Invasive well-differentiated adenocarcinoma
n Gastritis cystica profunda
n Neuroendocrine tumor
A
The submucosal location of the lesion brings about an
endoscopic differential of GI stromal tumors, lipomas,
and leiomyomas, which is easily resolved on histologic
examination. Invasive adenocarcinoma is an import-
ant microscopic differential diagnosis considering that
most pancreatic heterotopias arise in deep submucosa
or muscularis and can be misinterpreted, especially
during frozen sections. The key to the correct diag-
nosis is the lobulated arrangement of acinar and duct
structure (like in normal pancreas) and the lack of
malignant cytoarchitectural features and desmoplasia.
Gastritis cystica profunda occurs in stomal or anasto-
motic sites and consists of surface foveolar hyperplasia
with prominent features of mucosal prolapse, cystically
B dilated mucous glands located in the submucosa and
FIGURE 4.7
muscularis propria. The finding of acinar and islet
Heterotopic pancreatic tissue usually manifests as an intramural lesion (A)
tissue in pancreatic heterotopias is especially helpful
and is composed of pancreatic ducts and rare acini showing a lobulocentric in excluding this possibility. Pure endocrine hetero-
distribution interspersed among smooth muscle bundles (B). topia (the rarest among the pancreatic heterotopias)
may present a diagnostic challenge with neuroendo-

crine tumors (NETs). Endocrine heterotopias present
as microscopic nests scattered in the submucosa and
muscularis and are not associated with any stromal
response. NETs present as mass lesions with the tumor
cells arranged as trabeculae, tubules, and rosettes.
Pancreatic heterotopias are benign non-neoplastic

lesions, and reports of islet cell tumors or ductal ade-
nocarcinomas developing in the heterotopic tissue are
extremely rare. Symptomatic superficial lesions are
effectively treated by endoscopic resections. Deeper FIGURE 4.8
lesions may require wedge resection by laparoscopy. The typical endoscopic appearance of a gastric xanthoma. It usually consists
of a small, sessile yellowish nodule or plaque. (Courtesy of Shriram Jakate,
MD, Rush Medical College, Chicago.)
GASTRIC MUCOSAL XANTHOMA

Gastric xanthomas consist of loose collections of lip-
id-laden macrophages in the lamina propria. Gastric xanthomas consist of a loose cluster of lipid-laden
macrophages in the lamina propria. The macrophages
show abundant foamy cytoplasm containing cholesterol
and neutral fats with central bland nondescript nuclei
Clinical Features
(Figs. 4.9A and B). The surrounding gastric mucosa may
show chemical or bile reflux gastropathy, chronic gastritis
The stomach is a common site for these lesions, which with intestinal metaplasia, or Helicobacter gastritis.
also occur rarely in the esophagus, small intestine,
and colon. Gastric xanthomas present as sessile, sin-
gle, or multiple, 1- to 5-mm, yellowish-white mucosal
Ancillary Studies
nodules or plaques. They tend to be more common in
the antrum, especially the prepyloric area, lesser cur-
vature, and adjacent to gastric stoma. Adults in their Histochemistry and Immunohistochemistry
60 s are commonly affected with a three to one male
predominance. Notably, gastric xanthomas usually do Sudan Black and oil red O can demonstrate intracyto-
not show any relation to skin xanthelasmas or hyper- plasmic lipid, and CD68 (see Fig. 4.9B) stains the mac-
lipidemia but have been associated with bile reflux, rophages. Periodic acid–Schiff (PAS; see Fig. 4.9C),
and some studies have implied an underlying dyslip- mucicarmine, cytokeratins, and S-100 stains are all
idemia. Endoscopic studies have shown an incidence negative.
ranging from 0.3% to 7%. They can be seen in asso-
ciation with H. pylori gastritis, bile reflux, chemical Differential Diagnosis
gastropathy, gastric ulcers, after gastroenterostomies
(Billroth), chronic atrophic gastritis, and carcinomas. The differential diagnosis is broad and includes inflam-
The frequent association with various pathologies sug- matory and infiltrative disorders involving the lamina
gests that it represents a reparative response to a wide propria. Signet ring cell carcinoma contains cytoplasmic
array of mucosal injuries. mucin vacuoles, hyperchromatic eccentrically placed
atypical nuclei, and frequent mitoses and shows positive
staining with cytokeratins and mucin stains. Granular
cell tumor is composed of clusters of polygonal cells with
Pathologic Features
abundant eosinophilic granular cytoplasm, centrally
placed nuclei, that are positive for S-100 and CD68. Clear
Gross and Endoscopic Findings cell NETs can grossly resemble xanthomas, appearing
as yellow nodules. Positivity for chromogranin-A and
These are small, sessile, yellowish-white nodules or synaptophysin by immunohistochemistry are diagnos-
plaques, usually multiple, and 1 to 5 mm in size (Fig. 4.8). tic for NETs. Metastatic clear cell renal cell carcinoma
is a xanthogranulomatous reaction to gram-negative

bacterial infections such as Escherichia coli and can
rarely involve the stomach. Characteristic Michaelis-
Guttman bodies that stain with calcium stains such
as Von Kossa are diagnostic. Whipple disease can also
show foamy macrophages stuffed with bacillary forms
of Tropheryma whipplei and show positive staining with
PAS (intensely positive).
Benign lesions that may regress with time. If needed,

therapy is directed at the associated gastric pathology.
A
Gastric Xanthomas (Xanthelasmas)—Pathologic Features
Gross Findings
n Small, sessile, single or multiple yellowish white nodules
n 1 to 5 mm in size
n Lipid-laden macrophages in the lamina propria
n Macrophages contain foamy cytoplasm with centrally placed
bland nuclei
n No increase in mitoses
n Positive for Sudan black, oil red O, and CD68
B n Negative for mucicarmine, periodic acid–Schiff, cytokeratins, and
S-100
n Signet ring cell carcinoma
n Granular cell tumor
n Neuroendocrine tumor with clear cell phenotype
n Metastatic clear cell carcinoma (e.g., renal cell carcinoma)
n Epithelioid gastrointestinal stromal tumor
n Mycobacterium avium-intracellulare infection
n Malakoplakia
n Whipple disease
C GASTRIC CARCINOMAS, NEUROENDOCRINE

TUMORS, AND THEIR PRECURSOR LESIONS
FIGURE 4.9
Gastric xanthoma in a patient who had undergone Billroth surgery and Gastric carcinomas usually develop from precursor
presented with bile reflux gastropathy (A). Note the collection of foamy lesions, which can be broadly classified into gastric epi-
lipid-laden macrophages in the lamina propria. Special studies in gastric xan-
thelial dysplasia (GED) (flat [endoscopically invisible]
thoma with strongly positive CD68 in the gastric xanthoma cells (B), but the
result on periodic acid–Schiff stain is negative owing to the lipid content (C). lesions) and gastric adenoma (raised or polypoid visi-
ble lesions). The role of the endoscopist and patholo-
gist is to enable early detection, diagnosis, and complete
is positive for PAX8, CA-IX, and low-molecular-weight resection of precursor lesions to prevent the develop-
keratins. Mycobacterium avium-intracellulare infections ment of invasive carcinoma. Adenocarcinomas are the
occur in immunosuppressed patients (e.g., those with most common type of gastric malignancies, and these
AIDS) and are characterized by the accumulation of are divided into intestinal and diffuse subtypes in the
foamy macrophages containing abundant bacilli, which Lauren classification. Alternatively, the 2019 World
are intensely positive on an acid-fast stain. Malakoplakia Health Organization (WHO) classification subdivides
gastric carcinoma into tubular, papillary, mucinous, first endoscopy. Excluding cases that progress within the
poorly cohesive carcinoma, mixed adenocarcinoma, and first year of follow up, only approximately 5% of high-
other rare histologic subtypes. grade lesions transform into cancer within five years.
The diagnosis and grading of gastric epithelial neo-
plasms have historically differed between Japanese and
Western pathologists. A consensus approach led to the
GASTRIC DYSPLASIA AND ADENOMA—FACT SHEET
Vienna classification of GI epithelial neoplasia. This clas-
sification divided neoplastic lesions into the following Definition
categories: (1) negative for dysplasia, (2) indefinite for n Noninvasive neoplastic epithelial proliferation with variable risk of
dysplasia, (3) noninvasive low-grade dysplasia, (4) nonmalignant transformation into an invasive adenocarcinoma
invasive high-grade dysplasia (including carcinoma in
situ), and (5) invasive carcinoma (including both intra- Incidence and Location
mucosal carcinoma and submucosal invasive carcinoma). n Incidence varies (0.3%–20%) with geography; higher in
countries endemic for gastric cancer

n Associated with 40% to 100% of early gastric cancers and 5% to
80% of advanced carcinomas

GASTRIC EPITHELIAL DYSPLASIA AND n Antral location common; adenomas account for 7% to 10% of all
gastric polyps
GASTRIC ADENOMAS
Clinical Features n Half of all cases of low-grade gastric epithelial dysplasia (GED),
diagnosed by either biopsy or resection, may regress

n 3% of low-grade GED cases progress to carcinoma in 5 years in
It is widely recognized that GED and gastric adenomas contrast to 30% to 60% of high-grade GED cases
are precancerous lesions that can progress to gastric car-
cinoma. In contrast to GED, which is endoscopically Gender, Race, and Age
flat or invisible lesions, gastric adenomas are polypoid n Increasing incidence with age; more common in the Far East and
growths of dysplastic epithelium that project above Eastern Europe

the surrounding mucosa. GED is associated with 40%
to 100% of early gastric cancers and 5% to 80% of
Clinical Features
advanced carcinomas. In addition, approximately 60%
n GED is a flat, endoscopically invisible lesion incidentally picked up
of gastric cancers are discovered after a diagnosis of on a random biopsy
dysplasia. n Gastric adenomas are raised endoscopically visible lesions of
The incidence of GED or gastric adenoma increases variable size that can often be completely excised on endoscopy
with age and peaks after the seventh decade of life. n Variable risk of progression to adenocarcinoma (depending on
The male-to-female ratio is approximately 2 to 1. Most grade of lesion)

lesions are found incidentally at the time of endoscopy,
primarily in the antrum. Whereas Western populations
n Systematic biopsies to rule out concurrent carcinoma in patients
demonstrate a low prevalence of GED (0.7%–3.7%), it with GED
can be as high as 20% in high-risk areas such as Japan n Complete resection of gastric adenomas by endoscopy after
and Eastern Europe. A common cause is H. pylori gas- excluding the possibility of underlying invasive carcinoma on
tritis, and other risk factors for the development of GED endoscopic ultrasound
n Large lesions and those associated with deep submucosal
include autoimmune gastritis and polyposis syndromes.
invasion or evidence of locoregional spread on imaging are
Gastric adenomas follow fundic gland and hyperplas- treated with surgical resection
tic polyps in overall incidence, accounting for approxi-
mately 7% to 10% of gastric polyps in North America.
Half of all cases of low-grade GED, diagnosed by
either biopsy or resection, may regress. This observa-
tion raises the possibility that many lesions diagnosed as Gastric Dysplasia and Adenomas—Pathologic Features
low-grade dysplasia may instead be misdiagnosed atyp-
ical reactive lesions. In fact, only approximately 3% of Gross Findings
patients with low-grade GED (in a Western population) n Most common in the antrum
progress to adenocarcinoma within 5 years. Conversely, n Range in size from a few millimeters to several centimeters
n Gastric epithelial dysplasia: endoscopically poorly

about 30% to 60% of those with high-grade dysplasia
recognizable, mucosal irregularity, and erythematous changes
progress to adenocarcinoma. However, more than 80% can be seen
to 90% of high-grade dysplasia transform into adeno- n Gastric adenoma: pedunculated or sessile polypoid lesion;
carcinoma within the first year of follow-up, suggesting cannot be reliably distinguished from benign polyps by
that these are cases of prevalent invasive adenocarcino- endoscopy
mas that were missed because of undersampling at the
n Divided into intestinal type and gastric (foveolar) type
n Intestinal type defined by presence of goblet cells or Paneth cells;
mostly tubular, less frequently tubulovillous or villous architecture;

pseudostratified columnar epithelium with overlapping, elongated,
pencil-shaped nuclei
n Gastric-type composed of foveolar epithelial cells with apical
mucin cap; small round to oval, basally oriented nuclei, without

marked stratification
n High-grade dysplasia associated with back-to-back glands with
loss of intervening stroma, complex (e.g., cribriform) architecture,

and complete loss of nuclear polarity
n Background mucosa often shows chronic atrophic gastritis and
intestinal metaplasia
Genetics
n Associated with genetic alterations of APC, KRAS, TP53, and
FIGURE 4.10
microsatellite instability
Low-grade intestinal type dysplasia with nuclear enlargement and elongation,
n TP53-mutated gastric dysplasia may represent a subtype with an
nuclear crowding, and pseudostratification. Overall, the architecture is only
increased risk for progression into adenocarcinoma moderately distorted.
n Gastric adenoma indistinguishable endoscopically from other
gastric polyps
n Gastric adenoma and gastric epithelial dysplasia need to be
distinguished microscopically from reactive epithelial changes and

intramucosal adenocarcinoma
Pathologic Features
Gross Findings
Gastric dysplastic lesions occur throughout the stom-

ach with the antrum being the most common location.
GEDs are endoscopically flat or invisible lesions, also
referred to as flat dysplasia. These lesions are often
grossly unremarkable or virtually invisible by stan- FIGURE 4.11
dard endoscopy, although sometimes they may appear Low-power view of a foveolar-type adenoma with high grade-dysplasia.
as irregular, erythematous patches. Gastric adenomas

are localized polypoid growths of dysplastic epithelium
that by definition project above the surrounding gastric pattern. Tubulovillous or villous architecture is less
mucosa. They range in size from a few millimeters to frequent. The pseudostratified columnar epithelium
several centimeters and may be sessile or pedunculated. shows overlapping, elongated, and pencil-shaped nuclei.
Foveolar-type dysplasia is composed of gastric foveo-
lar epithelial cells containing neutral mucin forming
an apical mucin cap (Fig. 4.11). The epithelial lining is
characteristically nonstratified, with basally oriented,
round to oval, small nuclei. Both foveolar and intestinal
Gastric dysplastic lesions are divided histologically into types of gastric dysplasia show epithelial and nuclear
intestinal and foveolar types based on the type of glandu- changes ranging from low to high grade. Whether the
lar epithelium. Intestinal-type adenomas are more prev- foveolar or intestinal type has a higher likelihood to har-
alent than the gastric foveolar-type adenoma and often bor high-grade dysplasia or adenocarcinoma remains
arise in a background of intestinalized and atrophic controversial.
gastric mucosa. Intestinal-type lesions resemble conven- Low-grade dysplastic epithelial changes include mild
tional colonic adenoma and are defined by the presence to moderate architectural irregularity with mild nuclear
of cells specific to intestinal differentiation as absorp- enlargement, hyperchromasia, pleomorphism, and
tive cells with brush border, goblet cells, or Paneth cells increased mitotic activity. In high-grade dysplasia, the
(Fig. 4.10). Mostly, these cells form a tubular growth architecture becomes increasingly complex and crowded
with irregular branching, budding, a loss of interven- reactive epithelial change. Of note, in a single study of
ing stroma, and back-to-back and cribriform archi- epithelial dysplasia of the stomach, half of the cases con-
tecture. Intraluminal necrotic material may be seen. sidered to be dysplastic by general surgical pathologists
Cytologically, the nuclei show more severe atypia with were diagnosed as non-neoplastic by GI pathologists.
enlarged, hyperchromatic, vesicular nuclei and prom- Thus, when a definitive diagnosis of dysplasia cannot be
inent nucleoli. There is also complete loss of nuclear rendered, the use of the term indefinite for dysplasia is
polarity with the nuclei reaching the luminal surface of encouraged. As in other organs, interobserver variation
the epithelium and showing a rounded form. When an is diminished as the severity of the lesions increases. In
early infiltrating carcinoma confined to the lamina pro- differentiating low-grade dysplasia from reactive changes,
pria is identified within GED (i.e., laterally fusing gland it is important to note both the cytologic and architectural
manifesting in a lacy or overtly cribriform pattern), it is features of these lesions. In reactive changes, the cells
termed intramucosal adenocarcinoma (Fig. 4.12). are frequently cuboidal and appear immature with baso-
philic cytoplasm secondary to reduced mucus secretion.
Molecular Studies The regenerative nuclei are often large, vesicular, and at
times pleomorphic with smooth nuclear contours and red
Gastric dysplasias may harbor molecular alterations in conspicuous nucleoli. Architecturally, normal epithelial
the APC, KRAS, ERBB3, and TP53 genes and can also architecture is retained in reactive proliferations with
show mismatch repair (MMR) gene inactivation similar basally localized nuclei and only mild pseudostratification
to that described for colon cancer. However, although (Fig. 4.13). Mitotic figures, when present, are confined to
the colon demonstrates a well-characterized adenoma– the basal aspects of the glands. Finally, the transition of
carcinoma sequence of molecular genetic events, the pro- the epithelium from the basal portion of the glands to the
gression pathway is not fully elucidated in the stomach. luminal surface shows surface maturation, which is help-
For example, alterations in the APC gene are frequently ful in diagnosis of reactive change. The presence of active
seen in gastric adenomas but rarely in gastric adeno- inflammation or granulation tissue-like stroma is in favor
carcinomas. Instead, multiple studies have published of regenerative atypia, and one should be wary of diag-
data suggesting that the presence of APC mutation in nosing neoplasia in this setting unless the changes are
gastric dysplasia may be the sign of an indolent lesion prominent enough or not proportionate to the degree of
that infrequently progresses into adenocarcinoma, and inflammation. Conversely, abrupt transition of the atyp-
dysplasia with TP53 alterations could be a subtype more ical into evidently non-neoplastic epithelium is a sign of
prone for malignant transformation. neoplasia, although the border of metaplastic and native
epithelium can also show this phenomenon.
Endoscopically, all polyp types can enter into the differ-
ential diagnosis of gastric adenoma. Histologically, they Although it is frequently quoted that 50% of low-
should also be differentiated from dysplastic foci develop- grade GED regress, it is likely that some of these in fact
ing in other polyps (e.g., hyperplastic polyps or FAP asso- represent misdiagnosed reactive or regenerative epi-
ciated FGPs). The main differential diagnosis of GED is thelial change. Nevertheless, the importance of early
FIGURE 4.13
FIGURE 4.12 Reactive epithelial changes simulating epithelial dysplasia. The reactive changes
Example of intramucosal carcinoma. The neoplasm is characterized by include nuclear hyperchromasia and enlargement. Nuclear pseudostratification,
syncytial growth pattern with fused glands and single cells in lamina propria. crowding, and elongation are lacking.
detection is emphasized by the fact that more than also described. They have a mean size of about 2 cm
half of gastric cancers are discovered after a diagno- and are most often located in the gastric body. Whereas
sis of dysplasia. Among all low-grade dysplasia, 20% in the nonpolypoid mucosa, atrophic corpus gastritis
to 30% of cases persist without progression, and an can be recognized in patients with autoimmune gastri-
additional 3% of cases progress to carcinoma within tis, multiple FGPs can be noted studding the oxyntic
a 5-year period. A meta-analysis showed that a biopsy mucosa in patients with FAP.
diagnosis of low-grade gastric dysplasia was upgraded
after endoscopic resection to high-grade dysplasia or Microscopic Findings
cancer in 17% and 7% of the cases, respectively. In a
large population-based study, 30% of high-grade dys- Pyloric gland adenoma includes tubular glands com-
plasia progressed to infiltrating carcinoma during a 5 posed of cuboidal or columnar cells (Figs. 4.14A–C).
year follow-up, including cases “transforming” in the The cytoplasm is ground glass and either eosinophilic
first year. However, two similar studies have found that or amphophilic. In contrast to foveolar adenomas,
only about 5% of high-grade lesions progress on follow pyloric gland adenomas do not have a mucin cap. Most
up when cases detected within the first year of sur- examples show low-grade dysplasia with cells that
veillance are excluded. Recent guidelines for the man- are typically cytologically bland: cytoplasm is abun-
agement of gastric dysplasia published by the British dant, and nuclei are basally located and relatively uni-
Society of Gastroenterology recommend en bloc endo- form. In high-grade lesions, the architecture becomes
scopic resection of visible gastric dysplasia and early more complex and crowded with pseudostratified,
cancer. The same guidelines recommend that patients hyperchromatic, and markedly pleomorphic nuclei
with nonvisible dysplasia should undergo a second and prominent nucleoli with loss of nuclear polarity
endoscopy and extensive biopsy sampling. If persistent (Fig. 4.14D). The background mucosa may show vari-
nonvisible low-grade dysplasia is detected, endoscopy able degree of gastritis, which is most frequently auto-
should be repeated annually thereafter. In patients immune in origin (33.9%). Association with H. pylori
with nonvisible, high-grade dysplasia, 6-month inter- (41.5%) gastritis or chemical gastropathy (20.8%) has
val surveillance endoscopies are advised. also been reported.
Immunohistochemical studies have demonstrated
that pyloric gland adenomas typically show diffuse
MUC6 expression and variable MUC5AC positiv-
PYLORIC GLAND ADENOMA
ity, the latter either limited to the surface or inter-
mixed. This pattern of expression is in contrast to
Clinical Features
gastric foveolar–type gastric adenomas, which pre-
dominantly express MUC5AC and limited MUC6
Pyloric gland adenomas represent an uncommon neo- staining.
plastic polyp. They usually arise in patients with auto-
immune gastritis but are also detected in the setting Differential Diagnosis
of FAP, Lynch syndrome, and juvenile polyposis syn-
drome. A retrospective study, excluding FGPs, observed The main differential diagnoses for pyloric gland ade-
that pyloric gland adenomas represented up to 2.7% of nomas include gastric foveolar and intestinal-type
all gastric polyps. Pyloric gland adenomas were asso- adenomas and OGA. Pyloric gland adenomas are
ciated with adenocarcinoma in one-third of the cases difficult to distinguish from low-grade foveolar ade-
in one series. There is a female predominance (52%), nomas because pale cytoplasm and bland cytologic
and the mean age at diagnosis is in the seventh decade. appearance is present in both lesions. Histologic fea-
The genetics of pyloric gland adenoma has recently tures in favor of pyloric gland adenoma are the pale,
been described. Activating GNAS mutations are found ground-glass quality of the entire cytoplasm versus
in about 50% of cases and are often associated with a well-formed apical mucin cap, the lack of neutral
KRAS mutations. mucin on PAS stain, and the presence of MUC6
expression. OGA can be excluded on the basis of
parietal and chief cell differentiation that is diagnos-
tic of this lesion.
Pathologic Features

Gross Findings
Complete excision and careful evaluation of the lesion
Gastric pyloric gland adenomas are polypoid lesions, and the surrounding nonlesional mucosa are needed
although recently an inverted gross presentation was because of the association with adenocarcinoma.
A C
B D
FIGURE 4.14
Pyloric gland adenoma composed of tightly packed glands lined by composed columnar cells with amphophilic cytoplasm (A). Note the lack of apical mucin
cap using periodic acid–Schiff stain (B). MUC6 immunohistochemistry may help in supporting the diagnosis (C). A subset of cases may be associated with
high-grade dysplasia (D) or carcinoma.
PYLORIC GLAND ADENOMA—FACT SHEET n Helicobacter pylori gastritis and chemical gastropathy may be
present in background mucosa
n No abnormality is detected in background mucosa in a subset of
Definition
cases
n Neoplastic epithelial proliferation that shows pyloric gland type
differentiation Prognosis and Therapy
n Complete resection after excluding possibility of underlying
invasive carcinoma on endoscopic ultrasound in larger lesions
n Uncommon lesions; 2.7% of all gastric polyps (excluding fundic
n Proper evaluation of background mucosa to determine risk of
gland polyps) metachronous lesions and need for surveillance
n Most often located in the gastric corpus

n Most cases show low-grade dysplasia
n One-third may be associated with adenocarcinoma (usually large Pyloric Gland Adenoma—Pathologic Features
lesions)
Gross Features
n Predominantly in the body and fundus
n Cannot be reliably distinguished from benign gastric polyps
n Typically present in seventh decade of life
endoscopically
Clinical Features Microscopic Features

n Common associations include autoimmune gastritis, familial
n Background mucosa often with autoimmune gastritis (atrophy
adenomatous polyposis, Lynch syndrome, and juvenile polyposis and intestinal metaplasia)
n Amphophilic to eosinophilic cytoplasm with a ground-glass quality

n Low-grade dysplasia with well-organized glands of bland,
nonpleomorphic, basally located nuclei
n High-grade dysplasia with crowding of glands, cribriform glands,
nuclear stratification, cytologic atypia, and loss of nuclear polarity
Genetics
n Activating GNAS mutations, often associated with KRAS mutations
n Gastric foveolar or intestinal-type adenoma
n Oxyntic gland adenoma
n Hyperplastic polyp
OXYNTIC GLAND ADENOMA

FIGURE 4.15
Oxyntic gland adenoma displaying irregularly anastomosing tubules and
Clinical Features glands lined by bland chief and parietal cells.
Oxyntic gland adenomas are rare lesions that develop

exclusively in the oxyntic mucosa and are composed
primarily of chief cells with variable numbers of pari- Ancillary studies
etal and mucous neck cells. OGAs form the benign end
of the oxyntic gland neoplasia spectrum with gastric Gastric immunophenotypic markers MUC5AC and
adenocarcinomas of fundic gland type representing the MUC6 are usually positive. Pepsinogen-I and H+/
malignant counterpart. K+-ATPase immunohistochemistry may be used to
highlight chief cells and parietal cells, respectively.
Pathologic Features Molecular Studies
Similar to pyloric adenoma, activating GNAS muta-

Gross Findings tions associated with KRAS mutations are recognized
in these polyps.
The polyps range in size from 4 to 20 mm, with an equal
gender distribution and an average age at presentation Differential Diagnosis
of 65 years. The lesions are located in the gastric body or
fundus and can either be depressed or elevated. Pyloric gland adenoma represents the main differential
diagnosis. Helpful histologic features are the cytoplas-
mic basophilia of chief cells and the identification of
plump, intensely eosinophilic parietal cells with central
bland nuclei.
Oxyntic gland adenomas are composed of chief cells, pari- Prognosis and Therapy
etal cells, and mucous neck cells that line closely packed
tubules and anastomosing cords that can mimic a NET Assessing the presence of submucosal invasion and pre-
(Fig. 4.15). Most frequently, OGAs show a chief cell predicting the biological behavior of oxyntic gland neoplasms
dominant pattern, but a balanced admixture of chief can be difficult. Only limited data are available on the
and parietal cells resembling normal fundic glands and a follow-up of these lesions. However, in the largest series
mucous neck cell–dominated form have also been recog- available to date, no evidence of recurrence or metasta-
nized. Nuclear atypia, increased mitotic activity, necrosis, sis was documented. OGAs limited to the mucosa pur-
desmoplasia, perineural, and lymphovascular invasion are sue a benign course and can be managed by endoscopic
typically absent. The tumor can show “pseudoinvasion,” resection. Lesions with atypical cytoarchitectural features
but rare cases of true deep submucosal invasion and lymph and submucosal invasion have a low malignant potential,
node metastasis have also been reported. The surrounding rarely with lymphovascular invasion, and can be diag-
nonlesional oxyntic gastric mucosa is usually normal. nosed as “adenocarcinoma of fundic gland mucosa type.”
Gastric Cancer Risk Factors

Oxyntic Gland Adenoma—Pathologic Features
Several environmental risk factors have been associated
Gross Features with the development of gastric cancer. Whereas diets
n Exclusively in the body and fundus rich in nitrites, nitrates, salt, smoked foods, and com-
n May be elevated or depressed lesions; variable size
plex carbohydrates are linked to increased gastric can-
cer risks, consumption of fresh fruits and vegetables is
associated with reduced cancer risks. Cigarette smoking
n Closely packed tubules and cords that can mimic a
neuroendocrine tumor is also associated with a two- to threefold increased risk

n Lining epithelium composed predominantly of chief cells with of gastric cancer.
variable number of parietal cells and mucous cells Gastric carcinoma has a weak association with
n Nuclear atypia is minimal
chronic atrophic gastritis and intestinal metaplasia.
n A minor subset of cases may show submucosal invasion, and
Several studies have shown an association between
lymphovascular invasion is reported in extremely rare cases
(“adenocarcinoma of fundic gland mucosa type”) incomplete type of intestinal metaplasia and increased
risk of gastric carcinoma; however, screening for the
Genetics presence of this subtype is not a reliable tool in the
n Activating GNAS mutations, often associated with KRAS absence of endoscopic mapping to determine the extent
mutations, similar to pyloric gland adenomas of metaplasia. Gastric carcinomas of the intestinal type
have a greater association with intestinal metaplasia
than do the poorly cohesive (i.e., diffuse) type.
n Pyloric gland adenoma
H. pylori infection is now a well-established cause of
both intestinal and poorly cohesive (i.e., diffuse) types of
gastric carcinomas. The risk of gastric cancer is signifi-
GASTRIC ADENOCARCINOMA cantly increased if the H. pylori infection is acquired in
childhood or is present for longer than 10 years. The rela-
tive risk of developing gastric adenocarcinoma because of
Clinical Features
chronic infection with H. pylori has been reported to be
5.9 times higher. Furthermore, H. pylori eradication at the
Gastric cancer is the fifth most common cancer world- time of localized gastric cancer resection decreases recur-
wide and is a leading cause of cancer-related deaths. rence and the future risk of metachronous gastric cancer.
Overall, gastric cancer rates are higher in lower socioeco- H. pylori is a heterogeneous group of strains with var-
nomic groups. The incidence of gastric cancer also shows ious factors associated with colonization and pathogenic-
geographical differences, with the lowest rates found in ity. Strains that produce the CagA protein induce a greater
North America, Northern Europe, and Africa and the degree of inflammation and are associated with a higher
highest rates found in Korea, Japan, Costa Rica, East Asia, risk of cancer. In the West, H. pylori strains expressing
and Eastern Europe. Gastric cancer peaks in the seventh the vacA s1, m1, i1, or d1 genotypes have also been vari-
decade of life and affects men twice as often as women. ably associated with an increased risk of gastric cancer.
Over the past decades, the rate of gastric cancer has been Finally, the host response to H. pylori specific to the
declining in older patients; however, the number of early population infected is also important, as demonstrated
onset carcinomas is increasing in North America. by differing individual susceptibilities to gastric atro-
There is also a difference between the epidemiologic phy and carcinoma. Proinflammatory polymorphisms
trends of proximal and distal gastric cancers. Whereas of the interleukin (IL)-1β gene (initiating and amplify-
the incidence of cancers arising from the gastroesoph- ing the inflammatory response) and the IL-1 receptor
ageal junction (GEJ) and the gastric cardia have been antagonist gene (an inflammatory cytokine that com-
increasing, the number of distal carcinomas has been petitively binds to IL-1 receptors and modulates the
declining. These trends suggest that proximal gastric potentially damaging effects of IL-1) are associated with
cancers may have a distinct pathogenesis and may be individual or familial susceptibility to H. pylori–related
more closely related to esophageal adenocarcinomas. carcinogenesis.
Because of this, the eighth edition of the tumor, node, Other factors that increase the risk of gastric can-
metastasis (TNM) staging uses the following modifica- cer include a history of prior gastrectomy, autoimmune
tion from prior editions: “Cancers involving the GEJ gastritis, obesity, and Ménétrier’s disease. Although the
that have their epicenter within the proximal 2 cm of the vast majority of gastric cancers occur sporadically, syn-
cardia are to be staged as esophageal cancers. Cancers dromic associations are also well recognized. Patients
whose epicenter is more than 2 cm distal from the GEJ, with FAP, gastric adenocarcinoma and proximal polypo-
even if the GEJ is involved, will be staged using the sis of the stomach, MAP, Lynch syndrome, Peutz-Jeghers
stomach cancer TNM and stage groupings.” syndrome, juvenile polyposis syndrome, Li-Fraumeni
syndrome, and BRCA2 mutations all have increased risk

of developing gastric cancer. In addition, CDH1 muta-
tions affecting the adhesion molecule E-cadherin have
been associated with autosomal dominant hereditary
diffuse gastric cancer (HDGC).
Pathologic Features
Gross Findings
A
The majority of gastric carcinomas are located in the

pylorus and antrum (50%–60%) followed by the cardia
(25%) and the body or fundus (15%–25%). Advanced
cancers of the intestinal type commonly appear as pol-
ypoid, fungating masses with surface ulceration. In
contrast, poorly cohesive (diffuse-type) cancers usually
appear as deep infiltrating or depressed cancers with no
obvious mass present in the mucosa. Linitis plastica is
a rare lesion in which the majority of the stomach wall
is infiltrated by diffuse-type cancer, conferring a thick,
firm, leathery appearance to the stomach. B
Early gastric cancers are defined as those confined
to the mucosa or submucosa regardless of lymph node
status and are often incidental findings. The Japanese
Gastroenterological Endoscopic Society devised an
endoscopic classification for early gastric cancers, which
aids in the detection of early subtle cancers. This scheme
has a good correlation with the microscopic phenotype
and was later adopted in the Paris classification of GI
superficial neoplastic lesions. Most polypoid lesions
have a tubular phenotype, but flat and ulcerated lesions
are more commonly poorly cohesive.
The overwhelming majority (95%) of malignant gas- C

tric cancers are adenocarcinomas. The 2019 WHO
classification subdivides gastric carcinoma into the
following subtypes: tubular; papillary; mucinous
(Fig. 4.16); poorly cohesive carcinoma, including sig-
net ring cell carcinoma and other subsets (Fig. 4.17);
mixed adenocarcinoma; and other rare histologic sub-
types (including gastric adenocarcinoma with lym-
phoid stroma [Fig. 4.18] hepatoid and micropapillary
adenocarcinoma, and gastric adenocarcinoma of fun-
dic-gland type; Table 4.1). The historic Lauren scheme
separates gastric adenocarcinomas into intestinal and
diffuse subtypes. The intestinal type generally corre-
sponds to the tubular, papillary, and mucinous WHO
categories and resembles colorectal adenocarcinoma. It D
is characterized by well-formed glands lined by colum- FIGURE 4.16
nar epithelium, often with a luminal brush border. In Gross appearances of gastric carcinoma. A, Intestinal-type adenocarcinoma with
some cases, interspersed neuroendocrine cells can be a large, exophytic, polypoid mass. B, Linitis plastica with markedly thickened, firm,
detected. Intraluminal mucin is often present, but intra- and fibrotic gastric wall without a discrete mass. C, Early gastric cancer with a small
area of mucosal ulceration. D, On microscopy, intestinal type tumors are mostly
cytoplasmic mucin droplets are restricted to goblet cells. tubular adenocarcinomas characteristically composed of neoplastic tubules with an
Diffuse-type adenocarcinoma corresponds to the poorly infiltrative growth pattern and show variable grade of differentiation.
A A
B
FIGURE 4.17
B
Poorly cohesive carcinomas. The neoplasm is composed of single cells and
cells forming small aggregates some with various cytologic features. These FIGURE 4.18
tumors may show a signet ring cell morphology (A) or a small cell undif-
ferentiated phenotype with scant cytoplasm (B). Metastatic breast cancer Example of gastric carcinoma with lymphoid stroma characterized by irregu-
should be excluded before rendering a diagnosis of diffuse-type gastric can- lar sheets of epithelial cells embedded within a dense lymphocytic infiltrate
cer in these cases. (A). EBER ISH in situ hybridization confirms the diagnosis (B).
cohesive WHO category and is composed of individual of both intestinal and diffuse types; these are classified
cells or poorly formed nests growing in an infiltrative as mixed types. It is important to note that the terms
pattern. The amount of intracytoplasmic mucin pres- intestinal and diffuse are not synonymous with well- and
ent in these cells is highly variable. Sometimes these poorly differentiated carcinomas.
cells have abundant intracytoplasmic mucin pushing Gastric carcinoma with lymphoid stroma usually
the nucleus to the periphery, leading to a signet ring develops in the proximal stomach or in the gastric stump
appearance, hence the term poorly cohesive carcinoma– after partial gastrectomy. Typically, these tumors pres-
signet ring cell type. In other cases, including histio- ent a well-demarcated pushing margin and are composed
cytic, plasmacytoid, and pleiomorphic variants, mucin of irregular sheets, trabeculae, and ill-defined tubules,
may be inconspicuous. Such tumors are designated as resulting in a lace-like pattern embedded in a dense
poorly cohesive carcinoma not otherwise specified. lymphocytic infiltrate that may mimic a lymphoma (see
One rare presentation of diffuse-type gastric adeno- Fig. 4.18). Epstein-Barr virus (EBV) can be detected in
carcinoma occurs in the setting of hereditarty diffuse 22% to 100% of these tumors; furthermore, the infec-
gastric cancer (HDGC). In one-third of these families, tion likely occurs early because EBV can also be found
a germline E-cadherin mutation can be detected. These in adjacent dysplasia. Two other histologic variants of
patients may present with invasive carcinoma during EBV-associated gastric cancers have been recognized:
their teenage years. Although this presentation is rare, tubular carcinomas with prominent lymphoid follicles
examination of the histologic precursors of this hered- (i.e., “carcinoma with Crohn’s disease-like lymphoid
itary carcinoma is instructive for reviewing the vari- reaction”) and conventional-type adenocarcinomas
ous morphologic variants of signet ring cell carcinomas with scant lymphocytic infiltrate. Global CpG island
(Fig. 4.19). Some gastric adenocarcinomas show features hypermethylation with epigenetic silencing of tumor
TABLE 4.1
Examples of Rare Variants of Gastric Adenocarcinomas and Their Characteristics
Type Histology Other Characteristics
Hepatoid or AFP- • Hepatoid adenocarcinoma with large • AFP can be detected immunohistochemistry and in
producing polygonal eosinophilic cells the serum
adenocarcinoma • Well-differentiated tubular-papillary lesions • Bile and PAS(+) and diastase-resistant
with clear cytoplasm intracytoplasmic eosinophilic globules can be
• Yolk-sac tumor-like carcinoma detected in the hepatoid cells
Adenosquamous • Squamous component >25% of the tumor • Usually diagnosed at an advanced stage
carcinoma
Squamous cell • Carcinoma with uniform squamous cell • Usually diagnosed at an advanced stage
carcinoma differentiation and sometimes keratin pearls
AFP, Alpha-fetoprotein; PAS, period acid–Schiff.
A B
C D
FIGURE 4.19
In situ signet ring cells (A) in a prophylactic gastrectomy in a patient with hereditary diffuse gastric cancer syndrome that also showed foci of superficial invasion
into the lamina propria (B). Subtle replacement of a gland with neoplastic cells (C) with higher magnification of the tumor cells (D).
suppressor genes is a unique feature of this variant Ancillary Studies

and is considered to be crucial for its carcinogenesis.
Another subset of gastric carcinoma with lymphoid Gastric adenocarcinomas are cytokeratin, epithelial
stroma has been associated with microsatellite insta- membrane antigen (EMA), and carcinoembryonic anti-
bility and MMR protein deficiency but shows a distinct gen positive. CK7/CK20 profiles vary considerably with
transcriptomic profile. The prognosis of these carcino- the majority being CK7 positive and CK20 negative. The
mas is better than that of typical adenocarcinomas. testing for HER2 as a predictive biomarker of anti-HER2
therapy for unresectable and metastatic gastric cancer is cells of damaged and detached foveolar epithelium can
well established. Primary testing by immunohistochem- mimic signet ring cells. It may also mimic lymphoma
istry should be followed by in situ hybridization (ISH) because of its diffuse growth pattern and round, plas-
in equivocal cases. macytoid cell outlines. Therefore, pathologists should
Given the superior prognosis, a diagnosis of gastric always be alert when evaluating gastric biopsies and keep
carcinoma with lymphoid stroma should prompt testing this possibility in mind. Stains for cytokeratin, EMA,
for the presence of EBV by EBER ISH and MMR pro- and mucin can highlight the discohesive and infiltrat-
tein deficiency by immunohistochemistry. Although not ing neoplastic cells and help in diagnosis in some cases.
recommended by the WHO, immunophenotyping using Other cancers with discohesive cells may spread to the
p53, MMR proteins, E-cadherin, and EBER ISH can be stomach and mimic primary poorly cohesive carcinoma.
used as a surrogate technique to determine the recently The most common one is invasive lobular carcinoma of
reported molecular subtypes of gastric cancer and may the breast. Therefore, one should always consider the
have clinical relevance in the future. possibility of a metastasis and have a low threshold to
order immunohistochemical work-up to avoid this diag-
Molecular Pathology nostic pitfall, especially in female patients with normal
background mucosa.
Gastric adenocarcinomas also show marked heterogene-
ity at the molecular level.
The Cancer Genome Atlas performed a comprehen-
sive analysis and identified four major molecular sub-
types of gastric cancer:
Gastric adenocarcinoma has an overall poor prognosis
1. Genetically stable gastric cancers, which represent with 5-year survival rates of 10% to 30%. The best
about 20% of the cases. These tumors are usually predictor of prognosis is the pathologic stage, which
aneuploid and diagnosed at an earlier age. CDH1 includes the depth of invasion, the extent of nodal
somatic mutations are present in about 37% of the involvement, and the presence or absence of distant
cases. Inactivating mutations of ARID1A are also metastasis. Poor prognostic indicators include older
noted within this group, and mutations of RHOA are age, proximal tumor location, and venous or lymphatic
common as well. invasion. Surgical resection remains the standard of
2. Chromosomally unstable gastric cancers, which care, but patients with proximal cardia tumors with
represent about 50% of all gastric cancers. A large GEJ involvement are often treated with neoadjuvant
proportion (70%) of these cancers harbor TP53 therapy. More than 50% of patients present with
mutations. unresectable metastatic or locally advanced disease.
3. Microsatellite unstable gastric cancers represent about In these cases, palliative treatments include palliative
20% of the cases and are characterized by hypermeth- surgery, radiation, or endoscopic procedures to allevi-
ylation, including of the MLH1 promoter region, and ate obstruction. Testing for HER2 overexpression or
high rates of mutation in KRAS, ALK, ARID1A, and amplification is well established in routine practice
the PI3K-PTEN-mTOR pathway. These cancers tend now. Immunotherapy may be indicated in cases with
to occur in women of older age, arise in the antrum, PDL1 expression or deficient staining for MMR pro-
and have an intestinal phenotype. teins on immunohistochemistry.
4. Gastric cancers with EBV infection, which consti-
tute about 10% of gastric cancers and tend to affect
males. These lesions have a lower frequency of GASTRIC ADENOCARCINOMA—FACT SHEET
lymph node metastasis and a lower mortality rate.
EBV-positive tumors also show a high CpG island Definition
n Malignant gastric epithelial neoplasm with wide array of
methylator phenotype. Characteristics of these
morphological patterns and varying grades of histologic
tumors include CDKN2A promoter hypermethyla-
differentiation
tion and nonsilent mutations of PIK3CA in 80% of
the cases. Incidence and Location
n Fifth most common cancer worldwide
n Higher incidence in parts of the world endemic for

Helicobacter pylori
n Incidence of distal gastric cancer declining; proximal gastric cancer
Because of the frequently bland cytological features,
and diffuse-type gastric cancer incidence is increasing in the
poorly cohesive carcinoma can often be mistaken for a United States
variety of benign processes, including lymphoid infil- n Antrum or pylorus is commonest location followed by cardia and
trate in chronic gastritis, foamy macrophages, or reactive gastric body
endothelial cells seen in granulation tissue. Furthermore,
Morbidity and Mortality Immunohistochemical Findings

n Good prognosis for early gastric cancer confined to mucosa and n Variable CK7/CK20 profile (most common CK7+/CK20-)
submucosa n Carcinoembryonic antigen positive
n Advanced-stage tumors have a poor outcome (5-year survival
rate is only 10%–30%) Differential Diagnosis

n Lymphoma (for diffuse type)
Gender, Race, and Age n Metastatic carcinoma (especially invasive lobular carcinomas of
n Men affected twice as often as women; peak incidence in the the breast)
seventh decade of life n Gastritis cystica polyposa
n High incidence in Far East and Eastern Europe
Clinical Features
n Can be sporadic or syndromic (e.g., germline CDH1 mutation)
n Increased risk in patients with H. pylori gastritis and autoimmune
gastritis, which is related to mucosal atrophy and intestinal TABLE 4.2

metaplasia
n Abdominal pain or discomfort and unintentional weight loss are Gastric Cancer–Predisposing Polyposis and
common presenting symptoms Nonpolyposis Syndromes with Characteristic
n Lesions may be polypoid, flat, or depressed on endoscopic or Molecular Features
gross examination
Gastric Cancer
Prognosis and Therapy Syndrome Genes Risk (%)
n Complete resection after excluding possibility of underlying Hereditary diffuse CDH1 56–70
invasive carcinoma on endoscopic ultrasound in larger lesions gastric cancer
n Proper evaluation of background mucosa to determine risk of syndrome
metachronous lesions and need for surveillance Gastric adenocarcinoma APC Not determined
and proximal polyposis (promoter
syndrome 1B)
Lynch syndrome MLH1, MSH2, 2–30
MSH6, PMS2
Gastric Adenocarcinoma—Pathologic Features Peutz-Jeghers syndrome STK11 29
Juvenile polyposis SMAD4, 21
Gross Features BMPR1A
n May be exophytic, flat, or ulcerated
Hereditary breast BRCA1, 5.5, 2.6
n Linitis plastica corresponds to broad area of gastric wall
and ovarian cancer BRCA2
thickening, typically in diffuse-type gastric cancer syndrome
Li-Fraumeni syndrome TP53 3.1–4.9
Familial adenomatous APC 2.1–4.2
polyposis
n Classified as intestinal type or diffuse type (Lauren classification)
MUTYH-associated MUTYH (MYH) Very low
n Intestinal type: well-formed glands lined by columnar to cuboidal
polyposis
epithelial cells
n Diffuse type: individual or poorly formed nests of cells growing in Modified from Setia N, Clark JW, Duda DG, et al. Familial gastric cancers.
an infiltrative pattern Oncologist. 2015;20:1365–1377.
n Diffuse type (poorly cohesive type in World Health Organization
classification) may show signet ring cells, plasmacytoid or

histiocytoid cells and mimic lymphoma
n Intestinal-type tumors are often associated with Helicobacter
pylori or autoimmune gastritis in the background mucosa Syndromic Gastric Cancers

n Metastatic breast (lobular) carcinoma can mimic diffuse-type
gastric cancer and should be excluded in female patients The majority of gastric carcinomas are sporadic; how-
n Prominent lymphoid infiltrate may be present in tumors that are ever, approximately 10% show familial clustering, and
microsatellite instability (MSI) high or associated with Epstein-Barr a hereditary gene defect is recognized in 1% to 3% of
virus (EBV) infection
cases.
Molecular Pathology
Syndromic gastric cancer (Table 4.2) includes HDGC
n Four subtypes of sporadic gastric adenocarcinoma have been
syndrome (see Fig. 4.19), FAP, GAPPS, Lynch syn-
recognized: drome, Peutz-Jeghers syndrome, juvenile polyposis syn-
1. Genetically stable (∼20%) and corresponding to diffuse-type drome, hereditary breast and ovarian cancer syndrome,
gastric cancer Li-Fraumeni syndrome, FAP, and MAP.
2. Chromosomally unstable (50%) and showing TP53 mutations Heterozygous mutation in the tumor suppres-
3. Microsatellite unstable (20%) that are deficient in mismatch
repair protein expression on immunohistochemistry or show
sor gene CDH1, which encodes for the calci-
MSI um-dependent adhesion protein E-cadherin, is
4. Gastric cancers with EBV infection (10%) found in HDGC syndrome. Carcinomas start to
develop when the second allele is inactivated by
hypermethylation of the promoter, intragenic dele- Microscopic Findings

tions, or somatic mutations of CDH1. In addition,
germline mutations in CTNNA1 gene have also been The morphologic features are specific to the primary
reported. The inactivation of CDH1 leads to absent sites of origin because in many cases, they may overlap
or decreased E-cadherin protein expression by immu- with features of primary gastric carcinoma. The avail-
nohistochemistry on neoplastic cells. Because of the ability of clinical history and radiologic reports and
high lifetime risk of gastric carcinoma (70%) in male review of previous material are important in making
carriers, endoscopic surveillance biopsies to evalu- a definitive diagnosis. Ancillary immunohistochemi-
ate for microscopic carcinoma and/or prophylactic cal studies have a vital role to play in the differential
gastrectomy are often recommended for carriers of diagnosis, especially in the absence of sufficient clini-
CDH1 truncating mutations. cal information or in the case of poorly differentiated
neoplasms. Metastasis to the stomach is reported in
5.9% to 11.6% of patients with breast carcinomas.
In nearly half of the cases, the gastric metastases are
GASTRIC SECONDARY TUMORS
diagnosed at least 3 years after the primary diagnosis.
Metastases to the stomach are reported in 5.4% of Invasive lobular carcinoma is the source of the major-
patients with cancer. One-third of endoscopically ity (70%–75%) of cases, and the distinction with
detected secondary tumors in the GI tract are found in diffuse-type gastric cancer can be difficult because
the stomach. Malignant melanoma, breast (especially both tumors show single cell infiltration and cytoplas-
lobular carcinoma), pulmonary, and renal cell carci- mic lumen formation (Fig. 4.20). Furthermore, only
nomas represent the most common metastatic tumors a minor subset of metastases presents as localized
involving the stomach. Finally, reports of pancreati- lesions, and more than half of the cases show diffuse
cobiliary tract, gynecologic primaries (ovary, uterus), infiltration of the gastric wall. The use of immuno-
hepatocellular carcinoma, bladder, colon, prostate, tes- histochemistry is essential, with estrogen receptor
tis, head and neck, and bone and soft tissue primary (ER), progesterone receptor (PR), gross cystic disease
tumors have also been reported. fluid protein 15 (GCDFP-15), GATA binding protein
3 (GATA3), and mammaglobin expression favoring
a breast primary. Strong CDX2 labeling favors a gas-
tric primary but is seldom seen in diffuse-type gastri-
Clinical Features tis cancer, which is the main differential diagnosis.
Metastasis to the stomach is also reported in 2.4%
Abdominal pain, nausea, and vomiting are common to 6.8% of patients with lung carcinoma, and most
symptoms. Guaiac-positive stools or upper GI bleeding cases are recognized within 1 year after the diag-
can also be initial manifestations of the disease. Gastric nosis of the primary malignancy. Metastasis from a
metastases are usually indicative of advanced disease pulmonary primary is more frequently diagnosed in
with a reported overall survival of less than 1 year. In the autopsy setting and less commonly by endoscopic
many patients, the diagnosis is straightforward because
a history of primary neoplasm is already known.
Furthermore, in many cases, additional synchronous
sites of metastatic disease are recognized. Only in rare
cases is gastric metastasis the initial manifestation of
an occult malignancy.
Pathologic Features
Gross Findings
Metastatic tumors to the stomach are often nonspe-

cific and may mimic a primary gastric malignancy.
Only rarely, subtle findings such as multiple, small
black spots may be noted indicative of a metastatic
malignant melanoma. Furthermore, the metastases
may be submucosal with a smooth overlying mucosa, FIGURE 4.20
or they can present as a diffuse infiltration mimicking Lobular breast carcinoma metastatic to the stomach showing infiltrating sin-
gle cell mimicking a poorly cohesive carcinoma. Immunohistochemical stains
linitis plastica. are helpful to confirm the diagnosis of metastatic breast carcinoma.
biopsy, presumably because of the dismal prognosis designated as mixed adenoma neuroendocrine tumor
of advanced lung cancer. The detection of dysplasia (MANET). Other rare variants with a non-neuroen-
in the gastric mucosa is the most definitive way of docrine component other than adenocarcinoma (e.g.,
establishing the diagnosis of a gastric primary and acinar cell differentiation) have also been reported.
to exclude a metastatic adenocarcinoma. Ancillary
studies may be helpful as well because nearly 75% of
pulmonary adenocarcinomas are positive for thyroid
Neuroendocrine Tumors
transcription factor 1 (TTF-1). However, CDX-2 or
CK20, both markers of gastric adenocarcinomas, are
also frequently expressed in the mucinous, colloid, Gastric NETs are uncommon neoplasms usually
and enteric subtypes of pulmonary adenocarcinomas. detected in middle-aged adults. These lesions represent
To differentiate a pulmonary neuroendocrine carci- fewer than 2% of all gastric malignancies and about
noma (NEC) from a rare gastric primary, one has to 9% of all GI NETs. A rise in incidence, possibly related
rely on clinical investigation because the morphology to a greater use of endoscopy, has been recently recog-
is similar, and the expression of TTF-1 is not helpful nized. The clinical history and the microscopic appear-
because more than 10% of primary gastric NECs are ance of the background gastric mucosa is helpful in
positive. determining the site-specific subtype and the expected
Malignant melanoma metastasizes to the stomach prognosis.
in approximately 20% to 25% of patients and may be
detected synchronously at the time of diagnosis of the
primary lesion or years later as a recurrence. The micro-
Clinical Features
scopic features are similar to those seen in cutaneous
lesions with diffuse and strong immunoreactivity for
S-100, SOX10, HMB-45, and MART-1. The WHO classification of gastric NETs recog-
nizes three types divided primarily according to
their underlying pathogenesis related to presence or
absence of hypergastrinemia and autoimmune gastri-
NEUROENDOCRINE NEOPLASMS
tis. In type I NETs, the hypergastrinemia is caused
Neuroendocrine neoplasms (NENs) have prognoses that by chronic atrophic gastritis of the corpus caused
span from indolent to very aggressive. The 2019 edition by autoimmune gastritis and the attendant hypoch-
of the WHO classification of digestive tumors divides lorhydria. In type II NETs, the hypergastrinemia is
NENs into well-differentiated neoplasms also known as caused by Zollinger-Ellison syndrome (ZES), and the
NETs and poorly differentiated neoplasms also known tumors nearly always arise in the context of multiple
as NECs based on their distinctive histomorphology. endocrine neoplasia type I (rather than a sporadic
This new classification also uses a three-tier grading gastrinoma) and are accompanied by hyperchlo-
scheme for NETs, according to the mitotic count and rhydria. They represent 80% to 90% and 5% of all
Ki-67 proliferation index: gastric NETs, respectively, and are typically small,
multifocal, slow growing, and asymptomatic. Tumors
Grade 1: less than 2/10 hpf mitosis or less than 3%
smaller than 1 cm in diameter that are confined to
Ki-67 index
the mucosa and submucosa and show no angioin-
Grade 2: 2 to 20/10 hpf mitosis or 3% to 20% Ki-67
vasion on microscopy rarely metastasize. Type III
index
NETs, which represent 10% to 15% of all gastric
Grade 3: greater than 20/10 hpf mitosis or greater than
NETs, are fundamentally different because they are
20% Ki-67 index
sporadic, usually solitary, and larger neoplasms that
A rare subset of well-differentiated NENs may also do not arise within the context of hypergastrinemia
be grade 3 based on mitotic activity or proliferative or endocrine cell hyperplasia. These tumors tend to
index. Neoplasms with a mixture of distinct non-neu- be located in the prepyloric region, and their outcome
roendocrine and neuroendocrine components (the is usually more guarded because they may present
latter should constitute >30% of the lesion) should be with hemorrhage, obstruction, or metastasis. These
designated as mixed neuroendocrine–non-neuroen- lesions are more likely to spread, usually to regional
docrine neoplasm (MiNENs). The category of mixed lymph nodes and to the liver.
adenoneuroendocrine carcinoma (MANEC) with ade- Neuroendocrine carcinomas are highly aggressive
nocarcinoma and poorly differentiated NEC compo- neoplasm that account for 6% to 20% of gastric NENs.
nent is now considered a subtype of MiNEN because Most cases arise de novo, and there are only few exam-
it was recognized that in rare cases, the exocrine com- ples of progression from NET (G1 and G2) to high-
ponent of mixed tumors can be benign, but the neu- grade (G3) NEC. Cases with paraneoplastic syndromes
roendocrine component can be well-differentiated, are rare.
Pathologic Findings
Type I and II gastric NETs are usually multifocal, small,

(<1 cm) polypoid, firm, well-circumscribed elevations in
the corpus and fundus. Whereas the background corpus
mucosa typically shows chronic atrophic changes in type
I enterochromaffin-like cell NETs (related to autoimmune
gastritis), in type II, it may be hypertrophic with promi-
nent rugae, reflecting parietal cell hyperplasia that is typi-
cal of the ZES. Type III NETs tend to be solitary and larger
(>2 cm in diameter) and can show central umbilication A
with focal superficial erosion and hemorrhage. The back-
ground mucosa is usually normal in type III NETs
Neuroendocrine carcinomas usually form a large
fungating mass indistinguishable from typical adenocar-
cinomas. Larger tumors may present with central umbil-
ication and ulceration. Most cases are deeply infiltrating
and frequently present with nodal and hepatic metasta-
ses at the time of initial diagnosis.
Type I and II NETs are composed of ECL cells and usually

show a mixture of growth patterns with nests, ribbon-
like trabeculae, and rosettes, but sometimes acinar struc-
tures can also be seen. They are composed of small, B
uniform, polygonal or cuboidal cells with lightly eosino- FIGURE 4.21
philic, finely granular cytoplasm; regular, round, or oval Type I neuroendocrine tumors characterized by enlarging nests of small, uni-
nuclei; minimal nuclear pleomorphism; and a character- form, cuboidal cells with lightly eosinophilic cytoplasm and regular, round
istic stippled (“salt and pepper”) chromatin (Fig. 4.21). nuclei and minimal nuclear pleomorphism (A). The neoplasm is highlighted
by synaptophysin immunohistochemistry (B).
Type I and II gastric NETs usually display low mitotic
activity (<2/10 hpf) and Ki-67 index (≤2%) and usually
fall under the grade 1 category. Invasion into the submu- are characterized by an infiltrative growth pattern and
cosa is common but deeper infiltration and lymphovas- multifocal necrosis. Although the diagnosis of NECs
cular invasion is rarely seen. is now based on the histomorphology and not the pro-
Type III NETs can be composed of serotonin-proliferative activity a high mitotic rate (>20 mitoses/hpf)
ducing enterochromaffin cells and may display a higher and a Ki-67 labeling index of greater than 20% (typically
degree of nuclear pleomorphism, hyperchromasia, prom- >75%) are usually observed. Lymphovascular invasion is
inent nucleoli, or necrosis. With the increasing size, the commonly reported in these lesions.
risk of vascular or muscularis propria invasion, cyto-
logic atypia, and mitotic activity also increases. Finally, Precursor Lesions
the proliferative activity typically qualifies as grade 2 in
these tumors. The background oxyntic mucosa of patients with type I
Gastric NECs are by definition poorly differenti- NET shows features of autoimmune gastritis with atro-
ated grade 3 NENs and classified into small cell NEC phy, pseudopyloric, intestinal, and pancreatic acinar
(SCNEC) and large cell NEC (LCNEC) analogous to their metaplasia. In type II NETs, the corpus-fundus mucosa
pulmonary counterparts. SCNEC forms sheets of densely often shows a marked hypertrophy of the oxyntic glands
packed small round to ovoid tumor cells with finely gran- with hyperplasia of parietal cells, which is typical of ZES.
ular chromatin. LCNECs are composed of solid nests Whereas in both type I and II NETs, striking prolifera-
with large tumor cells that have abundant cytoplasm and tion of small, cuboidal, histamine-producing ECL cells
prominent nucleoli (Fig. 4.22). Although SCLCs only can be detected, hyperplasia of gastrin-producing G-cells
occasionally show features of neuroendocrine growth is only associated with type I tumors. The ECL cell hyper-
pattern, LCNECs frequently contain rosettes or show plasia can appear in three patterns representing stages
peripheral palisading and organoid nesting. Both types of disease progression: (1) the mildest diffuse scattered
the ECL cell nature. Immunohistochemical detection of

specific peptide hormones that may be expressed by the
tumor does not have any clinical implication.
Neuroendocrine carcinomas are reactive for general
neuroendocrine markers, including chromogranin A,
synaptophysin, and INSM1. TTF-1 expression is pres-
ent in more than 10% of primary gastric NECs and
should not be regarded as evidence for metastatic dis-
ease of a pulmonary origin.
The main differential diagnosis of gastric NETs is with

A glomus tumors. Glomus tumors are composed of small,
round cells with centrally placed hyperchromatic nuclei
and thus show considerable overlap with NETs, includ-
ing rare cases with patchy synaptophysin positivity.
However, glomus tumor cells have lumpy, coarse chro-
matin. In addition, these cells have a pale eosinophilic to
clear cytoplasm instead of the amphophilic cytoplasm of
NETs, usually surround blood vessels, and are positive
for myoid markers on immunohistochemistry.
The main differential diagnosis of NEC is with a
poorly differentiated adenocarcinoma and malignant
lymphoma. Appropriate use of immunohistochemistry
allows the diagnosis in most cases. Furthermore, it is
important to recall that whereas LCNEC presents fre-
quently with organoid, trabecular pattern, the cells have
B a prominent eosinophilic cytoplasm, coarse nuclear chro-
FIGURE 4.22 matin, and numerous nucleoli. Infrequently, NENs may
Neuroendocrine carcinoma characterized by infiltrative sheets of anaplastic show a morphology overlapping between NEC and grade
round cells (A). The carcinoma is positive for general neuroendocrine mark- 3 NET. Given that genetic alterations in TP53 and RB1
ers, including synaptophysin (B).
are more frequent in NECs than in NETs, identification
of such mutations or immunohistochemical detection of
ECL cell hyperplasia, (2) the moderate linear hyperpla- aberrant p53 and retinoblastoma expression s can help in
sia (forming chains of more than five contiguous cells), the differential diagnosis of these neoplasms.
and (3) the advanced nodular hyperplasia with small cell
nests which may extend into the lamina propria and/or Prognosis and Therapy
muscularis mucosae. The fusion of at least five micronod-
ules or the aggregates of nodules measuring greater than In general, gastric NETs have a relatively good progno-
150 microns in greatest dimension is designated as ECL sis compared with adenocarcinomas. The 5-year survival
cell dysplasia by some authors. The diagnosis of NET can rates of localized tumor versus regional spread versus
be used for ECL cell aggregates exceeding 0.5 mm in diam- distant spread are 73% versus 65% versus 25%, respec-
eter or those invading the submucosa. Type III NETs are tively. Type I NETs have the best 5-year survival rate of
not known to be associated with any underlying disease practically 100%, yet about 3% of these patients develop
or specific mucosal changes. lymph node or liver metastases. Not surprisingly, type
III tumors have the worst prognosis. It is estimated that
Ancillary Studies patients with these lesions have a 5-year survival rate of
50% with half of the patients developing lymph node or
The diagnosis of gastric NETs can be confirmed by liver metastases. Type II NETs have a prognosis between
immunohistochemistry for neuroendocrine markers types I and III. It is important to note that although a
such as chromogranin A, synaptophysin, or insulino- worse prognosis may depend on the NET type, the most
ma-associated protein 1 (INSM1). Vesicular monoamine important and worst prognostic factor for all NETs is a
transporter type II is a specific marker of ECL cells but tumor size of greater than 2 cm. Low-grade NETs can
is only rarely used in routine histopathology because be managed conservatively because they may regress
the recognition of autoimmune gastritis in the back- with long-acting somatostatin analogues or may be com-
ground mucosa is a sufficient surrogate tool to recognize pletely removed by endoscopic excision, with subsequent
endoscopic follow-up. In the few cases of type I NETs

with numerous polyps, antrectomy to remove the tro- Gastric Neuroendocrine Neoplasms—Pathologic Features
phic stimulus from antral G cells may be indicated. Only
patients with large or numerous tumors or dominant Gross Findings
grade 2 tumors should be considered for surgery. n Neuroendocrine tumors (NETs)are small, well-circumscribed
Patients with localized NEC should be considered submucosal lesions

n Larger tumors can show central umbilication
for resection that should include adequate regional n Type I and II NETs are small, often multiple, and are located in the
lymph node staging. In addition, intensive chemo- corpus fundus
therapy, with or without surgery, is recommended for n Type III tumors tend to be larger, solitary, and located in the
patients with gastric NEC at any stage. Chemotherapy prepyloric region

n NECs are deeply infiltrative and frequently ulcerated, grossly
is not standardized, and various mainly platinum-based
indistinguishable from adenocarcinomas
protocols, including cisplatin, etoposide, cyclophos-
phamide, and doxorubicin are used. The distinction Microscopic Findings
between NEC and grade 3 well-differentiated NET has n NETs: ribbon-like trabecular, nesting, or acinar growth patterns;
prognostic significance, but both groups are treated in uniform small round cells with salt-and-pepper chromatin
a similar fashion with platinum-based chemotherapy. n Grading of NETs is based on the mitotic count and Ki-67
proliferation index
n Gastric NETs are subcategorized based on their underlying
pathogenesis
n Type I NETs are associated with features of autoimmune gastritis
GASTRIC NEUROENDOCRINE NEOPLASMS—FACT SHEET and have an excellent prognosis
n Type II NETs are associated with features of Zollinger-Ellison
Definition syndrome and have an intermediate prognosis

n Type III NETs are not associated with other mucosal changes and
n Neoplastic endocrine proliferations that span a spectrum from
benign indolent tumors to highly aggressive tumors with dismal have a poor prognosis
n NECs: Subclassified into small cell NEC and large cell NEC similar
prognosis
to the pulmonary equivalents
n Neoplasms with a mixture of distinct non-neuroendocrine
and neuroendocrine components (>30% of the lesion) are
n Rare and make up 0.1% to 0.6% of all gastric neoplasms and
designated as mixed neuroendocrine–non-neuroendocrine
7% to 8% of all neuroendocrine tumors (NETs) neoplasm, including mixed adenoneuroendocrine carcinomas
n Increasing incidence may be related to greater access to upper
and other rare variants
endoscopy and higher detection
n NETs in autoimmune gastritis and Zollinger-Ellison syndrome
(ZES) typically involve the corpus; sporadic type III tumors are
n Positive immunoreactivity with synaptophysin, chromogranin A, or
usually present in the antrum
INSM1
n Thyroid transcription factor 1 may be positive in a subset of
primary gastric NECs
n Type I tumors are the most indolent, and type III carry the
n Positive immunoreactivity to pancytokeratin markers (frequently
worst prognosis among NETs with type II somewhere in the dotlike)
middle
n Neuroendocrine carcinomas (NECs) are highly aggressive tumors
with a dismal prognosis
n Glomus tumors
n Metastatic NET
n Poorly differentiated adenocarcinoma
n Type I tumors more frequent in women because of greater
n Lymphoma
prevalence of autoimmune gastritis
n Median age of patients is around 60 years
Clinical Features SUGGESTED READINGS

n Common predisposing conditions include autoimmune gastritis
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duodenum. J Pathol. 2013;229(4):579–587. 2009;33:626–632.
27. Choi WT, Brown I, Ushiku T, et al. Gastric pyloric gland ade- 48. Thomas RM, Baybick JH, Elsayed AM, et al. Gastric carcinoids.
noma: a multicentre clinicopathological study of 67 cases. An immunohistochemical and clinicopathologic study of 104
Histopathology. 2018;72(6):1007–1014. patients. Cancer. 1994;73:2053–2058.
28. Hashimoto T, Ogawa R, Matsubara A, et al. Familial adeno-
matous polyposis-associated and sporadic pyloric gland adenomas
of the upper gastrointestinal tract share common genetic features.
5
Non-Neoplastic and Inflammatory
Disorders of the Small Bowel
■ Scott Robertson, MD, PhD and Deepa T. Patil, MD
■ PATTERNS OF SMALL BOWEL DISORDERS enteropathy, common variable immunodeficiency

(CVID), and drug-related sprue-like enteropathy, among
The most common indication for histologic assessment others.
of small bowel mucosa is to evaluate for a malabsorp-
tion disorder. Although the spectrum of small intesti-
nal diseases that can result in symptoms of
malabsorption can seem daunting at first, most dis- Intact Villi Pattern
eases produce histologic findings that fall into a limited
number of injury patterns. A pattern-based approach is Several conditions result in small bowel mucosal injury
useful because, in practice, it is often difficult, if not without altering the villous architecture. These may or
impossible, for the pathologist to diagnose a specific may not be accompanied by prominent inflammation
cause. Furthermore, lack of available clinical history and can be further categorized based on the inflamma-
can add to this challenge. The small bowel disorders tory component into conditions with neutrophilic
presented here mostly fall into one of two major pat- inflammation, eosinophilic inflammation, lymphoplas-
terns of injury based on assessment of the architecture macytic inflammation, and disorders with minimal or
at low magnification: the flattened villi pattern and the no inflammation.
intact villi pattern (Table 5.1). Small bowel mucosa
with intact villi pattern can be further subdivided based Intact Villi with Neutrophilic Inflammation
on the nature of the inflammatory infiltrate into neutro-
philic inflammation, eosinophilic inflammation, lympho- The characteristic feature of this pattern is the pres-
plasmacytic inflammation, and disorders with minimal or ence of neutrophilic inflammation within the epithe-
no inflammation. Lastly, some disorders can alter the lium. In most cases, the lamina propria is also
lamina propria and result in villous blunting without sig- expanded by a mixed inflammatory cell infiltrate com-
nificant inflammation. These include infectious enteritis posed of neutrophils, eosinophils, lymphocytes, and
caused by Whipple disease, Mycobacterium avium-intra- plasma cells. The epithelium shows regenerative epi-
cellulare infection, and histoplasmosis and conditions thelial changes in the form of reactive mucin loss and
that alter the lacteals, including primary and secondary slight nuclear hyperchromasia, with preservation of
lymphangiectasia. the nucleus-to-cytoplasmic ratio. The potential causes
are drug injury (especially nonsteroidal antiinflam-
matory drugs [NSAIDs]), infections (including
Helicobacter pylori), peptic injury, inflammatory
Flattened Villi Pattern
bowel disease (IBD), Zollinger-Ellison syndrome
(ZES), and early ischemia.
The flattened villi pattern of injury has also been called
the malabsorption pattern and is characterized by villous Intact Villi with Eosinophilic Inflammation
blunting, crypt hyperplasia with or without significant
intraepithelial lymphocytosis, and expansion of the lam- This pattern is characterized by excessive number of
ina propria by lymphocytes and plasma cells. The proto- eosinophils in the mucosa along with eosinophil-mediated
typical malabsorption disorder is celiac disease (CD), but epithelial injury in the form of cryptitis or crypt abscesses.
a number of other disorders can produce similar histo- Similar to the rest of the gastrointestinal (GI) tract,
logic findings, including peptic injury, tropical sprue, col- increased eosinophils can be associated with idiopathic
lagenous sprue, nongluten protein sensitivity, small eosinophilic enteritis, parasitic infection, allergies, drug-
intestinal bacterial overgrowth (SIBO), autoimmune or medication-induced injury, connective tissue disease,
119
Intact Villi with Paucicellular Inflammation

TABLE 5.1
Some conditions are associated with intact villous archi-
Patterns of Small Intestinal Injury and
Differential Diagnosis tecture and minimal or no inflammation. These disor-
ders include certain infections, such as giardiasis,
FLATTENED VILLI PATTERN (WITH OR WITHOUT INTRAEPITHE- cytomegalovirus (CMV), radiation injury, amyloidosis,
LIAL LYMPHOCYTOSIS) chemotherapeutic agents, drugs or medications (espe-
• Celiac disease
cially mycophenolate mofetil [MMF]), graft-versus-host
• Peptic injury
• Medications disease (GVHD), and transplant rejection.
• Tropical sprue
• Nongluten protein sensitivity
• Small intestinal bacterial overgrowth
• Collagenous sprue Applying the Pattern-Based Approach
• Common variable immunodeficiency
• Autoimmune enteropathy
INTACT VILLI WITH NEUTROPHILIC INFLAMMATION Identifying the two major patterns of small bowel injury
• Peptic ulcer disease (flat villi and intact villi) is helpful in generating a differ-
• Infection ential diagnosis and determining the cause of mucosal
• Medications injury. However, the patterns are not etiologically spe-
• Inflammatory bowel disease
cific. For instance, many conditions can manifest with
• Zollinger-Ellison syndrome
• Radiation injury flattened villi pattern of injury. Furthermore, one spe-
• Vasculitis cific etiology may result in a variety of patterns of injury.
• Ischemia For instance, NSAID-related injury can manifest with
INTACT VILLI WITH EOSINOPHILIC INFLAMMATION all major patterns of injury. It is therefore important to
• Idiopathic eosinophilic enteritis identify the pattern of injury and provide a comment
• Medications
enlisting all the potential etiologies that may contribute
• Allergy
• Parasite infection to injury. The sections in this chapter have been orga-
• Inflammatory bowel disease nized based on causes of small bowel injury.
• Connective tissue disorder
• Vasculitis
• Systemic mastocytosis
• Langerhans cell histiocytosis ■ MALABSORPTION DISORDERS
INTACT VILLI WITH LYMPHOPLASMACYTIC INFLAMMATION
• Celiac disease
• Inflammatory bowel disease The term malabsorption is broadly used to describe any
• Medications (especially NSAIDs) type or degree of dysfunction in the uptake of sub-
INTACT VILLI WITH PAUCICELLULAR INFLAMMATION stances that are normally retained or absorbed by the
• Infections: giardiasis, CMV small intestine. Malabsorption can result from a multi-
• Radiation injury
tude of causes, which can be broadly categorized into
• Amyloidosis
• Chemotherapy agents disorders of inadequate digestion (pancreatic disor-
• Graft-versus-host disease ders, disorders of decreased intestinal bile salt concen-
• Transplant rejection tration), endocrine or metabolic disorders (diabetes
• Medications (e.g., MMF) mellitus, thyroid dysfunction, ZES), biochemical or
• Inflammatory bowel disease
genetic diseases (CD, disaccharidase deficiency, abeta-
• Medications (especially NSAIDs)
lipoproteinemia, hypogammaglobulinemia), mucosal
CMV, Cytomegalovirus; MMF, mycophenolate mofetil; NSAID,
disorders (infections, immunologic conditions, infiltra-
nonsteroidal antiinflammatory drug.
tive disorders), and postmucosal disorders (lymphatic
obstruction, cardiac failure, vascular obstruction).
Conditions that affect the small bowel mucosa may dras-
vasculitis, systemic mastocytosis, and Langerhans cell tically reduce the amount of villous surface area, pre-
histiocytosis (LCH). venting adequate uptake of nutrients. Microscopically,
malabsorption disorders often show villous blunting,
Intact Villi with Lymphoplasmacytic Inflammation crypt hyperplasia, and intraepithelial lymphocyto-
sis—the flattened villi pattern of injury. Having said that,
This pattern of injury is characterized by expansion of some malabsorption disorders have no specific patho-
the lamina propria by lymphocytes and plasma cells. logic findings (e.g., disaccharidase deficiency, trans-
The possible causes of this pattern of injury include porter defects), and lack of inadequate nutrient uptake
CD, IBD, and drug- or medication-related injury (espe- is not caused by global surface area loss but by defects
cially NSAIDs). in specific protein function.
CHAPTER 5 Non-Neoplastic and Inflammatory Disorders of the Small Bowel 121
■ CELIAC DISEASE the atypical symptomatic subtype, GI symptoms may be less

pronounced to absent. Instead, extraintestinal features such
as anemia, short stature, neurologic symptoms, dermatitis
Clinical Features herpetiformis, delayed puberty, osteoporosis, infertility, vita-
min and protein deficiencies, and elevated liver enzyme lev-
Once considered to be a rare childhood disorder, CD els are predominant. Some patients have asymptomatic or
(also known as gluten-sensitive enteropathy or celiac silent CD; they lack classic or atypical symptoms but have
sprue) is a chronic immune-mediated disorder induced unequivocal villous atrophy found incidentally for other rea-
by dietary exposure to gluten in genetically predisposed sons or after serologic screening. Finally, latent CD is defined
individuals. Confirmation of a diagnosis also requires by a positive serology but lack of villous atrophy on initial
prompt improvement of clinical symptoms and mucosal biopsies. Individuals are asymptomatic but may develop
pathology after withdrawal of dietary gluten. symptoms, histologic changes, or both.
Celiac disease occurs both in adults and children with High-risk groups to be screened for CD are those with
a female predominance (female-to-male ratio, 2–3 to 1). other autoimmune disorders such as type 1 diabetes
It is estimated to affect between 0.5% and 1% of indi- mellitus and autoimmune thyroiditis, a family history of
viduals in both Europe and the United States. The peak CD, selective immunoglobulin (Ig) A deficiency, or der-
age of incidence is the third to fourth decades of life. matitis herpetiformis. CD is also more common in cer-
However, up to 20% of individuals may be diagnosed tain pediatric populations, including those with Down
after 60 years of age. syndrome, in whom the frequency of CD is as high as
The classification and diagnosis of CD are based on GI 10%. In this group, CD is usually not detected on the
manifestations; however, patients with extraintestinal com- basis of GI symptoms.
plications are increasingly being recognized (Table 5.2). The Celiac disease is a clinicopathologic diagnosis that is
clinical presentation of CD ranges from asymptomatic to most often based on positive serology and specific histo-
severe malnutrition. CD may be divided into four clinical logic findings. Antitissue transglutaminase (anti-tTG)
subtypes, two symptomatic types and two asymptomatic antibodies are both highly sensitive (90%–98%) and
types. In the classic symptomatic subtype, patients present specific (95%–97%) for CD. Antiendomysial (EMA)
with chronic diarrhea, abdominal distension, and pain. In antibodies are specific (97%–100%) but have slightly
inferior sensitivity (85%–98%). Antigliadin antibody
testing should no longer be used because of its low posi-
tive predictive value. A diagnosis of CD may be made if
TABLE 5.2 both tissue biopsy and serologic testing are consistent
Extraintestinal Disorders Associated with with CD. CD may be excluded if results of both are
Celiac Disease negative.
Endocrine disorders Sometimes there is discordance between the histo-
Type 1 diabetes mellitus logic and serologic findings, which may occur for a
Autoimmune thyroid disorders number of reasons. First, IgA deficiency is more com-
Addison’s disease
mon in individuals with CD than in the general popu-
Reproductive disorders (infertility, miscarriages)
Osteoporosis lation. Because tTG and EMA serologic tests are based
Alopecia areata on IgA, they may be falsely negative in patients with
Neurologic disorders IgA deficiency. Total IgA can be measured to identify
Cerebellar ataxia these patients, and IgG-based assays, particularly
Neuropathy
deamidated gliadin peptide or IgG-tTG, may be used in
Epilepsy
Migraines these situations. Second, the flattened villi pattern of
Cardiac disorders injury is not specific for CD. Consideration of an alter-
Idiopathic dilated cardiomyopathy native cause (e.g., SIBO, tropical sprue, drug-associated
Autoimmune myocarditis enteropathy) should be explored in patients with nega-
Hepatic disorders
tive celiac serologies. Sometimes HLA genotyping is
Primary biliary cirrhosis
Autoimmune hepatitis useful from excluding the possibility of CD. HLA-DQ2
Autoimmune cholangitis or HLA-DQ8 is present in almost all cases of CD.
Other Negative testing for these alleles virtually eliminates
Dermatitis herpetiformis the possibility of CD. Human leukocyte antigen (HLA)
Anemia
typing is particularly useful in patients who may have
Selective immunoglobulin A deficiency
Sjögren syndrome initiated a gluten-free diet (GFD) before proper diag-
Juvenile chronic arthritis nostic work-up. This complicates diagnosis because
Turner syndrome both serologic and histologic abnormalities may nor-
Down syndrome malize with GFD. HLA genotyping can be used to rule
Dental enamel defects
out CD in a subset of these patients.
In patients who test positive for HLA-DQ2 or suggesting a link between CD and prior reovirus infec-
HLA-DQ8, a gluten challenge can be performed, in tion. It remains to be seen if other infectious agents can
which biopsy and serologic analysis takes place after elicit similar immunologic derangements.
gluten has been reintroduced for a period time. In
patients with CD, gluten challenge should elicit typical
serologic and histologic features. However, some patients
Genetic
may experience a return of their symptoms (e.g., abdom-
inal pain, bloating) but without serologic or histologic
evidence of CD. An alternate diagnosis should be con- The major genetic risk factors for CD are the HLA class
sidered in these patients, such as IgE-mediated wheat II genes HLA-DQ2 and HLA-DQ8. Approximately 95%
allergy or nonceliac gluten sensitivity. of all patients with CD have a DQ2 heterodimer, and
almost all remaining patients with CD have a DQ8 het-
erodimer. Gene dosage correlates with the risk for devel-
oping CD, with patients homozygous for DQ2 carrying
■ PATHOGENESIS
the greatest risk. CD is concordant in 70% to 80% of
monozygotic twins, 30% to 40% of HLA-identical sib-
The pathogenesis of CD is related to a combination of lings, and fewer than 20% of dizygotic twins, a rate sim-
environmental, genetic, and immunologic features and ilar to that for all first-degree relatives. However, recent
can be viewed as both luminal events and cellular events linkage studies suggest that non-HLA disease-associated
leading to the activation of immune cells and ensuing tis- genes may also play a role.
sue damage. Enteric exposures to certain glutamine-rich
proteins in the dietary grains wheat, rye, and barley are
essential for the development of CD. The actual proteins
CELIAC DISEASE—FACT SHEET
that trigger the disease are the gliadins in wheat, the
hordeins in barley, and the secalins in rye. In CD, many of Definition
these peptides are poorly digested by the intestinal tract n A multisystem autoimmune disorder caused by an immune
proteases and traverse through the epithelium into the response to dietary gluten and related proteins
lamina propria as intact molecules. tTG is a multifunc-
tional enzyme that is essential for the pathogenesis of CD. Incidence
tTG has two essential functions, deamidation of gluta- n 1% of the US population
mine to glutamic acid and cross-linking glutamine and n 1 in 133 patients with no risk factors
n 1 in 29 patients with at least one first-degree relative with celiac

lysine residues. After absorption, intact peptides are
disease (CD)
deamidated by tTG, converting the abundant glutamine
residues to glutamic acid, thus rendering them negatively Morbidity and Mortality
charged. The negatively charged peptides are more effi- n 20-fold higher risk for enteropathy-associated T-cell lymphoma
ciently bound to HLA-DQ2 or HLA-DQ8 receptors on n 30-fold higher risk for small intestinal adenocarcinoma
the surface of the antigen presenting cells. Intestinal n Two- to fourfold higher risk for oropharyngeal and esophageal
DQ2- or DQ8-restricted CD4+ T cells then recognize the carcinoma

deaminated gliadin peptides and elicit a cytokine-mediated
inflammatory response. Importantly, tTG also forms
n Wide age range: children and adults
complexes with gliadin, mediated by its glutamine-lysine n Common in Northern Europeans; rare in Southeast Asians and
cross-linking function. In an environment already primed Middle East
by gliadin peptide presentation on DQ2/8 T cells, tTG–
gliadin complexes serve as neoepitopes that stimulate the Clinical Features
formation of anti-tTG autoantibodies. n Variable: ranges from asymptomatic to severe malnutrition
n Most common presentation is weight loss, abdominal pain, and

Finally, it was recently discovered that infection with
diarrhea
certain viruses can trigger immunopathologic responses n Extraintestinal manifestations include infertility, osteoporosis,
to dietary gluten. Specifically, infection with reovirus, dermatitis herpetiformis, and various neuropathies
which is nonvirulent and otherwise nonpathogenic, can
trigger certain events critical for CD pathogenesis. In Prognosis and Therapy
mouse models, reovirus infection represses regulatory n Complete resolution of mucosal injury with a strict gluten-free
T-cell (Treg) conversion and promotes T helper-1 (TH1) diet (GFD)

n Refractory CD refers to patients on GFD for a period of 1 year or
immunity to dietary antigen. Reovirus infection also
longer without resolution of symptoms
breaks oral tolerance to gluten and promotes activation n Type II refractory CD is commonly associated with a clonal T-cell
of transglutaminase 2. In humans, patients with CD population and is at high risk for developing enteropathy-
were much more likely to have circulating antibodies associated T-cell lymphoma
against reovirus than normal control participants,
Pathologic Features
Gross Findings
If the mucosal biopsy specimen is examined under a dis-

secting microscope (which is seldom done), delicate villi
are found to be attenuated or even absent. Endoscopically,
a reduction in folds, scalloping, a mosaic pattern, or nod-
ular mucosa may be seen (Fig. 5.1).
Histologic abnormalities in the duodenum may be

patchy. Current guidelines from the American College of
FIGURE 5.2
Gastroenterology (ACG) recommend multiple biopsies
Celiac disease. The duodenal biopsy shows marked villous blunting with
of the duodenum, with one or two biopsies from the expansion of the lamina propria by lymphocytes and plasma cells along with
bulb and at least four biopsies from the distal duode- crypt hyperplasia.
num. CD produces the flattened villi pattern of injury—
intraepithelial lymphocytosis, villous blunting, and
crypt hyperplasia (Figs. 5.2 and 5.3). The earliest change
in CD is the presence of increased intraepithelial lym-
phocytes (IELs), most conspicuously within the villous
tips, with intact villous architecture (Fig. 5.4). With per-
sistent disease, epithelial damage ensues with reactive
mucin loss. The lamina propria is expanded by lympho-
cytes and plasma cells, thus contributing to partial or
complete villous blunting. Villous blunting is accompa-
nied by crypt hyperplasia. Active inflammation is occa-
sionally seen but is generally not prominent. Marked
neutrophilic epithelial injury should suggest an addi-
tional or alternative cause, such as peptic duodenitis,
NSAID injury, infection, or Crohn’s disease.
Duodenal biopsies exhibiting all the features of CD—
increased IELs, villous blunting, crypt hyperplasia—are FIGURE 5.3
easy to recognize. However, changes of early CD can be Higher magnification of duodenal biopsy with celiac disease showing marked
quite subtle and include intact villous and crypt archi- expansion of the lamina propria by lymphocytes and plasma cells. There is
crypt as well as surface intraepithelial lymphocytosis.
tecture with increased IELs. The increase in IELs is
sometimes obvious, but in some cases, an objective

Endoscopic appearance of celiac disease. The duodenal mucosa shows Early celiac disease. The duodenal biopsy shows preservation of the villous
characteristic scalloping with reduction in the mucosal folds. architecture with intraepithelial lymphocytes within the villous tips.
measure is needed to resolve borderline cases. The nor- confirmed with the knowledge of positive celiac serolo-
mal range of IELs has been reported as 11 to 23 per 100 gies. Without this information, the pathologist must be
enterocytes. According to ACG guidelines, more than 25 descriptive in the report by stating the pattern of injury
IELs per 100 enterocytes is abnormal. One rapid method (e.g., duodenal mucosa with villous blunting and
to determine this number is to evaluate 5 villous tips, increased IELs) and providing a comment with the dif-
counting the number of lymphocytes present within the ferential diagnosis. In biopsies showing well-developed
distal-most 20 enterocytes. The final values can be features of the flattened villi pattern of injury, the differ-
expressed as IEL per 100 enterocytes. When possible, ential diagnosis includes infection, protein intolerance,
evaluate only well-oriented villi that are anchored by tropical sprue, nongluten protein sensitivity, bacterial
intact muscularis mucosae because tangentially sec- overgrowth, Crohn’s disease, CVID, autoimmune
tioned lateral aspects of the villi may result in overesti- enteropathy (AIE), and medication injury (particularly
mation and inaccurate estimation of the lymphocyte from NSAIDs and olmesartan). In biopsies with
count. A CD3 immunostain can also be used to highlight increased IELs and normal villous and crypt architec-
IELs. However, the utility of this approach has not been ture, the differential diagnosis is slightly different and
established or validated for clinical practice. Some stud- includes viral infections, H. pylori infection, NSAID
ies have shown that CD3 immunohistochemistry (IHC) injury, peptic injury, tropical sprue, nongluten protein
does not improve detection of CD in cases in which the sensitivity, bacterial overgrowth, Crohn’s disease, and
hematoxylin and eosin–stained sections are normal. AIE.
Upon initiation of a GFD, patients often report a marked
improvement in clinical symptoms. Microscopically, intesti- Prognosis and Therapy
nal biopsies show diminished surface epithelial injury, a
reduced number of IELs, and partial to complete resolution A lifelong adherence to a GFD is the mainstay of safe
of villous architectural abnormalities. However, in some and effective treatment of patients with CD. Commonly
cases, despite resolution of clinical symptoms and normal substituted grains in the GFD include rice, corn, quinoa,
serology, the inflammatory component may persist for up to and buckwheat. Serologic testing may be used to check
a period of 1 to 2 years after GFD. If patients consume glu- the effectiveness of a GFD. Patients whose disease does
ten-containing products, there is a rapid return of all lesions, not respond to dietary therapy should undergo a system-
and malabsorption ensues. atic evaluation, including review of the patient’s diet by
an expert dietician.
Patients with CD have more than a 30-fold increased
risk for small bowel adenocarcinoma compared with the
Celiac Disease—Pathologic Features general population, and 13% of patients with a small
bowel adenocarcinoma have underlying CD. Other
Gross Findings
malignancies potentially associated with CD include
n Attenuated to absent villi (as seen under a dissecting
microscope) enteropathy-associated T-cell lymphoma (EATL), papil-

n Scalloping or mosaic appearance of the mucosa lary thyroid carcinoma, and malignant melanoma.
n Variable degrees of villous blunting
n Intraepithelial lymphocytosis, most prominent on villous tips (>25

■ NONRESPONSIVE OR REFRACTORY CELIAC
IELs per 100 enterocytes) DISEASE
n Crypt hyperplasia
Differential Diagnosis Nonresponsive CD is defined as persistent symptoms,

n Bacterial overgrowth signs, or laboratory abnormalities despite 6 to 12 months
n Infection of gluten avoidance. It is common, occurring in 7% to
n Tropical sprue 30% of patients. The most common cause is inadvertent
n Nongluten protein sensitivity
gluten ingestion. Other causes include SIBO, other food
n Crohn’s disease
n Protein intolerance
intolerances, irritable bowel disease, pancreatic insuffi-
n Autoimmune enteropathy ciency, and microscopic colitis. In patients with nonre-
n Medications (nonsteroidal antiinflammatory drugs, olmesartan) sponsive CD, the diagnosis of CD should be reconfirmed,
and the patient’s diet should be closely examined to rule
out inadvertent gluten ingestion. Additional studies,
including upper and lower endoscopy, may also be indi-
cated to exclude other diseases in the differential
diagnosis.
The flattened villi pattern of injury is not specific for If there are persistent signs and symptoms after 12
CD, and therefore, a diagnosis of CD can only be months on a strict GFD and if alternative disorders have
been ruled out, the diagnosis of refractory celiac disease lacking other T-cell markers, including CD4, CD5, and
(RCD) is appropriate. RCD is rare (1%–2% of patients CD8. CD30 expression is present in some cases. The
with CD) and can be subdivided into two types based on neoplastic cells have a cytotoxic T-cell phenotype with
the immunophenotype of the lymphocyte population. In expression of TIA-1, granzyme B, and perforin. Type II
type I RCD, the infiltrating lymphocytes are morpholog- EATL usually involves the jejunum, but in contrast to
ically and immunophenotypically similar to those seen type I EATL, it may also involve the stomach or colon.
in untreated CD. Patients with type I RCD usually Microscopically, EATL type II is composed of a more
respond to immunosuppressive regimens and are at low monotonous population of smaller cells, and there are
risk for progression to lymphoma. In type II RCD, the fewer admixed non-neoplastic inflammatory cells.
lymphocytes display an abnormal immunoprofile, lack- Immunohistochemically, type II EATL is similar to type
ing one or more normal T-cell markers (CD3, CD4, and I but more often expresses CD8 but less often expresses
CD8). Furthermore, monoclonal or oligoclonal T-cell CD30 (see Chapter 19 for additional details). The prog-
receptor rearrangements can be detected. Having said nosis is similarly poor for both types; the 5-year survival
that, a recent study has shown clonal T-cell populations rate is approximately 10%. About half of patients
even in typical patients with CD. Thus, the utility of require laparotomy for complications of hemorrhage,
TCR gene-rearrangement studies in this setting is some- perforation, or obstruction.
what limited. Given these findings, some consider RCD
II to be a form of in situ T-cell lymphoma, and there is a
much higher risk of progression to malignancy com-
■ COLLAGENOUS SPRUE
pared with RCD I. Patients with RCD II are often refrac-
tory to steroid therapy. Optimal treatment is unclear,
but a variety of immunomodulatory and chemothera- Collagenous sprue, also known as collagenous enteritis,
peutic agents have been used. is a rare but severe form of malabsorption disorder.
Enteropathy-associated T-cell lymphoma is a high- Given the limited number of small case series reported
grade T-cell non-Hodgkin’s lymphoma of the upper in the literature, the nature of collagenous sprue and its
small intestine. This rare T-cell disorder is 20 times relationship to other malabsorption disorder are unclear.
more common in patients with CD. Two types of EATL Initially, collagenous sprue was thought to represent an
are recognized and have slightly different clinical and uncommon variant of CD, enriched in patients who
pathologic features, though both are very aggressive. have refractory disease. However, it is now clear that a
Type I EATL is closely associated with CD. Type II proportion of cases occur in patients with no other evi-
EATL is less common and is not associated with CD. dence of CD (based on serology, genetics, or response to
Pathologically, type I EATL most commonly involves a GFD). Therefore, collagenous sprue seems to repre-
the jejunum or ileum. Plaques, nodules, or strictures can sent an unusual, nonspecific injury pattern associated
be seen grossly. Microscopically, there is a dense, diffuse with a variety of pathogenic mechanisms. Beyond its
proliferation of atypical medium to large lymphoid cells, association with CD, collagenous sprue has also been
usually in a background of mixed inflammatory cells reported in the context of collagenous gastritis, micro-
(Fig. 5.5). Immunohistochemically, the neoplastic cells scopic colitis, and olmesartan-induced injury. It is most
usually express CD45 and cytoplasmic CD3 while common in middle-age to older women, and, unlike col-
lagenous gastritis, it is rare in children.
Histologically, the key feature is a thick subepithelial
collagen layer (Fig. 5.6). The required thickness of the
collagen layer is not well defined, but some reports use
greater than 12 μm as a cut-off. Similar to collagenous
colitis, there are entrapment of capillaries and irregular
extension of the collagen layer into the lamina propria.
The background mucosa shows villous atrophy.
However, in contrast to CD, the crypts are typically atro-
phic rather than hyperplastic. The degree of intraepithe-
lial lymphocytosis can be variable.
Early descriptions of this entity indicated that
patients usually have a poor prognosis. However, more
recent studies have revealed that the clinical outcome
can be quite heterogeneous. GFD is sufficient treatment
FIGURE 5.5
for some patients, though about half are refractory to
Enteropathy-associated T-cell lymphoma. The duodenal biopsy shows
GFD, in which case immunosuppressive or chemothera-
marked villous blunting with expansion of the lamina propria by a monomor- peutic agents are needed. Some patients die of intracta-
phic population of atypical medium to large lymphoid cells. ble disease.
architecture of the mucosa is typically preserved in tropi-

cal sprue and a completely flat mucosa—like that seen in
patients with CD—is never seen. Intraepithelial lympho-
cytosis is very prominent in tropical sprue and is seen in
both the villi and crypts. In addition, there may be a sig-
nificant increase in the number of lamina propria eosino-
phils. Finally, unlike CD, in which mucosal changes are
greatest in the proximal small bowel, the lesions are simi-
lar throughout the entire small bowel in tropical sprue.
Mechanistically, this fits with the resulting secondary
vitamin B12 and folate deficiency states that are commonly
a consequence of tropical sprue. In fact, vitamin B12 and
folate deficiency may produce megaloblastic changes in
A the epithelium with enlarged nuclei and reduced mitotic
activity.
After the diagnosis is made, tropical sprue is emi-
nently treatable with antibiotics; a 3-month course of
doxycycline is generally sufficient. Folic acid vitamin B12
supplementations are also useful to correct nutritional
deficiencies. Unfortunately, given the rarity of the disor-
der, this diagnosis is often not considered either clini-
cally or pathologically.
■ PEPTIC DUODENAL DISEASE
Clinical Features
B
FIGURE 5.6
Peptic duodenitis and peptic ulcer disease (PUD) repre-
Collagenous sprue. A, Duodenal mucosa shows villous blunting and expan-
sion of the lamina propria by lymphocytes and plasma cells. A thick colla- sent a continuum of the same disease process, namely
gen layer is present beneath the epithelium. It has an irregular contour and damage to the duodenal mucosa caused by exposure to
entraps capillaries as well as stromal and inflammatory cells. In addition, excessive gastric acid. It is estimated to affect up to 10%
there is intraepithelial lymphocytosis. B, A trichrome stain highlights the col-
lagen layer. of the Western population. Peptic disease is more com-
mon among men who are older than 40 years. Patients
often present with burning epigastric pain relieved by
■ TROPICAL SPRUE eating. In severe cases, the pain may be constant and
accompanied by nausea and vomiting.
Chronic infection with H. pylori is highly correlated
Tropical sprue (also known as postinfective tropical with peptic disease of the duodenum and is associated
malabsorption) is a rare disorder that mimics several with more than 80% of peptic ulcers. Mechanistically,
aspects of CD. It is an intestinal malabsorption of this occurs with antrum-predominant H. pylori infec-
unknown etiology that occurs among residents in or vis- tion, which stimulates gastrin secretion, and in turn,
itors to the tropics. No single causative agent has been increases acid production. Furthermore, peptic injury
identified to account for tropical sprue. However, the often results in gastric foveolar metaplasia, which can
following evidence favors an infectious cause: infection become secondarily colonized with H. pylori, further
often initiates and sustains tropical sprue, tropical sprue contributing to mucosal injury. Gastric foveolar meta-
occurs in specific geographic areas (West Indies and the plasia may represent an adaptation to chronic exposure
Indian subcontinent) where enteric infections are com- to hyperacidity. Other factors, such as smoking, NSAIDs,
mon, tropical sprue is endemic in some areas, and recov- renal insufficiency, or duodenal dysmotility, compro-
ery from tropical sprue with antibiotics is usually rapid mise mucosal defense mechanism and allow prolonged
and dramatic. Protozoan infections such as with contact with gastric acid, resulting in peptic injury.
Cyclospora have been suggested to play a role. Patients with multiple duodenal ulcers represent the
Gross findings are not well described but may include most severe form of the disease; multiple duodenal or
an abnormal villous pattern. Microscopically, tropical jejunal ulcers should raise concern for ZES. In the
sprue produces a marked increase in IELs. The villous absence of ZES, refractory ulcers may be seen in patients
with chronic NSAID use, gastric outlet obstruction or

duodenal stenosis, or those with a history of gastric
bypass procedure.
Pathologic Features
Gross Findings
Peptic duodenitis is most commonly seen in the duode-

nal bulb. The endoscopic appearance varies from simple
erythema to friability, erosions, and nodularity of the
mucosa (Fig. 5.7). Nodularity and polypoid lesions most
often correspond to Brunner’s gland hyperplasia or FIGURE 5.8
prominent foveolar hyperplasia. In PUD, the ulcers are Peptic duodenitis. The duodenal biopsy shows expansion of the lamina pro-
pria by a mixed inflammatory cell infiltrate that is predominantly composed
usually circular and rarely exceed 3 cm in diameter. of neutrophils. In addition, there is neutrophilic cryptitis.
They are typically located along the posterior wall of the
duodenal bulb and are more likely to present with perfo-
ration and massive hemorrhage because of their proxim-
ity to pancreaticoduodenal and gastroduodenal arteries.
In general, peptic duodenal disease shows the intact

villi with a neutrophilic inflammation pattern of injury.
There are expansion of the lamina propria by neutro-
phils and neutrophil-mediated epithelial injury (Fig.
5.8). There are an accompanying increase in lamina
propria plasma cells, reactive epithelial changes (mucin
loss, nuclear hyperchromasia), gastric foveolar meta-
plasia (Fig. 5.9) and Brunner’s gland hyperplasia. In
some instances, the Brunner’s glands may extend from
the submucosa into the basal aspect of the mucosa. In FIGURE 5.9
severe cases, villous blunting can be present as well—a Peptic duodenitis. Duodenal biopsy shows gastric surface foveolar metapla-
feature more in keeping with the flattened villi pattern sia as well as extension of Brunner’s gland within the lamina propria.
of injury. Severe peptic injury leads to ulceration

Liver
(PUD).
Ancillary Studies
Duodenal
“Prepyloric”
bulb ulcer
ulcers Ancillary stains are not generally used for diagnosis of
peptic disease but may be used to highlight a few inter-
esting features. Gastric foveolar metaplasia can be high-
lighted by a combination periodic acid–Schiff (PAS) and
Alcian blue (AB) stain that highlights the presence of
neutral mucin characteristic of the gastric foveolar meta-
Rugal plasia (Fig. 5.10). H. pylori may colonize areas of meta-
hypertrophy
plastic gastric epithelium because these cells express the
Autopsy specimen
same surface receptors as the native gastric epithelium.
The organisms may be highlighted by special stains such
FIGURE 5.7
as IHC, Giemsa, or Diff-Quik (Fig. 5.11). However, eval-
Peptic duodenal ulcer. The specimen shows an acute duodenal ulcer within
the duodenal bulb. Several small acute ulcers are also present in the prepy- uation of the gastric mucosa, when provided, is a pre-
loric region. ferred method to detect H. pylori infection.
FIGURE 5.10
FIGURE 5.12
Peptic duodenitis. The periodic acid–Schiff stain highlights the neutral mucin
present within the gastric foveolar metaplastic epithelium and the intramuco- “Lipid hang-up.” Duodenal biopsy showing vacuolization of the enterocyte epithe-
sal Brunner’s glands. The only residual Alcian blue–positive epithelium con- lium. These are physiologically normal enterocytes that retain lipid after a meal.
sists of scattered goblet cells, which represent intestinal-type mucin.
finding is seen in abetalipoproteinemia; however, the vacu-

olization affects the tips as well as the lateral aspect of the
villi. Gastric heterotopia may also be included in the differ-
ential diagnosis with peptic duodenitis resulting from the
prominent gastric foveolar epithelium. However, unlike pep-
tic duodenitis, gastric heterotopia can be recognized by nor-
mal-appearing oxyntic glands in association with the surface
gastric mucinous epithelium. Finally, chronic peptic injury
can also cause villous blunting with a variable degree of
intraepithelial lymphocytosis. Therefore, these findings
should prompt consideration of other disorders that produce
the flattened villi pattern of injury (e.g., CD).
Finally, although marked histologic abnormalities are
highly correlated with H. pylori infection, many duode-
nal biopsies show mild changes, with increased lympho-
FIGURE 5.11 plasmacytic inflammation in the lamina propria, gastric
Peptic duodenitis with Helicobacter pylori organisms (Diff-Quik stain). There foveolar cell metaplasia, and reactive epithelial changes
is gastric surface foveolar metaplasia with H. pylori organisms. (hyperchromasia and apical mucin attenuation).
Neutrophils may or may not be present. If a concurrent
Differential Diagnosis stomach biopsy shows no suggestion of H. pylori infec-
tion, it is unclear what diagnosis is most appropriate.
Various terms are commonly used, including peptic duo-
Peptic duodenal disease typically shows a neutrophilic pat- denitis and peptic duodenopathy. However, in the absence
tern of inflammation, and other causes that produce this of H. pylori, there is little evidence that these changes
pattern of injury include drug or medication injury (partic- are caused by stomach acid or any other “peptic” etiol-
ularly from NSAIDs), infections (other than from H. ogy. Therefore, when these cases are encountered, it is
pylori), and IBD. Occasionally, there are specific clues to probably best to be descriptive and simply list the spe-
distinguish between these possibilities. For example, crypt cific histologic abnormalities that are present.
distortion and granuloma formation in conjunction with
involvement of the rest of the GI tract would be highly sus-
picious for Crohn’s disease. Some infectious causes, includ-
ing CMV and adenovirus, can be detected microscopically.
Although gastric foveolar metaplasia is a common fea-
ture of peptic duodenal disease, “lipid hang-up” is a common The eradication of H. pylori and the use of acid-suppres-
mimic. It results from physiologically normal vacuolization sive therapies improve symptoms in most patients with
of the enterocyte cytoplasm resulting from a recent fatty peptic duodenitis. Medical therapy is mainly intended to
meal (Fig. 5.12). Compared with gastric foveolar metaplasia, reduce gastric acid by small meals, antacids, and hista-
which is PAS positive, these vacuoles are PAS–AB negative mine-2 (H2) blockers. Patients should avoid substances
and are only localized to the tips of the villi. A similar that promote gastric acid secretion, such as alcohol.
Aspirin and other NSAIDs should also be avoided

because they inhibit mucosal defenses. Peptic Duodenal Disease—Pathologic Features
Bleeding ulcers are estimated to be responsible for up
to 50% of all cases of acute hemorrhage from the upper Gross Findings
n Circular ulcers in the duodenum, most commonly involving the
GI tract. Up to 5% of patients may have bleeding that is
duodenal bulb
brisk enough to cause hematochezia. Even if initially con- n Nodularity or polypoid areas may represent Brunner’s gland
trolled, rebleeding can affect up to one-third of patients, hyperplasia
most commonly patients in the seventh decade of life or
beyond or those with a visible vessel in the ulcer base. Microscopic Findings
Refractory ulcers heal slowly or follow a relapsing and n Neutrophilic inflammation (both in the lamina propria and
remitting course. Scarring of duodenal ulcers may lead to epithelium)

n Increase plasmacytic inflammation
duodenal stricturing and obstruction.
n Gastric foveolar metaplasia
Free perforation of a duodenal ulcer into the perito- n Brunner’s gland hyperplasia
neal cavity can be a catastrophic, life-threatening event. n Reactive epithelial changes (apical mucin loss, hyperchromasia)
Most patients with this complication are older adults, n Villous blunting is variable
and the perforations are associated with NSAID use in

up to half of cases. However, in patients younger than Differential Diagnosis
n Nonsteroidal antiinflammatory drug injury
75 years, smoking may be a stronger risk factor for per-
n Infection
foration than NSAIDs. n Inflammatory bowel disease
n Malabsorptive disorders (if villous blunting is prominent)
PEPTIC DUODENAL DISEASE—FACT SHEET
Definition
n Damage to the duodenal mucosa resulting from exposure to
excess gastric acid
Incidence
n Common; up to 10% of population in Western countries

n Severe disease can cause perforation or life-threatening bleeding

n More common among men who are older than 40 years
Clinical Features
n 70% of patients are asymptomatic
n Dyspepsia is most common symptom, classically 2 to 5 hours
after a meal
n In severe cases, bleeding and perforation may occur
FIGURE 5.13
Bacterial overgrowth. Small intestinal mucosa with intact callous architecture
Prognosis and Therapy and increased intraepithelial lymphocytes. The lamina propria is only slightly
expanded by chronic inflammatory cells.
n Antisecretory therapy to reduce acid production
n Helicobacter pylori eradication if H. pylori is present
n Prognosis usually favorable, though life-threatening ulcer
perforation is possible lesions, such as diverticula and surgical anastomoses.

n Surgical therapy occasionally indicated for refractory ulcers Certain drugs may also slow intestinal motility (e.g.,
narcotics and benzodiazepines). Stasis allows accumula-
tion of anaerobic bacteria that deconjugate bile salts,
deplete vitamin B12, and damage surface epithelium.
■ SMALL INTESTINAL BACTERIAL
Patients may experience bloating, abdominal pain, diar-
OVERGROWTH
rhea, dyspepsia, or weight loss, though some patients
are asymptomatic. The pathologic features can be quite
Bacterial overgrowth is another cause of small intestinal variable. There is often mild to moderate villous blunt-
malabsorption. Although the causes of bacterial over- ing, but complete villous blunting is uncommon. IELs
growth are numerous, most result in intestinal stasis; are also increased but typically not to the degree that is
thus, these disorders are also known as stasis syndrome. seen in CD (Fig. 5.13). The gold-standard test for SIBO
Causes of stasis in the small bowel include motor or neu- involves aspiration of small intestinal fluid and demon-
ral disorders that affect intestinal motility such as dia- stration of greater than 105 colony forming units per
betic neuropathy and scleroderma, as well as structural milliliter of fluid. A carbohydrate-based breath test can
also be used, which is simple and noninvasive. Breath Pathologic Features

tests are based on the principle that a test dose of carbo-
hydrate will be metabolized by bacterial flora, and cer-
tain metabolites can be detected in the breath. Gross Findings
The two main goals of SIBO treatment are to correct
the underlying disease process, if possible, and to Most commonly, NSAIDs injury consists of localized
decrease bacterial load. Antibiotics reduce the bacterial erosions and ulcers. More rarely, NSAID may cause
burden, which leads to symptomatic improvement. chronic damage that includes varying degrees of muco-
Dietary changes may also be helpful to provide nutrients sal and submucosal fibrosis, ultimately broadening and
that are quickly absorbed and less metabolized by bacte- forming flat strictures. There may also be mucosal mem-
ria, such as a high-fat, low-carbohydrate diet. Finally, branes that divide the lumen of the small intestine into
prokinetic agents (e.g., metoclopramide) may be useful, compartments, and this appearance is termed diaphragm
though their benefit is not well-established. disease.
■ NONSTEROIDAL ANTIINFLAMMATORY
DRUG–ASSOCIATED INJURY Microscopic Findings
Clinical Features Typically, NSAID damage shows the intact villi with
neutrophilic inflammation pattern of injury, with
expansion of the lamina propria by neutrophils.
Nonsteroidal antiinflammatory drugs are a widely pre- Epithelial injury is usually present and may be associ-
scribed class of medication and can cause injury throughout ated with erosion or ulcer surrounded by reactive epi-
the GI tract in those consuming the medication. NSAID thelial changes. NSAID injury may also take the form of
injury occurs via both local and systemic mechanisms. prominent mucosal eosinophilia, presumably via a
Locally, NSAIDs may pass directly into epithelial cells and hypersensitivity mechanism (Fig. 5.14). In resection
become ionized and trapped within. Inside the cell, these specimens, these changes are patchy in distribution with
compounds can disrupt oxidative phosphorylation and multifocal superficial ulcers.
deplete adenosine triphosphate stores. Systemically, NSAIDs In chronic NSAID injury, there are villous blunting
nonselectively inhibit cyclooxygenase isoenzymes and sup- and crypt hyperplasia—features of the flattened villi
presses prostaglandin synthesis. Certain prostaglandins pattern of injury. In other cases, crypt distortion and
downregulated by NSAIDs are important for maintaining pyloric gland metaplasia are often present. With ongo-
several aspects of mucosal protection, including supporting ing injury, there are thickening of the muscularis
mucin production, mucosal blood flow, and bicarbonate mucosae and a disorganized proliferation of smooth
secretion. Thus, although ulceration is relatively common, muscle fibers, nerves, and vessels within the submu-
chronic use can cause fibrosis, stricture, perforation, and for- cosa. These findings indicate reparative changes that
mation of mucosal diaphragms—so-called diaphragm disease. are most prominent in areas with stricture formation.
NONSTEROIDAL ANTIINFLAMMATORY DRUG–

ASSOCIATED SMALL BOWEL LESIONS—FACT SHEET
Definition
n Ulcers, strictures, and mucosal diaphragms associated with
nonsteroidal antiinflammatory drug (NSAID) use
Incidence
n Overall unknown
n Ulcers are most common, strictures less so, and “diaphragm
disease” is rare

n Data from 1997 showed 107,000 hospitalizations and 16,500
deaths resulting from NSAID consumption in the United States

alone (data are not specific to the gastrointestinal [GI] tract)
n The incidence of GI perforations, symptomatic gastroduodenal FIGURE 5.14
ulcers, and upper GI bleeding in persons known to be taking Nonsteroidal antiinflammatory drug (NSAID)–associated injury. The duode-
NSAIDs is about 3% over 2 years nal biopsy from a patient with history of NSAID use shows distortion of the
n A minority of these patients die of these complications villous and crypt architecture with expansion of lamina propria by eosino-
phils, lymphocytes, and plasma cells.
It has been suggested that ischemia, inflammation, and Differential Diagnosis

repeated mucosal injury contribute to these pathologic
changes.
Rarely, chronic injury can lead to diaphragm dis- Because NSAIDs injury can produce each of the major
ease. The pathogenesis of this phenomenon is not well patterns of small intestinal injury, the differential diag-
understood but likely involves repeated cycles of injury nosis depends on which pattern is present. The neutro-
and repair. There may be superficial annular or longi- philic inflammation pattern is most common, the
tudinal ulcers. The submucosa is widened, creating differential diagnosis for which includes H. pylori infec-
annular constriction of the lumen, and it is replaced by tion, Crohn’s disease, and reactive duodenopathy. In
disorganized fascicles of smooth muscles (i.e., muscu- patients with chronic NSAID use, chronic ischemia,
larization of the submucosa), bundles of unmyelinated Crohn’s disease, and Behçet’s disease are in the differen-
nerve fibers with scattered ganglion cells, and numer- tial diagnosis. Clinical findings are key in distinguishing
ous blood vessels. These changes may extend to the NSAID injury from Behçet’s disease. Behçet’s syndrome
serosa. is characterized by lymphocytic vasculitis that affects
Nonsteroidal antiinflammatory drugs can produce veins and less commonly the arteries. Crohn’s disease is
any major patterns of small intestinal injury that distinguished from NSAID injury by the presence of
includes neutrophilic inflammation, eosinophilic inflam- deep fissuring ulcers, transmural lymphoid aggregates,
mation, the flattened villi pattern, and the architectural and granulomas. Chronic ischemia is a close mimic and
distortion pattern. Again, NSAID injury can also pro- requires assessment of mesenteric vessels. When villous
duce lesions with a paucity of chronic inflammation, blunting is a prominent feature, it should prompt con-
which is a relatively distinct feature. Overall, the diagno- sideration of other malabsorptive disorders. Ultimately,
sis of NSAID injury always requires correlation with as with any other medication, confirmation of causal
clinical findings and exclusion of other causes. association requires correlation with history of drug
intake and resolution of symptoms after discontinuation
of the drug.
Nonsteroidal Antiinflammatory Drug–Associated Small

Bowel Lesions—Pathologic Features Prognosis and Therapy
Gross Findings
n Perforations and ulcers associated with nonsteroidal The prognosis is excellent for patients with NSAID
antiinflammatory drugs (NSAIDs) do not have a specific ulcers if the medication is discontinued. For patients
appearance, nor do the strictures of the small bowel requiring resections owing to strictures or diaphragm
n Diaphragm disease has a relatively unique pattern, consisting of
disease, the prognosis is good, and the risks are typically
mucosal membranes separating segments of the small bowel
those associated with the surgical procedure itself.
n Intact villi with numerous neutrophils within the lamina propria
along with neutrophilic epithelial injury; occasionally mucosal

eosinophilia
■ OLMESARTAN-ASSOCIATED SPRUE-LIKE
n Erosions and superficial ulcers may be present
ENTEROPATHY
n Chronic NSAID injury shows crypt architectural distortion, pyloric
gland metaplasia, thickening of muscularis mucosae, submucosal

fibrosis, and proliferation of nerves, vessels, and smooth muscle Olmesartan is an antihypertensive drug and a member
n Chronic NSAID injury may present as villous blunting with or of the angiotensin receptor blocker (ARB) family of
without intraepithelial lymphocytosis compounds. Recently, this drug has shown to cause a
n In patients with diaphragm disease, the submucosa is widened,
sprue-like enteropathy in some patients who have neg-
creating annular constriction of the lumen, and is replaced by
disorganized fascicles of smooth muscles (i.e., muscularization of
ative celiac serologies. Patients typically present with
the submucosa), bundles of unmyelinated nerve fibers with diarrhea and weight loss. The length of time between
scattered ganglion cells, and numerous blood vessels olmesartan use and onset of symptoms is highly vari-
able and ranges from a few weeks to 10 years.
Differential Diagnosis Histologically, olmesartan enteropathy may mimic all
n Peptic duodenal disease of the features of CD, with most cases showing villous
n Infection
blunting and increased IELs. Nearly one-third of cases
n Ischemia
n Inflammatory bowel disease

also show features of collagenous sprue (Fig. 5.15).
n Behçet’s disease Finally, these patients often have concomitant collage-
n Malabsorption disorders (if villous blunting is prominent or IELs nous or lymphocytic gastritis or colitis. Symptoms
are increased) quickly resolve with cessation of drug. Other members
of the ARB family result in a similar sprue-like

Olmesartan-associated sprue-like enteropathy. The duodenal biopsy shows Common variable immunodeficiency. The duodenal biopsy shows preserved
villous blunting, intraepithelial lymphocytosis, and crypt hyperplasia along architecture without any plasma cells in the lamina propria.
with thickening of the subepithelial collagen layer similar to collagenous
sprue.
Pathologic Features
enteropathy. In general, it is prudent to consider ARB- Gross Findings

induced mucosal injury in a patient with celiac-
seronegative enteropathy. In most cases, the mucosa is grossly unremarkable.
■ COMMON VARIABLE IMMUNODEFICIENCY
Common variable immunodeficiency has variable histo-
logic findings but is most consistent with the flattened villi
Clinical Features pattern of injury with villous blunting and intraepithelial
lymphocytosis. Prominent lymphoid aggregates, increased
crypt apoptosis, and granulomas are occasionally identi-
Common variable immunodeficiency is the second most fied. A feature specific for CVID is the pronounced paucity
common primary immunodeficiency syndrome (the first or even absence of plasma cells, which results from defects
being select IgA deficiency). Patients may present at any in B-cell maturation (Fig. 5.16). However, about one-third
age with heterogeneous symptoms, including recurrent of cases have relatively normal numbers, though, in these
infections, various autoimmune diseases, GI complaints, cases, the plasma cells are functionally abnormal. Given
and lymphoma. Consistent with its variable presentation, the susceptibility to infection, the histologic picture may be
CVID actually represents a group of diseases likely caused dominated by features caused by a specific infection, such
by a variety of different gene defects but ultimately lead- as Giardia or CMV. Finally, CVID is often not clinically
ing to immunoglobulin deficiency. Known gene defects suspected, and the absence of plasma cells is subtle.
account for only 10% of cases (mutations in inducible Therefore, it is prudent to verify the presence of plasma
T-cell costimulator [ICOS], calcium-modulating cyclophi- cells in at least one specimen from every case regardless of
lin ligand interactor [TACI], CD19, CD20, CD21, CD80, indication or histologic picture.
and B-cell activating factor receptor [BAFFR]). Nearly
80% of cases are sporadic in nature. CVID is primarily a
disorder of B-cell differentiation, though T-cell dysfunc-
tion is also present in about 40% of cases.
CVID is occasionally diagnosed in childhood, but Histologically, the differential diagnosis includes other
most patients are diagnosed between the ages of 20 and diseases that produce the flattened villi pattern of injury,
45 years. CVID is diagnosed by demonstrating low particularly CD. In fact, many patients ultimately diag-
immunoglobulin levels. IgG is most commonly depleted, nosed with CVID carry a prior, incorrect, diagnosis of
but IgA and IgM levels may be low as well. A poor or CD. For the pathologist, the best feature to separate the
absent response to vaccination can also be evidence of two entities is the lack of plasma cells. Granulomas and
underlying CVID. Finally, CVID is a diagnosis of exclu- prominent apoptosis are present in a minority of cases
sion and can only be made when a more specific immu- and should prompt consideration of Crohn’s disease and
nodeficiency disorder is ruled out. AIE, respectively. Ultimately, the diagnosis of CVID
must be confirmed by demonstrating low serum immu-

noglobulin levels. Common Variable Immunodeficiency—Pathologic Features
Gross Findings
n No characteristic gross findings
n Villous blunting
Therapy for most patients consists of mitigating the risk
n Intraepithelial lymphocytosis
of infectious disease. The mainstay of treatment for CVID n Prominent lymphoid aggregates
is IgG replacement, which reduces the incidence of recur- n Decreased plasma cells
rent infections and has been shown to reduce antibiotic n Granulomas
use and decrease hospitalizations. With respect to vacci-

nations, certain live vaccines are contraindicated. Patients Differential Diagnosis
n Celiac disease
should receive killed or inactivated vaccines, although
n Autoimmune enteropathy
patients may only mount a partial response.
n Crohn’s disease
Beyond infection, patients with CVID are also at risk
for autoimmune disease, chronic lung disease, granulo-
matous disease, and malignancy (specifically lymphoma
and gastric cancer). Therapy for these patients is tai- common in children, AIE may be seen in adults as well.
lored to the specific coexisting disease. The prognosis in In AIE, the immune system attacks the intestinal
CVID greatly improved after the introduction of IgG mucosa, leading to severe malabsorption symptoms.
therapy, before which death from bacterial infection was Patients usually generate a variety of autoantibodies
common. Currently, the prognosis is driven mostly by against self-antigens in different organs, including the
the presence of coexisting disease. Patients most com- pancreas, small intestine, and thyroid. Therefore, in
monly die of chronic lung disease or malignancy. addition to AIE, other autoimmune diseases such as dia-
betes mellitus, thyroiditis, or hemolytic anemia may also
be seen in these patients. Patients with AIE present
with severe and persistent inflammatory diarrhea,
COMMON VARIABLE IMMUNODEFICIENCY—FACT SHEET abdominal pain, weight loss, and malnutrition. Weight
loss and malnutrition can be so severe that parenteral
Definition
nutrition is often required. The symptoms are unre-
n Immunodeficiency disorder characterized by low circulating
immunoglobulins
sponsive to dietary restriction.
Circulating gut epithelial cell autoantibodies, such as
Incidence anti–goblet cell or antienterocyte antibodies, are often
n 1 in 25,000 present in AIE patients. The correlation between the
n Most commonly diagnosed between ages 20 and 45 years presence of these antibodies and AIE pathogenesis is
somewhat unclear; therefore, the diagnostic utility of
Morbidity and Mortality gut autoantibodies is also a matter of debate. The pres-
n Rate of infections greatly reduced with IgG therapy
ence of anti–goblet cell antibodies correlates with
n Long-term prognosis driven by coexisting disease (lung disease,
autoimmune disease, malignancy)

absence of goblet cells only in some patients.
Furthermore, although almost all patients with AIE
Clinical Features have detectable gut autoantibodies, they are not entirely
n Recurrent infections (most commonly upper respiratory, lower specific for AIE. These antibodies can also be detected
respiratory, and gastrointestinal) in patients with other enteropathies, including CD, IBD,
n Autoimmune disease
and irritable bowel syndrome.
n Chronic lung disease
AIE is known to be part of two inherited syndromes.
n Malignancy
Immunodysregulation, polyendocrinopathy, enteropa-
thy, and X-linked inheritance (IPEX) syndrome is a par-
ticular form of AIE seen in male infants caused by
mutations in FOXP3 gene on the X chromosome. The
■ AUTOIMMUNE ENTEROPATHY
other inherited syndromic association is autoimmune
polyendocrinopathy, mucocutaneous candidiasis, and
Clinical Features ectodermal dystrophy (APECED) syndrome, also
known as autoimmune polyendocrine syndrome type 1
(APS-1). Defects in the transcription factor autoim-
AIE is a rare disease that typically presents with chronic mune regulator (AIRE) underlie this syndrome. Patients
diarrhea in the first few months of life. Although more present with Candida infections and later develop
hypoparathyroidism, Addison’s disease, and possibly

autoimmune gastritis, autoimmune hepatitis, type 1 dia-
betes, gonadal dysfunction, and hair and nail loss.
AUTOIMMUNE ENTEROPATHY—FACT SHEET
Definition
n Gastrointestinal mucosal damage caused by antienterocyte or
anti–goblet cell antibodies
Incidence
n 25% of infants with intractable diarrhea
A
n Rare in adults

n Failure to thrive
Clinical Features
n Protracted hypersecretory diarrhea
n Weight loss
n Malnutrition
Prognosis
n High mortality rate (∼30%) for immunodysregulation,
polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX)
B
FIGURE 5.17
Pathologic Features
Autoimmune enteropathy. A, Duodenal mucosa shows normal villous archi-
tecture. Even at low magnification, one can see lack of goblet cells and
Gross Findings Paneth cells within this biopsy. B, The crypts characteristically show increased
apoptotic activity. Note the lack of Paneth cells. The crypts show more promi-
nent intraepithelial lymphocytosis compared with the surface epithelium.
Endoscopic findings include loss of the normal mucosal
folds with ulceration and hyperemia. The entire GI tract
can be involved, though the most severe disease is often
seen in the small bowel. AUTOIMMUNE ENTEROPATHY—PATHOLOGIC FEATURES
Microscopic Findings Gross Findings

n Villous atrophy
AIE has variable histology but falls best into the flat- n Mucosal erythema
tened villi pattern of injury with villous blunting as a

constant feature. Most cases show a relatively specific Microscopic Findings
pattern of additional features, with crypt lymphocytosis n Villous blunting and crypt hyperplasia
n Most cases have increased intraepithelial lymphocytosis in crypts

(more than those present within the villous tips),
greater than villous tips
increased crypt apoptosis, and a prominence of mono- n Increased crypt apoptosis
nuclear inflammatory cells in the lamina propria. n Absent goblet cells, Paneth cells, brush border, or
Additionally, some cases lack goblet cells, Paneth cells, enteroendocrine cells
enteroendocrine cells, and brush border (Fig. 5.17). n Increased mononuclear inflammation of the lamina propria
However, a significant proportion of cases, 20% to 50%,

have histology indistinguishable from that of CD. These
n Celiac disease
cases lack significant crypt apoptosis and have surface n Common variable immunodeficiency
intraepithelial lymphocytosis rather than deep crypt n Microvillus inclusion disease
lymphocytosis. n Congenital tufting enteropathy
Finally, the absence of goblet cells, Paneth cells, and n Enteroendocrine cell dysgenesis
enteroendocrine cells can easily go unnoticed,

especially when the histologic picture dominated by

villous blunting. Therefore, it is important to verify the
presence of these cell types in any abnormal small
intestinal mucosa.
AIE is commonly considered in infants with intractable

diarrhea when common illnesses, such as infections and
food sensitive enteropathies, have been excluded. CD is
the most common mimic. Presence of crypt apoptosis,
crypt lymphocytosis more than villous tip lymphocyto-
sis, and lack of goblet cells, Paneth cells, or enteroendo-
crine cells favor AIE compared with CD. Serologic tests
(circulating gut epithelial cell antibodies, celiac serolo-
gies) should be performed to help this distinction. Some
patients may receive an initial diagnosis of CD, but AIE
should be considered if symptoms persist on a gluten-
free diet. FIGURE 5.18
Common variable immunodeficiency can also be Microvillus inclusion disease. The duodenal biopsy shows complete loss of
associated with crypt apoptosis. However, paucity of the brush border and apical vacuolization on the left half of the image. The
plasma cells should raise the possibility of CVID and section of enterocytes on the right have an intact brush border but do have
early apical vacuolization.
prompt serum immunoglobulin quantification studies.
In the absence of significant inflammation, congenital
enteropathies should be considered, including microvil- defective organelle transport. It is inherited in an auto-
lus inclusion disease (MVID) and congenital tufting somal recessive pattern and results in mutations in
enteropathy. Lack of enteroendocrine cells should raise MYO5B, which codes for myosin-Vb. Myosin-Vb partic-
the possibility of enteroendocrine cell dysgenesis (see ipates in organelle transport and endosome recycling.
later). Although these disorders may show some fea- Infants present with intractable diarrhea, severe malab-
tures overlapping with AIE, they are not inflammatory sorption, and negative stool cultures.
disorders by nature, thus allowing distinction from AIE. Duodenal biopsy shows moderate to diffuse villous
blunting without significant inflammatory activity or
intraepithelial lymphocytosis. Because of increased crypt
cell apoptosis, either crypt hypoplasia or hyperplasia can
be found. The most characteristic finding of MVID is a
bubbly or vacuolated appearance of the apical enterocyte
The mainstay of treatment for AIE is immunosuppres- cytoplasm with extensive or patchy absence of the brush
sive therapy. In infancy, nutritional support and ade- border (Fig. 5.18). Definitive diagnosis requires ancillary
quate hydration are also needed to ensure optimal stains or methods. PAS is a useful ancillary stain that high-
growth and development. Most patients respond well to lights brush border. In MVID, there are disruption of the
this treatment with a high survival rate. Restoration of normal brush border and misplacement of brush border
goblet and Paneth cells is observed in some patients after within the enterocyte cytoplasm, resulting in the forma-
treatment. However, patients with IPEX syndrome usu- tion of cytoplasmic inclusions (Fig. 5.19A). The diagnosis,
ally have a poor response to therapy, show a high mortal- however, should be confirmed with a more specific method.
ity rate, and require hematopoietic cell transplantation In the past, electron microscopy (EM) was required for this
as a definitive form of therapy. purpose. EM characteristically shows reduced or complete
absence of microvilli on the surface of the enterocytes and
vacuoles filled with microvilli (Fig. 5.19B). In addition,
these cells show intracytoplasmic inclusions lined by
■ MICROVILLUS INCLUSION DISEASE
neatly arranged brush border microvilli. The crypt epithe-
lial cells show increased secretory granules. More recently,
Microvillus inclusion disease (also known as Davidson’s IHC for villin has been shown to produce a highly charac-
disease, familial microvillus atrophy, congenital micro- teristic staining pattern in MVID. The differential diagno-
villus atrophy, or intestinal microvillus dystrophy) is a sis includes other diseases that cause intractable diarrhea
rare congenital malabsorption disorder caused by in infancy (e.g., congenital tufting enteropathy,
FIGURE 5.20
Congenital tufting enteropathy. The duodenal biopsy shows disorganization
of the surface epithelium. These surface enterocytes show formation of clus-
ters or tufts of cells.
The small intestinal mucosa shows severe villous

atrophy. However, there is no significant increase in
lamina propria inflammatory cells, and intraepithelial
lymphocytosis is absent. Characteristically, the superfi-
cial epithelium shows disorganization of the surface
enterocytes, forming “tufts” (Fig. 5.20). In contrast to
MVID, the brush border is normal. Epithelial abnormal-
ities can vary over time and may be extremely subtle at
presentation. Immunostaining is helpful to make the
B
diagnosis because patients with EpCAM mutations have
FIGURE 5.19 decreased or absent expression of EpCAM, the target of
Microvillus inclusion disease. A, Duodenal biopsy stained with Alcian blue– the MOC31 antibody.
periodic acid–Schiff highlight the alcianophilic apical vacuoles. Notice the Although tufting enteropathy mimics other entities
complete absence of normal brush border. B, Electron microscopy shows
enterocytes containing vacuoles filled with microvilli. The overlying and adja- that cause intractable diarrhea of infancy, lack of
cent surface has abnormal villi. EpCAM staining is helpful in confirming the diagnosis
of tufting enteropathy. In most cases, the condition is
life threatening and requires TPN or small bowel trans-
enteroendocrine cell deficiency, AIE), though the biopsy plantation. However, there is a subset of patients with
findings are sufficient to discriminate between these possi- variant EpCAM mutations that have a more “benign”
bilities. The disease is life threatening and requires clinical course. Some patients in this category can even-
lifelong total parenteral nutrition (TPN) or small bowel tually be weaned from TPN.
transplantation.
■ ENTEROENDOCRINE CELL DYSGENESIS

■ CONGENITAL TUFTING ENTEROPATHY
(INTESTINAL DYSPLASIA)
Enteroendocrine cell dysgenesis is an autosomal
recessive disorder caused by mutations in NEUROG3,
Congenital tufting enteropathy is inherited in an autoso- leading to an absence of intestinal enteroendocrine
mal recessive pattern and is most prevalent among indi- cells. Patients have diarrhea and profound malabsorp-
viduals of Arabic origin. Clinical presentation is similar tion of all nutrients from birth. The hallmark histo-
to MVID. Infants present with intractable watery diar- logic feature is an absence of enteroendocrine cells in
rhea in the neonatal period. Mutations of epithelial cellu- the small bowel and colon. Otherwise, the histologic
lar adhesion molecule (EpCAM), a cell adhesion-receptor, changes are minimal, often showing only mild villous
and SPINT2, a serine protease inhibitor, have been impli- atrophy, if any. The differential diagnosis includes
cated in this condition. other causes of intractable diarrhea of infancy.
Although the absence of enteroendocrine cells is ■ CROHN’S DISEASE

highly suggestive of enteroendocrine cell dysgenesis,
some cases of AIE can show absence of these cells as
well. However, the histologic background should Clinical Features
allow separation of these entities because AIE is typi-
cally associated with intraepithelial lymphocytosis,
increased crypt apoptosis, and loss of goblet and Burrill Crohn published his seminal work on this entity
Paneth cells (see section on AIE). Patients with in 1932, describing “regional ileitis,” as a stricturing, fis-
enteroendocrine cell dysgenesis require lifelong TPN tulizing, inflammatory disease of the ileum. Crohn’s dis-
or small intestinal transplantation. ease is most prevalent in Western countries with an
annual incidence of approximately 10 per 100,000. The
cause of Crohn’s disease is unknown but is thought to be
an abnormal response to gut flora in a genetically sus-
■ ABETALIPOPROTEINEMIA
ceptible individual. Crohn’s disease has a strong genetic
component with a concordance rate of 50% in monozy-
Abetalipoproteinemia (also known as Bassen-Kornzweig gotic twin studies. Numerous susceptibility loci have
disease) is a disorder caused by mutations in microsomal been linked to the pathogenesis of Crohn’s disease. One
triglyceride transfer protein (MTTP) and is inherited in of the earliest genes identified was IBD1, which encodes
an autosomal recessive pattern. MTTP is essential for the the NOD2 protein (also known as CARD15). NOD2
formation of apo B–containing lipoproteins including activates nuclear factor κB (NF-κB) in response to frag-
chylomicrons, low-density lipoprotein, and very-low- ments of the bacterial cell wall. In one study, NOD2
density lipoprotein. Because this disorder leads to an mutations were found in 42% of children with early-
inability to package lipids such as chylomicrons, it mani- onset Crohn’s disease. Other susceptibility loci encode
fests with symptoms of fat malabsorption disorder and proteins involved in cell autophagy, adaptive immunity,
deficiency of fat-soluble vitamins. Patients typically pres- and epithelial function and underscore the importance
ent in early childhood with abdominal distension, ste- of these functions in the pathogenesis of Crohn’s dis-
atorrhea, and failure to thrive. Mental retardation, ease. Furthermore, various clinical features of Crohn’s
neuropathic changes, and coagulopathy occur as the dis- disease show heritable patterns and concordance within
ease progresses. Small bowel biopsies show prominent family members such as similar disease location (ileal vs
and diffuse vacuolization of the enterocytes. This histo- ileocolonic) and type (stenotic, fistulizing).
logic feature may mimic the much more commonly- Crohn’s disease may involve any portion of the tubu-
encountered phenomenon “lipid hang-up” caused by lar GI tract. The Montreal classification is commonly
postprandial lipid accumulation. However, the changes in used to classify the disease and incorporates age at dis-
abetalipoproteinemia are much more florid and not ease onset, principal anatomic location, and clinical
restricted to the villous tips. The villous architecture is behavior (Table 5.3). Most patients have small intestinal
preserved, and usually there is no significant epithelial disease (80%) usually in the distal ileum, with one-third
injury. Liver biopsy may reveal steatosis. The diagnosis is having ileal disease exclusively. The terminal ileum is
not solely a pathologic diagnosis, and affected patients the most commonly affected location. In contrast, duo-
have characteristic abnormalities in hematologic and denal involvement is much more uncommon (1%–7%).
lipid profiles. Treatment consists of strict adherence to a
low-fat diet and supplementation with essential fatty
acids and high doses of fat-soluble vitamins. Outcome is
TABLE 5.3
variable, but early diagnosis and strict compliance with
diet can prevent disease progression. Montreal Classification of Crohn’s Disease
AGE AT DIAGNOSIS
• A1: younger than 16 years
• A2: between 17 and 40 years
■ SMALL INTESTINAL INFLAMMATORY • A3: older than 40 years
BOWEL DISEASE LOCATION
• L1: ileal
• L2: colonic
Traditionally, IBD of the small intestine was considered • L3: ileocolonic
to be the exclusive domain of Crohn’s disease. We now • L4: isolated upper tract disease
appreciate that this dichotomy is not entirely accurate BEHAVIOR
because there are reports of the upper GI tract involve- • B1: nonstricturing, nonpenetrating
ment in patients with ulcerative colitis (UC) as well. In • B2: stricturing
this chapter, only Crohn’s disease is discussed. UC is • B3: penetrating
• p: perianal disease
presented in Chapter 10.
About 50% of patients show involvement of both the

small bowel and colon (usually localized to ileocolonic
region). In patients with involvement of both the small
bowel and colon, the rectum is normal in about half of
cases; this is a striking contrast to UC, in which the rec-
tum is nearly always involved. A minority of patients
have isolated colonic Crohn’s disease (20%). Among
these patients, about 50% have right-sided colitis, 40%
have left-sided colitis, and 6% have pancolonic involve-
ment. About one-third of patients have perianal disease, a
feature that is highly specific for Crohn’s disease over UC.
Most patients with Crohn’s disease present with a
variety of symptoms, including diarrhea, steatorrhea,
chronic abdominal pain, perianal disease, oral ulcers, FIGURE 5.21
and malabsorption symptoms (weight loss, fatigue, ane- Crohn’s disease. The small bowel resection specimen shows a segment of
mia). Patients with the stenotic form of Crohn’s disease stenotic bowel with longitudinal, fissuring ulcers, and cobblestone appear-
present with symptoms of intestinal obstruction. ance of the mucosa.
assessed on resection specimens. Early in the disease pro-

cess, the classic aphthous ulcer corresponds to a zone of
active inflammation with superficial erosion, typically over-
lying a lymphoid aggregate. As the disease becomes more
severe, these erosions may grow into “fissuring ulcers,”
Gross Findings
which are penetrating ulcers that extend into the submucosa
or muscularis propria.
Crohn’s disease has a number of distinct gross findings. The accompanying mucosal findings include variable
Fat wrapping, or creeping fat, is characteristic of Crohn’s degree of chronic mucosal injury with or without activ-
disease and is characterized by overgrowth of mesenteric ity (Fig. 5.22A). Features of chronic mucosal injury
fat around the serosal surface of the bowel. There may be include crypt or villous architectural distortion, basal
adhesions or fistula formation between the involved lymphoplasmacytosis, basal lymphoid aggregates, and
bowel and any nearby organs. Fat wrapping, adhesion pyloric gland metaplasia (Fig. 5.22B). Activity typically
formation, and fistula formation are related to the deep, consists of neutrophil- (or eosinophil-) mediated epithe-
transmural inflammatory activity that is characteristic of lial injury in the form of cryptitis and crypt abscesses.
Crohn’s disease. The bowel is typically fibrotic and stiff, Thickening of muscularis mucosae is often present and
forming “hose-like” segments that do not lie flat on the is best assessed on resection specimens. Overall, this
grossing bench. This stiffness is caused by a combination combination of features falls into the “chronic mucosal
of submucosal fibrosis, obliterative muscularization of injury” of injury as outlined in the introduction section
the submucosa, and hypertrophy of the muscularis proof this chapter. In segments of small bowel wall affected
pria. These factors also contribute to luminal stenosis by Crohn’s disease, the submucosa may show fibrosis
that becomes evident after opening the specimen. along with obliterative muscularization. Deep fissuring
Aphthous ulcers are the earliest mucosal lesions found ulcers usually extend into the submucosa and superficial
in Crohn’s disease. These are pinpoint erosions often muscularis propria. The bowel wall is characterized by
found in the distal terminal ileum and are a useful endo- transmural inflammation in the form of transmural lym-
scopic clue for Crohn’s disease. As the disease becomes phoid aggregates as well as lymphoid aggregates at the
more extensive, the mucosa shows characteristic fissuring, junction of muscularis propria and serosa (Fig. 5.22C).
forming “bear claw” ulcers that surround intact mucosa. Other findings include neural hyperplasia and lympho-
At this stage, mucosa often shows a “cobblestone” appear- cytic plexitis. Mural fibrosis, serositis, and adhesions are
ance that results from extensive anastomosing ulcers common in areas of fistula formation.
delimiting small patches of intact mucosa (Fig. 5.21). Nearly 50% to 60% of patients with Crohn’s disease
show granulomas in resection specimens. They are typ-
ically noncaseating and often poorly formed and peri-
vascular in distribution (Fig. 5.22D). These granulomas
need to be distinguished from crypt rupture–related
granulomas, which are more common in UC. One-third
The microscopic features of Crohn’s disease can be divided of patients with Crohn’s disease do not form granulo-
into mucosal and mural findings; the latter are considered to mas, so the absence of granulomas does not necessarily
be more pathognomonic of Crohn’s disease and can only be exclude a diagnosis of Crohn’s disease, especially in
A B
C D
FIGURE 5.22
Crohn’s disease. A, The duodenal mucosa shows villous blunting and crypt architectural distortion. The lamina propria is
expanded by mixed inflammatory cell infiltrate, and there is prominent neutrophilic epithelial injury with erosion B, Pyloric
gland metaplasia in a patient with Crohn’s disease. This finding indicates chronic or prior mucosal injury and may be seen
in conditions other than Crohn’s disease, such as nonsteroidal antiinflammatory drug–related chronic small bowel injury
(The black triangles are arrow heads). C, Small bowel resection specimen of Crohn’s disease showing chronic active enteri-
tis with mucosal erosion and characteristic transmural lymphoid aggregates with mural fibrosis. D, Duodenal mucosa with
granulomas in a patient with Crohn’s disease.
biopsy material, in which only a small sample of the activity) includes infections, drug injury, ischemia, and
mucosa is evaluated. In keeping with the transmural IBD. However, given that the pathognomonic findings of
nature of Crohn’s disease, granulomas may be seen in Crohn’s disease are transmural, a definitive diagnosis of
any layer of the bowel wall, including within and deep Crohn’s disease cannot be made on the basis of mucosal
to the muscularis propria. Granulomas are often present biopsy specimens. In the early phases of Crohn’s disease,
within regional lymph nodes and can occasionally be the biopsy may only show activity without features of
seen within lymphatic spaces as well. In cases in which chronic mucosal injury. In these cases, the differential
granulomas are far too numerous or show necrosis diagnosis primarily involves infections and drug- or
(“atypical” granulomas), special stains should be per- medication-related injury (especially NSAIDs) and less
formed to exclude an infectious cause. likely ischemia. When features of chronic mucosal
injury (crypt and villous distortion, pyloric gland meta-
plasia, diffuse lymphoplasmacytosis) are present, IBD is
more likely.
The differential diagnosis of granulomas includes
infection (e.g., mycobacterium, fungus, Yersinia spp.)
In biopsy specimens, the differential diagnosis for archi- and sarcoidosis. A rare cause of granulomas is chronic
tectural distortion pattern of injury (with or without granulomatous disease (CGD), a form of inherited
immunodeficiency. CGD patients are typically infants or colon, or the variability of involvement of the upper GI
children with recurrent infections. Besides granulomas, tract in Crohn’s disease or UC, may be entirely false.
the intestinal lamina propria also shows characteristic Interestingly, most, if not all, contemporary studies of
pigmented macrophages, which contain a yellow-brown presumed “backwash ileitis” reveal data that are not
lipofuscin-like pigment. compatible with the proposed mechanism of action of
A rare mimic of Crohn’s disease is Behçet’s disease, a backwash ileitis. The more likely possibility is that ile-
vasculitis that occurs primarily in Asians and is rare in itis in UC may simply represent a primary manifestation
Western countries. Behçet’s disease is a systemic disor- of UC in this portion of the GI tract, and this is a theory
der consisting of oral ulceration plus two of the follow- that needs to be tested further in future.
ing: recurrent genital ulcers, eye lesions, skin lesions,
and a positive pathergy test result (an abnormal response
to minor skin injury). Patients may experience symp-
toms similar to Crohn’s disease. In the GI tract, Behçet’s
CROHN’S DISEASE—FACT SHEET
disease most frequently involves the terminal ileum and
may produce ulcerated lesions histologically identical to
Definition
those seen in Crohn’s disease. In contrast to Crohn’s dis-
n Chronic multifocal relapsing and remitting inflammatory disease
ease, examination of the submucosa should reveal of unknown cause
small-vessel phlebitis (larger vessels are typically unaf- n May affect any portion of the gastrointestinal tract (mouth to
fected). Furthermore, strictures and fistulas are not fea- anus)

tures of Behçet’s disease, and other clinical findings are
usually sufficient to distinguish between these entities. Incidence. Prevalence and Location
n Incidence: approximately 1 to 10 per 100,000
In small bowel resection specimens, the differential
n Prevalence: 10 to 200 per 100,000
diagnosis for Crohn’s disease includes drug-induced n Higher incidence in North Americans and Northern Europeans
injury (especially NSAIDs), chronic ischemia, chronic
infection, and Behçet’s disease. NSAID-induced injury Gender, Race, and Age Distribution
usually occurs in older patients with a history of NSAID n Males and females equally affected
intake for chronic pain. Similar to Crohn’s disease, the n Higher incidence in North Americans and Northern Europeans
n Higher incidence in Ashkenazi Jews

mucosa shows chronic enteritis (with or without activ-
n Major peak at 20 to 30 years of age
ity) and submucosal or mural fibrosis in a segmental dis-
n Minor peak at 60 to 70 years of age
tribution. However, transmural lymphoid aggregates are
usually not seen in NSAID-related enteritis. Chronic Clinical Features
NSAID injury can show characteristic mucosal and sub- n Cramping pain, nonbloody diarrhea, fever, malaise, and anorexia
mucosal widening, creating annular constriction of the n Fistulas, stenosis
lumen (“diaphragm disease”) that may mimic stenotic n Hemorrhage and hematochezia uncommon
n Anal and perianal fissures and fistulas

Crohn’s disease, the results of repeated cycles of mucosal
n Inflammatory involvement can occur in joints, eyes, liver, and skin
injury and repair. Ultimately, confirming NSAID-related
injury is difficult because it requires a detailed examina- Prognosis and Therapy
tion of the patient’s clinical history, specifically the tim- n Cure: none
ing and dosage of the suspected drug. n Low mortality, high morbidity
Often, the differential diagnosis is primarily between n Medical treatment: 5-aminosalicylate, sulfasalazine, oral steroids,
UC and Crohn’s disease. The distribution of the disease antibiotics, infliximab

n Surgical management for obstruction or medically refractory
is important to consider as Crohn’s disease can affect
disease
any portion of the GI tract, often in a discontinuous n Increased risk of dysplasia and adenocarcinoma
fashion with intervening areas of normal mucosa (i.e., n Ileal pouch anal anastomosis procedure is contraindicated
“skip lesions”). In contrast, UC typically extends proxi-

mally from the rectum in a continuous fashion, gener-
ally sparing the small bowel.
Small bowel involvement can be seen in some patients
■ GRAFT-VERSUS-HOST DISEASE
with UC (see Chapter 10). This is believed to be caused
by reflux of colonic contents through the damaged ileo-
cecal valve and was termed “backwash ileitis.” A recent Clinical Features
critical review of the literature by Patil and Odze1 related
to “backwash ileitis” suggests that the originally pro-
posed theory of this condition, which has never been Graft-versus-host disease is one of the most common
proven experimentally and was postulated during a time complications after hematopoietic stem cell transplanta-
when little was known regarding the pathologic mani- tion (HSCT). It occurs when donor immune cells react
festation of Crohn’s disease in the GI tract, including the against recipient tissues that are not recognized as
Whereas acute GVHD principally involves the tubu-

Crohn’s Disiease—Pathologic Features lar GI tract, liver, and skin, chronic GVHD can also
affect the lungs, eyes, muscles, connective tissue,
Gross Findings joints, and nails. According to the National Institutes
n Patchy involvement of Health (NIH) consensus development project, fea-
n Firm, thickened, and pipe-like bowel
ture of chronic GVHD can be divided into “diagnostic
n Interloop adhesions
n Aphthous erosions
features” and “distinctive features.” Diagnostic fea-
n Longitudinal ulcers tures, when present, are sufficient for the diagnosis of
n Cobblestoning chronic GVHD without need for further investiga-
n Inflammatory polyps tion. Distinctive features, although suggestive of
n Fistulas
chronic GVHD, require additional studies, such as
biopsy or laboratory testing, to verify the diagnosis.
In the GI tract, the only diagnostic feature of chronic
n Aphthous or fissuring ulcers
n Granulomas (noncaseating, frequently poorly formed)

GVHD is the presence of esophageal webs, provided
n Chronic enteritis with or without activity, crypt and villous they were not present before HCST.
distortion, basal lymphoplasmacytosis, expansion of the lamina
propria by lymphocytes and plasma cells, and pyloric gland
metaplasia
n Submucosal fibrosis
GASTROINTESTINAL GVHD—FACT SHEET
n Transmural lymphoid aggregates
n Neural hyperplasia and lymphocytic plexitis

Definition
n Gastrointestinal mucosal damage caused by the engraftment of
donor T lymphocytes
n Infectious enteritis (especially Yersinia spp.)
n Medication-associated colitis (especially nonsteroidal

Incidence
antiinflammatory drugs)
n 10% to 40% of patients with allogeneic hematopoietic stem cell
n Ileal involvement in ulcerative colitis
n Ischemia
transplant
n Up to 13% of patients with autologous hematopoietic stem cell
n Behçet’s disease
n If granulomas present: sarcoidosis, chronic granulomatous

transplant
n Fewer than 1% of patients with solid organ transplant
disease, infections (e.g., Yersinia spp., mycobacteria, fungus)

n Responsible for approximately 50% of transplant-related deaths
“self.” GVHD has classically been divided into acute Clinical Features
and chronic forms, which vary in timing, patient symp- n Diarrhea
n Crampy abdominal pain

toms, end-organ involvement, treatment, and progno-
n Nausea and vomiting
sis. Historically, acute GVHD was diagnosed within
the first 100 days after HSCT; disease after this point Prognosis
was considered chronic GVHD. However, now it is rec- n Fewer than 50% of patients achieve a complete resolution after
ognized that acute GVHD may occur after 100 days, treatment
and features of chronic GVHD may start to appear n Transplant-related mortality for nonresponders is 49% to 75%
prior to 100 days.

Acute GVHD most often occurs 2 to 3 weeks after
HSCT and occurs in 40% to 50% of patients. The prin-
cipal targets are the tubular GI tract, the liver, and the
skin. GI symptoms include crampy abdominal pain,
diarrhea, nausea, and vomiting. Acute GVHD of the GI
tract is graded clinically according to volume of diar-
Gross Findings
rhea. There are additional clinical grading criteria for
skin and liver involvement.
With respect to chronic GVHD, it is unclear if it The gross endoscopic appearance of GVHD can be vari-
represents a late manifestation of acute GVHD or if it able. In most cases, the mucosa may either appear nor-
is a separate manifestation of immunologic injury. mal or show edema with or without erythema. In severe
Acute GVHD is a risk factor for the later development cases, ulcer, nodularity, friability, diffuse bleeding, or
of chronic GVHD. In contrast to acute GVHD, chronic mucosal sloughing can be seen. Although the entire GI
GVHD more resemble autoimmune or immunologic tract can be involved, the involvement is usually patchy.
disorders such as Sjögren syndrome, scleroderma, pri- Esophageal webs are a diagnostic feature of chronic
mary biliary cholangitis, and bronchiolitis obliterans. GVHD.
FIGURE 5.23
Graft-versus-host disease (GVHD). The duodenal biopsy shows prominent
apoptotic activity within the crypts. Epithelial cell apoptosis is a key histologic FIGURE 5.24
feature of GVHD (black arrows). Grade 4 graft-versus-host disease in a duodenal biopsy. There are extensive
crypt loss, mucosal denudation, and granulation tissue formation.
TABLE 5.4 Finally, “likely GVHD” is appropriate when there is clear

Graft-versus-Host Disease Guidelines: 2014 evidence of GVHD without a competing cause of injury
National Institutes of Health Pathology Working or mitigating factors. The minimal criteria for diagnosis
Group: Recommendations for Final Diagnosis of GVHD are not well established, but the NIH consensus
Categories. document recommends the presence of greater than one
NOT GVHD apoptotic body per fragment of the biopsy specimen is
• No evidence for GVHD sufficient for a diagnosis of GVHD.
POSSIBLE GVHD Graft-versus-host disease grading is still performed in
• Evidence of GVHD but other possible explanations (e.g., many centers because it provides some quantification of
CMV, possible drug reaction) mucosal injury, but it is unclear if pathologic grading offers
LIKELY GVHD much additional value over clinical grading alone. Various
• Clear evidence of GVHD without a competing cause of
grading schemes exist, but a system modified by Lerner is
injury
• Clear evidence of GVHD with mitigating factors most commonly used in daily practice: grade 1, isolated
• GVHD is most likely diagnosis, but relevant clinical apoptotic bodies; grade 2, loss or damage of individual
information is limited crypts; grade 3, loss of two or more contiguous crypts; and
• GVHD is validated by sequential biopsy or by absence of a grade 4, extensive crypt loss or denudation (Fig. 5.24).
competing diagnosis
GASTROINTESTINAL GRAFT-VERSUS-HOST DISEASE—
PATHOLOGIC FEATURES
Crypt apoptosis is the histologic hallmark of GVHD. It is
prominent in the deep aspects of the crypts (Fig. 5.23). Gross Findings
Early changes consist only of apoptotic activity. With n Mucosal edema and erythema
progressive injury, apoptosis is accompanied by crypt n Ulcer, nodularity, friability
dropout, neutrophilic epithelial injury, crypt abscesses, n Diffuse bleeding
n Mucosal sloughing
villous blunting, and ulceration. Paneth cell loss may
occur and is associated with poor prognosis. Small clus-
ters of enteroneuroendocrine cells may be present at the
n Crypt apoptosis
bases of crypts because these cells are much more resis- n Crypt dropout
tant to immunologic injury. n Crypt abscesses
The 2014 report from the NIH consensus project on n Ulcer
n Neuroendocrine cell clusters

GVHD recommended three diagnostic categories for
GVHD: not GVHD, possible GVHD, and likely GVHD
(Table 5.4). “Not GVHD” is appropriate when there is no
n Cytomegalovirus infection
evidence of GVHD. If there is some evidence of GVHD n Cryptosporidium infection
but there are other possible explanations (CMV coinfec- n Toxicity from conditioning regimen
tion, possibility of drug reaction such as MMF-induced n Mycophenolate mofetil-induced injury
injury), a diagnosis of “possible GVHD” is recommended.

When grade of GVHD is reported, the highest grade should second-line options include MMF, tacrolimus, antithy-
be reported per anatomic segment of involvement. mocyte globulin, cyclosporine, photophoresis, sirolimus,
and pentostatin. About 40% of patients achieve com-
plete resolution with initial therapy. In patients requir-
ing second-line therapy, there are a lower likelihood of
complete resolution and an increased incidence of recur-
rent episodes of GVHD. Patients with no response have
Infections and drug toxicities can mimic GI GVHD in a mortality rate as high as 75%.
patients who have received HSCT. Because treatments Chronic GVHD is the single most important determi-
for these conditions are very different compared with nant of long-term outcome in HSCT patients. It occurs
GVHD, differentiation of GI GVHD from its mimics is in 50% of long-term survivors of HLA-identical sibling
critical. transplants. Mortality rate varies with severity of dis-
Cytomegalovirus infection is a frequent complication ease, which can be graded based on the revised 2014
of HCST, and CMV enteritis may occur concomitantly NIH consensus guidelines. Mild disease involves two or
with GI GVHD. They also share a similar key finding: fewer organs or sites with no clinically significant func-
increased crypt apoptosis. However, CMV enteritis is tional impairment (97% 2-year survival rate). Moderate
often associated with neutrophilic cryptitis and crypt disease involves three or more organs or sites with no
abscesses. Sometimes nuclear inclusions in CMV enteri- clinically significant functional impairment or at least
tis maybe very sparse, and an immunohistochemical one organ or site with clinically significant functional
stain may be needed to demonstrate the inclusions. impairment but no major disability (86% 2-year sur-
Infection with cryptosporidium can also cause crypt vival rate). Severe disease involves major disability
apoptosis. These organisms appear as basophilic, round, caused by chronic GVHD (62% 2-year survival rate).
predominantly extracellular organisms located along the The mainstay of treatment is steroids. Unfortunately,
microvillous brush board (see Chapter 9 for additional there is a 50% failure rate of front-line steroid treat-
details). ment. Given the poorly understood nature of this dis-
Early GVHD must be differentiated from toxicity due ease, specific agents for the treatment of patients with
to the pretransplant conditioning regimen. The condi- chronic GVHD do not yet exist.
tioning regimen may result in changes nearly indistin-
guishable from GVHD, with increased apoptosis, mitotic
activity, and regenerative epithelial changes. However,
■ EOSINOPHILIC GASTROENTERITIS
the histologic changes caused by conditioning regimen
usually resolve within 20 days after transplantation.
Severe mucosal injury, such as ulcers, is unusual with Clinical Features
conditioning regimen (even at day 20), and thus is more
likely to represent GVHD.
Mycophenolate mofetil is a common immunosup- Eosinophilia in the small bowel can be seen in isolation
pressive drug used in transplant patients (see Chapter 10 (eosinophilic enteritis) or as part of eosinophilic gastro-
for details). In the ileum and colon, MMF may produce enteritis (EGE), which includes eosinophilic esophagi-
a variety of injury patterns such as those mimicking tis, eosinophilic gastritis, and eosinophilic colitis. EGE
GVHD (increased apoptosis), acute self-limited or infec- is a poorly characterized clinicopathologic entity. The
tious colitis (cryptitis, crypt abscesses), and IBD (archi- incidence rate in the United States is estimated to be 22
tectural distortion, crypt loss, Paneth cell metaplasia). to 28 per 100,000 persons. It can occur at any age but
The distinction between MMF toxicity and GVHD is presents most often in the third through fifth decades of
particularly challenging, though some histologic fea- life. An allergic component is suspected because some
tures can suggest one process over the other. Whereas patients improve with dietary modifications.
significant eosinophilia (>15 per 10 hpf) is more com- One early description of EGE classified it into three
mon in MMF toxicity, apoptotic crypt abscesses and forms, depending on the bowel layer involved: mucosal,
neuroendocrine cell aggregates are more suggestive of mural, and serosal. Patients with mucosal-predominant
GVHD. Finally, clinical information regarding the dos- disease present with diarrhea, hemorrhage, and pro-
age of MMF is helpful to confirm MMF toxicity. tein-losing enteropathy. Patients with mural disease
present with abdominal pain, intestinal obstruction,
nausea, and vomiting, and those with serosal involve-
ment may additionally develop ascites, which is rich in
eosinophils. Mucosal disease is the most common form
(50% of cases); the serosal EGE is much less common.
For acute GVHD, steroids are the first-line treatment. The laboratory findings in patients with EGE include
For patients who do not respond to initial therapy, a peripheral blood eosinophilia but are normal in 20%
of patients. Serum IgE is commonly elevated. Mucosal

EGE may cause iron deficiency, prolonged prothrom-
bin time, and hypoalbuminemia caused by
malabsorption.
Gross Findings
A
Mucosal EGE may show erosions or ulcers. In cases
with mural disease, the bowel wall shows thickening
and induration.
In the mucosal form of EGE, there are sheets of eosino-

phils within the lamina propria. Eosinophils may be
intact or degranulated. Features of epithelial injury,
such as eosinophilic cryptitis, eosinophilic crypts
abscesses, erosions, and ulceration, are usually present.
Because the disease can show patchy distribution, the
findings can vary between biopsy samples and within
each biopsy fragment.
The mural form is characterized by eosinophilic infil- B
tration and edema of the submucosa and muscularis
FIGURE 5.25
propria (Fig. 5.25). In the serosal form, the eosinophils
Eosinophilic enteritis, mural form. A, Segment of small bowel with ulcer and
are limited to the serosa and subserosa. In the absence of submucosal fibrosis. B, The bowel wall shows sheets of eosinophils with the
mucosal disease, a diagnosis of EGE can be difficult to muscularis propria.
establish. Serosal disease can be detected with ascitic
fluid analysis, but mural disease may require full-thick-
ness biopsy or resection. In these cases, a high degree of eosinophils/hpf as the cut-off. In the pediatric population,
suspicion is required. the peak numbers of eosinophils per hpf were reported as
26/hpf for duodenum and 28/hpf for the ileum in one
Differential Diagnosis study and 52/hpf for the duodenum and 68/hpf for the
ileum in another study. Although prototypical cases show
Mucosal eosinophilia can be seen in the context of a a conspicuous increase in eosinophils, often in sheets, the
variety of other diseases. In particular, increased eosin- pathologists often encounter cases with borderline find-
ophilia can be seen in the context of hypersensitivity ings. In these cases, the report can be descriptive (e.g.,
reactions, including allergies and hypersensitivity to “small bowel mucosa with increased intramucosal eosin-
drugs or medications, IBD, parasitic infection, connec- ophils”), and the comment can include a differential diag-
tive tissue disorders, and vasculitis. Systemic mastocy- nosis of intramucosal eosinophilia. A few additional
tosis also lead to mucosal eosinophilia because mast factors suggest a truly pathologic process. These include
cells appear to attract eosinophils. However, mast cells evidence of epithelial injury (e.g., eosinophilic crypt
can be rather inconspicuous, and the increase in eosin- abscesses or cryptitis), the presence of eosinophils in the
ophils may be the most eye-catching feature at first muscularis propria or submucosa, and eosinophilia in
glance. Finally, LCH is usually rich in eosinophils, more than one site or organ.
though LCH is usually an endoscopically discrete
lesion.
The histologic characteristic of this disorder is simple—
a marked increase the number of eosinophils.
Unfortunately, the normal range of eosinophils in the
small bowel mucosa is quite broad, and rigorous quantita- Patients are initially managed with dietary modification,
tive criteria for establishing this diagnosis do not exist. which includes eliminating the most common food aller-
Some of the proposed criteria include greater than 21 gens (milk, eggs, wheat, soy, peanuts, tree nuts, and
seafood). Alternatively, patients may be administered an form of treatment. Patients who experience relapses after
elemental diet, consisting of amino acids, fat, and sugars, initial therapy may require long-term treatment.
which contains no allergens. If necessary, oral prednisone
may be necessary to manage symptoms. Surgical manage-
ment is uncommon but occasionally indicated if obstruc-
■ ISCHEMIC OR HEMORRHAGIC ENTERITIS
tion occurs. The natural history of EGE is not well
defined. Some patients remit spontaneously without
treatment, and many respond completely to the initial Clinical Features
EOSINOPHILIC GASTROENTERITIS—FACT SHEET Ischemic or hemorrhagic enteritis results from multiple

causes that compromise the vascular supply of the small
Definition bowel. Depending on the clinical manifestation and onset
n Idiopathic inflammatory disorder characterized by eosinophil- of symptoms, intestinal ischemia is classified into acute
mediated injury versus chronic mesenteric ischemia. Patients with acute
mesenteric ischemia present with sudden-onset abdomi-
Incidence nal pain that lasts for more than 2 to 3 hours. In contrast,
n Approximately 22 to 28 per 100,000
chronic mesenteric ischemia (“intestinal angina”) is
n Most commonly presents in the third to fifth decades of life
characterized by postprandial abdominal pain and
Morbidity and Mortality chronic weight loss caused by malabsorption. Intestinal
n Not life threatening
ischemia results from occlusive or nonocclusive causes of
n Morbidity associated with obstruction and symptoms vascular compromise. Occlusive causes include vascular
thrombi, emboli, hypovolemia-induced vasoconstriction,
Clinical Features extrinsic compression caused by tumors, adhesion, stric-
n Mucosal disease (gastrointestinal bleeding, diarrhea, protein- tures, strangulation, and volvulus, among others. Patients
losing enteropathy) at risk include those with a history of previous arterial
n Mural disease (abdominal pain, nausea, vomiting)
n Subserosal disease (abdominal pain, nausea, vomiting, ascites)

emboli, vasculitis, deep vein thromboses, chronic post-
prandial pain, and hypercoagulable states (protein C and
Prognosis and Therapy S deficiencies, antithrombin III deficiency, and activated
n Oral steroids protein C resistance, among others). In younger patients,
n Surgical management for obstruction is occasionally needed use of oral contraceptives, polyarteritis nodosa, Henoch-
n Natural history is largely unknown Schönlein purpura, and other causes of systemic vasculi-
n Some patients have spontaneous remission
tis can result in mesenteric ischemia.
n Some patients have a recurring or continuous course
Nonocclusive ischemic enteritis is caused by arterial
hypoperfusion, often leading to spasm of the superior
mesenteric artery. Patients are often critically ill with
severe preexisting cardiovascular disease. Specific risks
include heart failure or cardiogenic shock, septic shock,
Eosinophilic Gastroenteritis—Pathologic Features peripheral artery disease, aortic insufficiency, cardiac
arrhythmias, and vasoconstrictive drugs or medica-
Gross Findings tions (e.g., alpha-adrenergics, digoxin, cocaine).
n Ulceration (mucosal disease) Ischemic enteritis has a poor prognosis, and mortality
n Thickening and induration of the bowel wall (mural disease) rates in large studies range from 30% to 65%. Diagnosis
before intestinal infarction is the key factor to improve
Microscopic Findings these poor results. Relief of persistent vasoconstriction,
n Marked mucosal, mural, or serosal eosinophilia
which is the cause of nonocclusive mesenteric ischemia
n Epithelial injury (eosinophilic cryptitis, eosinophilic crypt
abscesses)
and occurs in association with occlusive forms of isch-
n Erosion and ulceration in mucosal disease
emia, is another important factor.
Radiologic studies are important for diagnosis. Plain
Differential Diagnosis films are insensitive for ischemic enteritis but are useful to
n Allergy rule out other causes of abdominal pain (e.g., perforation).
n Drug reaction Abdominal computed tomography (CT) with intravenous
n Parasite infection
contrast is the most widely used study with a sensitivity of
n Vasculitis
93% and specificity of 96% for the detection of acute mes-
n Systemic mastocytosis enteric ischemia. If the CT scan is inconclusive, arteriogra-
n Langerhans cell histiocytosis phy can be used, which is considered the gold-standard
diagnosis.
ISCHEMIC OR HEMORRHAGIC ENTERITIS—FACT SHEET
Definition
n Injury to the bowel caused by insufficient blood flow
Prevalence
n Acute mesenteric ischemia accounts for 0.1% of all hospital
admissions

n High mortality for acute ischemic disease (30%–65%)

n Risk factors overlap those for vascular diseases
n Age older than 50 years A

n Nonocclusive ischemic enteritis associated with heart failure or
cardiogenic shock, septic shock, cardiac arrhythmias, peripheral

vascular disease, aortic insufficiency, and vasoconstrictive drugs or
medications
n Occlusive ischemic enteritis associated with arterial emboli,
vasculitis, deep vein thromboses, hypercoagulable states, stricture,

volvulus, and strangulation
n Oral contraceptive use, polyarteritis nodosa, Henoch-Schönlein
purpura, and other causes of systemic vasculitis in younger patients
Clinical Features
n Acute mesenteric ischemia: severe abdominal pain that persists
for more than 2 or 3 hours

n Chronic mesenteric ischemia (“intestinal angina”): postprandial
abdominal pain

n Poor prognosis for acute ischemia (70% mortality rate)
B
n Treatment includes anticoagulation and efforts to revascularize
the affected segment; chronic ischemia is treated by angioplasty FIGURE 5.26

or revascularization procedures Ischemic or hemorrhagic enteritis. A, Early acute ischemia characterized by
n When bowel wall necrosis and peritonitis have ensued, the enterocyte necrosis with luminal fibrinopurulent debris (top) and extensive
necrotic segment must be excised as promptly as possible lamina propria hemorrhage. B, Late ischemia with extensive submucosal
hemorrhage.
Pathologic Features With progressive ischemia, there are lamina propria

congestion with hyalinization and an atrophic or “with-
ered” appearance of the residual crypts (Fig. 5.26A).
Gross Findings Submucosa and muscularis propria are only affected in
cases of severe ischemia and may appear hemorrhagic
Bowel affected by acute mesenteric ischemia appears (Fig. 5.26B). Hemorrhage tends to be more pronounced
hemorrhagic. If gangrenous changes have ensued, bowel in cases caused by stricture, volvulus, or strangulation.
wall may be dilated. The mucosa surface shows features There may be prominent submucosal edema. In cases
of congestion, erosion, ulceration, and pseudomem- with transmural necrosis, there is often a prominent
brane formation. Perforation may be present in some serosal fibroinflammatory response. Mesenteric blood
cases. If there is pneumatosis, the segment of bowel wall vessels should be sampled to evaluate for possible causes.
may be crepitant. In long-standing cases of mesenteric These may show evidence of vasculitis or thrombi. The
ischemia, there may be evidence of stricture formation. presence of thrombi within a necrotic segment of bowel
usually represents a secondary phenomenon and should
not be considered as the cause of the ischemic episode.
In chronic ischemic enteritis, the lamina propria may
show marked hyalinization. There is crypt architectural
distortion with or without pyloric gland metaplasia.
In early acute ischemia, the tips of the villi appear hyper- Neutrophilic epithelial injury is usually not seen. The
emic and show mucin loss in the surface epithelium. bowel wall shows submucosal as well as muscular
propria fibrosis. This is usually prominent in areas with perfusion with a thrombolytic agent, intraarterial infu-
stricture formation. sion of vasodilators, and simple systemic anticoagula-
tion are choices of therapy. In severe cases, surgical
resection of the affected segment is the best treatment.
In cases of chronic mesenteric ischemia, if a surgical
Ischemic or Hemorrhagic Enteritis—Pathologic Features
revascularization is performed, success rates and recur-
Gross Findings
rence rates for surgical revascularization range from
n Acute ischemic disease: mucosal erosion, hemorrhage, ulceration,
59% to 100% and 0% to 26.5%, respectively.
and necrosis, with or without perforation and peritonitis
n Chronic ischemia: strictures
Microscopic Findings ■ INFECTIOUS ENTERITIS

n Acute: mucin loss, crypt withering, lamina propria hyalinization
and congestion, submucosal edema

The majority of infectious agents that affect the colon
n Chronic: architectural distortion, pyloric gland metaplasia, lamina
propria hyalinization, fibrosis of the submucosa and muscularis can also affect the small bowel. These are addressed in
propria Chapter 9. In particular, Yersinia spp., viral agents, and
histoplasmosis are found in the small bowel and may
Differential Diagnosis mimic Crohn’s disease. The most common infectious
n Crohn’s disease pathogens affecting the small bowel are Whipple disease
n Nonsteroidal antiinflammatory drug injury
and Giardia, Cystoisospora, and Microsporidia infec-
tions. In particular, Whipple disease and M. avium-
intracellulare can expand the lamina propria and cause
villous blunting without significant intraepithelial
lymphocytosis.
With features of acute ischemia (mucin loss, crypt

■ PRIMARY LYMPHANGIECTASIA
withering lamina propria hyalinization, congestion)
the differential diagnosis primarily includes a drug or
medication injury. In particular, NSAIDs can produce Clinical Features
findings that closely mimic those of ischemia. The
overall clinical presentation as well as history of
NSAID use is most useful in differentiating these Primary intestinal lymphangiectasia is a rare digestive
possibilities. disorder characterized by dilated lymphatic channels.
With features of chronic ischemia (architectural dis- Most patients are diagnosed before the age of 3 years
tortion, pyloric gland metaplasia), the differential diag- and present with signs of growth retardation. GI symp-
nosis includes IBD (typically Crohn’s disease). On toms include diarrhea, vomiting, abdominal pain, and
resected material, strictures may be seen in both dis- steatorrhea. If large segments of the gut are involved,
eases, but the presence of transmural inflammation secondary edema resulting from protein-losing enterop-
away from deep ulcers, granulomas, and anal or perianal athy and malabsorption may occur. The edema is usu-
disease favors Crohn’s disease over NSAID-related ally generalized, but asymmetric edema is common.
injury. Finally, because of the prominent lamina propria Lymphangiectasia also has a few characteristic radio-
hyalinization and reactive epithelial changes, radiation logic and shows thickening of the bowel wall, hypodense
enteritis is in the differential diagnosis of chronic isch- streaks in the bowel (which represent dilated lymphatic
emia. However, radiation injury is usually associated channels), and the so-called “halo sign,” which consists
with either epithelial or stromal “atypia” and usually of distinct “rings” seen on CT scan.
occurs only in patients who have received radiation
therapy for pelvic cancers.

Gross Findings
The prognosis of acute mesenteric ischemia is poor

because it is often difficult to recognize clinically. If rec- The mucosa show white spots or nodules, and the back-
ognized early, surgical revascularization, intraarterial ground mucosa may be nodular.
PRIMARY INTESTINAL LYMPHANGIECTASIA

(WALDMANN’S DISEASE)—FACT SHEET
Definition
n Rare digestive disorder characterized by abnormally enlarged
(dilated) lymph vessels supplying the lamina propria of the small

intestine
Incidence
n Unknown

n Growth retardation common
n Reduced life span
n Poor prognosis associated with delay in diagnosis
FIGURE 5.27
Primary intestinal lymphangiectasia. Duodenal biopsy shows dilated lymphat-
n Presents in infancy ics within the villi. In the appropriate endoscopic and clinical setting, this is
n No gender or racial predilection diagnostic of primary lymphangiectasia.
Clinical Features
n Edema and nonbloody diarrhea Differential Diagnosis
n Edema in primary intestinal lymphangiectasia is usually bilateral
n Secondary types often manifest as unilateral edema, which is
caused by various neoplastic, infiltrative, and inflammatory lesions

affecting one side of the body The bowel lymphatics can become dilated in other condi-
n Steatorrhea, malabsorption, lymphocytopenia, and tions resulting in “secondary lymphangiectasia.” This
hypogammaglobulinemia may result from cardiac disease caused by congestive
n Chylous ascites and chylous pleural effusions
heart failure or constrictive cardiomyopathy. Alterna-
tively, there can be a local obstruction of lymphatics
n The long-term course is variable
caused by mechanical abnormalities (e.g., malrotation,
n Slow progression with intermittent clinical remissions
stricture), infection (e.g., Tuberculosis), infiltrating neo-
n Treatment includes a high-protein, low-fat diet fortified with plasm, sarcoidosis, or Crohn’s disease or after radiation
medium-chain triglycerides; octreotides have been reported to therapy. Usually, the age of the patient and overall clinical
decrease intestinal protein losses context are sufficient to distinguish between primary and
secondary lymphangiectasia.
Biopsy samples usually show multiple dilated lacteals
within the tips of the villi as well as within the lamina The long-term course is variable, but the disease usually
propria. There is usually no accompanying inflamma- shows an indolent course, with intermittent clinical
tion or epithelial injury (Fig. 5.27). remissions. The medical treatment includes high-pro-
tein, low-fat diet along with medium-chain triglycerides.
Octreotides have been reported to decrease intestinal
Primary Intestinal Lymphangiectasia (Waldmann Disease)— protein loss.
Pathologic Features
Gross Findings
n Numerous white spots at endoscopy
■ INCIDENTAL PIGMENTATION
Mucosal pigmentation within the small bowel may
n Many dilated lacteals with no inflammatory process
occur as an incidental finding, with no clinical signifi-
cance. There are two pigments that are relatively
n Cardiac disease (congestive heart failure, constrictive
restricted to the small intestine. The first, pseudomela-
cardiomyopathy) nosis duodeni, as the name suggests, is typically found
n Local obstruction (malrotation, stricture, infection, infiltrating in the duodenum, though is occasionally detected in the
neoplasm, sarcoidosis, Crohn’s disease, radiation therapy) stomach as well. The pigment is not melanin, nor does it
have any relationship to melanocytes. In fact, the
pigment is usually composed mostly of iron in combina-

tion with calcium, magnesium, aluminum, potassium,
silica, and sulfur. This brown-black pigment is most
commonly found within the macrophages in the tips of
the villi (Fig. 5.28). An iron stain can be helpful in high-
lighting this pigment; however, it can be negative in
about 25% of cases. Pseudomelanosis duodeni has been
linked to a number of disease states, including GI bleed-
ing, renal failure, diabetes, and hypertension as well as
iron supplement intake.
The second pigment, titanium, is unique to the ter-
minal ileum and accumulates within the Peyer’s
patches. This pigment is also present within macro-
phages and has a distinct speckled and black to brown
appearance (Fig. 5.29). Titanium, specifically titanium FIGURE 5.29
dioxide, is a component of a number of food and Titanium pigment in terminal ileum. Dark brown or black pigment within
hygiene products. It provides texture to food items and macrophages in terminal ileum Peyer’s patches. This material originates from
food additives.
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30. Goulet O, Salomon J, Ruemmele F, et al. Intestinal epithelial dys-
plasia (tufting enteropathy). Orphanet J Rare Dis. 2007;2(1):20. 50. Uguralp S, Mutus M, Kutlu O, et al. Primary intestinal
31. Sivagnanam M, Mueller JL, Lee H, et al. Identification of EpCAM lymphangiectasia: a rare disease in the differential diag-
as the gene for congenital tufting enteropathy. Gastroenterology. nosis of acute abdomen. J Pediatr Gastroenterol Nutr.
2008;135(2):429–437. 2001;33(October):508–510.
6
Neoplasms of the Small Intestine
■ Reetesh K. Pai, MD
The small intestine represents 75% of the length and of the entity. The distinction between Brunner’s gland
90% of the surface area of the gastrointestinal (GI) tract, hyperplasia and Brunner’s gland hamartoma is of no clin-
yet neoplasms of the small intestine are rare, accounting ical significance, and a diagnosis of Brunner’s gland
for only 1% to 2% of all GI neoplasms and fewer than hyperplasia and hamartoma is usually sufficient in large
1% of all cancers in the United States. Four major types polypoid lesions. Brunner’s gland cyst may be used for the
of primary neoplasms arise in the small intestine. They rare incidental cystic lesion that shows an ectatic Brunner’s
are, in order of descending frequency, adenocarcinomas, gland duct lined by a benign epithelium. Rare adenocarci-
neuroendocrine tumors (NETs; “carcinoid tumors”), nomas of the small intestine may show a gastric pyloric
lymphomas, and sarcomas. The small intestine is also the gland–like phenotype with small tubular glands and strong
most common site in the GI tract for involvement by sec- MUC6 positivity, which may be mistaken for Brunner’s
ondary tumors, which are more than twice as common as glands. However, these patients are symptomatic and typi-
primary small intestinal tumors. This chapter discusses cally show large, obstructing mass lesions on endoscopy
hyperplasias and heterotopias of the small intestine, pol- unlike the incidental small nodules characteristic of
yps, primary adenocarcinomas, NETs, and common sec- Brunner’s gland hyperplasia and hamartoma.
ondary tumors of the small intestine. Mesenchymal
tumors and lymphomas and are discussed separately in
Chapters 17 and 19, respectively.
Pathologic Features
The diagnostic criteria for Brunner’s gland hyperplasia

■ BRUNNER’S GLAND HYPERPLASIA AND are subjective because Brunner’s glands may be normally
HAMARTOMA seen in the lamina propria of the duodenum, particularly
within the duodenal bulb. Brunner’s gland hyperplasia
may manifest as solitary or multiple nodules that are typ-
Clinical Features
ically small (<1 cm) and characterized by lobules of glands
that are increased in both size and number (Fig. 6.1). The
Brunner’s glands can proliferate to create small polypoid lobules extend into the mucosa and are separated by deli-
excrescences, or the gland ducts can be blocked and pres- cate fibrous septa. Cystic dilation of Brunner’s gland
ent as small cystic nodules. These Brunner’s gland lesions ducts may occur, and small case series of Brunner’s gland
are commonly encountered in the duodenal bulb usually cysts have also been reported. The cells are cytologically
as an incidental finding at endoscopy. However, they may bland with abundant neutral mucin and small, basally
also be seen as one of a constellation of findings indicative located nuclei with minimal to absent mitotic activity.
of peptic duodenitis, including villous shortening and
gastric foveolar mucous cell metaplasia of the villous epi-
thelium. The nomenclature of Brunner’s gland lesions is
not well established, and a number of diagnostic terms,
including Brunner’s gland hyperplasia, Brunner’s gland
adenoma, and Brunner’s gland hamartoma, have been If histologic features indicative of peptic-type duodenal
used. The distinction between these diagnoses is arbi- injury are seen, the presence of Brunner’s gland hyper-
trary; however, the term Brunner’s gland adenoma is plasia should be attributed to peptic duodenitis.
potentially misleading because these lesions do not dis- Histologic features of peptic-type duodenal injury
play epithelial dysplasia. The term Brunner’s gland hyper- include active inflammation within the lamina pro-
plasia is preferred to highlight the non-neoplastic nature pria or epithelium, Brunner’s gland hyperplasia, and
151
FIGURE 6.1
Brunner’s gland hyperplasia: The lesion is characterized by prominent lob- FIGURE 6.3
ules of Brunner’s glands within the submucosa and lamina propria.
Gastric heterotopia: Tightly packed gastric oxyntic glands involving the duode-
nal mucosa. The surface epithelium also demonstrates gastric foveolar-type
metaplasia.
nodules. Gastric heterotopia may be associated with

fundic gland polyps of the stomach, suggesting that the
increased use of proton pump inhibitors (PPIs) in the
general population may enhance its endoscopic detec-
tion. The presence of gastric foveolar metaplasia in duo-
denal biopsies should prompt a careful look for presence
of heterotopic oxyntic glands because the increased acid
secretion from these glands can also lead to metaplastic
change of the surface epithelium.
FIGURE 6.2
Peptic duodenitis: Prominent Brunner’s glands within the submucosa and
Pathologic Features
lamina propria associated with foveolar-type metaplasia on the villous sur-
face of the duodenum and partial villous shortening are characteristic. In
contrast to the absorptive cells of the small intestine, foveolar metaplastic Biopsies of gastric heterotopias display oxyntic glands
cells have small apical mucin vacuoles (top left). composed of chief and parietal cells involving small
intestinal mucosa (Fig. 6.3). Gastric foveolar-type mucin
is often seen on the surface epithelium adjacent to nor-
mal intestinal villi.
gastric foveolar metaplasia of the surface epithelium
(Fig. 6.2).
■ GASTRIC HETEROTOPIA
Gastric heterotopia differs from gastric foveolar meta-
plasia, which is likely a metaplastic response to inflam-
Clinical and Endoscopic Features
mation caused by peptic injury. Metaplastic gastric
foveolar epithelium seen in the setting of peptic injury is
Gastric heterotopias are most commonly identified in not associated with the oxyntic glands characteristic of
the duodenum and are usually incidental small (<1.0 cm) gastric heterotopia.
CHAPTER 6 Neoplasms of the Small Intestine 153
■ PANCREATIC HETEROTOPIA identified. Unlike pancreatic heterotopia, paraduodenal

wall cyst shows significant inflammation and fibrosis and
occurs in the so-called “groove” between the superior
Clinical and Endoscopic Features aspect of the pancreatic head, the common bile duct, and
the duodenum. Most cases are characterized by multiple
Pancreatic heterotopia is synonymous with the terms pan- or solitary cysts varying in size from 1 to 10 cm within the
creatic rest and ectopic pancreas. Pancreatic heterotopia of duodenal wall and pancreas (Fig. 6.5). Cystically dilated
the small intestine is most commonly located in the proxi- ducts partially lined by ductal epithelium and containing
mal duodenum and is typically asymptomatic. Mural het- inspissated eosinophilic material are characteristic of this
erotopias may develop in the periampullary region and entity. The adjacent stroma often shows pronounced
may be symptomatic resulting from duodenal obstruction, myofibroblastic proliferation, which at times may be mis-
intussusception, and stricture or stenosis of the ampulla. taken for a mesenchymal tumor.
Pathologic Features ■ PYLORIC GLAND ADENOMA
Pancreatic heterotopia is composed of pancreatic acini, These polyps are more common in the stomach, but
ducts, or islets either alone or in combination and may pyloric gland adenomas can also occur in the duodenum.
be histologically indistinguishable from normal pan- They are composed of tightly packed glands lined by
creas (Fig. 6.4). Most mucosa-based lesions are not asso- cuboidal epithelium with a monomorphic, monolayer of
ciated with inflammation, and the duodenal mucosa is round nuclei located at the base of the glands with abun-
otherwise normal. Rare cases of ductal adenocarcinoma, dant eosinophilic to foamy cytoplasm reminiscent of
mucinous neoplasms, and NETs have been reported to pyloric-type glands (Fig. 6.6). Given their resemblance to
develop in pancreatic heterotopia. Brunner’s glands, the distinction between Brunner’s
gland hamartoma and hyperplasia can be difficult.
However, pyloric gland adenomas often do not have over-
lying intestinalized epithelium when they occur in the
duodenum. Furthermore, there is no lobular configura-
tion in these lesions in contrast to Brunner’s gland ham-
Paraduodenal wall cyst (“groove pancreatitis”) may be artoma and hyperplasia.
confused with mural pancreatic heterotopias because Pyloric gland adenomas exhibit dysplasia, classified as
both may contain pancreatic ducts, acini, and islets. either low or high grade. Between 10% and 30% of pyloric
Paraduodenal wall cyst typically involves the area of the gland adenomas are associated with invasive adenocarci-
minor papilla where pancreatic tissue may be normally noma. Given their association with adenocarcinoma,
FIGURE 6.5
FIGURE 6.4 Solitary paraduodenal wall cyst (“groove pancreatitis”) present at the minor
Pancreatic heterotopia: Lobules of ancreatic heterotopia consists of tightly papillae of the duodenum. This cyst was filled with proteinaceous debris and
packed pancreatic acini (bottom right) associated with pancreatic ducts (bot- lined by fibrotic stroma with reactive myofibroblastic cells within the duo-
tom left) located in the duodenum. In this image, the pancreatic heterotopia denal wall. Some cases of paraduodenal wall cyst may be characterized by
involves the duodenal submucosa, but it can involve any layer of the bowel wall. multiple cysts that are partially lined by ductal-type epithelium.
risk for small intestinal adenocarcinoma (100- to 200-

fold) followed by Crohn’s disease and GSE, each of which
increases the risk 80-fold. Other syndromes with
increased risk include Lynch syndrome, Peutz-Jeghers
syndrome, and juvenile polyposis syndrome.
The majority of small intestinal adenomas are located in
the duodenum, and like their colonic counterparts, exhibit
three major histologic types: tubular, tubulovillous, and vil-
lous (Fig. 6.7). True traditional serrated adenomas, similar
to their colonic counterparts, are incredibly rare (Fig. 6.8).
Most adenomas occur singly, and the presence of multiple
adenomas in the small intestine is unusual in the absence of
FAP, attenuated FAP, or MUTYH-associated polyposis.
Because of their potential to undergo malignant transforma-
tion, adenomas should be removed completely. Endoscopic
polypectomy is appropriate for pedunculated tumors, but
FIGURE 6.6 large sessile lesions require endoscopic mucosal resection,
Pyloric gland adenoma: Tightly packed glands lined by cuboidal epithelium
with basally located round nuclei. The epithelial cells have abundant eosin-
ophilic cytoplasm with a “ground-glass” appearance and without an apical
mucin cap.
complete endoscopic removal is advised for pyloric gland

adenomas. Pyloric gland adenomas can also be seen as an
upper GI tract manifestation of familial adenomatous polyp-
osis (FAP), either classic or attenuated, and of Lynch
syndrome.
■ CONVENTIONAL ADENOMA, SERRATED

POLYPS, AND ADENOCARCINOMA OF THE
SMALL INTESTINE
FIGURE 6.7
Clinical Features
Duodenal adenoma with tubulovillous growth pattern and low-grade dyspla-
sia characterized by pseudostratified, enlarged hyperchromatic nuclei. These
cytologic changes extend from the crypts to involve the surface epithelium.
Primary (“nonampullary”) adenocarcinoma of the small
intestine is rare, accounting for only 2% of GI tract tumors
and 1% of all GI tract cancer deaths. They present in older
adults (median age, 72 years) and with a nearly equal gen-
der distribution. Compared with colorectal carcinoma, a
higher proportion of small intestinal adenocarcinomas are
seen in African Americans than in whites. Like colorectal
adenocarcinomas, most small intestinal adenocarcinomas
are sporadic and arise from adenomatous polyps. Serrated
polyps, both hyperplastic polyps and traditional serrated
adenoma-like lesions, may also occur in the duodenum,
but are quite rare. Colonic sessile serrated polyp-like lesions
have not been described in the duodenum.
Risk factors for sporadic small intestinal adenocarci-
noma include smoking and consumption of alcohol, red
meat, and fats. Increased body mass index may also be a
risk factor. The remaining adenocarcinomas arise in the
background of certain predisposing conditions, including
polyposis syndromes, Crohn’s disease, Lynch syndrome, FIGURE 6.8
gluten-sensitive enteropathy (GSE), and in ileostomies, Traditional serrated adenoma of the small intestine is rare and poorly defined
and ileal conduits. FAP carries the greatest increase in entity, unlike it's colorectal counterpart
endoscopic submucosal dissection, or surgical resection. and ampullary tumors are small exophytic masses at the
Adenocarcinomas arising sporadically and in the setting of time of presentation. Distal tumors tend to be large,
most predisposing conditions also occur most frequently in annular, constricting (“apple core”) lesions with cir-
the duodenum, where 65% are periampullary. The inci- cumferential involvement of the bowel wall. Rarely,
dence decreases progressively through the rest of the small tumors can have a linitis plastica–like appearance. As in
intestine. Adenocarcinoma arising in Crohn’s disease is a the colon, depth of invasion and serosal involvement
notable exception to this rule. In Crohn’s disease, 70% of must be documented.
adenocarcinomas are found in the ileum, the primary site of Duodenal adenocarcinomas require additional sam-
the inflammatory process (Fig. 6.9). pling to evaluate the depth of retroperitoneal extension
The most common presenting symptoms of small intes- and involvement of the pancreas.
tinal adenocarcinoma are abdominal pain, obstruction,
and occult GI bleeding. Whereas patients with duodenal Microscopic Findings
adenocarcinomas may present with gastric outlet obstruc-
tion, the combination of obstructive jaundice with occult Small intestinal adenocarcinomas are histologically sim-
GI bleeding is characteristic of ampullary tumors. More ilar to colorectal adenocarcinomas (Fig. 6.10). They are
distal lesions tend to result in severe, cramping abdominal characterized by cellular pleomorphism, complex glan-
pain. Intestinal obstruction can be caused by progression dular architecture, luminal necrosis (so-called dirty
of a constricting (“apple core”) lesion or by a large intralu- necrosis), and invasion of the lamina propria or muscu-
minal polypoid mass. Distal adenocarcinomas tend to pres- laris mucosae (intramucosal adenocarcinoma) or deeper
ent with advanced stage III or IV disease. into the bowel wall. Most adenocarcinomas are well- to
Duodenal lesions can typically be detected on routine moderately differentiated, and one-third are poorly dif-
endoscopy, whereas more distal lesions may require ferentiated. An extremely rare subset of these poorly
push or capsule enteroscopy, intraoperative endoscopy, differentiated tumors may be a manifestation of the
or radiographic imaging modalities. Endoscopic ultra- recently described SMARCA4 or INI-1 deficient carci-
sound may be of use to assess depth of invasion and nomas, which must be excluded. Histologic grading and
local lymph node metastasis. classification (e.g., mucinous, adenosquamous) have lit-
tle bearing on prognosis, which is primarily dependent
on anatomic extent, resectability, and lymph node
involvement. The majority of small intestinal adenocar-
Pathologic Features
cinomas have invaded through the bowel wall at the
time of diagnosis. Notably, intramucosal carcinomas of
Gross Findings the small bowel are staged as T1a tumors rather than
Tis. This is because of the presence of rich mucosal lym-
The macroscopic appearance depends largely on the site phatics that confer metastatic potential to these lesions.
of the adenocarcinoma. The majority of the duodenal Residual adenomatous epithelium from a preexisting
adenoma is present in the majority of proximal tumors
but often cannot be demonstrated in large, distal small
intestinal adenocarcinomas, presumably due to tumor
FIGURE 6.9
FIGURE 6.10
Adenocarcinoma of the terminal ileum in the setting of Crohn’s disease. An
invasive moderately differentiated adenocarcinoma invades the submucosa and Adenocarcinoma of the terminal ileum in the setting of Crohn’s disease.
muscularis propria and is present in association wtih dysplasia within the small Invasive adenocarcinoma in submucosa characterized by irregular glands,
intestinal mucosa. luminal necrosis, and stromal desmoplasia.
overgrowth. Another subset of cases arise in a back-

ground of gastric type dysplasia, presumably likely sec-
ondary to peptic duodenitis and gastric heterotopia.
Adenocarcinoma subtypes in the small intestine
are similar to those described in the colorectum (see
Chapter 12) with a few exceptions: pancreatobiliary-type
carcinoma and tubular adenocarcinoma have been more
commonly recognized in the small intestine whereas ser-
rated adenocarcinoma and micropapillary adenocarcino-
mas are more prevalent in the colorectum.
The main differential diagnostic consideration is meta-

static carcinoma. Immunohistochemistry (IHC) can be
A
helpful in excluding metastatic disease, specifically, meta-
static adenocarcinomas (e.g., breast, lung) or other mim-
ickers of poorly differentiated carcinoma (e.g., melanoma,
lymphoma). Distinguishing small intestinal adenocarci-
noma from metastatic colorectal adenocarcinoma can be
challenging. It may be difficult to distinguish adeno-
matous precursors from colonization of the mucosa by
the underlying invasive adenocarcinoma. Adenomatous
epithelium can be mimicked by tumors metastatic to the
GI mucosa, and a sharp transition from normal to overtly
malignant epithelium should raise suspicion for second-
ary involvement of the mucosa (Fig. 6.11). Knowledge of
clinical history in the patient, overall growth pattern
(serosal predominant growth), and evidence of dissemi-
nated peritoneal disease may be helpful in establishing a
diagnosis of metastatic adenocarcinoma to the small
intestine. Secondary tumors of the small intestine are dis- B
cussed in more detail later in this chapter. FIGURE 6.11
The epithelioid variant of gastrointestinal stromal This patient had mucosal colonization of a segment of ileum that resembled
tumor (GIST) (discussed in Chapter 7) may also mimic a villous adenoma of the small intestine with a sharp transition from normal
to overtly neoplastic epithelium (A). This patient had a known history of a
an adenocarcinoma. In such cases, a more solid growth primary appendiceal mucinous adenocarcinoma with evidence of dissemi-
pattern with lack of gland formation and the relatively nated peritoneal disease, numerous serosal tumor deposits, and one area of
bland monotonous appearance of most GISTs, in combi- transmural invasion into the bowel wall (B), arguing against a primary small
intestinal adenocarcinoma.
nation with strong labeling for CD117 and DOG1 by IHC
are helpful features. The epithelioid variant of peritoneal
malignant mesothelioma may also resemble a primary location after the colon. Endometriosis involving the small
adenocarcinoma. In contrast to primary small intestinal intestine is typically not a challenging diagnosis and is easy
adenocarcinoma, peritoneal malignant mesothelioma dif- to recognize, given the combination of cellular endometrial
fusely involves visceral organs, forming either multiple stroma and endometrial glands. However, a subset of cases
small tumor nodules or completely encasing segments of of endometriosis may demonstrate intestinal metaplasia
the intestine. Notably, some epithelioid peritoneal malig- and can mimic invasive adenocarcinoma. Typically, areas
nant mesotheliomas may demonstrate cytoplasmic vacu- of conventional endometriosis will be present, and IHC for
olization reminiscent of gland formation and may be markers of endometriosis such as estrogen receptor, pro-
associated with extracellular mucoid material mimicking gesterone receptor, and CD10 can aid in the diagnosis.
mucin. Most epithelioid malignant mesotheliomas
demonstrate strong immunohistochemical labeling for
one or more markers of mesothelial differentiation such
as calretinin, D2–40, WT1, and cytokeratin 5/6 and do
not express the epithelial markers BerEP4 and MOC31.
Endometriosis is a common disease that can involve the Small intestinal adenomas can be resected endoscopically.
GI tract in between approximately 5% and 40% of cases. Patients with FAP may have innumerable polyps in the
The small intestine is the second most frequently involved duodenum, making endoscopic resection difficult. A
the duodenal papilla and acts as a conduit for bile and

TABLE 6.1 pancreatic juices. This unique microenvironment may
account for the disproportionate incidence of periamp-
Modified Spigelman Score a for Duodenal
Adenomas in Patients with Familial ullary adenocarcinomas in the small intestine.
Adenomatous Polyposis
Factor 1 Point 2 Points 3 Points Clinical Features
Polyp number 1–4 5–20 >20

Polyp size in 1–4 5–10 >10 Adenocarcinoma of the ampulla of Vater is associated
millimeters with adenomas in 80% to 90% of cases. The average age
Architecture Tubular Tubulovillous Villous of presentation for ampullary adenomas is the mid-50s,
Grade of Low grade Low grade High
whereas adenocarcinoma typically presents in the mid-
dysplasia (mild) (moderate) grade
60s. Adenocarcinoma is more common in whites than
a
Stage grouping: stage 0, no polyps; stage I, 1 to 4 points; stage II, 5 to 6
points; stage III, 7 to 8 points; stage IV, 9 to 12 points
African Americans and more common in men than
Adapted from Saurin JC, Gutknecht C, Napoleon B, et al. Surveillance of women. Ampullary adenomas and adenocarcinomas are
duodenal adenomas in familial adenomatous polyposis reveals high cumulative far more likely to become symptomatic at an earlier
risk of advanced disease. J Clin Oncol. 2002;22:493–498. stage than neoplasms at other locations in the small
intestine. Obstruction of the ampulla frequently pro-
scoring scheme has been proposed (modified Spigelman duces jaundice and bile duct dilation and occasionally
scoring scheme) that takes into account polyp number, results in pancreatitis, cholelithiasis, or choledocholithi-
polyp size, polyp architecture (tubular, tubulovillous, and asis. Other findings are nonspecific and include weight
villous), and degree of dysplasia (low vs high) in an loss, abdominal pain, and occult bleeding. Ampullary
attempt to risk stratify patients with FAP for the develop- adenomas and adenocarcinomas are visualized endo-
ment of invasive adenocarcinoma (Table 6.1). Some scopically or, if large enough, by radiographic imaging.
patients with modified Spigelman stage IV (e.g., with >20
polyps, polyps >10 mm in size, villous histology, and high-
grade dysplasia) are at risk for developing adenocarci-
Pathologic Features
noma and may benefit from pancreaticoduodenectomy.
Small intestinal adenocarcinomas are aggressive
tumors, with a 5-year survival rate of approximately Gross Findings
35%. Survival is diminished in duodenal tumors and
in patients older than 75 years of age. Surgery is the Sporadic ampullary adenomas (Fig. 6.12) usually pres-
treatment of choice and the only modality with cura- ent as polypoid masses, between 1 and 3 cm. Adenomas
tive potential. Small polypoid or superficial tumors can also be located entirely intra-ampullary, in which
may be amenable to endoscopic polypectomy; endo- case the gross appearance would be of a bulging ampulla
scopic mucosal resection; or in the duodenum, sub-
mucosal dissection or a transduodenal resection.
Larger proximal lesions may require pancreaticoduo-
denectomy, and distal tumors require segmental resec-
tion with accompanying mesentery. Of note,
approximately 8% of small intestinal adenocarcino-
mas harbor deficient DNA mismatch repair, raising
concern of Lynch syndrome. Thus, in the absence of
known cancer-predisposing conditions such as
Crohn’s disease or FAP, screening of small intestinal
adenocarcinomas for mismatch repair protein defi-
ciency can be helpful in identifying patients with pos-
sible Lynch syndrome.
■ ADENOMA AND ADENOCARCINOMA OF

THE AMPULLA OF VATER FIGURE 6.12
Ampullary adenoma: Gross evaluation of a pancreaticoduodenectomy spec-
imen reveals an exophytic, broad-based lesion obstructing the common
The ampulla of Vater is the usual site for convergence of bile duct and resulting in dilation of the common bile duct. Adenomatous
lesions are localized to the mucosa and are freely mobile on palpation. Any
the common bile duct, main pancreatic duct (duct of evidence of induration is an ominous finding and should raise suspicion for
Wirsung), and duodenum. The ampulla opens through an underlying invasive adenocarcinoma.
rather than an exophytic mass. Adenocarcinomas appear

as an infiltrating mass invading nearby structures.
At times, ampullary carcinomas can be difficult to
distinguish from duodenal and pancreatic carcinoma.
A tumor should be designated as primary to the ampulla
in the following scenarios: (1) if the tumor epicenter is
located in the lumen or walls of the distal ends
(intra-ampullary component) of the bile duct or pan-
creatic duct or (2) if the epicenter is located at the junc-
tion of the duodenal and ampullary mucosa (the
“papilla of Vater”) and the ampullary orifice is located
clearly within the tumor. Ampullary carcinoma has
been further subdivided into four distinctive types pri-
marily based on gross evaluation: (1) intra-ampullary
type, defined as prominent intraluminal growth of pre-
invasive neoplasia in which nodules protrude into the
lumen of the ampulla; (2) ampullary-ductal type, FIGURE 6.14
defined as infiltrative tumor centered on the walls of Gross appearance of an ampullary adenocarcinoma, not otherwise specified,
with tumor centered on the papilla of Vater (black arrow) associated with a
the distal ends of the bile duct or pancreatic duct, form-
dilated common bile duct (BD) and pancreatic duct (PD).
ing a firm, constrictive lesion; (3) periampullary duo-
denal type (Fig. 6.13), defined as exophytic growth on
the duodenal surface of the ampulla surrounding the to an admixture of gastric foveolar-type epithelium
ampullary orifice and typically with minimal involve- with intermixed goblet cells and then pancreaticobili-
ment of the intra-ampullary segment; and (4) ampul- ary-type epithelium contiguous with the common bile
lary, not otherwise specified (Fig. 6.14), defined as duct and main pancreatic duct. Most ampullary adeno-
tumors of the papilla of Vater that do not show the mas demonstrate intestinal-type epithelium similar to
characteristics of the other three subtypes. other intestinal adenomas. A smaller number of adeno-
mas show a mixture of intestinal-type and pancreatico-
biliary-type epithelium. Fewer than 10% of adenomas
are composed entirely of pancreaticobiliary-type epi-
thelium. These lesions resemble papillary tumors of
the bile ducts and pancreas and have papillary projec-
The duodenum-facing surface of the ampulla is lined tions with cuboidal epithelium and scant fibrous cores.
by intestinal-type epithelium. The mucosa transitions They lack the abundant Paneth cells and mucin-depleted
appearance of polypoid intestinal-type adenomas. The
term intra-ampullary papillary-tubular neoplasm has
also been proposed in the most recent World Health
Organization classification (WHO; 2019) as a synonym
for these pancreaticobiliary type ampullary lesions. By
definition, the tumor should be confined almost exclu-
sively within the ampulla with minimal extension into
the main pancreatic duct, the distal common bile duct,
or the duodenal papilla. In addition to typical adeno-
mas, flat adenomas can also be seen in the ampulla.
Adenocarcinomas arising in the ampulla (Fig. 6.15)
may be of intestinal type (Fig. 6.16) or pancreaticobili-
ary type (Fig. 6.17) or display hybrid histologic fea-
tures. Intestinal-type adenocarcinomas of the ampulla
of Vater are identical to those found elsewhere in the
small and large intestines and are typically character-
ized by infiltrating glands lined by columnar cells
with elongated, pseudostratified, hyperchromatic
nuclei, often with luminal necrosis. The reported pro-
FIGURE 6.13 portion of ampullary carcinomas with predominant
Gross appearance of an ampullary adenocarcinoma, periampullary duodenal intestinal-type morphology varies widely in the liter-
type with tumor surrounding the papilla of Vater with prominent polypoid
involvement of the duodenal surface of the papilla. Both the pancreatic duct ature with a range between 30% and 70%.
(PD) and common bile duct (BD) are dilated. Pancreaticobiliary-type adenocarcinomas are very
similar to adenocarcinomas of the pancreas and extra-

hepatic bile ducts and are composed of small glands
lined by low cuboidal eosinophilic epithelium with
high nuclear-to-cytoplasmic ratio, pleomorphic nuclei,
vesicular chromatin, and irregular nuclear contours.
The glands are surrounded by a prominent desmo-
plastic stroma, and features of intestinal adenocarci-
nomas, such as pseudostratification and luminal
necrosis, are typically lacking. However, distinction
between intestinal and pancreaticobiliary-type adeno-
carcinoma can be challenging with only moderate
interobserver agreement noted in most studies. In
addition, as many as 40% of ampullary adenocarcino-
mas can display a hybrid intestinal and pancreaticobi-
liary morphology.
FIGURE 6.15 Immunohistochemistry using a panel of CDX2,
Ampullary adenocarcinoma invading through the muscle of the sphincter of MUC1, MUC2, and CK20 has been advocated to help
Oddi, which contains periampullary glands. The invasive adenocarcinoma subtype adenocarcinomas of the ampulla (Table 6.2).
closely approaches adjacent pancreatic parenchyma. In general, intestinal-type adenocarcinoma is positive
for CDX2, CK20, and MUC2 and negative for MUC1.
Pancreaticobiliary-type adenocarcinomas are positive
for MUC1 and negative for CDX2 and MUC2.
However, IHC does not always allow for definitive
subtyping, and a mixed or ambiguous immunopheno-
type is quite common. Other types of ampullary ade-
nocarcinomas (e.g., mucinous, signet ring cell,
medullary, adenosquamous, undifferentiated carci-
noma) have also been described but are infrequent.
Similarly, tumors with a rhabdoid phenotype with
SMARCA4 or INI-1 loss are also rarely seen in the
small intestine, either as primary or as metastasis
from another site.
FIGURE 6.16
Ampullary adenocarcinoma, intestinal type, characterized by large glands
lined by columnar cells with pseudostratified nuclei and associated with
luminal necrosis. TABLE 6.2
Immunohistochemistry in the Subtyping of
Adenocarcinoma of the Ampulla of Vater a
Immunohistochemical Staining
Immunohistochemical Pattern for CK20, CDX2, MUC2,
Subtype and MUC1
Intestinal 1. Positive for CK20 or CDX2 or

MUC2 and negative for MUC1
2. Positive for CK20, CDX2, and
MUC2, irrespective of MUC1
staining pattern
Pancreaticobiliary Positive for MUC1 AND
negative for CDX2 and MUC2,
irrespective of CK20 staining
pattern
Ambiguous Other combinations of
phenotypes, including negative
for all stains
FIGURE 6.17
a
Positive staining is defined as more than 25% of tumor staining.
As advocated by Ang DC, Shia J, Tang LH, et al. The utility of immunohistochemistry
Ampullary adenocarcinoma, pancreaticobiliary type, characterized by small in subtyping adenocarcinoma of the ampulla of Vater. Am J Surg Pathol.
glands lined by cuboidal eosinophilic epithelium with irregular nuclear. 2014;38:1371–1379.
Differential Diagnosis and 2% of all GI tumors. Small intestinal NETs are

derived from two separate embryonic divisions of the ali-
mentary tract: the foregut (duodenum) and the mid-
Pancreaticobiliary neoplasms arising in the common gut (jejunum and ileum). Most NETs are encountered
bile duct or pancreas can colonize the ampullary epithe- in the ileum (midgut). Duodenal NETs can be associ-
lium or, if invasive, may directly involve the ampulla ated with clinical syndromes caused by hormone
and be misdiagnosed as an ampullary adenoma or ade- hypersecretion detected by serologic evaluation for
nocarcinoma. Careful gross examination and review of elevated circulating hormones. Immunohistochemical
clinical and imaging information are necessary when staining for peptide hormones can be performed to
assigning the correct primary site to periampullary confirm the clinical impression of a syndromic NET.
tumors. Metastasis from distant sites to the ampulla of However, specific functional terms such as gastrinoma
Vater is rare but has been reported. should not be used to describe NETs in the absence of
When adenomatous epithelium extends into periamp- clinical and serologic findings indicative of a hor-
ullary glands in the smooth muscle of the sphincter of monal syndrome. Although the functional status of a
Oddi, care must be exercised to not misdiagnose the ade- NET is defined by the clinical and serologic findings,
noma as an invasive carcinoma. Lack of a desmoplastic it is useful to divide NETs into categories based on
response and a clear continuity with low-grade dysplastic location in the small intestine and corresponding cell
ductal epithelium supports a noninvasive diagnosis. subtype because it allows for discussion of site-related
differences between NETs.
Clinical Features
Pedunculated ampullary adenomas without high-
grade dysplasia can be resected endoscopically.
Adenomas that are large or demonstrate high-grade Gastrin-producing NETs account for approximately two-
dysplasia may be managed by transduodenal ampul- thirds of NETs in the duodenum. Gastrin-producing NETs
lectomy or pancreaticoduodenectomy. can be either nonfunctioning or associated with Zollinger-
Pancreaticoduodenectomy is the standard of care Ellison syndrome (ZES), a syndrome of hypergastrinemia,
for resectable ampullary adenocarcinomas. Most stud- gastrin hypersecretion, and refractory peptic ulcer disease.
ies have demonstrated that patients with intestinal-type The association with ZES is found in about 40% of duode-
ampullary adenocarcinomas have better overall sur- nal gastrin-producing NET. Most ZES NETs are sporadic
vival than those with pancreaticobiliary-type ampul- with approximately 25% associated with multiple endo-
lary adenocarcinoma, although not all studies have crine neoplasia type 1 (MEN-1) (Fig. 6.18). Nonfunctional
demonstrated that histologic subtype is an indepen- gastrin-producing NETs typically occur in the duodenal
dent predictor of survival. At present, chemotherapeu- bulb and are normally confined to the lamina propria and
tic decision making is influenced by the histologic submucosa. They are incidentally discovered during
subtype of ampullary adenocarcinoma. Oncologists
often use gemcitabine-based treatment regimens for
pancreaticobiliary-type adenocarcinomas and fluoro-
uracil-based treatment regimens for intestinal-type
adenocarcinoma. Given the importance of histologic
subtyping in selecting therapy, an attempt should be
made to determine the predominant or favored histo-
logic subtype for ampullary adenocarcinoma whether
by using routine histology or by using one of the pro-
posed immunohistochemical panels as detailed in
Table 6.2. However, separation into histologic sub-
types is not always possible, and an adenocarcinoma
with hybrid histologic features should be classified
as such.
■ NEUROENDOCRINE TUMORS OF THE

SMALL INTESTINE
FIGURE 6.18
Well-differentiated neuroendocrine tumor of the duodenum located primarily
Neuroendocrine tumors of the small intestine represent in the duodenal submucosa. This neuroendocrine tumor was associated with
approximately one-third of small intestinal neoplasms elevated serum gastrin and Zollinger-Ellison syndrome.
endoscopy performed for other reasons or in surgical resec-

tions for unrelated causes. Nonfunctioning gastrin-posi-
tive NETs of the duodenum are frequently associated with
Helicobacter pylori infection of the stomach or long-term
PPI therapy.
Somatostatin-producing NETs account for approxi-
mately one-third of NETs in the duodenum and have a
predilection for the ampulla and periampullary region,
which can result in symptoms and signs of abdominal
pain, obstructive jaundice, and biliary dilatation. The
somatostatinoma syndrome consisting of diabetes melli-
tus (caused by inhibition of insulin secretion), steator-
rhea (caused by inhibition of pancreatic enzyme secretion),
hypochlorhydria or achlorhydria, and cholelithiasis
(caused by suppression of cholecystokinin-pancreozymin
release and gallbladder contraction) is rarely observed in FIGURE 6.19
duodenal somatostatin-producing NETs. One-third of Well-differentiated neuroendocrine tumor of the duodenum characterized
somatostatin-producing ampullary or periampullary NETs by cytologically bland tumor cells with bland, round nuclei, “salt-and-pepper”
have been associated with von Recklinghausen’s disease chromatin, and eosinophilic cytoplasm.
(neurofibromatosis type 1 [NF1]).
The ileum is the single most common site for NETs in
the GI tract. These tumors also elicit peritumoral or mesen-
teric fibrosis that may produce symptoms of recurrent
small bowel obstruction, bowel ischemia and infarction,
and protracted abdominal pain. NETs of the distal jeju-
num and ileum are serotonin-producing enterochromaffin
cells and may produce the carcinoid syndrome that con-
sists of watery diarrhea, flushing, and endocardial fibrosis.
The carcinoid syndrome is usually, but not always, associ-
ated with metastasis to the liver and is seen in 5% to 7% of
cases. Nearly one-third of patients diagnosed with a jejun-
oileal NET have a synchronous or metachronous carci-
noma (e.g., colon, stomach, lung, or breast). Small (<1 cm)
ileal NETs can give rise to large mesenteric tumor deposits
and present as an occult primary.
FIGURE 6.20
Periampullary somatostatin-producing well-differentiated neuroendocrine
tumor with prominent pseudoglandular growth pattern involving the mucosa
Pathologic Features and submucosa of the periampullary duodenal mucosa.
Neuroendocrine tumors are characterized by a monoto-

nous proliferation of small bland polygonal cells with a
moderate amount of cytoplasm and round regular nuclei
with the typical “salt-and-pepper” chromatin (Fig. 6.19).
NETs demonstrate variable architectural growth pat-
terns, including insular or nested, trabecular, and acinar
growth patterns. These patterns often overlap, and mul-
tiple patterns may be seen within any single tumor.
Somatostatin-producing ampullary or periampullary
NETs have characteristic morphologic features that help
to distinguish these tumors from other NETs of the duo-
denum. Approximately 60% of somatostatin-producing
NETs display a characteristic mixed pseudoglandular
(Fig. 6.20) and trabecular architectural arrangement.
The pseudoglandular structures have central lumens FIGURE 6.21
that frequently contain proteinaceous secretions and Periampullary somatostatin-producing well-differentiated neuroendocrine
psammoma bodies (Fig. 6.21). Psammoma bodies are tumor with numerous intraluminal psammomatous calcifications.
seen in approximately 60% of sporadic somatosta-

tin-producing ampullary and periampullary NETs and TABLE 6.3
in almost all of NF1-associated somatostatin-producing
World Health Organization (WHO) 2019 Grading
NETs. However, psammoma bodies are not entirely spe- of Neuroendocrine Tumors a
cific for somatostatin-producing NETs and may also be
seen in nonfunctioning NETs in the ileum or other sites WHO Grade Mitotic Count Ki67 Index
within the GI tract.
G1 <2 per 2 mm 2 <3%
Jejunoileal NETs may have a variable gross appear- G2 2–20 per 2 mm 2 3%–20%
ance, ranging from the presence of polypoid tan-yellow G3 >20 per 2 mm 2 >20%
submucosal nodules to annular masses or strictures sec- a
The grading requires mitotic count in at least 50 hpf (1 hpf = 2 mm 2) and
ondary to marked fibrosis characteristic of these lesions. Ki67 index using the MIB antibody as a percentage of 500 to 2000 cells
One-quarter of tumors may present as multiple polypoid counted in areas of strongest nuclear labeling (“hot spots”). If grade differs for
mitotic count and Ki67 index, the higher grade should be assigned.
lesions (Fig. 6.22). Typically, the tumor cells are arranged hpf, High-power field.
in solid nests (Fig. 6.23) and are often associated with
densely fibrotic stroma that may compress the tumor
cells into a single-file and cordlike arrangement. Most

tumors demonstrate perineural and lymphovascular
invasion.
The WHO recommends grading NETs by the assess-
ment of mitotic activity and Ki67 proliferation index
(see Table 6.3). Well-differentiated NETs are defined by
a nested, trabecular or tubular architecture and express
markers of neuroendocrine differentiation such as chro-
mogranin A and synaptophysin. The mitotic activity
and proliferative index in well-differentiated tumors is
typically low and encompasses WHO grade G1 (<2
mitoses per 2 mm2 and <3% Ki67 index) and G2 (2–20
mitoses per 2 mm2 and/or 3%–20% Ki67 index) (see
Table 6.2). Rarely, tumors that are architecturally well
differentiated may show high proliferative activity and
qualify as WHO grade 3 (>20 mitosis per 2 mm2 and/or
FIGURE 6.22 >20% Ki67 index). In these cases, the Ki67 prolifera-
Well-differentiated neuroendocrine tumor involving the submucosa and tion index is usually in the 30% to 50% range unlike
muscularis propria of the ileum. Multiple polypoid lesions were identified in
the small intestine of this patient, and the overlying ileal mucosa demon-
typical high-grade neuroendocrine carcinomas, which
strated necrosis resulting from mesenteric ischemia. more often show positive labeling in more than 75% of
nuclei.
By IHC, small intestinal NETs express synapto-
physin and chromogranin A. Jejunoileal NETs are typ-
ically strongly positive for CDX2. However, jejunoileal
NETs are negative for PAX8, which may help to local-
ize the primary site of a NET in the setting of meta-
static disease to the liver with an unknown primary.
Duodenal NETs infrequently label with CDX2 but may
express PAX8 and PDX-1 by IHC. The adjacent duode-
nal mucosa can demonstrate gastrin-positive neuroen-
docrine hyperplasia in MEN1-associated gastrinomas
and in sporadic nonfunctional gastrin-producing NETs
associated with H. pylori gastritis and long-term PPI
therapy. Although immunohistochemical stains are
available for specific hormone products such as gastrin
and somatostatin, functioning tumors are those associ-
ated with clinical manifestations of hormone produc-
tion or secretion of measurable amounts of active
FIGURE 6.23
hormone. Immunohistochemical expression of hor-
Well-differentiated neuroendocrine tumor of the ileum with a nested growth
pattern. The tumor is composed of cells with bland, round nuclei, “salt-and- mone does not correlate with clinical functionality and
pepper” chromatin, and eosinophilic cytoplasm. therefore is not recommended in daily practice.
Neuroendocrine tumors with a prominent acinar pattern

may mimic adenocarcinoma. In such cases, the bland,
monotonous appearance of the NET and the strong label-
ing for neuroendocrine markers are helpful features. The
single-cell, linear growth pattern seen at the periphery of
NETs may be confused with metastatic lesions such as
lobular breast cancer. A nested pattern reminiscent of
NETs can be mimicked by lamina propria and lymphatic
invasion by melanoma, lymphoma, or other poorly differ-
entiated carcinomas. The nuclear features are high grade
in these latter instances, and when metastatic disease is a
concern, IHC can easily provide a definitive answer.
FIGURE 6.24
Gangliocytic paraganglioma of the periampullary duodenum. The neuroen-
docrine epithelioid cells are arranged in trabeculae and are set within spin-
Prognosis and Therapy dled stromal cells with eosinophilic cytoplasm. Occasional ganglion-like cells
(black arrow) are seen within the spindled stroma.
The overall behavior of NETs is difficult to predict but is

dictated primarily by the stage of disease. Duodenal non- with GI bleeding caused by mucosal erosion or with obstruc-
functioning gastrin-positive NETs of the duodenal bulb are tive jaundice. Gangliocytic paragangliomas may present as
generally indolent. In contrast, somatostatinoma-producing multiple lesions and may be associated with NF1.
and ZES-associated NETs may behave in a clinically malig-
nant fashion. Poor outcome in duodenal tumors is best pre-
dicted by invasion beyond the submucosa or by lymph node
Pathologic Features
and distant metastases. Rarely, a gastrin-producing NET
will be identified in lymph nodes in the pancreaticoduode-
nal region without a definite primary NET seen in the duo- Gangliocytic paragangliomas are composed of a variable
denum or pancreas. These so-called “primary lymph node mixture of (1) nests of uniform polygonal neuroendocrine
gastrinomas” represent metastases, in most instances, from cells, (2) ganglion-like cells, and (3) spindle cells with
microscopic primary duodenal or pancreatic NETs that are Schwannian differentiation arranged in fascicles (Fig. 6.24).
easily overlooked on routine examination. However, rare The neuroendocrine cell population typically stains for both
patients who have done well clinically on follow up after chromogranin A and synaptophysin. The spindle cells stain
resection of the nodal primary have also been described. intensely for S100 and neurofilament protein. The ganglion
Because of their relatively small size and submucosal cells may be seen dispersed singly or form small clusters and
location, jejunoileal NETs are rarely diagnosed until the are positive for synaptophysin.
development of metastatic disease to lymph nodes or dis-
tant sites, particularly the liver. Jejunoileal NETs have a
worse prognosis than those of the duodenum, with a 21%
mortality rate. Survival is negatively correlated with
tumor grade, distant metastases, multiple tumors, inva- Gangliocytic paragangliomas usually follow a benign
sion beyond submucosa, and female gender. Patients with course. However, there are reports of gangliocytic para-
jejunoileal NETs should be treated with segmental resec- gangliomas with metastasis to regional lymph nodes,
tion of the bowel and associated mesentery. Even in those particularly in large tumors (>2 cm). Most frequently,
with metastatic disease, resection may be required for pal- the metastatic tumor in lymph nodes consists of the
liation to relieve obstruction. neuroendocrine component of the tumor.
■ GANGLIOCYTIC PARAGANGLIOMA ■ NEUROENDOCRINE CARCINOMA OF THE

SMALL INTESTINE AND AMPULLA
Clinical Features
Clinical Features
Gangliocytic paragangliomas have a predilection for the
ampulla or periampullary region and typically present as Within the small intestine, neuroendocrine carcinomas
polypoid submucosal nodules. Some patients may present appear to more often occur in the ampulla or periampullary
area. If the tumor contains a significant component

(≥30%) of neuroendocrine carcinoma and adenocarci-
noma, the term mixed neuroendocrine–non-neuroendo-
crine neoplasm (MiNEN) should be used.
Pathologic Features
Neuroendocrine carcinomas are poorly differentiated

and composed of either small cells (small cell type) or
intermediate to large cells (large cell type) with expres-
sion of markers of neuroendocrine differentiation, typi-
cally diffuse expression of synaptophysin and focal
staining for chromogranin A. Neuroendocrine carcino-
mas also demonstrate a high mitotic rate (>20 per 2 FIGURE 6.25
mm2) and greater than 20% Ki67 index, corresponding Poorly differentiated neuroendocrine carcinoma, small cell type, of the
to WHO grade G3. These tumors should not be confused ampulla undermining ampullary mucosa. The tumor cells are arranged in
with the extremely rare examples of well-differentiated large sheets with nuclear molding and scant cytoplasm. Numerous mitotic
figures and a Ki67 index greater than 80% were identified. The tumor cells
tumors that resemble typical carcinoids on morphology demonstrated strong, diffuse synaptophysin expression and focal chromogr-
but show a high proliferative index that qualifies as anin staining, confirming neuroendocrine differentiation.
grade 3. In well-differentiated grade 3 tumors, the prolif-
erative index is usually in the 30% to 60% range and not
extremely high as in typical small and large cell neuroen-
docrine carcinomas. The use of the diagnostic term high-
grade neuroendocrine carcinoma is, therefore, discouraged
because it can apply to both categories of grade 3 tumors
with different genotypic abnormalities, treatment impli-
cations, and prognoses. Preliminary data suggest that
well-differentiated grade 3 NETs have a better prognosis
than poorly differentiated (small or large cell) grade 3
carcinomas but do not respond to platinum-based che-
motherapy. The pathologic diagnosis in all NETs should
clearly state the differentiation status (well or poor) and
provide the WHO grade based on mitotic activity and/or
Ki-67 immunostain to help guide therapy for these
patients. Small cell neuroendocrine carcinoma tumor
cells are typically less than three times the size of a small
lymphocyte and are arranged in large sheets with areas FIGURE 6.26
of necrosis (Fig. 6.25). The nuclei display finely granular Metastatic melanoma to the small intestine can morphologically resemble
chromatin and inconspicuous nucleoli, and nuclear a neuroendocrine tumor. This case demonstrates a nested growth pattern.
molding may be prominent. Large cell neuroendocrine Immunohistochemistry for markers of melanocytic differentiation (SOX10,
S-100, Melan A, and/or HMB45) are helpful in confirming the diagnosis.
carcinoma architecturally displays an organoid or tra-
becular architecture and may mimic a well-differenti-
ated NET, but the tumor cells have large, vesicular ■ SECONDARY TUMORS
nuclei; prominent nucleoli; and moderate amounts of
cytoplasm. Both small cell and large cell neuroendo-
crine carcinoma can be associated with adenomas of Secondary tumors are 2.5 times more common than pri-
the overlying surface epithelium. mary small intestinal neoplasms. Involvement of the small
intestine by secondary tumors can occur by direct exten-
sion, intraperitoneal spread, or lymphohematogenous
metastasis. Virtually any type of malignancy may second-
arily involve the small intestine. Melanoma (Fig. 6.26),
breast, colon, and lung carcinoma are among the most com-
Neuroendocrine carcinomas are clinically aggressive, mon metastatic tumors involving the small intestine.
and patients typically present with advanced disease. Pancreatic and gastric carcinomas may also involve the small
The overall prognosis is dismal. intestine by direct extension, whereas ovarian cancer is the
mostly likely to involve the small intestine by serosal implan-

tation. Secondary involvement of the small intestine may SMALL INTESTINAL ADENOCARCINOMA—FACT SHEET
present as a thickened bowel wall or mass lesion with
obstruction, intussusception, or perforation. Features favor- Definition
ing a metastatic tumor include the presence of multiple n Primary malignant epithelial tumor of the small intestine
lesions, extensive mural and serosal disease with minimal

mucosal involvement imparting a histologic appearance of
n Most common malignancy of the small intestine (30%–50% of
tumor being “bottom heavy” or encroaching from serosal
small bowel malignancies)
aspect to mucosal aspect of the bowel wall, and the absence n Overall rare lesions, 2% of gastrointestinal (GI) tumors, and 1%
of a dysplastic precursor. Small intestinal adenocarcinomas of GI cancer–related deaths
are of an intestinal type, and the presence of signet ring cell
differentiation or a diffuse-type growth pattern is uncom- Gender, Race, and Age Distribution
mon in primary carcinomas of the small intestine, especially n Presents in older adults (median, 72 years)
n Nearly equal gender distribution

in areas distal to the ampulla or in tumors unrelated to
n Compared with colorectal carcinoma, a higher proportion seen in
Crohn’s disease. Frequently, metastatic adenocarcinoma to African Americans than whites
the small intestine can demonstrate maturation of the neo-
plastic epithelium as it grows from the serosa toward the Clinical Features
bowel lumen. Metastatic carcinoma can also reach the n Vast majority of cases are sporadic
mucosal surface of the small intestine and exhibit an in situ n Similar to colorectal adenocarcinomas in risk factors and
growth pattern along intact basement membranes, simulat- development from sporadic adenomatous polyps
Minority arise in the background of predisposing hereditary or
ing a “precursor” dysplastic lesion (adenoma). Thus, the n
acquired risk factors: familial adenomatous polyposis, Crohn’s

presence of an apparent “in situ” dysplastic lesion does not disease, gluten-sensitive enteropathy, Lynch syndrome
provide definitive evidence for a primary small intesti- n Combination of obstructive jaundice with occult GI bleeding
nal carcinoma. characteristic of duodenal tumors
Immunohistochemistry should be used when the n 30% of patients present with stage IV disease
nature of the primary neoplasm is in doubt and is espe-
cially helpful in cases of poorly differentiated malignan-
n Poor outcome in all locations
cies. Immunohistochemical stains are particularly n 5-year disease-free survival rate is approximately 35%
helpful when considering metastasis from non-GI tract
primary sites, such as the lung (often positive for thy-
roid transcription factor 1), breast (positive for GATA-3,
gross cystic disease fluid protein [GCDFP] and variably Small Intestinal Adenocarcinoma—Pathologic Features
positive for estrogen receptor [ER] and progesterone
receptor [PR]), and ovary (often positive for ER, PR, Gross Findings
and PAX8). However, IHC is not helpful in distinguish- n Duodenum (most in the periampullary region) > jejunum (first
ing primary small intestinal adenocarcinoma from met- 30 cm) > ileum (Crohn’s disease)
n Duodenal tumors: smaller exophytic masses
astatic GI tract adenocarcinomas. Primary small
n Jejunoileal tumors: large, annular, constricting masses with
intestinal adenocarcinomas often demonstrate a CK7- circumferential bowel wall involvement
positive/CK20-negative or CK7-positive/CK20-positive n Rarely, tumors can have a linitis plastica appearance
immunophenotype. However, colorectal adenocarcino- n Sampling background mucosa to assess for adenoma is important
mas, particularly those with high levels of microsatellite

instability, can coexpress CK7 and CK20, limiting the Microscopic Findings
utility of CK7 and CK20 IHC in this setting. n Similar to colorectal adenocarcinomas and characterized by
complex glandular architecture, luminal necrosis, and nuclear

One of the most common malignancies to metastasize
pleomorphism
to the small intestine is malignant melanoma. Metastatic n Most are moderately differentiated, and one-third are poorly
melanomas to the GI tract can be either pigmented or differentiated
amelanotic and may mimic a variety of primary neo- n Degree of differentiation and special histologic subsets (e.g.,
plasms, including carcinomas, sarcomas or GISTs, and mucinous, adenosquamous) have little bearing on prognosis.
n The majority of small bowel adenocarcinomas have invaded
large cell lymphoma. Immunohistochemical stains
through the bowel wall
(S-100, HMB-45, A103 [MART-1], tyrosinase, microph- n Preexisting adenoma is present in the majority of proximal tumors
thalmia transcription factor, and SOX10) have been but often cannot be demonstrated in large distal tumors
shown to demonstrate high sensitivity and variable
specificity for melanoma. Importantly, when evaluating Immunohistochemistry
high-grade spindle cell lesions for which GIST is in the n Immunohistochemistry is primarily used to exclude metastatic
differential diagnosis, one or more of melanoma stains disease, specifically, metastatic adenocarcinoma (e.g., breast,
lung) and other mimickers of poorly differentiated tumor
should be included in the panel because up to 50% of (melanoma and lymphoma)
malignant melanomas express CD117.
n Variable CK7 positivity (ranging from 30% to 60%), CK20 Microscopic Findings
positivity (~60%) and CDX2 positivity (~70%) n Intestinal type characterized by large glands lined by columnar
n Distinguishing between primary small intestinal adenocarcinoma cells with elongated, pseudostratified hyperchromatic nuclei
and metastatic colorectal adenocarcinoma can be very difficult n The pancreaticobiliary type arises either from intra-ampullary
tubular and papillary neoplasms or from ampullary ductal

Differential Diagnosis neoplasia and are characterized by small glands lined by low
n Metastatic adenocarcinomas (e.g., colorectal, breast, ovary, lung) cuboidal eosinophilic epithelium with high nuclear-to-cytoplasmic
n Poorly differentiated malignancies (e.g., lymphoma, melanoma) ratio; rounded, vesicular nuclei; and irregular nuclear contours
n Epithelioid gastrointestinal stromal tumor n Many adenocarcinomas have mixed intestinal and
n Peritoneal malignant mesothelioma with epithelioid histology pancreaticobiliary histology

n Endometriosis n The degree of differentiation and special histologic subsets (e.g.,
mucinous, adenosquamous) have little bearing on prognosis
AMPULLARY ADENOCARCINOMA—FACT SHEET n The intestinal type is usually positive for CK20, MUC2, and CDX2
and typically negative for MUC1 (see Table 6.2)

n The pancreaticobiliary type is usually positive for MUC1 and
Definition
typically negative for CDX2 and MUC2
n Malignant epithelial tumor of the ampulla of Vater defined as
n Ambiguous or hybrid phenotypes are commonly seen, making
n Tumor epicenter in the lumen or walls of the very distal ends of
definitive distinction between intestinal and pancreaticobiliary
the bile duct and/or pancreatic duct
types difficult in some cases
n Tumor epicenter located at the junction of the duodenal and
ampullary mucosa (the “papilla of Vater”) with the ampullary

orifice located within the tumor
n Ampullary adenoma involving periampullary glands in the smooth
Incidence and Location muscle of the sphincter of Oddi can mimic adenocarcinoma
n Distinction from duodenal, pancreatic ductal, and distal common
n Rare lesions, 0.2% to 0.5% of gastrointestinal (GI) tumors and
bile duct adenocarcinoma requires careful gross evaluation to
approximately 0.2% of GI cancer–related deaths
determine the tumor epicenter

n Presents in older adults (median, 65 years)
n Male predominance (male to female ratio, 1.5 to 1) NEUROENDOCRINE TUMORS OF THE SMALL
INTESTINE—FACT SHEET
Clinical Features
n Vast majority of cases are sporadic Definition
n Minority arise in the background of predisposing condition, such n Well-differentiated neuroendocrine neoplasm composed of cells
as familial adenomatous polyposis with features similar to those of normal gut endocrine cells and
n Common symptoms and signs: obstructive jaundice, occult GI expressing general markers of neuroendocrine differentiation
bleeding, abdominal pain (synaptophysin and chromogranin A)
n Many patients present with regional disease (stages I and II) n Encompasses neoplasms previously termed carcinoid tumor
Prognosis and Therapy Incidence and Location

n Pancreaticoduodenectomy for resectable tumors n Represent 30% of small intestinal neoplasms and 40% of
n 5-year disease-free survival rate is approximately 40% gastrointestinal neuroendocrine tumors (NETs)
n Intestinal type has a better prognosis than pancreaticobiliary type n Seen primarily with roughly equal incidence in the duodenum
n Chemotherapy decision making is often affected by histologic and ileum
subtype
n Median age of approximately 60 years
n Duodenal tumors more common in men (male-to-female ratio,
Ampullary Adenocarcinoma—Pathologic Features 1.5 to 1), but no gender predilection is seen in jejunoileal tumors
Gross Findings Clinical Features

n Distinct types based primarily on gross appearance
Duodenum
n Intra-ampullary: prominent intraluminal growth of preinvasive n Two-thirds of NETs of the duodenum are gastrin producing
neoplasia protruding into the lumen of the ampulla n Approximately 40% of gastrin-producing NETs are functional and
n Ampullary ductal: firm, constrictive lesion within the walls of the associated with Zollinger-Ellison syndrome (ZES;
very distal ends of the common bile duct or pancreatic duct hypergastrinemia, gastric hypersecretion, refractory peptic ulcer
n Periampullary duodenal: exophytic growth on the duodenal disease). Twenty-five percent of ZES-associated gastrin-producing
surface of the ampulla surrounding the ampullary orifice NETs are associated with multiple endocrine neoplasia type 1
n Ampullary, not otherwise specified: tumors that do not show the n Approximately 60% of gastrin-producing NETs are nonfunctional,
characteristics of the other three subtypes typically located in the duodenal bulb, smaller than 1 cm in size,
n Sampling background mucosa to assess for precursor neoplasia is and associated with Helicobacter infection or long-term proton
important pump inhibitor therapy
n One-third of NETs of the duodenum are somatostatin producing. n Jejunoileal NETs and gastrin-producing NETs have variable
n Predilection for the ampullary and periampullary region histology and often a prominent nested growth pattern with more
n Abdominal pain, obstructive jaundice, and biliary dilation are trabecular and acinar growth peripherally
commonly seen n Jejunoileal NETs often invade deeply into the wall and can be
n One-third are associated with neurofibromatosis type 1 associated with significant fibrosis
n Rarely functional
Jejunoileal n Vast majority positive for synaptophysin and chromogranin
n Abdominal pain, bowel obstruction from fibrosis or n CDX2 is positive in jejunoileal NETs but can be negative in
intussusception, mesenteric ischemia duodenal NETs

n Approximately 5% to 7% are associated with carcinoid syndrome n Immunohistochemical expression of peptide hormones (e.g.,
(watery diarrhea, flushing, endocardial fibrosis) gastrin and somatostatin) can be performed but has limited utility
n Often have metastasis to the liver and lymph nodes because the functional status of tumors does not correlate with
immunohistochemistry
n Features associated with behavior, including World Health Differential Diagnosis
Organization grade (based on mitotic count and Ki67 index), size, n Somatostatin-producing NETs can superficially resemble
extent of invasion, and lymph node involvement adenocarcinoma because of a pseudoglandular growth pattern
n Duodenal nonfunctioning gastrin-producing NETs of the duodenal n Other metastatic lesions (e.g., melanoma or lobular breast
bulb are generally indolent cancer) that can have a nested and trabecular growth pattern
n Somatostatin-producing and ZES-associated NETs of the resembling NET
duodenum may behave in a malignant fashion
n Jejunoileal NETs have a worse prognosis than those of the
duodenum and are treated by resection of the involved segment

and small bowel mesentery
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Genta RM, Kinsey RS, Singhal A, et al. Gastric foveolar metaplasia
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tumors (NETs) located in the duodenal bulb logic role for Helicobacter pylori. Hum Pathol. 2010;41:1593–1600.
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7
Gastrointestinal Mesenchymal Tumors
■ David Papke, MD, PhD and Leona Doyle, MD
■ GASTROINTESTINAL STROMAL TUMOR GISTs are about twice as likely as gastric GISTs to
behave in a clinically aggressive fashion.
Clinical presentation depends on tumor size and
Gastrointestinal stromal tumors (GISTs) are the location. Large masses can cause abdominal pain, ane-
most common soft tissue tumors of the gastrointesti- mia, or GI bleeding. Micro-GISTs are found inciden-
nal (GI) tract, with a worldwide annual incidence of tally during surgery and may often be sent for frozen
about 15 cases per million. Although there was his- section analysis. GIST can also present as a component
toric controversy over the distinction between GIST, of multiple hereditary syndromes, including Carney-
smooth muscle tumors, and nerve sheath tumors, by Stratakis syndrome, Carney triad, and neurofibroma-
the late 1990s, it was established that GISTs exhibit tosis. Carney-Stratakis syndrome (the dyad of gastric
differentiation of interstitial cells of Cajal and repre- GIST and paraganglioma) is a familial syndrome caused
sent a distinct diagnostic entity. We now know that by mutations in SDHx genes; these mutations account
most GISTs harbor mutually exclusive mutations in for about 65% of SDH-deficient GISTs. Patients
KIT (80%) or platelet-derived growth factor recep- with SDHA germline mutations mostly present
tor-α (PDGFRA) (∼7%). The remaining 10% to 15% with GISTs as young to middle-aged adults, whereas
of so-called “wild-type GISTs” are a heterogeneous patients with other SDH germline mutations present
group of tumors that includes succinate dehydroge- in childhood and adolescence. Carney triad (gastric
nase (SDH)–deficient GIST (accounting for 8% of GIST, paraganglioma, and pulmonary chondroma) is
GISTs), as well as neurofibromatosis-associated and a nonfamilial syndrome associated with SDHC pro-
BRAF-mutant GIST (Table 7.1). Correct subclassi- moter hypermethylation and not germline mutations.
fication is critical for determining the prognosis and Neurofibromatosis type 1 (NF1) is the most common
appropriate treatment. autosomal dominant genetic disorder and is associ-
ated with development of neurofibromas, ganglioneu-
romas, and malignant peripheral nerve sheath tumors
(MPNSTs), among other tumor types. NF1 also predis-
Clinical Features
poses patients to GISTs that are predominantly found
in the small intestine and can be multiple in the same
In the United States, GIST has an estimated annual patient. These tumors are mostly low risk and are asso-
incidence of 3300 to 6000 cases per year and most com- ciated with interstitial cell hyperplasia. Last, there are
monly occurs in middle-aged to older adults (median rare instances of familial germline mutations in KIT
age, 60 years). Clinically detected tumors in the GI tract and PDGFRA; patients with these mutations develop
most commonly occur in the stomach (60%) and small GISTs with nearly 100% penetrance, in a background
intestine (35%), with most remaining cases accounted of interstitial cell hyperplasia. Patients with KIT germ-
for by colorectal tumors; GISTs of the esophagus and line mutations also develop urticaria pigmentosa and
appendix are rare. GIST can also present as omen- cutaneous hyperpigmentation.
tal, peritoneal, and retroperitoneal tumors, although
these are typically large tumors that very likely origi-
nally originated in the GI tract but may have detached
Radiologic Features
from their point of origin. GIST exhibits a wide range
of behavior, from benign “micro-GISTs,” present in
approximately 30% of the population based on autopsy Radiologic features are not specific, but most large mural
series, to aggressive sarcomas. Prognosis depends in gastric masses are GISTs. An example of a gastric GIST
part on tumor location; for example, small intestinal is shown in Fig. 7.1.
169
TABLE 7.1
Prevalence of Genetic Subtypes in Clinically
Identified Gastrointestinal Stromal Tumors a
Mutation Prevalence (%)
KIT 80
Exon 9 8
Exon 11 70
Exon 13 1
Exon 17 1
PDGFRA 7
Exon 12 1.5
Exon 14 0.5
Exon 18 5
SDH Deficiency 8
FIGURE 7.2
SDHA inactivating mutation ~3
SDHB, SDHC, SDHD inactivating mutations ~2 Small intestinal gastrointestinal stromal tumor involving the full thickness of
SDHC promoter hypermethylation ~3 the wall from mucosa to serosa, with hemorrhage at the serosal aspect.
NF1 Biallelic Inactivation 2–3
BRAF V600E <1
a
NF, Neurofibromatosis; PDGFRA, platelet derived growth factor receptor
a characteristic multinodular or plexiform growth
alpha; SDH, succinate dehydrogenase (subunits A-C). pattern. Fig. 7.2 shows a cross-section of a small intes-
tinal GIST.
About 70% of gastric GISTs and nearly all of those in

the small and large intestine exhibit spindle cell mor-
phology, with short fascicles of bland cells with indis-
tinct cell borders, palely eosinophilic cytoplasm, and
uniform, tapered nuclei with evenly dispersed chro-
matin (Figs. 7.3 and 7.4). Nuclear palisading is at least
focally present in more than half of tumors. About
20% of GISTs have purely epithelioid morphology;
these tumors nearly all occur in the stomach and are
associated with PDGFRA mutations (Fig. 7.5) or SDH
deficiency (Fig. 7.6). Epithelioid GISTs are composed
of sheets and nests of cells with palely eosinophilic
cytoplasm and uniform nuclei, often in a myxohya-
line stroma (Fig. 7.7; see also Figs. 7.5 and 7.6). The
FIGURE 7.1 cell membranes are often better defined than spindle
Imaging study from a patient with a large heterogenous gastric gastrointesti- cell variants. SDH-deficient GIST has a characteristic
nal stromal tumor, which was hard to distinguish from a primary liver lesion. multinodular or plexiform growth pattern and the cyto-
morphology is usually epithelioid (see Fig. 7.6). Gastric
GISTs commonly have paranuclear vacuoles (see
Figs. 7.3 and 7.7), and nearly half of small intestinal
Pathologic Features
GISTs contain skeinoid fibers. Mitotic activity varies
widely and is an important prognostic factor. Treatment
Gross Findings effect can manifest as stromal hyalinization, decreased
cellularity, or reduced mitotic activity. Rarely, tumors
Gastrointestinal stromal tumors vary in greatest can develop heterologous rhabdomyosarcomatous dif-
dimension from smaller than 1 cm (micro-GISTs) to ferentiation after treatment, and both treated and treat-
larger than 20 cm, and they can be submucosal, intra- ment-naïve tumors can undergo dedifferentiation, in
muscular, or subserosal, although most are centered which there is a sharp transition from conventional
in the muscularis propria. They can be solid or cys- morphology to high-grade pleomorphic regions that do
tic with variable hemorrhage and necrosis, and there not resemble GIST (Fig. 7.8). Both rhabdomyosarcoma-
may be overlying mucosal ulceration. Generally, GISTs tous differentiation and dedifferentiation are associated
are well circumscribed. SDH-deficient GISTs have with imatinib resistance and a poor prognosis.
CHAPTER 7 Gastrointestinal Mesenchymal Tumors 171
B
FIGURE 7.3
Gastric gastrointestinal stromal tumor (GIST) with spindle cell features exhibiting paranuclear vacuoles. A, Frequent vacuoles, as shown here, are a helpful fea-
ture within the differential diagnosis of spindle cell neoplasms of the stomach to support a diagnosis of GIST. Tapered nuclei are also a feature of GIST but not
of leiomyoma or leiomyosarcoma. B, Myxoid stroma is seen in a subset of GISTs and is an uncommon finding in smooth muscle tumors.
Ancillary Studies KIT overexpression. DOG1 (discovered on GIST1), a chlo-

ride channel normally expressed in the interstitial cells of
Immunohistochemistry Cajal, was also found to be expressed in GIST (hence the
name “discovered on GIST 1”). Overall, KIT is positive in
KIT (also known as CD117) is a receptor tyrosine kinase 95% of GISTs (Fig. 7.9), and DOG1 is also positive in 95%
expressed in interstitial cells of Cajal, mast cells, mela- (Fig. 7.10). Fewer than 3% of tumors are negative for both
nocytes, a variety of epithelia, fetal endothelial cells, markers; these tend to be epithelioid PDGFRA-mutant
and a subset of CD34-positive hematopoietic stem cells. GISTs, and PDGFRA immunohistochemistry (IHC) is
Oncogenic KIT mutations were discovered in the late strongly and diffusely positive in essentially 100% of these
1990s to be present in the majority of GISTs, along with tumors (see Fig. 7.5). PDGFRA is also weakly expressed in
stromal cells, presenting a potential pitfall; only strong and 2% (especially duodenal GISTs), and desmin in 1% to 2%
diffuse staining should be used to support the diagnosis of (but up to 10% in epithelioid PDGFRA-mutant GISTs; see
GIST. CD34 is positive in about 70% of GISTs, although Fig. 7.5D). Keratin positivity is rare.
its diagnostic utility is now limited, given the superior sen- Immunohistochemistry is also useful for diagnosing
sitivity and specificity of KIT, DOG1, and PDGFRA IHC. SDH-deficient GIST, which are generally positive for KIT
Caldesmon is positive in 70% of GISTs, S-100 in 1% to and DOG1. The four SDH subunits (A–D) form a protein
complex that is necessary to stabilize the SDHB protein.
Therefore, loss of expression of any one of the subunits
leads to loss of expression of SDHB. Thus, SDHB IHC
can be used to screen for loss of expression of any sub-
unit. SDHA expression is lost in about 35% of tumors, an
event that is reliably detectable using SDHA IHC and that
generally indicates underlying SDHA mutations. Of the
65% of SDH-deficient GISTs that express SDHA, about
30% have mutations in SDHB, SDHC, or SDHD, and the
remaining 35% have SDHC promoter hypermethylation.
Molecular Genetics, Pathologic Phenotypes, and

Prognosis
FIGURE 7.4
Small intestinal gastrointestinal stromal tumor (GIST). This spindle cell GIST Gastrointestinal stromal tumors are not classi-
is highly cellular and mitotically active. fied as benign or malignant tumors; instead, a risk
A B
C D
FIGURE 7.5
Platelet-derived growth factor receptor-α (PDGFRA)–mutant gastric gastrointestinal stromal tumor (GIST). A, The morphology shown here is typical of PDGFRA-
mutant GIST, with epithelioid neoplastic cells dispersed singly and in small clusters within a myxohyaline stroma. Tumor cells have eosinophilic cytoplasm and rela-
tively uniform nuclei with evenly dispersed chromatin. PDGFRA-mutant GIST has a striking predilection for the gastric wall, where this tumor occurred. B, In contrast
to the KIT-mutant GIST in Fig. 7.9, KIT staining shows weak, scattered positivity in neoplastic cells. DOG1 (discovered on GIST1) was more diffusely positive (not
shown). C, PDGFRA is strongly and diffusely positive in neoplastic cells. D, Desmin shows scattered positivity, a feature seen in about 10% of PDGFRA-mutant GISTs.
A B
C D
FIGURE 7.6
Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST). A, At low power, SDH-deficient GIST has a multinodular or plexiform growth
pattern. B, The neoplastic cells are epithelioid, with abundant eosinophilic cytoplasm, relatively uniform nuclei, and a plasmacytoid appearance. C, SDH-B
expression is lost in all SDH-deficient GISTs, regardless of the subunit mutation. D, SDH-A IHC is specifically negative in tumors with underlying SDHA muta-
tions, which represent approximately 35% of SDH-deficient GISTs and are associated with Carney-Stratakis syndrome. Note that SDH-B and SDH-A are
expressed in the mitochondria of adjacent non-neoplastic cells in C and D.
FIGURE 7.8
Dedifferentiated gastrointestinal stromal tumor (GIST). There is a sharp juxtapo-
sition between conventional GIST (above) and dedifferentiated GIST (below),
the latter of which appears to be a high-grade pleomorphic sarcoma that would
not be easily recognized without the adjacent conventional component.
FIGURE 7.7
Epithelioid gastric gastrointestinal stromal tumor (GIST). Note the prominent
GISTs behave in a clinically aggressive fashion, they
paranuclear vacuoles and uniform nuclei; nuclear pleomorphism is unusual
in GIST, and its presence should prompt consideration of other diagnoses. most commonly metastasize to the abdominal cavity
and liver. Metastasis can occur more than 10 years after
stratification scheme is used, with prognosis deter- surgical resection, underscoring the need for long-term
mined by using site, size, and mitotic index (Table 7.2). follow-up.
Mitoses should be counted in a 5-mm2 area; on most Several studies have established relationships between
modern microscopes, 5 mm2 is close to 20 hpf. When specific GIST genotypes and their corresponding
exon 11 deletions behave more aggressively. Recent

clinical trials demonstrated that patients with exon 11
deletions benefit from an extended course of adjuvant
imatinib therapy.
Exon 9 (dimerization motif domain) mutations
occur in tumors typically located in the small and large
intestines; these tumors have spindle cell or mixed
morphology, and they require higher doses of imati-
nib to achieve treatment response. Exon 13 and exon
17 mutations together account for 2% of GISTs; these
tumors mostly occur in the small intestine, have spin-
dle cell morphology, and have inconsistent responses
to imatinib.
About 8% of GISTs harbor mutations to PDGFRA;
FIGURE 7.9
as in KIT-mutant GISTs, these occur in different exons
KIT staining in a KIT-mutant gastrointestinal stromal tumor (GIST). KIT shows
diffuse membranous positivity in this tumor, and in general, it is positive
corresponding to different protein domains. PDGFRA
in 95% of GISTs. KIT most commonly stains with a cytoplasmic pattern, mutations occur in exon 18 (accounting for 7% of GISTs
although it can exhibit membranous (as shown here) and dot-like perinu- overall), exon 12 (1.5%), and exon 14 (0.5%). PDGFRA-
clear staining.
mutant GISTs predominantly occur in the stomach,
and essentially all have purely epithelioid morphology.
A particular missense mutation (D842V) accounts for
the majority of exon 18 mutations and confers imatinib
resistance; recently, the Food and Drug Administration
(FDA)-approved avapritinib to treat patients with these
GISTs. Exon 12– and exon 14–mutant GISTs have vari-
able responses to imatinib.
PDGFRA mutations, KIT mutations, and biallelic
NF1 inactivation are thought to be initiating events
in GIST tumorigenesis; all three subtypes undergo
the same additional chromosomal deletions as part
of an apparent stepwise progression toward higher-
risk tumor biology. Given that they share the same
progression, it is perhaps not surprising that the
FIGURE 7.10 prognosis of these three GIST subtypes can be deter-
DOG1 (discovered on GIST1) staining in a succinate dehydrogenase– mined using the same risk stratification system (see
deficient gastrointestinal stromal tumor (GIST). DOG1 shows diffuse mem- Table 7.2).
branous positivity in this tumor along with scattered perinuclear dot-like
positivity; cytoplasmic positivity is also seen in some tumors. In general, SDH deficiency is seen in about 8% of GISTs and is
DOG1 is positive in about 95% of GISTs. mutually exclusive with PDGFRA and KIT mutations
and NF1 inactivation. SDH-deficient GIST represents
the majority of pediatric GIST but also occurs in a signif-
clinicopathologic phenotypes. The protein structures of icant subset of adults. SDH-deficient GISTs are almost
KIT and PDGFRA receptors are similar, and activating always gastric and show an epithelioid morphology with
a mutation in either one of these two genes leads to acti- a unique plexiform architectural growth pattern (see Fig.
vation of similar signal transduction pathways and these 7.6). SDHA, SDHB, SDHC, and SDHD proteins form a
mutations are thought to be initiating events in GIST multimeric complex in the inner mitochondrial mem-
tumorigenesis. brane that is critical for cellular metabolism. Whereas
Eighty percent of GISTs have KIT mutations, and SDHA mutations are present in about 35% of SDH-
7% have PDGFRA mutations. KIT mutations occur in deficient GISTs, about 30% have mutations in SDHB,
exon 11 (overall accounting for 70% of GISTs), exon SDHC, or SDHD. The remaining 35% of SDH-deficient
9 (8%), exon 13 (1%), and exon 17 (1%) (see Table GISTs have SDHC promoter hypermethylation, which
7.1). Exon 11 (juxtamembrane domain) mutant GISTs silences expression of SDHC, leading to SDH deficiency.
occur in the stomach and small intestine, and they have SDHB, SDHC, or SDHD mutations are usually present
spindle cell or mixed morphology. Exon 11 mutations in the germline, and these patients also develop para-
include in-frame deletions (60%–70%), missense gangliomas in the familial Carney-Stratakis syndrome,
point mutations (20%–30%), and internal tandem as discussed earlier.
duplications; whereas exon 11 point-mutant GISTs The prognosis of SDH-deficient GIST is differ-
have a better prognosis than other GISTs, tumors with ent from the other described genetic subtypes, so
TABLE 7.2
Site-Specific Risk Stratification for Gastrointestinal Stromal Tumors a
Tumor Parameter Risk of Progressive Disease b (%)
Mitotic Index Size (cm) Stomach Duodenum Jejunum/ileum Rectum

≤5 per 5 mm 2
≤2 None (0%) None (0%) None (0%) None (0%)
>2–≤5 Very low (1.9%) Low (8.3%) Low (4.3%) Low (8.5%)
>5–≤10 Low (3.6%) Insufficient data Moderate (24%) Insufficient data
>10 Moderate (10%) High (34%) High (52%) High (57%)
>5 per 5 mm 2 ≤2 None Insufficient data High High (54%)
>2–≤5 Moderate (16%) High (50%) High (73%) High (52%)
>5–≤10 High (55%) Insufficient data High (85%) Insufficient data
>10 High (86%) High (86%) High (90%) High (71%)
a
Does not apply to succinate dehydrogenase–deficient gastrointestinal stromal tumors.
b
Defined as metastasis or tumor-related death.
Adapted from Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors.
J Natl Compr Canc Netw. 2010;8(suppl 2):S1–S41; quiz S42–S44 and Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites.
Semin Diagn Pathol. 2006;23(2):70–83.
the risk stratification system developed for KIT- and β-catenin positivity in 70% to 80% of desmoid fibroma-
PDGFRA-mutant tumors does not apply. Instead, toses, which is negative in GIST. Desmoid fibromatosis
SDH-deficient GISTs frequently give rise to slowly does not express KIT or DOG1.
growing lymph node metastases that progress over The differential diagnosis for epithelioid GIST
the course of several years to decades. SDH-deficient includes neuroendocrine tumors and gastric adenocar-
GISTs do not respond to imatinib therapy, and as of cinoma. Neuroendocrine tumors usually have smaller
now, there is no targeted therapy to treat patients cells and darker nuclei with speckled chromatin. IHC for
with these tumors. synaptophysin, chromogranin, KIT, and DOG1 readily
BRAF-mutant GISTs are rare. Tumors harboring distinguishes the two. Gastric adenocarcinoma exhibits
BRAF V600E occur in the small intestine and have significant nuclear pleomorphism and hyperchromasia,
spindle cell morphology. Although they do not respond in contrast to the uniform nuclei and evenly dispersed
to imatinib, they have been shown to respond to dab- chromatin of epithelioid GIST.
rafenib, a BRAF inhibitor.
Treatment
Surgical excision is the treatment for patients with resect-
The differential diagnosis for spindle cell GIST able GIST. Narrow margins suffice because tumors tend
includes leiomyoma, leiomyosarcoma, schwannoma, not to recur at the surgical site; the exception is SDH-
and desmoid fibromatosis. Leiomyoma and leiomyo- deficient GISTs, likely because of their multinodular,
sarcoma have more brightly eosinophilic cytoplasm, infiltrative growth pattern. For most KIT-mutant GISTs
and they exhibit distinct cell borders in contrast to and some PDGFRA-mutant GISTs, imatinib is the
the indistinct cell borders of GIST. Leiomyoma and first-line therapy in the setting of metastases or locally
leiomyosarcoma also have blunt-ended nuclei, unlike advanced disease and as adjuvant therapy in GISTs
the tapered nuclei of GIST. IHC is useful to resolve that stratify into intermediate- or high-risk groups (see
the differential diagnosis: leiomyoma and leiomyo- Table 7.2). Neoadjuvant imatinib is also used in some
sarcoma commonly have diffuse desmin expression, cases to reduce the size of locally advanced tumors prior
which would be unusual in GIST, and they are nega- to surgery. Imatinib resistance eventually develops in
tive for KIT and DOG1. all treated GISTs, usually by means of secondary KIT
Gastric schwannoma typically has a peripheral cuff mutations. Sunitinib and regorafenib are FDA-approved
of lymphocytes and neural cytomorphology with buck- second- and third-line therapies, respectively, that are
led nuclei and mild atypia. The cells of schwannoma used in the setting of imatinib resistance. As mentioned
show diffuse S-100 expression and are negative for earlier, avapritinib was recently FDA approved for
DOG1 and KIT. first-line treatment of patients with PDGFRA exon 18–
Desmoid fibromatosis is more infiltrative than GIST mutant GIST, which is resistant to imatinib, sunitinib,
and has longer fascicles. IHC demonstrates nuclear and regorafenib.
GASTROINTESTINAL STROMAL TUMORS—FACT SHEET Molecular Testing

n Determines optimal treatment
Definition n KIT mutations (80%) in exon 11 (70%), exon 9 (8%), exon 13
n Gastrointestinal stromal tumor (GIST) is the most common (1%), exon 17 (1%), or exon 8 (rare)
mesenchymal tumor in the gastrointestinal (GI) tract and exhibits n PDGFRA mutations (7%) in exon 18 (5%), exon 12 (1.5%), or
differentiation of the interstitial cells of Cajal exon 14 (0.5%)

n Succinate dehydrogenase (SDH) deficiency (8%): SDHA mutations
Incidence and Location (35%); SDHB, SDHC, or SDHD mutations (30%); SDHC promoter
hypermethylation (35%); no KIT or PDGFRA mutations
n 3300 to 6000 cases per year in the United States
n Biallelic NF1 inactivation (2%–3%); no KIT or PDGFRA mutations
n Most commonly occurs in the stomach (60%) and small
n BRAF V600E mutation (<1%)
intestine (35%)
n Spindle cell GIST: leiomyoma or leiomyosarcoma (desmin positive,
n Tumor mortality depends in part on primary site: intestinal GISTs are
KIT/DOG1 negative); schwannoma or malignant peripheral nerve
about twice as likely to behave aggressively compared with gastric GISTs.
sheath tumor (S-100 positive, KIT negative); desmoid fibromatosis
n Tumor size and mitotic count also influence clinical behavior
(70%–80% nuclear β-catenin positivity; 95% negative for KIT)
n Epithelioid GIST: neuroendocrine tumor (synaptophysin
and chromogranin positive, KIT and DOG1 negative), gastric
n No sex predilection
adenocarcinoma (keratin positive, more atypical or pleomorphic)
n May be overrepresented in African Americans
n Most commonly occurs in adults, with a median age at
presentation of 60 years
n Pediatric tumors are typically succinate dehydrogenase deficient SMOOTH MUSCLE TUMORS OF THE
GASTROINTESTINAL TRACT
Clinical Features
n Clinical presentation depends on primary site but usually includes
abdominal pain, symptoms of GI bleeding such as anemia or

melena or obstruction
n Small tumors are often detected incidentally
Smooth muscle tumors of the GI tract consist of leio-
Prognosis and Therapy myoma and the much rarer leiomyosarcoma. Colonic
n Tumors are not classified as benign or malignant; instead, they leiomyomas classically arise in association with the mus-
are risk stratified based on anatomic site, tumor size, and mitotic cularis mucosae and present as distal polyps on screen-
activity (see Tables 7.2) ing colonoscopy, usually in men in their seventh decade.
n Prognosis and treatment are determined based on the driving
mutation and risk category

Esophageal leiomyomas often present as intramural
n Food and Drug Administration-approved treatment includes imatinib, masses; patients have a median age of 35 years, there is
sunitinib, and regorafenib (nonspecific tyrosine kinase inhibitors) and, a male predominance (∼70%), and the clinical course is
more recently, avapritinib (used for PDGFRA exon 18-mutant GIST) indolent. In the esophagus, the vast majority of spindle
cell tumors are leiomyomas. Smooth muscle tumors of
the stomach and small intestine are rare; GIST is much
more common at these locations. Leiomyosarcoma of the
Gastrointestinal Stromal Tumors—Pathologic Features
GI tract is very rare and generally follows an aggressive
Gross Findings
course. Leiomyosarcoma of the colon shows a slight male
n Mural mass, sometimes with protrusion into the gastrointestinal lumen
predominance and presents in adults. Leiomyosarcoma
n Fibrous to fleshy cut surface, with variable hemorrhage and/or is exceptional in the stomach. Leiomyomatosis has been
cystic degeneration described in the small intestine and colon.
n Spindled or epithelioid cells with uniform nuclei and relatively Radiologic Features
limited atypia
n Nuclear palisading common
n Gastric gastrointestinal stromal tumors (GISTs) commonly have

The radiologic features are not specific and are not dis-
paranuclear vacuoles tinguishable from those of GIST.
n About half of small intestinal GISTs have skeinoid fibers
Immunohistochemistry Pathologic Features

n Positive: DOG1 (discovered on GIST1; 95%), KIT (95%), CD34 (70
n Variable: smooth muscle actin (30%), S-100 (5%)
n Platelet-derived growth factor receptor-α (PDGFRA)–mutant

Gross Findings
GISTs: positive for PDGFRA (nearly 100%), DOG1 (95%), KIT
(85%), desmin (≤10%) Esophageal leiomyomas form whorled white to pale yel-
low masses similar to uterine leiomyomas. Leiomyomas

Gastric leiomyoma that has arisen in association with the muscularis muco- Submucosal leiomyoma of the colon. In contrast to leiomyomas in the esoph-
sae. The bright eosinophilia of the cytoplasm is evident at low magnification. agus, those in the colon tend have more ovoid nuclei and paler cytoplasm.
arising in the muscularis mucosae of the colorectum

present as mucosal polyps, usually smaller than 1 cm.
Leiomyosarcomas of the colorectum tend to be intralu-
minal bulging exophytic and polypoid masses, which
may show necrosis and hemorrhage.
Smooth muscle tumors of the GI tract have the same

features of smooth muscle differentiation seen at other
anatomic sites, namely perpendicularly oriented fasci-
cles of spindle cells with distinct cell borders, brightly
eosinophilic cytoplasm, longitudinal striations, and
blunt-ended or cigar-shaped nuclei (Figs. 7.11 to 7.15).
Leiomyomas are bland and resemble normal smooth mus-
cle. They lack atypia and pleomorphism and generally
show no or minimal mitotic activity. Leiomyosarcoma is
characterized by conspicuous mitotic activity, cytologic A
atypia, and necrosis.
Ancillary Studies
Smooth muscle tumors show expression of smooth mus-

cle actin (SMA), desmin, and caldesmon, but expression
of the latter two markers may be variable in extent, espe-
cially in leiomyosarcoma. KIT, CD34, and S-100 protein
are generally not expressed. Approximately 40% of leio-
myosarcomas show variable keratin expression, which
may be extensive occasionally and make distinction B
from sarcomatoid carcinoma difficult. Esophageal leio-
FIGURE 7.13
myomas often contain numerous mast cells that are KIT
Leiomyosarcoma showing perpendicularly oriented fascicles of spindle cells
positive, which may result in an erroneous diagnosis of with eosinophilic cytoplasm (A and B). Compare the cellularity of this lesion
GIST. to that seen in Figs. 7.11 and 7.12.
Differential Diagnosis Microscopic Findings

n Fascicular spindle cell neoplasm; tumor cells have brightly eosinophilic
cytoplasm, distinct cell borders, and blunt-ended cigar-shaped nuclei

The differential diagnosis is primarily with GIST and n Leiomyomas are bland, resemble normal smooth muscle, and
schwannoma, and the majority of lesions are readily sepa- lack atypia and necrosis
rable by IHC. Sarcomatoid carcinoma may mimic leiomyo- n Leiomyosarcomas show cytologic and nuclear pleomorphism and
sarcoma because both are composed of fascicles of atypical atypia, mitotic activity, and necrosis
spindle cells, which may express keratins. Identification of
a more epithelioid or conventional carcinomatous compo-
n Positive for desmin, smooth muscle actin, caldesmon
nent allows for recognition of sarcomatoid carcinoma. In n Negative for KIT, DOG1 and S-100 protein
addition, the latter does not show desmin expression. n Focal keratin expression is common in leiomyosarcoma
n Usually negative for CD34

n Gastrointestinal stromal tumor: cytoplasm is paler; may show
skeinoid fibers or paranuclear vacuoles; KIT and DOG1 positive

The prognosis of leiomyomas is excellent in all sites because
and desmin negative
they are benign. In general, GI tract leiomyosarcomas have n Schwannoma: usually larger gastric lesions with a peripheral
a poor prognosis, and about 75% of patients die of disease. lymphoid cuff or smaller polypoid colonic lesions that entrap
colonic crypts, different from the growth pattern of leiomyoma;
tumor cells are positive for S-100
SMOOTH MUSCLE TUMORS OF THE GASTROINTESTINAL n Sarcomatoid carcinoma: may be difficult to distinguish from
TRACT—FACT SHEET leiomyosarcoma, given that both can show keratin expression;
identification of an epithelioid or overtly carcinomatous component
Definition is particularly helpful and may require extensive sampling
n Benign or malignant neoplasms with smooth muscle differentiation

n Leiomyoma is far more common than leiomyosarcoma, and
leiomyoma is the most common spindle cell tumor of the esophagus.

n Small polypoid leiomyomas arise in association with the
muscularis mucosae of the colorectum

n Leiomyomas are benign; in contrast, 75% of patients with
leiomyosarcomas of the gastrointestinal tract die of disease

n Occur in adults (average, 60 years); slight male predominance
Clinical Features
n Whereas smooth muscle tumors of the esophagus present as an
intramural mass, smooth muscle tumors of the colon present as FIGURE 7.14
polypoid lesions Leiomyosarcoma with marked pleomorphism and nuclear atypia.
n Smooth muscle tumors of the small intestine can present as
either intramural masses or polypoid lesions

n Poor prognosis for leiomyosarcomas; leiomyomas are benign.
n All lesions except small polypoid leiomyomas of the colorectum
are treated surgically when possible; there is no targeted

chemotherapy as there is for gastrointestinal stromal tumor
Smooth Muscle Tumors of The Gastrointestinal

Tract—Pathologic Features
Gross Findings
n Esophageal leiomyomas are whorled, whitish masses
n Leiomyosarcomas are large, exophytic, mural-based masses, with FIGURE 7.15

variable amounts of necrosis and hemorrhage Leiomyosarcoma. The nuclei have blunt ends typical of smooth muscle dif-
ferentiation, and there are scattered paranuclear vacuoles.
GRANULAR CELL TUMOR Ancillary Studies
■ CLINICAL FEATURES Immunohistochemistry
Granular cell tumors are benign tumors that exhibit Diffuse strong expression of S-100 protein and SOX10
Schwannian differentiation. Although they can occur is present in esophageal granular cell tumors (Fig. 7.18).
anywhere along the luminal GI tract, they have a strik- Granular cell tumors also overexpress transcription fac-
ing predilection for the esophagus. Granular cell tumors tor enhancer 3 (TFE3), but they do not harbor underly-
usually occur in middle-aged adults and are more coming TFE3 rearrangements.
mon in women and African Americans. Although they
usually occur as unifocal tumors in the distal esophagus, Molecular Studies
they can also present as multiple sporadic esophageal
tumors. Granular cell tumors were recently found to have recurrent
loss of function mutations in ATP6AP1 and ATP6AP2,
which are endosomal pH regulatory proteins; loss of
expression of these proteins was shown to be oncogenic
Endoscopic Features
and to lead to accumulation of intracytoplasmic granules.
Granular cell tumors are often found incidentally on

endoscopy, and they appear as small polyps or plaques.
The differential diagnosis is limited because the cyto-

Pathologic Features
morphology of granular cell tumor is unique. Nested
Gross Findings
Most granular cell tumors are small (<1 cm) with a yel-
low-white cut surface and infiltrative peripheral growth.
Granular cell tumors are composed of sheets and nests

of large polygonal cells with brightly eosinophilic, gran-
ular cytoplasm, and centrally located, small, hyperchro-
matic nuclei (Figs. 7.16 and 7.17). There is frequently
overlying squamous cell hyperplasia, a useful diagnostic
clue. Occasionally, tumors can have spindle cell mor- FIGURE 7.17
phology, although the spindle cells still contain abun- Granular cell tumor. Tumor cells have abundant granular cytoplasm and
dant granular cytoplasm. In conventional granular cell small hyperchromatic nuclei.
tumor, mitotic activity is low, and there is no necrosis.
FIGURE 7.18
FIGURE 7.16 Granular cell tumor. S-100 is diffusely positive in tumor cells and highlights
Granular cell tumor. Tumor cells are present in sheets and nests deep to the the predominantly nested tumor architecture.
squamous epithelium.
examples can sometimes resemble alveolar soft part

sarcoma, which also overexpresses TFE3; however,
n Alveolar soft part sarcoma: both overexpress transcription factor
alveolar soft part sarcoma has significantly more
enhancer 3 (TFE3), but granular cell tumor lacks the TFE3
cytologic atypia. Granular cell tumors with spindle rearrangement of alveolar soft part sarcoma
cell morphology could be mistaken for schwannoma, n Schwannoma: can resemble spindle cell granular cell tumor,
but the latter does not contain abundant granular and both diffusely expression S-100 and SOX10; however,
cytoplasm. schwannoma lacks abundant granular cytoplasm
CLEAR CELL SARCOMA-LIKE TUMOR

OF THE GASTROINTESTINAL TRACT/
MALIGNANT GASTROINTESTINAL
The vast majority of granular cell tumors are benign and
NEUROECTODERMAL TUMOR
do not recur even if incompletely excised. The rare malig-
nant granular cell tumors tend to have worrisome features
such as increased mitotic activity and necrosis, neither of
which are features of conventional granular cell tumor.
Clear cell sarcoma-like tumor of the GI tract, also known as

malignant GI neuroectodermal tumor (malignant GNET),
GRANULAR CELL TUMOR—FACT SHEET is a rare tumor with distinctive pathologic and genetic fea-
tures, different from conventional clear cell sarcoma of ten-
Definition
dons and aponeuroses. These tumors have also been called
n Benign neoplasm with Schwannian differentiation composed
“osteoclast-rich tumors of the GI tract with features resem-
of large polygonal cells with bright eosinophilic granular cytoplasm
bling clear cell sarcoma of soft parts.” In contrast to conven-
Incidence and Location tional clear cell sarcoma of tendons and aponeuroses, these
n Most commonly occur in the distal esophagus and rarely occur at
tumors usually show less nested growth pattern, contain
other sites in the gastrointestinal tract osteoclast-like giant cells, and lack evidence of melanocytic
differentiation ultrastructurally and immunohistochemi-
Gender, Race, and Age Distribution cally. They both, however, express S-100 and harbor the
n Wide age distribution, with a peak in middle age EWSR1-ATF1 or EWSR1-CREB1 fusion genes.
n More common in women than men
The most common site of involvement is the small
n More common in African American patients
intestine followed by the stomach and colon. Patients are
Clinical Features usually young to middle-aged adults (mean age, 42 years;
n Small incidental polyps or plaques found during endoscopy
range, 17–77 years), and there is no apparent gender pre-
dilection. Presenting symptoms and signs include abdom-
Prognosis and Therapy inal pain, intestinal obstruction, weight loss, anemia, and
n Mostly benign and do no recur even with positive margins fever. Metastasis at the time of presentation is common.
n Rare malignant granular cell tumors have worrisome features
such as high mitotic activity and necrosis
Radiologic and Endoscopic Features
Tumors grow as exophytic masses that protrude into the

lumen of the intestine. Overlying mucosal ulceration is
Granular Cell Tumor—Pathologic Features often present. Tumors may also grow as circumferential
masses, mimicking carcinoma or lymphoma.
Gross Findings
n Subepithelial mass with a yellow cut surface and infiltrative borders
Pathologic Features
n Sheets and nests of large polygonal cells with abundant
eosinophilic granular cytoplasm; uncommonly, neoplastic cells Gross Findings

can have spindled morphology
n Overlying squamous cell hyperplasia may be present
Tumors typically involve both submucosa and muscu-
laris propria and range in size from 2 to 15 cm. Extension
Immunohistochemistry into mucosa may occur. Tumors are usually solid and
n Strong and diffuse expression of S-100 and SOX10 firm, with a tan-white cut surface. Hemorrhage, necro-
sis, and cystic change may be present.

Malignant gastrointestinal neuroectodermal tumor (GNET). GNET is com- Malignant gastrointestinal neuroectodermal tumor (GNET) immunohistochemis-
posed of sheets and large nests of epithelioid and spindle cells, in contrast try. GNET is diffusely positive for S-100 (pictured) and SOX10, but it is negative
to the smaller nests of clear cell sarcoma. for secondary melanocytic markers such as HMB45 (human melanoma black)
and Melan-A. Because melanoma can also lose expression of secondary mela-
nocytic markers, fluorescence in situ hybridization for EWSR1 rearrangement can
be helpful when this differential diagnosis is otherwise difficult to resolve.
contrast, melanocytic markers HMB45 (human mela-

noma black), Melan-A, microphthalmia transcription
factor (MiTF), and tyrosinase are negative. Tumor cells
are also negative for KIT, DOG1, CD34, glial fibrillary
acidic protein (GFAP), keratins, desmin, and SMA.
Expression of synaptophysin and neuron-specific eno-
lase (NSE) is seen in up to 50% of cases. Ultrastructural
features of neural differentiation are seen by electron
microscopy.
FIGURE 7.20
Malignant gastrointestinal neuroectodermal tumor (GNET). Whereas at low Molecular Genetics
power, GNET resembles melanoma, at higher power, the tumor cells are
usually less atypical. Rarely, GNET can exhibit pleomorphism, making the dif-
Malignant GNET is a translocation-associated tumor,
ferential diagnosis with melanoma challenging to resolve.
with EWSR1-ATF1 and EWSR1-CREB1 fusion genes
in approximately 90% of cases caused by t(12;22)
Microscopic Findings (q13;q12) or t(2;22)(q34;q12), respectively. FISH for
EWSR1 rearrangement is useful to exclude a diagnosis
of malignant melanoma.
Malignant GNET is composed of sheets of round to
epithelioid cells and in some cases ovoid to spindled
cells (Fig. 7.19). Tumor cells have small amounts of
pale eosinophilic cytoplasm and round to oval nuclei
with vesicular chromatin and small nucleoli (Fig. 7.20).
Mitotic activity is variable. The growth pattern is usu- Conventional clear cell sarcoma typically arises in ten-
ally mixed, with focal areas of nested, pseudoglandular, dons or aponeuroses of the extremities of young adults
pseudopapillary, microcystic, and fascicular architec- and rarely involves the GI tract. Clear cell sarcoma is
ture. Osteoclast-like giant cells are present in 50% of characterized by epithelioid or spindle-shaped tumor
cases. cells (or both) with clear or pale eosinophilic cyto-
plasm, in a nested or fascicular growth pattern with
a delicate fibrovascular stroma. The nested growth
pattern is more prominent than in malignant GNET.
Ancillary Studies
Melanin pigmentation is rarely seen, and osteoclast-
like giant cells are not typical, in contrast to malig-
Immunohistochemistry nant GNET. In addition to S-100 protein expression,
the tumor cells express secondary melanocytic mark-
Strong diffuse expression of S-100 is present in all cases ers such as HMB45, MART1, tyrosinase, and MiTF.
(Fig. 7.21). SOX10 expression is also seen, reflecting Tumors usually harbor a t(12;22)(q13;q12), similar to
the neuroectodermal differentiation of this tumor. In malignant GNET.
Metastatic melanoma is common in the small

Clinical Features
intestine. Given the morphologic and immunohis-
n Pain, gastric outlet obstruction, bleeding, anemia, fever
tochemical overlap, malignant GNET may easily be
mistaken for metastatic melanoma and vice versa. As Prognosis and Therapy
noted, malignant GNET lacks expression of second- n Aggressive tumors with frequent metastasis
ary melanocytic markers, but this can also be the case
in some metastatic melanomas. Clinical correlation to
determine if there is a history of melanoma at other
sites is essential, and demonstration of EWSR1 rear-
rangement can confirm the diagnosis of malignant
GNET. Malignant Neuroectodermal Tumor—Pathologic Features
Monophasic synovial sarcoma rarely involves the GI
tract, but when it does, it has a predilection for the stom- Gross Findings
ach. The spindled tumor cells of synovial sarcoma typ- n Intramural, 2- to 15-cm, solid masses, often with hemorrhage or
necrosis
ically have overlapping nuclei and less cytoplasm than
those of malignant GNET and show a more uniform fas- Microscopic Findings
cicular growth pattern without the heterogeneity of the n Sheets of epithelioid, round or spindled cells
former. By IHC, the tumor cells are negative for S-100 n Osteoclast-like giant cells in 50%
and instead show expression of keratin, epithelial mem- n Mixed growth patterns: sheets-like, pseudoglandular,
brane antigen (EMA), and TLE1. Identification of SS18 pseudopapillary, or nested

(SYT) rearrangement can help confirm the diagnosis in
difficult cases.
n Positive for S-100
Gastrointestinal stromal tumors showing mixed
n Negative for secondary melanocytic markers, KIT, DOG1
epithelioid and spindled cell morphology may mimic (discovered on GIST1), and CD34
malignant GNET. However, pseudoglandular areas and
osteoclast-like giant cells are not typical of GIST. IHC Molecular Genetics
readily distinguishes the two tumor types; expression of n EWSR1-ATF1 and EWSR1-CREB1 fusion genes in 90%
KIT, DOG1, and CD34 is seen in virtually all GIST but

not in malignant GNET. Focal S-100 expression is seen Differential Diagnosis
in a small subset of duodenal GIST. n Gastrointestinal stromal tumor: especially myxoid or
succinate dehydrogenase–deficient types: positive for KIT

and DOG1
n Metastatic melanoma: may be positive for secondary melanocytic
markers; lacks EWSR1 rearrangement

n Conventional clear cell sarcoma: rarely involves the
gastrointestinal tract; more prominent nested growth pattern;

also expresses HMB45 (human melanoma black), MART1,
Malignant GNET pursues an aggressive clinical course
tyrosinase
in most cases and has a poor prognosis. Metastasis to n Synovial sarcoma: more uniform fascicular growth pattern; lacks
lymph nodes and liver is common. A study with clinical osteoclast-like giant cells; positive for EMA and TLE1; SS18 gene
follow-up for 12 patients showed 50% died of disease rearrangement
with a mean survival period of 32 months.
MALIGNANT NEUROECTODERMAL TUMOR—FACT SHEET

INFLAMMATORY FIBROID POLYP
Definition
n Malignant neuroectodermal tumor

Inflammatory fibroid polyp is a benign tumor that most
n Extremely rare; usually arises in the small intestine
commonly arises in the gastric antrum or ileum and
rarely in other intestinal locations. Patients usually
n Malignant tumors with frequent metastases and death from disease
present in their sixth decade, and there is a slight female
predominance. Large gastric tumors can cause abdom-
Gender, Race, and Age Distribution inal pain, gastric outlet obstruction, and GI bleeding,
n No gender predilection and large intestinal tumors commonly cause intus-
n Young to middle-aged adults susception, often requiring emergent surgery. Smaller
tumors can be found incidentally during endoscopy.
Endoscopically, there may be a small polypoid mass or

a larger mass bulging into the lumen, with or without
mucosal ulceration.
Pathologic Features
Gross Findings A
Gastric tumors are typically small (<3 cm) polypoid

masses; small intestinal tumors tend to be larger (3 to
>10 cm). They involve the lamina propria or submucosa
and can extend into muscularis propria or serosa. The
cut surface appears glistening and fleshy, consistent
with the edematous stroma microscopically.
Tumors exhibit a diffuse growth pattern of stellate,

ovoid or short spindled fibroblastic cells, most com- B
monly in an edematous or myxoid stroma (Fig. 7.22). FIGURE 7.23
Sometimes the stroma can appear more collagenous, Inflammatory fibroid polyp. A, At higher power, neoplastic cells are stellate,
and some tumors exhibit perivascular onion-skinning with vesicular nuclei and small nucleoli. There are admixed eosinophils, a
useful diagnostic clue when present. B, The tumor cells typically show strong
fibrosis. Inflammatory fibroid polyp is usually hypocel- diffuse expression of platelet-derived growth factor receptor-α (PDGFRA),
lular, and neoplastic cells have at most minimal atypia. reflecting the presence of PDGFRA mutations.
The lesion can resemble a non-neoplastic inflammatory
lesion. Mitotic activity is low or absent. There are fre-
quently admixed eosinophils, a useful diagnostic clue, as desmin, and S-100, which can be useful to exclude histo-
well as lymphocytes and histiocytes (Fig. 7.23A). logic mimics. IHC for PDGFRA, when available, is help-
ful as it is diffusely positive in essentially all inflammatory
fibroid polyps; because background stromal cells express
Ancillary Studies PDGFRA at lower levels, it is important to only interpret
strong diffuse positivity as a positive result (Fig. 7.23B).
Molecular Studies
Neoplastic cells are positive for CD34 and, in 20% of cases,
SMA. They are virtually always negative for KIT, DOG1, Inflammatory fibroid polyp harbors mutations in
PDGFRA, including some of the same mutations present
in PDGFRA-mutant GIST. The exonic mutations cor-
relate with tumor location, with mutations in exon 12
more commonly occurring in small intestinal tumors and
exon 18 more commonly occurring in gastric tumors.
Myxoid GIST can appear similar to inflammatory fibroid

polyp but is typically more densely cellular and lacks
an eosinophil-rich inflammatory infiltrate. Many myx-
FIGURE 7.22 oid GISTs are PDGFRA mutant, such that PDGFRA
Inflammatory fibroid polyp. Inflammatory fibroid polyp commonly occurs in the IHC is not useful to resolve this differential diagnosis.
stomach and small intestine. When tumors arise in the small intestine, patients
frequently present with intussusception, as happened with this ileal tumor. At However, in contrast to inflammatory fibroid polyp, the
low power, this tumor contains scattered vessels in an edematous stroma. tumor cells of GIST are positive for KIT and DOG1.
Plexiform fibromyxoma arises in the gastric antrum,

but in contrast to inflammatory fibroid polyp, it exhibits a
n Submucosal location, sometimes with infiltration into the
multinodular or plexiform growth pattern and is predom-
muscularis propria
inantly located in the muscularis propria. Although plexi- n Hypocellular neoplasm with edematous or myxoid stroma rich in
form fibromyxoma is also composed of bland spindle cells, eosinophils
it does not have the eosinophil-rich inflammatory infil- n Bland stellate, ovoid, or short spindled neoplastic cells
trate characteristic of inflammatory fibroid polyp. IHC for n Perivascular onion-skinning fibrosis is common
PDGFRA can be used to distinguish these entities.

Inflammatory myofibroblastic tumor (IMT) also con-
n Positive for CD34, platelet-derived growth factor receptor-α
tains an inflammatory infiltrate, but its neoplastic cells (PDGFRA), and smooth muscle actin (20%)
exhibit a fascicular growth pattern. IHC for PDGFRA n Negative for S-100, KIT, DOG1 (discovered on GIST1), and desmin
and anaplastic lymphoma kinase (ALK) can discrimi-
nate between these tumor types. Molecular Genetics
n Mutations in PDGFRA gene, with a different but somewhat
overlapping exonic distribution compared with PDGFRA-mutant

gastrointestinal stromal tumor (GIST)
n GIST: especially myxoid or PDGFRA-mutant GIST, which is usually
Complete excision is curative. Very rarely, inflammatory more cellular; positive for KIT and DOG1; both inflammatory
fibroid polyp occurs in the inherited Devon polyposis fibroid polyp and PDGFRA-mutant GIST are positive for PDGFRA
syndrome. n Plexiform fibromyxoma: usually intramural rather than submucosal,
has plexiform growth, lacks prominent inflammatory infiltrate
n Inflammatory myofibroblastic tumor: more cellular, with fascicles
of neoplastic myofibroblasts; negative for PDGFRA, 50% positive
INFLAMMATORY FIBROID POLYP—FACT SHEET for anaplastic lymphoma kinase
Definition
n Benign fibroblastic proliferation that commonly manifests as a
gastric antral polyp or an intestinal mass causing intussusception PLEXIFORM FIBROMYXOMA

n Rare tumor that typically arises in the lamina propria/submucosa of
the gastric antrum, ileum, or, less commonly, other intestinal sites
Morbidity and Mortality Plexiform fibromyxoma is a benign tumor that virtually

n Inflammatory fibroid polyps are benign and only rarely occur in a
always arises in stomach, most often at the gastric antrum.
familial syndromic setting (Devon polyposis syndrome) Very rare cases arise in the small intestine. Patients are
usually in their fifth decade, and there is no gender pre-
Gender, Race, and Age Distribution dilection. Presenting symptoms include abdominal pain,
n Slight female predominance gastric outlet obstruction, and GI bleeding.
n Wide age range, with peak in the sixth decade of life
Clinical Features
n Gastric tumors sometimes present with pain, gastric outlet Radiologic and Endoscopic Features
obstruction, or bleeding
n Small intestinal tumors can present with intussusception
n Small tumors can be incidentally found during endoscopy Endoscopically, there may be a bulging mass into the
gastric lumen, with or without mucosal ulceration.
n Benign and cured by simple excision
Pathologic Features
Gross Findings
Inflammatory Fibroid Polyp—Pathologic Features
Tumors usually measure between 2 and 15 cm. They
Gross Findings
are typically intramural but may extend into mucosa or
n Wide size range (1–>10 cm); gastric tumors tend to be smaller
serosa. Tumors are lobulated and the cut surface vari-
than intestinal tumors
n Uniform fleshy or glistening cut surface
ably red, tan, or white, with a gelatinous and glistening
appearance because of the myxoid stroma.
Microscopic Findings always negative for KIT, DOG1, CD34, and S-100 pro-
tein. Focal expression of desmin or caldesmon has been
Tumors arise within the muscularis propria and show a reported in a small subset of tumors. IHC may be helpful
multinodular or plexiform growth pattern on low power to exclude histologic mimics.
examination, resulting in separation of smooth muscle
bundles (Fig. 7.24). The nodules are relatively hypocellular Molecular Studies
and contain bland oval-spindled tumor cells with at most
minimal atypia, within a variably myxoid and collagenous A subset of tumors harbor MALAT1-GLI1 fusion, GLI1
stroma (Fig. 7.25). There is typically a prominent cap- polysomy, or PTCH1 loss, all of which are expected to
illary proliferation. The tumor cells have indistinct cyto- activate the hedgehog pathway.
plasm and small nuclei. Mitotic activity is low or absent.
Extension into mucosa may result in mucosal ulceration.
Subserosal or serosal tumor nodules may be present. Differential Diagnosis
Purely myxoid GIST is uncommon but can mimic plexi-

form fibromyxoma. Myxoid GIST lacks the multinodular
Ancillary Studies
or plexiform growth pattern of plexiform fibromyxoma
Immunohistochemistry and is composed of a uniform proliferation of spindled or
epithelioid tumor cells. Many myxoid GIST are PDGFRA
The immunoprofile is nonspecific: the spindled cells mutant. SDH-deficient GIST also shows a plexiform
express SMA, either diffusely or focally, and are virtually growth pattern but is less often myxoid and is usually
more cellular, and the tumor cells are usually epithelioid.
Unlike plexiform fibromyxoma, tumor cells of GIST are
positive for KIT, DOG1, and CD34. Additional IHC for
SDHB can confirm a diagnosis of SDH-deficient GIST.
Inflammatory fibroid polyp also arises in the gastric
antrum but in contrast to plexiform fibromyxoma is
predominantly submucosal in location. Inflammatory
fibroid polyp is also composed of bland spindle cells, but
the cells form a characteristic “onion-skin” pattern of
condensation around blood vessels, and the tumor lacks
a plexiform growth pattern. In addition, the characteris-
tic inflammatory infiltrate associated with inflammatory
fibroid polyp is not present in plexiform fibromyxoma.
Desmoid fibromatosis lacks a multinodular or plexi-
form growth pattern and is composed of more uniformly
cellular long fascicles of bland spindled cells with small
nucleoli and variable amounts of palely eosinophilic
FIGURE 7.24 cytoplasm. IHC for β-catenin, which shows nuclear expre-
Plexiform fibromyxoma. Plexiform fibromyxoma has a characteristic plexiform ssion in 70% to 80% of desmoid fibromatoses can be
growth pattern and is composed of bland fibroblastic cells in a variably myx- helpful in making this distinction.
oid or collagenous stroma.
Complete excision is curative. Vascular invasion is often

present and has no apparent significance; metastasis has
not been described.
PLEXIFORM FIBROMYXOMA—FACT SHEET
Definition
FIGURE 7.25 n Benign fibroblastic proliferation with a multinodular growth
Plexiform fibromyxoma cytomorphology. Neoplastic cells in this tumor pattern and myxoid stroma
appear myofibroblastic, with eosinophilic cytoplasm and cytoplasmic tails.

n Rare tumor that typically arises in the gastric antrum

n Plexiform fibromyxomas are benign and not syndromic

n No gender predilection
n Most common in adults in fifth decade of life
Clinical Features
n Pain, gastric outlet obstruction, bleeding
FIGURE 7.26
Prognosis and Therapy Calcifying fibrous tumor. This example contains numerous psammomatous
n Benign and cured by simple excision calcifications in a hypocellular collagenous stroma.
or mesenteric, with a smaller number being serosal.

Peritoneal tumors may be multifocal.
Plexiform Fibromyxoma—Pathologic Features There is a wide age range, there is no gender predi-
lection, and tumors are rarely familial (usually multiple
Gross Findings
lesions in young adults). Presenting symptoms depend
n Intramural, nodular, 2 to 15 cm
on the site and depth of involvement but include pain,
obstruction, and intussusception. Small tumors are
n Multinodular or plexiform lesion
often detected incidentally. These are benign lesions,
n Bland spindle cells with no or minimal atypia
and recurrence is rare.
n Prominent capillary proliferation
n Variably myxoid and collagenous stroma
Immunohistochemistry Microscopic Findings

n Positive for smooth muscle actin
n Negative for S-100, KIT, DOG1 (discovered on GIST1), and CD34

Histologically these tumors are usually paucicellular and
Molecular Genetics have abundant hyalinized collagen. The lesional cells are
n Hedgehog pathway activation through MALAT1-GLI1 fusion, GLI1
bland spindled CD34 positive fibroblasts. A plasma cell
polysomy, or PTCH1 inactivation in subset of cases infiltrate is common. Dystrophic or psammomatous cal-
cifications are present in most cases (Fig. 7.26), but 20%
Differential Diagnosis lack calcifications, making recognition difficult. IHC is
n Gastrointestinal stromal tumor: especially myxoid or succinate helpful to exclude other tumors that may fall into the
dehydrogenase–deficient types, usually more cellular; positive for
differential diagnosis, particularly GIST, schwannoma,
KIT and DOG1
n Inflammatory fibroid polyp: lacks plexiform growth; shows
and IMT.
perivascular condensation of spindled cells and a prominent
inflammatory infiltrate
n Desmoid fibromatosis: long sweeping fascicles, nuclear β-catenin
expression in 70% to 80%

SCHWANNOMA OF THE
GASTROINTESTINAL TRACT
CALCIFYING FIBROUS TUMOR

Schwannomas are benign nerve sheath tumors, and
when located in the GI tract, they harbor features dis-
Calcifying fibrous tumor is a rare benign mesenchymal tinctive from schwannomas occurring at other sites.
lesion that typically involves serosal surfaces (pleura, Almost all schwannomas of the GI tract arise in the
peritoneum), but it can also arise in viscera and soft stomach and involve the submucosa and muscularis pro-
tissue. Within the GI tract, the most common site of pria. Rare cases involve the colon. Tumors usually occur
involvement is the small intestine followed by colon in middle-aged or older adults (50–70 years). Gastric
and stomach. Most tumors are either submucosal schwannomas are more common in women than men
and present with symptoms of upper GI tract bleed-

ing, abdominal pain, or obstructive symptoms. Colonic
cases may be detected incidentally or may present with
lower GI tract bleeding. There is no known associa-
tion between isolated schwannoma of the GI tract and
neurofibromatosis.
Gastric schwannomas are usually not distinguish-

able from GISTs by imaging. Endoscopically, there is
a submucosal mass with or without overlying mucosal
ulceration.
FIGURE 7.28
Gastric schwannoma. The cellularity is usually moderate, with mild atypia on
Pathologic Features low power.
Gross Findings
Tumors are well circumscribed and have a yellow fleshy

cut surface. Cystic change may be present. The average
size is 3 cm, with a range of 0.5 to 11 cm.
Gastrointestinal tract schwannomas are not encapsulated

and there is a peripheral cuff of lymphocytes, which may
show germinal center formation. There may also be intra-
tumoral lymphocytes, scattered plasma cells, and aggre-
gates of foamy histiocytes. Tumors have a fascicular or
whorled growth pattern of spindled cells with tapering
nuclei, uniform fine chromatin with a small nucleolus and
indistinct pale cytoplasm. (Figs. 7.27 to 7.30). Nuclear FIGURE 7.29
typia may be present but is usually mild and degenera- Gastric schwannoma. At intermediate magnification, a lymphocytic infiltrate
is apparent.
tive in nature. Mitotic activity is low, and necrosis is not

Gastric schwannoma. Note the striking lymphoid cuff at low magnification, a Gastric schwannoma cytomorphology. Neoplastic cells have palely eosino-
helpful diagnostic feature. philic, fibrillary cytoplasm, and nuclei with tapered ends.
present. Additional distinguishing features from conven- more monotonous than the tumor cells of schwannoma.
tional schwannoma are less conspicuous thick-walled or IHC is helpful in this differential diagnosis; the tumor cells
hyaline vessels and an absence of nuclear palisading and of GIST are positive for KIT and DOG1 in 95% of cases.
Verocay bodies. Finally, schwannomas of the GI tract lack Metastatic melanoma frequently involves the GI tract
alternating Antoni A and B patterns and instead tend to and usually presents as a well-circumscribed intramu-
be uniformly cellular. The tumor stroma is usually collag- cosal nodule. Melanoma typically shows marked cyto-
enous and may show myxoid change. logic pleomorphism, nuclear atypia, and high mitotic
activity and lacks a peripheral lymphoid cuff. Although
the tumor cells of both lesions have diffuse expression
Ancillary Studies of S-100, in contrast to schwannoma, melanoma shows
expression of second-line melanocytic markers, such as
Immunohistochemistry HMB45 and Melan-A/MART1.
Malignant GNET/CCS-like tumor of the GI tract may
Diffuse strong expression of S-100 protein and SOX10 is potentially mimic gastric schwannoma, particularly
characteristic (Fig. 7.31). Focal expression of CD34 and because both show diffuse S-100 positivity. However,
GFAP may be present. Schwannomas of the GI tract lack malignant GNET shows infiltrative growth; a mixed
an EMA-positive capsule. Schwannoma is negative for nested, sheet-like, and pseudoglandular growth patterns;
KIT, DOG1, secondary melanocytic markers, keratins, and greater cytologic atypia. Identification of EWSR1
and desmin. gene rearrangement helps confirm this diagnosis.
Inflammatory myofibroblastic tumor may mimic
Molecular Studies schwannoma in that it is also a fascicular spindle cell
neoplasm with a prominent inflammatory infiltrate.
Gastric schwannomas lack alterations in the NF2 gene, IMT is usually less circumscribed and lacks a periph-
in contrast to somatic soft tissue schwannomas; instead, eral lymphoid cuff, but because these features cannot be
about half of the cases exhibit NF1 inactivation. evaluated in small biopsies, IHC is particularly helpful.
The tumor cells express SMA, desmin, and ALK (50%
of tumors) and are negative for S-100 and SOX10.
Differential Diagnosis Pure smooth muscle tumors are very rare in the
stomach. The tumor cells have brightly eosinophilic
Particularly in small biopsies, the morphologic differential cytoplasm, and the nuclei are blunt ended, unlike the
diagnosis of schwannoma includes GIST, metastatic mel- buckled wavy and tapering nuclei of schwannoma cells.
anoma, and clear cell sarcoma-like tumor of the GI tract/ The tumor cells express SMA, desmin, and caldesmon
malignant GNET. IMT and smooth muscle neoplasms may and are negative for S-100 and SOX10. Neurofibroma
also show some histologic similarities to schwannoma. is exceptionally rare in the stomach. It is composed of a
Gastrointestinal stromal tumors also arise in the mus- mixed population of Schwann cells, perineural cells, and
cularis propria but lack a peripheral lymphoid cuff. The fibroblasts, which is reflected in the more heterogeneous
tumor cells may be spindled or epithelioid and are usually staining pattern for S-100, EMA, and CD34. There is a
syndromic association with NF1.
Gastrointestinal schwannomas are benign, and excision

is curative.
SCHWANNOMA OF THE GASTROINTESTINAL

TRACT—FACT SHEET
Definition
n Benign nerve sheath tumors that differ from schwannoma of other
sites by the absence of a capsule, absence of Antoni A and B zonation,

and presence of a prominent peripheral lymphocytic infiltrate
FIGURE 7.31 Incidence and Location

n Rare and usually arise in the gastric wall
Gastric schwannoma. There is diffuse nuclear and cytoplasmic S-100 protein
expression.
present as small intramucosal polyps, occasional cases

involve the submucosa and are similar to perineurioma
n Occur in adults
of soft tissue. Tumors can arise in the colon or small
n Gastric schwannomas are more common in women
intestine, but most are colonic and occur in the rectosig-
Clinical Features moid region and are typically identified during screening
n Site specific, often incidental
colonoscopy. The tumor shows a female predominance,
n May present with symptoms of gastrointestinal tract bleeding or and patients are usually in their sixth decade. Most
obstruction lesions previously described as “benign fibroblastic
polyp of the colon” represent perineuriomas.
n Benign and treated by simple excision
n No syndromic associations
Endoscopic Features
Schwannoma of the Gastrointestinal Tract—Pathologic Features Colonic mucosal perineuriomas are small and sessile
polyps, usually around 0.4 cm in greatest dimension.
Gross Findings Submucosal lesions may be significantly larger, in the
n Well circumscribed but not encapsulated, in contrast to most range of 3 to 5 cm.
schwannomas at other sites
n Generally intramural in the stomach and polypoid in the colon
Microscopic Findings Pathologic Features

n Unencapsulated uniformly cellular spindle cell neoplasm
n Tumor cells have indistinct pale cytoplasm and tapering nuclei
with uniform fine chromatin and small nucleoli

Gross Findings
n Striking lymphoid cuff at periphery of tumor
n Lack palisading, hyalinized vessels, and alternating Antoni A and B The tumors often present as colonic polyps with size
zonation ranging from 0.2 to 0.6 cm (median, 0.4 cm). Rarely,
tumors arise as submucosal masses and may be signifi-
cantly larger, between 3 and 5 cm. The cut surface of
n Strong diffuse S-100 protein and SOX10
n May be positive for CD34

larger tumors is well circumscribed and has a white,
n Negative for KIT, desmin, and caldesmon solid, myxoid appearance without necrosis.
n Gastrointestinal stromal tumor: lacks a lymphoid cuff and is more
likely to show palisading; positive for KIT and DOG1 (discovered The lesion is composed of a monotonous population of
on GIST1), usually negative for S-100
n Metastatic melanoma: greater cytologic atypia, may have
bland spindle cells with oval to elongated nuclei and pale
epithelioid as well as spindled morphology, and lacks a lymphoid eosinophilic cytoplasm (Figs. 7.32 and 7.33). Elongated
cuff; secondary melanocytic markers (HMB45 [human melanoma cytoplasmic processes may be seen by hematoxylin and
black], MART1) are positive
n Malignant gastrointestinal neuroectodermal tumor: infiltrative;
heterogenous growth pattern; EWSR1 gene rearrangement

n IMT: less circumscribed; variable expression of smooth muscle
actin (SMA), desmin, and anaplastic lymphoma kinase; negative

for S-100 and SOX10
n Smooth muscle tumors: very rare in the stomach; tumor cells have
brightly eosinophilic cytoplasm, and the nuclei are blunt ended;

express SMA and desmin and are negative for S-100 and SOX10
MUCOSAL PERINEURIOMA (“BENIGN

FIBROBLASTIC POLYP”)
FIGURE 7.32
Mucosal perineurioma is a benign nerve sheath tumor Mucosal perineurioma of the colon. The proliferating cells expand the lamina
showing perineurial cell differentiation. Although most propria.
Expression of the latter two may be variable in extent.

The cells do not express S-100, GFAP, SMA, CD117/
KIT, or pan-keratin.
The differential diagnosis includes Schwann cell hamar-

toma, ganglioneuroma, neurofibroma, and leiomyoma.
Schwann cell hamartoma may be very difficult to
distinguish morphologically from perineurioma, but
Schwann cells are plumper and lack the long cytoplasmic
processes of perineurial cells. IHC readily distinguishes
the two: whereas Schwann cell hamartoma shows dif-
fuse expression of S-100, perineurioma is negative.
Ganglioneuroma is distinguished by the presence
FIGURE 7.33
of ganglion cells and admixed Schwann cells, both of
Higher magnification of a mucosal perineurioma of the colon. The cells have
pale eosinophilic cytoplasm and bland nuclei. which are S-100 positive, as well as neurofilament pro-
tein (NFP) positive axons.
Neurofibroma of the GI tract is extremely rare and
is highly associated with NF1. Most mucosal lesions
previously classified as neurofibroma likely represent
Schwann cell hamartomas. Neurofibroma is composed
of a mixed population of Schwann cells, perineurial
cells, fibroblasts, and axons; this mixed population of
cell types is reflected in the immunohistochemical pro-
file, with expression of S-100, NFP, and EMA.
Leiomyoma also presents a small polypoid lesion in
the colon but is usually readily distinguished by obvi-
ous smooth muscle differentiation—bright eosinophilic
cytoplasm and cigar-shaped nuclei, as well as positivity
for SMA, desmin, and caldesmon.
FIGURE 7.34
Mucosal perineuriomas are frequently associated with serrated polyps.
Mucosal perineurioma is a benign tumor; local recurrences
after excision or polypectomy have not been reported.
eosin but are highlighted by immunohistochemical

stains EMA and CD34. The cells grow in a whorled pat- MUCOSAL PERINEURIOMA—FACT SHEET
tern, entrapping colonic crypts. The stroma is collage-
Definition
nous. There is generally no cytologic atypia, necrosis,
n Benign nerve sheath tumor composed of perineurial cells
or mitotic activity. The adjacent crypt epithelium may
show hyperplastic change (Fig. 7.34), or the perineural Incidence and Location
proliferation may be present in association with a ser- n Tumor arises in the colon and less often the small intestine
rated polyp, either hyperplastic polyp or sessile serrated n Most common location is the rectosigmoid region
polyp, in which case it seems to be a secondary process
induced by the epithelial proliferation. Gender, Race, and Age Distribution
n Female predominance
n Median age is 51 years
Ancillary Studies
Clinical Features
n Usually incidentally detected during colonoscopy
Perineurioma shows expression of markers of peri- n Benign tumor; excision is curative
neural differentiation: EMA, claudin-1, and CD34.
Mucosal Perineurioma—Pathologic Features
Gross Findings
n Present as small colonic polyps or as intramural mass arising in
submucosa of the colorectum or, rarely, the small bowel
n Proliferation of bland spindle cells centered in the lamina propria,
muscularis mucosae, and superficial submucosa, sometimes with

adjacent serrated polyp
n Tumor cells express epithelial membrane antigen, claudin-1, and
CD34, the latter two sometimes variably in extent
n Mucosal Schwann cell hamartoma: plumper cells; S-100 positive FIGURE 7.35
n Ganglioneuroma: mixed population of cells including S-100– Mucosal Schwann cell hamartoma. Short fascicles of Schwann cells entrap
positive ganglion and Schwann cells colonic crypts. The lesional cells are spindled to ovoid with pale, fibrillary
n Neurofibroma: mixed population of Schwann cell, perineurial cytoplasm and no significant nuclear atypia.
cells, fibroblasts, and axons
n Leiomyoma: bright eosinophilic cytoplasm; smooth muscle actin
and desmin positive
MUCOSAL SCHWANN CELL HAMARTOMA
This benign intramucosal Schwann cell proliferation

differs from schwannoma, perineurioma, and neuro-
FIGURE 7.36
fibroma. It is a sporadic rather than syndromic lesion.
S-100 is diffusely positive in mucosal Schwann cell hamartoma and is nega-
These lesions arise in the colon and are usually detected tive in mucosal perineurioma, its closest differential diagnostic consideration.
during screening endoscopy; the lesion appears as a small
(<1 cm) polyp. The mean age at presentation is about 60 the circumscription, peritumoral lymphoid aggregates,
years, and there is a slight female predominance. dense collagenous stroma, and nuclear heterogeneity of
GI schwannoma and usually presents as a small polyp-
oid lesion in the colon, unlike GI schwannoma, which
involves stomach and is submucosal or mural.
Pathologic Features
Ancillary Studies
These mucosal lesions are variably circumscribed, and the
spindle cells usually show entrapment of colonic crypts Immunohistochemistry
(Fig. 7.35). The cells are spindled to ovoid and tend to
be plumper than perineurial cells, which they may other- Lesional cells show diffuse expression of S-100 protein, con-
wise resemble. The cells show Schwannian morphology sistent with their Schwannian origin (Fig. 7.36). The cells
in that they have wavy nuclei, eosinophilic cytoplasm, are negative for KIT, CD34, EMA, claudin-1, and SMA.
and indistinct cell borders. There is no cytologic atypia or
pleomorphism, and mitoses are generally not seen.
The relationship between Schwann cell hamartoma
and GI schwannoma is unclear, but the differing his-
tologic features favor classification as distinct entities.
Although both lesions are composed of a pure popula- Other mucosal benign nerve sheath tumors may
tion of Schwann cells, Schwann cell hamartoma lacks mimic mucosal Schwann cell hamartoma. Mucosal
perineurioma also shows entrapment of colonic crypts

by bland spindle cells. Perineurial cells are less plump Mucosal Schwann Cell Hamartoma—Pathologic Features
than those of Schwann cell hamartoma and have elon-
gated cytoplasmic processes that are highlighted by
n Small proliferations of Schwann cells in the lamina propria that
CD34 and EMA. Expression of S-100 is not seen in entrap colonic crypts
perineurioma.
Mucosal neuroma occurs in the oral cavity in patients Immunohistochemistry
with multiple endocrine neoplasia IIb (MEN2B) on the n Diffuse expression of S-100 protein
lips or tongue and is extremely rare in the GI tract. Many n Negative for C34, CD117, epithelial membrane antigen, smooth
Schwann cell hamartomas were previously classified as muscle actin, and claudin-1
“neuroma,” but true mucosal neuroma is composed of
bundles of hyperplastic nerves with admixed axons,
n Perineurioma
which are highlighted by NFP IHC. n Neurofibroma
Schwann cell hamartoma is distinguished from neuro- n Ganglioneuroma
fibroma by the following features: (1) most neurofibromas
of the GI tract are mural lesions involving submucosa or
muscularis propria, which may extend into the overlying
mucosa; (2) neurofibroma is composed of a mixed popu- GANGLIONEUROMA
lation of Schwann cell, perineurial-like cells, fibroblasts,
and axons, in contrast to the single Schwann cell popula-
tion of Schwann cell hamartoma; (3) expression of S-100 ■ CLINICAL FEATURES
is present in only a subset of cells in neurofibroma, in
contrast to the diffuse staining pattern seen in Schwann Ganglioneuromas occur in two general settings: (1) spo-
cell hamartoma; and (4) neurofibromas of the GI tract are radically as solitary lesions and (2) syndromically as
strongly associated with NF1. multiple lesions either producing multiple exophytic pol-
Polypoid ganglioneuroma may resemble mucosal yps (ganglioneuromatous polyposis, Cowden syndrome)
Schwann cell hamartoma because there is usually a pre- or poorly demarcated transmural proliferations (diffuse
dominance of Schwann cells; however, ganglioneuroma ganglioneuromatosis; MEN2B and NF1). For solitary
also contains ganglion cells and axons. cases, there is no gender predominance, and lesions
Mucosal benign epithelioid nerve sheath tumor is a occur in adults over a broad age range, with a peak inci-
similar and possibly related lesion composed of Schwann dence between 40 and 60 years. The majority are found
cells with epithelioid features entrapping colonic crypts. in the colon, usually on the left side; are asymptomatic;
and are detected during screening colonoscopy. Solitary
lesions are not associated with genetic syndromes.
In contrast, ganglioneuromatous polyposis is associated
with Cowden syndrome (PTEN hamartoma syndrome)
and familial adenomatous polyposis (FAP), and diffuse gan-
Schwann cell hamartoma is benign and managed by glioneuromatosis is associated with MEN2B and with NF1
polypectomy. (von Recklinghausen’s disease). Diffuse ganglioneuromato-
sis is found in virtually all patients with MEN2B and often
antedates the development of the endocrine neoplasms.
MUCOSAL SCHWANN CELL HAMARTOMA—FACT SHEET Patients with MEN2B and ganglioneuromatosis present
with diverse GI symptoms, likely reflecting disruption of
Definition the myenteric plexus, including constipation, diarrhea,
n Benign Schwann cell proliferation vomiting, and crampy abdominal pain. Most syndromic GI
tract ganglioneuromas are found in the colorectum and in
Incidence and Location younger patients (mean age, ∼35 years). Other conditions
n Rare; arises in colonic mucosa
that have been reported to associate with ganglioneuroma-
tosis include tuberous sclerosis and juvenile polyposis.
Pathologic Features
Clinical Features
n Incidental finding, small (<1 cm) mucosal polyp
Gross Findings
n Benign tumor Polypoid isolated ganglioneuroma presents as a small ses-
sile or pedunculated polyp (usually <2 cm) that grossly

Ganglioneuroma. Ganglioneuroma is composed of spindled Schwann cells Ganglioneuroma immunohistochemistry. S-100 protein is diffusely positive
expanding the lamina propria, with admixed ganglion cells. in spindled Schwann cells and ganglion cells.
resembles juvenile polyp or adenoma. The polyps in gan- Schwann cells, perineurial cells, fibroblasts, and axons
glioneuromatous polyposis are multiple (20–40) and may and show a correspondingly mixed immunoprofile with
be larger than sporadic cases. Diffuse ganglioneuromato- expression of S-100, NFP, and EMA.
sis results in a poorly demarcated mural thickening.
Microscopic Findings Prognosis and Therapy

Polypoid ganglioneuromas (sporadic or syndromic) are
mucosal. They are poorly circumscribed and show an Sporadic isolated ganglioneuromas are treated by polyp-
expanded lamina propria and entrapment of colonic ectomy and seldom recur. These polyps are not associ-
crypts by a mixed population of spindled Schwann ated with MEN2B and NF1. Patients with syndromic
cells, axons, and ganglion cells, which may be clus- ganglioneuromas must be carefully followed based on
tered or present as scattered isolated cells (Fig. 7.37). their specific syndromes. Multiple polypoid ganglioneu-
Occasionally, polypoid lesions may extend into submu- romas are associated with Cowden syndrome, whereas
cosa. In diffuse ganglioneuromatosis, the same mixed the diffuse type is most likely associated with NF1 and
cell population is centered around the myenteric plexus. MEN2B. The latter may cause strictures requiring resec-
tion, but the ganglioneuromas themselves are benign.
Patients with NF1 may develop other neural lesions,
Ancillary Studies including malignant peripheral sheath tumors, and
those with MEN2B may develop endocrine neoplasms.
These lesions are easily diagnosed without IHC, but

GANGLIONEUROMA—FACT SHEET
the spindle cells react with S-100 protein and GFAP
(Fig. 7.38); the ganglion cells with S-100 protein, NSE, Definition
and synaptophysin; and axons with NFP. n Ganglioneuromas are composed of a mixed population of S-100-
positive Schwann cells, neurofilament protein–positive axons, and

ganglion cells. Multiple lesions are usually syndromic
Differential Diagnosis Incidence and Location

n Rare
n Majority arise in the left colon

The main mimics are mucosal Schwann cell hamar-
toma and neurofibroma. Schwann cell hamartoma Gender, Race, and Age Distribution
lacks ganglion cells and is composed of a pure pop- n No gender or racial predominance
ulation of Schwann cells, which are also S-100 pos- n Syndromic lesions present at an earlier age (mean, 35 years)
itive. Neurofibroma of the GI tract is very rare and is than sporadic examples (mean, 48 years)
associated with NF1. Neurofibromas are composed of
Clinical Features Pathologic Features

n Most polypoid lesions detected during routine colonoscopy
n Solitary lesions not associated with genetic syndromes

Gross Findings
n Ganglioneuromatous polyposis associated with Cowden
syndrome
n Diffuse ganglioneuromatosis associated with multiple endocrine These lesions are typically centered in the submucosa,
neoplasia IIb and neurofibromatosis type 1 with extension into the mucosa, and measure 3 to 4 cm
n Patients with ganglioneuromatosis present with diverse
in diameter. The cut surface is pale yellow, and they are
gastrointestinal symptoms
usually soft in consistency. They have infiltrative borders.
n Benign Microscopic Findings
n Sporadic cases are treated by polypectomy
n Because diffuse ganglioneuromas may be transmural, there can Tumors are composed of three cell types: (1) spindled
be associated strictures requiring surgery Schwann cells with eosinophilic cytoplasm arranged in
fascicles or whorls; (2) ganglion cells with round nuclei
and prominent nucleoli, scattered throughout the lesion
or arranged in clusters; and (3) epithelioid neuroendo-
crine cells arranged in nests, trabeculae, or papillae. The
proportion of the cell types is variable (Figs. 7.39 to 7.42).
Ganglioneuroma—Pathologic Features Psammomatous calcifications may be present.
Gross Findings
n Solitary or multiple mucosal polyps
n Diffuse lesions are transmural
n Spindled Schwann cells with admixed ganglion cells
n In diffuse ganglioneuromatosis, the lesion is centered around the
myenteric plexus
n Schwann cell population expresses S-100 and glial fibrillary acidic
protein
n Ganglion cells express S-100, neuron-specific enolase,
synaptophysin and axons stain with neurofilament protein
n Usually easy to recognize; lesions that have few ganglion cells
may mimic neurofibromas FIGURE 7.39

This gangliocytic paraganglioma arose in the ampulla. Disorganized ampullary
(biliary type) glands are at the right side of the field; the lesion is at the lower left.
GANGLIOCYTIC PARAGANGLIOMA
These are rare tumors, the vast majority of which are

found in the duodenum in adult patients (average age,
54 years). They typically arise in the ampullary region
as polypoid submucosal masses. Extremely rare cases
have been reported to occur in the jejunum, pylo-
rus, colon, and appendix. The typical presentation is
bleeding caused by overlying mucosal ulceration, but
because of their ampullary location, some patients may
present with painless jaundice. The majority of cases FIGURE 7.40
are sporadic, with a small subset being associated with This gangliocytic paraganglioma shows spindle cells similar to those of a
neurofibromatosis. schwannoma, nests of epithelioid cells, and dysmorphic ganglion cells.
Ancillary Studies
Immunohistochemically, the tumors show S-100 protein

expression in spindled Schwann cells, synaptophysin in
ganglion cells, and synaptophysin and chromogranin in the
epithelioid neuroendocrine cells. About half of cases show
keratin expression in the epithelioid cells. The neuroen-
docrine cells can express a variety of hormones, including
somatostatin, human pancreatic polypeptide, serotonin,
gastrin, glucagon, insulin, and vasoactive intestinal peptide.
FIGURE 7.41 Differential Diagnosis

Epithelioid cells predominate in this gangliocytic paraganglioma; this lesion
could be mistaken for a carcinoid tumor on a small mucosal biopsy.
In spindle cell–predominant lesions, the differential diag-
nosis includes GIST and nerve sheath tumors: S-100 pro-
tein expression virtually excludes GIST, and finding the
admixture of other cell types excludes other nerve sheath
tumors. Epithelioid-predominant lesions are distinguished
from carcinoid tumors and carcinomas by the admixture of
other cell types and prominent S-100 expression.
Gangliocytic paragangliomas are benign and surgical exci-

sion is curative. There are rare reports of regional lymph
node metastases but not of tumor-associated deaths.
GANGLIOCYTIC PARAGANGLIOMA—FACT SHEET
A Definition
n Unusual neoplasm displaying “triphasic” differentiation

n Rare tumors that almost always occur in the duodenum

n Vast majority are benign
n Morbidity is generally related to surgical removal

n No reported gender or race predilection
n Occurs in adults (average age, 54 years)
Clinical Features
n Abdominal pain, gastric outlet obstruction, or bleeding
n Rare association with neurofibromatosis
B Prognosis and Therapy

FIGURE 7.42 n Treatment is excision
Gangliocytic paraganglioma. This field is from a more diagnostic area of the n Rare reports of regional spread to lymph nodes but no disease-
neoplasm depicted in Fig. 7.41. A, Numerous spindle cells. B, Epithelioid associated reported deaths
nests are predominant.
may be ulceration of the overlying mucosa. The tumor

Gangliocytic Paraganglioma—Pathologic Features cells within the nodules are organized in solid sheets or
nests surrounding dilated capillaries that show branch-
Gross Findings ing or hemangiopericytoma-like features (Fig. 7.43).
n Centered in submucosa with infiltrative borders and yellowish Tumor cells also tend to be present in the muscular walls
surface of larger vessels. The tumor cells are round with sharply
defined cell membranes, pale cytoplasm, and uniform
round nuclei with fine chromatin (Figs. 7.44 and 7.45).
n Three cell types: (1) S-100–positive spindle cells, (2) ganglion cells,
and (3) epithelioid neuroendocrine cells in variable proportions In some cases, the tumor cells have oncocytic cytoplasm.
n Psammoma bodies may be present Myxoid change, calcification, and metaplastic bone may
be present. Within somatic soft tissue, features associ-
Immunohistochemistry ated with malignant clinical course include large tumor
n Spindle cells are positive for S-100 size (>5 cm), nuclear atypia, spindled morphology, and
n Ganglion cells are positive for synaptophysin
high mitotic activity. However, these criteria for malig-
n Epithelioid component expressed neuroendocrine markers and
variably keratin
nancy do not appear to apply to GI glomus tumors, and
the vast majority of glomus tumors greater than 2 cm in
Differential Diagnosis size pursue a benign clinical course.
n Spindle cell–predominant lesions are distinguished from
schwannomas by identifying the other cellular components
n Epithelioid-predominant lesions are distinguished from
neuroendocrine tumors by identifying the admixed spindle cell
population
GLOMUS TUMOR
Glomus tumor is composed of modified perivascular

smooth muscle cells, and although far more common in
somatic soft tissue sites, they also occur in the GI tract.
The stomach is the most common site, antrum more than
corpus, but there are reports of glomus tumor arising in FIGURE 7.43
the small intestine and colon. There is a slight female Glomus tumor. Glomus tumors are composed of uniform small neoplastic
predominance, and the median age at presentation is 53 cells with round nuclei; neoplastic cells are prominent around hemangioperi-
cytoma-like vessels.
years. Presenting symptoms include ulcer-like pain; severe
bleeding producing melena, anemia; or hematemesis; and
obstructive symptoms. Some cases are incidentally detected
at the time of surgery or endoscopy for other reasons.
Pathologic Features
Gross Findings
Tumors are circumscribed intramural masses with a

median diameter of 2.5 cm. They can bulge either into
the mucosa or externally toward the serosa. They are yel-
lowish and occasionally calcified or cystic on cut surface.
Glomus tumors are composed of multiple nodules sep- FIGURE 7.44

arated by strands of residual muscularis propria. There Glomus tumor. Note the prominent cell borders.

Glomus tumor. This lesion has somewhat clear cells and characteristic prom- Glomus tumor immunohistochemistry. Gastric glomus tumors consistently
inent cell borders. express smooth muscle actin but not desmin.
Ancillary Studies It is difficult to predict which tumors will have an unfa-

vorable outcome, but some histologic features have been
Immunohistochemistry associated with malignant behavior.
The tumor cells express SMA (Fig. 7.46) in virtually all

cases, and h-caldesmon in 60% but usually lack desmin GLOMUS TUMORS—FACT SHEET
expression. SMA and caldesmon expression usually
highlights the well-defined cell borders of the tumor Definition
cells. Some cases show focal CD34 expression. Glomus n Mesenchymal neoplasms composed of perivascular smooth
tumors are negative for KIT. Approximately 20% of muscle cells; gastrointestinal tract glomus tumors resemble their
cases show synaptophysin expression (usually weak or peripheral soft tissue counterparts
focal), which can lead to an erroneous diagnosis of neu-
roendocrine tumor, especially in small biopsies, but glo-
n Rare, usually arise in the stomach
mus tumors are negative for chromogranin and keratin.
Molecular Genetics n Tumors of adults (median age, 53 years)
A small subset has MIR143-NOTCH gene fusion.

Clinical Features
n Gastrointestinal bleeding is common, and some are associated
Differential Diagnosis with ulcer-like pain
n About 20% are found incidentally
The differential diagnosis includes neuroendocrine tumor Prognosis and Therapy

and GIST with epithelioid features. Neuroendocrine n The vast majority are benign
tumors are usually mucosal based, lack the distinctive n Treatment is surgical
membranous pattern of SMA expression seen in glomus n Histologic features do not reliably predict the rare occurrence of
tumors, and typically show chromogranin expression. metastasis

Epithelioid GIST is also easily distinguished by IHC, but
because many epithelioid GIST (those with PDGFRA
mutations) are KIT negative, DOG1 should be evaluated
if KIT is negative and the suspicion for GIST remains.
Glomus Tumors—Pathologic Features
Prognosis and Therapy Gross Findings

n Tumors are usually circumscribed with a yellowish often lobulated
cut surface
Most glomus tumors behave in a benign fashion. n Some have calcifications
However, rare cases pursue an aggressive clinical course.

n Uniform round cells with sharply defined cell membranes and
Microscopically, the lesion is usually poorly defined
uniform nuclei
n Cells condense around vessels that show a hemangiopericytoma-
with infiltrative margins; even tumors that are grossly
like pattern circumscribed usually show infiltrative edges. Tumors
are composed of long fascicles of uniform bland spin-
Immunohistochemistry dled fibroblasts separated by a dense collagenous
n Positive for smooth muscle actin and caldesmon stroma (Fig. 7.47). Scattered thin-walled (Fig. 7.48),
n Negative for desmin, endocrine markers, keratin, and KIT
elongated, and compressed vessels are seen. The tumor
cells have tapering nuclei with delicate nucleoli and
smooth nuclear membranes (Fig. 7.49). Mitotic figures
n Gastrointestinal stromal tumor with epithelioid features: positive
for KIT and DOG1 (discovered on GIST1), with variable smooth are infrequent. Fasciitis-like features, with storiform
muscle actin expression growth and looser myxoid matrix, are common in mes-
n Neuroendocrine tumors (carcinoids): keratin positive, usually enteric fibromatosis. Keloid-like hyalinization is often
express both synaptophysin and chromogranin, and are negative present and may be so extensive as to obscure the orig-
for smooth muscle actin
inal pattern of the tumor. Rarely, calcification or chon-
dro-osseous metaplasia is present.
INTRAABDOMINAL DESMOID
FIBROMATOSIS
Intraabdominal (desmoid) fibromatosis may involve mes-

entery of the small intestine, abdominal wall, or retroper-
itoneum. It usually presents as a slowly growing mass,
and in some cases, there is a history of prior surgery
such as cesarean section. A subset of patients, especially
young patients, have Gardner’s syndrome, an autosomal
dominant familial disease with a female predilection con-
sisting of colorectal adenomatous polyposis, osteomas,
cutaneous cysts, and desmoid fibromatosis. Gardner’s FIGURE 7.47
syndrome is related to FAP, a disorder caused by germ- Desmoid fibromatosis. Desmoid fibromatosis is composed of long, sweeping
fascicles of myofibroblasts with abundant stromal collagen deposition.
line adenomatous polyposis coli (APC) gene mutations.
It is associated with a 7% to 12% incidence of develop-
ing fibromatosis. Desmoid fibromatosis in patients with
Gardner’s syndrome appears to have a higher recurrence
rate than in patients without this syndrome.
Radiologic Features
Although not specific, imaging studies show a mass lesion

with a mesenteric epicenter, an infiltrative pattern, and a
low signal on all magnetic resonance imaging sequences.
Pathologic Features
Gross Findings
Grossly, the tumor is firm with coarse white trabecula- FIGURE 7.48
tion resembling a scar, and a gritty texture is detected Desmoid fibromatosis. When it involves the mesentery, desmoid fibromato-
sis tends to exhibit thin-walled vessels that appear to be “pulled open” by
when the tumor is cut. the proliferating myofibroblasts.
tumors in non-FAP patients occur either through

somatic biallelic APC inactivation or somatic mutation
of a single β-catenin allele.
The differential diagnosis includes low-grade dedifferen-

tiated liposarcoma and benign fibroblastic proliferative
lesions. Dedifferentiated liposarcoma is distinguished
from fibromatoses by having at least scattered hyper-
chromatic nuclei in contrast to the bland nuclei of fibro-
matosis. Identification of areas of well-differentiated
liposarcoma is obviously helpful, but if not present, then
identification of MDM2 gene amplification or MDM2
FIGURE 7.49
and CDK4 nuclear expression by IHC helps confirm the
Desmoid fibromatosis. Desmoid fibromatoses typically have small pinpoint
nucleoli and bland cytologic features at high magnification. diagnosis. Reactive myofibroblastic proliferations after
surgery or trauma may be histologically very similar,
especially on small biopsies. The presence of associated
fat necrosis and lack of β-catenin expression favors a
reactive process. Correlation with clinical history is
essential. Sclerosing mesenteritis or idiopathic retroper-
itoneal fibrosis is also in the differential diagnosis and is
discussed in the following section.
Desmoid fibromatoses show locally aggressive growth

and frequent recurrence but do not metastasize.
Although surgical excision used to be the mainstay of
FIGURE 7.50
therapy, now a more conservative approach is followed,
Nuclear β-catenin staining in fibromatoses. Cytoplasmic staining is not
specific; only nuclear staining should be used to support a diagnosis of with observation or chemotherapy with doxorubicin for
fibromatosis. cases that show aggressive growth. Surgery is still per-
formed in certain patients, but there is no longer a need
to obtain wide margins, given the recent recognition
Ancillary Studies that margin status is less predictive of recurrence than
mutation type.
Because fibromatoses are myofibroblastic lesions, they

INTRAABDOMINAL DESMOID FIBROMATOSIS—FACT SHEET
express SMA and less frequently desmin. They typically
lack CD34. Nuclear β-catenin is detected in 70% to 80% Definition
of fibromatosis cases (Fig. 7.50) and is not present in n Myofibroblastic proliferation that shows locally aggressive
most histologic mimics. behavior but does not metastasize

n Usually arise in somatic soft tissue, but a subset is found
Other Studies intraabdominally or in the mesentery
Molecular Genetics Gender, Race, and Age Distribution

n No gender predominance in childhood; female predominance
during young adulthood; no gender predominance in older adults

Among patients with FAP, intestinal and extraintesti- n No report of racial predilection
nal neoplasms typically arise through biallelic (germline n Arises in patients of all ages
then somatic) inactivation of the APC gene, whereas

In one large study, the patient age ranged from 23 to

Clinical Features
87 years (mean, 60 years) without a gender predilection.
n Mass lesions; may be a component of familial adenomatous
Most patients presented with nonspecific symptoms
polyposis or Gardner’s syndrome
such as abdominal pain, palpable mass, and symptoms
Prognosis and Therapy related to bowel obstruction.
n Local recurrence is common, and aggressive growth may be
associated with significant morbidity and even mortality

n Treatment was traditionally surgical, but contemporary approaches
are conservative Radiologic Features

n Chemotherapy with doxorubicin is used for some locally
aggressive cases
n Risk of recurrence is better predicted by specific mutation type
The computed tomography appearance of sclerosing mes-
rather than margin status enteritis can vary from subtle increased attenuation in the
n Mesenteric fibromatoses in Gardner’s syndrome more likely to recur mesentery to a solid soft tissue mass. Sclerosing mesen-
teritis most commonly appears as a soft tissue mass in the
small bowel mesentery, although infiltration of the region
of the pancreas or porta hepatis is also possible. The mass
Intraabdominal Desmoid Fibromatosis—Pathologic Features
may envelop the mesenteric vessels, and over time, col-
Gross Findings lateral vessels may develop. There may be preservation
n Large infiltrative masses with firm, white cut surfaces
of fat around the mesenteric vessels, a phenomenon that
is referred to as the fat ring sign. This finding may help
Microscopic Findings distinguish sclerosing mesenteritis from other mesenteric
n Long fascicles of bland spindled myofibroblasts processes such as lymphoma, carcinoid tumor, or carcino-
matosis. A tumoral pseudocapsule may be present.
n May be positive for actin
n Most lack desmin
n 80% show nuclear β-catenin positivity Pathologic Features

n Low-grade dedifferentiated liposarcoma: atypical hyperchromatic
Gross Findings
cells; may be identifiable well-differentiated component; positive
for MDM2 gene amplification Lesions typically consist of a whitish, firm mass with
n Gastrointestinal stromal tumor: lacks long sweeping fascicles;
extensions of firm, fibrous tissue into surrounding
cytoplasm is slightly more eosinophilic; KIT and DOG1 (discovered
on GIST1) expression, and absence of nuclear β-catenin
normal-appearing fat or adherent to adjacent tissues.
n Reactive myofibroblastic proliferations: associated fat necrosis;
shorter fascicles, lacks β-catenin expression or CTNNB1 mutations Microscopic Findings
Lesions consist of fascicles of bland spindled fibroblasts

and myofibroblasts infiltrating fat (Figs. 7.51 to 7.53) with
SCLEROSING MESENTERITIS
associated fat necrosis. There may be admixed inflamma-
tory cells, typically lymphocytes, plasma cells, and eosin-
ophils. Obstructive phlebitis and prominent plasma cell
infiltrate with storiform fibrosis suggests the possibility of
IgG4-related sclerosing disorder (see Fig. 7.53).
Sclerosing mesenteritis is a non-neoplastic fibroinflam-
matory lesion that most commonly affects mesentery of
the small intestine, presenting as an isolated large mass,
Ancillary Studies
although 20% of patients have multiple lesions. The cause
of these lesions remains unknown, and although they are
assumed to reflect a reparative response, usually to trauma Immunohistochemistry
or surgery, in many cases, no such history is found. A sub-
set of patients with sclerosing mesenteritis are found to The spindle cells are fibroblastic or myofibroblastic, and
have immunoglobulin (Ig) G4-related sclerosing disease, this is reflected by expression of SMA and rarely desmin.
have elevated serum IgG4 levels, and often have additional S-100, caldesmon, KIT, ALK, and β-catenin are negative.
histologic features characteristic of this entity. However, If there is suspicion for IgG4-related sclerosing disease,
whereas most patients with classic IgG4-related scleros- then evaluation of the IgG/IgG4 ratio in admixed plasma
ing disorders respond to systemic steroid therapy, patients cells can be helpful, with a ratio greater than 40% sug-
with sclerosing mesenteritis usually do not. gestive of the latter (Fig. 7.54).

Sclerosing mesenteritis. A disorganized sclerotic process involves mesenteric Sclerosing mesenteritis. Prominent immunoglobulin G4 expression can be
fat, usually accompanied by a lymphoplasmacytic inflammatory response but encountered in these lesions, although its significance remains unclear.
not by neutrophils.
Sclerosing mesenteritis is distinguished from desmoid

fibromatosis by its abundance of inflammation and fat
entrapment with fat necrosis. Fibromatosis, although infil-
trative at its periphery, grows as a solid mass composed of
sweeping fascicles of fibroblasts with minimal inflamma-
tion. Inflammatory well- or dedifferentiated liposarcoma
can appear similar but differs by the presence of enlarged
hyperchromatic cells. Expression of MDM2 and CDK4 or
identification of MDM2 gene amplification can help con-
firm a diagnosis of well- or dedifferentiated liposarcoma.
Care should be taken when interpreting MDM2 because
expression is common in histiocytes, which may be abun-
FIGURE 7.52 dant in sclerosing mesenteritis; therefore, CDK4 should
Sclerosing mesenteritis. Note the bland cytologic features in a sclerotic area. also be evaluated and fluorescence in situ hybridization
performed if there is any ambiguity.
Treatment has included medical therapy alone, sur-

gery alone, and surgery followed by medical therapy,
but about half of patients seem to require no treatment.
Tamoxifen in combination with prednisone has resulted
in improvement in 60% of patients. Sclerosing mesen-
teritis can have a prolonged debilitating course in a sub-
set of patients, but the overall prognosis is favorable.
SCLEROSING MESENTERITIS—FACT SHEET
Definition
n A fibroinflammatory condition of uncertain etiology affecting the
FIGURE 7.53 mesentery
Many examples of sclerosing mesenteritis display a lymphocytic phlebitis n A subset of cases may represent immunoglobulin G4–related
pattern. Note the damaged inflamed vein beneath the uninvolved artery in sclerosing disease
this field.
rare metastasis. Half of the cases harbor ALK gene rear-

rangement, and a smaller subset harbor rearrangements in
n Rare and usually involves small bowel mesentery
other receptor tyrosine kinases such as ROS and RET. IMT
most often arises in lung or abdominal soft tissues (omen-
n No gender or racial predominance
tum, retroperitoneum, viscera) of children and young
n Adults affected (average age, 60 years)
adults, but there is a wide age range and anatomic distri-
bution. Patients with IMT of the GI tract are usually older,
Clinical Features with an average age of 43 years. Within the GI tract, the
n Patients present with abdominal pain, abdominal mass, or colon and small intestine are most often involved, followed
obstruction by the stomach and esophagus. The clinical presentation
n May be a history of trauma or prior surgery
may be with abdominal pain or mass, and some patients
Radiologic Features
have systemic symptoms such as fever and weight loss.
n Soft tissue mass in mesentery, sometimes with preservation of fat
Abnormalities in serologic inflammatory markers, includ-
around mesenteric vessels (“fat ring sign”) ing elevated erythrocyte sedimentation rate and hypergam-
maglobulinemia, may be found and typically resolve after
Prognosis and Therapy tumor resection. Epithelioid inflammatory myofibroblastic
n Treatment can be surgical or medical using steroids and sarcoma is a distinct variant of IMT that usually arises in
tamoxifen the abdominal cavity of young men and pursues a very
n Recurrence is uncommon, and only rare cases are associated with
aggressive clinical course. A RANBP2-ALK fusion gene is
significant morbidity, usually because of obstructive symptoms
commonly identified in this variant.
Radiologic Features
Sclerosing Mesenteritis—Pathologic Features
Imaging studies show poorly marginated mass, and a
Gross Findings small number of cases have calcifications.
n Infiltrative solitary (80%) whitish mass lesion with extension into
surrounding fat
Pathologic Features
n Fascicles of bland spindle cells with associated fat necrosis
n Variable degree of admixed inflammatory cells

Gross Findings
Immunohistochemistry These tumors form firm white infiltrative masses (aver-

n Spindle cells show variable expression of smooth muscle actin age, 6–7 cm) that appear fibrous, myxoid, or occasionally
n Negative for keratin, S-100 protein, KIT, and β-catenin fleshy on cut surface. Within the tubal gut, the tumors
may involve any layer from serosa to mucosa (Fig. 7.55).
n Desmoid fibromatosis: lacks associated fat necrosis and
prominent inflammation; 70% to 80% show nuclear β-catenin

expression
n Inflammatory myofibroblastic tumor: lacks associated fat necrosis,
anaplastic lymphoma kinase positive in 50%

n Dedifferentiated liposarcoma: at least focal atypical
hyperchromatic nuclei, presence of a well-differentiated

liposarcoma component; MDM2 and CDK4 expression or MDM2
gene amplification
INFLAMMATORY MYOFIBROBLASTIC TUMOR
Inflammatory myofibroblastic tumor (historically also FIGURE 7.55
referred to as inflammatory pseudotumor or inflammatory Inflammatory myofibroblastic tumor centered in the adipose tissue outside the
gastric muscularis propria (although it has focally extended into the smooth
fibrosarcoma) is a mesenchymal neoplasm of intermediate muscle). In contrast to gastric schwannoma, the inflammation is more uni-
biologic potential with a tendency for local recurrence but formly distributed throughout the tumor rather than forming a peritumoral cuff.
Microscopic Findings one-third show expression of keratins. ALK protein

expression is present in approximately 50% of cases (more
Histologically, IMT is composed of fascicles of spindle cells common in younger patients) and reflects the presence of
with eosinophilic cytoplasm and ovoid to tapered nuclei ALK gene rearrangement (Fig. 7.58). Similarly, approxi-
(Fig. 7.56). Typically, there is admixed prominent chronic mately 5 % to 10% show expression of ROS1. Epithelioid
inflammation. IMT can range from highly cellular to pauciinflammatory myofibroblastic sarcoma has a characteristic
cellular, and some tumors have prominent myxoid stroma. nuclear membranous staining pattern in most cases and
Epithelioid inflammatory myofibroblastic sarcoma a cytoplasmic pattern with Golgi dot-like accentuation in
exhibits epithelioid to round cell cytomorphology in the remaining minority of cases (Fig. 7.59).
an abundant myxoid stroma, and in contrast to IMT, it
most commonly features a neutrophilic inflammatory Other Studies
infiltrate (Fig. 7.57). Neoplastic cells have pink cyto-
plasm, vesicular nuclei, and prominent nucleoli. Gene fusions involving the ALK gene, a receptor tyro-
sine kinase at chromosome 2p23, occur in approxi-
mately 50% of cases. A smaller number of tumors have
Ancillary Studies rearrangements of other receptor tyrosine kinases such
as ROS, RET, and NTRK, and treatment with crizo-
Immunohistochemistry tinib can be effective in advanced disease. The fusion
partners with ALK include ATIC, CARS, CLTC, TPM3,
Smooth muscle actin expression is seen in 80% to 90% TPM4, CLTC, RANB2, and SEC31L.
of cases and desmin and HHF35 in 60%. Approximately
FIGURE 7.58
FIGURE 7.56 Inflammatory myofibroblastic tumor immunohistochemistry. Anaplastic lym-
Inflammatory myofibroblastic tumor consisting of a storiform proliferation of phoma kinase is positive in approximately 50% of inflammatory myofibro-
spindle cells with abundant plasma cells. blastic tumors.
FIGURE 7.57
Epithelioid inflammatory myofibroblastic sarcoma. Neoplastic cells are epithelioid, FIGURE 7.59
with palely eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. There Epithelioid inflammatory myofibroblastic sarcoma immunohistochemistry.
is a background myxohyaline stroma, and there are scattered admixed inflamma- Perinuclear anaplastic lymphoma kinase staining is characteristic in epitheli-
tory cells, including a prominent neutrophilic component, typical of this entity. oid inflammatory myofibroblastic sarcoma.
INFLAMMATORY MYOFIBROBLASTIC
TUMOR—FACT SHEET
The differential diagnosis of IMT can sometimes be dif-
ficult to resolve, particularly in cases negative for ALK Definition
n Neoplasm composed of cells with myofibroblastic differentiation,
or ROS1 by IHC. The differential diagnosis includes
usually with a prominent inflammatory infiltrate
inflammatory well-differentiated liposarcoma (WDLPS),
dedifferentiated liposarcoma, desmoid fibromatosis and
inflammatory leiomyosarcoma, as well as inflammatory
n Rare; occurs in mesentery, omentum, and retroperitoneum
conditions including retroperitoneal fibrosis and scle- (>80% of cases), with occasional cases in the mediastinum,
rosing mesenteritis. abdominal wall, liver, and gastrointestinal (GI) tract proper
Inflammatory WDLPS is a distinctive variant of n Most tubal gut lesions arise in the colon or small intestine
WDLPS with prominent mixed inflammation con-

taining scattered neoplastic cells. The neoplastic cells Morbidity and Mortality
n Multicentricity may be a feature
are much more atypical than those of IMT, exhibiting
n Patients may die of local disease rather than systemic spread
prominent nuclear pleomorphism and hyperchroma-
sia. DDLPS can also closely mimic IMT because it can
exhibit fascicles of mildly atypical spindle cells with
n Average age of patients with GI tract tumors is 43 years, but the
admixed inflammation. The inflammatory component range is wide
in WDLPS is usually lymphoplasmacytic, whereas in n No gender or race predominance
DDLPS, it is usually neutrophilic. IHC for MDM2

and CDK4 is useful to resolve this differential diagno- Clinical Features
sis because it is positive in most cases of WDLPS and n Patients present with mass lesions, abdominal pain, or
DDLPS. constitutional symptoms (anemia, weight loss, malaise)

Desmoid fibromatosis is also composed of myofibro-
blastic neoplastic cells, but it does not have a prominent
n Local recurrence or local growth is the main cause of morbidity
inflammatory infiltrate, and it has longer fascicles and
n Metastases are rare but do occur
usually no significant cytologic atypia. There is nuclear n Most examples are indolent; treatment is surgical and relatively
β-catenin expression in 70% to 80% of cases but not conservative
in IMT. Inflammatory leiomyosarcoma contains promi-
nent mixed inflammatory infiltrates that can sometimes
make it difficult to recognize the admixed neoplastic
cells. However, the neoplastic cells are more myoid,
with brightly eosinophilic cytoplasm and blunt-ended
nuclei.
Retroperitoneal fibrosis and sclerosing mesenteritis Inflammatory Myofibroblastic Tumor—Pathologic Features
both contain spindle cells with admixed chronic inflam-
mation. However, retroperitoneal fibrosis is clinically Gross Findings
distinctive, presenting with bilateral retroperitoneal n Firm, white infiltrative mass
involvement, often including bilateral ureteral obstruc-
tion. In contrast to IMT, sclerosing mesenteritis has Microscopic Findings
associated fat necrosis. n Inflammatory myofibroblastic tumor (IMT): fascicular spindle cell
neoplasm with admixed chronic inflammatory infiltrate

n Epithelioid inflammatory myofibroblastic sarcoma: epithelioid
neoplastic cells in abundant myxoid stroma with admixed

Prognosis and Therapy neutrophils
Inflammatory myofibroblastic tumor of the abdomen n Positive: smooth muscle actin (80%–90%), desmin (60%),
and pelvis has one of the highest recurrence rates HHF35 (60%), keratin (~30%), anaplastic lymphoma
among all IMT at 25%. Metastasis occurs in fewer than kinase (ALK) (50% of IMT, approaching 100% of epithelioid
5% of patients. The much rarer epithelioid inflamma- inflammatory myofibroblastic sarcoma), ROS1 (5%–10%)
tory myofibroblastic sarcoma pursues a much more
aggressive course, with early recurrences and death
n Fibromatosis; less inflamed, express β-catenin in 70% to 80% of
from disease in almost all patients. Surgical excision cases and lack expression of ALK or ROS
is often performed. Targeted tyrosine kinase inhibitor n Sclerosing mesenteritis: older patients; associated fat necrosis is
therapy (e.g., crizotinib) has shown efficacy in patients common
with advanced disease.
LYMPHANGIOMA
Lymphangioma is a benign proliferation of lymphatic

spaces lined by a single layer of endothelium and is rela-
tively rare in the GI tract. Lymphangiomatosis is a multi-
centric lymphatic proliferation. However, the incidence of
small lesions has increased, probably because of increased
detection. Lymphangiomas can occur at any site in the GI
tract but are most common in small intestine followed by
the large intestine and esophagus. In the abdominal cav-
ity, most occur within the mesentery and retroperitoneum.
Diffuse lymphangiomatosis involves either a single organ
or multiple organs, such as the liver, spleen, lungs, or bones.
Lymphangiomas primarily occur in children and
young adults, although the age range is wide, and there is
an overall slight male predominance. Presentation may
be with bleeding, intussusception, or an acute abdomen.
FIGURE 7.60
Small lesions are usually incidentally detected.
Lymphangioma of the duodenum. Dilated lymphatics are present in the lam-
ina propria and submucosa of this polypoid duodenal lesion. Lymphatic fluid
can be seen in some vessels.
Lymphangiomas of the GI tract occur in two main forms:

(1) small (<2 cm) polypoid white or yellow mucosal
lesions that are usually incidentally detected at endos-
copy and (2) larger masses that may be transmural or
may involve mesenteric fat.
Pathologic Features
Gross Features
Lymphangiomas are usually polypoid with a soft,

spongy texture. Thick gelatinous or milky fluid is seen
in the cystic spaces.
Histologic Features FIGURE 7.61

Lymphangioma. The dilated lymphatics are lined by simple inconspicuous
Lesions can involve one or all layers of the GI tract, usu- endothelial cells, and some contain intraluminal foamy histiocytes.
ally mucosa, submucosa, or muscularis propria (Fig. 7.60),
and consist of dilated cystic lymphatic channels lined by cavities, and vessel abnormalities such as shunt vessels and
a simple layer of bland lymphatic endothelial cells (Fig. wall excrescences. Esophageal lesions can sometimes dis-
7.61). Some lymphatic channels are partially surrounded play cavernous morphology. Lymphangioma of the liver is
by a layer of smooth muscle. The spaces contain clear lym- usually multiloculated and composed of cystically dilatated
phatic fluid, prominent foamy histiocytes, or both (see lymphatic vessels within hepatic parenchyma.
Figs. 7.60 and 7.61). Deep lesions may be associated with
overlying mucosal clusters of small lymphatics. Scattered
lymphoid aggregates, granulation tissue, or foci of xan- Ancillary Studies
thogranulomatous inflammation may be present, especially
in mesenteric or retroperitoneal lesions, and can obscure Immunohistochemistry
the underlying lymphatic abnormality. Other associated
vascular abnormalities may be present, such as vascular The endothelial cells express CD31, D2-40, and podo-
malformations with thick-walled arteries, aneurysm-like planin and show variable CD34 expression. SMA is
positive in smooth muscle cells around larger lymphat-

May involve any layer of the intestine
ics. The smooth muscle component where present is n
n Spaces contain clear lymphatic fluid and/or prominent foamy

negative for melanocytic markers, distinguishing it from histiocytes
lymphangioleiomyomatosis (perivascular epithelioid n Other associated vascular abnormalities may be present
cell tumor [PEComa]).
n Positive for CD31, D2-40, and podoplanin, with variable CD34
expression
n Hemangioma: vascular spaces contain blood; lining endothelial
Distinction from hemangiomas is aided by detection of cells are negative for D2-40
blood in the dilated spaces in hemangioma and expres- n Lymphangioleiomyomatosis: usually occurs in lung; perivascular
sion of D2-40 in lymphangioma. condensation of spindle myoid cells; expression of HMB45

(human melanoma black), Melan-A, and smooth muscle actin,
and desmin in lesional cells
PECOMA
Endoscopic removal of small polypoid lesions and surgical
excision of larger lesions is curative, and lesions usually
do not recur. Lymphangiomatosis with visceral involve- ■ CLINICAL FEATURES
ment often pursue a more aggressive clinical course.
PEComas are mesenchymal neoplasms that show an

unusual line of differentiation toward modified perivas-
LYMPHANGIOMA—FACT SHEET
cular smooth muscle cells that also show melanocytic dif-
Definition ferentiation; there is no known normal counterpart to the
n Benign proliferation of lymphatic spaces
tumor cells. PEComas can arise at virtually any anatomic
n Lymphangiomatosis is multicentric or extensively infiltrating site, but within the GI tract, the most common site is the
lymphangioma colon followed by the small intestine and stomach. The
PEComa family of tumors includes angiomyolipoma of
Incidence and Location the kidney and liver. Tumors usually arise in adults, and
n Rare
occurrence in children is rare. Whereas PEComas gener-
n Most common in small intestine; also arise in mesenteric fat
ally show a female predilection, this difference is not so
Gender, Race, and Age Distribution clear in tumors of the GI tract. There is a wide spectrum
n Slight male predominance
of biologic behavior, from benign to highly aggressive
n Wide age range but usually children and young adults tumors. Most PEComas of the GI tract are sporadic, with
only a small subset being associated with the tuberous
Clinical Features sclerosis complex, in contrast to the more significant asso-
n Incidental or bleeding, intussusception ciation with PEComas at other sites. Presenting symp-
toms depend on the site of involvement and can include
pain, obstruction, and bleeding.
n Benign; majority cured by simple excision
n Lymphangiomatosis may pursue a more aggressive clinical course
Tumors may present as polypoid or intramural masses.

Lymphangioma—Pathologic Features Imaging studies may identify features of increased vas-
cularity within the mass but are often nonspecific.
Gross Findings
n Wide size range; mucosal polypoid lesions are usually
smaller than2 cm, but mural or mesenteric masses may be Pathologic Features
significantly larger
Microscopic Findings Gross Findings

n Dilated lymphatic channels lined by a single of bland lymphatic
endothelial cells Tumors are usually well circumscribed but unencap-

sulated and may involve any layer of the GI wall but
most often involve muscularis propria and subserosa. of pleomorphism. A prominent delicate capillary net-
They may also involve the mesentery without definite work surrounds tumor cells, often resulting in the
attachment to the bowel wall. The cut surface is white nested pattern. A perivascular growth pattern is char-
and solid, and necrosis or hemorrhage may be present. acteristic, with tumor cells arranged radially around
There is a wide size range (1–22 cm), but tumors usually vessel walls and replacing the muscular wall of larger
measure between 3 and 8 cm. vessels (Fig. 7.64). Necrosis may be present. The scle-
rosing variant virtually always occurs in retroperito-
neal soft tissue and shows a spindled cytomorphology.
Angiomyolipoma of the liver consists of thick-walled
vessels, admixed epithelioid or spindled tumor cells,
and variable amounts of mature fat. Malignant
The growth pattern of PEComa is usually nests or PEComa of the GI tract shows diffuse pleomorphism,
sheets of epithelioid cells (Fig. 7.62). Less often, a marked cytologic atypia, and mitotic activity of 2/10
fascicular spindle cell growth pattern may be pres- hpf or greater.
ent. The tumor cells, epithelioid or spindled, clas-
sically have eosinophilic or granular cytoplasm
(Fig. 7.63), prominent nucleoli, and variable degrees
Ancillary Studies
Immunohistochemistry is usually needed to con-

firm the diagnosis given the wide differential con-
siderations. A panel that encompasses myoid and
melanocytic markers is recommended, including
HMB45, Melan-A/MART1, MiTF, SMA, desmin, and
caldesmon. Expression of these markers is usually
variable in terms of intensity and extent; expression
of just one muscle or one melanocytic marker may
be seen (Figs. 7.65 and 7.66). S-100 may show focal
positivity in 10% to 20% of cases. TFE3 expression is
present in 5% to 10%, is associated with TFE3 gene
rearrangements, and is usually mutually exclusive with
MiTF expression. KIT, keratin, and CD34 expression
FIGURE 7.62
is typically absent.
Perivascular epithelioid cell tumor (PEComa). Sheet-like and vaguely nested
growth pattern of PEComa of the liver with epithelioid cytomorphology.

Perivascular epithelioid cell tumor (PEComa). Characteristic granular and Perivascular epithelioid cell tumor (PEComa). The tumor cells of PEComa
eosinophilic cytoplasm of the tumor cells of PEComa; the nuclei have small often show an intimate association with vessels, being radially arranged and
nucleoli, and there is cytologic pleomorphism. appearing to replace the vessel wall.
leiomyosarcoma. When PEComa is composed entirely

of spindled cells, distinction from pure smooth muscle
tumor may be impossible without IHC that demon-
strates expression of melanocytic markers.
Metastatic renal cell carcinoma and metastatic mel-
anoma may mimic PEComa with their typical nested
growth pattern, epithelioid cells with variable amounts
of clear or palely eosinophilic cytoplasm, and a promi-
nent vascular network among tumor cells. Correlation
with clinical history is crucial. Renal cell carcinoma
is positive for PAX8 and EMA, unlike PEComa.
Melanoma is more likely to show diffuse S-100 and
SOX10 protein expression and is usually negative for
SMA and desmin.
Epithelioid GIST may mimic PEComa; however,
the tumor cells of GIST are usually less pleomorphic
FIGURE 7.65 and lack the granular cytoplasm and the perivascu-
Perivascular epithelioid cell tumor (PEComa). Diffuse cytoplasmic expression lar arrangement of tumor cells present in PEComa.
of HMB45 (human melanoma black) in PEComa with epithelioid features. Although there may be expression of SMA and desmin
in GIST, the cells are negative for melanocytic markers.
PEComa may rarely show focal expression of DOG1.
PEComa may show similar morphologic features
to malignant GNET or clear cell sarcoma-like tumor
of the GI tract in that both tumors are typically com-
posed of an admixture of spindled and epithelioid cells,
with varying degrees of atypia. Furthermore, PEComa
may show focal expression of S-100. Distinction is
made by careful morphologic evaluation and further
aided by IHC and molecular tests when necessary.
GNET frequently contains osteoclast-like giant cells
and pseudoglandular areas, and the tumor cells do
not show the close association with vessel walls typ-
ical of PEComa. The tumor cells show strong diffuse
S-100 positivity and are negative for SMA, desmin, and
melanocytic markers (unlike conventional clear cell
sarcoma). Molecular studies to evaluate for EWSR1
FIGURE 7.66 rearrangement (caused by the presence of EWSR1-
Perivascular epithelioid cell tumor (PEComa). Focal cytoplasmic expression ATF1 or EWSR1-CREB1 fusion genes) can help con-
of desmin in PEComa with epithelioid features. firm a diagnosis of malignant GNET.
Immunohistochemistry can also distinguish
Molecular Genetics PEComa from paraganglioma because the cells of
paraganglioma are positive for synaptophysin and
Both sporadic and syndromic cases are associated with chromogranin and negative for smooth muscle and
abnormalities in the tuberous sclerosis gene complex. melanocytic markers.
Mutations in TSC2 (less often TSC1) are present in
approximately 80% of cases and result in activation of
the mTOR (mammalian target of rapamycin) pathway.
A smaller subset of PEComas has TFE3 gene rearrange-
ments; the most common fusion partner with TFE3 is
PSF/SFPQ. PEComas may be benign or may pursue a clinically
aggressive course. The most common metastatic sites
are the liver, lymph nodes, lungs, and bone. mTOR path-
way inhibitors such as sirolimus and everolimus have
shown efficacy in advanced disease. In a series of 35
patients with PEComa of the GI tract, 13 (37%) devel-
Pure smooth muscle tumors of the GI tract include oped metastases, and 5 died of disease, with a median
the more common leiomyoma and far less common interval from time of diagnosis to death of 22 months.
PEComa—FACT SHEET
n Gastrointestinal stromal tumor: especially myxoid or succinate
dehydrogenase–deficient types: positive for KIT and DOG1

Definition
n Metastatic melanoma: may be positive for secondary melanocytic
n Mesenchymal neoplasm showing dual myoid and melanocytic
markers; lacks EWSR1 rearrangement
differentiation n Conventional clear cell sarcoma: rarely involves the
gastrointestinal tract; more prominent nested growth pattern; also

Incidence and Location expresses HMB45, MART1, and tyrosinase
n Rare; in the gastrointestinal (GI) tract, colon is the most common
site
n Angiomyolipoma is a subtype of perivascular epithelioid cell
tumor (PEComa) that occurs in the liver and kidney

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8
Non-Neoplastic and Neoplastic Disorders
of the Appendix
■ Deepa T.Patil, MD
■ CONGENITAL AND ACQUIRED ANATOMIC greatly increased in patients with cystic fibrosis (CF),
ANOMALIES OF THE APPENDIX in whom they are found in up to 22% of appendectomy
specimens. Patients may be completely asymptom-
Abnormal Location, Size, and Absence of the atic or may present with signs and symptoms of acute
Appendix appendicitis.
Grossly, the appendix may appear edematous and
dilated. However, in most cases, diverticula cannot be
The appendix can have a host of anatomic abnormali- easily identified. In case of perforation, the serosa shows
ties, including atypical location, duplication, and con- purulent exudate. In the presence of dilated appendix,
genital absence. The position of appendix is determined the lumen may be filled with mucin, and there may be
by the rotation of the gut and position of the cecum evidence of extraappendiceal mucin. Histologically, there
during embryonic development. Retrocecal appendix is is outpouching of appendiceal mucosa through the mus-
the most common abnormal location of the appendix. cularis propria, with or without periappendiceal fibrosis
An abnormally long appendix (normal is 7–10 cm) has (Fig. 8.1). The muscularis propria is usually attenuated.
been linked to primary acute torsion, although torsion The epithelium may show reactive or hyperplastic epi-
has also been reported in appendices of normal length. thelial changes that may be difficult to distinguish from
There can be complete or incomplete septa, which low-grade appendiceal mucinous neoplasm. Diverticular
are seen principally in children and young adults and disease can be associated with acellular mucin within
associated with acute appendicitis. Complete absence the appendiceal wall, resulting in diagnostic mimicry
of appendix or atresia is extremely rare. This diagno- with an appendiceal mucinous neoplasm. Preservation
sis in only made after a thorough search of the ileoce- of the mucosal architecture with intact lamina propria
cal region has failed to reveal an abnormally located and muscularis mucosae and lack of unequivocal cyto-
appendix. logic dysplasia support a diagnosis of diverticular disease.
Diverticular Disease
■ FIBROUS OBLITERATION OF THE
APPENDICEAL LUMEN (NEURAL
Diverticula of the appendix can be congenital, in which
HYPERPLASIA)
case the muscularis propria is part of the diverticular
wall, or acquired, in which case the diverticulum results
from increased intraluminal pressure and mucosal her- CLINICAL FEATURES
niation through a defect in the muscularis propria.
This defect usually corresponds to the site of a pene-
trating artery. Acquired diverticula are more common There are no specific features because this is typically
than congenital diverticula and are seen in 1% to 2% an incidental finding in about one-third of appendices
of the population. However, acquired diverticula are excised for a variety of reasons.
211
Pathologic Features
Gross Findings
The tip of the appendix is usually affected. No definite

lumen is identified. Instead, the cut surface appears tan
to white.
The appendiceal lumen is obliterated by a prolifera-

tion of bland spindle cells in a collagenous and myxoid
A background. The individual cells may have “wavy” or
“buckled” nuclei (Fig. 8.2). These cells consist of an
admixture of fibroblasts, Schwann cells, and axons. The
process may be confined to the mucosa (“intramucosal
variant”) or may replace the entire lumen. These phe-
nomena are believed to be overall proliferative, with
attendant phases of growth, involution, and finally
fibrosis. Immunohistochemical staining shows S-100
protein and neuron-specific enolase–reactive spindle
cells (intermingled Schwann cells and axons, respec-
tively), and scattered endocrine cells. The fibroblasts
may be positive for CD34.
B
FIGURE 8.1
A, Appendiceal diverticular disease. The appendiceal tip shows numerous
outpouchings composed of mucosa and submucosal tissue with atten-
uation of the corresponding muscularis propria. B
, Higher magnification of
the mucosa shows normal epithelial lining with intact lamina propria and
muscularis mucosae.
FIBROUS OBLITERATION OF THE APPENDICEAL LUMEN

(NEURAL HYPERPLASIA)—FACT SHEET
Definition
■ A spindle cell proliferation that fills and "obliterates" the appendix
lumen, usually at the tip

■ Found in about one-third of excised appendices

■ None
B
■ All ages, without race or gender predisposition FIGURE 8.2
Fibrous obliteration of appendix. A, The bisected appendiceal tip shows
Clinical Features completer obliteration of the appendiceal lumen by spindle cells and inflam-
matory cells. B, Higher magnification shows that the spindle cell population
■ Incidental finding in appendices excised for all reasons
is composed of bland cells with wavy nuclei. These cells express S-100 pro-
tein and are often admixed with fibroblasts.
CHAPTER 8 Non-Neoplastic and Neoplastic Disorders of the Appendix 213
sign that is specific for appendicitis is an enlarged, non-

Fibrous Obliteration of the Appendiceal Lumen (Neural compressible appendix measuring greater than 6 mm in
Hyperplasia)—Pathologic Features maximal diameter. CT signs of acute appendicitis include
a distended appendix greater than 7 mm in maximal diam-
Gross Findings eter, appendiceal wall thickening and enhancement, an
■ Normal appendix diameter with lumen being replaced by tan-
appendicolith, circumferential or focal cecal apical thicken-
white fibrous tissue
ing, pericecal fat stranding, adjacent bowel wall thickening,
Microscopic Findings focal or free peritoneal fluid, mesenteric lymphadenopathy,
■ Bland spindle cell proliferation amid fibromyxoid stroma
and intraperitoneal phlegmon or abscess.
ACUTE APPENDICITIS—FACT SHEET
■ S-100– and neuron-specific enolase–positive cells with scattered
endocrine cells
Definition
Differential Diagnosis ■ An acute inflammatory process attributed to local obstruction and
infection involving the appendix

■ With benign mesenchymal tumors, the luminal location is the key

■ Involves the appendix
Differential Diagnosis ■ Incidences reported up to 7%

The differential diagnosis is with the host of spindle cell
■ Complications include wound infection, urinary retention, bowel
tumors of the gastrointestinal (GI) tract that are discussed obstruction, intraabdominal abscesses, urinary tract infections,
in Chapter 7. However, the location (with its epicenter in and pneumonia, all more likely if the appendix has perforated
the lumen of the appendix) and nature of the spindle cell ■ Overall mortality rate for appendectomy is about 0.3%; in
proliferation are helpful in distinguishing it from other individuals older than 65 years, this percentage is closer to 5%
mesenchymal neoplasms, especially those of neural origin.
■ Peak presentation is from 5 to 15 years, but it occurs at any age
■ Male predominance in all races, but acute appendicitis is more

Prognosis and Therapy common in whites than in African Americans and Asian Americans
Fibrous obliteration is a benign and incidental lesion. Clinical Features

■ Classically, right lower quadrant pain accompanied by fever and
elevated white blood cell count, but many variants occur

ACUTE APPENDICITIS
■ Treatment is appendectomy
■ CLINICAL FEATURES ■ Preoperative antibiotics followed by appendectomy (“interval
appendectomy”) have been advocated in patients with perforated

appendices
Acute appendicitis most commonly affects children and ■ Overall prognosis is good
adolescents (5–15 years) but occasionally may present in

older individuals as well. The approximate incidence of
acute appendicitis is 7% to 10%. It results from muco- Pathologic Features
sal injury secondary to luminal obstruction by a fecalith,
parasite, fragment of undigested food, or lymphoid hyper-
plasia followed by bacterial infection that progressively Gross Findings
spreads from the mucosa to involve the appendiceal wall.
Perforation is more common in the very young and in The appendix may appear grossly normal when inflam-
the older age groups. In older patients, the inflammatory mation is limited to the mucosa and submucosa.
process is often associated with neoplasms. Some observ- However, when inflammation extends into the muscu-
ers believe that all appendices should be removed during laris propria, the appendix frequently becomes swol-
surgery for suspected acute appendicitis, even when len and erythematous. When the serosa is affected, the
grossly normal, because nearly 20% of normal-appearing serosal aspect is initially dull and gray followed by a
appendices may have acute inflammation on microscopic fibrinous or purulent exudate. Gangrenous appendici-
examination. A possible exception is patients who might tis may show a purple, green, or blackish discoloration.
require urologic surgery in the future because their appen- Perforation secondary to mural necrosis can follow,
dices may later serve as urinary conduits. which may lead to abscess formation. Cut surface shows
Both ultrasound and computed tomography (CT) are use- edema and hyperemia of the wall, with or without
ful in diagnosing acute appendicitis. The only sonographic intraluminal purulent contents. At times, an appendix
resected in the clinical setting of acute appendicitis is tissue indicate prior rupture. Submucosal fibrosis, serosi-
grossly and histologically normal, even after submission tis, and fibrous adhesions can be present as well. In some
of the complete specimen for histologic examination. In cases, mucin extravasation may be a prominent feature and
these cases, a cause is rarely found. may lead to confusion with an appendiceal mucinous neo-
plasm. However, typical appendiceal mucinous neoplasms,
Microscopic Findings even those that perforate, seldom show a prominent acute
inflammatory component within the wall of the appendix
Early acute suppurative appendicitis (phlegmonous and often display a dense fibrocollagenous stroma that
appendicitis) usually shows mucosal erosions and scat- is distinct from the acute edematous appearance of the
tered cryptitis and crypt abscesses (Figs. 8.3 and 8.4). stroma in acute appendicitis. A second pattern, which has
Later, the inflammation extends to involve the appendi- been termed x anthogranulomatous appendicitis, consists of
ceal wall. Collection of neutrophils within the appendiceal an inflammatory infiltrate rich in foamy histiocytes, mul-
lumen is considered insufficient for a diagnosis of acute tinucleate giant cells, abundant hemosiderin, and luminal
appendicitis. Gangrenous appendicitis is associated with obliteration with sparing of lymphoid follicles. These latter
transmural necrosis extensive serosal fibroinflammatory cases share features with Crohn’s disease but differ by lack-
reaction and can lead to perforation if left untreated. ing epithelioid granulomas, having fewer lymphoid aggre-
As the appendix heals, two basic patterns may be seen. gates, and having less profound subserosal fibrosis.
In the first, more typical pattern, there is a mixed inflam- Commonly, patients who present with ruptured acute
matory infiltrate ranging from patchy and mild to diffuse appendicitis are treated with antibiotic therapy and
and transmural inflammation. Intramural or serosal for- drainage followed by a delayed or “interval appendec-
eign body–type giant cells surrounded by granulation tomy” (Figs. 8.5 and 8.6). In this setting, about two-thirds

Acute appendicitis. The appendix shows an edematous and thickened wall Gross specimen prepared from an “interval appendix.” Antibiotic treatment
with extensive mucosal ulceration and transmural suppurative inflammation. was carried out for 4 weeks prior to appendectomy. Note the fibrous thick-
There is marked serosal fibroinflammatory reaction. ened wall, which suggests the possibility of Crohn’s disease.

Acute appendicitis. Higher magnification of the mucosa shows reactive “Interval appendix.” A, Low magnification shows thickened appendiceal
epithelial changes characterized by loss of mucin, cytoplasmic eosinophilia, wall with mural lymphoid aggregates arranged in a concentric pattern. This
slight nuclear hyperchromasia, and nuclear enlargement. There are neutro- pattern has been linked to a “string of pearls.” B
, Higher magnification shows
philic cryptitis and crypt abscess formation. giant cells and epithelioid granulomas within the appendiceal submucosa.
of patients have granulomas compared with fewer than bowel obstruction, intraabdominal abscesses, urinary tract
10% of acute appendicitis control participants. About infections, and pneumonia, all more likely if the appendix
one-third of interval appendectomy patients have xan- has perforated. Rarer complications include fistula forma-
thogranulomatous inflammation, and about half show a tion, pylephlebitis, and liver abscesses. The overall mor-
Crohn’s-like infiltrate. This is analogous to changes seen tality rate for appendectomy is about 0.3%. In individuals
in sigmoid colon resections after antibiotic therapy for older than 65 years, the mortality rate approaches 5%.
acute diverticulitis and should not be misinterpreted as
manifestations of Crohn’s disease.
It is common for patients with neoplastic processes PERIAPPENDICITIS
to present with clinical signs and symptoms of acute
appendicitis only to reveal a neuroendocrine tumor
(NET) or goblet cell neoplasm within the wall of the Periappendicitis is characterized by serosal fibroinflamma-
appendix. These cases require careful histologic evalua- tory reaction with or without adhesions in the absence of
tion to prevent misdiagnosis. mucosal or mural inflammation. Although intraoperative
mechanical manipulation of the appendix alone may result
in mild granulocytic infiltration of the serosa, the presence
Acute Appendicitis—Pathologic Features of fibrinous exudate is a potentially clinically significant
finding. Periappendicitis is found in 1% to 5% of appen-
Gross Findings dices resected for clinically acute appendicitis. The vast
■ Thickened diameter, depending on severity of process, with or majority of cases are secondary to salpingitis. In two large
without perforation. Serosa may be dull from periappendicitis series, the causes of periappendicitis included gonococcal
and chlamydial salpingitis, yersiniosis, Meckel’s diverticu-
litis, and associated intraperitoneal abscess, urologic disor-
■ Early lesions display mucosal erosions and scattered crypt
abscesses; later, the inflammation extends into the wall of the ders, colon neoplasms, infectious colitis, abdominal aortic
appendix aneurysm, bacterial peritonitis, and GI perforation.
■ When the inflammation extensively damages the muscularis Grossly, the appendix is normal in size, and depend-
propria, mural necrosis can lead to perforation ing on the severity of periappendicitis, the serosal
■ In appendectomies performed in patients with prior appendicitis,
surface appears dull or tan to gray. The lumen and
there are mixed inflammatory infiltrates ranging from patchy and
mild to diffuse and transmural mucosa appear normal. Histologically, there is a sero-
■ In some appendices, there may be intramural or serosal foreign sa-confined (or possibly with extension into muscularis
body–type giant cells surrounded by granulation tissue suggestive propria) inflammatory cell infiltrate consisting of neu-
of prior rupture trophils and fibrin if the process is acute (Fig. 8.7) or
■ Serositis and fibrous adhesions, as well as prominent submucosal
with adhesions and chronic inflammation if the pro-
fibrosis, may be present
■ Mucin extravasation is often seen but is admixed with a
cess is chronic. The lumen is unaffected. The pathol-
prominent inflammatory component, which is helpful in ogist’s finding of periappendicitis on an appendectomy
distinguishing this from a ruptured low-grade appendiceal specimen in the absence of luminal disease should alert
mucinous neoplasm the surgeon to take measures to identify the source of
■ Xanthogranulomatous appendicitis: features an infiltrate of foam
the serosal injury. If the patient is a woman, the gen-
cells, scattered multinucleated histiocytes, abundant hemosiderin,
and luminal obliteration with spared lymphoid follicles ital tract is a likely source, but as noted previously,
■ Interval appendectomy specimens share features with Crohn’s
disease but differ by lacking epithelioid granulomas and having

fewer lymphoid aggregates and less mural fibrosis, and these
patients lack prior and concurrent clinical symptoms and
endoscopic or radiologic signs of Crohn’s disease
■ Appendiceal involvement as part of an infectious enterocolitis
and mechanical trauma associated with fecaliths. Both these

conditions can cause superficial cryptitis and crypt abscesses.
However, mural inflammation is typically present only in acute
appendicitis. Inflammatory bowel disease involving the appendix
is also in the differential (discussed later)

FIGURE 8.7
The definite form of treatment is appendectomy. Periappendicitis with acute and chronic serositis with fibrosis and adhesions.
Complications include wound infection, urinary retention, In these cases, the mucosa is usually completely normal.
any abdominal process may result in periappendicitis. counterpart of ulcerative colitis, is typically present in
The treatment and prognosis depend on the inciting patients with pancolitis but is also common as a “skip lesion”
extraappendiceal lesion. in patients who have left-sided or rectal disease. It has an
overall prevalence of 50% in patients with ulcerative colitis.
Grossly, the appendiceal mucosa appears erythem-
PERIAPPENDICITIS—FACT SHEET atous and ulcerated. Ulcerative appendicitis shows the
same histologic features as ulcerative colitis. Active muco-
Definition sal inflammation is characterized by cryptitis and crypt
■ Inflammatory process confined to the appendix serosa without abscesses. Chronic changes include crypt architectural
luminal involvement (and thus with an extraappendiceal source) distortion, basal lymphoplasmacytosis, and basal lym-
phoid aggregates. Ulcerative appendicitis is distinguished
from early acute appendicitis partly on the basis of clinical
■ Periappendicitis alone is found in 1% to 5% of appendices
resected for clinically acute appendicitis, the majority of which are

history, although early acute appendicitis shows minimal
attributable to salpingitis crypt architectural distortion and basal plasmacytosis.

■ Depends on the source of the periappendicitis
ULCERATIVE COLITIS INVOLVING THE APPENDIX—FACT
SHEET
Clinical Features
■ Attributable to a variety of processes: gonococcal and chlamydial Definition
salpingitis; yersiniosis, Meckel’s diverticulitis, and associated ■ Appendiceal inflammatory disease (usually chronic active) in
intraperitoneal abscess; urologic disorders; colon neoplasms; patient with ulcerative colitis
infectious colitis; abdominal aortic aneurysm; bacterial peritonitis;
and gastrointestinal perforation
■ Common in patients with ulcerative colitis and predominantly
involving the orifice rather than the appendiceal tip
■ Depends on the source of the periappendicitis

■ Same as for ulcerative colitis
Periappendicitis—Pathologic Features Gender, Race, and Age Distribution

■ Same as for ulcerative colitis
Gross Findings
■ Serosal thickening or exudates with normal muscularis propria
and mucosa
Ulcerative Colitis Involving the Appendix—Pathologic
Microscopic Findings Features
■ Serosal fibroinflammatory process with normal rest of the
appendiceal wall Gross Findings

■ Found either in continuity with pancolitis in ulcerative colitis or as
Differential Diagnosis a “skip” lesion in left-sided disease
■ Acute appendicitis
■ Chronic appendicitis: The term c hronic appendicitis has been Microscopic Findings
variably used in the past to describe pathologic changes ■ Similar to those of ulcerative colitis elsewhere, featuring cryptitis,
following recurrent episodes of acute appendicitis, for interval crypt distortion, and basal plasmacytosis
appendectomy when resection for perforated appendix is
delayed as a result of initial conservative therapy with antibiotics Differential Diagnosis
and drainage, and other chronic inflammatory conditions
■ Acute appendicitis
of the appendix, such as ulcerative colitis, Crohn’s disease,
granulomatous appendicitis, infections, diverticular disease, and
cystic fibrosis
■ CROHN’S DISEASE INVOLVING THE APPENDIX
■ ULCERATIVE COLITIS INVOLVING THE Most appendices resected in patients with Crohn’s
APPENDIX disease are unremarkable. Appendiceal involvement
by Crohn’s disease has been reported in up to 20% of
The appendix has been shown to play a protective role in patients and is typically associated with extensive ile-
ulcerative colitis. The prevalence of prior appendectomy ocolonic involvement. Most patients who present with
is lower in patients with ulcerative colitis than in the gen- granulomatous appendicitis do not later manifest typical
eral population. Ulcerative appendicitis, the appendiceal Crohn’s disease elsewhere in the GI tract.
CROHN’S DISEASE INVOLVING THE APPENDIX—FACT

SHEET
Definition
■ Appendiceal inflammatory disease in a patient known to have
Crohn’s disease

■ Uncommon; may be found in any part of the appendix

■ Same as for Crohn’s disease

FIGURE 8.8
■ Same as Crohn’s disease: Grossly, the appendiceal wall is thick
Appendiceal Crohn’s disease. The specimen shows presence of active
and fibrotic in patients with Crohn’s disease, and involvement may inflammation along with a deep fissuring ulcer.
be patchy. In patients with clinical Crohn’s disease, the appendices
have the typical histologic features of Crohn’s seen elsewhere
in the gastrointestinal tract, with fissures, ulcers, active or chronic
active inflammation, lymphoid aggregates, and occasional
granulomas (see F igs. 8.8and 8 .9and T able 8.1). Diagnosis
of Crohn’s disease of the appendix requires clinicopathologic
correlation. Determination of the type of inflammatory bowel
disease should not be performed based on the findings in an
appendectomy specimen because several causes may result in
granulomatous appendicitis (see later). The prognosis for patients
with Crohn’s disease of the appendix is that of Crohn’s disease
in general (see C hapter 10) because those with appendiceal
involvement usually have extensive ileocolic involvement
Crohn’s Disease Involving the Appendix—Pathologic

Features
Gross Findings
■ Thickened appendix, usually without grossly visible mucosal
lesions
■ Segmental involvement with fissuring ulcers, chronic active
inflammation, transmural lymphoid aggregates, epithelioid

granulomas, and mural fibrosis FIGURE 8.9
Appendiceal Crohn’s disease. The specimen shows chronic active colitis with
Differential Diagnosis granulomatous inflammation.
■ If disease is limited to the appendix, one should not label
a de novo patient as having Crohn’s disease, and “interval”

appendicitis should be considered
■ Sarcoidosis
TABLE 8.1
Chronic Inflammatory Disorders of the Appendix
Idiopathic Granulomatous
Finding Appendicitis Crohn’s Disease Healing Acute Appendicitis
Neutrophilic cryptitis or crypt + + +

abscesses
Fissures or fistulae Occasional fissures + -
Transmural lymphoid aggregates Often Often Occasionally
Fibrosis Often Often Often
Granulomas Numerous Occasional No, but may have numerous
foam cells
Other Studies Symptoms vary from person to person owing in part to

the more than 1000 mutations of the C FTR gene. The
sweat chloride test is the standard diagnostic test for CF.
Newer microbiologic techniques may provide some clues Although recurrent pulmonary infections and pulmo-
to the causes of granulomatous appendicitis. For exam- nary insufficiency are the hallmarks, GI symptoms com-
ple, in a 2001 study by Lamps and her colleagues, 10 of monly antedate the pulmonary findings and may suggest
40 (25%) cases of granulomatous appendicitis were found the diagnosis in infants and young children. The protean
to have evidence of pathogenic Y ersinia species by poly- GI manifestations of CF result primarily from abnormally
merase chain reaction. However, now that some of the viscous luminal secretions within hollow viscera and the
features of Crohn’s disease are believed to reflect an immu- ducts of solid organs. Bowel obstruction may be present at
nologic defect in processing organisms that do not affect birth because of meconium ileus or meconium plug syn-
normal individuals, the interest in search for a unifying drome. Overall, patients with CF have a lower frequency
infectious cause of Crohn’s disease has diminished greatly. of acute appendicitis (1.5%) than the general population
(∼7%). In some cases, the engorged appendix itself can
cause clinical symptoms of appendicitis even though his-
■ GRANULOMATOUS APPENDICITIS tologic examination reveals no inflammation. The inci-
dence of acquired appendiceal diverticula is also markedly
Granulomatous appendicitis was first described in 1953 increased in patients with CF.
by Meyerding and Bertram and was initially believed to
be a manifestation of Crohn’s disease. However, studies
that have appendiceal pathology in patients with doc-
umented idiopathic inflammatory bowel disease have
shown that only a minority of patients with granulo- CYSTIC FIBROSIS INVOLVING THE APPENDIX—FACT
matous appendicitis are a true manifestation of Crohn’s SHEET
disease. Based on our current understanding, granulo-
Definition
matous appendicitis results from several conditions such
■ Involvement of the appendix in a patient known or subsequently
as interval appendicitis, infections (bacterial— Yersinia found to have cystic fibrosis (CF)
spp., tuberculosis; parasitic—schistosomiasis, strongyloi- ■ Gastrointestinal tract involvement may be the first presentation
dosis; fungal—Candida spp., Histoplasma spp.), sarcoid-

osis, Crohn’s disease, and foreign body reaction. When a Incidence and Location
cause cannot be found, the condition is termed i diopathic ■ CF occurs in approximately 1 in every 3200 live white births (1 in
granulomatous appendicitis. This histologic hallmark is every 3900 live births of all Americans)
the presence of granulomas that may involve any layer
of the appendiceal wall. The presence of numerous gran-
■ Same as for CF in general
ulomas, large-sized granulomas ( >
200 microns), and ■ Patients usually have numerous respiratory infections and
those with caseous necrosis or suppurative inflammation gastrointestinal (GI) tract complications
should prompt a search for infectious pathogens. The ■ Adults are prone to diabetes, osteoporosis, and GI tract
management of granulomatous appendicitis depends on malignancies

the underlying cause, so appropriate ancillary infectious
work-up and clinical information is essential.
■ Most cases of CF are diagnosed in early childhood
■ No gender prevalence
■ Most common in white populations

CYSTIC FIBROSIS
Clinical Features
■ Patients with CF have a variety of symptoms, including very salty-
■ CLINICAL FEATURES tasting skin; persistent coughing, at times with phlegm; wheezing
or shortness of breath; excessive appetite but poor weight gain;
and greasy, bulky stools
Cystic fibrosis occurs in approximately 1 of every ■ Symptoms vary owing in part to the more than 1000 mutations
3200 live white births (in 1 of every 3900 live births of the C
FTR gene. Many patients present with GI tract symptoms,
of all Americans). Approximately 1000 new cases of but the incidence of appendicitis is lower in these people than in
CF are diagnosed each year. More than 80% of patients control subjects (1%–2% vs 7%–10%)
are diagnosed by age 3 years; however, nearly 10% of
newly diagnosed patients are age 18 years or older.
■ Same as for CF
People with CF have a variety of symptoms, including ■ Treatment of the underlying disease is directed at reducing
very salty-tasting skin; persistent coughing, at times with pulmonary infections
phlegm; wheezing, or shortness of breath; an excessive ■ Most patients with CF live into their 30s
appetite but poor weight gain; and greasy, bulky stools.

Pathologic Features also be differentiated from mucinous neoplasms of the

appendix, which are typically associated with abun-
dant luminal mucin. Evaluation of the epithelium helps
Gross Findings exclude mucinous neoplasms.
On gross examination, the appendiceal lumen contains
thick viscous tenacious mucus. In some cases, there may
be evidence of a mucus plug. This abnormal mucin can Prognosis and Therapy
cause marked engorgement of the appendix and can lead
to a “sausage-like” appendix. The treatment of patients with CF depends on the
stage of the disease and the organs involved. Chest
Microscopic Findings physical therapy, TOBI (tobramycin solution for inha-
lation), dornase alfa (Pulmozyme), and azithromycin
In CF, the most common histologic finding is enlarged are administered with the goal of clearing and thinning
and distended goblet cells containing normal-appearing mucus secretions and controlling bacterial (especially
mucin, although this can be a subtle finding in many cases. Pseudomonas aeruginosa) infections.
The most readily identifiable abnormality is the presence
of the thick inspissated eosinophilic mucin in the appen-
diceal lumen as well as within the crypts (Fig. 8.10). INFECTIOUS CAUSES OF ACUTE
APPENDICITIS
Cystic Fibrosis Involving the Appendix—Pathologic Features
Gross Findings
■ The appendix is enlarged and distended with mucus
Infections of the appendix can be caused by bacte-

ria, viruses, fungi, or parasites. In most cases of acute
■ Enlarged and distended goblet cells containing normal-appearing
appendicitis, no organisms are identified by histology.
mucin along with thick inspissated eosinophilic mucin in the
lumen as well as within the crypts Although specific infectious causes of acute appendicitis
are only rarely identified, certain agents can occasion-
Differential Diagnosis ally be implicated. A few specific infections are noted in
■ Evaluation of the epithelium excludes neoplasms (sometimes the following sections (see C
hapter 9for more details).
multiple sections are required), and correlation with the clinical
history is best in establishing a diagnosis of cystic fibrosis
Actinomyces spp.
Differential Diagnosis Actinomyces israelii is a rare cause of appendicitis.

A. israelii can rarely lead to infections of the small intes-
Patients without CF sometimes have prominent inspis- tine, appendix, or colon. Histologically, the long filamen-
sated mucus in their appendices. The clinical history is tous organisms stain dark blue on routine hematoxylin
helpful in this regard. CF involving the appendix should and eosin preparations and are particularly easy to rec-
ognize when associated with characteristic sulfur gran-
ules. Active inflammation in the mucosal wall is typically
present, and fistula formation, rupture of the appen-
dix, and abscess formation may complicate the clinical
course. A ctinomyces turicensis has also been implicated
in appendicitis and is frequently accompanied by aerobic
bacterial isolates of the S
treptococcus anginosus group.
Malakoplakia
Malakoplakia is most commonly seen in the urinary

tract but can occasionally be found in the appendix
FIGURE 8.10 (Figs. 8.11 and 8.12). In general, malakoplakia results
Cystic fibrosis (CF). The goblet cells are more prominent, and the luminal sur- from an abnormal immune response in which bacteria
face as well as the crypts contain thick inspissated mucin characteristic of CF. are incompletely digested and accumulate in histiocytes.
The histologic findings typically consist of a diffuse or which close to 22,000 appendices were evaluated, granu-
nodular thickening of the mucosal wall resulting from lomatous inflammation and increased eosinophils in the
the accumulation of numerous macrophages, including lamina propria were quite rare and were both noted in
many that are eosinophilic, with scattered lymphocytes fewer than 2% of infections. There is an inverse relation-
and plasma cells. Most characteristics are the admixed ship between active mucosal inflammation and pinworm
Michaelis-Gutmann bodies, which are round, laminated, infection. Mucosal inflammation, when present, has
bluish-black structures with a targetoid appearance that been more strongly linked to the presence of parasite ova.
can be highlighted with iron or calcium stains.
Viral Infections
Parasite Infections
Viral gastroenteritis does not typically result in appen-
Enterobius vermicularis is one of the most common par- dectomy. Viral enteritis classically results in surgi-
asites seen in the appendix. Individuals in late child- cal excision of the appendix when it leads to ileocecal
hood and early adolescence have the highest frequency
of infection (ages 5–15 years). The organism is most
commonly found in the lumen with no mucosal inflam-
matory response (Figs. 8.13 and 8.14). In one study, in
FIGURE 8.11
Malakoplakia showing sheets of histiocytes expanding the lamina propria. FIGURE 8.13
Enterobius vermicularis. Endoscopic appearance of the cecum in a patient
with appendiceal disease. The image shows tiny, white parasites adherent to
the mucosal surface.
FIGURE 8.12
Malakoplakia. Note the admixed Michaelis-Gutmann bodies in this example FIGURE 8.14
of malakoplakia (round, laminated bluish-black structures with a targetoid Enterobius vermicularis in the appendiceal lumen. Note the characteristic
appearance). cuticular crests.
intussusception. Intussusception is common in infants ENDOMETRIOSIS, DECIDUOSIS,

and young children and is most often attributable to GLIOMATOSIS
lymphoid hyperplasia in the terminal ileum, which can
form a “leading edge.” The viral agents implicated in
this setting are rotavirus, echovirus, and adenovirus, of ■ CLINICAL FEATURES
which adenovirus is the most common infectious agent.
In appendices infected with adenovirus, in addition to
prominent lymphoid hyperplasia, erosions may be iden- Endometriosis affects the GI tract in up to 40% of
tified. However, viral inclusions are usually found only patients with pelvic endometriosis. The sigmoid colon
in intact epithelial cells. Zones in which inclusions are is the most common site, but the appendix may be
more likely to be found are selected by scanning for areas involved in up to 15% of cases. Although appendiceal
with frayed-appearing epithelium showing loss of nuclear endometriosis can masquerade clinically as acute appen-
polarity and an eosinophilic appearance imparted by dicitis, it usually has a nonspecific presentation. In some
reactive mucin loss. Such zones are frequently seen in instances, there may be history of pain that waxes and
close association with lymphoid follicles. Intranuclear wanes with the menstrual cycle.
adenovirus inclusions are typically of the Cowdry B type, A similar phenomenon, termed d eciduosis (ectopic
consisting of basophilic inclusions with nuclear smudg- decidua), has been found in the appendices of pregnant
ing, although Cowdry A inclusions, featuring sharply women. In contrast to endometriosis, deciduosis typically
demarcated globules surrounded by a clear zone, may be presents with signs and symptoms of acute appendicitis.
found in a minority of cases (Figs. 8.15 and 8.16). When present, pelvic gliomatosis can also affect the
serosal aspect of the appendix. Gliomatosis peritonei
is found in patients with ovarian teratomas and man-
ifests as foci of mature glial tissue deposited ubiqui-
tously over the serosal surfaces. It has been reported to
be a rare complication of ventricular shunts, and cases
of malignant transformation have also been recorded.
ENDOMETRIOSIS, DECIDUOSIS, GLIOMATOSIS—FACT

SHEET
Definition
■ Deposition of endometrial-type glands and stroma, decidualized
endometrial-type tissue, or glial tissue in the appendix

■ Affects the gastrointestinal tract in about 40% of patients with
FIGURE 8.15 endometriosis; appendix in 15%
Adenovirus infection with epithelial cells containing both Cowdry A and B ■ Deciduosis and gliomatosis are rare
inclusions.
■ Benign processes that can result in adhesions and obstruction

■ Affects women in their reproductive years
Clinical Features
■ Patients have nonspecific symptoms that may wax and wane with
the menstrual cycle

■ Deciduosis presents with symptoms and signs of acute
appendicitis
■ Gliomatosis presentation is nonspecific

■ Benign clinical course
■ Rarely, carcinomas can arise in association with endometriosis
and malignant degeneration may be seen in patients with

gliomatosis
■ Treatment is same as that for endometriosis (hormonal
FIGURE 8.16 manipulation, lysis of adhesions)
Strong nuclear expression of adenovirus on immunohistochemical staining.
Pathologic Features obstruction of the appendiceal lumen and marked

dilation of the proximal appendix. The latter findings
mimic an appendiceal mucinous neoplasm, especially
Gross Findings when endometriosis is associated with significant
On gross examination, endometriosis appears as hem- subepithelial fibrosis, flattening of the appendiceal
orrhagic areas that may contain cysts filled with brown luminal epithelium, and foci of intestinal metaplasia
fluid. The appearances of deciduosis and gliomatosis are within endometrial glands. Lack of cytologic atypia
less specific; both appear as whitish plaques. within the lining epithelium is helpful in excluding an
appendiceal mucinous neoplasm.
Microscopic Findings Deciduosis is characterized by the presence of nests
and sheets of large polyhedral cells with abundant glassy
Most examples of endometriosis affect the serosa or eosinophilic cytoplasm and bland round to oval nuclei
muscularis propria and are accompanied by abundant (Fig. 8.20). These foci are usually located within in
fibrosis and adhesions. The characteristic histologic the serosa or outer muscularis propria. Such cells can
features include endometrial-type glands and stroma sometimes be mistaken for malignant (often epithelial)
associated with hemosiderin deposition. ( Figs. 8.17 lesions. If deciduosis raises a concern for carcinoma,
and 8.18). The endometrial-type epithelium changes immunohistochemical stains may be performed to aid
with the menstrual cycle. A stromal decidual reac- this distinction. Decidualize cells usually express vimen-
tion may be found in endometriotic foci in pregnant tin but are negative for keratin. They may show desmin
patients. In some instances, there may be prominent or smooth muscle actin positivity.
smooth muscle hyperplasia of the appendiceal wall
(Fig. 8.19). Repeated foci of hemorrhage, fibrosis, and
smooth muscle hyperplasia may result in focal, complete
FIGURE 8.19
FIGURE 8.17 Appendiceal endometriosis with smooth muscular hyperplasia causing com-
plete obliteration of the appendiceal lumen.
Endometriosis. The appendix shows marked thickening of the appendiceal
wall with cystically dilated glands surrounded by cellular stroma within the
muscularis propria.
FIGURE 8.20
Deciduosis. The image shows appendiceal serosa with a nodule composed
FIGURE 8.18 of bland epithelioid or polygonal cells with abundant eosinophilic glassy cyto-
Endometriosis. Higher magnification shows benign endometrial-type glands plasm. Multiple such nodules were identified on the serosal aspect of this
surrounded by endometrial stroma. appendectomy specimen from a 30-year-old pregnant woman.

Endometriosis, Deciduosis, Gliomatosis—Pathologic Features
Gross Findings These processes are benign, but endometriosis of the

■ Endometriosis: hemorrhagic lesions, often with cysts containing appendix is associated with adhesions (just as endome-
brown fluid triosis in general).
■ Deciduosis and gliomatosis: white plaques
■ Endometriosis: endometrial glands and stroma with associated ■ EPITHELIAL NEOPLASMS OF THE
fibrosis and adhesions (usually serosal) APPENDIX (NONENDOCRINE)
■ Deciduosis: large polyhedral cells with glassy eosinophilic
cytoplasm arranged in sheets

■ Gliomatosis: nodules of glial tissue localized to the serosa
The nomenclature and classification of appendiceal
mucinous neoplasms have been subjects of considerable
controversy. This is primarily because of variability in
■ Endometriosis: adenocarcinoma (lacks stroma), appendiceal
mucinous neoplasm (when intestinal metaplasia is present and histologic criteria, sampling, and clinical follow-up across
the appendix is significantly dilated) clinical studies. In an effort to develop a standardized sys-
■ Deciduosis: epithelioid malignant neoplasms (lacks mitoses) tem, the Peritoneal Surface Oncology Group International
■ Gliomatosis: spindle cell neoplasms
(PSOGI) proposed guidelines to report appendiceal neo-
plasms and pseudomyxoma peritonei (PMP) ( Table
8.2). Based on this system, epithelial neoplasms of the
appendix are classified into adenoma, serrated polyp,
low-grade appendiceal mucinous neoplasm (LAMN),
high-grade appendiceal mucinous neoplasm (HAMN),
and invasive adenocarcinoma (mucinous or non-muci-
nous type). The term a denoma has been removed from
Differential Diagnosis the fifth edition of the Digestive System World Health
Organization (WHO) Classification of Tumours but
The appearances of endometriosis, deciduosis, and glio- still remains in use in clinical practice. An algorithmic
matosis are quite characteristic. approach to these lesions is presented in F ig. 8.21.
TABLE 8.2
The Peritoneal Surface Oncology Group International Consensus Classification of Noncarcinoid
Epithelial Neoplasia of the Appendix
Lesion Terminology
Adenoma, resembling traditional colorectal type, confined to the mucosa; Tubular, tubulovillous or villous adenoma, low-grade
muscularis mucosae intact or high-grade dysplasia
Tumor with serrated features, confined to the mucosa; muscularis Serrated polyp with or without dysplasia (low or high
mucosae intact grade)
Mucinous neoplasm with low-grade cytologic atypia and any of Low-grade appendiceal mucinous neoplasm (LAMN)
Loss of muscularis mucosae
Fibrosis of submucosa
“Pushing invasion” (expansile or diverticulum-like growth)
Dissection of acellular mucin in wall
Undulating or flattened epithelial growth
Rupture of appendix
Mucin and/or cells outside appendix
Mucinous neoplasm with the architectural features of LAMN and no High-grade appendiceal mucinous neoplasm (HAMN)
infiltrative invasion but with high-grade cytologic atypia
Mucinous neoplasm with infiltrative invasion (tumor budding and/or Mucinous adenocarcinoma: well, moderately, or
small, irregular glands within a desmoplastic stroma) poorly differentiated
Neoplasm with signet ring cells (≤ 5 0% of cells) Poorly differentiated (mucinous) adenocarcinoma with
signet ring cells
Neoplasm with signet ring cells (> 5 0% of cells) (Mucinous) signet ring cell carcinoma
Nonmucinous adenocarcinoma resembling traditional colorectal type Adenocarcinoma: well, moderately, or poorly
differentiated
Adapted from Carr NJ, Cecil TD, Mohamed F, et al. A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal
neoplasia: the results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. A m J Surg Pathol. 2016;40:14–26.
Algorithmic approach to appendiceal mucinous neoplasms
“Mucocele” (grossly distended appendix filled with mucin)

• Is the specimen completely submitted?
• Is the appendiceal wall intact or perforated?
• Is there visible mucin on the serosal surface?
Serrated epithelium
Yes No
Serrated polyp with Dysplastic epithelium (villiform or flattened)

or without dysplasia • Nuclear hyperchromasia, enlargement, apoptotic activity
Yes No
• Adenoma • Diverticulum
• LAMN • Endometriosis
• HAMN • Retention cyst
• Invasive adenocarcinoma
Obliteration of muscularis mucosae,

lymphoid atrophy, submucosal fibrosis,
dissecting pools of mucin within wall,
undulating/flattened epithelial lining
Yes No
LAMN Adenoma
HAMN
Invasive adenoca
Angulated glands with

stromal desmoplasia
Yes No
Invasive adenocarcinoma LAMN/HAMN with or without

extraappendiceal mucin
(cellular or acellular)
FIGURE 8.21
Algorithmic approach to appendiceal mucinous neoplasms.
ADENOMA
Adenomas that resemble conventional colorectal adenoma
are rare in the appendix. These lesions were formerly
known as mucinous cystadenoma. They are frequently
encountered as incidental findings. Most manifest clinically
with appendicitis related to neoplastic luminal obstruction.
A
ADENOMA—FACT SHEET
Definition
■ Epithelial neoplasm resembling traditional colorectal adenoma

■ Less common than low-grade appendiceal mucinous neoplasm

■ Causes acute appendicitis

■ Males more than females
■ No clear racial difference

B
Clinical Features FIGURE 8.22
■ Most are incidental findings Adenoma of the appendix.
■ Patients may present with acute appendicitis
is intact. This finding is helpful in distinguishing conven-

tional adenomatous lesions from LAMNs. The finding of
■ Complete excision is curative for adenomas
adenomatous change should prompt submission of the
entire appendix to exclude a higher grade lesion.
The descriptive term c ystadenoma was to describe an
Pathologic Features adenomatous lesion that grows and causes cystic dila-
tion of the appendix but shows intact lamina propria.
Gross Findings However, the use of the term mucinous cystadenoma is
no longer recommended by the PSOGI consensus guide-
Gross examination may show features similar to those lines published in 2016. Using the diagnosis of LAMN
found in the colon, including a visible lesion within the in this scenario can result in an unnecessary concern for
mucosa. However, in most instances, these are inciden- subsequent pseudomyxoma in these patients who are
tal lesions found in a dilated appendix. Compared with essentially cured and do not need any future surveillance.
LAMNs and NETs, which are frequently found in the
tip of the appendix, colonic-type adenomas reside at
the appendiceal orifice. The term m ucocele does not
describe a histologic entity but rather a gross finding Adenoma—Pathologic Features
describing a cystically dilated appendix containing
mucin and should be reserved for clinicians, radiolo- Gross Findings
gists, and gross descriptions. Superimposed appendicitis ■ Mucosal thickening or ulceration
■ Rarely has mucocele formation

may be associated with a purulent exudate.
■ Rarely has a polypoid lesion
Microscopic Findings Microscopic Findings

■ Identical to adenomas found in colon
The lesions consist of conventional tubular, tubulovillous,
or villous adenomas with or without high-grade dysplasia, Differential Diagnosis
similar to those encountered in the rest of the colon (Fig. ■ Adenomas should be differentiated from retention cysts and low-
8.22). All of these lesions are restricted to the mucosa; the grade appendiceal mucinous neoplasms
lamina propria is preserved, and the muscularis mucosae
Serrated Polyps of the Appendix—Fact Sheet
Retention cysts also form a dilation of the appendix. Definition

However, although the epithelial lining of a retention ■ Epithelial neoplasm characterized by serrated crypt architecture
cyst is attenuated and not dysplastic, a cause of luminal either focally or diffusely involving the circumference of the
appendiceal lumen
obstruction, such as an incidental well-differentiated
■ Harbor molecular alterations that are differ from their colonic
NET or serosal adhesion, is often found. Simple reten- counterparts (KRAS more common than B RAF )
tion cysts rarely exceed 2 cm in diameter.
■ Rare neoplasm; incidental finding
Prognosis and Therapy Morbidity and Mortality

■ Appendectomy is usually curative
Adenomatous lesions are treated with appendectomy

alone and require no additional follow-up. Colonoscopy
■ No clear gender predilection
should be considered to exclude synchronous colorectal ■ Mean age is the sixth decade
neoplasia.
Clinical Features
■ Patients may present with acute appendicitis
■ SERRATED POLYPS Prognosis and Treatment

■ Complete excision is curative
Serrated epithelial polyps of the appendix show a

spectrum of morphologic features that resemble ser-
rated polyps of the colorectum. The most recent
WHO Digestive System Tumours Classification fur-
ther divides these into hyperplastic polyps (HPs) Pathologic Features
and sessile serrated lesions (SSLs) with and without
dysplasia. For the purpose of the discussion in this Gross Findings
chapter, these two categories are discussed together
as a group. Recent molecular studies have shown Depending on the indication for surgery, the appendix
that serrated lesions of the appendix harbor different may show a completely normal appearance or show con-
mutations compared with their colonic counterparts. gested and edematous appearance. On cut section, there
In particular, a large proportion of appendiceal ser- is only slight luminal dilation. The mucosa may show
rated lesions do not harbor either KRAS or BRAF foci of hemorrhage, and there may be luminal puru-
mutations. When present, harbor KRAS mutations lent material. Mucin or mass formation is generally not
are common, but B RAF are relatively infrequent. present.
Therefore, the PSOGI consensus panel recommends
using a descriptive term serrated polyp with or with-
out dysplasia for serrated lesions of the appendix.
A pathologist may choose to specify the type of
dysplasia as resembling a colorectal adenoma (conven-
tional adenomatous dysplasia) or traditional serrated Serrated nondysplastic polyps resemble conventional
adenoma. HPs or SSLs seen in the colorectum (Fig. 8.23). HPs
are usually smaller in size (<1 cm); SSLs tend to be
larger. Both these lesions may either present as soli-
tary polyps (approximately one-third of cases) or as
diffuse circumferential proliferations (approximately
two-thirds of cases). Cytologic atypia is only present
Serrated appendiceal polyps usually affect older adults within the proliferative compartment of the crypts.
(mean age, 60 years) and do not show any gender pre- The surface epithelium shows an admixture of goblet
dilection. Nearly half of the patients may present with cells, tall columnar cells with or without eosinophilic
signs and symptoms of acute appendicitis. However, cytoplasm.
most are incidentally discovered in resection specimens. Serrated dysplastic polyps often show circumfer-
They are usually not associated with concurrent col- ential involvement of the appendiceal lumen with ser-
orectal neoplasia. rated luminal architecture. Histologically, they show
low- or high-grade cytologic dysplasia that resembles a

conventional adenomatous polyp or traditional serrated
adenoma seen in the colorectum (see C hapter 13).
Serrated Polyps of the Appendix—Pathologic Features
Gross Findings
■ Normal or dilated, cystic appendix, typically without significant
mucin
■ Serrated nondysplastic polyps resemble hyperplastic polyps and
sessile serrated lesions (SSLs) of the colorectum

■ Serrated nondysplastic polyps may either present as solitary,
FIGURE 8.23
discrete polyps (one-third of cases) or occupy the entire
Serrated polyp of the appendix. The specimen shows a lesion composed
circumference of the appendiceal lumen (two-thirds of cases)
of serrated crypts lined by cells with mucinous cytoplasm. In some areas, the
■ Serrated dysplasia polyps show dysplasia resembling conventional
serrations reach the basal aspects of the crypts. This lesion resembles a ses-
adenomatous dysplasia or traditional serrated adenoma of the sile serrated polyp of the colon. Per the Peritoneal Surface Oncology Group
colorectum International Consensus recommendations, these lesions are classified as
serrated polyps with or without dysplasia.
■ Reactive hyperplastic epithelial changes in acute appendicitis
■ Adenoma
■ Low- or high-grade appendiceal mucinous neoplasm
■ Serrated polyps should be distinguished from reactive with cellular extraappendiceal spread, these lesions
hyperplastic epithelial changes that are often encountered often pursue an indolent but progressive clinical course
within mucosa adjacent to an ulcer. Within these areas, the with significant morbidity and mortality. A multitude of
surface epithelium shows luminal serrations, and the individual
cells harbor mild cytologic atypia with or without loss of mucin.
potentially confusing terms and competing classification
Because these cytoarchitectural changes are only present schemes have been used to characterize these lesions,
adjacent to inflamed and ulcerated mucosa, they can be readily including terms such as pseudomyxoma peritonei, dis-
distinguished from hyperplastic or serrated polyps that present as seminated peritoneal adenomucinosis, cystadenoma,
discrete lesions in noninflamed mucosa low-grade appendiceal mucinous neoplasm, mucinous
■ Similar to colonic counterparts, tubular, tubulovillous and villous
adenomas need to be differentiated from serrated dysplastic

borderline tumor of the appendix, mucinous tumor of
polyps with low- or high-grade dysplasia. Dysplasia in this setting uncertain malignant potential, and low-grade mucinous
is usually of the conventional adenomatous type, and a diagnosis carcinoma. The PSOGI consensus guidelines now clas-
of SSL with low or high-grade dysplasia is typically rendered only sify these neoplasms into LAMN and HAMN. By defi-
when cytologic atypia is present in continuity with a nondysplastic nition, these neoplasms are considered mostly low-grade
serrated polyp
■ It is important to distinguish serrated polyps from low- or high-
carcinomas but lack the infiltrative invasion characteris-
grade appendiceal mucinous neoplasms because the latter tic of conventional adenocarcinoma.
are now considered “low-grade carcinoma” per the American
Joint Committee on Cancer staging system and have their own
staging system. The key distinguishing feature of serrated polyps
is that these proliferations are confined to the mucosa and show ■ CLINICAL FEATURES
intact muscularis mucosae. Appendiceal mucinous neoplasms
are characterized by loss of muscularis mucosae, submucosal
fibrosis with or without expansile growth pattern, and dissection Mucinous neoplasms are detected in only 0.3% of sur-
of acellular mucin within the appendiceal wall. Furthermore, gically removed appendices but account for nearly one-
true villi and copious amounts of cytoplasmic mucin is generally a third of all appendiceal epithelial tumors. Patients may
feature of appendiceal mucinous neoplasms rather than serrated
polyps
present with symptoms of acute appendicitis, obstruc-
tion, or a palpable mass. Intussusception into the colon
is a rare but well-recognized complication of appendi-
ceal m
ucocele. Patients late in the disease process may
■ LOW-AND HIGH-GRADE APPENDICEAL present with pseudomyxoma peritonei (meaning false
MUCINOUS NEOPLASMS mucinous tumor of the peritoneum), a term that should
be reserved for the clinical syndrome in which patients
experience slowly increasing abdominal girth caused
Appendiceal mucinous neoplasms are a group of epi- by mucinous ascites resulting from prior “mucocele”
thelial neoplasms that demonstrate banal cytoarchitec- rupture or transmural extension. The abdominal
tural features but are associated with extraappendiceal cavity relentlessly fills with mucin produced by the neo-
spread in a minor subset of cases. In perforated lesions plastic cells.
When a m ucocele-like gross appearance is encoun-

LOW-AND HIGH-GRADE APPENDICEAL MUCINOUS tered, it is extremely important to determine whether
NEOPLASMS—FACT SHEET the wall of the appendix is intact or disrupted (Fig. 8.24).
A gross assessment of the appendix at the time of
Definition surgery and at the grossing bench is essential. Proper
■ Epithelial neoplasm usually demonstrating low- or high-grade
surgical management of the m ucocele is essential because
mucinous morphology but associated with extraappendiceal
spread
iatrogenic rupture of the LAMN may lead to pelvic or
peritoneal dissemination.
■ Rare neoplasm (0.3% of appendectomies) Microscopic Findings
■ Outnumbers colonic-type epithelial neoplasms in appendix by
9 to 1 Peritoneal Surface Oncology Group International con-

sensus guidelines classify appendiceal mucinous neo-
plasms as LAMN or HAMN. Both LAMN and HAMN
■ Peritoneal spread leads to clinical syndrome of pseudomyxoma
peritonei
frequently show effacement of the lamina propria with
■ Spread to ovaries can cause confusion regarding primary site of obliteration of the muscularis mucosae and submuco-
peritoneal disease sal fibrosis. There is decreased lymphoid tissue, and the
■ Spread is usually via direct extension and infrequently by appendiceal wall is fibrotic and can even be hyalinized.
lymphatic or hematogenous routes Low-grade appendiceal mucinous neoplasms are
composed of a villous, undulating, or flat proliferation
of mucinous epithelium that shows circumferential
■ Females more than males

involvement of the dilated appendiceal lumen. The epi-
■ Mean age sixth decade thelial cells show uniform, hyperchromatic, stratified
nuclei with only mild nuclear enlargement. Nucleoli are
Clinical Features usually inconspicuous, and nuclear polarity is preserved
■ Patients present with acute appendicitis, obstruction, palpable (Figs. 8.25 and 8.26). The cells show abundant intra-
mass, and intussusception cytoplasmic mucin. Regardless of the overall growth
■ Mucinous ascites (pseudomyxoma peritonei) is a late,
uncommon finding
pattern (villous, undulating, or flat), the cells are gener-
ally arranged in a monolayer.
Prognosis and Treatment High-grade appendiceal mucinous neoplasms have
■ Patients with periappendiceal spread of acellular mucin have an cytoarchitectural atypia in the form of markedly hyper-
excellent prognosis chromatic and enlarged nuclei, prominent nucleoli, loss
■ Patients with periappendiceal spread of mucin with neoplastic
of nuclear polarity, numerous or atypical mitotic figures,
cells (even if paucicellular) are more likely to develop mucinous
and cribriform or micropapillary growth patterns.
ascites
■ Complete excision of a confined appendiceal neoplasm is
The dilation of the appendix causes weakness of
curative; hemicolectomy is not recommended the muscular wall, leading to extension of neoplastic
■ Follow-up includes regular computed tomography and tumor epithelium into the appendiceal wall. This may occur
marker evaluation in two forms: (1) pushing invasion characterized by
■ After peritoneal spread, aggressive surgical debulking
tongue-like protrusions, diverticulum-like structures or
(cytoreduction) and hyperthermic chemotherapy are treatments
of choice broad-based extensions of epithelium and (2) dissecting
Pathologic Features
Gross Findings
On gross examination, the appendix is often dilated or

cystic with tenacious mucin in the lumen. The wall is
thick and fibrotic, sometimes with mural calcification
(“porcelain appendix”). The term m ucocele is used to FIGURE 8.24
describe the gross and clinical appearance of a dilated, Low-grade appendiceal mucinous neoplasm. The appendectomy specimen
shows glistening mucin confined to the lumen (the appendix has been opened
mucin-filled appendix but does not indicate whether the longitudinally). The serosal surface appears to be uninvolved by this process.
histologic appearance is benign or malignant. Clinically, a dilated appendix containing mucin is referred to as a mucocele.

Low-grade appendiceal mucinous neoplasm. A representative section of the Low-grade appendiceal mucinous neoplasm with acellular mucin dissecting
dilated lumen shows an undulated epithelial lining composed of cells with through the muscularis propria.
stratified and hyperchromatic nuclei. There are fibrosis of the lamina propria
and obliteration of the muscularis mucosae. The rest of the wall appears
unremarkable.

Low-grade appendiceal mucinous neoplasm. Higher magnification shows Extraappendiceal mucin in a case of low-grade appendiceal mucinous neo-
cells with enlarged, hyperchromatic, and stratified nuclei with maintained plasm. This finding should be distinguished from artifactual “carry-over”
nuclear polarity consistent with low-grade dysplasia. Most of the cells still contamination from tissue sectioning or processing. To qualify as extraap-
retain their mucinous cytoplasm. pendiceal mucin, the mucinous deposits should be located beyond the
muscular wall of the appendix and should be associated with a granulation
tissue–like response or neovascularization.
pools of acellular mucin through the appendiceal wall
(Fig. 8.27). Both these processes of epithelial extension
can lead to intraperitoneal spread either through direct
rupture with or without concurrent appendicitis. (AJCC) staging system for LAMNs. LAMN or HAMNs
Rupture or extraappendiceal spread of mucin may be that extend only up to the muscularis propria are staged
localized to the periappendiceal area. This periappen- as pTis (LAMN), regardless of whether the extension
diceal spread may contain mucin that is acellular is merely acellular mucin or contains mucinous epithe-
(Fig. 8.28) or cellular, harboring strips or clusters of neo- lium. T1 and T2 stages are not applicable to LAMN or
plastic epithelia. Because patients with acellular mucin HAMN. Acellular mucin or mucinous epithelium that
have an excellent prognosis, it is critical to accurately extends into the subserosa or serosa should be classified
assess the presence or absence of epithelial elements. as T3 or T4a, respectively.
Microscopic examination of the entire appendix as well
as all of the periappendiceal mucin is necessary because
lesions with cellular extraappendiceal mucin are more
likely to progress to disseminated disease and result in
the death of the patient, even if the mucin is paucicellu-
lar and confined to the periappendiceal region. The differential diagnosis for appendiceal mucinous
Appendiceal mucinous neoplasms are now staged neoplasms, especially LAMN, include adenoma and
according to the American Joint Committee on Cancer invasive mucinous adenocarcinoma as well as a variety
of non-neoplastic entities such as retention cyst, appen- Appendiceal diverticular disease can be associ-
dicitis and diverticulitis with mucin extravasation, and ated with mild cytologic atypia, hyperplastic epithelial
endometriosis with intestinal metaplasia. changes, and extravasation of mucin within the appen-
It is important to distinguish LAMN from an ade- diceal wall or into the periappendiceal tissue. In well-ori-
noma because LAMNs now need to be staged in the ented sections, one may see two distinct lumens or even
AJCC eighth edition. Whereas adenomas (tubular, tubu- multiple luminal profiles with intact mucosal archi-
lovillous, or villous) are usually confined to the mucosa tecture that suggest diverticular disease. Similar to the
and do not show gross luminal dilation, LAMNs are colon, an attenuated muscularis propria may be present
characteristically associated with dilated lumen that is as well. Diverticular disease usually lacks villous archi-
filled with copious amounts of mucin. Histologically, tecture, effacement of lamina propria, crowded crypts,
adenomas retain muscularis mucosae as well as lym- and cytologic dysplasia that are typically associated with
phoid tissue, but LAMNs by definition show oblitera- LAMN.
tion of the lamina propria, muscularis mucosae, and Rarely, endometriosis with intestinal metaplasia may
submucosal fibrosis or hyalinization. be associated with dissecting acellular mucin and mimic
Pushing type or broad-based invasion can mimic LAMN. In most instances, endometriosis is readily
invasive mucinous adenocarcinoma. However, the pat- recognized by the presence of endometrial stroma sur-
tern of invasion is key in differentiating these entities. rounding these glands.
Invasive adenocarcinoma is diagnosed only on the basis
of an infiltrative pattern of invasion in which the glands
show angulated profiles or tumor budding and are sur-
rounded by stromal desmoplasia. The pushing invasion
of LAMNs or HAMNs is usually associated with fibro-
sis or hyalinization that is dense and paucicellular com-
pared to stromal desmoplasia.
Retention cyst of the appendix can show marked
dilation of the lumen and can present as a mucocele.
Retention cysts are rare and are generally smaller than
2 cm in diameter. Lack of atypia within this epithelial
lining as well as presence of intact muscularis mucosae
supports a diagnosis of retention cyst rather than LAMN
(Figs. 8.29–8.31). Distinguishing these from LAMN can
be particularly challenging in cases that show extensive
denudation and ulceration of the epithelial lining. If the
entire appendix has been sampled and there is no evi-
dence of a neoplasm, the possibility of a retention cyst
FIGURE 8.30
should be considered.
Retention cyst of the appendix. A representative section of the appendiceal
wall shows flattened epithelial lining without cytologic atypia. The underly-
ing lamina propria is somewhat fibrotic. However, the muscularis mucosae
is intact.

Retention cyst of the appendix. The specimen shows cystically dilated Retention cyst of the appendix. Desmin immunohistochemical stain high-
appendiceal lumen. Grossly, the lumen shows abundant mucin. lights the intact muscularis mucosae.
does not seem to result in recurrent disease based on

Appendiceal Mucinous Neoplasm—Pathologic Features limited data. Residual tumor has been documented in
follow-up resection specimens and reported to be associ-
Gross Findings ated with poor disease-free survival.
■ Dilated, cystic appendix filled with mucin The PSOGI consensus guidelines do not recommend
■ Thickened wall, sometimes with mural calcification (porcelain
routine right hemicolectomy for LAMN because these
appendix)
neoplasms usually do not show lymph node involve-
■ Status of intact vs ruptured appendix is critical to patient
outcome ment. Furthermore, there is always a potential that

subsequent treatment consisting of peritonectomy and
Microscopic Findings heated intraperitoneal chemotherapy (HIPEC) may
■ Mucinous neoplasm with no invasion but with any of the not reach the extraappendiceal neoplastic cells that are
following features: embedded in scar tissue from previous surgery. Thus,
■ Loss of muscularis mucosae
patients diagnosed with LAMN or HAMN must be fol-
■ Fibrosis of submucosa
■ Expansile or diverticulum-like growth

lowed to exclude development of PMP. The risk of PMP
■ Dissection of acellular mucin in wall is low when the lesion is confined to the appendix and
■ Undulating or flattened epithelial growth there is no extraappendiceal mucin. However, there is a
■ Rupture of appendix small risk in patients with acellular mucin and a signifi-
■ Mucin and/or cells outside appendix
cant risk in those with cellular extraappendiceal mucin.
■ Low-grade appendiceal mucinous neoplasm: epithelial lining
composed of low-grade cytologic atypia: hyperchromasia,

Per PSOGI guidelines, the follow-up schedule for LAMN
stratification of nuclei, no architectural complexity includes abdominopelvic CT scans and tumor markers
■ High-grade appendiceal mucinous neoplasm shows at 1 year, annually at first, and then with decreasing
severe cytologic abnormalities: loss of nuclear polarity, frequency over time. If there is no evidence of cells or
prominent nucleoli, complex cribriform and papillary mucin beyond the appendix, a 5- to 10-year follow-up is
architecture
■ Extension of mucin outside of appendix may be acellular or have
considered appropriate.
strips, clusters, or single epithelial cells Aggressive surgical debulking for mucinous-type
■ Involvement of peritoneum may be acellular or show cells with tumors improves survival rate and reduces recurrence
low- or high-grade morphology rates in patients with generalized PMP compared with
simple appendectomy. Intraperitoneal hyperthermic
■ Adenoma of colonic type (tubular, tubulovillous or villous)
■ Invasive adenocarcinoma
■ Retention cyst APPENDICEAL ADENOCARCINOMA—FACT SHEET

■ Diverticular disease
■ Endometriosis
Definition
■ Neoplastic proliferation of epithelium characterized by angulated,
atypical glands showing an infiltrative growth pattern and

surrounded by stromal desmoplastic response
Prognosis and Therapy Incidence and Location
■ 0.97 per 100,000 population
Gross examination of the appendix at the time of appen- Morbidity and Mortality
dectomy and an assessment of the size of the mucocele ■ Related to depth of invasion and nodal stage
cannot determine whether the m ucocele is benign or ■ May be associated with peritoneal implants or pseudomyxoma
malignant. The prudent surgical approach is to regard peritonei
every m ucocele of the appendix as potentially malignant.
This means that special care in the resection of an appen- Gender, Race, and Age Distribution
■ Females more than males
diceal m ucocele must occur to avoid trauma and possi-
ble rupture of the appendix as it is removed. Often, this
■ Peak age of incidence in the sixth decade of life
means conversion of a laparoscopic appendectomy to an
open laparotomy. Clinical Features
Unfortunately, there is a paucity of evidence-based ■ Abdominal mass, acute appendicitis, or diffuse enlargement of
literature regarding appropriate clinical management abdominal girth caused by pseudomyxoma peritonei
and surveillance of appendiceal mucinous neoplasms
that are confined to the appendix. It is important to Prognosis and Treatment
■ Right hemicolectomy with lymph node dissection
sample all of the appendiceal tissue and periappendiceal
■ Treated similar to colonic adenocarcinoma
mucin to provide accurate information for predicting
■ If evidence of peritoneal implants or pseudomyxoma peritonei,
clinical behavior of these lesions. Involvement of the cytoreductive therapy with heated intraperitoneal chemotherapy
proximal margin by appendiceal mucinous neoplasm
chemotherapy after cytoreduction of tumor bulk is the Pathologic Features

current standard of treatment for patients with peritoneal
spread.
Gross Findings
Appendiceal Adenocarcinoma Grossly, the appendix is enlarged and may show pres-
ence of extraappendiceal mucin. Cut section often
Adenocarcinomas of the appendix are defined by reveals extensive luminal mucin, a thickened appendi-
the presence of infiltrative invasion and desmoplas- ceal wall with or without a distinct mass.
tic stromal response. They are categorized into muci-
nous or nonmucinous type. Similar to their colonic Microscopic Findings
counterparts, mucinous adenocarcinomas are defined
as malignant tumors in which more than 50% of the Similar to colorectal adenocarcinomas, adenocarci-
cross-sectional area of the lesion is composed of extra- nomas of the appendix show an infiltrative pattern of
cellular mucin. invasion characterized by angulated atypical glands sur-
rounded by desmoplastic stromal response (Fig. 8.32).
These changes may be accompanied by foci of tumor
budding or single cell infiltration.
If more than 50% of the neoplastic cells show sig-
net ring cell morphology, the tumor should be classi-
The incidence of appendiceal adenocarcinoma has fied as signet ring cell carcinoma. The nonmucinous
gradually increased since the year 2000, such that the adenocarcinomas are classified similar to colorectal
reported incidence in year 2009 was 0.97 per 100,000
population. Women are more commonly affected
than men, and the peak age of incidence is during the
sixth decade of life. Patients may present with signs
and symptoms of acute appendicitis, obstruction, or
palpable mass or with a diffuse increase in abdominal
girth.
Appendiceal Adenocarcinoma—Pathologic Features
Gross Findings
■ Dilated appendix with mucin
■ Circumferential thickening with or without a distinct mass

A
■ Infiltrative invasion characterized by angulated, atypical glands
surrounded by stromal desmoplasia

■ Tumor budding or single-cell infiltration may be present
■ Two subtypes: mucinous and nonmucinous adenocarcinoma
■ Mucinous adenocarcinoma
■ >50% of cross-sectional area contains extracellular mucin
■ Signet ring cell carcinoma: if more than 50% of tumor is
composed of signet ring cells

■ Often associated with serrated polyps, low-grade
appendiceal mucinous neoplasms (LAMNs) or high-grade

appendiceal mucinous neoplasms (HAMNs)
■ Nonmucinous adenocarcinoma
■ Shows morphologic features that are similar to colonic
counterparts B
■ Often associated with an adenomatous precursor
FIGURE 8.32
Differential Diagnosis Invasive adenocarcinoma of the appendix. A , An invasive adenocarcinoma
■ LAMN or HAMN
B, Higher
infiltrating transmurally into the periappendiceal adipose tissue.
magnification of the neoplastic glands. Similar to conventional colonic ade-
■ Diverticular disease
nocarcinoma, the neoplastic glands show angulated, infiltrative profiles and
are surrounded by desmoplastic stroma.
adenocarcinomas. They are more likely to be associated PMP are appendiceal in origin. Rarely, mucinous neo-
with an adenomatous precursor, but mucinous adeno- plasms originating from the colon, ovary, pancreas, and
carcinomas usually arise in a background of serrated urachus may result in PMP. Based on multiple studies,
polyps, and rarely LAMNs or HAMNs. we now know that primary mucinous neoplasms of the
ovary are not the most common source of PMP. In fact,
patients with borderline mucinous tumors or mucinous
adenocarcinoma of the ovary either do not progress or
tend to follow a course that is similar to conventional
adenocarcinoma rather than PMP. Therefore, it is
The differential diagnosis includes appendiceal muci- extremely important to sample the appendix completely
nous neoplasms and diverticular disease. Mucinous even if the appendix appears grossly unremarkable.
adenocarcinomas can be difficult to distinguish from The diagnostic criteria and classification of intraab-
LAMNs. In contrast to invasive adenocarcinoma, which dominal mucin and PMP proposed by PSOGI are out-
at least focally shows infiltrative and angulated glandu- lined in Table 8.3. Histologically, the neoplastic cells
lar contours with stromal desmoplasia, the advancing may be extremely scant within abundant mucinous
edge of LAMNs is associated with paucicellular hyaline material (Figs. 8.33 and 8.34). Extensive sampling may
stroma. be required to demonstrate them.
Diverticular disease can be associated with dissect- Low-grade mucinous carcinoma typically has a
ing pools of mucin and thus mimic invasive adenocarci- scant epithelial component, arranged in strips or rare
noma. However, lack of cytologic atypia, preservation of gland-like structures. Cytologic atypia is mild, and
the mucosal architecture, lack of an infiltrative glandu- cells may appear really bland. High-grade lesions show
lar pattern, or stromal desmoplasia supports diverticular increased cellularity and cytologic atypia characterized
disease-related changes rather than invasive mucinous by enlarged, vesicular nuclei with prominent nucleoli,
adenocarcinoma. loss of nuclear polarity, and cribriform growth pattern.
Last, poorly differentiated adenocarcinoma may raise Destructive invasion of underlying or adjacent organs
the possibility of undifferentiated carcinoma. As in is also a feature of high-grade disease. Tumors that
other sites of the GI tract, undifferentiated carcinomas contain signet ring cells should be classified separately
lack any glandular, squamous, or neuroendocrine differ- from other high-grade lesions because they have a worse
entiation and can also rarely occur in the appendix. prognosis.
Right hemicolectomy with lymph node dissection is the TABLE 8.3

treatment of choice. In general, the treatment is similar The Peritoneal Surface Oncology Group
to that of colonic adenocarcinoma. If there is evidence of International Consensus Classification of
peritoneal implants or PMP, cytoreductive therapy with Pseudomyxoma Peritonei (PMP; Peritoneal
HIPEC is indicated. Disease Component)
Lesion Terminology
Mucin without Acellular mucin

Pseudomyxoma Peritonei epithelial cells
PMP with low- Low-grade mucinous carcinoma peri-
grade histologic tonei o
r
Pseudomyxoma peritonei is not a histologic term and features Disseminated peritoneal adenomuci-
is used to describe a clinical syndrome characterized nosis (DPAM)
by development of mucinous ascites and peritoneal PMP with high- High-grade mucinous carcinoma
grade histologic peritonei o
r
implants. Underlying this phenomenon is invariably a features Peritoneal mucinous carcinomatosis
ruptured appendiceal mucinous neoplasm with perito- (PMCA)
neal spread or mucinous adenocarcinoma arising from PMP with signet High-grade mucinous carcinoma peri-
the appendix. Mucin usually accumulates within the ring cells tonei with signet ring cells o
r
pelvis, paracolic gutters, liver capsule, and omentum. Peritoneal mucinous carcinomatosis
with signet ring cells (PMCA-S)
The ovaries may show involvement by low- or high-
grade lesions and often appear as multiloculated masses. Adapted f rom Carr NJ, Cecil TD, Mohamed F, et al. A consensus for classification
and pathologic reporting of pseudomyxoma peritonei and associated
The reported incidence is 0.2 per 100,000 per year. appendiceal neoplasia: the results of the Peritoneal Surface Oncology Group
Patients present with abdominal distension or symp- International (PSOGI) Modified Delphi Process. A m J Surg Pathol. 2016;40:
toms related to intestinal obstruction. Most cases of 14–26.
A A
B B
FIGURE 8.34
Another patient with pseudomyxoma peritonei. A, Sampling of the perito-
neal cavity shows clusters of epithelial cells in abundant mucin. B, A high-
power view of sample in A shows high-grade cytology with loss of polarity,
high nuclear-to-cytoplasmic ratio, and pleomorphism. Patients with this
unfavorable histology have a significantly worse prognosis. These lesions are
referred to as peritoneal mucinous carcinomatosis or high-grade mucinous
carcinoma peritonei.
Based on the eighth edition classification for appen-

diceal adenocarcinomas and LAMNs, in cases in which
an appendectomy shows a mucinous neoplasm that has
ruptured with extraappendiceal cells and mucin, the
term P MP should only be used if there is evidence of
C spread beyond the right lower quadrant of the abdomen.
Histological grade is a component of the TNM classifi-
FIGURE 8.33 cation of stage IV appendiceal neoplasms without nodal
A patient with clinical pseudomyxoma peritonei syndrome. A , Examination metastasis.
of the appendix shows a low-grade appendiceal mucinous neoplasm with
rupture and extraappendiceal spread of tumor cells. B , A sample from the Because of prognostic implications, it is prudent for
peritoneum shows abundant mucin with free-floating clusters of epithelial the pathologist to indicate whether the lesional cells
cells, which can be called d iffuse peritoneal adenomucinosis or low-grade have histology that correlates with an aggressive or
mucinous carcinoma peritonei. C , On high power, the epithelial cells have
low-grade cytology and are identical to the mucinous neoplasm found in the an indolent clinical course and whether the mucin is
appendix. acellular or cellular. The initial treatment of choice is
surgical debulking for symptomatic disease. This treat-

ment is not curative but aims to resect gross disease to NEUROENDOCRINE TUMORS OF THE APPENDIX—FACT
limit the accumulation of abdominal mucin and prevent SHEET
the ensuing complications. A more aggressive approach
includes radical resection of all intraabdominal and pel- Definition
■ A neuroendocrine tumor showing enterochromaffin cell or L-cell
vic disease and the administration of HIPEC. However,
differentiation
despite this radical therapy, the penetration of HIPEC
into tumor tissue is limited to a maximum depth of Incidence and Location
1 to 2 mm. The outcome of this therapy depends on ■ Most frequent tumor of the appendix, occurring in 0.2% to 1.8%
completeness of cytoreduction, the histopathology of of all appendectomy specimens
the appendiceal malignancy, and the extent of previous
surgical interventions. Studies have shown that whereas Morbidity and Mortality
patients who underwent complete cytoreduction for ■ Metastasis is rare, usually to regional nodes
■ Hematogenous spread is exceptional

PMP with low-grade histologic features had a 5-year sur-
vival rate of 86%, those with higher grade features had a
5-year survival rate of 50%.
■ Females more than males (2:1 ratio)
■ Can occur at any age; peak incidence in young adults; mean age
is 42 years
NEUROENDOCRINE TUMORS OF THE Clinical Features

APPENDIX ■ Most are incidental findings
■ Often occurs in children and have excellent long-term outcomes
■ Carcinoid syndrome is very rare and is associated with metastatic
liver disease
The pathogenesis of appendiceal NETs is unknown.
The majority show either enterochromaffin (EC) or Prognosis and Treatment
L-cell differentiation. Similar to the rest of the GI tract, ■ Complete excision is curative
■ Incomplete resection or tumors larger than 2 cm should be

NETs of the appendix are graded based on mitotic activ-
staged with computed tomography or magnetic resonance
ity and Ki-67 index.
imaging. If no distant disease is identified, reexploration with right
hemicolectomy is performed
Neuroendocrine tumors can be found throughout the GI

tract and are detected in 1.8% of all appendectomies. Pathologic Features
The appendix follows small intestine (41.8%) and rec-
tum (27.4%) in frequency. Well-differentiated NETs
comprise 75% of all neoplasms found in the appendix. Gross Findings
Patients tend to be much younger compared with those
diagnosed with other appendiceal neoplasms or NETs The majority of appendiceal NETs are localized to the
at other sites—approximately 20 years younger than tip of appendix at the time of diagnosis. Therefore, it
for NETs from other sites. These tumors occur more is a common protocol to bisect and sample the tip of
often in women, with a male-to-female ratio of 1 to 2. the appendix in its entirety. The majority of the lesions
Appendiceal NETs are also the most common GI neo- are smaller than 1 cm in diameter. They are round or
plasm in childhood. It is unclear whether these demo- oval and sometimes palpable. The cut surface is tan to
graphic data represent the actual distribution of tumor yellow.
or the age range of the population that typically under-
goes appendectomy for inflammatory appendicitis or Microscopic Findings
incidental appendectomy during pelvic surgery for other
reasons. Neuroendocrine tumors of the appendix are morpho-
The most common clinical presentation is that of logically similar to their small intestinal and rectal
an incidental nodule detected at the time of appendec- counterparts (Fig. 8.35). They are characterized by a
tomy for presumed appendicitis. Others may be found monotonous proliferation of uniform cells with a mod-
incidentally during laparotomy or at autopsy. Rarely, erate amount of eosinophilic to amphophilic cytoplasm.
patients present with an abdominal mass, pain, or the Nuclei are round with inconspicuous nucleoli and finely
carcinoid syndrome. stippled chromatin (“salt and pepper” chromatin).
Pleomorphism and mitoses are rare. Morphologic fea- available for review.
tures of the cells do not differ by cell of origin. NETs Similar to rest of the NET in the GI tract, the College
demonstrate variable architectural growth patterns of American Pathologists recommends the following
including nested (insular), trabecular, acinar, and tubu- grading system for well-differentiated NETs:
lar (Fig. 8.36). Trabecular and glandular growth pat-
terns are more common in L-cell NETs. These tumors • Well-differentiated NET (grade 1): mitotic rate, less
usually secrete proglucagon-related peptides such as glu- than 2 per 2 mm2 and/or Ki-67 index less than 3%
cagon-like peptide 1. EC cell NETs may show S-100 pos-
itive sustentacular-like cells. These patterns do not have
prognostic significance. The stroma can range from del-
icate and vascular to dense and fibrous. The vast major-
ity of NETs are diffusely positive for chromogranin and
synaptophysin, as well as CD56 (Fig. 8.37). However,
per recent National Comprehensive Cancer Network
guidelines, these ancillary stains are not required to
diagnose NETs when sufficient histologic material is
FIGURE 8.37
Well-differentiated neuroendocrine tumor with strong, diffuse chromogranin
immunoreactivity.
Neuroendocrine Tumors of the Appendix—Pathologic

Features
FIGURE 8.35
Well-differentiated neuroendocrine tumor. The neoplasm is composed of
Gross Findings
nested of uniform cells with round to oval nuclei and a distinct stippled or
“salt and pepper” chromatin pattern. ■ Round or oval lesion usually found at the tip of the appendix
■ Most are smaller than 1 cm in diameter
■ Cut surface is gray or yellow
■ Nested and insular pattern, sometimes with acinar or tubular
structures
■ Cells are uniform, round to polygonal
■ Nuclei are round with inconspicuous nucleoli and speckled
chromatin
■ Eosinophilic or amphophilic cytoplasm may contain small
granules
■ Variants include tubular or clear cell neuroendocrine tumor
■ Grading is performed based on mitotic activity (per 10 hpf) and
Ki-67 index (per College of American Pathologists guidelines)

■ Grade 1 (well-differentiated NET): < 2 mitoses/10 hpf and/or
<3% Ki-67 index
■ Grade 2 (well-differentiated NET): 2–20 mitoses/10 hpf and/
or 3%–20% Ki-67 index

■ Grade 3 (well-differentiated NET): > 20 mitoses/10 hpf and/or
>20% Ki-67 index

■ Goblet cell adenocarcinoma
Tubular pattern of neuroendocrine tumor (NET). As the name indicates, this
variant of NET is composed of small acini or tubules of neuroendocrine cells ■ Adenocarcinoma
within a loose stroma.

• Well-differentiated NET (grade 2): mitotic rate, 2 to ■ GOBLET CELL ADENOCARCINOMA

20 per mm2 and/or Ki-67 index, 3% to 20%
• Well-differentiated NET (grade 3): mitotic rate,
greater than 20 per 2 mm2 and/or Ki-67 index greater Appendiceal GCA (formerly known as goblet cell carci-
than 20% noid and adenocarcinoma ex goblet cell carcinoid) was
first recognized as a distinct entity in 1969 and remains
Poorly differentiated neuroendocrine carcinomas a rare appendiceal neoplasm with uncertain histogene-
(large cell and small cell type) are now staged as colorec- sis. These infiltrative tumors have a mixed phenotype,
tal carcinomas. Mixed adenocarcinoma-large (or small) with partial neuroendocrine differentiation and intes-
cell neuroendocrine carcinomas are rare and reminis- tinal-type goblet cell morphology. As such, they have
cent of their colonic counterparts. been classified in the past with other neoplasms that
show both neuroendocrine and glandular differentia-
tion as a denocarcinoid tumors, a term that encompasses
biologically diverse neoplasms such as tubular pattern
NET and a collision tumor of typical NET with a de
novo adenocarcinoma. The term a denocarcinoid is no
Most cases of NETs do not pose any diagnostic prob- longer used by the WHO and is termed goblet cell adeno-
lem. Goblet cell adenocarcinoma (GCA) remains in the carcinoma and graded as low or high, recognizing that
differential diagnosis because of its appendiceal origin both goblet cell carcinoid and adenocarcinoma ex goblet
and reactivity to synaptophysin and chromogranin. cell carcinoid are part of the same spectrum of tumors
However, GCAs have well-defined goblet cells with and not two separate histologic types. Distinguishing
eccentric nuclei that are displaced and compressed by GCA from these other entities is important because the
cytoplasmic mucin, which is not present in appendiceal clinical characteristics and prognoses are distinct. In
neuroendocrine neoplasms. The cytoplasmic mucin can the past, GCA has also been proposed as crypt cell car-
be demonstrated with a mucicarmine or Alcian blue cinoma, mucinous carcinoid, microglandular carcinoid,
stain. Neuroendocrine neoplasms with a predominantly or amphicrine carcinoma to distinguish the entity from
tubular architecture may mimic an adenocarcinoma. classical NET tumor of the appendix.
However, the presence of more conventional foci of
invasive adenocarcinoma is helpful in distinguishing it
form NET.
Goblet cell adenocarcinomas occur in adults, with a

mean age of 50 years. There is a female predominance
with a male-to-female ratio of about 1 to 2. The most
The prognosis for patients with well-differentiated common clinical presentation is abdominal pain and
appendiceal NETs is better than that for those in all a palpable mass (50%). Other patients present with
other anatomic sites and demonstrates a 5-year survival symptoms related to acute appendicitis, and only 3%
rate greater than 95%. Clinical behavior and prognosis of patients are diagnosed incidentally. Patients with
are best predicted by tumor size. Tumors smaller than advanced disease most frequently present with abdom-
2 cm (found in ∼ 95% of patients) are unlikely to have inal masses. In female patients with stage IV disease,
metastasized, but up to one-third of larger lesions are 83% present with ovarian masses and a presumptive
metastatic at diagnosis, usually to regional nodes rather diagnosis of a primary ovarian neoplasm. Overall, fewer
than to the liver. than 1% of patients have a preoperative diagnosis of a
Treatment by appendectomy is curative in most primary appendiceal tumor.
cases, particularly for tumors smaller than 2 cm in
greatest dimension that are confined to the appendix Pathologic Features
because metastasis is very uncommon in these patients.
However, some controversy exists regarding the man-
agement of appendiceal NETs measuring less than 2 cm Gross Findings
with more aggressive histologic features. Patients with
an incomplete resection or tumors larger than 2 cm are The appendix in patients with GCA can appear grossly
at risk for locoregional or distant metastases. These unremarkable. A discrete nodule or mass is only rarely
patients should be staged with abdominal or pelvic CT identified. Because of the circumferential pattern of
or magnetic resonance imaging with contrast. If no dis- involvement, there may be some thickening of the wall.
tant disease is identified, they should undergo reexplora- Most tumors are larger than 2 cm in size (representing
tion with right hemicolectomy. length of tumor extension rather than diameter).
GOBLET CELL ADENOCARCINOMA—FACT SHEET
Definition
■ Appendiceal tumor with mixed phenotype: partial neuroendocrine
differentiation and intestinal-type goblet cell morphology of

uncertain histogenesis

■ Rare; essentially exclusive to the appendix

■ Metastatic spread is present in more than half of patients at time
of presentation (peritoneum, omentum, ovaries)

■ Commonly has direct extension into the right colon
■ Lymph node metastasis is present in more than one-third of
cases

■ Females more than males (2:1 ratio)
■ Occurs in adults; mean age is 50 years

■ Nearly 50% patients present with abdominal pain and a palpable Goblet cell adenocarcinoma. Low-power view of the appendix emphasizes
mass the subtle, concentric infiltrating pattern of this tumor.
■ Forty percent present with acute appendicitis symptoms
■ Fewer than 5% are incidental

■ Prognosis is related to tumor stage at presentation and histologic
grade
■ Nearly 95% of patients have transmural invasion at the time of
diagnosis
■ Surgical resection is the most effective treatment for early-stage
disease
■ Advanced disease and peritoneal spread may require additional
debulking, oophorectomy, and intraperitoneal chemotherapy
Microscopic Findings A
Goblet cell adenocarcinomas arise without a recogniz-

able precursor lesion. These tumors infiltrate in a con-
centric manner with small clusters, linear rows, or single
cells that can be difficult to appreciate on low-power
examination (Fig. 8.38). They usually appear to be most
prominent along the deep aspect of lamina propria and
submucosa and display a wide range of histologic pat-
terns. For a lesion to be classified as a GCA, the tumor
must demonstrate a component of classic low-grade
GCA characterized by tubules composed of goblet-like
mucinous cells, variable numbers of endocrine cells,
and Paneth cells. There is minimal cytologic atypia, and B
mitoses are infrequent (Fig. 8.39). Some lesions may
FIGURE 8.39
show extensive extracellular mucin.
Goblet cell adenocarcinoma with low-grade features A, Well-defined goblet
High-grade histologic features include complex anas- cells are arranged in tight clusters. B
, The cells may also show a cohesive
tomosing tubules, tumor infiltrating as single mucinous linear pattern with minimal atypia and no desmoplasia.
B
FIGURE 8.40
Goblet cell adenocarcinoma with high-grade features A, The neoplastic
goblet cells or signet ring cells are arranged in irregular, large, disorganized
clusters that have lost cohesion. B , The individual cells show a discohesive
growth pattern and infiltrate as single atypical cells. B
FIGURE 8.41
Goblet cell adenocarcinoma with high-grade features. A, The poorly differen-
tiated tumor cells are present in the form of a mucinous adenocarcinoma.
The left half of the image shows well-formed clusters of goblet cells B , An
example of an undifferentiated carcinoma arising from a goblet cell carcinoid.
Although this area does not demonstrate signet ring or goblet cell features,
other areas of the same tumor had focal goblet cell morphology.
or nonmucinous cells, cribriform architecture, sheets

of tumor cells, and large aggregates of goblet-like or sig-
net ring–like cells. (Figs. 8.40 and 8.41) In some cases,
there may be foci of conventional adenocarcinoma.
Desmoplasia, cytologic atypia, numerous mitoses, and
atypical mitotic figures may be seen.
Unlike classic NET, mitotic count or Ki-67 index is TABLE 8.4
not used to classify or predict clinical behavior of GCAs. Three-Tiered Grading system for Goblet Cell
They are graded using a three-tiered system (Table 8.4) Adenocarcinoma
They are staged using the TNM (tumor, node, metasta-
Loss of Tubular or
sis) system for appendiceal carcinoma. Tubular or Clustered Clustered Growth (Any
Nearly all GCAs stain for cytokeratin (CK) 20, Growth (Low-Grade Combination of High-
and up to 70% coexpress CK7. The neoplastic cells at Grade Pattern) (%) Grade Patterns) (%)
least focally show immunoreactivity with endocrine
1 >75 <2 5
markers chromogranin and synaptophysin (Fig. 8.42). 2 50–75 25–50
Intracytoplasmic mucin can be demonstrated with 3 <5 0 >5 0
mucicarmine.
Neuroendocrine tumor with a tubular pattern (tubular

carcinoid) was previously regarded as “adenocarcinoid”
tumor. These can be distinguished from GCAs by their
formation of glandular structures, lack of prominent
goblet or signet ring cells, and strong diffuse staining
with endocrine markers. GCAs, by comparison, have a
patchy or focal staining pattern with endocrine markers.
Tubular NETs behave indolently like classical NETs
and should not be confused with the more aggressive
GCA.
FIGURE 8.42
Goblet cell adenocarcinoma with patchy chromogranin immunoreactivity. In
comparison, typical neuroendocrine tumors express strong, diffuse staining
of these endocrine markers. Prognosis and Therapy
Compared with classic NETs of the appendix, GCAs

behave more aggressively. Most patients (97%) have
transmural extension of the tumor at the time of diag-
Goblet Cell Adenocarcinoma—Pathologic Features nosis, and more than half present with metastatic dis-
ease. Metastatic disease to other solid organs (e.g., lung,
Gross Findings liver, bone) is exceptionally rare. The most commonly
■ Does not produce a discrete mass lesion; appendix may look involved extraappendiceal sites include direct extension
normal into the right colon and ileum followed by spread to the
■ Circumferential thickening with longitudinal infiltration peritoneum and omentum. The ovary is the most com-
■ Most are larger than 2 cm (tumor involvement along length of
mon site of metastasis in women (88%), usually pre-
appendix)
senting as Krukenberg tumor. Lymph node metastases
Microscopic Findings are detected in more than one-third of patients, depend-
■ Arises within the deep lamina propria or submucosa without a
ing on the histologic subtype.
precursor lesion Surgical management with right hemicolectomy is
■ Concentric, infiltrative growth pattern of goblet-shaped or signet- recommended after appendectomy. Additional debulk-
ring cells and neuroendocrine cells ing procedures may be needed, followed by chemo-
therapy. Chemotherapy regimens are similar to those
Morphologic Subtypes
used for colonic adenocarcinomas. Intraperitoneal
■ Low-grade features
■ Minimal cytologic atypia

spread may warrant oophorectomy and intraperitoneal
■ Tubules of goblet-like mucinous cells with variable endocrine chemotherapy.
and Paneth cells
■ Mitoses infrequent
■ High-grade features
SUGGESTED READINGS
■ Discohesive single file or single infiltrating cells of mucinous or
nonmucinous cells 1. LampsLW, GrayJr GF, DildayBR, et al. The coexistence of low-
■ Significant cytologic atypia grade mucinous neoplasms of the appendix and appendiceal
■ Desmoplasia and destruction of the appendiceal wall
diverticula: a possible role in the pathogenesis of pseudomyxoma
■ Sheets of atypical cells
peritonei. Mod Pathol. 2000;13(5):495–501.
2. SahamiS, KooijIA, MeijerSL, et al. The link between the appen-
■ Cribriform pattern
dix and ulcerative colitis: clinical relevance and potential immu-
■ Large clusters of goblet-like cells
nological mechanisms. Am J Gastroenterol. 2016;111(2):163–169.
3. BronnerMP. Granulomatous appendicitis and the appendix in
Immunohistochemistry idiopathic inflammatory bowel disease . Semin Diagn Pathol.
■ Cytokeratin (CK) 20 positive (with coexpression of CK7 in 70%)
2004;21(2):98–107.
■ Patchy, focal reactivity with endocrine markers (chromogranin,
4. GuoG, GreensonJK. Histopathology of interval (delayed) appen-
dectomy specimens: strong association with granulomatous and
synaptophysin)
xanthogranulomatous appendicitis. Am J Surg Pathol. 2003;27(8):
1147–1151.
Differential Diagnosis 5. MisdrajiJ, YantissRK, Graeme-CookFM, et al. Appendiceal
■ Tubular pattern classical neuroendocrine tumor (NET) mucinous neoplasms: a clinicopathologic analysis of 107 cases.
■ Collision tumor of adenocarcinoma and NET
Am J Surg Pathol. 2003;27(8):1089–1103.
■ Classical NET with entrapped benign epithelium
6. MisdrajiJ, YoungRH. Primary epithelial neoplasms and other
epithelial lesions of the appendix (excluding carcinoid tumors).
■ Metastatic adenocarcinoma with signet ring features
Semin Diagn Pathol. 2004;21(2):120–133.
7. MisdrajiJ, Graeme-CookFM. Miscellaneous conditions of the 13. CarrNJ, BibeauF, BradleyRF, et al. The histopathological clas-
appendix. Semin Diagn Pathol. 2004;21(2):151–163. sification, diagnosis and differential diagnosis of mucinous
8. YantissRK, PanczykowskiA, MisdrajiJ, et al. A comprehensive appendiceal neoplasms, appendiceal adenocarcinomas and pseu-
study of nondysplastic and dysplastic serrated polyps of the ver- domyxoma peritonei. Histopathology. 2017;71(6):847–858.
miform appendix. Am J Surg Pathol. 2007;31(11):1742–1753. 14. CarrNJ, CecilTD, MohamedF, et al. Peritoneal Surface
9. Yantiss RK, Shia J, Klimstra DS, Hahn HP, Odze RD, Misdraji J. Oncology Group International. A consensus for classification
Prognostic significance of localized extra-appendiceal mucin and pathologic reporting of pseudomyxoma peritonei and asso-
deposition in appendiceal mucinous neoplasms. Am J Surg Pathol. ciated appendiceal neoplasia: the results of the Peritoneal Surface
2009;33(2):248-255. Oncology Group International (PSOGI) Modified Delphi Process.
10. ArnasonT, KamionekM, YangM, et al. Significance of proxi- Am J Surg Pathol. 2016;40(1):14–26.
mal margin involvement in low-grade appendiceal mucinous neo- 15. BarriosP, LosaF, Gonzalez-MorenoS, et al. Recommendations
plasms. Arch Pathol Lab Med. 2015;139(4):518–521. in the management of epithelial appendiceal neoplasms and peri-
11. PaiRK, BeckAH, NortonJA, et al. Appendiceal mucinous neo- toneal dissemination from mucinous tumours (pseudomyxoma
plasms: clinicopathologic study of 116 cases with analysis of peritonei). Clin Transl Oncol. 2016;18(5):437–448.
factors predicting recurrence. Am J Surg Pathol. 2009;33(10): 16. MorisD, TsilimigrasDI, VagiosS, et al. Neuroendocrine neo-
1425–1439. plasms of the appendix: a review of the literature. Anticancer Res.
12. PaiRK, HartmanDJ, GonzaloDH, et al. Serrated lesions of the 2018;38(2):601–611.
appendix frequently harbor KRAS mutations and not BRAF 17. TangLH, ShiaJ, SoslowRA, et al. Pathologic classification and
mutations indicating a distinctly different serrated neoplastic clinical behavior of the spectrum of goblet cell carcinoid tumors
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9
Infectious Diseases of the Gastrointestinal Tract
■ Nicole C. Panarelli, MD
Surgical pathologists who evaluate specimens from the an opportunistic pathogen in patients with many condi-
gastrointestinal (GI) tract for possible infections must tions that compromise immunity, including those with
first attempt to differentiate histologic changes suggest- acquired immunodeficiency syndrome (AIDS) or solid
ing infection from other inflammatory processes. After organ or bone marrow transplant recipients, as well those
this determination, dedicated attempts must be made to who receive prolonged immunomodulator or steroid ther-
diagnose the specific infectious organisms. The surgical apy for immune-mediated or autoimmune disorders.
pathologist’s ability to detect infectious processes in tis-
sue sections has grown exponentially with the advent of
new histochemical and immunohistochemical stains, in
situ hybridization, and polymerase chain reaction (PCR)
analysis. Of note, multiplexed PCR assays performed on
stool samples have become widely available and are slowly Symptoms vary with the immune status of the patient
replacing traditional stool culture for identification of caus- and the specific site of infection. In immunocompro-
ative bacterial and viral pathogens in many centers. Use of mised individuals, CMV esophagitis causes odynophagia,
these techniques has resulted in an increase in our knowl- whereas gastroenteritis is marked by abdominal pain,
edge of the pathologic features of specific infections. diarrhea (either bloody or watery), fever, and weight loss.
Most GI infections are self-limited. Patients who undergo Hypertrophic gastropathy with protein-losing enteropathy
endoscopic evaluation and biopsy generally have unusual resembling Menetrier’s disease has rarely been reported
clinical features such as debilitating diarrhea, evidence of in association with CMV gastritis. Primary infections in
systemic disease, or a history of immunocompromise. One healthy, immunocompetent persons are often self-limited.
of the most valuable (and least expensive) diagnostic aids CMV superinfection is known to exacerbate other chronic
for a surgical pathologist is a discussion with the gastroen- GI diseases, such as ulcerative colitis and Crohn’s disease;
terologist regarding specific symptoms, colonoscopic find- in such cases, it is associated with toxic megacolon, refrac-
ings, travel history, food intake history (e.g., sushi, poorly toriness to medical therapy, and high mortality.
cooked beef), sexual practices, and immune status.
CYTOMEGALOVIRUS—FACT SHEET
Definition
VIRAL INFECTIONS n Viral infection
A wide variety of viruses affect the GI tract. Manifestations Incidence and Location
of disease vary with the type of virus, specific site of infec- n Anywhere in the gastrointestinal tract
tion, and immune status of the patient.

Clinical Features
n Most common in, but not limited to, immunocompromised patients
n Odynophagia, diarrhea (with or without blood), abdominal
■ CYTOMEGALOVIRUS pain, fever, weight loss

n May cause an ischemic picture, both clinically and
pathologically
Cytomegalovirus (CMV) infection occurs in both immu- n May be reactivated in Crohn’s disease or ulcerative colitis after
immunosuppressive therapy
nocompromised and immunocompetent persons and
may be found throughout the GI tract. The pathogene- Prognosis and Therapy
sis in truly healthy patients is poorly understood. An n Infections in healthy persons are usually self-limiting
underlying immunocompromised state should be con- n Ganciclovir often in combination with newer drugs
sidered when CMV infection is diagnosed because it is
243
Pathologic Features
Gross Findings
Cytomegalovirus causes a wide variety of gross lesions

with ulcers being the most common finding (Fig. 9.1);
they may be single or multiple and either superfi-
cial or deep. The ulcers often have a well-demarcated,
“punched-out” appearance. Other gross findings include
hemorrhagic colitis, pseudomembranous colitis, and
obstructive mass lesions.
Segmental colonic involvement with linear ulcers
mimicking Crohn’s disease have been well documented
in colonic CMV infection. Rarely, severe ulcerative CMV A
infection may lead to bowel perforation.
The histologic spectrum of CMV infection also varies

widely, often depending on the patient’s immune status.
Typical histologic features include mixed inflammation
with numerous neutrophils and mucosal ulceration
with prominent granulation tissue. Epithelial cell apop-
tosis may be prominent (Fig. 9.2A). Virtually no asso-
ciated inflammatory reaction may be seen in severely
immunocompromised patients. Inclusions are prefer-
entially found in endothelial cells and stromal cells and
only rarely in epithelial cells; thus, they are usually seen
deep in ulcer bases.
B
The characteristic “owl’s eye” intranuclear inclu-
sions are visible on routine (hematoxylin and eosin) FIGURE 9.2
preparations, as are brightly eosinophilic, granular intra- A, Abundant apoptotic crypt epithelial cells simulate graft-versus-host disease
cytoplasmic inclusions (Fig. 9.2B). Occasionally, CMV in cytomegalovirus infection (hematoxylin and eosin [H&E]). B, Characteristic
“owl’s eye” inclusions (thin arrow) are seen within the nuclei of endothelial
infection of endothelial cells of mucosal and submucosal and mesenchymal cells in the lamina propria. The cytoplasm contains granu-
vessels of the bowel initiates inflammatory mediators, lar eosinophilic inclusions (thick arrow) (H&E).
leading to vascular thrombosis and subsequent bowel
ischemia. Segmental bowel ischemia caused by infection
with CMV shows histologic features that are similar Cytomegalovirus—Pathologic Features
to other causes of ischemia (hemorrhagic necrosis and
crypt withering). In addition to CMV inclusions, the Gross Findings
vessels may show marked inflammation and necrosis. n Most commonly ulcers, single or multiple, shallow or deep
n May also manifest as colitis (hemorrhagic or
pseudomembranous) or obstructive mass

n Segmental or linear ulceration may mimic Crohn’s disease grossly
n Characteristic inclusions: “owl’s eye” inclusions in the nuclei of
endothelial and stromal cells

n Granular eosinophilic inclusions in the cytoplasm of endothelial
and stromal cells

n Mixed inflammation with prominent neutrophils and apoptosis
n No associated inflammatory reaction may be seen, particularly in
severely immunocompromised patients

n Endothelial infection may cause ischemia
n Other viral infections, particularly adenovirus
n Crohn’s disease
FIGURE 9.1
n Graft-versus-host disease
Colon resected from a renal transplant patient with cytomegalovirus colitis. n Ischemic colitis
Note the sharply demarcated area of coalescing ulcers.
CHAPTER 9 Infectious Diseases of the Gastrointestinal Tract 245
Ancillary Studies
Examination of multiple levels and immunohisto-

chemical stains facilitates detection of rare CMV
inclusions in cases when clinical suspicion is high but
characteristic findings are lacking or when exuberant
inflammation obscures diagnostic features, such as in
samples from patients with corticosteroid-dependent
IBD. Detection of isolated CMV-positive cells may
be of clinical import for patients with GI complaints
because some experience symptomatic improvement
with antiviral therapy. Findings on immunohisto-
chemical stains should always be correlated with rou-
tine sections because granulocytes and plasma cells
may show nonspecific staining. Other useful diagnos-
tic aids include viral culture, PCR assays, and in situ
hybridization. Isolation of CMV in culture, however,
does not imply active infection because virus may be
excreted for months to years after a primary infection.
Similarly, positive serologic studies may indicate prior
or primary infection.
A
The differential diagnoses are primarily other viral
infections, particularly adenovirus. CMV inclusions
and are present within both the nucleus and cytoplasm.
Adenovirus inclusions, by comparison, are crescent
shaped or have irregular outlines, are generally within
surface epithelium, and are only intranuclear. The dis-
tinction between CMV infection and graft-versus-host
disease (GVHD) in bone marrow transplant patients
may be particularly difficult because both clinical and
histologic features are similar. Immunohistochemistry
(IHC) may be used to rule out CMV infection in this set-
ting. As mentioned previously, CMV infection may pro-
duce architectural distortion, deep “fissuring” ulcers,
and skip lesions that simulate Crohn disease but does
not produce neural hyperplasia, transmural lymphoid B
aggregates, muscularis mucosae hypertrophy, or pyloric
metaplasia. Of course, a careful search for inclusions FIGURE 9.3
should confirm the diagnosis of CMV infection in cases Cytomegalovirus (CMV) infection superimposed on chronic Crohn’s disease. A,
Note active ulcer overlying thickened colon wall with marked neural hyperplasia
with features of both disorders (although the two may (hematoxylin and eosin [H&E]). B, CMV inclusions are seen within endothelial
coincide; Fig. 9.3). cells at the base of the ulcer (H&E). Case courtesy of Dr. Brian Quinn.

problems with toxicity and poor oral bioavailability,
The vast majority of infections in healthy persons and resistant strains are evolving. Newer drugs such
are self-limiting. Ganciclovir has historically been as foscarnet are now often used in combination with
the mainstay of medical therapy, but this drug has ganciclovir.
■ HERPESVIRUS the most typical finding is multiple and confluent ulcers.

The surrounding mucosa is often hemorrhagic and fria-
Herpetic infection is most commonly seen in the esoph- ble, and “cobblestoning” of the mucosa may be seen.
agus and anorectum. The symptoms and pathologic
features of herpes simplex virus type 1 (HSV-1) versus Microscopic Findings
HSV-2 are indistinguishable. Herpetic proctitis is the most
common cause of nongonococcal proctitis in homosexual Ulcers are associated with increased neutrophils in the
men. In immunocompetent patients, herpes outbreaks are lamina propria, and perivascular lymphocytic cuffing.
often self-limiting; immunocompromised persons may be The inflammatory exudate often contains sloughed epi-
at risk for dissemination and life-threatening illness. thelial cells. Two types of characteristic nuclear inclu-
sions may be found: (1) the more common smudged,
ground-glass nuclear inclusion with peripheral darker,
marginated chromatin (Fig. 9.4), and (2) the acidophilic
Clinical Features
inclusions with a surrounding clear halo and periph-
eral chromatin margination (Cowdry type A inclusion).
Herpetic esophagitis causes dysphagia, vomiting, and They are usually present in squamous epithelial cells at
hematemesis. Proctitis presents with severe anorectal the edges of ulcers and are often multiple.
pain, bloody discharge or frank bleeding, tenesmus, con-
stipation, and fever. Concomitant neurologic symptoms
(difficulty in urination and paresthesias of the buttocks
Ancillary Studies
and upper thighs) are well described, as is inguinal
lymphadenopathy. Herpes colitis is most often seen in
immunocompromised patients and may be a fulminant, Fewer than half of biopsy specimens contain inclusions.
life-threatening condition. Viral culture is the most valuable aid to diagnosis; IHC,
in situ hybridization, and PCR assays may also be of use.
HERPES SIMPLEX VIRUS—FACT SHEET
Definition
n Viral infection, often in immunocompromised patients

n Predominantly esophageal and anorectal; rarely colonic
n Most common cause of nongonococcal proctitis in homosexual men
Clinical Features
n Most common in, but not limited to, immunocompromised patients
n Esophagitis: dysphagia, vomiting, hematemesis

n Proctitis: anorectal pain, discharge, often with neurologic
symptoms, and inguinal lymphadenopathy; perianal vesicles

n Colitis: diarrhea, lower gastrointestinal bleeding; fulminant
colitis with perforation may develop A

n Acyclovir is first line of medical therapy; surgery may be required
if fulminant colitis or perforation develops
Pathologic Features
Gross Findings
Ulcers are the most common findings in the esophagus,

but one may also see intact vesicles. Severe cases may be B
characterized by diffuse erosive esophagitis. In herpetic FIGURE 9.4
proctitis, perianal vesicles are common, and they may Typical herpes simplex virus inclusions. Note the smudged, ground-glass
extend into the anal canal and rectum. In herpetic colitis, nuclei with peripheral darker, marginated chromatin (hematoxylin and eosin).
it has recently gained much attention as a cause of

Herpes Simplex Virus—Pathologic Features diarrhea in immunocompromised patients, especially
those with AIDS and patients who have undergone
Gross Findings transplantation (particularly bone marrow trans-
n Ulcers, vesicles plantation). Adenovirus infection of the GI tract is
n Mucosal friability and hemorrhage, “cobblestoned” mucosa in the
strongly associated with concomitant acute GVHD.
colon
n Ulceration, inflammatory exudate with sloughed epithelial cells
n Viral inclusions in epithelial cells, consisting of a smudged,
ground-glass nucleus with peripheral darker, marginated

chromatin
Virtually all patients present with diarrhea, sometimes
accompanied by fever, weight loss, lower GI bleeding,
n Other viral infections, particularly varicella
n Crohn’s disease
and abdominal pain.
Differential Diagnosis ADENOVIRUS—FACT SHEET
Definition
The differential diagnosis predominantly includes n Viral infection, often in immunocompromised or transplant
other viral infections, such as CMV and varicella zos- patients

ter (VZV). Morphology and location of the inclusions
distinguishes HSV from CMV. Herpetic inclusions
n Small intestine, colon
are most often in the epithelial cells of the mucosa,
whereas CMV preferentially involves the endothelial Clinical Features
and stromal cells. Co-infection may also occur, par- n Diarrhea sometimes accompanied by fever, weight loss,
ticularly in the immunocompromised. Rarely, seg- abdominal pain, or gastrointestinal bleeding
mental ulceration and cobblestoning of mucosa may
mimic Crohn’s disease, as in the case of CMV infec- Prognosis and Therapy
tion. Unlike CMV infection, HSV complicating idio- n Ribavirin
pathic IBD is rare, and data are limited to case reports.

Serologic studies play a limited role in the diagnosis
of HSV colitis owing to the high prevalence of HSV
seropositivity overall; IHC may be used when suspi-
Pathologic Features
cion is raised on morphologic grounds. HSV may be
detected in colonic tissue samples via PCR but is not
routinely used. Varicella zoster inclusions are indis- Gross Findings
tinguishable from HSV on H&E sections, but tend to
be occur at all levels in infected mucosa, rather than Endoscopic findings typically include erythematous, fri-
in a superficial distribution. Patients often have a skin able, and granular mucosa.
rash. VZV inclusions are negative on HSV immunos-
tains; immunostains targeting VZV are available. Microscopic Findings
Histologic features of adenovirus infection include

epithelial changes such as superficial cellular degen-
eration, apoptosis of epithelial cells, and focal acute
Acyclovir is the mainstay of medical therapy. Segmental inflammation. Severe cases may show ulceration and
resection to control bleeding and prevent perforation exudate. Characteristic homogeneous, smudgy, eosin-
may be required in severe cases of herpetic colitis. ophilic inclusions may be seen lining the nucleus.
Adenovirus inclusions are, except in rare circum-
ADENOVIRUS stances, limited to epithelial cells; inclusions are most
common within surface epithelium but may also be
seen in the crypt epithelium. Inclusions are particu-
Adenovirus infection is second only to rotavirus as larly common in surface goblet cells, in which they are
a cause of self-limiting childhood diarrhea. However, often crescent shaped (Fig. 9.5).
overlooked; a high index of suspicion should be main-

tained in immunosuppressed populations.
The antiviral drug ribavirin is the mainstay of therapy.
■ HUMAN IMMUNODEFICIENCY
VIRUS–ASSOCIATED ULCERATIVE
FIGURE 9.5
ESOPHAGITIS
Homogeneous, smudgy, eosinophilic inclusions fill the nuclei of the surface
enterocytes in adenovirus infection (hematoxylin and eosin). Courtesy of Dr. Human immunodeficiency virus (HIV) has been impli-
Joel Greenson.
cated in the pathogenesis of chronic esophageal ulcers
in infected patients, due, in part, to detection of viral
proteins in ulcerated mucosa. The diagnosis is one of
Adenovirus—Pathologic Features exclusion; thus, one should thoroughly evaluate other
possibilities, including other viral infections and med-
Gross Findings ication-induced injuries. Ulcers may contain atypi-
n Erythematous, friable, and granular mucosa cal-appearing fibroblasts, and the associated squamous
mucosa may be atrophic.
n Superficial cellular degeneration, apoptosis of epithelial cells, and focal
acute inflammation; severe cases may show ulceration and exudate

n Inclusions ■ AIDS ENTEROCOLOPATHY
n Homogeneous, smudgy, eosinophilic inclusions fill the nucleus.
n Inclusions can be crescent shaped or targetoid
n Most common within surface epithelium, particularly goblet AIDS enterocolopathy is a term that describes mor-
cells, but can be seen in crypt epithelial cells; almost never in phologic changes seen in the gut of patients with
endothelial and mesenchymal cells
HIV/AIDS and chronic diarrhea, for which no other
Differential Diagnosis infectious cause has been identified. Some argue that
n Other viral infections, particularly cytomegalovirus
these changes represent either primary infection of gut
epithelial cells with HIV or a secondary autoimmune
reaction to viral infection. Others believe that this is
a poorly understood term that does not clearly repre-
sent a specific disease entity and thus should not be
Ancillary Studies
used at all. The controversy arises because asymptom-
atic patients may have similar morphologic findings on
Immunohistochemistry is useful aid for adenovirus biopsy, and conversely, severely symptomatic patients
detection. may have normal biopsy findings. In addition, there is
always the added concern that a causative pathogen
simply has been missed.
Patients with AIDS enterocolopathy often have
chronic diarrhea, but some are asymptomatic.
Colonoscopy is usually normal. The small bowel is
The differential diagnosis primarily includes other more commonly affected than the colon. Histologic fea-
viral infections, especially CMV. Morphologic differ- tures include increased apoptotic activity (Fig. 9.6) and
ences between the two viruses, as well as differences in decreased numbers of mitotic figures relative to extent
location within the gut (epithelium vs endothelium or of mucosal injury; the changes resemble those seen in
stromal cells) usually help resolve the differential diag- mild GVHD and chemotherapy-related mucosal injuries.
nosis. Because adenovirus often coexists with GVHD, The differential diagnosis includes conditions that are
it may be overlooked if a careful search for inclusions associated with prominent apoptosis, such as GVHD,
is not undertaken. Adenovirus inclusions also show chemotherapy- and drug-related injury, and other viral
morphologic overlap with reactive and degenerative infections Other infectious agents should be rigorously
nuclear changes in intestinal epithelia and may be easily excluded.
stricture, or prior surgery. Clinical and imaging find-

ings usually reveal an alternate explanation for gas-
tric obstruction, raising the possibility that Sarcina
organisms do not cause disease but are a marker of
luminal stasis. Patients report epigastric pain, dyspep-
sia, bloating, and vomiting. Sarcina organisms have
been implicated in rare cases of acute emphysematous
gastritis.
SARCINA VENTRICULI—FACT SHEET
Definition
n Gram-positive anaerobic coccus that can grow in acidic
environments

n Stomach
n Infection is rare
Clinical Features
n Nausea, vomiting
FIGURE 9.6 n Abdominal pain
n Melena, hematemesis
Numerous apoptotic enterocytes are present in this case of AIDS-related
enterocolopathy (hematoxylin and eosin). n Emphysematous gastritis
n Perforation
n May be asymptomatic
■ BACTERIAL INFECTIONS n History of prior gastric surgery
n Presence of an obstructing mass
A seemingly endless array of bacterial species are Prognosis and Therapy

pathogenic in the GI tract. Many produce nonspe- n Metronidazole with or without other antibiotics
n Relief of gastric outlet obstruction

cific changes, but others may be identified in tissue
n Antiacid therapy
sections or produce inflammatory patterns that are
suggestive of specific infections. This section covers
major bacterial pathogens, emphasizing features that
guide pathologists and clinicians in reaching a correct
diagnosis.
Pathologic Features
Gross Findings
■ SARCINA VENTRICULI AND RELATED
ORGANISMS
Endoscopic findings include retained food and bile,
masses, gastritis, and ulcers.
Sarcina spp. are gram-positive cocci that may be found
associated with ulcerated gastric mucosa. Severe com- Microscopic Findings
plications for S. ventriculi infection are rare, and the
organism is found in stool of healthy individuals; thus, Sarcina organisms do not invade the gastric mucosa and
its pathogenicity remains controversial. do not typically evoke an inflammatory response. This
supports the notion that the organisms are not pathogenic;
however, they may colonize preexisting ulcers, which
increases the risk of perforation or emphysematous gastri-
Clinical Features
tis (Fig. 9.7A). They are spherical to cuboidal organisms
that span 1.8 to 3 μm and have refractile cell walls, resem-
Sarcina organisms are identified in patients with bling vegetable matter (Fig. 9.7B). They occur in a “tetrad
delayed gastric emptying and gastric outlet obstruc- packet” arrangement of four organisms or multiples of
tion, often in the setting of an obstructing mass, four, reflecting cell division in multiple planes.
A B
FIGURE 9.7
A, Sarcina organisms are present in surface debris of a gastric ulcer. B, High magnification shows tetrads of the bacteria clustered into larger groups (hematoxy-
lin and eosin). Courtesy of Dr. Kathryn E. Tanaka.
than S. ventriculi and are aerobes. Staphylococci are also

Sarcina ventriculi—Pathologic Features gram positive but measure only 1 μm and occur in grape-
like clusters rather than tetrads.
Gross Findings
n Ulcers
n Gastritis
n Retained food
n Tetrads of non-invasive spherical to cuboidal organisms
Therapy is aimed at eliminating the underlying cause of
n Associated mucosal ulceration
n Differential Diagnosis
gastric outlet obstruction. Eradication of the organisms
n Micrococcus with metronidazole therapy in combination with other
n Staphylococcus antibiotics has been reported. Some patients report
symptomatic relief with proton pump inhibitors, H2
receptor blockers, and antiemetic therapy.
Ancillary Studies
S. ventriculi can usually be diagnosed in routine sections,

but tissue Gram stain may highlight the organisms. If TROPHERYMA WHIPPLEI (WHIPPLE
necessary, PCR amplification of the 16 S rRNA gene can DISEASE)
confirm the diagnosis.
Whipple disease is a rare, multisystemic infectious dis-
order caused by the bacillus, Tropheryma whipplei (for-
Differential Diagnosis merly T. whippelii). The disease predominantly occurs
in middle-aged white men; however, recent studies show
Micrococcus spp. are also gram-positive cocci that occur increased incidence in women. It has historically shown
in tetrads, but they are considerably smaller (0.5 μm) a predilection for farmers and carpenters. Some point to
detection of T. whipplei in asymptomatic individuals and Pathologic Features

familial cases as evidence of a possible genetic suscepti-
bility to a commensal organism.
Gross Findings
The duodenal mucosa may show thickened small intesti-

nal folds that are coated with yellow-white plaques. The
adjacent mucosa may appear erythematous or friable.
Whipple disease may affect virtually any organ system,
but the classic presentation includes diarrhea, weight Microscopic Findings
loss, fever, abdominal lymphadenopathy, and arthralgia.
A substantial proportion of patients experience cardio- Whipple disease is most commonly diagnosed in duode-
vascular and pulmonary symptoms. The most severe nal biopsy specimens. Involvement of the liver, esoph-
form of disease includes neuropsychiatric manifestations, agus, stomach, colon, and mesenteric lymph nodes has
such as ophthalmoplegia, myoclonus, and dementia. also been documented. In small bowel biopsies, the villi
are blunted by expansion of the lamina propria with
foamy macrophages (Fig. 9.8A). In addition, there may
be neutrophilic activity, fat vacuoles (small collections
TROPHERYMA WHIPPLEI—FACT SHEET of extracellular lipid droplets), and lymphangiecta-
sia. Foamy macrophages contain periodic acid–Schiff
Definition
(PAS)–positive bacillary organisms (Fig. 9.8B).
n Gram-positive bacillus responsible for rare multisystem disorder
characterized by diarrhea and malabsorption
Tropheryma whipplei—Pathologic Features

n Small intestine; rarely the esophagus stomach, colon, and
Gross Findings
mesenteric lymph nodes
n Enlarged mucosal folds
n Yellow-white plaques
Clinical Features
n Diarrhea, weight loss, abdominal lymphadenopathy
n Fever
n Villous blunting
n Arthralgias
n Foamy macrophages expand the lamina propria and submucosa
n Cardiac failure, pericarditis
n Periodic acid–Schiff–positive bacillary organisms within foamy
n Cough and pleuritic chest pain
macrophages
n Dementia and neuromuscular symptoms
n Neutrophilic infiltrates
n Fat droplets and lymphangiectasia in the mucosa

n Months to years of antibiotic therapy may be necessary Differential Diagnosis
n Supportive care for malabsorption
n Histoplasma capsulatum
n Relapse may occur
n Mycobacterium avium-intracellulare complex
A B
FIGURE 9.8
A, The duodenal lamina propria is filled with abundant macrophages in a case of Whipple disease (hematoxylin and eosin). B, The macrophages contain peri-
odic acid–Schiff–positive bacteria, consistent with Tropheryma whipplei. Courtesy of Dr. Maria Westerhoff.
Differential Diagnosis colitis. Typical histologic features include cryptitis, with

or without increased neutrophils in the lamina propria
and crypt abscesses; preservation of crypt architecture;
The differential diagnosis includes other organisms that and lack of basal plasmacytosis. The acute inflammatory
infect the mononuclear phagocytic system. Histoplasma component may be most prominent in the mid to upper
capsulatum organisms are ovoid with a surrounding crypts. The lack of crypt distortion and basal lymphop-
halo and stain with Gomori methenamine silver (GMS). lasmacytosis helps distinguish acute self-limited colitis
Mycobacterium avium-intracellulare (MAI) are filamen- from early IBD.
tous, pale blue intracellular organisms on H&E stain.
They can be PAS positive but are distinguished from T.
whipplei by positive staining with Ziehl-Neelsen or other
■ ESCHERICHIA COLI
acid-fast stains. Both of these infections may elicit gran-
ulomatous inflammation in immunocompetent hosts.
Diarrheagenic E. coli organisms are classified into five
groups: enterotoxigenic, enteropathogenic, enteroadher-
ent, enteroinvasive, and enterohemorrhagic. If patho-
Ancillary Studies
genic E. coli is suspected, the clinical laboratory should
be notified to search for it specifically because cultures
Culture of T. whipplei has met with limited success may be a valuable diagnostic aid.
because of the organism’s slow growth and need for an Enterotoxigenic E. coli is a major cause of traveler’s
acidic environment that simulates intracellular condi- diarrhea, but patients are seldom examined via biopsy,
tions. IHC is available to confirm this diagnosis. PCR and the pathology has not been well characterized in
assay is a highly sensitive and specific method to con- humans. Enteropathogenic E. coli (EPEC) predomi-
firm this diagnosis in suspicious cases. Given the avail- nantly affects infants and neonates. Biopsy is not gener-
ability of IHC and PCR assays, electron microscopy is ally performed and is not diagnostically useful, although
less commonly used for confirmation. occasionally gram-negative rods may be seen at the sur-
face of the mucosa (Fig. 9.9). EAEC is similar to the
enteropathogenic group and is also an important cause
of traveler’s diarrhea and pediatric diarrhea worldwide.
■ BACTERIAL ENTEROCOLITIS
Both EPEC and EAEC have been increasingly recog-
nized as causes of chronic diarrhea and wasting in AIDS
Diarrhea resulting from bacterial infection is a signif- patients. Endoscopic findings are usually unremarkable,
icant worldwide health problem. Escherichia coli and but histologic examination shows a coating of adher-
Salmonella, Shigella, and Campylobacter spp. are the ent bacteria at the surface epithelium, which may stain
most commonly identified pathogens. Many bacterial gram negative. Degenerated surface epithelial cells with
infections of the gut are related to ingestion of contam- associated intraepithelial inflammatory cells may also
inated water or food or travel to countries where these be present. Enteroinvasive E. coli (EIEC) is similar to
organisms are endemic. Although bacteria are often Shigella both genetically and in its clinical presentation
recovered by culture or identified by molecular means, and pathogenesis. Given its capacity for invasion, EIEC
surgical pathologists may play a valuable role in diag- produces a severe dysentery-like diarrheal illness that
nosis. A general classification of colonic bacterial infec- can be a particular problem in patients with AIDS. The
tions by histologic pattern is given in Table 9.1. gross and microscopic pathology of EIEC has not been
Despite the large number of infectious agents that well described.
may affect the colon, the histologic features that they
produce may be generally categorized as follows:
1. Organisms producing very mild or no histologic ENTEROHEMORRHAGIC ESCHERICHIA

changes (e.g., enteroadherent E. coli [EAEC]) COLI
2. Organisms producing the histologic features of acute
infectious/self-limited colitis or focal active colitis, The most common strain of EHEC is 0157:H7. This
such as Campylobacter spp. infectious disease is probably markedly underdiagnosed.
3. Organisms producing suggestive or diagnostic histo- This organism adheres to intestinal epithelial cells and
logic features, such as pseudomembranes, granulo- produces a cytotoxin similar to that produced by Shigella
mas, or ischemic changes dysenteriae; however, there is no invasion. Although
contaminated meat is the most frequent mode of trans-
The pattern of acute self-limited colitis or focal active mission, infection may also occur through contaminated
colitis is one of the most common seen in infectious water, milk, produce, and person-to-person contact.
TABLE 9.1
Classification of Bacterial Infections of the Colon According to Histologic Pattern
CHAPTER 9 Infectious Diseases of the Gastrointestinal Tract
Minimal or No Marked
Inflammatory Acute Self-Limited Pseudomembranous Predominantly Predominantly Architectural
Change Colitis Pattern Pattern Granulomatous Diffuse Histiocytic Lymphohistiocytic Distortion Ischemic Pattern
Enteropathic Shigella spp. Enterohemorrhagic Yersinia spp. Rhodococcus equi LGV S. typhimurium Enterohemorrhagic
Escherichia coli Campylobacter spp. E. coli Mycobacterium MAI (immuno- Salmonella Shigella spp. E. coli
Enteroadherent Aeromonas spp. C. difficile tuberculosis compromised patients) typhimurium Klebsiella oxytoca
E. coli Salmonella spp. Occasionally Actinomycosis (mixed
Spirochetosis (nontyphoid) Shigella spp. suppurative and
Neisseria spp. Occasionally granulomatous)
Vibrio cholerae Clostridioides MAI (immunocompetent
difficile patients)
Syphilis (± increased Rarely syphilis
plasma cells)
LGV, Lymphogranuloma venereum; MAI, Mycobacterium avium-intracellulare complex.
253
Pathologic Features
Gross Findings
Endoscopically, patients have colonic edema, erosions,

ulcers, and hemorrhage, and the right colon is usually
more severely affected. The edema may be so marked as
to cause obstruction.
The histopathologic features are those of ischemic coli-

tis because the toxin is believed to induce an ischemic
insult. These features include lamina propria and sub-
mucosal hemorrhage (Fig. 9.10), with associated muco-
FIGURE 9.9
sal acute inflammation, crypt withering, and necrosis.
Enteroadherent Escherichia coli in a patient with AIDS. A coating of
Intimal thickening and luminal thrombi may be seen
gram-negative rods with little inflammatory reaction is noted at the surface of in small vessels, and pseudomembranes are occasion-
the colonic mucosa (Twort Gram stain with oil immersion). ally present (Fig. 9.11). Necrosis and hemorrhage
Symptoms usually consist of bloody diarrhea with

severe abdominal cramps and mild or no fever.
Nonbloody, watery diarrhea may occur, however. Only
one-third of patients have fecal leukocytes. Rarely, this
infection leads to frank lower GI bleeding. Affected
persons may develop hemolytic-uremic syndrome or
thrombotic thrombocytopenic purpura, and children
and older adults are at particular risk for serious, sys-
temic illness.
FIGURE 9.10
Enterohemorrhagic Escherichia coli infection. Hemorrhagic mucosal necro-
sis of the upper epithelium, crypt withering, lamina propria hyalinization, and
microthrombi (hematoxylin and eosin).
ENTEROHEMORRHAGIC ESCHERICHIA COLI—FACT

SHEET
Definition
n Diarrheagenic Escherichia coli strain producing hemorrhagic colitis

n Preferentially involves the right colon
Clinical Features
n Bloody diarrhea with severe abdominal cramps
n Mild or no fever
n Sometimes leads to obstructive edema or massive bleeding

n Patients at risk for hemolytic-uremic syndrome and thrombotic
thrombocytopenic purpura

n Mainly supportive care
n Role of antibiotics controversial
n Surgery may be required to relieve obstruction or control FIGURE 9.11

bleeding Enterohemorrhagic Escherichia coli can have prominent necroinflammatory
exudates that resemble pseudomembranes (hematoxylin and eosin).
of the superficial colonic crypts with sparing of the Prognosis and Therapy
deeper compartment is characteristic of enterohem-
orrhagic E. coli but may also be seen in other types
of ischemia. A combination of ischemic changes and There is no proven therapy for EHEC, and the role of
features of acute colitis should raise suspicion for antibiotic treatment is controversial, although most
infection. strains are susceptible. Surgical resection of the affected
colon may be required to relieve obstruction from edema
or to control bleeding.
Enterohemorrhagic Escherichia coli—Pathologic Features
Gross Findings SALMONELLOSIS

n Colonic edema, erosions, ulcers, and hemorrhage
Salmonella, which are gram-negative bacilli, are transmit-

ted through food and water and are particularly prevalent
n Mimics ischemic colitis of other causes
n Microthrombi may be seen within small vessels

where sanitation is poor. They are an important cause
n Pseudomembranes may be present
of both food poisoning and traveler’s diarrhea. The dis-
cussion of Salmonella spp. may be generally divided into
Differential Diagnosis typhoid and nontyphoid species. Enteric (typhoid) fever
n Ischemic colitis of other causes is usually caused by S. typhi; the most common nonty-
n Clostridioides difficile–related pseudomembranous colitis phoid species include Salmonella enteritidis, Salmonella
n Rarely, idiopathic inflammatory bowel disease
typhimurium, Salmonella muenchen, Salmonella anatum,
Salmonella paratyphi, and Salmonella give. Although
historically enteric fever was considered much more
severe than nontyphoid salmonellosis, more recent liter-
ature suggests a greater degree of overlap (both clinically
Ancillary Studies
and pathologically). The infective dose is relatively low
(∼103 organisms may cause human disease). Patients
Examination of stool samples by PCR has recently with low gastric acidity and patients with AIDS have
become a crucial diagnostic aid. Routine stool cultures a greater risk for Salmonella infection and associated
do not distinguish 0157:H7 from normal intestinal flora, complications.
and successful culture may be impossible more than 4
days after onset of symptoms. Microbiologic diagnosis
requires screening on sorbitol–MacConkey agar and
testing of colonies with antisera. An immunohistochem-
ical stain for this organism is described, but is not used
in clinical practice. There are numerous manifestations of Salmonella infec-
tion, including an asymptomatic carrier state (often the
organism is harbored in the gallbladder), a self-limited
gastroenteritis, typhoid fever, and septicemia. Patients
with typhoid (enteric) fever typically present with fever
(which generally rises over several days), abdominal
The differential diagnosis includes ischemic colitis, pain, headache, and occasionally initial constipation.
Clostridioides difficile–related colitis, and idiopathic Abdominal rash (“rose spots”), delirium, hepatospleno-
IBD. Histologic features of ischemia in the right colon, megaly, and leukopenia are fairly common. The diar-
particularly in patients who are not at risk for athero- rhea, which begins in the second or third week of
sclerotic disease, should prompt consideration of EHEC infection, is first watery but may progress to severe
and the appropriate cultures. The histologic features of GI bleeding and perforation. Nontyphoid Salmonella
ischemia generally serve to distinguish EHEC from idio- spp. generally cause a milder, self-limited gastroenteri-
pathic IBD. If pseudomembranes are present, differenti- tis with vomiting, nausea, fever, and watery diarrhea.
ation from C. difficile–related colitis may be difficult, and Occasionally, these species cause bloody diarrhea or toxic
cultures or the C. difficile toxin assay may be required. megacolon.
deep, with the base at the muscularis propria. Typhoid

SALMONELLOSIS—FACT SHEET fever may also show features more consistent with acute
self-limited colitis, including prominent neutrophils,
Definition
cryptitis, crypt abscesses, and overlying fibrinous exu-
n Gram-negative enteric bacterium causing typhoid (enteric) fever
or milder gastroenteritis
date. Granulomas are occasionally seen. In nontyphoid
salmonellosis, the pathologic features are those of acute
Incidence and Location self-limited colitis of any infectious cause. Occasionally,
n Any segment of colon; typhoidal form typically involves ileum, significant crypt distortion may be seen.
right colon, and appendix
Clinical Features
n Typhoidal form Salmonellosis—Pathologic Features
n Fever (rising over several days), abdominal pain, headache, and
occasionally constipation Gross Findings

n Abdominal rash (rose spots) and leukopenia
n Typhoid
n Diarrhea begins in the second or third week
n Characteristic pathology most prominent in ileum, appendix, and
n Diarrhea is initially watery but may progress to severe
right colon
gastrointestinal bleeding n Markedly thickened bowel, raised nodules correspond to
n Nontyphoidal form
hyperplastic Peyer’s patches
n Milder, self-limited gastroenteritis with vomiting, nausea, fever,
n Aphthoid ulcers overlying Peyer’s patches, linear ulcers, discoid
and watery diarrhea ulcers, or full-thickness ulceration and necrosis are common
n More clinical and pathologic overlap between the typhoidal and
n Perforation and toxic megacolon rarely seen
nontyphoidal forms than previously thought n Suppurative mesenteric lymphadenitis may be present
n Nontyphoid
Prognosis and Therapy n Generally milder findings, including mucosal redness, ulceration,
n Antibiotics, supportive care and exudates
n Typhoid
n Macrophage is the predominant inflammatory cell

Pathologic Features n Hyperplastic Peyer’s patches with overlying acute inflammation;
eventually, frank ulceration begins in Peyer’s patch and spreads to

Gross Findings surrounding mucosa
n Lymphoid follicles are infiltrated and obliterated by macrophages
n Neutrophils are usually limited to erosions overlying hyperplastic

In enteric fever, any anatomic segment of the alimentary Peyer’s patches
tract may be involved, but the characteristic pathology n Ulcers are typically very deep, with the base at the muscularis propria.
is most prominent in the ileum, appendix, and right n Rare granulomas
n Nontyphoid
colon and is associated with Peyer’s patches. Grossly,
n Features of acute self-limited colitis
the bowel wall is thickened, and raised nodules may
be seen corresponding to hyperplastic Peyer’s patches. Differential Diagnosis
Aphthoid ulcers overlying Peyer’s patches, linear n Other bacterial infections (Yersinia spp., Shigella spp.)
ulcers, discoid ulcers, or full-thickness ulceration and n Crohn’s disease
necrosis are common as disease progresses. Perforation n Ulcerative colitis
and toxic megacolon may also be seen, as may sup-

purative mesenteric lymphadenitis. Occasionally, the
mucosa is grossly normal or only mildly inflamed and
edematous. Endoscopic findings in nontyphoid salmo-
Ancillary Studies
nellosis include mucosal redness, ulceration, and exu-
dates, but the characteristic nodularity and marked
edema are not generally seen. Stool cultures followed by serologic typing are the gold
standard for detection, and blood cultures may also be of
Microscopic Findings use if the patient is septic.
Macrophages predominate in enteric fever (Fig. 9.12A).

Peyer’s patches become hyperplastic, and then acute
inflammation of the overlying epithelium is seen
(Fig. 9.12B). Eventually, the lymphoid follicles are infil-
trated and obliterated by macrophages. Necrosis begins The differential diagnosis of typhoid fever includes
in the Peyer’s patch and spreads to surrounding mucosa, yersiniosis and other infectious processes, as well as
which eventually ulcerates. The ulcers are typically Crohn’s disease, and there may be significant histologic
A B
FIGURE 9.12
Mononuclear cells comprise the inflammatory infiltrate in enteric fever, with a dearth of neutrophils (hematoxylin and eosin [H&E]) (A). Ulcer overlying a
Peyer’s patch in typhoid fever (H&E) (B). Case courtesy of Dr. A. Brian West.
overlap. Neutrophils and granulomas are often more persons, and patients with cardiac valve abnormalities
prominent in the latter two diseases. The differen- or indwelling prostheses. Salmonella spp. are sensitive
tial diagnosis of nontyphoid Salmonella infection also to several antibiotics, including ciprofloxacin, penicil-
includes other causes of acute self-limited infectious coli- lins, and quinolones.
tis, as well as ulcerative colitis. In addition, Salmonella
infection may complicate preexisting idiopathic IBD.
Although significant crypt distortion has been reported
in some cases of salmonellosis, it is likely to be more pro- SHIGELLOSIS
nounced in ulcerative colitis. Clinical presentation and
stool culture may be helpful in resolving the differential Shigella spp. are virulent, invasive, gram-negative bacilli
diagnosis. that cause severe bloody diarrhea. They are a major
cause of infectious diarrhea worldwide. Shigella dysen-
teriae is the most common species isolated, although
Shigella sonnei and Shigella flexneri are increasingly
reported in the United States. The infective dose is low
(as few as 10–100 in S. dysenteriae type 1). Shigella
Although the vast majority of Salmonella infections spp. are generally ingested from water contaminated
in developed countries resolve with antibiotics and with feces, but person-to-person transmission is also
supportive care, illness may progress to septicemia possible through the fecal–oral route. Infants; young
and death, particularly in older adults and very young children; and malnourished, immunocompromised,
people and in patients who are ill for other reasons. and debilitated patients are most commonly affected
Delayed treatment is associated with higher mortal- in developed countries. Like salmonellosis, rare cases
ity rates, and antibiotics are particularly important of chronic shigellosis may simulate IBD grossly and
for neonates, older patients, immunocompromised microscopically.
Shigellosis—Pathologic Features
Gross Findings
Symptoms include abdominal pain, fever, and watery
n Hemorrhagic mucosa, with exudates that may form
diarrhea followed by bloody diarrhea. Chronic disease pseudomembranes
is rare. Perforation and hemolytic-uremic syndrome n Ulcerations may be present
associated with Shigella infection have been rarely
described. Most studies of mortality in shigellosis were Microscopic Findings
performed in underdeveloped nations, and figures range n Early infection
n Acute self-limited colitis with cryptitis, crypt abscesses, ulceration

from 2% to 10%. The mortality rate is significantly
n Pseudomembranes or aphthoid ulcers may be seen
higher (>20%) if patients become septic.
n Later infection
n Increased mucosal destruction with a predominantly neutrophilic
n Marked architectural distortion to an extent that mimics idiopathic
SHIGELLOSIS—FACT SHEET inflammatory bowel disease
Definition Differential Diagnosis

n Gram-negative bacterium causing severe bloody diarrhea n Other infections, especially Clostridioides difficile and
enteroinvasive Escherichia coli

Incidence and Location n Inflammatory bowel disease
n Colon, with the left colon most severely affected
Clinical Features
n Abdominal pain, fever
n Watery diarrhea followed by bloody diarrhea

Ancillary Studies
n Chronic disease is rare (and may mimic ulcerative colitis and
Crohn’s disease)
n Perforation and hemolytic-uremic syndrome occasionally develop
n Severity worse in debilitated or immunocompromised patients Stool culture requires rapid inoculation onto appro-
priate culture plates because Shigella organisms are
Prognosis and Therapy fastidious and die quickly. Multiple cultures may be
n Supportive care necessary. Stool cultures are more sensitive than rec-
n Selected antibiotics because Shigella organisms have multidrug
tal swabs. PCR, DNA probes, and serologic studies are
resistance
also available.
Pathologic Features Differential Diagnosis
Gross Findings The differential diagnosis of early shigellosis is primar-

ily that of other infections, particularly EIEC and C. dif-
The large bowel is typically affected, with the left ficile. As disease progresses, it may be extremely difficult
colon more severely involved. The mucosa is hemor- to distinguish shigellosis from Crohn’s disease or ulcer-
rhagic, with exudates that may form pseudomembranes. ative colitis both endoscopically and histologically. Stool
Ulcerations may be present as well. cultures and clinical presentation may be helpful in this
instance.
Early infection manifests as acute self-limited colitis with

cryptitis, crypt abscesses (often superficial), and ulcer-
ation. Pseudomembranes similar to C. difficile infection
may be seen, as may aphthoid ulcers similar to those of Treatment includes supportive care with fluid and
Crohn’s disease. As disease progresses, there is increased electrolyte replacement and antibiotics, particularly in
mucosal destruction with a mixed inflammatory infil- children, people who are severely ill, and HIV-positive
trate containing many neutrophils in the lamina propria. patients. Antibiotics lessen the mortality rate and shorten
Marked architectural distortion to an extent that mimics the duration of the illness. Most Shigella spp. have at least
idiopathic IBD is the best-described histologic pattern in some degree of antibiotic resistance; trimethoprim–sulfa-
mucosal biopsies, most likely because patients do not typ- methoxazole, third-generation cephalosporins, and some
ically undergo colonoscopy early in the disease course. fluoroquinolones are drugs of choice.
CAMPYLOBACTER SPP. Pathologic Features
Campylobacter spp., particularly Campylobacter jejuni, Gross Findings

are major causes of diarrhea worldwide. Campylobacter
is the most common stool isolate identified in the United Endoscopic findings include friable colonic mucosa with
States. It is transmitted by the fecal–oral route; is found associated erythema and hemorrhage.
in contaminated meat, water, and milk; and is a common
animal pathogen. C. jejuni is most commonly associated Microscopic Findings
with gastroenteritis; Campylobacter fetus and the other
less common species are more often seen in immuno- Histologic examination most frequently shows features of
suppressed patients and homosexual men. The impor- acute infectious or self-limited colitis, including cryptitis,
tance of C. fetus may be underrecognized as a result of crypt abscesses, surface epithelial damage, and a lymph-
the difficulty of culturing it under conditions used for oplasmacytic infiltrate in the lamina propria (Fig. 9.13).
other Campylobacter strains. The infective dose is low Marked edema and superficial mucosal erosion with asso-
(ingestion of as few as 500 organisms may cause dis- ciated hemorrhage may be seen. Findings may be patchy.
ease), and invasion may occur. Although the mucosal architecture is usually well-pre-
served in Campylobacter infection, mild crypt distortion
may occasionally be seen.
Patients typically have fever, malaise, abdominal pain

(often severe), and watery diarrhea, often bloody and Campylobacter spp.—Pathologic Features
with fecal leukocytes. Symptoms generally present
Gross Findings
within 1 to 5 days of exposure and last for 4 to 10 days.
n Friable colonic mucosa
Relapse is common, although it is usually less severe n Erythema and hemorrhage
than the original attack. Immunosuppressed patients
have a higher incidence of symptomatic infection, and Microscopic Findings
symptoms are more severe. Most infections are self-lim- n Acute self-limited colitis pattern
ited, especially in healthy patients. Of note, Guillain-

Barré syndrome and reactive arthropathy are associated Differential Diagnosis
with Campylobacter infection. n Other infections that cause the acute self-limited colitis pattern
CAMPYLOBACTER SPP.—FACT SHEET
Definition
n Gram-negative bacterium
n Most common stool isolate in United States

n Colon
Clinical Features
n Fever, malaise, abdominal pain, watery diarrhea, often bloody and
with fecal leukocytes

n Symptoms generally present within 1 to 5 days of exposure and
last for 4 to 10 days

n Infection is generally self-limited, although relapse is frequent

n Supportive care in most cases FIGURE 9.13
n Erythromycin in severe cases and in immunocompromised patients Campylobacter jejuni infection showing cryptitis, surface epithelial injury, and
preservation of crypt architecture (hematoxylin and eosin).
Ancillary Studies YERSINIA SPP.—FACT SHEET
Definition
Culture and PCR on stool specimens are mainstays cul-
n Common cause of granulomatous appendicitis, enterocolitis in
ture of Campylobacter detection. Preliminary diagnosis the United States and Europe
may be made by detection of organisms in fresh stool
smears by dark-field microscopy. Rapid enzyme immu- Incidence and Location
noassay tests have also been developed, but should be n Ileum, appendix, and colon
correlated with culture results.

Clinical Features
n Signs and symptoms of enterocolitis, acute appendicitis
Differential Diagnosis n Usually self-limiting; occasionally causes chronic disease
n May have mesenteric adenopathy
The differential diagnosis primarily includes other Prognosis and Therapy

forms of infectious enterocolitis that produce the acute n Usually self-limiting
self-limited colitis pattern; stool culture may be essential n Severe cases and debilitated patients require antibiotics
to resolving the differential diagnosis.

Pathologic Features
In most uncomplicated cases of Campylobacter infection,
fluid and electrolyte replacement is the principal therapy. Gross Findings
Antibiotics are not generally indicated unless there is
high fever, severe or bloody diarrhea, or symptoms lon- Grossly, involved bowel has a thickened, edematous wall
ger than 1 week or the patient is immunocompromised or with nodular inflammatory masses centered around
septic. Erythromycin is the antibiotic of choice. Peyer’s patches. Aphthoid and linear ulcers may be
seen. Involved appendices are enlarged and mimic sup-
purative granulomatous appendicitis; perforation is
YERSINIOSIS often seen. Involved lymph nodes may show gross foci
of necrosis.
Yersinia enterocolitica and Yersinia pseudotuberculosis are
the two Yersinia species pertinent to human GI disease. Microscopic Findings
Yersinia is one of the most common causes of bacterial
enteritis in Western and Northern Europe, and numer- Both suppurative and granulomatous patterns of inflam-
ous cases have been documented in North America and mation may be seen, and a mixture of the two is common.
Australia. Yersinia spp. may be found in many food GI infection with Y. pseudotuberculosis has characteris-
products, including meats (particularly undercooked tically been described as a granulomatous process with
pork), dairy products, and water. central microabscesses, almost always accompanied
by mesenteric adenopathy. Infection with Y. enteroco-
litica has not typically been associated with discrete
granulomas but has been characterized by hyperplastic
Peyer’s patches with overlying ulceration and accom-
These gram-negative coccobacilli are causative agents in panying acute inflammation, hemorrhagic necrosis,
appendicitis, ileitis, colitis, and mesenteric lymphadeni- and palisading histiocytes. Recent studies have shown
tis. In addition, they are responsible for many cases of iso- that there is significant overlap between the histologic
lated granulomatous appendicitis. Infection with either features of Y. enterocolitica and Y. pseudotuberculosis
species may cause symptoms and signs of an acute abdo- infection and that either species may show epithelioid
men, chronic abdominal pain, and diarrhea. Although granulomas (Fig. 9.14A), lymphoid hyperplasia (see
yersiniosis is usually a self-limited process, chronic infec- Fig. 9.13B), epithelioid granulomas with prominent
tions (including chronic colitis) and persistent abdominal lymphoid cuffing (see Fig. 9.13C), transmural lymphoid
pain have been well documented. Immunocompromised aggregates, giant cells, mucosal ulceration, cryptitis,
and debilitated patients, as well as patients on deferoxam- and concomitant lymph node involvement. Some cases
ine or with iron overload resulting from other causes, are show only nonspecific features of acute self-limited
at significant risk for serious disease. colitis.
Yersinia spp.—Pathologic Features
Gross Findings
n Thickened, edematous wall with nodular inflammatory masses
centered around Peyer’s patches

n Aphthoid and linear ulcers may be seen
n Involved appendices are enlarged and mimic typical suppurative
appendicitis; perforation is frequent

n Mesenteric lymph node involvement is common
n Often mix of both suppurative and granulomatous patterns of
inflammation
A
n Lymphoid hyperplasia, epithelioid granulomas with prominent
lymphoid cuffing and sometimes central abscesses, transmural

lymphoid aggregates, giant cells, mucosal ulceration, and cryptitis
n There is significant overlap between the histologic features of
Yersinia enterocolitica and Yersinia pseudotuberculosis infection

n Rare cases show only acute self-limited colitis
n Primarily Crohn’s disease
n Other infections such as Mycobacterium tuberculosis, Salmonella
spp.
B
Ancillary Studies
Cultures, serologic studies, and particularly PCR assays

are the most useful diagnostic aids.
The major differential diagnoses of Yersinia infection

include other similar infectious processes, particularly
mycobacterial infection and salmonellosis. Acid-fast
stains and culture results should help to distinguish
C
mycobacterial infection; clinical features and the pres-
ence of granulomas may help to distinguish yersiniosis
FIGURE 9.14
from salmonellosis.
Yersinia enterocolitica infection. A, Mucosal ulceration, lymphoid hyperplasia,
Crohn’s disease and yersiniosis have a long and compli- and epithelioid granulomas are seen (hematoxylin and eosin [H&E]). B, Linear
cated relationship. Both may show similar histologic fea- arrangement of mural and serosal lymphoid aggregates in Yersinia infection
tures, and, in fact, isolated granulomatous appendicitis has can mimic Crohn’s disease (H&E). C, Yersinia pseudotuberculosis infection.
Granulomatous inflammation with central microabscess formation (H&E).
in the past frequently been interpreted as primary Crohn’s
disease of the appendix. However, patients with granu-
lomatous inflammation confined to the appendix rarely Prognosis and Therapy
develop idiopathic IBD. Features that may favor Crohn’s
disease include cobblestoning of mucosa and creeping fat
grossly and changes of chronicity microscopically, includ- Most cases of yersiniosis resolve spontaneously. Yersinia
ing crypt distortion, thickening of the muscularis mucosa, spp. are susceptible to many antibiotics, and therapy is rec-
and prominent neural hyperplasia. However, some cases ommended in patients with severe infections or bacteremia
are indistinguishable on histologic grounds alone. and in the context of immunocompromise or debilitation.
VIBRIO CHOLERAE AND RELATED Microscopic Findings

ORGANISMS
The small intestinal mucosa usually appears unremark-
able. Mucin depletion of the small intestinal epithelium,
Vibrio cholerae and other members of the genus, Vibrio increased chronic inflammation in the lamina propria,
(Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio algi- and epithelial cell disarray have been reported.
nolyticus), are gram-negative bacilli found in saltwa-
ter environments. Consequently, infection is usually
acquired from consumption of contaminated raw or Vibrio cholerae—Pathologic Features
undercooked seafood. The illness known as cholera is
caused by toxigenic serogroups of V. cholerae O1 and Gross Findings
O139. Toxigenic V. cholerae has been responsible for sev- n Colonoscopy is usually unremarkable
eral global pandemics of life-threatening gastroenteritis.

The O75 and O141 serogroups produce less severe dis- Microscopic Findings
ease. In the United States, the Florida Gulf coast and n Usually normal
n Mucin depletion
Atlantic coast are the most common sources of infection.
n Increased lamina propria inflammation
n Degenerative epithelial cell changes
Clinical Features
n Other cause of bacterial enterocolitis
Cholera is characterized by voluminous watery diarrhea,

sometimes exceeding 1 L/hr, in the absence of pain or fever.
The intestinal mucosal lining may also be shed, appearing
as white flecks of tissue in so-called “rice water stool”.
Ancillary Studies
Vomiting is also common. The copious release of fluids can
lead to severe dehydration and electrolyte imbalance.
Culture, PCR, and serologic studies may aid the diagnosis.
VIBRIO CHOLERAE—FACT SHEET Differential Diagnosis

Definition
n Gram-negative bacillus found in saltwater environments V. cholerae is indistinguishable from other causes of bac-
terial enterocolitis that produce minimal changes in the
Incidence and Location intestinal mucosa. Enterocolitis caused by some non-O1
n Small intestine strains of V. cholerae and other Vibrio spp. assumes an
acute self-limited colitis pattern.
Clinical Features
n Voluminous watery diarrhea
n Vomiting
n Dehydration Prognosis and Therapy

n Electrolyte imbalances
n Absence of pain and fever
Antibiotic therapy (tetracyclines, fluoroquinolones,

Prognosis and Therapy macrolides) can shorten the course and reduce the vol-
n May lead to hypovolemic shock or cardiac arrest
ume of diarrhea. Untreated cases of cholera may result
n Antibiotics (tetracyclines, fluoroquinolones, macrolides)
in death from hypovolemic shock or cardiac arrest.
AEROMONAS SPP.
Pathologic Features
Aeromonas spp., initially thought to be nonpathogenic
Gross Findings gram-negative bacteria, are increasingly recognized as
causes of gastroenteritis in both children and adults.
Despite the severity of disease, Vibrio spp. are nonin- The motile Aeromonas hydrophila and Aeromonas sobria
vasive; thus, colonoscopic findings are usually normal. most often cause GI disease in humans.
The typical presentation is bloody diarrhea, sometimes

chronic, accompanied by nausea, vomiting, and cramp-
ing pain. The diarrhea may contain mucus as well as
blood. The duration of illness varies widely, ranging from
a few days to several years, indicating that Aeromonas
infection can cause a chronic colitis.
AEROMONAS SPP.—FACT SHEET
Definition
n Gram-negative bacterium initially believed nonpathogenic; now
increasingly recognized as cause of infectious enterocolitis

n Colon; often segmental distribution
Clinical Features
n Bloody diarrhea, which can be chronic; nausea, vomiting,
cramping pain

n Most cases resolve spontaneously; susceptible to multiple
antibiotics if needed
Pathologic Features

Cryptitis and mucosal ulceration with slight basal lymphoplasmacytosis in
Endoscopically, signs of colitis may be seen, including culture-proven Aeromonas infection (hematoxylin and eosin).
edema, friability, erosions, exudates, and loss of vascular
pattern; the features are often segmental and may mimic
ischemic colitis or Crohn’s disease. A pancolitis mimick- Ancillary Studies
ing ulcerative colitis has also been described.
PCR or stool cultures are used to make the diagnosis.
The histologic features are usually those of acute Differential Diagnosis

self-limited colitis. However, basal lymphoplasmacytosis
may be seen (Fig. 9.15). The differential diagnosis includes other infectious
processes, ischemic colitis, and chronic idiopathic IBD.
Culture should help exclude other infections, and typical
Aeromonas spp.—Pathologic Features features of ischemia (crypt withering, mucosal necrosis)
are not present with Aeromonas spp. When architectural
Gross Findings
distortion is present in a patient with chronic symptoms,
n Edema, friability, erosions, exudates, and loss of vascular pattern
it may be very difficult to resolve the issue of Aeromonas
n Often segmental
n Pancolitis mimicking ulcerative colitis has been seen

infection versus Crohn’s disease or ulcerative colitis.
Some authorities recommend culturing for Aeromonas
Microscopic Findings spp. in all patients with refractory chronic IBD.
n Usually those of acute self-limited colitis
n Ulceration and basal lymphoplasmacytosis may be seen

n Crohn’s disease
Most cases resolve spontaneously. Aeromonas spp. are
n Ischemic colitis (particularly grossly)
n Ulcerative colitis (grossly, if pancolitis present)

susceptible to many antibiotics, which can be used in
severe or chronic infections.
CLOSTRIDIAL INFECTIONS OF THE GUT Necrotizing enterocolitis (typhlitis) is a serious

complication of neutropenia as a result of chemother-
apy in patients with hematopoietic and solid tumors,
Clostridial organisms are some of the most potent col- as well as in patients with primary neutropenia. Most
lections of toxigenic bacteria in existence. The most patients have received chemotherapy within the previ-
important GI pathogens are Clostridioides difficile ous month before the onset of colitis. C. septicum has
and Clostridium septicum, as discussed subsequently. been frequently reported as a causative organism, espe-
Clostridium perfringens (welchii) causes a rare form of cially in adults. C. septicum infection is also associated
life-threatening necrotizing enteritis. The largest out- with malignancies (particularly adenocarcinoma) in the
breaks have been reported in Papua New Guinea among colon and distal ileum. Patients usually present with the
patients who consumed large amounts of sweet pota- abrupt onset of GI hemorrhage, fever, abdominal pain
toes and inadequately cooked pork contaminated with and distention, and diarrhea. Perforation is a complica-
pig intestine; the infection has been referred to as “pig- tion that may result in peritonitis, sepsis, and death.
bel” in this region. Cases in developed countries have
been reported in patients who consume large amounts
of food after starvation or who have diabetes. Resected CLOSTRIDIOIDES DIFFICILE–RELATED
small intestinal segments are dusky red with serosal PSEUDOMEMBRANOUS COLITIS—FACT SHEET
exudate. The mucosa may contain pseudomembranes.
Microscopic examination reveals transmural necrosis Definition
with hemorrhage and mucosal and submucosal pneu- n Colitis caused by overgrowth of Clostridioides difficile, usually
matosis. Gram stains reveal club-shaped gram-positive after antibiotic administration

n Most common nosocomial gut pathogen
organisms adherent to necrotic mucosa.
n Anywhere in colon, often patchy distribution; the rectum may be
■ CLINICAL FEATURES spared
C. difficile is the most common nosocomial GI pathogen. Clinical Features

Infection is usually related to prior antibiotic exposure n Usually prior, orally administered antibiotic exposure; diarrhea can
(especially orally administered antibiotics) because happen weeks after antibiotic therapy
n Ranges from mild diarrhea to fulminant colitis with toxic
the organisms cannot infect in the presence of normal
megacolon
colonic flora. n Watery diarrhea initially; may be accompanied by abdominal pain,
The majority of patients are old, although infection is cramping, fever, and leukocytosis
certainly not limited to this group. In addition, the inci- n Bloody diarrhea sometimes seen
dence of C. difficile infection has increased in patients

with chronic idiopathic IBD and negatively affects clin- Prognosis and Therapy
ical outcome in terms of both increased hospitalization n Remove offending drug
n Supportive measures
and need for colectomy.
n Oral vancomycin or Flagyl
Recurrent disease is common despite successful treat-
ment and is seen in up to 50% of cases; the incidence of
recurrent disease appears to be increasing. Furthermore,
the incidence of severe or life-threatening C. difficile coli-
tis in North America has increased recently. This increase CLOSTRIDIUM SEPTICUM–RELATED NECROTIZING
ENTEROCOLITIS—FACT SHEET
has been linked to an epidemic strain of C. difficile known
as strain BI/NAP1; this strain is hypervirulent, with
Definition
increased production of both toxins A and B, and is resis-
n Neutropenic enterocolitis
tant to fluoroquinolones. n Usually in the context of previous chemotherapy
Presentation ranges from mild diarrhea to pseu-
domembranous to fulminant colitis with perforation Incidence and Location
or toxic megacolon. Watery diarrhea is most common n Right colon preferentially involved
initially and may be accompanied by abdominal pain,

cramping, fever, and leukocytosis (sometimes marked). Clinical Features
Bloody diarrhea is variably seen. Symptoms can occur n Gastrointestinal hemorrhage, with fever, abdominal pain and
distention, diarrhea
up to several weeks after discontinuation of antibiotic
n Perforation a frequent complication
therapy. Patients with more severe disease may not have
diarrhea, and the only clues to diagnosis may be fever, Prognosis and Therapy
marked leukocytosis, and a markedly tender, distended n Antibiotics and supportive measures
abdomen. An associated reactive polyarthritis also has n Surgery may be required to prevent or treat perforation
been described.
Pathologic Features
Gross Findings
Endoscopically, classic pseudomembranous colitis shows

yellow-white pseudomembranes, most commonly in the
left colon. The plaques bleed when scraped. The distribu-
tion may be patchy, and the rectum may be spared. Less
striking findings may also be seen, including erythema
and friability of the mucosa without pseudomembranes.
Typical histologic findings may be seen, however, even
in the absence of grossly visible pseudomembranes.
The right colon is preferentially involved in necro-
tizing enterocolitis, although the ileum and other sites
in the colon may be affected. Gross findings include
diffuse dilation and edema of the bowel, with varying
severity of ulceration and hemorrhage. Exudates and
pseudomembranes resembling C. difficile colitis may be
seen.
Classic pseudomembranous colitis features “volcano”

lesions with intercrypt necrosis and ballooned crypts
giving rise to the typical laminated pseudomembrane
composed of fibrin, mucin, and neutrophils (Fig. 9.16).
Dilated crypts lined by attenuated epithelium are filled FIGURE 9.16
with neutrophils and mucin. They may also contain “Volcano” lesion of Clostridioides difficile–related pseudomembranous coli-
sloughed epithelial cells in their lumina or near the tis. Note the ballooned crypts containing neutrophils, intercrypt necrosis, and
laminated pseudomembrane composed of fibrin, mucus, and neutrophils
mucosal surface that simulate signet ring cells. More (hematoxylin and eosin).
severe and prolonged pseudomembranous colitis may
lead to full-thickness mucosal necrosis. Less charac-
teristic lesions, usually focal active colitis with occa-
sional crypt abscesses but lacking pseudomembranous
features, have been well described in association with
other evidence of C. difficile infection. C. difficile infec-
tion can complicate idiopathic IBD. Unfortunately,
pseudomembranes are inconsistently present in biopsy
samples from these patients and, in fact, may be pres-
ent in active IBD in the absence of C. difficile infec-
tion. Biopsy samples from patients with persistent or
recurrent C. difficile colitis may display overlapping fea-
tures with IBD. Stool-based diagnostic assays are thus
invaluable for confirming the diagnosis of C. difficile
infection.
In necrotizing enterocolitis, microscopic changes
range from mild hemorrhage to prominent submuco-
sal edema, ulceration, marked hemorrhage, and focal FIGURE 9.17
necrosis, often with a striking absence of neutrophils Necrotizing enterocolitis in a chemotherapy patient. Note the sections of
and other inflammatory cells (Figs. 9.17 and 9.18). ileum and cecum with ulceration, hemorrhagic necrosis, and a coating of
surface bacteria (hematoxylin and eosin).
However, neutrophils are sometimes present despite
peripheral neutropenia, although the severity of muco-
sal and mural damage appears out of proportion to
inflammation. A pseudomembranous exudate resem- organisms can be detected in the wall of the bowel on
bling C. difficile–related colitis may be seen. Sometimes Gram stain.
Clostridioides difficil–Related Pseudomembranous

Colitis—Pathologic Features
Gross Findings
n Yellow-white pseudomembranes, most commonly in the left
colon; distribution may be patchy

n Plaques bleed when scraped
n Erythema and friability of the mucosa may be present, without
pseudomembranes
n Classic features
n “Volcano” lesions with intercrypt necrosis and ballooned crypts
giving rise to laminated pseudomembrane composed of fibrin,

mucin, and neutrophils
n Dilated crypts filled with neutrophils and mucin
FIGURE 9.18
n Exceptions Necrotizing enterocolitis. Note the lack of neutrophils (hematoxylin and
n Severe and prolonged pseudomembranous colitis may lead to eosin).
full-thickness mucosal necrosis
n Some cases show only focal active colitis and lack
pseudomembranes
n Stool-based assays are the key to diagnosis
The term pseudomembranous colitis is a description
n Ischemia
n Other infections, including Shigella spp. and enterohemorrhagic

of an inflammatory pattern, not a specific diagnosis.
Escherichia coli Although most cases of pseudomembranous colitis are
related to C. difficile infection, other infectious entities
as well as ischemic colitis may have similar appear-
ances. A hyalinized lamina propria favors the diagno-
Clostridium septicum–Related Necrotizing sis of ischemia; other features, such as crypt withering,
Enterocolitis—Pathologic Features
pseudomembranes, and mucosal necrosis, may be seen
in either entity. Endoscopically, pseudomembrane for-
Gross Findings
mation is also seen more often in pseudomembranous
n Right colon is preferentially involved
n Diffuse dilation and edema of bowel; varying severity of

colitis, although this finding may be present in isch-
ulceration and hemorrhage emia as well.
n Exudates and pseudomembranes common History of antibiotic use and stool assay for C. difficile
toxin may be invaluable in sorting out this differential
Microscopic Findings diagnosis. Early laboratory tests for C. difficile involved
n Range from mild hemorrhage to prominent submucosal edema,
enzyme immunoassays for toxins A and B produced by
ulceration, marked hemorrhage, and focal necrosis
n Often with a striking absence of inflammatory cells
the bacteria but displayed suboptimal sensitivity. Adding
n Neutrophils sometimes found despite peripheral neutropenia
detection of glutamate dehydrogenase, an enzyme pro-
n Overall, severity of injury out of proportion to inflammation duced by C. difficile, improved sensitivity but did not
n Pseudomembranous exudate resembling Clostridioides difficil– distinguish toxigenic from nontoxigenic strains. Highly
related colitis may be seen sensitive and specific PCR-based assays that detect genes
n Sometimes organisms are seen in the bowel wall with Gram
stain
for toxins A, B, and C are now the preferred definitive
tests, and enzyme immunoassays may be used for rapid
Differential Diagnosis screening.
n Ischemic colitis The differential diagnosis for necrotizing enteroco-
n Pseudomembranous colitis litis includes ischemic colitis and pseudomembranous
colitis. The appropriate clinical setting is most helpful is
supporting a diagnosis of necrotizing enterocolitis.
Ancillary Studies
The C. difficile toxin enzyme immunoassays and nucleic
acid amplification tests are the most helpful diagnostic
aids in pseudomembranous colitis. Culture is the most Treatment of pseudomembranous colitis includes a
helpful technique for confirming the diagnosis of C. sep- combination of removal of the offending drug, sup-
ticum infection. portive measures, and antibiotics (oral vancomycin or
metronidazole). Treatment of necrotizing enterocolitis Mycobacterium avium-intracellulare complex is the

is controversial; whereas some recommend antibiotics most common atypical Mycobacterium organism iso-
and supportive measures, others recommend segmental lated from the GI tract. The small bowel is preferentially
resection of the involved bowel. Surgery may be required involved, but colonic involvement may also be present,
to prevent or treat perforation in severe cases. as may mesenteric adenopathy.
■ KLEBSIELLA OXYTOCA Clinical Features
Klebsiella oxytoca is a cytotoxin-producing gram negative Symptoms of colonic tuberculosis are nonspecific and
bacillus. It causes antibiotic-associated diarrhea, usually include weight loss, fever, abdominal pain, diarrhea,
in young, otherwise healthy individuals who take pen- or a palpable abdominal mass. Complications include
icillin and its derivatives. K. oxytoca has also been iso- hemorrhage, perforation, obstruction, or malabsorp-
lated from the stools of healthy patients and thus may tion. Mesenteric adenopathy is common. Symptoms
not be pathogenic in the absence of antibiotic treatment. in MAI infection are similar and often reflect systemic
Patients experience bloody diarrhea and abdominal disease.
cramps within 3 to 7 days of starting antibiotic treat-
ment. Laboratory findings include leukocytosis and
elevated C-reactive protein. Most patients recover com-
pletely within 4 days of stopping antibiotic treatment. MYCOBACTERIAL INFECTIONS OF THE GUT—FACT SHEET
Colonoscopy reveals segmental hemorrhagic colitis
Location
with rectal sparing. The right colon is preferentially
n Mycobacterium tuberculosis: anywhere in colon, but ileocecum
affected, but disease may extend to the transverse and preferentially involved
descending segments. Mucosal edema, erosion, and lon- n Mycobacterium avium-intracellulare complex: small bowel more
gitudinal ulcers are also typical, but pseudomembranes often involved than the colon
are not usually observed. The histologic picture is that
of ischemic colitis, including “withered” crypts with Clinical Features
increased mitotic figures, crypt loss and apoptosis, and n Mycobacterium tuberculosis: weight loss, fever, abdominal pain,
diarrhea, or a palpable abdominal mass

mucosal hemorrhage
n Complications include hemorrhage, perforation, obstruction, and
The differential diagnosis includes ischemia and malabsorption
other infections. The distinction between EHEC colitis n Mesenteric adenopathy is common
or Shigellosis and K. oxytoca is best made using culture n Mycobacterium avium-intracellulare complex: similar to M.
results; furthermore, the former two infections are not tuberculosis; often reflects systemic disease
associated with antibiotic use. Finally, C. difficile colitis
is antibiotic associated but usually occurs in ill and hos-
n Multidrug antimycobacterial regimens
pitalized patients and shows pseudomembranes endo- n Surgery required for obstruction, perforation, and bleeding
scopically and histologically.
MYCOBACTERIAL INFECTIONS OF THE GUT

Pathologic Features
Although more common in developing countries and
immigrant populations, there has been a remarkable Gross Findings
resurgence of tuberculosis in Western countries largely
because of AIDS but also because of institutional over- The ileocecal valve is often deformed and gaping in
crowding and immigrant populations. Although many cases of ileocecal M. tuberculosis infection. Multiple
patients present with pulmonary symptoms, GI symp- and segmental lesions with skip areas are common.
toms may be the initial presenting findings in these Strictures and ulcers are the most common endoscopic
patients, and primary GI tuberculosis has been well doc- findings, along with thickened mucosal folds and
umented. The ileocecal and jejunoileal areas are the most inflammatory nodules. The ulcers are often circumfer-
commonly involved areas of the gut in M. tuberculosis ential and transverse. Large inflammatory masses, usu-
infection followed by the appendix and ascending colon; ally involving the ileocecum, may be seen. Endoscopic
duodenal, gastroesophageal, and anorectal involvement findings with MAI infection are usually unremarkable,
are much less common. This distribution is probably except for occasional white nodules, small ulcers, or
caused by the organism’s affinity for lymphoid tissue. hemorrhages.
In M. tuberculosis infection, the characteristic histo-

logic lesion is caseating granulomas, which may be
present at any level of the wall of the gut (Fig. 9.19).
Granulomas are often confluent, with a peripheral rim
of lymphocytes. Granulomas may be hyalinized and
calcified. Aphthoid ulcers or frank ulceration, as well
as inflammation of submucosal vessels, may be seen
as well. Acid-fast stains may demonstrate organisms,
but culture may be required; in addition, excellent PCR
assays are available. Purified protein derivative tests
are unreliable in immunocompromised and debilitated
patients.
In MAI infection, histology varies with immune sta-
tus. Immunocompetent patients show a granulomatous
response (Fig. 9.20), either necrotizing or non-necro-
tizing. Immunocompromised patients generally have a FIGURE 9.20
diffuse infiltration of histiocytes containing the bacilli, Mycobacterium avium-intracellulare complex infection. Note the epithelioid,
noncaseating granulomas in the ileocecum of an immunocompetent person
with little inflammatory response (Fig. 9.21). Rarely, (hematoxylin and eosin).
poorly formed granulomas occur in immunocompro-
mised patients.
B
FIGURE 9.21
Gastrointestinal Mycobacterium avium-intracellulare complex infection.
FIGURE 9.19 A, Infiltrate of foamy macrophages in a patient with AIDS (hematoxy-
Colonic Mycobacterium tuberculosis with confluent caseating granulomas in lin and eosin). B, Numerous acid-fast bacilli within foamy macrophages
the mucosa (hematoxylin and eosin). (Ziehl-Neelsen).
Mycobacterial Infections Of The Gut—Pathologic Features Prognosis and Therapy
Gross Findings
Gastrointestinal tuberculosis responds to the same med-
n Mycobacterium tuberculosis
n Deformed and gaping ileocecal valve

ication regimen as pulmonary tuberculosis. Surgical
n Segmental lesions with skip areas, thickened mucosal folds, therapy may be required for obstructive disease, perfora-
and raised nodules tion, or hemorrhage. MAI of the GI tract is also treated a
n Strictures and ulcers are the most common endoscopic with multidrug antimycobacterial regimens.
findings; ulcers are often circumferential and transverse
n Large, obstructing inflammatory masses
n Usually normal colonoscopy; rare findings include white
nodules, small ulcers, or hemorrhages

SYPHILIS (TREPONEMA PALLIDUM)
Microscopic Findings Gastrointestinal syphilis commonly involves the ano-

n Mycobacterium tuberculosis
rectum. Homosexual men are at particularly high risk
n Characteristic histologic lesion is caseating granulomas in any
of infection, and many authorities believe that syphilis,
part of gut wall
n Often confluent, with a rim of lymphocytes at the periphery
particularly anorectal syphilis, is markedly underdiag-
n May be rare or hyalinized and calcified nosed as a result of the variability of the clinical findings
n Inflammation of submucosal vessels and a low index of suspicion.
n Acid-fast stains may demonstrate organisms
n Immunocompetent patients show a granulomatous response,
either necrotizing or non-necrotizing ■ CLINICAL FEATURES

n Immunocompromised patients have a diffuse infiltration of
histiocytes containing the bacilli, with little inflammatory response

Patients are often asymptomatic, but common pre-
Differential Diagnosis senting symptoms in patients with syphilitic proctitis
n Other infectious processes causing granulomas, histiocytic
include pain, often with defecation; tenesmus; constipa-
infiltrate
n Crohn’s disease
tion; bleeding; and anal discharge, which may be mucoid
or bloody.
Ancillary Studies
SYPHILIS—FACT SHEET
The bacilli stain with acid-fast stains, as well as PAS
stains. Organisms are generally abundant in immunocom- Definition
n Sexually transmitted infection with Treponema pallidum
promised patients but may be hard to detect in healthy
patients. Culture and PCR assays may also be helpful.
n Usually anorectal

n Often asymptomatic
n Bleeding, discharge, ulceration may be present
The differential diagnosis of M. tuberculosis infection

includes other granulomatous infections, especially Prognosis and Therapy
n Penicillin is the treatment of choice
yersiniosis and fungal diseases. The granulomas of
yersiniosis are typically noncaseating, but there may be
considerable histologic overlap. Crohn’s disease may be
difficult to distinguish from tuberculosis; features favor-
Pathologic Features
ing Crohn’s disease are linear rather than circumferen-
tial ulcers, transmural lymphoid aggregates, and deep
fistulas and fissures. Tuberculosis also commonly lacks Gross Findings
mucosal cobblestoning. Atypical mycobacteria, such
as Mycobacterium kansasii and Mycobacterium bovis, Gross findings in primary anorectal syphilis include anal
may yield a similar histologic picture. The differential chancres (indurated, circular lesions, single or multiple,
diagnosis of MAI includes other infectious processes with variable tenderness) or a mild proctitis. Signs of sec-
causing a histiocytic infiltrate, such as infection with ondary syphilis typically present 6 to 8 weeks later and
Rhodococcus equi. include masses, mucocutaneous rash, or condyloma lata
(raised, moist, smooth warts that secrete mucus and are Ancillary Studies
associated with itching and a foul odor). Inguinal ade-
nopathy is typical. The gross features of primary and sec-
ondary infection sometimes coexist. The mass lesions of Immunohistochemical stains for T. pallidum are avail-
secondary syphilis may mimic malignancy, and surgical able but results are negative in the majority of cases.
removal without a prior biopsy should be avoided. When present, spirochetes cluster at the junction of the
lamina propria and anal squamous epithelium.
Histologically, syphilitic proctitis features lympho-

histiocytic infiltrate with prominent plasma cells
and lymphoid aggregates, mild acute inflammation,
crypt distortion, and rare, poorly formed granulomas., The gross differential diagnosis of chancre includes
Prominent capillary endothelial cells with perivascular anal fissures, fistulas, and traumatic lesions. Condyloma
plasma cells (proliferative endarteriolitis) are a clue to acuminata are drier and more keratinized than condy-
the diagnosis. Syphilitic proctitis may be nonspecific, loma lata.
showing only features of acute infectious-type colitis Several other types of infectious proctocolitis are
without a significant increase in plasma cells (Fig. 9.22). common among homosexual men and should be con-
Gastritis is a rare complication of syphilis and incites a sidered in the differential diagnosis of sexually acquired
similar inflammatory reaction, including intense lymph- infectious proctocolitis. Patients generally present
oplasmacytic inflammation and occasional granulomas. with similar symptoms regardless of infectious agent,
including anal discharge, pain, diarrhea, constipation,
bloody stools, and tenesmus. Proctoscopic findings
Syphilis—Pathologic Features range from normal to mucosal friability, erosions, and
erythema.
Gross Findings
Substantial overlap between the features of syph-
n Primary syphilis: anal chancres and/or an associated mild proctitis
n Secondary syphilis: masses, a mucocutaneous rash, or condyloma lata

ilitic proctitis and IBD underscores the need for
n Inguinal adenopathy is typical
pathologists to maintain a high index of suspicion for
infectious causes of proctitis and obtain clinical history
Microscopic Findings that includes HIV infection status and sexual practices
n Syphilitic chancres: dense mononuclear cell infiltrate with if infection is suspected. Idiopathic IBD is observed to
prominent plasma cells display more active cryptitis, crypt architectural distor-
n Syphilitic proctitis: nonspecific, with features of acute self-limited
tion, and basally oriented inflammation than syphilis.
or focal active colitis with or without increase in plasma cells
n Granulomas have been reported
Unfortunately, reliable distinguishing features are yet to
be identified.
n Other infectious processes
n Anal fissures, fistulas, and traumatic lesions
n Condyloma acuminata
Penicillin is the treatment of choice in most cases of

syphilis. HIV-positive patients should be monitored par-
ticularly closely because the infection may have a more
aggressive course in this population.
■ CHLAMYDIA TRACHOMATIS
Chlamydia trachomatis (serotypes L1, L2, and L3) is

the causative agent of lymphogranuloma venereum
(LGV). Although the anorectum is the most common
site, LGV has been described in the ileum and colon as
well. It also causes periappendicitis in women with pel-
FIGURE 9.22 vic inflammatory disease. Most patients have a lymph-
Syphilitic proctitis with increased plasma cells in the lamina propria (hema- oplasmacytic infiltrate in the mucosa and submucosa,
toxylin and eosin). Courtesy of Drs. Rodger C. Haggitt and Mary P. Bronner. but neutrophils may also be prominent. Granulomatous
inflammation is sometimes present. Crypt distortion, (especially gonorrhea), thus complicating the clinical
crypt abscesses, ulceration, fissuring ulcers, neural picture.
hyperplasia, and fibrosis have also been described. In
addition, LGV may produce a striking follicular proc-
titis. Because of these latter features, LGV may be
difficult to distinguish from Crohn’s disease or ulcer- INTESTINAL SPIROCHETOSIS—FACT SHEET
ative colitis, and culture, direct immunofluorescence
studies, and IHC may provide valuable diagnostic aids. Definition
Granuloma inguinale (Calymmobacterium granuloma- n Coating of the colonic luminal surface with spirillar bacteria,
tis) may cause anal and perianal disease that can be primarily in homosexual men
clinically and histologically similar to LGV, although
rectal involvement favors LGV. Chlamydia infection Incidence and Location
n Colon and appendix
should also be considered in the setting of periappen-
dicitis, in which it may be seen as a complication of
Clinical Features
pelvic inflammatory disease. Warthin-Starry or Giemsa
n Usually asymptomatic; some patients have diarrhea
stains may aid in visualizing the Donovan bodies typi-
cal of granuloma inguinale. Prognosis and Therapy
n Metronidazole or other antimicrobials; treatment of asymptomatic
persons is controversial
■ NEISSERIA GONORRHEAE
Pathologic Features
Gonorrhea has been reported in up to 20% of homo-
sexual men and is frequently asymptomatic. The ano-
rectum (alone or in combination with pharyngitis and Gross Findings
urethritis) is a common site of gonorrheal infection.
Proctoscopic examination is usually unremarkable. Endoscopic abnormalities are mild or absent.
Most histologic biopsy results in rectal gonorrhea
are normal; some contain a mild increase in neutro- Microscopic Findings
phils and mononuclear cells or focal cryptitis. Gram-
negative cocci can occasionally be seen on Gram stain On H&E, spirochetosis resembles a fuzzy, “fringed”
of anal discharge, and culture can also be a valuable blue line at the luminal border of the colonic mucosa
diagnostic aid. (Fig. 9.23A). Invasion is not seen. The changes can
be very focal. Most show no associated inflammatory
infiltrate, although occasionally an associated cryptitis
may be seen. Warthin-Starry or similar silver stains stain
INTESTINAL SPIROCHETOSIS the organisms intensely (Fig. 9.23B). The organisms
will also stain with Alcian blue (pH, 2.5) and PAS.
Intestinal spirochetosis is primarily seen in homosexual
men, although it has been described in a wide variety
of other conditions, including diverticular disease, ulcer-
ative colitis, and adenomas. Spirochetosis represents Intestinal Spirochetosis—Pathologic Features
infection by a heterogeneous group of related organisms,
most importantly Brachyspira aalborgi and Brachyspira Gross Findings
n Usually normal colonoscopy
pilosicoli, which are genetically unrelated to T. pallidum.
Patients with spirochetosis may harbor one or both of
these species.
n Fuzzy, “fringed” blue line at the luminal border of the colonic
mucosa
n Invasion is not seen
n May be focal
■ CLINICAL FEATURES n Most have little or no associated inflammatory infiltrate
n Warthin-Starry or similar silver stains highlight organisms
Although patients with this histologic finding often Differential Diagnosis

have symptoms such as diarrhea or anal pain and dis- n Enteroadherent Escherichia coli
charge, it is not clear that spirochetosis causes these n Prominent glycocalyx of colonic mucosa
symptoms. Many patients have concomitant infections
■ ACTINOMYCOSIS
Actinomycosis is caused by Actinomyces spp., filamen-

tous anaerobic gram-positive bacteria that are normal
inhabitants of the oral cavity and upper GI tract. They
rarely cause disease of the alimentary tract, usually
as a chronic, nonopportunistic infection, particularly
Actinomyces israelii. Infection may be at any level of
the GI tract but is usually in a solitary site. Sometimes
this infection is associated with diverticular disease.
Symptoms include fever, weight loss, abdominal pain,
and sometimes a palpable mass. Perianal fistulas and
chronic (often granulomatous) appendicitis resulting
from actinomycosis have also been described.
A Grossly, Actinomyces spp. Often produce a large, sol-
itary mass, with or without ulceration, usually with
significant mural infiltration that may extend into sur-
rounding structures and grossly mimic carcinoma. The
organisms typically produce actinomycotic (“sulfur”)
granules consisting of irregularly rounded clusters of
bacteria bordered by eosinophilic, clublike projections
(Splendore-Hoeppli material). The inflammatory reac-
tion is predominantly neutrophilic, with abscess forma-
tion (Fig. 9.24). Palisading histiocytes and giant cells,
as well as frank granulomas, often surround the neutro-
philic inflammation. There may be a marked associated
fibrotic response.
Gram stains will reveal the filamentous, gram-positive
organisms (Fig. 9.25). GMS and Warthin-Starry stains
also stain actinomycosis. Immunofluorescence studies
B are also available.
The gross differential diagnosis includes abscess of
FIGURE 9.23
other infectious causes, lymphoma, and carcinoma. The
A, “Fringe” of bacteria along luminal surface in spirochetosis. No attendant
inflammation (hematoxylin and eosin with oil immersion). B, Spirochetes are histologic differential primarily includes other infectious
intensely positive with silver impregnation staining (Warthin-Starry). processes, particularly Nocardia spp. Unlike Nocardia
spp., this organism is not at all acid fast. Care should
also be taken not to confuse actinomycosis with fungi
or other bacteria that may form clusters and chains but
The differential diagnosis primarily consists of a prom-

inent glycocalyx, which should not stain with Warthin-
Starry stains. Occasionally EAEC can give a similar
appearance, but E. coli should stain gram negative and
not have spirillar morphology.
Treatment is somewhat controversial. Some authorities

do not advocate treating asymptomatic patients. Others
advocate treatment with metronidazole or other anti- FIGURE 9.24
microbials. There are few long-term follow-up data on Clusters of Actinomyces with associated Splendore-Hoeppli material and acute
treatment effects. inflammation (hematoxylin and eosin). Courtesy of Dr. George F. Gray, Jr.
FUNGAL INFECTIONS—FACT SHEET
Location
n Anywhere in the gastrointestinal (GI) tract
Clinical Features
n Usually occurs in immunocompromised patients
n Signs and symptoms of GI fungal infections are similar regardless
of type of fungus: diarrhea, vomiting, melena, frank GI bleeding,

abdominal pain, and fever
n Occasionally mass lesions may form, obstructing the bowel
n Often a part of a disseminated disease process
n GI symptoms and signs may be the presenting manifestations of
disease
FIGURE 9.25
Filamentous gram-positive bacteria characteristic of actinomycosis are seen
on Gram stain (Twort Gram stain).
are not truly filamentous, such as Pseudomonas spp. and Most commonly, IV amphotericin B is used.
E. coli. Most cases require surgical removal of the affected
area or at least drainage of any abscess. Prolonged anti-
biotic therapy, often intravenous (IV) in route and for
■ CANDIDA SPP.
several months to 1 year, is recommended after surgi-
cal therapy. Actinomyces spp. Are susceptible to many
antimicrobial agents. Follow-up computed tomography Candida spp. may be seen at any level of the GI tract,
is recommended to assess therapy. and the GI tract is a major entryway for disseminated
candidiasis. Although immunocompromised patients
are most frequently affected, immunocompetent
patients can also contract GI candidiasis. Infection
FUNGAL INFECTIONS with Candida albicans is most common, but Candida
tropicalis and Candida (torulopsis) glabrata may pro-
The importance of fungal infections of the GI tract has duce similar infections. It is unclear whether Candida
increased in parallel with the numbers of patients with organisms produce a true primary infection or rather
organ transplants, AIDS, and other immunodeficiency secondarily superinfect preexisting ulcerative lesions
states. Signs and symptoms of GI fungal infections of any cause.
are generally similar regardless of type of fungus and
include diarrhea, vomiting, melena, frank GI bleeding,
abdominal pain, and fever. Although fungal infections
Pathologic Features
of the GI tract are often a part of a disseminated disease
process, GI symptoms and signs may well be the present-
ing manifestations of disease. Gross Findings
Fungi can often be appreciated in routine H&E sec-
tions in fulminant infections, but GMS and PAS stains Candida is the most common infection of the esopha-
remain invaluable diagnostic aids. Fungi can also be gus. The squamous mucosa is coated with white plaques
correctly classified in tissue sections based on mor- that may be peeled off to reveal ulcerated mucosa.
phologic criteria. It should be stressed, however, that Gross features of colonic candidiasis include ulceration,
if there is any doubt as to classification, fungal culture enterocolitis that may feature pseudomembranes, and
should be relied on as the gold standard for speciation; inflammatory masses. If vascular invasion is promi-
antifungal therapy may vary according to the type of nent, the gross appearance of infarcted bowel may be
fungus identified. The differential diagnosis of the seen. Involvement may be diffuse or segmental; by some
various types of fungal infection (Table 9.2) as well as reports, C. tropicalis is more likely to be diffuse, more
helpful ancillary studies are discussed at the end of this extensively invasive, and involve the entire alimentary
section. tract.
TABLE 9.2
Morphologic Features of Fungi Involving the Colon
Organism Morphologic Features Histologic Response Major Differential Diagnoses
Aspergillus spp. Hypha-septate uniform width Ischemic necrosis with angioinva- Mucormycosis
Branching-regular acute angles sion Fusarium spp.
Conidial head formation in cavitary Acute inflammation Pseudallescheria boydii
lesions Occasionally granulomatous
Mucormycosis Hypha-pauciseptate ribbon-like Similar to Aspergillus spp. Similar to Aspergillus spp.
thin walls
Branching-haphazard
Optically clear on cut section
Basidiobolus Thin walled, broad, pauciseptate Hyphae surrounded by a radiating, Mucormycosis
ranarum hyphae intensely eosinophilic cuff
(Splendore-Hoeppli phenomenon)
Necrotizing granulomas
Candida albicans Mixture of budding yeast and Usually suppurative Trichosporon spp.
Candida tropicalis pseudohyphae; occasional May be necrotic and ulcerative
septate hypha Occasionally granulomatous
Candida glabrata Budding yeast; no true hyphae; Similar to other Candida spp. Histoplasmosis
no “halo” effect Cryptococcus spp.
Cryptococcus Pleomorphic Usually suppurative Histoplasmosis
neoformans Narrow-based buds May have extensive necrosis Blastomycosis
Usually mucicarmine positive Sometimes granulomatous C. glabrata
Variable in size
Histoplasma Ovoid, narrow-based buds Lymphohistiocytic infiltrate with Cryptococcus spp.
capsulatum Intracellular parasitized histiocytes P. marneffei
“Halo” effect around organism Occasional granulomas C. glabrata
on H&E Intracellular parasites
P. carinii
Penicillium marneffei Round and elongated (“pill Diffuse macrophage infiltrates Leishmania donovani
capsule”) yeast forms within Granulomas Histoplasma spp. capsulatum
macrophages Neutrophilic inflammation Cryptococcus neoformans
H&E, Hematoxylin and eosin staining.
Candidiasis spp.—Pathologic Features
The associated inflammatory response ranges from min- Gross Findings

imal if any tissue reaction to organisms (especially in n White plaques in the esophagus
immunocompromised patients) to prominent neutro- n Enterocolitis that may feature pseudomembranes or inflammatory
philic infiltrates, erosion or ulceration, abscess forma- masses

tion, and necrosis. Granulomas are not usually seen. n Involvement may be diffuse or segmental
n Appearance of infarction if vascular invasion is prominent

A characteristic feature of esophageal candidiasis is
pseudohyphae and yeast forms within exfoliated squa- Microscopic Findings
mous cells and keratin debris. Pseudohyphae are often n Yeasts and pseudohyphae: often found in sloughed keratin in the
arranged perpendicular to keratin fibers (Fig. 9.26). esophagus
Fungi may invade to any level of the wall, from submu- n Prominent neutrophilic infiltrates, erosion or ulceration, abscess
cosa to transmural invasion and perforation. Invasion formation, and necrosis

n Granulomas rare
of mucosal and submucosal blood vessels is also a prom-
n Minimal tissue reaction in many immunocompromised patients
inent feature of invasive candidal infection. C. albicans n Fungi may invade to any level of the gut wall, from submucosa to
and C. tropicalis produce a mixture of budding yeast transmural invasion and perforation; may also invade vessels
forms, hyphae, and pseudohyphae. C. (torulopsis) gla-
brata features tiny budding yeast forms similar to Differential Diagnosis
Histoplasma spp. and does not produce hyphae or n Other fungi (see Table 9.2)
pseudohyphae.
by hemorrhage (Fig. 9.27). The bowel may appear

grossly infarcted, and transmural infarction is common.
The characteristic histologic lesion of aspergillosis is

a nodular infarction consisting of a zone of ischemic
necrosis centered on a blood vessel containing fungal
organisms (Figs. 9.28 and 9.29). The fungal hyphae
FIGURE 9.27
Targetoid lesions in the stomach represent vascular thrombosis and sur-
rounding infarcted tissue produced by invasive Aspergillus spp. (Courtesy Dr.
Laura W. Lamps.)
FIGURE 9.26
A, Candida infection with active esophagitis and abundant luminal keratin
debris. Abundant yeast forms are present in the debris. B, Pseudohyphae
are arranged perpendicularly to the keratin and desquamated epithelial cells
(hematoxylin and eosin).
Intravenous amphotericin B is the treatment of choice

for invasive candidiasis.
■ ASPERGILLUS SPP.
Aspergillus species infection of the GI tract occurs

almost exclusively in immunocompromised patients.
The majority of patients with GI Aspergillus infection
have coexistent lung lesions. GI signs and symptoms
and gross pathologic findings are similar to infection
with Candida spp.
Pathologic Features
Gross Findings
FIGURE 9.28
Invasion of vessels often produces the classic “target Bowel infarction due to aspergillosis. Note nodular focus of ischemic necro-
lesion” consisting of a necrotic central area surrounded sis (hematoxylin and eosin).

Aspergillus organisms penetrate a submucosal vessel (hematoxylin and eosin). Aspergillus organisms have septate hyphae that branch at acute angles
(Gomori methenamine silver).
often extend outward from the infarct in parallel or Prognosis and Therapy
radial arrays. Inflammatory response ranges from min-
imal to marked neutrophilic infiltrate; granulomatous Amphotericin B is the most commonly used antifungal
inflammation is occasionally seen. The typical hyphae agent for Aspergillus infection, particularly in neutro-
of Aspergillus spp. are septate and branch at acute angles penic patients. Other useful antifungal agents include
(Fig. 9.30). ketoconazole, fluconazole, and itraconazole.
MUCORMYCOSIS AND RELATED

Aspergillus spp.—Pathologic Features INFECTIONS
Gross Findings Mucormycosis (previously called zygomycosis) are ubiq-

n Prominent neutrophilic infiltrates, erosion or ulceration, abscess uitous soil fungi. They are uncommon pathogens in the
formation, and necrosis GI tract and are seen predominantly in immunocompro-
n Granulomas rare
n Target lesions resulting from vascular invasion

mised patients. Infections are usually caused by species
n Bowel appears grossly infarcted
in the Rhizopus and Mucor genera. These fungi usually
superinfect tissues that have been previously ulcerated;
Microscopic Findings invasive disease is often fatal. Although many cases of GI
n Characteristic nodular infarction consisting of a zone of ischemic mucormycosis are part of a disseminated fungal infection,
necrosis centered on a blood vessel containing fungal organisms infection limited to the GI tract has been described.
n Fungal hyphae extend outward from the infarct in parallel or radial
arrays
n Inflammatory response ranges from minimal to a marked
neutrophilic infiltrate
n Granulomatous inflammation is occasionally seen
n Typical hyphae of Aspergillus spp. are septate and branch at
acute angles
Immunocompromised patients, particularly those with
diabetes or other causes of systemic acidosis, appear to
n Other fungal infections (see Table 9.2)
be at increased risk for developing mucormycosis.
Pathologic Features
Gross Findings
Any segment of the GI tract may be involved, and the
cecum is a common location. The gross features are
The differential diagnosis consists primarily of other similar to those produced by Aspergillus spp. Ulcerative
fungal infections (see Table 9.2). lesions are the most common gross manifestation, and
ulcers containing these organisms tend to be large with Differential Diagnosis

rolled, irregular edges that may mimic malignancy. The
often invades through the wall to involve and destroy
other structures and may produce large, obstructive The differential diagnosis is that of other fungal infec-
masses. Similar to aspergillosis and candidiasis, if large tions (see Table 9.2).
vessels are penetrated and occluded by fungi, infarction
may develop, and the gross picture is that of ischemia.
The inflammatory reaction and presence of intravas- Amphotericin B and posaconazole are the most com-
cular thrombotic lesions are markedly similar to that monly used antifungal agents in invasive mucormycosis.
seen in aspergillosis. Typical organisms have broad, rib-
bonlike, pauciseptate hyphae that branch randomly at
various angles. Transected hyphae have optically clear
centers in tissue sections (Fig. 9.31).
BASIDIOBOLUS RANARUM
Basidiobolus ranarum is an environmental fungus

found in soil and decaying organic matter. Although
Mucormycosis—Pathologic Features
it has historically been limited to tropical and sub-
Gross Findings tropical climates, including Africa, the Middle East,
n Similar to Aspergillus spp., often mimicking infarction
and Southeast Asia, B. ranarum is now recognized
n Ulcerative lesions are the most common gross manifestation, as an emerging fungal pathogen in the American
often large with rolled, irregular edges southwest.
n Process often invades through wall to involve and destroy other
structures
n May produce large, obstructive masses
n If vessels are penetrated, produces ischemic picture

n Inflammatory reaction and presence of intravascular thrombotic B. ranarum usually causes chronic subcutaneous myco-
lesions are markedly similar to aspergillosis sis, and extracutaneous involvement is rare. GI disease
n Typical organisms have broad, ribbon-like, pauciseptate hyphae
is marked by abdominal pain and tenderness, some-
that branch randomly at various angles
n Transected hyphae have optically clear centers in tissue sections
times associated with a palpable mass that creates the
clinical impression of malignancy or IBD. Risk factors
Differential Diagnosis include pediatric age group, peptic ulcer disease, and
n Other fungi (see Table 9.2) diabetes. Infection is usually seen in immunocompe-
tent hosts.
BASIDIOBOLUS RANARUM—FACT SHEET
Definition
n Environmental fungus in the order Entomophthorales

n Colon and rectum
Clinical Features
n Abdominal pain
n Nausea, vomiting
n Palpable mass

n Posaconazole is the drug of choice
FIGURE 9.31
n Surgical resection of involved bowel segment is sometimes
Mucor organisms, present within a vessel, have broad, ribbon-like pauci-
septate hyphae with optically clear centers on cut section (hematoxylin and necessary
eosin). (Courtesy of Dr. Neriman Gokden.)
Pathologic Features Basidiobolus ranarum—Pathologic Features
Gross Findings Gross Findings

n Masses
n Strictures, adhesions
Endoscopically, infection produces a mass, strictures, or n Yellow-white nodules in all levels of the colon wall
adhesions. Resection specimens reveal mural thickening
and yellowish transmural nodules. Microscopic Findings
n Thin walled, broad, pauci-septate hyphae
n Splendore-Hoeppli phenomenon
Microscopic Findings n Necrotizing granulomas
n Tissue eosinophilia
The inflammatory reaction is characterized by transmu- n Charcot-Leyden crystals
ral necrotizing granulomas (see Table 9.2). Thin walled, n Differential Diagnosis
broad, pauci-septate fungal hyphae, often surrounded n Other fungal infections, especially mucormycosis
by a cuff of radiating, intensely eosinophilic material

(Splendore-Hoeppli phenomenon), are key to the dia
gnosis (Fig. 9.32). Tissue eosinophilia and Charcot- Ancillary Studies
Leyden crystals may also be seen.
Fungal culture is the best means of making an unequiv-
ocal diagnosis of basidiobolomycosis.
The main differential diagnosis is mucormycosis, which

also form broad, pauci-septate hyphae; however, B. rana-
rum is not angioinvasive and therefore is not associated
with intestinal infarction. Mucormycosis, on the other
hand, does not elicit intense eosinophilic infiltrates and
necrotizing granulomatous inflammation and may show
little inflammatory response, particularly in immuno-
compromised patients.

A
Surgical resection of the affected bowel segment with
debridement of involved tissue in combination with
long-term antifungal therapy appears to be effective
treatment of patients with GI disease. Rare cases have
proven fatal because of delayed diagnosis and subse-
quent disseminated disease.
■ HISTOPLASMOSIS
Histoplasma capsulatum is endemic to the central United

States but has been described in many nonendemic areas
as well. It is most abundant in soil enriched with bat or
avian droppings. Although disseminated histoplasmosis
occurs mostly in immunocompromised patients, immu-
B nocompetent patients may be affected as well, especially
young children and older adults. GI involvement occurs
FIGURE 9.32 in approximately 80% or more of patients with dissemi-
A, Granulomatous inflammation and striking tissue eosinophilia are char- nated infection. Patients may initially present with signs
acteristic of basidiobolomycosis (hematoxylin and eosin). B, Gomori meth-
enamine silver stain demonstrates the “cellophane ball” appearance of B. and symptoms of GI illness and do not always have con-
ranarum hyphae. Courtesy of Dr. Laura W. Lamps. comitant pulmonary involvement.

Histiocytic infiltrate in a colon biopsy from a patient with AIDS with dissem- Fungal stain shows uniformly small yeast forms with buds at the more
inated histoplasmosis. Note the “halo” around the organisms (hematoxylin pointed pole, consistent with histoplasmosis (Gomori methenamine silver).
and eosin).
Pathologic Features
Histoplasmosis—Pathologic Features
Gross Findings Gross Findings

n Terminal ileum most commonly involved
Any part of the GI tract may be involved, but the termi- n Ulcers, nodules, obstructive mass lesions most common gross
nal ileum is the most common site. Gross lesions include lesions; often a combination
n Normal mucosa in immunocompromised patients
ulcers, nodules, obstructive mass lesions, and normal
mucosa (often in immunocompromised patients). A
combination of these lesions is commonly seen in a sin-
n Diffuse lymphohistiocytic infiltrates and nodules, usually involving
gle patient. the mucosa and submucosa, with associated ulceration
n Discrete granulomas and giant cells seen in only a minority of cases
n In immunocompromised patients, large numbers of organisms

may be seen with virtually no tissue reaction
n Histoplasma organisms are small, ovoid, usually intracellular yeast
Histologic findings include diffuse lymphohistiocytic
forms with small buds at the more pointed pole
infiltrates (Fig. 9.33) and nodules, usually involving
the mucosa and submucosa, with associated ulcer- Differential Diagnosis
ation. Often these lesions are present overlying Peyer’s n Other fungal infections (see Table 9.2)
patches. Discrete granulomas and giant cells are seen
in only a minority of cases. In immunocompromised
patients, large numbers of organisms may be seen
with virtually no tissue reaction. Histoplasma organ- Differential Diagnosis
isms typically are small, ovoid, usually intracellular
yeast forms with small buds at the more pointed pole The differential diagnosis is primarily that of other fun-
(Fig. 9.34). gal infections (see Table 9.2).
Prognosis and Therapy Cryptococci have a global distribution and are abun-
dant in avian (especially pigeon) habitats. Virtually all
patients with GI cryptococcosis have hematogenously
Amphotericin is the most commonly used antifungal disseminated disease with multisystem organ involve-
agent in histoplasmosis. ment, and most have pulmonary and meningeal disease.
■ PENICILLIUM MARNEFFEI Pathologic Features
Penicillium marneffei is a dimorphic fungus and intra- Gross Findings

cellular pathogen. It causes disseminated infection in
endemic areas, including southeast Asia, southern China, The colon is the most common site of cryptococcal
and Hong Kong, and travelers to these areas. P. marneffei infection followed by the esophagus. Endoscopic lesions
is an increasingly important cause of invasive mycosis in include nodules and ulcers, sometimes associated with a
immunocompromised hosts, particularly those with AIDS. thick white exudate; however, no mucosal abnormalities
The infection usually affects the lungs and liver followed are present in many cases of GI cryptococcosis.
by the GI tract. Patients experience respiratory distress
and may require intubation. Those with GI disease experi- Microscopic Findings
ence abdominal cramping and watery or bloody diarrhea.
Dissemination occurs rapidly in immunocompromised Histologic features include typical round to oval yeast
hosts and may be fatal if untreated. forms with narrow-based budding; cryptococci may
Gross abnormalities may be seen at any level of the GI show considerable variation in size. Occasionally, cryp-
tract. Endoscopic abnormalities include ulcers, erosions, tococci produce hyphae and pseudohyphae. Often a
and petechiae. Mass lesions that simulate malignancy “halo” effect can be seen on H&E staining, representing
have been reported in several cases. Most cases show dif- the capsule of the organism. Both superficial and deep
fuse macrophage infiltrates. Macrophages are distended involvement may occur, and lymphatic involvement is
by intracellular, 2- to 5-μm yeast forms. The macro- frequent. The inflammatory reaction is variable and
phages may lyse and release free organisms. Occasional depends on the immune status of the host, ranging from
elongated (“pill capsule”) forms with central septation a suppurative, necrotizing inflammatory reaction often
may be seen and can span up to 20 μm. P. marneffei with granulomatous features to virtually no reaction
reproduce by fission; budding is not seen. The inflamma- at all in anergic hosts. The mucopolysaccharide capsu-
tory response may include granulomas and neutrophils, lar material stains with Alcian blue, Fontana-Masson,
particularly in immunocompetent patients. Similar to mucicarmine (Fig. 9.35), and colloidal iron; GMS stains
other fungi, the organisms can be highlighted by GMS are, of course, positive as well. Capsule-deficient crypto-
and PAS stains. Fungal culture confirms the diagnosis coccal infection may present a diagnostic challenge, but
but may take weeks to produce results. most have sufficient capsular material left to be seen on
The differential diagnosis includes other yeasts (see mucin stains.
Table 9.2). H. capsulatum are also intracellular and
of similar size (2–4 μm) but are endemic to the cen-
tral United States. Unlike P. marneffei, H. capsulatum
have easily identifiable buds at their pointed poles.
Intracellular H. capsulatum yeast have a surrounding
“halo,” reflecting their cell walls. Cryptococcus neofor-
mans frequently infects immunocompromised patients
but is a rare pathogen in the GI tract. It also appears
as small yeast forms (4–7 μm) and shows narrow-based
budding. C. neoformans is extracellular and has a muco-
polysaccharide capsule that creates a halo effect on H&E
and stains magenta with mucicarmine.
■ CRYPTOCOCCUS SPP.
FIGURE 9.35
C. neoformans is an unusual but important cause of GI Cryptococcus within a giant cell (mucicarmine). Courtesy of Dr. George F.
infection, particularly in immunocompromised patients. Gray, Jr.
Cryptococcus spp.—Pathologic Features
Gross Findings The differential diagnosis consists of other fungal infec-

n Present in the colon and/or esophagus tions (see Table 9.2).
n Endoscopic lesions include nodules and ulcers, sometimes
associated with a thick white exudate

n No mucosal abnormalities are present in many cases

n Round-to-oval yeast forms with narrow-based budding and
considerable variation in size Amphotericin B is the most commonly used antifungal

n Often a “halo” effect can be seen on hematoxylin and eosin
agent.
staining, representing the capsule
n Both superficial and deep involvement may occur, and lymphatic
The differential diagnosis of fungal infections most often
involvement is frequent includes other infectious processes; occasionally Crohn’s
n The inflammatory reaction ranges from a suppurative, necrotizing disease, ulcerative colitis, sarcoidosis, and ischemic colitis
inflammatory reaction, often with a granulomatous feature, to enter the differential diagnosis as well. The bigger chal-
virtually no reaction at all in anergic hosts lenge, after a fungus has been identified, is to properly clas-
n Organisms are Gomori methenamine silver positive;
mucopolysaccharide capsular material stains with Alcian blue,

sify it. Although definite speciation must rely on culture
mucicarmine, and colloidal iron techniques, some attempt can and should be made to clas-
sify the organisms on morphologic grounds (see Table 9.2;
Differential Diagnosis Fig. 9.36). It is important to remember that fungi exposed
n Other fungal infections (see Table 9.2) to antifungal therapy or ambient air may produce bizarre
A B
C D
FIGURE 9.36
(Continued)
E F
G H
I J
FIGURE 9.36
A, Aspergillus spp. have septate hyphae that branch at acute angles (Gomori methenamine silver [GMS]). B, The hyphae of Mucor are broader and pauci-
septate. They branch at irregular angles and appear clear when sectioned transversely (hematoxylin and eosin [H&E]). C, Basidiobolus ranarum are often
associated with granulomatous and eosinophil-rich inflammation (H&E). D, Their hyphae are broader than those of Mucor and have thinner walls (Gomori
methenamine silver [GMS]). (Courtesy of Dr. Laura W. Lamps.) E, The yeast and pseudohyphae of Candida spp. are admixed with keratin debris in the esopha-
gus (H&E). F, Periodic acid–Schiff D stain highlights elongated pseudohyphae and round yeast forms. G, Cryptococcus neoformans are variably sized and round
(H&E). H, A mucicarmine stain highlights their mucopolysaccharide capsule (mucicarmine). I, Foamy macrophages fill the lamina propria in a case of histoplas-
mosis (H&E). J, A GMS stain reveals yeasts with narrow-based budding (GMS).
and unusual forms. Helpful diagnostic aids, in addition to Pathologic Features

culture, include serologic assays and antigen tests.
Gross Findings
■ PARASITIC INFECTIONS OF THE Small ulcers are the early lesion, which may coalesce to
GASTROINTESTINAL TRACT form large, irregular ulcers that are often “geographic”
or serpiginous. Intervening mucosa is often normal. The
Protozoa ulcers have associated inflammatory exudate or adjacent
inflammatory polyps. Ulcers may undermine adjacent
Entamoeba Histolytica mucosa to produce the classic “flask-shaped” lesion. The
cecum is the most common site of involvement. Indeed,
Approximately 10% of the world’s population is infected the presence of multiple ulcers in the ileocecal region
with this parasite, and the prevalence is much higher in may simulate Crohn’s disease endoscopically, particu-
tropical and subtropical locations. Homosexual men are larly when aphthae are present. Any part of the colon or
also at increased risk for harboring this pathogen. appendix may be involved. Fulminant colitis resembling
ulcerative colitis, pseudomembranous colitis resembling
that caused by C. difficile, and toxic megacolon have been
■ CLINICAL FEATURES described. Colonoscopy may be normal in asymptomatic
patients and those with mild disease.
Many infected patients are asymptomatic or have only
vague, nonspecific GI complaints that may mimic irritable Microscopic Findings
bowel syndrome. Symptomatic patients most commonly
have diarrhea, abdominal cramps, and variable right lower The earliest lesion is a mild neutrophilic infiltrate. In
quadrant tenderness; this may be referred to as “nondysen- more advanced disease, ulcers are often deep, extend-
teric” amebiasis. Invasive disease, most often manifested ing at least into the submucosa (Fig. 9.37), with under-
as amoebic dysentery or liver abscess, reportedly occurs mining of adjacent normal mucosa. There is associated
in fewer than 10% of infected persons. Amebic dysentery necroinflammatory debris; the organisms are generally
presents suddenly, approximately 1 to 3 weeks after expo- found within this purulent material (Fig. 9.38). Invasive
sure, with severe abdominal cramps, tenesmus, fever, and amebae are occasionally seen within the bowel wall. The
diarrhea (which may be mucoid or bloody). adjacent mucosa is usually normal but may show gland
distortion and inflammation. The organisms, which
may be very few in number, resemble macrophages with
AMEBIASIS—FACT SHEET foamy cytoplasm and a round, eccentric nucleus; the
presence of ingested red blood cells is pathognomonic
Definition of Entamoeba histolytica. In patients who are asymp-
n Common protozoal infection, affecting approximately 10% of the tomatic or have mild symptoms, histologic changes
population worldwide
may range from normal to a heavy mixed inflammatory
infiltrate. Organisms may be particularly difficult (if not
n Any level of the colon or appendix; cecum most frequent
impossible) to find in these patients.
Clinical Features
n Many patients asymptomatic or with vague, nonspecific
gastrointestinal symptoms
n Some patients have fulminant colitis Amebiasis—Pathologic Features
n May form large inflammatory masses
n Homosexual men at increased risk for infection Gross Findings

n Early lesion: small ulcers, may coalesce to form larger ones
Prognosis and Therapy n Ulcers may undermine adjacent mucosa to form classic “flask-
n Antiparasitic drugs such as metronidazole shaped” ulcer
n Normal intervening mucosa
n May grossly resemble ulcerative colitis, pseudomembranous
Complications of intestinal amebiasis include bleed- colitis, Crohn’s disease

n Colonoscopy may be normal in asymptomatic patients or those
ing; perforation; dissemination to other sites, particu-
with mild disease
larly the liver; fistula formation between the intestine
and the skin, peritoneum, and urogenital tract; and Microscopic Findings
toxic megacolon. The latter complication is often associ- n Early lesion: mild neutrophilic infiltrate
ated with corticosteroid use. Rarely, large inflammatory n Advanced disease: deep ulcers, undermining adjacent normal mucosa
masses (amebomas) may be formed.

n Associated necroinflammatory debris, which may harbor organisms Differential Diagnosis

n Intervening mucosa may have architectural distortion, inflammation
n Organisms resemble macrophages with foamy cytoplasm and
round, eccentric nucleus The differential diagnosis most often is that of amebae
n Ingested red blood cells pathognomonic of Entamoeba histolytica versus macrophages within an inflammatory exudate.
n Amebas are trichrome positive Amebae are trichrome positive. Amebiasis can also be con-
fused with Crohn’s disease or ulcerative colitis, as well as
other types of infectious colitis. The ciliate Balantidium
n Ulcerative colitis
n Crohn’s disease
coli produces a spectrum of clinical and pathologic
n Balantidium coli changes similar to that of E. histolytica. However, B. coli
organisms are distinguished from amebae by their larger
size, kidney bean–shaped nuclei, and cilia (Fig. 9.39).
Two other species of amoeba, Entamoeba dispar and
Entamoeba moshkovskii, which are histologically indis-
tinguishable from E. histolytica, have recently received
attention because they have been recovered from the
stool of patients with GI symptoms. To date, there is no
convincing evidence that E. dispar causes symptomatic
GI disease, and many studies on both species are con-
founded by coinfection with E. histolytica and other GI
pathogens. Some authorities refer to the organism as
FIGURE 9.38
Colonic amebiasis. Deep ulcer with overlying exudate (hematoxylin and eosin).
B
FIGURE 9.37
A, Chagas disease results in absence of ganglion cells in the myenteric
plexus (hematoxylin and eosin [H&E]). B, Over time, nerves may exhibit
fibrosis with collagen deposits (H&E).
Ancillary Studies
FIGURE 9.39
Entamoeba histolytica organisms have foamy cytoplasms and a round,
Examination of stool for parasites is a helpful diagnostic eccentric nucleus. The presence of ingested red blood cells is pathognomonic
test, and serologies are also available. of E. histolytica (hematoxylin and eosin). Case courtesy of Dr. Rickey Ryals.
“E. histolytica–E. dispar” complex, resulting from the striking lymphocyte-rich inflammation. The organisms
high rate of coinfection. are rarely identified histologically but when present are
seen in ganglion cells. Helpful laboratory assays include
PCR, serologic studies, and culture. Infection may be dif-
Prognosis and Therapy ficult to detect serologically, however, because circulat-
ing organisms are usually relatively scarce.
Antiparasitic drugs such as metronidazole are effective, The main differential diagnosis is primary achalasia
even against invasive amebiasis. and causes of pseudoachalasia, such as diffuse esoph-
ageal spasm, hypertensive lower esophageal sphincter,
and malignant infiltration of the distal esophagus. Other
■ TRYPANOSOMA CRUZI (CHAGAS DISEASE)
causes of neuronal dysfunction in the colon, such as
Hirschsprung disease, are usually easily excluded on
Chagas disease is caused by infection with the proto- clinical grounds because manifestation of Chagas dis-
zoan parasite Trypanosoma cruzi, which is transmitted ease is rarely isolated to the GI tract.
by insect vectors and affects several million people in
Latin America. The disease may also be transmitted
through blood transfusion, organ transplantation, and FLAGELLATES
congenitally. Intestinal dysfunction is caused by damage
to the enteric nervous system induced by T cell–medi- Giardia Lamblia
ated inflammatory response to T. cruzi proteins. Acute
infection with Chagas disease is usually subclinical, and Giardia lamblia is a flagellated protozoan parasite that
most patients develop lifelong asymptomatic infection. is a common cause of diarrheal disease worldwide. It
Those who develop chronic disease most commonly is spread via fecal–oral transmission through contami-
experience cardiac and intestinal complications. Upper nated water and food. G. lamblia are ingested as cysts
digestive tract involvement takes the form of secondary and complete their life cycle in the intestine. Cysts are
achalasia or megaesophagus, causing dysphagia, ody- also found in the stool of farm animals and household
nophagia, and severe reflux and regurgitation. Colonic pets. Illness is more common among children. Patients
involvement results in megacolon, constipation, obsti- with primary immunodeficiencies may experience
pation, and abdominal pain. The disease may be suc- repeated or prolonged G. lamblia infections.
cessfully eradicated with adequate antiparasitic therapy
with benznidazole and nifurtimox. Most deaths from
Chagas disease are caused by cardiac complications.
Clinical Features
The esophagus and colon are markedly dilated. The
esophageal squamous mucosa may appear thickened and
irregular because of stasis of luminal contents. Histologic Up to 40% of Giardia infections are asymptomatic.
findings include smooth muscle fibrosis and lympho- Symptomatic patients present with explosive, foul-smell-
cytic inflammation and fibrosis around the myenteric ing, watery diarrhea. Symptoms also include cramps,
and submucosal plexuses, which contain reduced bloating, nausea, and vomiting. Infections are usually
numbers of neurons and ganglion cells (Fig. 9.40). self-limiting, but chronic diarrhea may develop, espe-
The esophageal squamous mucosa also often shows cially in children and immunocompromised patients.
GIARDIA LAMBLIA—FACT SHEET
Definition
n Flagellated protozoan with worldwide distribution

n Duodenum, terminal ileum
Clinical Features
n Explosive watery diarrhea
n Abdominal cramping
n Bloating
n Nausea, vomiting
FIGURE 9.40 Prognosis and Therapy

n Usually self-limited
The ciliate Balantidium coli is distinguished from Entamoeba histolytica
by its larger size, kidney bean–shaped nucleus, and cilia (hematoxylin and n Metronidazole
eosin). Case courtesy of Dr. David Owen.

Pathologic Features appears normal. Organisms may be few and inconspicu-

ous. Poorly preserved organisms may resemble sloughed
epithelial cells or extruded mucin. Pathologists should
Gross Findings consider a diagnosis of giardiasis when the clinical his-
tory is suggestive of infection and be mindful of organ-
Endoscopy is usually unremarkable or reveals non-spe- isms in intervillous spaces because tissue invasion is not
cific findings, such as edema and patchy erythema. a feature of giardiasis.
Giardiasis is most commonly diagnosed in duodenal
biopsy specimens; however, terminal ileal biopsies may Treatment is recommended only if patients develop pro-
reveal G. lamblia trophozoites, especially in the chronic longed disease and typically includes a course of met-
phase of infection. The duodenal mucosa often appears ronidazole and supportive care. Disease eradication is
unremarkable; however, biopsy samples may show particularly important for children, as chronic giardiasis
villous blunting and increased lamina propria inflam- has been associated with cognitive impairment.
mation, including lymphocytes, plasma cells, and eosin-
ophils, and lymphoid aggregates (Fig. 9.41A). In some
cases, intraepithelial lymphocytes may also be increased.
The diagnostic finding is trophozoites clustered at the VISCERAL LEISHMANIASIS (KALA-AZAR)
tips of villi or in the intervillous spaces (Fig. 9.41B). The CAUSED BY LEISHMANIA DONOVANI
organisms are pear shaped when viewed en face or may AND RELATED SPECIES
appear crescentic or “kite shaped” when tangentially
sectioned. They contain two ovoid nuclei and a central
karyosome. Flagella are usually not appreciable in rou- The prevalence of leishmaniasis is increasing worldwide
tine sections. as a result of immigration, urbanization, and increased
numbers of immunocompromised patients. It is endemic
in more than 80 countries in Africa, Asia, South and
Central America, and Europe. The causative parasite,
Giardia lamblia—Pathologic Features Leishmania spp., is transmitted via sandfly bites.
Gross Findings
n Endoscopy is usually unremarkable
n Preserved villous architecture Gastrointestinal involvement is generally part of widely
n Increased lamina propria inflammation, lymphoid aggregates
disseminated disease. GI signs and symptoms include
n Increased intraepithelial lymphocytes
n Pear- or kite-shaped trophozoites in intervillous spaces

fever, abdominal pain, diarrhea, dysphagia, malabsorp-
tion, and weight loss.
n Sloughed epithelial cells
n Extruded mucin
LEISHMANIASIS—FACT SHEET
Definition
Ancillary Studies n Parasitic infection transmitted by sandfly bites, endemic in more than
80 countries in Africa, Asia, South and Central America, and Europe
Trichrome stains may help to highlight G. lamblia in Incidence and Location

cases with rare organisms. Stool antigen tests and PCR n Anywhere in the bowel; rarely the esophagus
assays are also available. Clinical Features

n Part of widely disseminated disease
n Fever, abdominal pain, diarrhea, dysphagia, malabsorption, and
weight loss
Giardia organisms may be easily overlooked in biopsy n Pentavalent antimony, amphotericin, pentamidine
samples, particularly when the duodenal mucosa
A B C
FIGURE 9.41
A, A reactive lymphoid aggregate is present in the duodenal mucosa of a patient with giardiasis. B, Giardia lamblia organisms in the intervillous space have a
crescentic contour in some sections. C, The organisms are pear shaped when sectioned lengthwise (hematoxylin and eosin).
Pathologic Features Ancillary Studies
Gross Findings
Serologic studies and IHC may aid in diagnosis.
Leishmania organisms may be found anywhere in the
small intestine and colon, and rarely in the esophagus.
Endoscopic findings include normal examination, focal Differential Diagnosis
ulceration, and changes grossly consistent with enteritis.
The differential diagnosis is primarily that of other par-
Microscopic Findings asitic and fungal infections, and Leishmania spp. may
be confused with similar organisms such as Histoplasma
Histologic changes in immunocompetent and immuno- spp. and T. cruzi. All but T. cruzi lack a kinetoplast, and
compromised persons are similar. Histologic features Leishmania spp. are GMS, mucicarmine, and PAS neg-
typically consist of macrophages within the lamina ative. T. cruzi is seldom visualized in the GI tract, and
propria containing amastigotes. Often, an associated the resultant inflammatory lesion affects the myenteric
inflammatory infiltrate is absent. The amastigotes are plexus rather than the lamina propria.
round to oval, tiny organisms with a nucleus and kine-
toplast in a “double-knot” configuration.
Leishmaniasis—Pathologic Features
Pentavalent antimonial compounds are the first line of
Gross Findings
therapy in most cases. Other drugs such as amphotericin
n Range from normal to focal ulceration, changes of enteritis
B and pentamidine are also used.
n Macrophages within the lamina propria containing amastigotes
n Amastigotes are round to oval, tiny organisms with a nucleus and

kinetoplast in a “double-knot” configuration
COCCIDIANS AND RELATED ORGANISMS
n Histologic changes in immunocompetent and
immunocompromised persons are similar

Unicellular protozoa formerly considered coccidians
n Inflammatory infiltrate is often absent
have recently undergone substantial reclassification.
Differential Diagnosis These organisms, including Cryptosporidium parvum,
n Histoplasma capsulatum
Cryptosporidium hominis, Cryptosporidium melea-
n Trypanosoma cruzi (Chagas disease) gridis, Cyclospora cayetanensis, Cystoisospora belli, and
Microsporidia spp. are important causes of malabsorptive
diarrhea worldwide. Cryptosporidia spp. are now classi- Pathologic Features

fied as gregarines, a subclass of conoidasida related to
coccidians. C. cayetanensis and C. belli remain in the
coccidians class, whereas Microsporidia spp. are now Gross Findings
considered fungi. These organisms are discussed as a
group herein because of their overlapping clinical and Endoscopic findings are usually absent or mild. When
morphologic features. present, they may include mild erythema, mucosal gran-
ularity, mucosal atrophy, and mild erosions.
■ CLINICAL FEATURES Microscopic Findings
1. C. parvum. Although most commonly seen in the small

Coccidians, conoidasida, and Microsporidia spp. often bowel, Cryptosporidium spp. may be seen in the colon
produce asymptomatic infections in both immunocom- as well. The characteristic appearance of the organ-
promised and healthy patients. All except Microsporidia ism is a 2- to 5-μm basophilic spherical body protrud-
spp. (which is thought to be limited to immunocompro- ing from the apex of the enterocyte (Fig. 9.42). It can
mised individuals) can cause diarrhea (often prolonged) be found in the crypts or at the surface. Associated
in healthy patients, especially infants and children, mucosal changes include a mixed inflammatory
travelers, and institutionalized people. Diarrhea may infiltrate, and crypt abscesses. Organisms stain with
be accompanied by fever, weight loss, abdominal pain, the Giemsa stain. Cryptosporidium spp. may be dis-
and malaise. The stool does not usually contain red tinguished by their unique apical location; although
blood cells or leukocytes. In immunocompetent persons, Cyclospora organisms are similar in appearance, they
infection is usually self-limited. Immunocompromised are much larger, and some forms are banana shaped.
patients are at risk for chronic, severe diarrhea with mal- 2. Toxoplasma gondii. GI toxoplasmosis is primarily a
absorption, dehydration, and death.. They are worldwide disease of immunocompromised persons. Intestinal
pathogens that are more common in, but not limited involvement is a rare feature. Ulcers have been
to, developing countries. Transmission is via the fecal– described in the bowel, with Toxoplasma organisms
oral route, either directly or via contaminated food and in the ulcer base. Both crescent-shaped tachyzoites
water. and cysts containing bradyzoites may be seen within
tissue sections.
3. Microsporidia spp. Enterocytozoon bieneusi and
Encephalitozoon intestinalis are the most commonly
seen in human infection. They are usually seen in
the small bowel, but the colon and biliary tree may
COCCIDIANS AND RELATED ORGANISMS—FACT SHEET be affected. These stain with modified trichrome
(Fig. 9.43), tissue Gram stain, and silver impregna-
Definition tion stains. Microsporidia organisms can be very
n Unicellular organisms causing chronic diarrhea, most often in
immunocompromised patients; transmitted through fecal–oral

route and contaminated food and water

n Most commonly the small bowel; rarely the colon and gallbladder
Clinical Features
n Chronic diarrhea, with or without fever, weight loss, abdominal
pain, and malaise

n Stool lacks red blood cells and leukocytes
n Infection is self-limited in immunocompetent persons
n Immunocompromised patients are at risk for chronic, severe
diarrhea with malabsorption, dehydration, and death

n Cryptosporidium: no effective treatment
n Microsporidium: some efficacy with drugs such as albendazole
n Toxoplasmosis: numerous effective antibiotics, especially sulfa
drugs FIGURE 9.42

n Cyclospora: sulfa drugs
Colon biopsy from a patient with AIDS. Numerous Cryptosporidia organ-
n Cystoisospora: sulfa drugs
isms are seen bulging beneath the surface of enterocytes (hematoxylin and
eosin).
A B
FIGURE 9.43
A, Microsporidia infection produces epithelial disarray; the organisms may be appreciable as tiny clusters of intracytoplasmic “dots” on hematoxylin and eosin
(arrow). B, Tiny Microsporidia organisms are present within enterocytes, with minimal inflammatory response (modified trichrome).
difficult to detect in H&E sections. The histologic

features include a subtle vacuolization of the surface
epithelium and a patchy lymphoplasmacytic infiltrate
in the lamina propria. Sometimes Microsporidia spp.
polarize within tissue biopsies because the chitin-rich
internal polar filament of the organism is birefrin-
gent under polarized light. However, this method is
unreliable because of the unpredictability of spore
birefringence, as well as variability depending on the
microscope and light source used.
4. Cyclospora cayetanensis can infect immunocompetent
or immunocompromised patients. The organisms
appear as 2- to 3-μm schizonts or 5- to 6-μm banana-
shaped merozoites within a parasitophorous vacuole
in enterocytes (Fig. 9.44).
5. Cystoisospora belli is usually found in the small bowel
but may also involve the colon or gallbladder. It is the
largest coccidian, appearing as 15- to 20-μm forms at
all stages of the organism’s life cycle. Whereas schi-
zonts and merozoites are crescent shaped, the sexual
FIGURE 9.44
forms are round with prominent nuclei. They may be
Cyclospora cayetanensis organisms are present within intracytoplasmic vac-
found in epithelial cells or macrophages, often within uoles. Both round schizonts (thick arrow) and elongated merozoites (thin
a parasitophorous vacuole (Fig. 9.45). arrow) can be seen.
Coccidians And Related Organisms—Pathologic Features
Gross Findings
n Usually absent or mild
n Can have mild erythema, mucosal granularity, mucosal atrophy,
and mild erosions
n Cryptosporidium parvum
n 2- to 5-mm basophilic spherical body protruding from the
apex of the enterocyte

n In the crypts or at the surface
n Tissue reaction includes mixed inflammatory infiltrate, crypt
abscesses
n Toxoplasma gondii
n Almost always immunocompromised
n Intestinal involvement is a rare feature
n Both crescent-shaped tachyzoites and cysts containing
bradyzoites can be seen

n Microsporidia spp.
n Tiny organisms in apex of enterocytes
n Stain with modified trichrome, tissue Gram stain, and silver
impregnation stains
n Cyclospora cayetanensis
n 2- to 3-μm schizonts or 5- to 6-μm banana-shaped
merozoites within a parasitophorous vacuole in enterocytes

n Gomori methenamine silver (GMS), periodic acid–Schiff,
Gram, and trichrome negative

FIGURE 9.45
n Cystoisospora belli
n Intracellular crescent-shaped schizonts and merozoites, often

Cystoisospora belli are round to banana-shaped eosinophilic organisms with
prominent nucleoli found within parasitophorous vacuoles (hematoxylin and
within a parasitophorous vacuole
eosin). (Courtesy of Dr. Laura W. Lamps.)
n Crescent-shaped schizonts and merozoites
n Round sexual forms with prominent nuclei
n Highlighted with GMS and Giemsa stains
provide symptomatic relief. Agents such as albendazole

are at least anecdotally effective against microsporid-
n Primarily other unicellular protozoa
ial infection in some studies. Antibiotics may be effec-
tive against Cyclospora spp., Cystoisospora spp., and
toxoplasmosis.
Ancillary Studies
Although electron microscopy was once considered

■ HELMINTHS (NEMATODES, TREMATODES,
the gold standard for diagnosis of these organisms, it is
AND CESTODES)
expensive, subject to sampling bias, and not widely used.
Examination of stool specimens may be helpful in many
cases. Enzyme-linked immunosorbent assay techniques, Although the most common method of diagnosing GI
IHC, and PCR studies have been developed, although these helminth infections is examination of stool for ova
tests are not widely available to practicing pathologists. and parasites, these organisms are occasionally seen
in biopsy or resection specimens. GI helminths have a
worldwide distribution, but their clinical importance
Differential Diagnosis varies with geographic region. They are more often
a cause of serious disease in underdeveloped nations
The differential diagnosis is primarily other unicellular because deficient sanitation systems; poor socioeco-
protozoa. nomic status; and hot, humid climates are predisposing
factors. Helminthic infections are becoming an increas-
ingly important problem in immunocompromised
patients. The nutritional problems caused by helminths
can be severe and even life threatening, particularly in
children. The anatomic site of infection is most often the
Most antimicrobial agents are ineffective against cryp- small bowel, although the large bowel may certainly be
tosporidial infection, although antimotility agents may involved.
The differential diagnosis of helminthic infections Pathologic Features

often involves differentiating between types of worm.
Other entities to be considered include other causes of
ulcerative inflammation, eosinophilic infiltration, and Gross Findings
granulomatous inflammation, such as tuberculosis, ame-
biasis, allergic enteritides, and Crohn’s disease. Grossly, the worms are 2 to 5 mm in length and may be
seen with the naked eye. Although the mucosa of the GI
tract often appears normal upon examination, hemor-
rhage and ulceration are occasionally seen in invasive
NEMATODES infection.
■ ENTEROBIUS VERMICULARIS (PINWORMS) Microscopic Findings
Pinworms are one of the most common parasites affect- Although even invasive pinworms usually incite little
ing humans. They have a worldwide distribution but or no inflammatory reaction, as discussed previously,
are more common in cold or temperate climates and an inflammatory infiltrate composed predominantly of
developed countries. They are extremely common in the eosinophils may occasionally be seen. Granulomas, some-
United States and Northwestern Europe. The infective times with necrosis, may be seen as well, often associ-
larva-containing egg resides in dust and soil, and trans- ated with degenerating worms or eggs. These lesions have
mission is believed to be fecal–oral. School children and been described within the omentum and peritoneum, as
adolescents, especially those who live in institutions, well as in the appendix, anus, and colon in rare cases.
have the highest prevalence of infection. The worms
live and reproduce in the ileum, cecum, proximal colon,
and appendix, and the female migrates to the anus to Enterobiasis—Pathologic Features
lay her eggs and die. The ability of Enterobius spp. to
cause colitis and actual mucosal damage is controversial. Gross Findings
However, they have been noted to rarely invade the GI n Worms are 2 to 5 mm in length
mucosa. n Mucosa often appears normal on examination
n Hemorrhage and ulceration are occasionally seen in invasive
infection
■ CLINICAL FEATURES Microscopic Findings

n Usually little or no inflammatory reaction
The eggs and worms produce the classic symptom of noc- n Rarely, an inflammatory infiltrate composed of neutrophils is
turnal pruritus ani. Many infections are asymptomatic, present

but heavy infections may cause abdominal pain, nausea, n Granulomas, sometimes with necrosis, can be associated with
degenerating worms or eggs

and vomiting. Appendicitis, vulvovaginitis, colitis, and
n Worm morphology: lateral ala with easily visible intestine and
peritoneal involvement have been described secondary uterus (in the female); eggs are ovoid with one flat side and have
to pinworm infection. a bilayered refractile shell
n Other helminths
ENTEROBIASIS—FACT SHEET
Ancillary Studies
Definition
n Common helminthic infection; rarely causes colitis Stool examination for ova and parasites has a relatively
low yield. Inspection of the perianal area for worms, and
Incidence and Location the anal “scotch tape test” are the most helpful diagnos-
n Anus, appendix, large bowel
tic aids.
Clinical Features
n Perianal itching, primarily nocturnal
n Rarely, colitis and appendicitis

n Antiparasitic drugs such as mebendazole The differential diagnosis is primarily other types of
worms. Pinworms have lateral ala (Fig. 9.46) with an
but is most common in the tropics. These worms are

ingested from soil contaminated with feces. Hookworms
(Necator americanus and Ancylostoma duodenale) are a
common parasite in virtually all tropical and subtrop-
ical countries. Whipworms (T. trichiura) are also soil-
borne helminths with a worldwide distribution.
Clinical findings in Ascaris infection are variable and

include appendicitis, massive infection with obstruc-
tion and perforation, childhood growth retardation,
and pancreaticobiliary obstruction. Hookworms attach
to the intestinal wall and suck blood from villous cap-
illaries, resulting in anemia. Other clinical symptoms
include abdominal pain, diarrhea, hypoproteinemia,
and an associated cough with eosinophilia as the worms
migrate. Mesenteric adenitis secondary to hookworm
infection has also been described. The anemia may lead
to significant growth retardation in children. Whipworm
infection is often asymptomatic, but infection may cause
FIGURE 9.46
diarrhea, GI bleeding, malabsorption, anemia, and
Pinworms have prominent lateral ala and an easily visible intestine (hema-
appendicitis.
toxylin and eosin).
easily visible intestine and uterus (in the female). The ROUNDWORM, HOOKWORM, WHIPWORM—FACT SHEET
eggs are ovoid with one flat side and have a bilayered
refractile shell. It may be difficult to distinguish between Definition
primary Enterobius infection and infection complicating n Common helminthic infections with a worldwide distribution
a preexisting inflammatory lesion such as an inflamed
anal fissure. Incidence and Location
n Small and large bowel
Clinical Features
Prognosis and Therapy n In general, bleeding, malabsorption, anemia, obstruction, and
diarrhea
n Ascaris spp. may cause bowel obstruction
Most infections clear spontaneously, although this may n Hookworm known to cause anemia
require several weeks. However, treatment with antipar- n All may cause significant growth problems in children
asitic drugs such as mebendazole is recommended to pre-

vent transmission to others, and for symptomatic cases. Prognosis and Therapy
n Antihelminthic drugs; surgery if obstructed; iron supplementation
if anemic
ASCARIS LUMBRICOIDES (ROUNDWORM),

ANCYLOSTOMA DUODENALE Pathologic Features
(HOOKWORM), AND TRICHURIS
TRICHIURA (WHIPWORM) Ascaris organisms are very large worms (≤20 cm) that
may be identified endoscopically or at resection if obstruc-
These worms are rarely a problem in diagnostic biop- tion occurs (Fig. 9.47). Tissue damage occurs primarily at
sies but may cause significant GI complications, includ- attachment sites. Hookworms affect all levels of the GI
ing bleeding, malabsorption, anemia, obstruction, and tract. Endoscopically, the worms (∼1 cm in length) are
diarrhea. Ascaris spp. are some of the most frequent visible to the naked eye. Pieces of worm may be visible
parasites in humans. It has a worldwide distribution on biopsy; although other histologic changes are usually
FIGURE 9.48
Numerous eggs are seen in a cross section of Trichuris trichiura (whipworm)
FIGURE 9.47 Ancillary Studies

Ascaris organisms measure up to 20 cm in length and are easily seen with
the naked eye.
Stool examination for ova and parasites is a helpful diag-
nostic test.
minimal, an eosinophilic infiltrate is sometimes seen.

Whipworms are found predominantly in the right colon
and ileum. They may cause gross mucosal hemorrhage
and ulceration; the worms are 3 to 5 mm long with a The differential diagnosis is primarily that of other hel-
characteristic whiplike tail and can be seen endoscopi- minthic infections. An ulcerative inflammatory process
cally. Histologically, the worms thread their anterior ends similar to Crohn’s disease has been described associated
under mucosal epithelium, which may produce entero- with both whipworm and hookworm infection.
cyte atrophy and an associated mixed inflammatory infil-
trate; crypt abscesses may be present as well. Whipworm
infection also may rarely mimic Crohn’s disease. Prognosis and Therapy
Antihelminthic treatment is recommended, and similar

Roundworm, Hookworm, Whipworm—Pathologic Features
drugs may be used against all three worms. Intestinal
obstruction (particularly in Ascaris infection) may
Gross Findings require surgery. Iron supplementation may be required
n Ascaris spp. are very large worms (≤20 cm) for infections causing anemia.
n Hookworms measure about 1 cm in length
n Whipworms are 3 to 5 mm long, with whiplike tails (Fig. 9.48)
n Hookworm- and whipworm-associated tissue damage may mimic
Crohn’s disease grossly STRONGYLOIDES STERCORALIS

n Ascaris-related tissue damage occurs primarily at attachment
This nematode has a worldwide distribution. In the United
sites States, it is endemic in the Southeast, urban areas with
n Hookworm causes minimal histologic change; rarely an large immigrant populations, and mental institutions. This
eosinophilic infiltrate infection occurs primarily in adults, many of whom are
n Whipworm may cause mixed inflammatory infiltrate and crypt
hospitalized, have chronic illnesses, or are immunocom-
abscesses, usually associated with attachment site
promised. Strongyloides stercoralis penetrates the skin,
Differential Diagnosis enters the venous system, travels to the lungs, and then
n Other helminths migrates up the respiratory tree and down the esophagus to
n Crohn’s disease eventually reach the small intestine. The female lives in the
small intestine and lays eggs there, thus perpetuating the
cycle. This capability of autoinfection allows it to reside in

the host and produce illness for upwards of 30 years. Strongyloidiasis—Pathologic Features
Gross Findings
■ CLINICAL FEATURES n Ulcers, which may be aphthoid
n Pancolitis
n Pseudomembranous colitis rarely reported

Symptoms and signs include diarrhea, abdominal pain
and tenderness, nausea, vomiting, weight loss, malabsorp- Microscopic Findings
tion, and GI bleeding. GI symptoms may be accompanied n Both adult worms and larvae may be found in the crypts
by rash, eosinophilia, urticaria, pruritus, and pulmonary n Adult worms typically have sharply pointed tails that may be curved
symptoms. However, many patients are asymptomatic. n Histologic features include ulcers (which may be fissuring),
S. stercoralis can disseminate in immunocompromised edema, and a dense eosinophilic and neutrophilic infiltrate
n Granulomas may also be seen
patients, causing severe and even fatal illness.
n Other infectious processes, especially other helminthic infections
n Crohn’s disease
STRONGYLOIDIASIS—FACT SHEET
n Pseudomembranous colitis from other causes
Definition
n Helminthic infection infecting the bowel; may cause fatal
disseminated disease in immunocompromised patients
Incidence and Location Ancillary Studies

n Large bowel, small bowel, stomach
Clinical Features
Stool examination is the primary ancillary technique for
n Diarrhea, abdominal pain and tenderness, nausea, vomiting,
diagnosis.
weight loss, malabsorption, and gastrointestinal bleeding
n Often accompanied by rash, eosinophilia, urticaria, pruritus, and
pulmonary symptoms
n Many patients are asymptomatic
n May disseminate in immunocompromised patients, causing fatal
illness
The differential diagnosis is primarily that of other hel-
minthic infections and infectious processes, although the
histologic inflammatory pattern may mimic pseudomem-
branous colitis, Crohn’s disease, and ulcerative colitis.
Pathologic Features
Gross Findings
Lesions may be seen in the stomach, as well as the small and

large intestines. Endoscopically, colonic findings include
ulcers, which may be aphthoid, and pancolitis; features of
pseudomembranous colitis have also been reported.
Histologically, both adult worms and larvae may be

found in the crypts (Fig. 9.49), but they may be dif-
ficult to detect. Adult worms typically have sharply
pointed tails that may be curved. Other histologic fea-
tures include ulcers (which may be fissuring), edema,
and a dense eosinophilic and neutrophilic infiltrate.
Granulomas may also be seen, often mixed with eosin-
ophilic and neutrophilic infiltrates. In biopsies with an FIGURE 9.49
eosinophil-rich inflammatory infiltrate, step sectioning Strongyloides organisms within colonic crypts have pointed tails (hematoxy-
may reveal degenerating parasitic forms or eggs. lin and eosin).
Prognosis and Therapy Microscopic Findings
Histologic findings include an inflammatory infiltrate

Antihelminthic treatment with agents such as thiaben- rich in eosinophils, which often extends transmurally
dazole is required. into serosal and mesenteric tissues. Eosinophilic microab-
scesses, granulomas, and giant cells may also be seen. The
inflammatory changes may be centered around a worm.
ANISAKIS SIMPLEX (ANISAKIASIS) Larvae (ranging from 0.5–3.0 cm in length) are occasion-
AND RELATED SPECIES ally seen in tissue sections.
These nematodes parasitize fish and sea mammals, and

humans generally ingest them when eating raw and Anisakiasis—Pathologic Features
pickled fish.
Gross Findings
n Mucosal edema, friability, hemorrhage, erosions, and ulcers
n Larvae may be seen endoscopically

The most common clinical manifestations are those of n Inflammatory infiltrate rich in eosinophils, often extends
transmurally into serosal and mesenteric tissues
acute gastric anisakiasis, including epigastric pain, nau- n Eosinophilic microabscesses, granulomas, and giant cells may
sea, and vomiting, often within 12 hours of consuming also be seen
contaminated food. Colonic manifestations have also n Inflammatory changes may be centered around a worm
been well described, presenting with abdominal pain n Larvae are occasionally seen in tissue sections
and distention, often accompanied by peripheral eosin-
ophilia. Anisakis spp. also have allergenic potential, and
n Primarily other helminths
some patients with gastroallergic anisakiasis manifest
both GI and hypersensitivity symptoms such as urti-
caria, angioedema, eosinophilia, and anaphylaxis.
Ancillary Studies
ANISAKIASIS—FACT SHEET
Definition No ancillary studies are helpful in anisakiasis because

n Parasitic infection most often associated with consumption of raw fish
worms and larvae are rarely seen in stool samples.

n Common in stomach; rare in colon and small bowel Differential Diagnosis
Clinical Features The differential diagnosis primarily includes other worms.

n Abdominal pain and distention
The size and morphology of the worm usually confirm the
n Peripheral eosinophilia
diagnosis.
n May cause gastroallergic anisakiasis, featuring both gastrointestinal
and hypersensitivity symptoms

n Endoscopic or surgical removal of worm
Endoscopic removal of the worm is the therapy of choice.
Pathologic Features
TREMATODES
Gross Findings
■ SCHISTOSOMIASIS
The stomach is the most frequent site of involvement,
although the small bowel, colon, and appendix may All species of Schistosoma are capable of causing signifi-
also be involved. Endoscopic findings include muco- cant GI disease. In addition, patients with Schistosoma-
sal edema, friability, hemorrhage, erosions, and ulcers. related liver disease may also have associated portal
Sometimes larvae may be seen endoscopically. colopathy and GI bleeding.
Patients generally present with diarrhea (often bloody)

accompanied by anemia, weight loss, and protein-losing
enteropathy. More dramatic GI presentations have also
been described, including profound dysentery-like illness,
obstruction, perforation, intussusception, rectal prolapse,
fistulas, and perianal abscesses. Intestinal schistosomiasis
is most often caused by Schistosoma mansoni, Schistosoma
japonicum, Schistosoma mekongi, and Schistosoma interca-
latum. Schistosoma haematobium may cause appendicitis.
Pathologic Features

Remote colonic infection with schistosomes may show calcified eggs with no
Any level of the alimentary tract may be affected. inflammatory reaction (hematoxylin and eosin).
Endoscopically, schistosomiasis can cause a striking
inflammatory polyposis (particularly in the distal colon)
with associated mucosal granularity, friability, and Schistosomiasis—Pathologic Features
punctate ulcers and hemorrhages.
Gross Findings
n Any level of the alimentary tract may be affected
n Striking inflammatory polyposis (particularly in the distal colon)
with associated mucosal granularity, friability, and punctate ulcers

Histologically, inflammatory polyps and mucosal ulcers with and hemorrhages
associated granulomatous inflammation and eosinophilic
infiltrates are typical. Eggs are occasionally seen in histo- Microscopic Findings
logic specimens, and sometimes they are calcified. Remote n Inflammatory polyps and mucosal ulcers with associated
disease may show only calcified eggs with no inflammatory granulomatous inflammation and an eosinophilic infiltrate
n Eggs are occasionally seen in histologic specimens
infiltrate (Fig. 9.50). Eggs of different Schistosoma spp. may
n Remote disease may show only calcified eggs with no
be distinguished from one another by the presence and
location of spines. For example, Schistosoma mansoni eggs
have a lateral spine, whereas S. haematobium eggs have a Differential Diagnosis
terminal spine, and spine are minute or absent on S. japoni- n Other helminthic infections
cum eggs. Schistosome eggs are variably acid fast.
SCHISTOSOMIASIS—FACT SHEET Ancillary Studies
Definition Stool for ova and parasites is a helpful ancillary test.

n Parasitic disease causing numerous gastrointestinal and hepatic Serologic testing may also be helpful, especially outside
manifestations of endemic areas. History of travel to an endemic area
may be invaluable.
n Any level of the alimentary tract
Clinical Features
n Diarrhea (often bloody), accompanied by anemia, weight loss,
and protein-losing enteropathy The differential diagnosis is primarily that of other hel-
n Profound dysentery-like illness, obstruction, perforation, minthic infections or other granulomatous infections if
intussusception, rectal prolapse, fistulas, and perianal abscesses eggs or worms are not visible.
have also been described
n Patients with schistosome-related cirrhosis may have varices and
portal colopathy
n Antiparasitic agents such as praziquantel Antiparasitic agents, such as praziquantel, are the treat-
ment for schistosomiasis.
■ ACKNOWLEDGEMENT Salmonellosis
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10
Non-neoplastic Disorders of the Colon
■ Rish K. Pai, MD, PhD
Mucosal biopsies from the colon are obtained most com- or an abnormal subepithelial collagen layer and defines
monly (1) in acutely symptomatic patients with the lymphocytic and collagenous colitis (CC), respectively.
possibility of an ischemic, infectious, or drug-induced A diagnosis of chronic colitis is based on inflamma-
colitis; (2) when graft-versus-host disease (GVHD) tory, architectural, or metaplastic features (Fig. 10.1C)
needs to be ruled out; or (3) in those with chronic symp- and is discussed in greater detail later. Epithelial injury
toms in whom the main consideration is inflammatory from vascular causes typically results in an ischemic or
bowel disease (IBD). In other instances, patients with hemorrhagic pattern of colitis (Fig. 10.1D). Finally, a
diarrhea and normal colonoscopy results are biopsied spectrum of disorders may be associated with minimal
to rule out lymphocytic or collagenous (“microscopic”) or no inflammation and should be considered before
colitis. An understanding of normal variations and arti- diagnosing a biopsy as within normal limits. Common
facts is essential while interpreting mucosal biopsies disorders in this category include infections in immuno-
from the colon. The bowel preparation itself induces compromised hosts, GVHD (Fig. 10.1E) and its mimics,
some artifacts, and minor foci of lamina propria hem- and amyloidosis. A mucosal biopsy diagnosis based on
orrhage, surface erosion without lamina propria inflam- the specific morphologic pattern of injury rather than a
mation, and scattered crypt epithelial apoptosis are descriptive one greatly aids gastroenterologists in formu-
common and should not be misinterpreted as abnormal lating a differential diagnosis and working up patients
findings. Similarly, knowledge of normal variations in with any ancillary testing that may be needed. Whereas
histology is also helpful to avoid misdiagnosis. The cecal focal or diffuse active colitis is usually associated with
and right colon mucosa normally has a higher density infections, drugs, or early IBD, chronic colitis is a hall-
of lamina propria mononuclear cell infiltrate, which mark of IBD or one of its mimics. Infectious colitis is
should not be confused with a colitis, and the rectal discussed in detail in Chapter x, and the distinction of
mucosa often shows slight architectural disarray that acute self-limited colitis from IBD is discussed in detail
must not be misinterpreted as manifestation of a chronic later under the differential diagnosis of IBD.
colitis.
Despite the wide array of underlying causes, the
histologic alterations in inflammatory disorders of the
colon are limited and can be classified only into one of ■ IDIOPATHIC INFLAMMATORY BOWEL
few categories. The pattern of colitis may be catego- DISEASE
rized as focal or diffuse (Fig. 10.1A and B) based on the
extent of inflammatory lymphoplasmacytic infiltrate in Chronic injury in mucosal biopsies is typically diagnosed
the lamina propria. Diffuse colitis is graded into mild, based on inflammatory, architectural, or metaplastic fea-
moderate, or severe depending on the degree of activ- tures. Basal lymphoplasmacytosis is by far the most use-
ity, which in the vast majority of cases implies neutro- ful inflammatory feature that helps in establishing the
philic infiltration into the surface or crypt epithelium diagnosis of a chronic colitis and manifests as a deep
(or both). Rarely, eosinophils may be the predominant band of lymphocytes and plasma cells that separates
acute inflammatory cell type in the lamina propria with the base of the crypts from the muscularis mucosae.
significant intraepithelial infiltration, a pattern that can Architectural crypt disarray; crypt branching, shorten-
be classified as eosinophilic colitis. Abnormal neoplas- ing, or loss; and pyloric gland or Paneth cell metapla-
tic infiltrate in the lamina propria in systemic mastocy- sia are also features typically used to favor a chronic
tosis or Langerhans cell histiocytosis may also induce colitis. A diagnosis of chronic colitis usually implies a
a prominent eosinophilic infiltrate and mimic a colitis high probability of IBD, but a number of well-defined
and should be considered in the differential diagnosis IBD mimics are known that should always be ruled out
of an eosinophilic colitis. A diffuse colitis may also be before giving patients a serious diagnosis that carries
associated with increased intraepithelial lymphocytes important lifelong surveillance implications.
299
A C
B D
E
FIGURE 10.1
Common morphologic patterns of injury in mucosal biopsies from the colon. Focal active colitis shows a localized, sharply demarcated increase in lamina propria
inflammation that may be associated with cryptitis, crypt abscess or erosion (A). Diffuse active colitis shows a uniformly increased lamina propria infiltrate with
variable degrees of activity (B). Chronic colitis is characterized by a basal lymphoplasmacytic infiltrate that separates the base of the crypts from the muscularis
mucosae (C). Architectural disarray is not necessary for a diagnosis of chronic colitis. Lamina propria hemorrhage or hyalinization is typical for acute ischemic
colitis pattern of injury (D), but some disorders such as graft-versus-host disease are quite pauciinflammatory and may be mistaken for a normal biopsy (E).
Ulcerative colitis and Crohn’s disease are the two strategies, underscore the importance of distinguishing
most common manifestations of IBD and differ signifi- between the two entities. Although classic cases can be
cantly in their clinical presentation, morphologic pat- easily separated, there may be gross, clinical, and his-
terns of injury, natural history, therapy, and response tologic overlap not only between ulcerative colitis and
to treatment. These differences, particularly with regard Crohn’s disease but also with other inflammatory disor-
to recommended treatment options and surveillance ders of the colon.
CHAPTER 10 Non-neoplastic Disorders of the Colon 301
ULCERATIVE COLITIS
Ulcerative colitis is a chronic colitis of unknown cause

characterized by bloody diarrhea, mucosa-limited dis-
ease, and a fluctuating clinical course.
Ulcerative colitis has a slightly higher incidence in males

and occurs at all ages, with the major peak incidence in
the age range of 15 to 25 years and a minor peak in the
seventh decade of life. There is a familial association,
with up to 25% of patients having a family member
affected with IBD.
Clinically, ulcerative colitis is characterized by recur- FIGURE 10.2
rent episodes of bloody diarrhea that can undergo Chronic ulcerative colitis. Colonoscopy image with diffuse erythema and
spontaneous or therapy-induced remission. The initial granular appearance
presentation may be indolent in onset or severe and
acute, presenting with a fulminant colitis. Ulcerative
proctitis occurs in 30% to 50% of patients at presen-
tation. Approximately one-third present with left-sided
colitis and the remaining with a pancolitis. The terminal
ileum may also be involved in a subset of those with a
severe pancolitis and rarely upper gastrointestinal (GI)
involvement may be present in an otherwise typical
ulcerative colitis. However, the distribution of disease is
not static and may change over time. Between 20% and
30% of patients with ulcerative colitis require a colec-
tomy during the course of their disease.
Radiologic Features
Endoscopy with biopsy has replaced radiology in the ini-

FIGURE 10.3
tial diagnosis of IBD. Features that may be seen radio-
Quiescent chronic ulcerative colitis. Mucosa is granular with minimal ery-
graphically in patients with ulcerative colitis include thema and friability. Mucosal folds are flattened, and the submucosal vascu-
continuous involvement of the colon with ulcers or polyps lar pattern is lost.
and the occasional finding of megacolon. Strictures, fis-
tulas, “thumbprinting,” and skip areas are not seen. most cases, the normal submucosal vascular pattern is
lost and is an important clue to the endoscopist in favor
of a chronic colitis. In patients who have had repeated
bouts of colitis, the normal haustral folds may be lost,
Endoscopic Features
giving the lumen a tubelike appearance. The transition
between normal and abnormal mucosa is generally grad-
The gross endoscopic appearance of ulcerative colitis ual but may be abrupt. Variations to this classic appear-
varies with the degree of activity, duration of disease, ance may occur in some patients and are discussed next.
and response to therapy. It is characterized by diffuse
disease, with rectal involvement extending proximally.
In the more active phases, the mucosa is typically ery-
thematous and friable, with a granular appearance Pathologic Features
(Fig. 10.2). Erosions and ulcers are common. Quiescent
disease may appear normal or granular with areas of Gross Findings
punctuate erythema (Fig. 10.3). Pseudopolyps that rep-
resent mucosal remnants and inflammatory polyps may The colonic wall is usually of normal thickness with an
be seen in active or quiescent disease (Fig. 10.4). In unremarkable serosa, and strictures are rare in patients
Biopsy Findings. Morphologically, diagnostic fea-

tures of a chronic colitis can be broadly divided into archi-
tectural, inflammatory, and metaplastic. Architectural
features include crypt disarray and branching and result
from cycles of recurrent mucosal injury and inadequate
repair. Most patients with suspected IBD undergo colo-
noscopy much earlier in their disease course than in the
past. As a result, architectural features of chronicity are
seldom pronounced in mucosal biopsies at initial pre-
sentation, and pathologists often rely merely on inflam-
matory and metaplastic features to make a diagnosis
of a chronic colitis. Inflammatory features of a chronic
colitis include basal lymphoplasmacytosis, which results
from a marked increase in lamina propria inflammatory
cells involving the entire thickness of the mucosa and
creates a distinct band of lymphoplasmacytic inflam-
mation between the base of the crypts and the muscu-
laris mucosa (Fig. 10.6). The lamina propria infiltrate is
heterogeneous with a variable number of lymphocytes,
plasma cells, and eosinophils. Eosinophils and lymphoid
FIGURE 10.4 aggregates at the mucosal–submucosal interface can be
Chronic ulcerative colitis. Mucosa is diffusely involved by polyps and areas of quite prominent in some cases. Neutrophils are the hall-
bridging.
mark of disease activity and may be present within the
lamina propria, crypt epithelium (cryptitis), or crypt
lumens (crypt abscesses) (Fig. 10.7). Disease activity in
chronic colitis is subjectively graded in mucosal biopsies
as mild (cryptitis only), moderate (crypt abscesses), and
severe (ulcerated mucosa). A loose collection of histio-
cytes may be present around ruptured crypts and is var-
iously referred to as mucin granulomas or crypt rupture
reaction (Fig. 10.8) and should not be confused with
compact sarcoid-like granulomas of Crohn’s disease. The
injured colonic epithelium is mucin depleted and attenu-
ated, but these findings are not helpful in distinguishing
FIGURE 10.5
Ulcerative colitis. Diffusely hemorrhagic mucosa extends from the anorectal
junction to the cecum. The bowel wall thickness is grossly normal.
with ulcerative colitis. The mucosa may be flattened,

hemorrhagic, and friable (Fig. 10.5) with numerous
inflammatory polyps. Disease involvement grossly
extends in a continuous manner from the rectum prox-
imally and may involve the entire colon and appendix
and even the terminal ileum (“backwash ileitis”). Skip
FIGURE 10.6
areas are not a feature of ulcerative colitis outside of well
Ulcerative colitis. Biopsy shows crypt architectural distortion and branching.
recognized exceptions to the rule, discussed in greater Crypt abscess extends into lamina propria; basal plasmacytosis diagnostic of
detail later. a chronic colitis is present.
an acute from a chronic colitis. Metaplastic features of

chronicity include pyloric gland metaplasia, which is
more common in terminal ileum biopsies, and Paneth
cell metaplasia, which is helpful in left colon and rectal
biopsies. Paneth cells are normal in the proximal colon
but are an indicator of chronic mucosal injury and
repair in the distal colon. It is important to emphasize
that low-grade ischemic injury, radiation, GVHD, and
medications can also result in architectural and meta-
plastic features similar to IBD, and an initial diagnosis
of untreated ulcerative colitis or Crohn’s disease should
not be rendered in the absence of diagnostic inflamma-
tory features of a chronic colitis.
Posttreatment biopsies in patients with IBD may
show complete normalization of the mucosa, continued
disease activity similar to the initial biopsies, or partial
resolution with some evidence of residual injury. The
latter group may show a chronic inactive colitis with
increased lymphoplasmacytic infiltrate but without
neutrophilic infiltration in the epithelium or a chronic
quiescent colitis with only mild architectural disarray
and/or Paneth cell metaplasia but without any increase
in lamina propria inflammation (Fig. 10.9).
Flares of ulcerative colitis occur quite commonly.
Endoscopic evaluation with biopsy is done to confirm
active ulcerative colitis and to exclude other causes
such as Clostridium difficile colitis and cytomegalovi-
rus (CMV) infection. CMV infection is quite common
in patients with ulcerative colitis, and the presence
of numerous CMV inclusions in a patient with active
colitis warrants treatment with antiviral medications
FIGURE 10.7 (Fig. 10.10). The significance of only rare CMV inclu-
Ulcerative colitis. Biopsy shows marked inflammation, crypt distortion, and sions in an otherwise typical active ulcerative colitis
crypt abscesses. biopsy is less clear, although these patients are often
treated with both immunosuppression and antiviral
FIGURE 10.8
Rupture of inflamed crypts may lead to mucin extravasation and a loose his- FIGURE 10.9
tiocytic reaction (“crypt rupture reaction”) that should not be mistaken for Quiescent ulcerative colitis. Mild crypt distortion, minimal inflammation, and
compact sarcoid-like granulomas of Crohn’s disease. Paneth cell metaplasia.

Cytomegalovirus (CMV) infection in ulcerative colitis. A singe CMV inclusion Backwash ileitis in ulcerative colitis. Mild active inflammation is present in the
is seen in the background of severe chronic active colitis. surface epithelium. Rarely, features of a chronic ileitis may also be present.
medications. Corticosteroids are often used to induce

remission of the underlying IBD.
Variants of Ulcerative Colitis
There are defined variants of ulcerative colitis that devi-

ate from the typical appearance already described and
deserve mention. Up to 30% of patients with left-sided
colitis may have patches of active disease in the right
colon, particularly in the cecum near the appendiceal FIGURE 10.12
orifice. This finding, often referred to as the cecal patch, Ulcerative colitis, resection specimen. Low-power shows diffuse mucosal
inflammation that abruptly stops at the mucosa–submucosa interface.
should not be confused with Crohn’s disease. Similarly,
patchy disease involvement may be seen in patients with
severe fulminant ulcerative colitis who present acutely Resection Findings. The inflammatory process is
and undergo a total colectomy to prevent perforation or confined to the mucosa in most cases (Fig. 10.12) and
in patients who have undergone treatment. Ulcerative shows a cellular inflamed lamina propria on low power,
colitis in the pediatric population may show relative or often with crypt architectural disarray and crypt loss.
complete rectal sparing. In adults, rare cases may show Lymphoid aggregates at the mucosal–submucosal inter-
relative rectal sparing with decreased disease activity face may be present and can be numerous in some cases.
compared with the more proximal colon, but complete Disease activity can be variable, ranging from mild cryp-
rectal sparing is not seen. Ileal involvement by ulcer- titis to mucosal ulcers with associated granulation tissue.
ative colitis (“backwash ileitis”) may occur in patients Mounds of residual mucosal remnants surrounded by
who have severe pancolitis, and this should not be con- ulcer may stand out as pseudopolyps. (Fig. 10.13). Most
fused with Crohn’s disease (Fig. 10.11). Inflammation in patients receive some form of medical therapy before
the ileum in this setting is often mild, limited to the dis- a colectomy, so it is not unusual to see patchy disease
tal few centimeters, and characterized by mild inflam- involvement in resection specimens. The submucosa may
mation in the lamina propria and active neutrophilic be edematous and congested but is typically without sig-
infiltration in the crypt or villous epithelium. Chronic nificant inflammation or fibrosis. Lymphoid aggregates
changes such as pyloric gland metaplasia, reminiscent of may be prominent underneath areas of mucosal ulcer-
Crohn’s disease, may also be seen but are rare. Finally, ation and should not be mistaken for Crohn’s disease.
biopsies from the upper GI tract may show histologic Occasionally, resection specimens for presumed
abnormalities in a subset of patients with ulcerative coli- ulcerative colitis show atypical histologic features that
tis, the most common being a focal active gastritis. A preclude a definitive diagnosis of ulcerative colitis and
diffuse duodenitis and even a pan-enteritis have been raise the possibility of Crohn’s disease. The presence
described in rare patients with ulcerative colitis after of strictures, fistulas, perianal disease, transmural lym-
total colectomy and ileal pouch anal anastomosis. The phoid aggregates, granulomas away from injured crypts
cause of this diffuse enteritis is unclear. or deeper in the intestinal wall, and segmental disease in
In the chronic phase of the disease, the differential

diagnosis is limited to a chronic infectious colitis or a
handful of well-recognized IBD mimics. Infections that
can have a chronic relapsing course, such as C. difficile,
may induce mucosal changes that mimic IBD. Similarly,
architectural changes of IBD may be seen in radiation or
low-grade ischemic injury, but these can be easily distin-
guished based on the lack of a prominent inflammatory
component. The distinction from diverticular disease
associated colitis and diversion colitis can be challeng-
ing and is discussed in detail under these entities later.
Ancillary Studies
FIGURE 10.13
No specific tests for ulcerative colitis are available.
Ulcerative colitis, resection specimen. Low power shows diffuse involve-
Initially, patients should be tested for infectious causes
ment by inflammatory polyps and pseudopolyps with mucosal bridging. that are known to be associated with long-standing
Inflammation is confined to the mucosa. colitis, particularly to exclude Shigella spp., Salmonella
spp., Escherichia coli O157:H7, Campylobacter jejuni,
an untreated setting are diagnostic features in favor of and C. difficile. Stool studies for ova and parasites as
Crohn’s disease. A diagnosis of Crohn’s disease in a total well as exclusion of Giardia spp. may be warranted in
colectomy for presumed ulcerative colitis has significant patients with specific risk factors or relevant travel his-
clinical consequences because these patients are not tory. Patients who have a flare of ulcerative colitis while
considered candidates for ileal pouch anal anastomosis being treated with immunosuppressive therapy may also
at most centers. Conversely, defined histologic variants benefit from testing for CMV and C. difficile infection,
of ulcerative colitis described in the previous section which can present with deep ulcers in the background
should not be mistaken for Crohn’s disease. Despite of ulcerative colitis. C. difficile infections in the setting
meticulous work-up and systematic review, rare cases of ulcerative colitis seldom show the typical pseudo-
are difficult to classify, and such resection specimens membranous colitis pattern, and microbiologic work-up
may be diagnosed as IBD, unclassified type. The use of is necessary for diagnosis. Results of serologic tests for
the term indeterminate colitis is discouraged. At most perinuclear antineutrophil cytoplasmic antibody are
centers, these patients are followed closely for definitive often positive in patients with ulcerative colitis but have
signs of Crohn’s disease, and an ileal pouch anal anas- limited utility in differentiating ulcerative colitis from
tomosis is eventually performed if no signs of Crohn’s Crohn’s disease in difficult cases.
disease are seen on follow-up.
Differential Diagnosis. In the early phase of the
disease, features of chronicity may not be well estab-
■ DYSPLASIA IN ULCERATIVE COLITIS
lished in mucosal biopsies obtained from patients with
ulcerative colitis. In this scenario, the main differential
diagnosis is with acute self-limited colitis and drug-in- Long-standing ulcerative colitis is associated with an
duced colitis. Acute self-limited colitis is a clinical term increased risk for dysplasia and adenocarcinoma. This
often used for diarrheal disorders of short duration re- risk is even higher in patients with concurrent ulcer-
lated to an infectious cause. The biopsy findings in acute ative colitis and primary sclerosing cholangitis. Periodic
self-limited colitis are those of a focal or diffuse active surveillance biopsies are the mainstay of management
colitis of varying severity. The increased lymphoplas- for early detection of dysplasia and adenocarcinoma.
macytic infiltrate in the lamina propria is typically de- Four quadrant biopsies every 10 cm of colon that has
scribed as being confined to the upper half of the mucosa been involved by disease are usually recommended, in
but may be full thickness in severe cases. However, the addition to sampling or removal of any visible lesions.
characteristic basal lymphoplasmacytosis of a chronic Pathologists should record any evidence of chronic
colitis is absent, and normal colonic crypt architecture is colitis, degree of activity, and the presence or absence
preserved. Similarly, a variety of medications may cause of dysplasia in their reports from surveillance biopsies.
a similar pattern of injury. The most recent addition to Dysplasia is categorized into negative, indefinite, low
this group are immune checkpoint receptor inhibitors grade, and high grade. Intramucosal or invasive adeno-
that are being used with increasing frequency in the carcinoma may also be seen in surveillance biopsies, the
management of a variety of solid tumors. latter usually in tissue obtained from visible lesions.
Pathologic Features
Gross Findings
Dysplasia can be found in two distinct forms: endoscop-

ically invisible (also described as “flat”) dysplasia that
are picked up in random biopsies and endoscopically
visible dysplasia that may present as a discrete polyp-
oid lesion or a sessile ill-defined mass. The endoscopic
findings are critical, even more so than the grade of dys-
plasia, when deciding management of patients. This is
discussed in greater detail later.
FIGURE 10.14
Dysplasia in ulcerative colitis may show cytologic and Invisible low-grade dysplasia in ulcerative colitis. A random colonic biopsy
architectural changes that vary with grade of dysplasia. demonstrating nuclear enlargement, nuclear stratification, and loss of surface
Architecturally, the crypts may be normal or show crypt maturation. Note the abrupt change from adjacent normal colonic mucosa,
which is helpful in the diagnosis of dysplasia.
budding, crowding, or prominent serration, the latter in
the case of serrated dysplasia. Nuclear hyperchromasia,
enlargement, and irregularity are often present, and the
cytoplasmic features are variable and range from com-
plete mucin depletion to abundant eosinophilic, hyper-
mucinous, or clear cytoplasm reminiscent of foveolar
type dysplasia seen in the upper GI tract. Low-grade
dysplasia is similar to sporadic tubular adenomas and
is characterized by elongated penicillate, hyperchro-
matic nuclei perpendicular to the basement membrane
with variable degree of pseudostratification. An abrupt
change from adjacent normal mucosa is helpful in diag-
nosis of dysplasia (Fig. 10.14). High-grade dysplasia is
characterized by more pronounced nuclear changes,
including round nuclei no longer perpendicular to the
basement membrane (loss of polarity), nuclear pleo-
morphism, marked hyperchromasia, and nucleolar
prominence (Fig. 10.15). In many instances, high-grade
dysplasia in the setting of IBD, particularly flat invis- FIGURE 10.15
ible dysplasia, may not show architectural features of Dysplasia in ulcerative colitis, high grade. Hyperchromatic and enlarged
nuclei, with loss of polarity and marked pleomorphism.
crypt crowding and budding. Diagnostic cytologic fea-
tures described earlier are sufficient to classify such
biopsies as high-grade dysplasia. Surveillance biopsies The presence of a visible dysplastic lesion in the back-
in ulcerative colitis, particularly those obtained during ground of ulcerative colitis may either represent a spo-
chromoendoscopy, may show serrated lesions with mor- radic adenoma or colitis-associated dysplasia. Although
phological appearance similar to sporadic hyperplastic some molecular differences exist between these two
polyps, sessile serrated adenoma or polyp (SSP), or a forms of visible dysplasia, it is impossible to separate
traditional serrated adenoma (TSA). The presence of these lesions based on morphology alone. Fortunately,
hyperplastic polyp-like change in flat mucosal biopsies making this distinction is of little practical importance
in IBD has been referred to as serrated epithelial change because management of visible lesions in the setting
and does not lead to increased surveillance. SSP and of ulcerative colitis depends mostly on the endoscopic
TSA morphology in IBD is almost always seen in biop- appearance. Patients with well-circumscribed lesions
sies obtained from endoscopically visible lesions. The (Fig. 10.16) that can be removed endoscopically can
significance of hyperplastic polyp or SSP in patients be safely followed with surveillance after complete
with IBD with respect to recommended surveillance polypectomy. Irregular lesions with indistinct borders
intervals is unclear, but the overall risk of cancer often require surgical intervention, although advanced
appears to be low as long as complete excision of visible endoscopic techniques such as endoscopic muco-
lesions is performed. sal resection and endoscopic submucosal dissection
A B
FIGURE 10.16
Visible dysplasia in ulcerative colitis. A, Low-grade dysplasia arising in a well-circumscribed polyp. B, Nuclear hyperchromasia and stratification and dystrophic
goblet cells in low-grade dysplasia.
A B
FIGURE 10.17
Visible dysplasia in ulcerative colitis. A, A large, flat, irregular plaque-like lesion in ulcerative colitis. B, These lesions can now be treated by endoscopic submuco-
sal dissection, which allows complete removal with negative margins.
(Fig. 10.17) are increasingly used at tertiary academic and diffuse colonic involvement. The clinical setting,
centers. lack of significant basal lymphoplasmacytosis, and
Invisible dysplasia is becoming increasingly less com- microbiologic work-up are all key to avoiding a misdiag-
mon with the advent of chromoendoscopy. A single nosis of IBD at initial presentation. Medications, partic-
focus of invisible low-grade dysplasia may be followed ularly nonsteroidal antiinflammatory drugs (NSAIDs),
by increased surveillance. Persistent or multifocal flat may present with focal active colitis, chronic active
low-grade dysplasia and invisible high-grade dysplasia colitis, or one or many ulcers throughout the colon.
usually warrant a colectomy because of the high risk of Histologically, NSAID ulcers are small and discrete and
concurrent adenocarcinoma. lack the confluent mucosal involvement typically seen
in ulcerative colitis on endoscopy. Recently, chronic
colitis has also been described in patients on immune
checkpoint receptor inhibitor–associated chemother-
apy. The presence of a concomitant increase in intraep-
ithelial lymphocytes and prominent apoptosis along
Ulcerative colitis must be distinguished from a large with features of a chronic colitis are helpful features
number of mimics, including infectious colitis, medi- in favor of an immunotherapy-associated colitis. Like
cation-induced colitis, ischemic colitis, Crohn’s disease, with other drug-induced colitides, correlation with
diversion colitis, and diverticular disease associated timeline of disease course and resolution of symptoms
colitis, among others. Long-standing infectious coli- after cessation of drug or immunosuppression is needed
tis may have many of the features of ulcerative colitis, to establish the diagnosis. Chronic ischemic or radia-
including increased chronic inflammation, neutrophils, tion colitis can also be mistaken for ulcerative colitis,
particularly because ischemia resulting from low vas-

cular flow often affects the left colon, and repeated ULCERATIVE COLITIS—FACT SHEET
injury and repair may lead to architectural changes
of a chronic colitis. However, these cases lack the typ- Definition
ically inflammatory component of ulcerative colitis, n Idiopathic chronic colitis that presents with bloody diarrhea and
and an initial diagnosis of IBD should never be made is histologically characterized by a chronic colitis limited to the
mucosa with continuous involvement from the rectum extending
only on architectural features in an untreated patient. proximally
The patchy distribution of the disease is only helpful
in distinguishing Crohn’s disease from ulcerative coli- Incidence and Location
tis at initial presentation. After institution of medical n Uncommon (4–20 per 100,000 population annually)
therapy, the mucosa of patients with ulcerative colitis n Higher incidence in North America, Western Europe, South Africa
often heals in a patchy distribution. Diverticular dis-

ease–associated colitis can have features identical to Age, Gender, and Race, Distribution
n Rare in first decade of life
ulcerative colitis. The distribution of the colitis involv-
n Major peak at 15 to 25 years of age
ing the interdiverticular mucosa in a colonic segment n Minor peak at 60 to 70 years of age
involved with diverticular disease and sparing of the n Incidence slightly higher in men than women
rectum and remaining colon are helpful in making this n Whites show higher incidence than other ethnic groups
distinction. Segments of colon that are excluded from n Jews have a higher incidence than other religious groups
n 25% have an affected relative with inflammatory bowel disease

the fecal stream develop a diversion colitis character-
ized by marked lymphoid hyperplasia, cryptitis, and
Clinical Features
crypt architectural distortion, which mimics ulcerative
n Recurrent episodes of bloody diarrhea
colitis. Knowledge of the clinical setting is important to
avoid misdiagnosis. Endoscopic Features
n Active phase: erythema, abnormal vascular pattern, spontaneous
bleeding, friability, granularity, erosions, and ulcers

n Quiescent phase: may appear normal; often there are granularity
Prognosis and Therapy and erythema; loss of haustral folds (tubelike appearance)
n Polyps: pseudopolyps (mucosal remnants) and inflammatory
polyps in active disease and postinflammatory polyps in active or

The goals of medical treatment in ulcerative colitis quiescent disease
include inducing and maintaining remission, min- n All phases: submucosal vascular network is usually abnormal
imizing side effects, and improving the quality of life.

Standard therapy includes antiinflammatory drugs, spe- Prognosis and Therapy
n Low mortality, high morbidity
cifically, the 5-aminosalicylic acid (5-ASA) compounds
n Treatment: antiinflammatory and immunosuppressive drugs;
(sulfasalazine and other salicylates), which are effective
surgery if not responsive to medications and may be potentially
in preventing exacerbations in patients in remission. curative
Steroids, either topical (enemas) or systemic, are effec- n Increased risk for dysplasia and adenocarcinoma
tive in treating acute flares of disease. Biologic therapy is n Surveillance for dysplasia annually, starting 8 years after initiation
becoming increasingly common, particularly antibodies presentation

n Total colectomy for fulminant ulcerative colitis, adenocarcinoma,
against tumor necrosis factor-α (TNF-α) and antibodies
and endoscopically invisible (“flat”) dysplasia or endoscopically
against adhesion molecules that affect lymphocyte traf- unresectable visible dysplasia
ficking. Patients with acute fulminant colitis, refractory n Ileal pouch (J-pouch) anal anastomosis performed in most
disease, or persistent invisible dysplasia or endoscopi- instances

cally unresectable visible dysplasia are all treated with
total colectomy. Resection with subsequent ileal pouch
anal pouch anastomosis allows the patient to have rel-
atively normal bowel function by maintaining the anal
Ulcerative Colitis—Pathologic Features
sphincter after colectomy.
Patients who are detected to have adenocarcinoma Gross Findings
on surveillance have a significantly better prognosis n Mucosa flattened, bloody, friable, and granular with variable
than those in whom carcinoma is detected after the numbers of polyps
development of clinical symptoms. Additional long- n Continuous involvement from rectum proximally but may have
term complications and associated conditions of ulcer- patchy appearance due to medical therapy or in acute fulminant
cases
ative colitis include chronic anemia, hypoalbuminemia,
n May involve terminal ileum in cases with severe pancolitis
sclerosing cholangitis, ankylosing spondylitis, arthritis, n Cecal or appendiceal involvement may be present in patients
uveal disease, arthritis, vasculitis, and drug-associated with left sided ulcerative colitis
complications.
between 20 and 30 years of age. The initial presentation

Relative or absolute rectal sparing may be present; more
n
may be indolent in onset or may be acute and severe.
commonly in children
n Upper gastrointestinal tract involved in rare cases The symptoms are variable but often include cramping
abdominal pain, typically localized to the right lower
Microscopic Findings quadrant; nonbloody diarrhea; and fever, malaise, and
Biopsy anorexia. These findings may mimic acute appendicitis.
n Architectural features include crypt distortion, branching, loss, or Although the appendix may be involved with Crohn’s
shortening disease, appendicitis as a presenting feature is rare.
n Inflammatory features include basal lymphoplasmacytosis, with
Hemorrhage and hematochezia are uncommon, but
variable activity
n Neutrophils, the hallmark of active disease, are located within
chronic blood loss can occur as a result of bleeding ero-
crypt epithelium (cryptitis) and crypt lumens (crypt abscesses) sions and ulcers. Patients with upper intestinal disease
n Eosinophils and intraepithelial lymphocytes may be prominent in may present with dyspepsia, weight loss, hypoalbu-
posttreatment biopsies minemia, and iron-deficiency anemia mimicking celiac
n Lymphoid aggregates may be seen at the mucosal–submucosal
disease. Patients with strictures present with symp-
interface
n Inflammation is usually more severe distally
toms and signs of bowel obstruction. Enterovaginal,
n Metaplastic features include pyloric gland metaplasia in the ileum enterovesical, and enterocutaneous fistulas may result
or colon or Paneth cell metaplasia in left colon biopsies in the passage of blood, feces, pus, and air from the
vagina, urethra, or perineal skin. Inflammatory
Resection changes can occur in joints, eyes, liver, and skin. The
n Inflammatory process is confined to mucosa; deeper layers may
genetic association is stronger in Crohn’s disease com-
be involved in fulminant cases with broad ulcers but do not show
pared with ulcerative colitis with 10% of the patients
transmural lymphoid aggregates
n Superficial fissuring ulcers may be present in fulminant colitis
having another affected family member.
cases in areas of confluent mucosal denudation
n Architectural, inflammatory, and metaplastic features of chronic
injury are present

n Pseudopolyps and inflammatory polyps present in variable Radiologic Features
numbers
n Transmural lymphoid aggregates, deep fissuring ulcers, strictures,
fistulas, and granulomas away from ruptured crypts or deep to As with ulcerative colitis, endoscopy has replaced
the mucosa not present radiology in the diagnosis of Crohn’s disease; however,
visualization of small bowel lesions often requires radio-
Differential Diagnosis logic imaging, particularly with magnetic resonance
n Infectious colitis
imaging or computed tomography (CT) enterography.
n Medication-induced colitis
n Chronic low-grade ischemic colitis

Radiographic features typical of Crohn’s disease include
n Crohn’s disease asymmetric ileal involvement, longitudinal ulcers, cob-
n Diverticular disease–associated colitis blestone appearance, mural thickening and fat strand-
n Diversion colitis ing, segmental stenosis and fistulas.
Endoscopic Features
CROHN’S DISEASE
The gross endoscopic appearance of Crohn’s disease is
Crohn’s disease, also referred to as regional enteritis, most consistently characterized as a multifocal process.
granulomatous enterocolitis, and terminal ileitis, is a Aphthous erosions (Fig. 10.18), longitudinal ulcers
chronic relapsing and remitting inflammatory disease of (train track or rake ulcers) (Fig. 10.19), and adjacent
unknown cause that is often multifocal and can affect areas of erythematous or unremarkable mucosa are
any portion of the GI tract. It is typically characterized by characteristic of Crohn’s disease. Additional endoscopic
aphthous erosions, serpiginous ulcers, chronic mucosal findings include cobblestoning resulting from alternat-
injury, and transmural lymphoid aggregates with or with- ing ulcers and edematous mucosa, strictures, fissures,
out granulomas, strictures, fistulas, and perianal disease. and fistula. The rectum is often spared, unlike in ulcer-
ative colitis. A variable number of inflammatory polyps
may be present and are at times large and numerous, a
phenomenon described as giant filiform polyposis in the
literature. In both Crohn’s disease and ulcerative colitis,
the normal submucosal vascular network is lost in the
Crohn’s disease has a slightly higher incidence in females involved areas, assisting the endoscopist in the diagnosis
and occurs at all ages, with the major peak incidence of chronic colitis.
FIGURE 10.20
Crohn’s enterocolitis. Narrow, constricted lumen with greatly thickened wall,
“pipe stem” bowel.
are usually prominent. The subserosal fat is often firm

FIGURE 10.18
and contracted over stenotic areas of involvement,
Crohn’s enterocolitis. Aphthous erosions: small, irregular white mucosal ero-
sions with erythematous borders. so-called creeping fat. Longitudinal opening of the bowel
may reveal areas with normal bowel wall thickness
and other areas of the bowel that are firm, thick, and
pipelike (Fig. 10.20). Interloop adhesions may occur.
The mucosa may show a variety of changes, including
aphthous erosions, longitudinal ulcers, cobblestoning,
polyps, fissures, and fistulas. The process is usually
multifocal, often with rectal sparing, but may become
confluent. When confluent, the firm, pipelike nature of
the bowel may help to distinguish Crohn’s disease from
ulcerative colitis, in which fibrosis is unusual.
Biopsy Findings. It is hard to distinguish Crohn’s

disease from ulcerative colitis based on microscopic
findings in mucosal biopsies since the characteristic
features are present deeper in the bowel wall. The pres-
ence of granulomas away from inflamed crypts or in
superficial submucosa is helpful but is seen only in a
minority of patients. In most instances, knowledge of
clinical and endoscopic findings is critical for diagnosing
FIGURE 10.19 Crohn’s disease. Aphthous erosions or ulcers, character-
Crohn’s enterocolitis. Longitudinal “rake” ulcers with intervening normal-ap- ized by focal surface epithelial injury associated with
pearing mucosa. a mixed inflammatory infiltrate and sometimes associ-
ated with underlying lymphoid aggregates, are typical
Pathologic Features early lesions. Variability of inflammation within a sin-
gle biopsy sample and among several biopsy fragments
Gross Findings from the same anatomic location is often seen but not
diagnostic because acute fulminant or early ulcerative
Resection is typically performed only in patients who colitis and posttreatment biopsies in ulcerative coli-
have severe complications such as obstruction result- tis may show the same pattern of injury. The areas of
ing from strictures, abscess, fistulas, or perforation. inflammation show architectural changes of chronic
Because the milder forms of the disease are not resected, crypt destructive colitis, but adjacent crypts may appear
the gross pathologic findings in resection specimens totally normal (Fig. 10.21). Granulomas tend to occur
FIGURE 10.21
Crohn’s enterocolitis. Biopsy of an aphthous erosion with focal mucosal dis-
ruption and polymorphs over a lymphoid nodule. Adjacent crypts appear rel-
atively normal.
FIGURE 10.23
Crohn’s enterocolitis resection. Aphthous erosion associated with transmural
inflammation and submucosal fibrosis.
FIGURE 10.22 distorted with flattened villi resulting from underlying

Crohn’s enterocolitis. Poorly formed, non-necrotizing granuloma associated expansion of lymphoid nodules in nonspecific reactive
with marked chronic inflammation.
hyperplasia or from infections such as Yersinia spp.
Resection Findings. The inflammatory process is
more frequently in pediatric patients, usually present typically multifocal with a chronic enteritis or colitis,
away from inflamed crypts and in the submucosa, and superficial and deep fissures, fistulas, and prominent
are non-necrotizing (Fig. 10.22). transmural lymphoid aggregates (Figs. 10.23 to 10.25).
Crohn’s disease involving the terminal ileum may Ulcers are typically longitudinally oriented, separated by
show a focal active ileitis or a chronic active ileitis pat- histologically normal edematous mucosa. Granulomas,
tern of injury. Aphthous erosions, increased lamina pro- when present, may be located at any level of the bowel
pria infiltrate leading to villous blunting, and cryptitis wall. Lymphoid aggregates are often around dilated lym-
are often seen at initial presentation. Crypt disarray is phatics or nerves. Neural hyperplasia is common in the
often difficult to assess in the small intestine in the pres- submucosa and muscularis propria.
ence of marked inflammation, but metaplastic features
are very helpful in this setting. Pyloric gland metaplasia
consisting of simple mucus glands reminiscent of the
Ancillary Studies
antral or pyloric mucosa are the most reproducible fea-
tures of chronicity in ileal biopsies. Peyer’s patches are
a normal component of the terminal ileum, particularly No specific tests for Crohn’s colitis are available.
in young individuals, and should not be mistaken for However, as with ulcerative colitis, exclusion of infec-
increased lymphoplasmacytic inflammation of Crohn’s tious causes is important, particularly Yersinia infec-
disease. The mucosa over Peyer’s patches may be tion. Antibodies to Saccharomyces cerevisiae are present
in approximately 70% of patients with Crohn’s disease

and are usually absent in patients with ulcerative colitis.
In contrast, p-ANCA test results are positive in approx-
imately 70% of patients with ulcerative colitis and in
10% to 30% of patients with Crohn’s disease. There is
overlap of results between Crohn’s disease and ulcer-
ative colitis, and although these tests may be helpful in
rare instances, they are seldom performed to distinguish
ulcerative colitis from Crohn’s disease.
Crohn’s disease must be distinguished from infections,

ulcerative colitis, ischemic colitis, medication-associ-
ated injury, diverticular disease–associated colitis, and
isolated asymptomatic ileitis. The endoscopic finding
of focal aphthous erosions of early Crohn’s disease may
be similar to erosions caused by medications and infec-
tions. Histologically, the erosions of Crohn’s colitis and
ileitis are associated with a dense lymphoplasmacytic
infiltrate. Focal active ileitis is most commonly caused
by medications, particularly NSAIDs, but a small sub-
set may be associated with Crohn’s disease, which is
why correlation with clinical and endoscopic findings is
essential. Isolated chronic active ileitis in an asymptom-
atic patient may be seen in patients undergoing routine
screening colonoscopy and is associated with chronic
NSAID use or low-grade ischemia and is not a mani-
FIGURE 10.24 festation of Crohn’s disease (Fig. 10.26). Biopsies from
Crohn’s enterocolitis resection. Marked submucosal fibrosis associated with other sites of the GI tract, including upper tract biopsies,
transmural and subserosal lymphoid aggregates. Fissuring ulceration. are often helpful in establishing a diagnosis of Crohn’s
disease.
Nonsteroidal antiinflammatory drug ulcers may be
multiple and deep, and chronic blood loss may lead to
FIGURE 10.26
Chronic nonsteroidal antiinflammatory drug (NSAID) ileitis. This ileal biopsy
FIGURE 10.25 demonstrates prominent pyloric gland metaplasia indicative of chronic
Crohn’s enterocolitis resection. Greatly thickened bowel wall with distorted mucosal injury. Active injury with neutrophilic inflammation is not seen in this
mucosa, fissure, submucosal fibrosis, and transmural lymphoid aggregates. particular example of chronic NSAID use.
a curative resection. These ulcers tend to be found on

the top of mucosal folds and are circumferential rather
than longitudinal. There is usually minimal inflamma-
tion away from the ulcers. Strictures may form in these
cases and when circumferential, they appear like “dia-
phragms.” Yersinia infection causes a granulomatous
ileocolitis with preferential involvement of the right
colon. Granulomas with central neutrophil-rich sup-
puration, marked mesenteric lymph node enlargement
with a necrotizing lymphadenitis should favor Yersinia
infection over Crohn’s disease. Necrotizing granulo-
mas predominate in tuberculosis and should be worked
up with acid-fast bacilli stains or with more sensitive
polymerase chain reaction techniques in cases in which
clinical suspicion is high. Diverticular disease–associ-
ated colitis usually only involves the sigmoid colon, and FIGURE 10.27
the inflammation is confined to the area involved with Well-differentiated adenocarcinoma arising in Crohn’s disease extending into
diverticulosis. the bowel wall. The transition from low to high grade dysplasia to adenocar-
Fulminant Crohn’s colitis can be difficult or impos- cinoma is not necessarily seen inflammatory bowel disease–associated car-
cinomas. The surface may look like low-grade dysplasia, and the carcinomas
sible to distinguish from ulcerative colitis in a mucosal often show a low-grade tubuloglandular pattern.
biopsy specimen because many of the distinguishing fea-
tures are deep to the mucosa. Furthermore, in fulminant
ulcerative colitis, inflammation may be transmural but of stricture, or within fistula tracts, making diagnosis
is composed of dispersed acute and chronic inflamma- difficult. Synchronous or metachronous adenocarci-
tory cells without the characteristic lymphoid aggregates nomas may occur and involve the large or small intes-
of Crohn’s disease. tine. Well-differentiated adenocarcinomas may arise in
mucosa that has subtle low-grade dysplasia and infiltrate
as deceptively bland glandular structures (Fig. 10.27).
Well-differentiated mucinous adenocarcinomas that
arise in chronic anal fistulas can be difficult to distin-
guish from non-neoplastic fistula lining.
Standard therapy includes antiinflammatory drugs, spe-
cifically the 5-ASA compounds (sulfasalazine and other
salicylates), and steroids. Budesonide, a topical steroid
that is taken orally, is effective in treating patients with
ileal Crohn’s disease. It is locally absorbed and metab- CROHN’S DISEASE—FACT SHEET
olized in the liver minimizing the systemic side effects
seen with other steroids. Infliximab, a monoclonal anti- Definition
body against TNF-α, has been found to be helpful in n Idiopathic, chronic multifocal relapsing and remitting,
treating acute episodes of Crohn’s colitis, particularly inflammatory disorder of the gastrointestinal tract
n Small intestine, colon, or upper gastrointestinal tract may be
fistulas and other complications. Vedolizumab, a mono- involved
clonal antibody against α4β7 integrin, is also approved n Uncertainly etiology; combination of genetic and environmental
for treatment of patients with Crohn’s disease. Surgery factors
is reserved for patients with refractory disease and those n Typically characterized by aphthous erosions or serpiginous ulcers,
with obstruction, nonresponsive fistulas, sepsis, or car- chronic colitis, transmural lymphoid aggregates, granulomas,
strictures, fistula, and perianal disease
cinoma. Patients who have undergone surgical inter-
vention are at increased risk for requiring additional Incidence
surgery resulting from anastomotic complications such n Uncommon (5–20 per 100,000 population annually)
as strictures, anastomotic leaks, and fistulas. n Higher incidence in North Americans and Northern Europeans
There is a 4 to 20 times increased risk for adenocar-

cinoma in patients with Crohn’s disease compared with Gender, Race, and Age Distribution
the general population. Dysplasia occurs in patients n Incidence slightly higher in females than males
n Whites and Ashkenazi Jews with higher incidence than other

with Crohn’s disease similar to those with ulcerative
ethnic groups
colitis. Surveillance of patients with Crohn’s colitis n Major peak at 20 to 30 years of age; minor peak at 60 to 70
follows those with ulcerative colitis and depends on years of age
the extent and duration of disease. Adenocarcinomas n Familial association: approximately 10% have an affected relative
may arise in a morphologically normal bowel, in areas

Clinical Features
ILEAL POUCH ENTERITIS (POUCHITIS)
n Cramping pain, nonbloody diarrhea, fever, malaise, and anorexia
n Hemorrhage and hematochezia uncommon ■ CLINICAL FEATURES

n Upper intestinal disease: dyspepsia, weight loss,
hypoalbuminemia, and iron-deficiency anemia

n Inflammatory changes can also occur in the joints, eyes, liver, and After total proctocolectomy, construction of an ileal
skin pouch anal anastomosis (J-pouch) is often performed to
restore continence and improve quality of life. This is
Endoscopic Features
often performed in the setting of ulcerative colitis, but
n Aphthous erosions; longitudinal ulcers (train track or rake ulcers);
cobblestone appearance
a J-pouch may also be created in patients with other
n Strictures, fistulas, anal and perianal disease
colonic disease, particularly hereditary colorectal can-
n Terminal ileal involvement cer syndromes such as familial adenomatous polyposis.
n Often rectal sparing; esophagus, stomach, and duodenum may Inflammation of the pouch (“pouchitis”) is a common
be involved in a subset of cases complication that is diagnosed clinically based on symp-
toms of diarrhea, bleeding, urgency, low-grade fever,
and occasionally abdominal pain. Although more than
n Low mortality, high morbidity
n Treatment: antiinflammatory, immunosuppressive drugs, and

half of patients with a J-pouch experience at least one
biologic therapy episode of pouchitis, pouch failure and excision are
n Surgery for refractory disease, strictures, fistulas extremely rare. Pouchitis also decreases dramatically
n Increased risk for dysplasia and adenocarcinoma after the first 6 months of surgery and is likely related
n Ileal pouch anal anastomosis (J-pouch) usually contraindicated
to an alteration in the small intestinal microbiome.
Pouchitis is a clinical term that translates to histologic
patterns of acute and/or chronic mucosal injury. First-
line therapy for pouchitis is with antibiotics. Patients
with chronic symptoms and refractory disease who
do not respond to antibiotics are often treated with
immunosuppression.
Crohn’s Disease—Pathologic Features
Gross Findings Pathologic Features

n Subserosal fat is firm and wraps around bowel wall in stenotic
areas (“creeping fat”)

The pouch is constructed from the ileum, and even
n Firm, thick, and pipelike appearance with adhesions in some
cases healthy pouches demonstrate some abnormal histologic

n Aphthous erosions, longitudinal ulcers, cobblestone appearance, features in the ileal mucosa such as villous blunting,
and inflammatory polyps mild expansion of the lamina propria, increased eosino-
n Fissures, fistulas, and anal or perianal disease in distal resections
phils, and increased intraepithelial lymphocytes. These
are part of the “adaptive response” as the small intestine
transitions to functioning as a neorectum. Patients with
Biopsy
clinically diagnosed pouchitis demonstrate neutrophilic
n Chronic enteritis or colitis, aphthous erosions with underlying
lymphoid aggregates
inflammation in both the crypt and surface epithelium.
n Pyloric gland metaplasia in ileal biopsies Ulcers and erosions may be seen. Chronic pouchitis
n Granulomas more common in pediatric age group and are seen often demonstrates villous architectural distortion and
in a minority of adult patients pyloric gland metaplasia, but this should not be taken as
evidence of Crohn’s disease (Fig. 10.28).
Resection
n Chronic enteritis or colitis, sharp deep fissuring ulcers distinct
from broad confluent ulcers seen in ulcerative colitis, fistula, or

perianal disease Differential Diagnosis
n Submucosal or mural fibrosis in areas of stricture
n Transmural lymphoid aggregates, granulomas, or both
Occasionally, patients may develop Crohn’s disease of

Differential Diagnosis the pouch. This occurs mainly in patients with Crohn’s
disease who were mistakenly thought to have ulcerative
n Medication-associated colitis or enteritis
n Ulcerative colitis (including backwash ileitis)

colitis on the prior colectomy. Therefore, review of the
n Ischemic colitis prior colectomy specimen is very useful when a diagno-
n Diverticular disease–associated colitis sis of Crohn’s disease of the pouch is being considered.
It must be emphasized again that no histologic feature
ILEAL POUCH INFLAMMATION (POUCHITIS)—FACT SHEET
Definition
n Inflammation of the ileal pouch following total proctocolectomy

n Common after total colectomy for ulcerative colitis; rare in
noninflammatory bowel disease

n May involve any aspect of the pouch

n No known predilection
Clinical Features
n Diarrhea, bleeding, low-grade fever, urgency
FIGURE 10.28 Prognosis and Therapy

Pouchitis with marked architectural distortion, expanded lamina propria, and n Incidence decreases over time
numerous foci of neutrophilic inflammation. Pyloric gland metaplasia is also n First-line therapy with antibiotics and immunosuppression in
seen. refractory cases
Ileal Pouch Inflammation (Pouchitis)—Pathologic Features

in a pouch biopsy allows one to make a Crohn’s disease
diagnosis with certainty. Architectural alterations and Gross Findings
n Edema, granularity, exudates, ulcers
pyloric gland metaplasia that suggest a chronic ileitis
in a native ileum biopsy are not helpful in making this
diagnosis when evaluating biopsies from the pouch.
n Neutrophilic infiltration of the crypt and surface epithelium
Granulomas may be helpful but are also not diagnos- n Erosions and ulceration
tic of Crohn’s disease in this setting. Inflammation of n Chronic pouchitis may demonstrate architectural distortion and
the prepouch ileum may be a risk factor for subsequent pyloric gland metaplasia
pouch failure but also does not qualify as definitive evi-
dence of Crohn’s disease. The diagnosis of Crohn’s dis- Differential Diagnosis
n Crohn’s disease of the pouch
ease in this setting is entertained if definitive features
n Ischemia of the pouch
of Crohn’s disease, such as fistulas, perianal disease, or
definite upper GI tract involvement, are present.
The pouch may also sustain ischemic injury as a
result of surgical complications when the ileum is
COLLAGENOUS COLITIS
brought into the pelvis and the necessary lengthening
procedures stretch the ileal mesentery. Chronic isch- Microscopic colitis is a term used to describe a distinctive
emia of the pouch is primarily an endoscopic diagnosis constellation of clinical, endoscopic, and histologic find-
and often demonstrates an asymmetric distribution of ings. Patients with microscopic colitis typically present
inflammation, often with sharp demarcation between with watery diarrhea, colonoscopy is normal or shows
the inflamed and noninflamed parts of the pouch. The subtle nonspecific alterations, and random biopsies from
affected mucosa is mainly located in the distal pouch, the colon show a colitis with increased intraepithelial
along the staple line, or at the afferent limb side of the lymphocytes (lymphocytic colitis [LC]) or an abnormal
pouch body. subepithelial collagen layer (CC). Both forms of micro-
scopic colitis typically involve the entire colon, but there
may be relative or absolute sparing of the distal sigmoid
and rectum in a subset of cases. A full colonoscopy is,
therefore, needed to establish the diagnosis.
Most patients respond to antibiotic therapy, and pouch

excision is extremely rare. The risk of pouch failure ■ CLINICAL FEATURES
rises with increasing number of episodes of pouchitis.
Antibiotic refractory pouchitis is much more difficult to Patients with CC present with chronic watery diar-
treat and may require immunosuppressive medications. rhea. Females significantly outnumber males, and
most patients are middle aged or older. Colonoscopy higher magnification, the lamina propria shows increased
typically shows normal or near normal mucosa, with a lymphocytes, plasma cells, and eosinophils, which
few reports of linear mucosal tears that were thought to may involve the full thickness of the mucosa, mimick-
occur upon insufflation during endoscopy. In addition, ing IBD, or may be confined to the upper half similar
there are rare reports of CC with pseudomembranes. to the appearance in acute self-limited colitis. The sur-
A luminal antigen or antigens may be important in face epithelium has a patchy increase in intraepithelial
the pathogenesis of CC because diversion of the fecal lymphocytes with areas of surface damage. The surface
stream causes the histologic changes of CC to regress, epithelium is often stripped off from the thickened col-
while reestablishing the fecal stream induces a relapse. lagen table. The subepithelial collagen is irregular and
Studies have shown a strong association of CC with usually blends imperceptibly with the basement mem-
medications, including NSAIDs, selective serotonin brane and often entraps small capillaries and inflamma-
reuptake inhibitors, proton pump inhibitors, simvas- tory cells, which can be better visualized on a trichrome
tatin, ticlopidine, antihypertensive medications, and stain (Fig. 10.30). The thickness of the collagen often
immune checkpoint receptor inhibitors. There is also a varies from site to site in individual patients and should
reported association with celiac disease. be evaluated only in well-oriented sections. Whereas the
normal basement membrane of the colon measures 2 to
5 μm, in CC, the collagen typically has a thickness of 10
to 30 μm. Biopsies from the rectum and sigmoid colon
Pathologic Features
may show less thickening and may be within a normal
range. When in doubt, a trichrome stain can be used to
At low power, biopsy specimens of CC often show a highlight the thick and irregular collagenous band. The
variably thick and irregular eosinophilic subepithelial irregular character of the subepithelial collagen rather
“stripe” with an intact crypt architecture and an increase than the absolute thickness is helpful in making a diag-
in lamina propria mononuclear cells (Fig. 10.29). At nosis of CC. Care should be taken not to overinterpret a
FIGURE 10.29
Collagenous colitis. This low-power view shows intact crypt architecture with a superficial plasmacytosis of the lamina propria. The thickened subepithelial colla-
gen table appears as a pink stripe just beneath the surface epithelium. Even at this low magnification, increased intraepithelial lymphocytes are apparent.
A B
FIGURE 10.30
A, High-power view showing increased intraepithelial lymphocytes in the surface epithelium as well as the characteristic subepithelial collagenous thickening.
There is Paneth cell metaplasia at the base of the mucosa, a marker of chronic colitis. B, A trichrome-stained section highlights the thick and irregular subepithe-
lial collagen that entraps small capillaries and lymphocytes.
thickened basement membrane as CC because this may may require a diverting ileostomy. The overall course of
be a normal finding in the left colon. Surface epithelial the disease tends to wax and wane, but it is generally not
damage with increased intraepithelial lymphocytes are as severe as ulcerative colitis or Crohn’s disease.
always present in cases of CC. Intraepithelial neutrophils
may be seen but are less prominent than the intraepithe-
lial lymphocytes. Large numbers of crypt abscesses are COLLAGENOUS COLITIS—FACT SHEET
probably indicative of either superimposed infection or
another colitis. Paneth cell or pyloric gland metaplasia Definition
and mild crypt architectural distortion may also be pres- n Colitis with characteristic abnormal subepithelial collagen
ent in a minority of cases because CC is a chronic colitis. deposition
The collagen layer abnormalities normalize in a signifi-
cant proportion of patients on therapy, and recurrence of Incidence and Location
symptoms should not always be taken as a manifestation n 1 to 2.3 per 100,000 population
n Generally involves the entire colon, but relative rectal or left-sided

of relapsed CC. The terminal ileum may also be involved
sparing can be seen
in a minor subset of cases with CC, and rare cases show a
giant cell histiocytic response with multinucleated giant Gender, Race, and Age Distribution
cells beneath the abnormal collagen layer. n Female predominance (male-to-female ratio, 1 to 8)
n Primarily affects middle-aged to older adults
n Mean age is 59 years

n Chronic watery diarrhea with normal or near-normal endoscopy
results
Lymphocytic colitis is identical to CC except for the
absence of abnormal subepithelial collagen. Eosinophils Prognosis and Therapy
are typically less prominent in the lamina propria in LC. n Most patients respond to withdrawal of offending medication,
Chronic IBD typically shows more architectural distor- antidiarrheal therapy, or budesonide
tion, and the clinical presentation is very different from
that of CC. IBD patients present with bloody diarrhea
and show mucosal abnormalities on colonoscopy. In
extremely rare cases, features of both IBD and CC may Collagenous Colitis—Pathologic Features
be present in different part of the colon at the same pro-
cedure, and most such patients are clinically diagnosed Gross Findings
and treated as having IBD. Mucosal prolapse shows n Usually normal endoscopic appearance or mild nonspecific
fibromuscular proliferation in the lamina propria and alterations

architectural distortion, but the distinctive subepithe- n Rarely, linear ulcers or pseudomembranes
lial band is not present in these cases. Enema effect may

strip off the surface epithelium and make it difficult to
n Abnormal thick (10–30 μm) and irregular subepithelial collagen
evaluate the surface epithelium, but the lamina propria deposition
and collagen layer are both normal. Ischemia often has n Collagen layer irregular and entraps capillaries and lymphocytes;
fibrosis and hyalinization of the lamina propria that may better visualized on trichrome or Sirius red stains
be misdiagnosed as CC but does not show the increased n Rectum or left colon may be spared in about 20% cases; ileum
intraepithelial lymphocytosis seen in CC or the charac- may be involved in a small subset

n Surface epithelial damage with increased intraepithelial
teristic abnormal subepithelial abnormal collagen layer. lymphocytes
Radiation colitis also shows hyalinization of the lamina n Increased lamina propria plasma infiltrate that may be full-
propria, usually with telangiectatic blood vessels and thickness mimicking inflammatory bowel disease or in superficial
atypical endothelial cells and fibroblasts. The hyaline half similar to acute self-limited colitis
n Occasional foci of cryptitis or neutrophils in surface epithelium
material does not stain as intensely on the trichrome
may be present
stain as the thick and irregular collagen layer in CC. n Crypt distortion and Paneth cell or pyloric gland metaplasia seen
in a subset of cases
n Lymphocytic colitis
n Radiation colitis
n Ischemic colitis
Some patients with CC have a spontaneous remission,
n Mucosal prolapse or solitary rectal ulcer syndrome
but others respond to simple over-the-counter antidi- n Inflammatory bowel disease
arrheal agents. Most patients, however, require some n Normal left colon with a thick basement membrane
form of antiinflammatory therapy (steroids, 5-ASA com- n Enema effect
pounds, or both). Rarely, patients with refractory disease

LYMPHOCYTIC COLITIS avoid evaluating the number of intraepithelial lympho-

cytes overlying a lymphoid follicle because numerous
intraepithelial lymphocytes are normal in this location.
■ CLINICAL FEATURES One should also recognize that normally, there are more
intraepithelial lymphocytes in the right colon than the
There is considerable overlap of clinical and pathologic left colon. A few foci of cryptitis or a rare crypt abscess
features between LC and CC. Patients have chronic may be seen in LC, but striking neutrophilic inflam-
watery diarrhea with normal or near-normal endoscopic mation is usually suggestive of another diagnosis, such
findings. There tends to be less of a female predominance as infection or medication-induced colitis. Recently, it
in LC than in CC, but the age range is quite similar. was recognized that some cases of LC have less surface
Many medications known to cause CC, including damage and more intraepithelial lymphocytes in the
ranitidine, sertraline, ticlopidine, NSAIDs, aspirin, deeper crypt epithelium. Another variation of LC has
immune checkpoint receptors, and proton pump inhib- been described with collections of histiocytes and poorly
itors, have also been reported to cause LC. The associa- formed granulomas underneath the surface epithelium.
tion between LC and celiac disease is even stronger than
the association between CC and celiac disease. These
findings again support the notion that luminal antigens
somehow induce this colitis. In addition, human leuko-
cyte antigen (HLA) studies have shown an increased
incidence of HLA A1, DQ2, DQ1, and DQ3 in patients The resolving phase of an infectious colitis can mimic
with LC, as well as other autoimmune processes. LC because of surface damage and mild increase in
intraepithelial lymphocytes. LC-like changes have also
been described in outbreaks of chronic diarrhea linked
to the water supply on a cruise ship. This so-called
Pathologic Features
colonic epithelial lymphocytosis seemed to have less
surface damage than LC. Reports have also been made
In general, LC is similar to CC but lacks the thick of LC-like histology in patients with constipation as
and irregular abnormal subepithelial collagen layer. well as in patients with endoscopic abnormalities.
Eosinophils are usually less prominent in the lamina Hence, it is important for the pathologist to make sure
propria than in CC, and when increased, a careful look the clinical history is consistent with LC before mak-
for subepithelial collagen irregularities is warranted ing this diagnosis. Colon biopsies in patients with IBD
because diagnostic changes can be mild and patchy. may show an LC-like pattern either at initial presenta-
Special stains for collagen are also useful in this scenario tion or in posttreatment biopsies. Patients in the latter
to unmask subtle changes. The surface epithelial dam- scenario are asymptomatic, and this likely represents
age with increased intraepithelial lymphocytes is often the resolving phase of inflammation similar to what is
more prominent in LC. Just as in CC, there is generally seen in those with infectious colitis. CC may be con-
a superficial plasmacytosis without significant crypt dis- fused with lymphocytic cases when only rectal biopsy
tortion (Figs. 10.31 and 10.32). The pathologist must samples are obtained or when the subepithelial collagen

Lymphocytic colitis. This low-power view shows intact crypt architecture with Lymphocytic colitis. This high-power view shows a marked increase in
a plasmacytosis of the lamina propria. Note the normal basement mem- intraepithelial lymphocytes and a normal basement membrane. Note the
brane and the increase in intraepithelial lymphocytes. increase in lamina propria plasma cells and lack of prominent eosinophils.
irregularities are mild and patchy. As mentioned ear-

Minimal crypt distortion
lier, prominent eosinophils in the lamina propria should n
prompt a closer look at the subepithelial collagen layer, Differential Diagnosis

and a trichrome stain should be performed in cases in n Collagenous colitis
which a subtle abnormality is suspected. n Resolving infectious colitis
n Crohn’s disease
n Normal mucosa overlying a lymphoid aggregate
n Lymphocytic enterocolitis
Therapy for patients with LC is variable and is largely ISCHEMIC COLITIS

identical to that used for those with CC. Some patients’
symptoms resolve spontaneously, but others may
require over-the-counter antidiarrheal medications, bis-
muth subsalicylate, 5-ASA compounds, or immunosup-
pressants. Overall, the prognosis is good because most Ischemia can give rise to a wide range of clinical presenta-
patients eventually respond to some form of therapy. tions depending on the duration and severity of the under-
However, there is a small subset of patients who have lying pathology. Although many cases of ischemia occur
LC and spruelike changes in their small bowel biop- in older patients with known cardiovascular disease,
sies that seem refractory to all therapy. These patients ischemic colitis can also be seen in younger, seemingly
have been classified as having lymphocytic enterocolitis. healthy people secondary to endothelial toxin-mediated
Some patients with this finding may have autoimmune infections, hypercoagulable states, medications, vasculi-
enteropathy, common variable immunodeficiency, or in tis, or previous abdominal surgery. Drugs implicated in
rare instances a lymphoproliferative disorder. inducing an ischemic mucosal injury include antihyper-
tensive and migraine medications, oral contraceptives
and hormone replacement therapy, pseudoephedrine,
LYMPHOCYTIC COLITIS—FACT SHEET
NSAIDs, antibiotics, and chemotherapeutic agents.
Definition
Symptoms may range from transient bloody diarrhea and
n Colitis characterized by increased intraepithelial lymphocytes and
abdominal pain to a surgical emergency resulting from an
surface epithelial damage infarcted bowel. In some cases, usually in the right colon,
marked submucosal edema may give rise to a masslike
Incidence and Location appearance that mimics malignancy.
n 3.1 per 100,000 population A variety of disorders can lead to a lack of blood
n Generally involves the whole colon but may have distal sparing flow to the mucosa, which is the ultimate cause of
ischemic colitis. Ischemic necrosis may be caused by
thromboembolic disease secondary to atherosclerosis,
n Primarily affects middle-aged to older adults

low-flow states secondary to hypovolemia, vasculitis,
n Mean age of onset is 51 years
adhesions, drugs, and even long-distance running. In
some instances, the drug may induce vasospasm (cate-
Clinical Features cholamines, cocaine), but in other cases, the medication
n Chronic watery diarrhea with normal or near normal endoscopy may lead to thrombosis (estrogens). Enterohemorrhagic
strains of E. coli (e.g., E. coli O157:H7) and C. difficile
Prognosis and Therapy infection can also cause an ischemic-type colitis, pre-
n Most patients respond to antidiarrheal or antiinflammatory therapy
sumably resulting from endothelial injury from the tox-
in-mediated infection.
Lymphocytic Colitis—Pathologic Features

Radiologic Features
Gross Findings
n Usually normal colonoscopic appearance
The classic radiologic finding of ischemia on a barium

Microscopic Findings enema study is that of “thumbprinting.” This finding
n Surface damage with increased intraepithelial lymphocytes
is produced by marked submucosal edema. CT findings
n Increased lamina propria inflammation, often superficial, and less
prominent eosinophils than collagenous colitis

of circumferential bowel wall thickening may also be
n May have occasional foci of cryptitis or neutrophils in surface
a marker for ischemia. Rare cases, particularly in the
epithelium right colon, may present as a mass lesion mimicking
malignancy.
Pathologic Features stages of organization may be detected. The chronic

phase of ischemia is often more difficult to diagnose
Gross Findings because the only histologic findings may be areas of sub-
mucosal fibrosis in the strictured segment. The presence
In resection specimens, ischemic colitis typically shows of architectural changes of chronic injury in the mucosa
geographic areas of ulceration that may have pseudo- or abnormal vasculature may be helpful in suggesting
membranes. This is often accompanied by marked sub- the correct diagnosis.
mucosal edema. Endoscopically, this submucosal edema
can be prominent enough to mimic a tumor or mass
lesion. The watershed areas around the splenic flexure
are the most common sites for ischemia, but nearly any
site can be involved, including the proximal rectum.
Chronic or healed ischemic lesions may form isolated The differential diagnosis of ischemic colitis includes
strictures that resemble Crohn’s disease. infectious such as C. difficile and enterohemorrhagic
E. coli–associated colitis, NSAID-associated mucosal
Microscopic Findings injury, CC, radiation colitis, and Crohn’s disease.
Ischemic and C. difficile colitis may be particularly diffi-
In biopsies from symptomatic patients, acute ischemic cult to differentiate because pseudomembranes may be
lesions of the colon show superficial mucosal necro- present in both conditions. The presence of a hyalinized
sis that often spares the deeper portions of the colonic
crypts (Figs. 10.33 and 10.34). The remaining crypts
typically have a withered and atrophic appearance.
Ischemic colitis may show pseudomembranes, as well
as hemorrhage and hyalinization of the lamina propria.
A trichrome stain can be used to highlight the hyalin-
ization of the lamina propria (Fig. 10.35). Cryptitis and
crypt abscesses are usually not prominent. Depending on
the severity of the decreased blood flow, these ischemic
lesions may regress on their own or lead to perforation
or stricture formation. There may be striking cytologic
atypia, in some cases to the point at which they mimic
dysplasia. The presence of mucin depletion, localiza-
tion of the atypia to the basal crypts, and the associated
hemorrhage and hyalinization of the lamina propria are
helpful in excluding dysplasia. Degenerating epithelial
cells can also mimic signet ring cells. Mesenteric ves-
FIGURE 10.34
sels in resection specimens from patients with ischemic
Ischemic colitis. This high-power view shows atrophic-appearing “micro
colitis caused by thromboembolic disease show athero- crypts,” which are typical of ischemia. There is also a prominently hyalinized
sclerotic changes and intravascular thrombi in varying lamina propria. Note the marked regenerative atypia, which can be mistaken
for dysplasia.
FIGURE 10.33
Ischemic colitis. This low-power view shows superficial mucosal necro-
sis with loss of surface epithelium and preservation of deep portions of FIGURE 10.35
colonic crypts. There is hyalinization of the lamina propria with a paucity of Ischemic colitis (trichrome stain). This trichrome-stained section shows blue
inflammation. staining of the lamina propria in areas of hyalinization.
lamina propria and withered, atrophic-appearing crypts

Clinical Features
are specific findings in ischemia that are not seen in C.
n Presentation is variable depending on the severity and underlying
difficile colitis. In addition, C. difficile colitis is typically
etiology
a pancolitis, but ischemia is segmental. Even within n Abdominal pain, bloody diarrhea, vomiting, and fever may be seen
involved segments, pseudomembranes tend to be more
diffuse in C. difficile and patchy in ischemic colitis. The Radiologic Features
presence of an ischemic-appearing lesion in the right n Barium enema shows “thumbprinting”
colon should also make one think of enterohemorrhagic n Computed tomography shows “target lesions”
n Angiography can be used to identify vascular lesions

E. coli, especially if fibrin thrombi are present.
n Some cases may present as a masslike lesion mimicking
Differentiating chronic ischemic ulcers from NSAID- malignancy
induced damage or Crohn’s disease may be impossible,
especially on biopsy material. Chronic ischemic damage Prognosis and Therapy
shows prominent architectural changes of chronicity n A majority of ischemic colitis cases resolve with supportive care,
without the marked inflammatory component typically but 15% to 20% require surgical intervention
seen in untreated IBD. Radiation exposure often causes n Complications include perforation, peritonitis, and stricture
formation
arterial damage that can manifest itself as ischemia in
the gut. In some instances, the hyalinized appearance
of the lamina propria in radiation colitis and the sub-
epithelial collagen in CC can mimic the hyalinized lam-
ina propria seen in ischemic colitis. The presence of
telangiectatic vessels and atypical endothelial cells and Ischemic Colitis—Pathologic Features
fibroblasts should help identify radiation colitis, and
the inflammatory component and abnormal subepithe- Gross Findings
lial collagen is diagnostic of CC. Last, the regenerative n Geographic ulcers or infarcts, pseudomembranes, submucosal
epithelial changes in ischemia may mimic dysplasia and edema, strictures

recognition of the surrounding ischemic changes is key
to avoiding this pitfall.
n Superficial mucosal necrosis and withered or atrophic crypts
n Hyalinized lamina propria
n Pseudomembranes, strictures

n Clostridium difficile colitis
The prognosis for ischemic colitis depends entirely n Enterohemorrhagic Escherichia coli
n Nonsteroidal antiinflammatory drug damage

on the underlying etiology and severity. Ischemia in
n Crohn’s disease
a long-distance runner is likely to be transient and n Radiation colitis
self-limited, but severe thromboembolic disease may lead n Collagenous colitis
to a life-threatening bowel infarct with perforation and n Dysplasia
peritonitis. Overall, 35% of cases resolve with simple

supportive care, and 15% to 20% may require surgery.
ISCHEMIC COLITIS—FACT SHEET RADIATION COLITIS
Definition ■ CLINICAL FEATURES

n Damage to the colon secondary to decreased blood flow
Acute radiation damage is often subclinical, but patients

with chronic radiation damage may complain of diar-
n 3 per 10,000 population
n The splenic flexure and descending and sigmoid colon are the
rhea, abdominal pain, or rectal bleeding. Patients receiv-
most common sites of ischemia, but any site in the colon can be ing radiation therapy for cervical and prostate cancer
involved have the highest risk for radiation colitis.
n The rectum is the least common site for ischemia Acute radiation injury occurs within hours to days
of radiation exposure and leads to epithelial injury that
usually heals within 2 months. Chronic radiation colitis
n Males and females affected equally
occurs secondary to damage to mesenchymal tissues of
n Most patients are older than 50 years, but younger patients and
even children can have ischemia, depending on the underlying the gut. These changes may remain clinically silent for
disease process a long period or cause persistent symptoms for the life
of the patient.
Pathologic Features in the lamina propria and the abnormal subepithelial

collagen is absent. The presence of crypt distortion may
Gross Findings mimic quiescent ulcerative colitis or proctitis. Many of
the changes of radiation colitis are secondary to ischemia,
Endoscopy may shows edema and a dusky mucosa in which also enters the differential diagnosis of ischemic
the early acute phase of injury. Much of the damage colitis. The regenerative atypia seen in acute radiation
induced by radiation is caused by chronic ischemic dam- damage may mimic dysplasia, but a history of radiation
age to mesenteric vessels, and ulcers, strictures, fistulas, exposure is imperative to make the correct diagnosis.
and adhesions may be seen in this stage. Endoscopically,
there is typically patchy erythema secondary to telangi-
ectasia of the mucosal capillaries.
The damage caused by radiation is permanent, and symp-
Acute radiation damage is rarely seen, but the changes tomatic patients may require surgical resection. Steroid
are those of epithelial damage, including increased therapy may be of some benefit. Laser therapy may be
apoptosis, decreased mitoses, and regenerative atypia. used to induce hemostasis in areas of active bleeding.
Increased numbers of eosinophils may also be seen.
In addition to telangiectasia of the mucosal capillaries,
chronic radiation damage often has areas of hyaliniza- RADIATION COLITIS—FACT SHEET
tion around these dilated vessels with atypical “radia-
tion fibroblasts” (Fig. 10.36). The endothelial cells may Definition
n Colonic damage secondary to radiation exposure
also show similar radiation-induced atypia. Crypt dis-
tortion mimicking IBD may be seen.
n 5% to 15% of patients receiving radiation to the pelvis
n Most common in the rectum
n Older men treated with radiation for prostate cancer
An accurate history is paramount if one is to make a n Middle-aged to younger women treated with radiation for cervical
diagnosis of radiation colitis. Chronic radiation damage cancer

can be subtle in biopsy specimens because the vascular
Clinical Features
changes in the capillaries are easily overlooked. These
n Diarrhea, abdominal pain, rectal bleeding
vascular changes mimic the telangiectasia seen in portal
colopathy or angiodysplasia. A hyalinized lamina propria Prognosis and Therapy
or radiation fibroblasts is not present in these latter con- n Radiation damage is permanent
ditions. Occasionally, the hyalinized changes in the lam- n May require surgery if steroids or laser coagulation do not work
ina propria can mimic CC, but the inflammatory changes
A B
FIGURE 10.36
Radiation colitis. This medium-power photomicrograph shows telangiectatic blood vessels throughout the superficial lamina propria. There is also focal hyaliniza-
tion of the lamina propria, similar to that seen in ischemia (A). Regenerative epithelial and stromal changes in radiation colitis may be mistaken for neoplasia (B).
Radiation Colitis—Pathologic Features
Gross Findings
n Acute: erythema, dusky mucosa
n Chronic: patchy erythema, ulcers, strictures, fistulas
n Acute: increased apoptosis, decreased mitoses, abundant
cytoplasm with vacuolation, and regenerative atypia; increased

numbers of eosinophils
n Chronic: telangiectasia of mucosal capillaries, hyalinized lamina
propria, radiation fibroblasts, atypical endothelial cells, crypt

distortion
n Acute: dysplasia caused by nuclear enlargement and
hyperchromasia FIGURE 10.37

n Chronic: collagenous colitis, inflammatory bowel disease, portal
Diversion colitis. This low-power photomicrograph was taken from a patient
colopathy, angiodysplasia, and ischemia
with paraplegia with long-standing colonic diversion. There is marked lym-
phoid hyperplasia in addition to crypt architectural distortion and neutrophilic
cryptitis. These features may mimic idiopathic inflammatory bowel disease.
DIVERSION COLITIS
Diversion colitis is usually a mild colitis that occurs in

segments of the colon excluded from the fecal stream
and is most often seen in a Hartmann’s pouch. Although
diversion colitis is often an incidental finding in asymp-
tomatic patients, some patients may present with
mucoid or bloody discharge or abdominal pain. The coli-
tis occurs 3 to 36 months after the initial surgical bypass
and completely regresses within 3 months of reestab-
lishment of the fecal stream.
A deficiency of short-chain fatty acids is thought to be
the cause of diversion colitis. Short-chain fatty acids are
the main source of energy for colonocytes, and they are
usually derived from fermentation of dietary starches by FIGURE 10.38
normal colonic bacterial flora. This lack of colonocyte Diversion colitis. This high-power photomicrograph shows an aphthous
lesion (erosion overlying a lymphoid aggregate). Note the neutrophils in the
nutrition leads to an inflammatory reaction. The inflam- surface epithelium and luminal exudates.
mation can be reversed by giving short chain fatty acids
via enemas several times a week or by reestablishing the centers (Fig. 10.37). The remaining features of diversion
fecal stream. colitis are variable. In some instances, the inflammation
may mimic severe ulcerative colitis with crypt distortion
and marked chronic inflammation of the lamina propria
(Fig. 10.38). In other cases, patchy cryptitis and aph-
Pathologic Features thous lesions may mimic Crohn’s disease. As a result of
the nonspecific nature of these histologic changes, it is
Gross Findings imperative that the pathologist be aware that the speci-
men is from a diverted segment of colon which, as men-
The gross and endoscopic features of diversion colitis tioned earlier, is usually a Hartmann’s pouch.
include erythema, friability, edema, and nodularity with
aphthous ulcers.
Histologically, the nodularity seen grossly corresponds Many people with diverted segments of colon have IBD,
to large lymphoid aggregates with prominent germinal and the main differential diagnosis of diversion colitis
is generally with recurrent Crohn’s disease or ulcerative DIVERTICULAR DISEASE–ASSOCIATED

colitis. The aphthous lesions may also mimic infectious COLITIS
colitis. Definitive diagnosis requires the knowledge
of the clinical context that the pathologic changes are
occurring in a diverted colonic segment. ■ CLINICAL FEATURES
Diverticular disease is common in patients older than

age 60 years, particularly in the sigmoid colon, and
patients often present with hematochezia. Diverticular
disease–associated colitis is a chronic segmental colitis
Prognosis is excellent because diversion colitis com- restricted to the colonic segment involved with diver-
pletely regresses after the fecal stream is reestablished. ticulosis that mimics IBD, particularly ulcerative coli-
If this is not possible, then the inflammation can be tis. There is also a form of diverticulitis that mimics
reversed by giving short-chain fatty acid enemas. Crohn’s disease. This form of colitis occurs in patients
Therapy is often not necessary because diversion colitis with diverticulitis who do not have evidence of Crohn’s
is frequently asymptomatic,. disease elsewhere in the GI tract. The resection speci-
men demonstrates a Crohn’s disease–like reaction to the
diverticulitis.
DIVERSION COLITIS—FACT SHEET
Definition Pathologic Features

n Inflammation in a diverted segment of colon characterized by a
diffuse colitis with lymphoid follicular hyperplasia

Gross Findings
Incidence and Location Colonoscopic evaluation generally reveals patchy or
n Present (histologically) in 50% to 100% of patients with a
confluent hyperemia, often accentuated on the crests of
diverted segment of colon
n Typically, the rectum or rectosigmoid in patients with a
mucosal folds. The mucosa may appear granular, and an
Hartmann’s pouch is involved but can occur in any bypassed exudate is variably present. The distribution is predom-
portion of colon inantly in the descending and sigmoid colon, the region
most commonly involved with diverticular disease. The
rectum is typically spared.
n Equal in males and females
n Any age can be affected

Clinical Features
n Often asymptomatic but may have mucoid or bloody discharge Histologically, one can find a range of changes in the
or abdominal pain mucosa, from a mild plasmacytosis and mild crypt dis-
tortion to a full-blown ulcerative colitis–like appear-
Radiologic Features
ance. Cryptitis and crypt abscesses are typically seen
n Double-contrast barium enemas show lymphoid follicular
hyperplasia (Figs. 10.39 and 10.40).

n Reestablishing the fecal stream is curative
n Short-chain fatty acid enemas also reverse the histologic changes
Diversion Colitis—Pathologic Features
Gross Findings
n Nodular mucosa with aphthous ulcers, erythema, and edema
n Lymphoid follicular hyperplasia, aphthous ulcers, cryptitis, mild
crypt distortion, and chronic inflammation of the lamina propria
FIGURE 10.39
n Crohn’s disease
Diverticular disease–associated colitis. This low-power photomicrograph from
the sigmoid colon shows crypt distortion and a chronically inflamed lamina
propria. There is a crypt abscess in the center of the image. These changes
resemble ulcerative colitis.
Clinical Features
n Patients typically present with hematochezia

n Increased dietary fiber intake, antibiotics, antiinflammatory
therapies used for ulcerative colitis
Diverticular Disease–Associated Colitis—Pathologic

Features
Gross Findings
n Granular mucosa with exudates and crescentic hyperemia within
the colonic segment involved with diverticulosis

FIGURE 10.40
Diverticular disease–associated colitis. This high-power photomicrograph Microscopic Findings
of the sigmoid colon shows a forked crypt with Paneth cell metaplasia and
basal plasma cells, all features indicative of chronic colitis. n Cryptitis and crypt abscesses with increased lamina propria
chronic inflammation and crypt distortion
Differential Diagnosis Differential Diagnosis

n Ulcerative colitis and Crohn’s disease
The main differential diagnosis is between diverticular

disease–associated colitis and ulcerative colitis. The key
to the correct diagnosis is to recognize that the distri- MUCOSAL PROLAPSE OR SOLITARY
bution of disease is confined to the segment of diver- RECTAL ULCER SYNDROME
ticulosis coli. Crohn’s disease is also in the differential
diagnosis because of the usual rectal sparing in divertic-
ular disease–associated colitis.
Mucosal prolapse injury occurs in a variety of clinical

scenarios such as solitary rectal ulcer syndrome (SRUS),
in association with diverticular disease (polypoid pro-
lapsing mucosal folds), and at ostomy sites. SRUS pres-
The treatment of patients with diverticular disease– ents with alternating diarrhea and constipation, pain
associated colitis varies from therapies aimed at diver- or difficulty defecating, and rectal bleeding. The cause
ticulitis, such as increased fiber intake and antibiotics, is thought to be malfunction of the puborectalis mus-
to antiinflammatory therapies similar to those used for cle such that excessive straining on defecation leads to
ulcerative colitis. Some cases are refractory to medical mucosal prolapse that may subsequently ulcerate and
management and require surgical resection. form polypoid masses.
Prolapse polyps also occur in association with diver-
ticular disease, at ostomy sites, and adjacent to other
mass lesions, the common denominator being an abnor-
mality that causes mucosal prolapse and resultant injury.
DIVERTICULAR DISEASE–ASSOCIATED COLITIS—FACT When this process occurs at the anal verge and forms a
SHEET polyp, it has been described as inflammatory cloacogenic
polyp, a term that is no longer used. These other forms
Definition of mucosal prolapse are typically asymptomatic but are
n Segmental colitis resembling ulcerative colitis confined to colonic important to recognize so as not to be confused with
segment involved with diverticulosis coli adenomas or chronic IBD.
n Sigmoid colon with rectal sparing
Radiologic Features
n Men and women are affected equally
n Patients are generally 60 years of age or older Anal endosonography and defecography can be used
to make the diagnosis, with the latter being the gold
standard. Prolapse polyps throughout the GI tract may

be picked up on barium enemas.
Pathologic Features
Gross Findings
Grossly, prolapse polyps are friable, ulcerated polyps with
an irregular shape and a beefy red appearance. The sur-
face may be granular and ulcerated, and occasionally, the
polyps have an unusual brown color if they contain abun-
dant hemosiderin. Endoscopically, these lesions can look
quite threatening because the mass lesions mimic carci-
noma, and the ulcerative lesions mimic Crohn’s disease.
Whereas SRUS is typically located on the anterior rectal FIGURE 10.41
wall between 4 and 10 cm from the anal verge, prolapse Mucosal prolapse or solitary rectal ulcer syndrome. This low-power photo-
polyps associated with diverticular disease are typically micrograph of a solitary rectal ulcer shows villiform hyperplasia with surface
found in the sigmoid colon at the mouths of diverticula. ulceration. This villiform growth pattern can be mistaken for a villous ade-
noma. The base of the crypts is separated by proliferating smooth muscle.
SRUS can have a varied gross appearance, including ery-
thema, ulcer(s), and polypoid or mass lesions.
The characteristic finding in mucosal prolapse at any site

is the presence of fibromuscular hyperplasia of the lam-
ina propria. The presence of strands of smooth muscle
growing perpendicular to colonic crypts is diagnostic of
prolapse. Occasionally, the amount of fibrosis can over-
shadow the smooth muscle proliferation. The epithe-
lium is often inflamed and ulcerated, and in some cases,
an ischemic appearance may be present with small pseu-
domembranes. There may be significant crypt architec-
tural distortion. The lamina propria is often vascular,
with numerous congested capillaries and hemosiderin
deposition. The surface mucosa may be serrated and
tufted with goblet cell hypertrophy. In polypoid cases,
FIGURE 10.42
the mucosa often takes on a villiform configuration that
Mucosal prolapse or solitary rectal ulcer syndrome. This high-power view
can mimic a villous adenoma (Figs. 10.41 and 10.42). In smooth muscle twigs growing parallel to the colonic crypts. This smooth
some cases, glands may become trapped in the submu- muscle proliferation is the hallmark of mucosal prolapse and may be mis-
cosa, forming what is known as colitis cystica profunda. taken for Peutz-Jeghers polyps.
hyperplasia of the lamina propria, an errant diagnosis of

chronic IBD may be rendered.
Prolapsing polypoid mucosal folds may be confused
Perhaps the most crucial differential diagnosis is between with Peutz-Jeghers polyps caused by the increase in
mucosal prolapse and colorectal neoplasia. SRUS can smooth muscle associated with prolapse. One can usu-
easily be misinterpreted as a villous adenoma or even an ally differentiate the two based on the lack of an arbor-
invasive carcinoma, with disastrous consequences for the izing architecture and lobular configuration of the
patient. It is important to evaluate the epithelium criti- glandular component in prolapse polyps.
cally and notice that the changes are reactive or hyper-
plastic rather than dysplastic. Cases of SRUS with colitis
cystica profunda may be mistaken for a well-differentiated
mucinous carcinoma. Recognition that the lining epithe-
lium in the cysts is not dysplastic is the key to an accurate
diagnosis. Similarly, if the ulcerative component of SRUS Prolapse changes are completely benign, and the patient
is recognized without the characteristic fibromuscular outcome is determined by the underlying disorder.
If diverticular disease–associated polyps cause prob- EOSINOPHILIC PROCTOCOLITIS

lematic bleeding, they may be excised. Patients with
SRUS may respond to nonsurgical management
such as bulk laxatives and stool softeners. Patients
with severe rectal prolapse may require surgical
intervention. Eosinophilic proctocolitis is a disease of infants in the
first year of life who develop an allergy to formula or
breast milk. Occasionally, the allergy is related to food
ingested by the mother that is passed to the child via
breast milk rather than the breast milk itself. These chil-
MUCOSAL PROLAPSE OR SOLITARY RECTAL ULCER
SYNDROME—FACT SHEET
dren present with blood-streaked stools, diarrhea, vom-
iting, or anemia.
Definition
n Benign fibroinflammatory process secondary to mucosal prolapse
Pathologic Features
n Incidence of 1 in 100,000 Gross Findings
n Solitary rectal ulcer syndrome (SRUS) in anterior rectum
n Prolapsing polypoid mucosal folds at mouths of diverticula

Endoscopic features of eosinophilic proctocolitis include
(sigmoid colon) and near colostomy and ileostomy stomas
n Inflamed prolapse-type polyps at anal verge
focal erythema and friability; ulcers and erosions are
rare.
n Slight female predominance (SRUS) Microscopic Findings
n SRUS in young adults
n Prolapsing polypoid mucosal folds in older patients with

The histologic features of eosinophilic proctitis are often
diverticular disease (older than 60 years)
focal and may be subtle. The major finding is that of
Clinical Features increased eosinophils, which can be in the lamina pro-
n Alternating diarrhea and constipation, pain or difficulty defecating,
pria and within the epithelium and muscularis mucosae
and rectal bleeding (Fig. 10.43). Studies from the northern United States
have found that the presence of greater than 60 eosino-
Radiologic Features phils per 10 hpf in the lamina propria correlates with an
n Anal endosonography, defecography eosinophilic proctocolitis. Because the normal number
of eosinophils in the lamina propria of the colon varies
by geographic region, this number may be inappropriate
n Responds well to bulk laxatives and stool softeners
in more southern climates, where eosinophil counts are
n May require rectopexy or resection
higher. The distribution of eosinophils is also important
because their presence in the epithelium and muscularis
mucosae and at the periphery of lymphoid aggregates
correlates with allergy. One may also find foci of crypti-
tis in eosinophilic proctocolitis.
Mucosal Prolapse or Solitary Rectal Ulcer Syndrome—

Pathologic Features
Gross Findings
n Friable ulcerated polyps or masses on anterior rectal wall or at
mouths of diverticula and stomas
n Fibromuscular hyperplasia of the lamina propria
n Hyperplastic regenerative epithelium
n Crypt distortion
n Ulcers
FIGURE 10.43
n Adenoma or carcinoma
Eosinophilic colitis. This medium-power photomicrograph of the left colon
n Chronic inflammatory bowel disease
shows dense eosinophilic infiltrate with clusters of eosinophils in the lam-
n Peutz-Jeghers polyp
ina propria, as well as several intraepithelial infiltration and crypt injury by
eosinophils.
Differential Diagnosis SYSTEMIC MASTOCYTOSIS
Eosinophilic proctocolitis needs to be distinguished from
infectious colitis, necrotizing enterocolitis, medication-as-
sociated colitis, and colitis associated with Hirschsprung’s Systemic mastocytosis is a neoplastic proliferation of mast
disease. Because all of these conditions may show cryp- cells within at least one extracutaneous organ. The GI
titis, the diagnosis of allergy rests on finding abnormal tract is a common site of involvement and may be the first
numbers and distributions of eosinophils. Crohn’s manifestation of the disease in a significant proportion of
disease may show prominent eosinophils; however, patients. Mast cells secrete multiple inflammatory media-
eosinophilic proctocolitis lacks chronic mucosal injury. tors, including histamine, serotonin, and prostaglandins.
These inflammatory mediators result in GI symptoms
such as abdominal pain, diarrhea, nausea, and vomiting.
Treatment revolves around dietary manipulation to Pathologic Features

exclude whatever nutrient seems to be causing the
symptoms. The prognosis is excellent because most chil- Gross Findings
dren outgrow this condition.
The colonic mucosa usually appears erythematous,
granular, or nodular.
EOSINOPHILIC PROCTOCOLITIS—FACT SHEET
Definition Microscopic Findings

n A disease of infants in the first year of life who develop an allergy
to formula or breast milk

A major criterion for the diagnosis systemic mastocy-
tosis involving the GI tract is the presence of multifocal
Incidence and Location dense aggregates of 15 or more mast cells within a muco-
n 0.5% to 10% of pediatric population (lower in exclusively sal biopsy. Minor criteria include (1) more than 25%
breastfed infants) of the mast cells with atypical morphology (often spin-
n Rectum most common site of involvement dled), (2) aberrant expression of CD2 and/or CD25, (3)
detection of KIT point mutation at codon 816, and (4)
serum total tryptase persistently greater than 20 ng/mL.
n Males equal to females
n Ages 1 month to 1 year

A definitive diagnosis of systemic mastocytosis may be
rendered in the presence of one major plus one minor
Clinical Features criterion or three minor criteria. The mast cell aggre-
n Blood-streaked stools, diarrhea, vomiting, and anemia gates are often most prominent directly beneath the
surface epithelium (Fig. 10.44). Involvement of the
Prognosis and Therapy mucosa may be quite patchy and multiple biopsies may
n Change diet to eliminate allergen be needed to demonstrate the abnormal infiltrate. Subtle
n By age 3 years, most children outgrow the allergy
infiltration of abnormal mast cells may also be present,
making the diagnosis quite difficult. Prominent eosino-
philic infiltrates may be a clue that mast cell disease is
Eosinophilic Proctocolitis—Pathologic Features
present because increased eosinophils are seen in more
than 40% of biopsies from patients with systemic masto-
Gross Findings cytosis. Given the patchy and subtle nature of mast cell
n Focal erythema and friability, as well as rare ulcers or erosions infiltration, immunohistochemical stains for CD117 and
CD25 should be performed on biopsies to rule out mast
Microscopic Findings cell disease in patients in whom the clinical suspicion is
n Greater than 60 eosinophils per 10 hpf in the lamina propria high (Figs. 10.45 and 10.46).
n Eosinophils in the epithelium, muscularis mucosae, and at the
More recently, there has been increased interest in
periphery of lymphoid aggregates
mast cells as the cause of irritable bowel syndrome.
n Cryptitis
Although mast cells may be involved in irritable bowel
Differential Diagnosis syndrome, immunohistochemical staining for CD117
n Infectious colitis, necrotizing enterocolitis, and colitis associated and counting mast cells has no value in this setting
with Hirschsprung’s disease because it is likely the increased secretion of inflam-
matory mediators from mast cells rather than mast cell

Systemic mastocytosis. Aggregates of ovoid to spindle cells present as Aberrant expression of CD25 on CD117-positive mast cells is diagnostic of
a band underneath the surface epithelium associated with increased systemic mastocytosis.
eosinophils.
Systemic mastocytosis is not a curable disease. The

prognosis is variable. Treatment is aimed at controlling
symptoms.
SYSTEMIC MASTOCYTOSIS—FACT SHEET
Definition
n Clonal, neoplastic proliferation of mast cells that accumulates in
one or more extracutaneous organs

n Rare disease; true incidence is unknown

FIGURE 10.45 n Slight male predominance in childhood, slight female
Immunohistochemical stain for CD117 highlights the band of mast cells in predominance in adulthood
the lamina propria beneath the surface epithelium
Clinical Features
n Diarrhea, abdominal pain, nausea, vomiting
number that contributes to the pathogenesis. Similarly,

patients with mast cell activation syndrome often have Prognosis and Therapy
normal number and distribution of mast cells. n No cure; treatment is aimed at controlling symptoms
n Oral cromolyn, antihistamines, proton pump inhibitors
Systemic Mastocytosis—Pathologic Features
If mast cell disease is suspected, immunohistochemi-
Gross Findings
cal confirmation is recommended because histiocytes
n Erythema, nodularity, granular mucosa
and spindle cell lesions can be mistaken for mast cells.
Prominent eosinophilia should raise the possibility of Microscopic Findings
mast cell disease, but other causes of mucosal eosino- n Aggregates of mast cells (>15) within the mucosa often with
philia (drug reaction, infection, idiopathic eosinophilic ovoid or spindle morphology
gastroenteritis) should be considered.
n Most commonly subepithelial bandlike infiltrate

n Prominent eosinophilia characteristic
n CD117-positive mast cells with coexpression of CD25 and CD2
n If eosinophils are prominent, other causes of mucosal
eosinophilia should be excluded
MYCOPHENOLATE MOFETIL COLITIS
Mycophenolate mofetil (MMF) is a drug used for immu-

nosuppression, largely in patients who have undergone FIGURE 10.47
solid organ transplants. It is also used in bone marrow Mycophenolate mofetil colitis. This high-power photomicrograph shows a
transplant patients to treat GVHD, and it may be used to few apoptotic cells within the colonic crypts similar to the changes seen in
help treat various autoimmune diseases. Patients taking mild graft-versus-host disease.
MMF may present with a wide variety of GI complaints,
including diarrhea, abdominal pain, malabsorption,
weight loss, and bleeding. Symptoms are more likely to
occur if MMF therapy is started later after transplantation
or if the patient has an elevated creatinine measurement.
Pathologic Features
Gross Findings
Ulcers, erosions, and granularity may be seen through-

out the GI tract.
Mycophenolate mofetil damage in the colon is charac- FIGURE 10.48
terized by apoptosis similar to GVHD (Fig. 10.47). In Mycophenolate mofetil colitis. This high-power photomicrograph shows a
dilated crypt containing eosinophils and neutrophils. Such dilated crypts with
addition, one may find dilated attenuated crypts con- attenuated epithelium are more typical of mycophenolate damage than
taining a few eosinophils or neutrophils floating within graft-versus-host disease.
the crypt lumen (Fig. 10.48). In severe cases, there may
be crypt dropout with only small nests of residual neu- However, none of these features is entirely specific, and
roendocrine cells in the lamina propria. Over time, a fair correlation with clinical findings, timeline of symptoms,
amount of crypt distortion may develop such that the and the presence of extraintestinal manifestations of
changes mimic chronic IBD. Often the lamina propria GVHD are all useful in making this distinction. In some
appears hypocellular resulting from the immunosup- cases, the amount of crypt distortion can mimic quies-
pressive effects of MMF. cent ulcerative colitis. In addition, the amount of epithe-
lial damage with minimal inflammation may also bring
up the possibility of ischemia.

Graft-versus-host disease can mimic MMF colitis to
the point that they are indistinguishable. Prominence
of an eosinophilic infiltrate has been reported to favor Discontinuing the drug or decreasing the dosage typi-
MMF colitis, whereas marked apoptosis and endocrine cally leads to rapid symptomatic improvement, often
cell clusters are more in favor of a diagnosis of GVHD. within 5 to 7 days.
MYCOPHENOLATE MOFETIL COLITIS—FACT SHEET Pathologic Features
Definition Gross Findings

n Damage to the colon secondary to the drug mycophenolate
mofetil (CellCept)
The colon may demonstrate an abnormal vascular pat-
Incidence and Location tern, exudates, granularity, and ulcers.
n Incidence is unknown, but more likely if patient’s creatinine level
is elevated or if drug is started later in the transplant course Microscopic Findings

n Location can be anywhere in the gastrointestinal tract
The lamina propria is hypercellular with increased lym-

phocytes and plasma cells. There are neutrophilic crypti-
n None known
tis, increased intraepithelial lymphocytes, and increased
Clinical Features crypt apoptosis (Fig. 10.49). Erosions and ulcers may be
n Diarrhea, abdominal pain, weight loss, bleeding
seen. The crypt architecture is usually preserved, but
some cases may show features of a chronic colitis with
Prognosis and Therapy prominent basal lymphoplasmacytosis.
n Rapid response after drug is discontinued or dose is lowered
The main differential diagnosis is with an infectious

Mycophenolate Mofetil Colitis—Pathologic Features colitis. Exclusion of CMV infection by immunohisto-
chemistry may be warranted. Stool studies are often
Gross Findings
needed to exclude other infectious colitides. The lack
n Ulcers, erosions, and granularity throughout gastrointestinal tract
of chronic mucosal injury such as crypt architectural
distortion usually allows distinction from IBD. The
n Apoptosis, dilated crypts with eosinophils or neutrophils, crypt
combination of a moderate to severe active colitis with
distortion increased intraepithelial lymphocytes and prominent
apoptosis should prompt consideration of an immuno-
Differential Diagnosis therapy associated colitis.
n Graft-versus-host disease, chronic inflammatory bowel disease,
ischemia
IMMUNE CHECKPOINT RECEPTOR

INHIBITOR–ASSOCIATED COLITIS
Ipilimumab, a monoclonal antibody against cytotoxic

T lymphocyte–associated protein 4 (CTLA-4), is now
used to treat patients with a wide variety of malignan-
cies. Ipilimumab activates the immune system by dis-
rupting negative regulation of T cells. Such immune
activation can cause numerous side effects, of which
GI side effects, particularly moderate to severe watery
diarrhea, are quite common. Other immunotherapies
such as pembrolizumab and nivolumab that activate the
immune system by blocking the action of programmed
cell death protein-1 (PD-1) may also produce similar GI FIGURE 10.49
symptoms. Additional immunotherapies are in develop- Ipilimumab colitis. This high-power photomicrograph shows a colonic
mucosa with increased intraepithelial lymphocytes, increased crypt apopto-
ment, and complications from this class of medications sis, and focal neutrophilic cryptitis. This mixed pattern of injury is often seen
are likely to increase. with ipilimumab use.
Prognosis and Therapy Bradyrhizobium enterica. Patients with cord colitis

syndrome respond to antibiotics.
This condition usually improves after discontinuation

of the medication. Immunosuppression with steroids or
Pathologic Features
infliximab may be necessary in severe cases.
Gross Findings
IPILIMUMAB COLITIS—FACT SHEET
The colon may demonstrate edema, erythema, and ulcers.
Definition
n Colitis associated with administration of ipilimumab, nivolumab, Microscopic Findings
or pembrolizumab
Cord colitis syndrome is characterized by a chronic
Incidence and Location active colitis pattern of injury with crypt distortion,
n Between 25% and 50% of patients treated with ipilimumab
neutrophilic cryptitis, and increased lamina propria
n More commonly affects left colon
inflammatory cells (Fig. 10.50). There is often only a
Gender, Race, and Age Distribution mild increase in crypt apoptosis. Crypt rupture granu-
n None known
lomas and occasionally well-formed granulomas away
from injured crypts may be seen.
Clinical Features
n Persistent watery diarrhea occurring within a few days to weeks of
therapy
n Generally responsive to discontinuation of medication
The main differential diagnosis is with acute GVHD and
n Severe cases may require immunosuppression with steroids or
infliximab or other anti–tumor necrosis factor agents IBD. GVHD usually lacks increased lamina propria lym-
phocytes and plasma cells and prominent neutrophilic
cryptitis.
Ipilimumab Colitis—Pathologic Features

Gross Findings
n Mucosal erythema, edema, exudate, and ulcers Patients with cord colitis syndrome usually respond well
to antibiotics, but prolonged therapy may be warranted
to prevent relapse.
n Neutrophilic cryptitis, increased intraepithelial lymphocytes,
increased crypt apoptosis

n Increased lamina propria cellularity with increased lymphocytes
and plasma cells
CORD COLITIS SYNDROME
Cord colitis syndrome occurs in about 10% of patients

who undergo cord-blood hematopoietic stem cell trans-
plant. Cord colitis syndrome presents with a persistent
FIGURE 10.50
diarrheal illness not caused by GVHD, viral infection, or
Cord colitis syndrome. The histologic features of this case are identical to
any other identifiable cause. More recent evidence sug- those of inflammatory bowel disease with crypt architectural distortion, neu-
gests that this syndrome may be caused by the bacterium trophilic inflammation, and basal lymphoplasmacytosis.
CORD COLITIS SYNDROME—FACT SHEET Pathologic Features

n Persistent diarrheal illness occurring in cord-blood hematopoietic
stem cell transplant patients without identifiable cause

Ulcers and erosions may be seen throughout the GI
tract. The terminal ileum and right colon, as well as the
Incidence and Location rectum (suppositories), are the most common sites of
n Occurs in 10% of cord-blood hematopoietic stem cell transplant NSAID damage in the lower gut. Diaphragm disease is a
patients rare complication most often seen in the small intestine,
n Location can be anywhere in the colon
but this has also been reported in the colon.
n None known
Clinical Features A number of different patterns of mucosal damage

n Persistent diarrheal illness (>7 days’ duration)
in the colon have been reported with NSAIDs. Focal
active colitis has been mentioned in several studies as
Prognosis and Therapy being associated with NSAID use. Other articles have
n Response to antibiotics (fluoroquinolone and metronidazole) described a more mixed or lymphocytic infiltrate in the
mucosa. Nonspecific ulcers or erosions are common,
but crypt distortion like that seen in ulcerative colitis is
generally not seen. There are also numerous reports of
NSAIDs causing an injury identical to ischemic colitis
Cord-Colitis Syndrome—Pathologic Features as well. NSAIDs are also known to increase the amount
of apoptosis seen in the gut or colon.
Gross Findings
n Mucosal erythema, edema, and ulcers
Microscopic Findings Differential Diagnosis

n Crypt architectural distortion with neutrophilic cryptitis
n Mixed lamina propria infiltrate with increased lymphocytes,
plasma cells, histiocytes, and neutrophils Whereas NSAID lesions in the terminal ileum and right
colon can mimic Crohn’s disease, the focal active colitis
Differential Diagnosis pattern mimics resolving infectious colitis. NSAIDs can
n Graft-versus-host disease also cause colonic lesions that are identical to ischemic
colitis. History is of paramount importance in making
the correct diagnosis.
NONSTEROIDAL ANTIINFLAMMATORY Prognosis and Therapy

DRUG COLITIS
Discontinuing the drug is the first line of defense, but
■ CLINICAL FEATURES patients may require surgical intervention for perfo-
rations, strictures, or bleeding ulcers. Metronidazole
Nonsteroidal antiinflammatory drug use is ubiquitous, and sulfasalazine have been used as medical therapy.
and doses as small as a baby aspirin a day can cause dam- Misoprostol or proton pump inhibitors can be given
age to the GI tract. Not only do these drugs have direct with NSAIDs to protect the mucosal barrier (upper GI
toxic effects on the mucosa, but they also inhibit pros- tract). Selective cyclooxygenase-2 inhibitors may cut
taglandin synthesis, which helps protect the mucosa. down on NSAID damage in the gut.
Symptoms from mucosal injury include abdominal
pain, bloody diarrhea, iron-deficiency anemia, and mal-
absorption. The risk of GI complications increases with
NONSTEROIDAL ANTIINFLAMMATORY DRUG
dose, duration of therapy, age, and concurrent use of ste- COLITIS—FACT SHEET
roids or anticoagulants. It has been estimated that sev-
eral thousand patients in the United States experience Definition
exsanguination from GI bleeding caused by NSAIDs n Damage to the colon secondary to nonsteroidal antiinflammatory
each year. NSAIDs are also known to complicate or drugs (NSAIDs)
exacerbate ulcerative colitis and diverticular disease.
Incidence and Location Pathologic Features

n Incidence is unknown, but 40% of those with NSAID damage
have lower gastrointestinal (GI) tract involvement Gross Findings

n Location can be anywhere in the GI tract, but terminal ileum, right
colon, and rectum more common Ulcers and erosions are endoscopic findings typical of
chemotherapy damage.
n Age older than 60 years increases risk of GI damage from
NSAIDs
Chemotherapy leads to epithelial damage with little, if
Clinical Features
any, inflammation. There are usually attenuated crypts
n Abdominal pain, bloody diarrhea, iron-deficiency anemia
with apoptosis, and the surviving cells have atypical
Prognosis and Therapy hyperchromatic nuclei suggestive of CMV or herpes
n May resolve with discontinuation of drug but may require medical
virus infection (Fig. 10.51). The atypia may also mimic
or surgical intervention dysplasia. In general, one can usually exclude viral infec-
n Thousands die every year from massive GI bleeding secondary to tion, in that there are many cells with atypical nuclei but
NSAIDs none with classic viral inclusions.
Nonsteroidal Antiinflammatory Drug Colitis—Pathologic

Features As previously mentioned, the nuclear changes induced by
chemotherapy often resemble CMV inclusions; however,
Gross Findings exhaustive searching will not yield any classic inclusions
n Ulcers or erosions throughout the gastrointestinal tract despite finding many atypical cells. Immunostains can
n Diaphragm disease also be helpful in excluding this possibility. In patients
receiving bone marrow transplant, it generally takes
Microscopic Findings 3 weeks for the apoptosis induced by conditioning che-
n Focal active colitis, ischemic-type mucosal injury, increased
motherapy to completely disappear. Therefore, extreme
apoptosis, nonspecific ulcers or erosions
care should be taken in diagnosing GVHD before day
Differential Diagnosis 21 after transplantation. Chemotherapy effect can also
n Crohn’s disease, resolving infection, ischemia
mimic ischemia, in that both processes have epithelial
damage with minimal inflammation. A hyalinized lam-
ina propria favors the diagnosis of ischemia (as does a
geographic distribution of disease).
CHEMOTHERAPY EFFECT OR MUCOSITIS
About 5% to 15% of patients on chemotherapy deve

lop mucositis; this number jumps to 30% to 40%
when radiation is added to the regimen. It has been
theorized that chemotherapy generates reactive oxy-
gen species that damage epithelial cell DNA, leading
to apoptosis and clonal cell death. However, recent
evidence suggests that cytokine activation may also
play a role in causing mucositis. Even though chemo-
therapy damage is much more common in the small
bowel, stomach, and esophagus, the colon can still be
affected. Diarrhea and bleeding (rather than nausea
and vomiting) are related to colonic injury. Overall
FIGURE 10.51
mucositis is a major cause of morbidity that often leads
Chemotherapy effect. This medium-power photomicrograph shows reac-
to infection and causes delay or decreased dosing of tive cytologic atypia, which raises the question of dysplasia, as well as viral
chemotherapy. infection.
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11
Gastrointestinal Polyposis Syndromes
■ Amitabh Srivastava, MD
Nearly every histologic type of polyp involving the a significant proportion of patients may be negative
gastrointestinal (GI) tract can occur in a sporadic or on germline testing, and for some syndromes, such
syndromic setting. In general, a syndromic diagno- as serrated polyposis syndrome (SPS), no germline
sis must be suspected when multiple polyps type are defect has been identified thus far. The discussion in
present concurrently or sequentially on surveillance this chapter is restricted to the most common forms of
colonoscopy; when the polyps occur at a very young polyposis syndromes and excludes lymphomatous pol-
age; when extraintestinal manifestations of particular yposis, which is a peculiar macroscopic manifestation
syndromes are identified; and when there is a family of lymphoproliferative disorders, and inflammatory
history of similar polyps or cancer involving the GI polyposis, which is a non-neoplastic entity that most
tract or other organs known to be at risk in syndromic commonly occurs in the setting of inflammatory bowel
settings. The diagnosis is often challenging for multi- disease (IBD). The organ-specific polyposis syndrome
ple reasons. Very early age at presentation or an atten- gastric adenocarcinoma with proximal polyposis syn-
uated phenotype may not reveal the classic features drome (GAPPS) is discussed in the chapter on neoplas-
of the syndrome, information regarding extraintesti- tic gastric lesions (Chapter 4).
nal manifestations may be lacking, and relevant fam-
ily history may be missing in patients with de novo
germline mutations. It is therefore incumbent upon
pathologists to flag any potential syndromic cases for ■ ADENOMATOUS POLYPOSIS SYNDROMES
further testing and genetic counseling that may prove
beneficial not only to the index proband but also to
Clinical Features
the entire family.
Cancers arising in the setting of GI polyposis syn-
dromes are rare and responsible for fewer than 1% of Numerous conventional adenomas occur in the colon
all lower GI tract malignancies. However, research into and in the upper GI tract in three major familial set-
the pathogenesis and longitudinal outcome of polypo- tings: the classic and attenuated FAP syndrome and the
sis syndromes has provided valuable insight into the MUTYH-associated polyposis (MAP) syndrome.
genetic alterations that underlie neoplasia involving Classic FAP is an autosomal dominant syndrome
the GI tract. The most common polyposis syndromes caused by pathogenic germline mutations in the ade-
are summarized in Table 11.1and may be broadly cat- nomatous polyposis coli (APC) gene, affecting approx-
egorized into those that result in numerous adenomas, imately 1 in 8000 to 10,000 individuals. Males and
multiple serrated polyps, in hamartomas with defined females are equally affected, and fewer than 1% of all
phenotype, or an admixture of polyps with different colorectal cancers occur in patients with FAP. The disor-
morphology. Syndromes that cause adenomatous pol- der is characterized by the development of adenomas at
yps most commonly include familial adenomatous an early age along with characteristic extracolonic mani-
polyposis (FAP) and its phenotypic variants, whereas festations. Patients with classic FAP have more than 100
syndromes that cause hamartomatous polyps include adenomas at presentation, and the colon may be com-
Peutz-Jeghers syndrome (PJS), juvenile polyposis syn- pletely carpeted with hundreds to thousands of adeno-
drome, and P TEN (phosphatase and tensin homolog) mas in severe cases. The polyp burden can be lower in
hamartoma syndrome (PTHS), which is often used children because adenomas usually appear in the second
synonymously with CS. It is also important to empha- decade of life. Colorectal cancers occur at an average of
size that although most polyposis syndromes are hered- 39 years, and nearly all patients develop cancer by the
itary with well-defined germline genetic aberrations, time they are 45 to 50 years of age. However, cancer is
337
adrenocortical tumors, and brain tumors, particularly

TABLE 11.1 medulloblastoma.
Gardner’s and Turcot syndromes were terms used in
Classification of Gastrointestinal Polyposis
Syndromes the past to describe a subset of patients with FAP, but
their use is no longer recommended; the former because
Hereditary Polyposis Syndromes nearly all patients with FAP have this constellation of
findings and the latter because many of these patients
Adenomas
Familial adenomatous polyposis coli ended up being eventually diagnosed as having Lynch
Attenuated familial adenomatous polyposis coli syndrome rather than FAP.
Gardner’s syndrome An attenuated form of FAP (AFAP) is also recog-
Turcot’s syndrome nized that shows autosomal dominant inheritance
MUIYH-associated polyposis
and is distinguished from classic FAP by the presence
Hamartomas
Peutz-Jeghers syndrome of fewer adenomas (<100), later onset of adenomas
Juvenile polyposis syndrome (35–45 years of age), later onset of colorectal cancer
Cowden’s disease (mean age, 55 years), and a lower lifetime risk of col-
Bannayan-Riley-Ruvalcaba syndrome orectal cancer (80%). However, it must be recognized
Devon family syndrome
that colonoscopic methods using enhanced visualiza-
OTHER SYNDROMES
tion may show more than 100 adenomas, which is
Hereditary mixed polyposis syndrome
Neurofibromatosis type 1 an arbitrary threshold for distinguishing the classic
Multiple endocrine neoplasia type 2 and attenuated forms of the disease. Adenomas show
preferential right colon involvement in AFAP, and
Nonhereditary polyposis syndromes
the rectum may be relatively spared. Upper GI adeno-
Serrated polyposis syndrome mas and fundic gland polyps occur similar to classic
Cronkhite-Canada syndrome
FAP but extracolonic manifestations may be limited.
Lymphomatosis polyposis
Nodular lymphoid hyperplasia The diagnosis of AFAP can be excluded if any fam-
Pneumatosis cystoides intestinalis ily member shows more than 100 adenomas before
Colitis cystica profunda 30 years of age.
MUTYH- (formerly known as M YH-) associated
exceedingly rare before 15 years of age, and prophylactic polyposis (MAP) syndrome is an autosomal recessive
colectomy is typically performed around this age in most syndrome caused by biallelic germline mutations in the
patients. MUTYH gene. Patients typically present in the fifth or
Duodenal adenomas occur in almost all patients with sixth decade of life and show between 10 and 100 ade-
FAP and typically involve the periampullary region and nomas, but more than 100 adenomas may be seen in
the distal duodenum. Duodenal adenocarcinomas occur one-third of all patients. Germline M UTYH mutations
in 5% to 10% patients and are a common cause of death are identified in roughly 30% of A PC-negative patients
in patients who have undergone a prophylactic colec- with 10 to 100 adenomas and 14% of APC-negative
tomy. Gastric involvement occurs in more than half of patients with 100 to 1000 adenomas. Duodenal pol-
patients with FAP and typically manifests as numerous yposis occurs in about 25% of patients and duodenal
fundic gland polyps, some of which may show cytologic cancer in 4%. Sebaceous gland tumors and congen-
dysplasia. However, gastric cancer in the setting of FAP ital hypertrophy of retinal pigmentary epithelium is
occurs in association with conventional or pyloric gland uncommon, and the lifetime risks of extraintestinal
adenomas and not fundic gland polyps. A distinct FAP manifestations, similar to FAP, is about 38%. Serrated
variant called GAPPS has been recently described and polyps also occur in almost 50% of patients with MAP
is discussed in greater detail in the chapter on gastric and are caused by KRAS gene mutations that are typi-
neoplasms (Chapter 4). cally G:C to T:A transversions that are a consequence
Extraintestinal manifestations in FAP are common of defective DNA repair.
and include osteomas, epidermoid cysts, fibromas, According to current screening guidelines for adeno-
supernumerary teeth, odontomas, and congenital hyper- matous polyposis syndromes, patients with a personal
trophy of the retinal pigment epithelium. These lesions history of more than 10 cumulative colorectal adenomas
are usually asymptomatic and are not associated with or those with fewer than 10 adenomas but a positive
malignant potential. One exception, however, is des- family history or adenomas with FAP-type extracolonic
moid tumor, occurring in 10% of patients with FAP. manifestations (duodenal or ampullary adenoma, des-
The small intestinal mesentery and the abdominal wall moids; papillary thyroid cancer, congenital hypertrophy
or the extremities are common sites of involvement with of the retinal pigment epithelium [CHRPE]), epider-
this tumor. FAP is also associated with an increased risk mal cysts, and osteomas should be tested. Genetic test-
of extracolonic tumors, such as papillary thyroid carci- ing should include APC and M UTYH gene mutation
noma, childhood hepatoblastoma, benign and malignant analysis.
CHAPTER 11 Gastrointestinal Polyposis Syndromes 339
Pathologic Features
ADENOMATOUS POLYPOSIS SYNDROMES—FACT SHEET

n Genetic syndromes associated with germline A PC or MUTYH
gene mutations that manifest as numerous adenomas Adenomas develop throughout the entire colorectum
involving the colon and upper gastrointestinal (GI) tract, and appendix and macroscopically resemble their spo-
an increased risk of cancer, and a variety of extracolonic radic counterparts in classic FAP. The number, size,
manifestations
and shape of the adenomas can vary greatly between
patients. Although they tend to be evenly dispersed,
adenomas are relatively larger in the rectosigmoid, giv-
n Familial adenomatous polyposis (FAP) is the most common
ing the appearance of a greater density of polyps in this
polyposis syndrome (1 in 8000–10,000)
n Inheritance is autosomal dominant for FAP and an attenuated
region. In the classic and most dramatic form, the entire
form of FAP (AFAP) and autosomal recessive for MUTYH mucosa becomes carpeted with adenomatous polyps
n 1% to 2% of population carries monoallelic germline MUTYH so that no intervening normal mucosa is recognizable
pathogenic variant (Figs. 11.1A–D). The size can vary from diminutive to
n 80% to 100% patients develop colorectal cancer in AFAP and
large, and lesions may be sessile, pedunculated, or flat
FAP, respectively
n 30% of patients with FAP have de novo mutations of the APC
lateral spreading type. Colorectal carcinoma, when pres-
gene and may not have a positive family history ent, may be multifocal and shows a relative predilection
for the left colon.
Morbidity and Mortality In AFAP, the polyp burden is much lower and typ-
n Average age of colorectal cancer diagnosis is 39 years ically less than 100, preferentially involving the right
in FAP; older in AFAP and M UTYH-associated polyposis colon ( Fig. 11.1E ). Sparing of the rectum by adeno-
(MAP) matous polyps may also be suggestive of a diagnosis of
n Vast majority of patients in all three syndromes have
AFAP, as can the presence of numerous flat adenomas.
upper GI polyps, typically fundic gland polyps, and may
also have conventional adenomas and pyloric gland The latter is not a specific feature and may be seen in
adenomas patients with Lynch syndrome as well.
n Duodenal adenomas and carcinomas and desmoids are also In addition to conventional adenomas, patients with
major causes of morbidity and mortality in classic FAP MAP can also harbor a variable number of serrated pol-
yps. The polyp burden is much lower than classic FAP
Gender, Race, and Age Distribution in most patients, but a subset may present with severe
n Males and females equally affected
polyposis similar to FAP.
n No racial or ethnic predominance
n Average ages of onset of adenomas are in second decade of life
in classic FAP and a decade later in AFAP and MAP Microscopic Findings
Clinical Features The adenomas and carcinomas that arise in FAP, AFAP,
n Most patients asymptomatic; adenomas often present years
and MAP are morphologically indistinguishable from
before any symptoms occur their sporadic counterparts (Fig. 11.2A). Similar to spo-
n The most common symptoms are rectal bleeding or radic lesions, the incidence of malignancy is related to
diarrhea adenoma number, size, and histology. Single, double, or
n Synchronous cancers occur in 40% and metachronous cancers in
tricryptal adenomas are common in sections taken from
70% of patients with classic FAP
n Adenomas of variable size and number involve the colon,
grossly normal mucosa (Figs. 11.2Band C) in classic
stomach, and duodenum in all three syndromes FAP and can be seen in AFAP as well. A variable num-
n Serrated polyps may also be present in MAP ber of serrated polyps can be seen in MAP, and they may
n Extraintestinal manifestations include desmoid tumors,
resemble sporadic hyperplastic polyps or sessile serrated
epidermal cysts, osteomas, and congenital hypertrophy of
polyps. The predominance of adenomas is indicative of
retinal pigmentary epithelium and may be seen in FAP, AFAP,
or MAP the correct diagnosis in such cases, but in patients with
n Risk of some extraintestinal cancers such as papillary a low polyp burden and a combination of adenomas and
thyroid cancer, hepatoblastoma, and brain tumors such as serrated polyps, it may be virtually impossible to distin-
medulloblastoma is also increased in FAP and AFAP guish MAP from serrated polyposis syndrome (SPS; see
later), and genetic testing is key to establishing the diag-
Prognosis and Therapy nosis. Carcinomas in MAP often show a high number
n 100% risk of colon cancer without prophylactic colectomy in
of intratumoral lymphocytes and a mucinous adenocar-
classic FAP
cinoma phenotype, mimicking microsatellite instability
n Most common cause of mortality after prophylactic colectomy is
periampullary duodenal cancer high (MSI-H) colorectal carcinomas, but DNA mismatch
repair immunohistochemistry (IHC) shows intact stain-
ing in the tumor cells.
A B
C D
E
FIGURE 11.1
The number, size, and location of adenomas varies in familial adenomatous polyposis (FAP). The colon may be carpeted with lesions with barely visible normal
colonic mucosa (A). Concurrent carcinoma may be present in some cases (B), and adenomas may cluster together (C and D). In attenuated FAP, the ade-
noma burden is lower than classic FAP, and preferential involvement of the right colon may be seen (E).
Upper GI polyps are found in virtually 100% of hyperchromasia, and loss of polarity within dilated
patients with FAP, most commonly fundic gland polyps oxyntic glands that extends to the polyp surface.
and small bowel adenomas involving the ampulla and However, high-grade dysplasia or carcinoma arising in
distal duodenum (Fig. 11.3). The histologic features of a fundic gland polyp in FAP is extremely rare. In addi-
fundic gland polyps in FAP are similar to their sporadic tional to conventional adenomas, pyloric gland ade-
counterparts, but dysplasia is more common in the syn- nomas (Fig. 11.4), traditional serrated adenomas, and
dromic setting and manifests as nuclear enlargement, adenomas with hybrid features have also been described
Adenomatous Polyposis Syndromes—Pathologic Features
Gross Findings
n Hundreds to thousands of adenomas evenly distributed
throughout colorectum and appendix in classic familial

adenomatous polyposis (FAP); lower polyp burden in attenuated
form of FAP (AFAP) and M UTYH-associated polyposis (MAP)
n Adenomas tend to be larger in the rectosigmoid in FAP; right-
sided dominance, relative rectal sparing, and flat adenomas more

A
common in AFAP; serrated polyps more common in MAP
n Adenomas range in size from microscopic (crypt adenomas) to
pedunculated lesions greater than 1 cm in diameter

n Colorectal carcinomas may be multifocal
n Adenomas in FAP, AFAP, and MAP are identical to sporadic
adenomas
n Random sections of grossly normal mucosa may show early
adenomas consisting of small tubules lined by adenomatous

epithelium involving one or just a few crypts
n Adenomas may be tubular, tubulovillous, or villous
n Pyloric gland adenomas and traditional serrated adenomas can
also occur
n Fundic gland polyps can be numerous and show dysplasia
n Carcinomas in MAP have high number of intratumoral
lymphocytes and may be of a mucinous phenotype

n Gastric adenocarcinomas in FAP arise in adenomas and not in
B
fundic gland polyps
n Duodenal adenoma and adenocarcinomas and desmoid tumors
also resemble their sporadic counterparts

n Gardner fibroma is a distinctive mesenchymal tumor in children
affected with FAP
Genetics
n Germline A PC gene mutations in FAP and AFAP
n Mutations within the mutation cluster region in exon 15 is
associated with classic FAP

n Mutations in the 5′or 3′region or exon 9 of the APC gene
associated with AFAP

n Biallelic germline mutation involving the M UTYH gene in MAP
n Adenomatous polyposis related to other germline mutations
(NTHL-1, POLE, MSH-3, AXIN2)

C n Constitutional mismatch repair deficiency syndrome
n Immune deficiency–associated polyposis

FIGURE 11.2 n Serrated polyposis syndrome
Scanning view of the colonic mucosa from a patient with familial adeno- n Hereditary mixed polyposis syndrome
matous polyposis (FAP) reveals four different polypoid tubular adenomas
(A). Single crypt adenomas (B) or adenomas involving two or three crypts
(C) are commonly seen in FAP in random sections taken from macroscopi-
cally normal colonic mucosa.
in FAP. The spectrum of upper GI findings in AFAP and MUTYH gene is now universally included in the pan-
MAP is similar to classic FAP, but the polyp burden is els used for germline testing of patients with suspected
much lower than in FAP. Mesenchymal tumors, such as hereditary polyposis syndromes.
desmoid and Gardner fibroma, that occur in association
with adenomatous polyposis syndromes are discussed in
Chapter 7.
Genetic testing for germline mutations in the APC
gene identifies most patients with FAP and AFAP. As
mentioned earlier, germline mutations in the MUTYH Classic FAP is easy to recognize when the adenoma bur-
gene are detected in a subset of patients resembling FAP den is massive. AFAP and MAP may be hard to distin-
or AFAP who are negative for germline APC mutation. guish from each other, but the presence of a significant
A B
C
FIGURE 11.3
Upper gastrointestinal involvement in familial adenomatous polyposis (FAP) manifests as numerous fundic gland polyps (A) involving the stomach. Dysplastic
fundic gland polyps are also quite common in patients with FAP (B). Duodenal and ampullary adenomas (C) are also prevalent; the latter may not be amena-
ble to surveillance and necessitate a Whipple procedure for definite treatment.
A B
FIGURE 11.4
Although dysplastic fundic gland polyps are common in patients with familial adenomatous polyposis (FAP) gastric adenocarcinoma seldom arises in these
lesions. Gastric cancer in FAP typically arises in conventional adenomas (A) or in pyloric gland adenomas (B).
number of serrated polyps is in favor of MAP. A combi- may be delayed in AFAP given the later onset of ade-
nation of adenomas and serrated polyps can also be seen nomas and carcinomas. Apart from polyp burden in a
in SPS, discussed later, but the predominant polyp types patient, the youngest age for diagnosis of cancer in the
in the latter entity are hyperplastic polyps and sessile family can also be a reasonable guide for timing a pro-
serrated polyps, whereas MAP shows a predominance phylactic colectomy. MAP shows an autosomal recessive
of adenomas. inheritance, and no relevant family history of adenomas
NHTL1-associated polyposis (NAP) is an autosomal or cancer may be detected. In view of limited longitudi-
recessive base excision repair disorder that may resem- nal data, the screening and surveillance recommenda-
ble a Lynch-like syndrome or MAP because of the pres- tions for MAP are currently similar to those for AFAP.
ence of sebaceous skin tumors and MSI-H phenotype of Patients with a prophylactic colectomy typically receive
carcinomas. However, the tumors in the setting of NAP a small intestinal J-pouch reconstruction that serves as
have a characteristic C→T somatic mutation spectrum. a neorectum. The remnant native rectum and the ileal
Polymerase proofreading–associated polyposis (PPAP) J-pouch continue to be at risk, and periodic surveillance
is an autosomal dominant disorder caused by mutations is recommended for early detection and removal of ade-
in POLD1 and POLE. Adenomas occur in the colon as nomas and cancer.
well as the upper GI tract, similar to classic FAP, but Patients who undergo prophylactic colectomy may
at a later age of onset. The morphology of adenomas still die of carcinomas arising in other sites, most com-
and carcinomas resembles sporadic lesions, but a char- monly periampullary duodenal carcinomas or from
acteristic hypermutant somatic mutation genotype is desmoid tumors. Management of duodenal polypo-
typically seen. M
SH-3- and A XIN2-associated polyposis sis is often stratified using the Spiegelman classifica-
syndromes have also been described and can result in tion that includes polyp number, size, histology, and
multiple adenomas involving the colon similar to FAP. degree of dysplasia. Surveillance may not be a viable
Constitutional mismatch repair deficiency syndrome is option after adenomas develop or involve the ampulla,
an autosomal recessive disorder caused by biallelic inac- and a Whipple resection may be indicated for these
tivation in one of the four DNA mismatch repair genes patients. Gastrectomy is seldom indicated given the
(MLH1, MSH2, MSH6, PMS2). This contrasts with the low risk of malignant transformation of gastric fundic
autosomal dominant inheritance in Lynch syndrome gland polyps and adenomas. Endoscopic resections of
caused by germline mutation in the same DNA mismatch any large lesions are the standard of care, and surgical
repair genes. Brain tumors, particularly glioblastomas, resection is reserved for patients with deeply invasive
are present in nearly 50% of patients, and tumors of the adenocarcinomas.
GI tract and hematologic malignancies are commonly
seen. Similar to FAP, patients are susceptible to devel-
oping multiple adenomas and carcinoma of the colon in
■ SERRATED POLYPOSIS SYNDROME
childhood or young adulthood. Immunohistochemistry
shows loss of the involved DNA mismatch repair pro-
tein in both the normal epithelium and the tumor cells. Serrated polyposis syndrome is now the preferred desig-
Hereditary mixed polyposis syndrome (HMPS) is a nation for the entity previously described as hyperplas-
rare condition caused by abnormalities in the GREM1 tic polyposis and serrated adenomatous polyposis. It is
gene. Patients develop not just conventional adenomas characterized by the presence of multiple, large, proxi-
but also inflammatory polyps, hyperplastic polyps, and mal serrated polyps, and these patients are at high risk
mucosal prolapse-type polyps and have a high risk of for synchronous or metachronous colorectal cancer and
colorectal cancer. benefit from close surveillance.
Prognosis and Therapy Clinical Features
The key to the management of FAP, AFAP, and MAP is Serrated polyposis syndrome is an underrecognized
to identify presymptomatic individuals, predominantly entity characterized by the presence of multiple serrated
through screening of relatives of affected patients. The polyps throughout the colorectum. Concurrent carci-
diagnosis can easily be made or excluded by sigmoidos- noma may be present at initial diagnosis in a subset of
copy or barium enema examinations performed annu- patients. There is no sex predominance. Prevalence in
ally beginning at 10 to 12 years of age with histologic screening colonoscopy patients may be as high as 0.1%,
confirmation of an adenoma. Prophylactic colectomy and the majority of patients are diagnosed in the sixth
is recommended in classic FAP even in asymptomatic decade of life. However, the age range at first diagnosis is
individuals who may not have completed puberty. This quite broad. A diagnosis of SPS may be rendered when
one of two criteria is met: (1) five or more serrated pol- Pathologic Features
yps (any histological subtype) proximal to the rectum,
with all being at least 5 mm in size and at least two being Gross Findings
10 mm or more in greatest dimension or (2) more than
20 serrated polyps of any size distributed throughout The number of polyps is variable but usually reported
the colon with at least five being proximal to the rec- to be within the 10 to 60 range. A more severe polyposis
tum. The criteria are applied in a cumulative manner phenotype is rare which is why the disease often goes
over several examinations and do not require all polyps undiagnosed. The polyps show macroscopic appearance
to be present concurrently at the same colonoscopy. No of a hyperplastic polyp or sessile serrated polyp. This is
germline mutation has been identified, although R NF43 partly determined by the predominant location of the
mutations have been reported in some families. Cigarette polyp burden. More proximal lesions are likely to be
smoking and high body mass index are risk factors, and flat sessile polyps that blend into colonic mucosal folds
the risk of colorectal cancer is increased not just in the and are easily missed. Distal lesions are more commonly
patient but also in first-degree relatives. sessile but elevated polyps that resemble sporadic hyper-
plastic polyps. Concurrent carcinoma may be present
(Fig. 11.5) as a polypoid, flat, or depressed mass with
ulceration.
SERRATED POLYPOSIS SYNDROME—FACT SHEET
Definition
n Defined by the cumulative presence of either of these
Hyperplastic polyps, sessile serrated polyps with or
criteria:
n ≥5 serrated polyps (any histological subtype: hyperplastic,
without dysplasia, traditional serrated adenomas, or
sessile serrated polyp or traditional serrated adenoma) of unclassified serrated polyps are included in the polyp
which at least 2 are ≥
10 mm in size and all polyps are ≥ 5 mm count when rendering a diagnosis of SPS. The polyps in
in size OR SPS resemble their sporadic counterparts. Hyperplastic
n >20 serrated polyps (any histologic subtype or size) distributed
polyps (Fig. 11.6A) show elongated colonic crypts with
throughout the colon with at least 5 being proximal to the rectum
serrated architecture and a narrow base lined by cells
Incidence and Location with abundant microvesicular type mucin. Sessile ser-
n Reported prevalence varies but as high as 0.1% in patients rated polyps are larger in size and show architectural
undergoing screening colonoscopy distortion with dilated crypt bases and crypt disarray
(Figs. 11.6Band C). Dysplastic change may be present
Morbidity and Mortality and can resemble either traditional serrated adenoma or
n Increased risk for colorectal cancer; first-degree relatives also have
a conventional tubular adenoma (Fig. 11.7). Traditional
a five times greater risk of colorectal cancer compared with the
serrated adenomas also resemble their sporadic coun-
general population
terparts and show serrated crypts with abundant
Gender, Race, and Age Distribution eosinophilic cytoplasm and nuclear stratification and
n No gender predilection hyperchromasia similar to an adenoma. Conventional
n Most patients diagnosed between 50 and 60 years, but age at adenomas may also be present in SPS and are an inde-
presentation varies widely pendent predictor of high risk for progression to car-
cinoma. The histologic type of polyp or largest polyp
Clinical Features
size or distribution of polyps within the colon are not
n Family history of serrated polyposis or colorectal cancer may be
present
n First presentation may be with carcinoma
n Underdiagnosed condition because flat serrated polyps may be
missed during colonoscopy and gross examination of cancer

resections
n Most patients (40%) fall into the second diagnostic criterion
above, about a quarter into the first, and the rest fulfill both
criteria
n Smoking and high body mass index are common risk factors

n Close surveillance by colonoscopy FIGURE 11.5
n Presence of concurrent adenomas is best predictor of cancer risk
Serrated polyposis syndrome (SPS) is characterized by multiple, usually
n Colectomy may be indicated if number of polyps too numerous
more than 20, or large (>10 mm) serrated polyps of any histologic subtype.
for adequate surveillance These patients are at high risk for colon cancer and need close surveillance.
Two synchronous adenocarcinomas are present, along with multiple serrated
polyps, in this patient with SPS.
A B
C
FIGURE 11.6
Serrated polyps in serrated polyposis syndrome resemble their sporadic counterparts. Hyperplastic polyps (A) show a narrow proliferative mucin depleted base
with serrations in the upper half. Sessile serrated polyps show crypt disarray with mucin-rich, cystically dilated basal zone with boot- or anchor-shaped crypts
(B). Submucosal misplacement (C) is also seen in some large sessile serrated polyps.
A B
FIGURE 11.7
Dysplasia in serrated polyps in serrated polyposis syndrome (SPS) may show features similar to a traditional serrated adenoma (A) or a conventional tubular
adenoma (B). The presence of concurrent adenomas is the best predictor of cancer risk in patients with SPS.
PEUTZ-JEGHERS SYNDROME
Serrated Polyposis Syndrome—Pathologic Features
Gross Findings Clinical Features

n Variable number and size of polyps, typically 10 to 60 in number
n Flat, sessile lesions more common proximally
n Distal small sessile elevated polyps resemble sporadic Peutz-Jeghers syndrome is the second most common
hyperplastic polyps form of intestinal polyposis, with an incidence of 1 in
n Concurrent mass lesions may be present in cases with carcinoma
120,000. PJS is inherited in an autosomal dominant
pattern and caused by germline mutations in the LKB1
(STK11) gene, which is detected in more than 90% of
n Serrated polyps in serrated polyposis syndrome (SPS) resemble
sporadic hyperplastic polyps, sessile serrated polyps, and these patients. Unlike FAP, the disease shows an incom-
traditional serrated adenoma plete penetrance. Patient presentation is typically with
n Sessile serrated polyps may show cytologic dysplasia abdominal pain, obstruction, or bleeding. Two major
n Concurrent conventional adenomas can be seen and are
and characteristic components of the syndrome include
predictive of a higher risk of cancer
hamartomatous PJ polyps involving the GI tract and
n Adenocarcinoma in SPS may show features of microsatellite
instability high phenotype, but half of all cancers are microsatellite pigmented macules involving the mucous membranes
stable and skin.
The diagnosis of PJS can often be made in early
Genetics childhood because mucocutaneous pigmentation is
n No high prevalence germline mutations identified so far present at birth in 95% of patients, and small intesti-
n RNF43 germline mutations reported in some families
nal hamartomatous polyps are frequently symptomatic
n Increased risk of colorectal cancer in first- and second-degree
relatives is indicative of a familial predisposition

(Fig. 11.8). Common sites of mucocutaneous pigmen-
tation include the lips, buccal mucosa, eyelids, and dig-
Differential Diagnosis its. The pigmentation of PJS can easily be distinguished
n MUTYH polyposis syndrome from freckles because freckles are not present at birth,
n Hereditary mixed polyposis syndrome are sparse near the lips, and never involve the mucous
membranes. Whereas the pigmentation of the skin may
fade, the melanin deposits of the buccal mucosa persist
predictive of cancer risk. Cancers in SPS may resem- throughout life.
ble MSI-H tumors, but nearly half of all cancers that Benign complications of PJS predominate in the
occur in this setting are microsatellite stable with intact pediatric population. Jejunal and ileal hamartomatous
expression of DNA mismatch repair proteins.
A combination of serrated polyps and adenomas can

also be seen in MAP but the predominant histologic type
in the latter is a conventional adenoma, whereas SPS
is characterized by a preponderance of serrated polyps.
HMPS is characterized by presence of serrated polyps
and adenomas in addition to juvenile-type hamartoma-
tous polyps, some of which may be dysplastic.
Up to 35% of patients with SPS have a synchronous

colon cancer, indicating the increased malignant poten-
tial associated with this condition. Annual colonoscopic
surveillance is typically recommended after complete
removal of all large polyps. Colectomy is reserved for FIGURE 11.8
those with a high polyp burden that precludes complete Peutz-Jeghers polyps most commonly occur in the small intestine. Large
polyp removal and close surveillance. pedunculated lesions may cause intussusception and obstruction.
polyps can produce intussusception, leading to a par- one or more intestinal PJ-type polyp or the presence of
tial or total bowel obstruction. When located within the two or more PJ-type polyps. In patients with a positive
rectum, hamartomatous polyps may prolapse, resulting family history, the diagnosis can be made if either mel-
in torsion, infarction, and GI bleeding. Tumors can anotic macules or one PJ-type polyp or an LKB1 muta-
develop in multiple organ sites in addition to the GI tion is present.
tract, including the breast, lung, pancreas, uterus, ovary,
cervix, and Sertoli cells of the testis. Sex cord tumor
with annular tubules is a unique ovarian neoplasm that
may affect up to 12% of female patients with this syn- Pathologic Features
drome, whereas hormonally active Sertoli cell testicu-
lar tumors may occur in males. Most common sites of Gross Findings
cancer development are the GI tract, pancreas, breast,
gynecologic tract, and lung, and the risk of malignancy Peutz-Jeghers–type hamartomatous polyps occur
increases with age. The diagnosis can be established by throughout the GI tract. In decreasing frequency, the
the presence of characteristic melanotic macules and most common sites affected are the jejunum, ileum,
colon, stomach, duodenum, and appendix. Polyps may
be sessile or pedunculated and often show a smooth, lob-
ulated surface. The size of PJ-type polyps ranges from
a few millimeters to several centimeters in diameter.
PEUTZ-JEGHERS POLYPOSIS—FACT SHEET
Large polyps in the small intestine can cause obstruc-
Definition
tion with the polyp head forming the leading edge of the
n An autosomal dominant syndrome with incomplete penetrance
intussusception.
characterized by Peutz-Jeghers (PJ)–type hamartomatous polyps
involving the gastrointestinal (GI) tract and pigmented macules Microscopic Findings
on the mucous membranes and skin
Peutz-Jeghers–type polyps have distinctive micro-
scopic appearance characterized by lobulated epithe-
n 1 in 120,000 live births
lial compartments divided by broad bands of mature
n Second most common intestinal polyposis syndrome
n Jejunum and ileum commonly involved but any part of GI tract

smooth muscle (Figs. 11.9 and 11.10). The epithelium
can be affected is appropriate to the anatomic site, and the muscle
fibers fan out from the center of the polyp to form a
Morbidity and Mortality tree-like appearance. Absorptive enterocytes, Paneth
n Benign complications (intussusception and obstruction, torsion, cells, goblet cells, and endocrine cells are all present
infarction and bleeding) predominate in the pediatric population
n 85% cumulative lifetime risk of cancer, most often involving GI
tract, pancreas, breast, lung, and gynecologic tract

n No gender or ethnic predilection
n Symptoms can begin in infancy

n Average age at diagnosis of intestinal polyps is 25 years
Clinical Features
n Abdominal pain, obstruction, and bleeding are common
presentations
n Pigmented lesions of the mucous membranes develop by 2
years of age and are present at birth in most patients

n Hamartomatous PJ-type polyps are present throughout the
intestinal tract, most commonly the jejunum and ileum

n Polyp burden is typically low, and more than 20 polyps are rare
in PJP

n Increased lifetime risk of cancer in both intestinal and
extraintestinal organs
n Periodic monitoring of high-risk organs for cancer should include
the GI tract, breast, pancreas, and gynecologic tract

n Lung cancer risk is also increased, but no specific screening FIGURE 11.9
recommendations are available; annual chest radiography or On low-power, Peutz-Jeghers polyps have a characteristic leaf-like appear-
computed tomography in smokers is often performed ance with smooth muscle bundles dividing the epithelial compartment into
discrete lobules.
Peutz-Jeghers Polyposis—Pathologic Features
Gross Findings
n Hamartomatous polyps present throughout the gastrointestinal
(GI) tract
n Jejunum and ileum are the most common sites followed by the
colon, stomach, duodenum, and appendix

n Sessile or pedunculated appearance
n Smooth, lobulated surface
n Wide size range (millimeters to several centimeters)
n Regenerative epithelium appropriate to the site of origin divided
into discrete lobules by arborizing bands of mature smooth

muscle
A n Cellular constituents of normal GI tract mucosa such as goblet
cells, Paneth cells, absorptive cells, and endocrine cells are

present within the polyp epithelium
n Lamina propria is not significantly edematous or inflamed
n Surface commonly eroded with underlying areas of reactive
epithelial change
n Dysplastic change is rare, and cancers typically do not arise within
the hamartomatous polyps in the GI tract
Genetics
n Inactivation of the S
TK11/LKB1 gene identified in up to 90% of
affected families
n Mucosal prolapse polyp
n Sporadic Peutz-Jeghers–type hamartomatous polyp
n Juvenile polyposis
n Cowden’s syndrome
B n Filiform polyp of inflammatory bowel disease
FIGURE 11.10
Histologic examination of the same polyp shown in Fig. 11.9reveals regen-
erative epithelium separated by broad bands of smooth muscle (A). A tri-
chrome stain highlights the bands of smooth muscle that are characteristic of
these polyps (B). Gastric PJ-type polyps ( Fig. 11.11F
) can be diffi-
cult to distinguish from sporadic hyperplastic polyps
within the epithelium of small intestinal PJ-type polyp (Fig. 11.11G) and other syndromic polyps, particularly
(Figs. 11.11A–C). The lamina propria does not show sig- when polyp size is small. Large, well-developed lesions
nificant edema or inflammation. Erosion of the surface show features similar to their small intestinal and
epithelium is common, particularly for larger polyps, and colonic counterparts (Fig. 11.11H).
may be associated with reactive and regenerative epithe-
lium containing prominent mitoses. Intussusception
may cause herniation of epithelium deep into the mus-
cularis propria, which can be mistaken for an invasive
carcinoma.
Colonic PJ-type polyps demonstrate similar histologic Sporadic mucosal prolapse polyps also have a prominent
features but are less developed than those seen for their fibromuscular proliferation in the lamina propria and
small bowel counterparts. Specifically, PJ polyps of the can be difficult to distinguish from PJ-type syndromic
colon contain elongated, branched crypts that may simu- polyps. The smooth muscle proliferation in mucosal
late a villous architecture. Intussuscepted segments may prolapse polyps is haphazard and does not divide the
show crypt architectural disarray that can be mistaken epithelial compartment into discrete lobules, unlike
for sessile serrated polyps (Fig. 11.11D). Smooth muscle PJ-type polyps. Sporadic PJ-type polyps are incredibly
is not present in all polyps, particularly small lesions. rare, and limited data suggest these patients may also
The sharp demarcation of epithelial lobules by smooth be at high risk for metachronous cancers. Small PJ-type
muscle is in contrast to the more haphazard muscu- polyps can be particularly difficult to differentiate from
lar proliferation in the lamina propria seen in colonic juvenile polyps and hamartomatous polyps in Cowden’s
mucosal prolapse polyps (Fig. 11.11E). syndrome (CS). However, in contrast to juvenile polyps,
F
FIGURE 11.11
In Peutz-Jeghers (PJ) syndrome, polyps involving the small intestine show reactive epithelium (A) goblet cells, neuroendocrine cells, and Paneth cells within
the bases of hyperplastic crypts (B). Polyps that arise within the colon contain predominantly goblet cells (C). Large colon PJ polyps often show crypt disarray
with dilated crypt bases and boot-shaped crypts that should not be mistaken for sessile serrated polyps (D). Mucosal prolapse polyps are typically located in the
rectosigmoid colon and may be mistaken for PJ polyps. The smooth muscle proliferation in prolapse-type polyps is more haphazard, and the epithelium is not
divided into discrete well-demarcated lobules like a PJ polyp (E). Gastric involvement in PJ syndrome may occur as solitary or multiple polyps without a distinc-
tive appearance (F). Small PJ polyps in the stomach are indistinguishable from sporadic hyperplastic polyps
Continued
G H
FIGURE 11.11 cont'd
(G), and knowledge of multiplicity or small intestinal or colonic involvement is necessary for definite diagnosis. Large gastric lesions, like this antral polyp, show
characteristic smooth muscle arborization enclosing discrete epithelial lobules (H).
PJ polyps are more common within the small bowel and of age. Juvenile polyposis coli syndrome (JPS) is defined
do not have an inflamed lamina propria. Granulation by more than five juvenile polyps in the colorectum or
tissue may be seen in association with both PJ and juve- juvenile polyps throughout the GI tract or any number
nile polyps, but in PJ polyps, granulation tissue is typ- in a patient with a positive family history. Patients with
ically present in association with surface erosion, and JPS tend to present in the second or third decade of life.
histologic examination of deeper regions of the polyp The incidence is 1 to 2 cases per 100,000 live births a
reveals the lack of inflammation. Hamartomas in CS do year. Germline mutations in S MAD4 or B MPR1A genes
not have a distinctive appearance and resemble juvenile are identified in 25% and 20% patients, respectively. A
polyps. However, lamina propria inflammation is much family history can be elicited in up to 50% of affected
less prominent in CS. Filiform polyps of IBD are inflam- patients.
matory polyps with a slender finger-like gross appear- Four clinical forms of juvenile polyposis are described:
ance, the lamina propria is inflamed, the crypts show (1) juvenile polyposis coli with lesions restricted to the
architectural disarray, and the adjacent mucosa shows colorectum is the most common form with presenta-
features of a chronic colitis. tion typically in the first decade of life; (2) generalized
polyposis coli with polyps distributed throughout the
GI tract; (3) gastric juvenile polyposis associated with
protein-losing enteropathy; (4) and juvenile polyposis
of infancy, which is a rare lethal autosomal recessive
disorder with death in infancy. Congenital birth defects
The lifetime risk for developing cancer in individuals are present in 15% of patients and include cardiac and
with PJS is estimated to be around 85%, with a mean cranial abnormalities, cleft palate and polydactyly, mal-
age of 43 years at cancer diagnosis. Although a variety of rotation and Meckel’s diverticulum, and undescended
neoplasms have been reported, the greatest risk for can- testes. Digital clubbing and failure to thrive are also con-
cer in patients with PJS is in the GI tract, particularly sidered to be extraintestinal manifestations of JPS.
the colorectum, stomach, and pancreas. At this time, Children with JPS usually present with painless rec-
management of patients with PJS involves periodic sur- tal bleeding or anemia. Fewer than 10% have symptoms
veillance of high-risk organs for which early detection such as abdominal pain, rectal prolapse or polyp extru-
and screening are reasonable. sion, anal pruritus, constipation, or diarrhea. Extensive
and extracolonic polyposis in the small bowel or stom-
ach may cause GI and systemic dysfunction such as
■ JUVENILE POLYPOSIS SYNDROME intussusception, protein-losing enteropathy, malabsorp-
tion, diarrhea, or significant hemorrhage.
Clinical Features
Pathologic Features
Juvenile polyps may occur in a sporadic or syndromic
setting. Sporadic juvenile polyps are the most common Gross Findings
type of polyp diagnosed in children and are estimated to
be present in as many as 2% of asymptomatic children. The majority of juvenile polyps are solitary. Some
They are first diagnosed in patients ranging from 1 to 10 series have reported that one-third to half of cases may
years of age with a peak incidence between 2 and 4 years be multiple, which likely reflects variable extent of
(Figs. 11.12Cand D). The smooth surface seen grossly

JUVENILE POLYPOSIS SYNDROME—FACT SHEET corresponds to a cap of granulation tissue. The lamina
propria is expanded with a mixed inflammatory infil-
Definition trate. In the colon, cystically dilated crypts with crypti-
n Defined by the presence of one of the following: tis and crypt abscess are often present. Bands of smooth
n More than five juvenile polyps in the colorectum
muscle and thick-walled blood vessels may be present in
n Juvenile polyps throughout the gastrointestinal (GI) tract
n Any juvenile polyp in a patient with a positive family history

large pedunculated juvenile polyps raising concern for
PJ-type or mucosal prolapse–type polyps (Fig. 11.12E).
Incidence and Location Diminutive and small juvenile polyps can be virtually
n 1 in 100,000 live births indistinguishable from sporadic inflammatory polyps
n Colon or any other part of the GI tract may be affected and other hamartomatous polyps (Fig. 11.12F).
n Gastric involvement more common in S MAD4 mutant patients Extracolonic juvenile polyps also show a prominent
cystic component that is lined by mature epithelium
appropriate for the site involved. There are some data to
n Painless rectal bleeding and anemia are the most common
presentations
suggest that whereas lamina propria expansion predom-
n 10% of patients present with abdominal pain, rectal prolapse, inates in polyps with BMPR1A mutation, the epithelial
anal pruritus, constipation, or diarrhea compartment is predominant in those with S MAD4
n Extracolonic polyposis may present with intussusception, protein- mutation. In addition, SMAD4 mutations are known to
losing enteropathy, or malabsorption be more often associated with hereditary hemorrhagic
n Death from protein-losing enteropathy in infancy or cancer in
adulthood
telangiectasia and gastric polyposis.
Juvenile polyps in the stomach (Fig. 11.13) resemble
Gender, Race, and Age Distribution sporadic hyperplastic polyps and show exuberant cys-
n No gender, racial, or ethnic predilection tically dilated and inflamed foveolar epithelium sepa-
n Mean age at presentation is 9.5 years rated by an edematous and inflamed lamina propria
(Fig. 11.14). As in the colon, small juvenile polyps can-
Clinical Features not be distinguished from sporadic hyperplastic polyps
n Juvenile polyps in the colorectum or anywhere else in the GI tract
or other syndromic polyps involving the stomach, and
n Rare cases with polyps restricted to stomach have been
described
correlation with patient history and findings elsewhere
n Congenital birth defects in 15% include cardiac and cranial in in the GI tract is necessary for definite diagnosis.
abnormalities, cleft palate, polydactyly, intestinal malrotation or The epithelium in juvenile polyps may show a range
diverticulum, and undescended testis of cellular atypia varying from reactive changes to frank
dysplasia (Fig. 11.15). Reactive changes are most prom-
inent underneath the eroded surface epithelium and
n Dysplasia reported in 8% to 31% of polyps
can mimic dysplasia caused by mucin-depletion and
n Reported risk of colorectal cancer is 39% to 68%
n Screening and regular upper endoscopy and colonoscopy

increased mitotic activity. True dysplastic change, on
recommended for surveillance the other hand, shows abrupt transition from adjacent
epithelium with crowded, large hyperchromatic nuclei
with prominent nucleoli, pseudostratification, and
colonoscopic evaluation. The vast majority are located mucin depletion. Patients with multiple polyps or gener-
in the rectum or rectosigmoid colon. Multiple juvenile alized juvenile polyposis have an increased frequency of
polyps are usually discrete, but multilobular or clus- dysplastic change. Dysplasia in a juvenile polyp is found
tered polyps may also occasionally be encountered. The more frequently in polyps exceeding 1 cm in diameter,
macroscopic appearance ranges from relatively smooth and thorough examination of large lesions is necessary
homogeneous, pale, sessile polyps to large, pedunculated to rule out neoplastic change.
polyps with a coarsely nodular surface (Figs. 11.12A
and B). These pedunculated polyps may rotate on their
stalks, causing ischemia and hemorrhage leading to
autoamputation or avulsion. Surface granulation tissue
is common, often with visible capillaries and venules
and occasionally coated with exudates. Patients with The differential diagnosis of a syndromic juvenile polyp
SMAD4 mutations are more likely to have gastric polyps includes sporadic juvenile polyps and inflammatory pol-
and hemorrhagic telangiectasia. yps. The distinction between sporadic and syndromic
juvenile polyps rests on the syndromic definition
Microscopic Findings already mentioned. Inflammatory polyps that arise in
IBD or any other form of colitis can mimic juvenile
The classic features of a juvenile polyp include a well- polyps. In these cases, examination of the surrounding
circumscribed contour with extensive surface ulceration nonpolypoid mucosa can identify the presence of colitis
and colonoscopy screening for affected patients begins

Juvenile Polyposis Syndrome—Pathologic Features in adolescence. Any polyps found are removed, and
patients are followed up with annual surveillance.
Gross Findings Polyps are submitted entirely for histological evaluation
n More than 75% are pedunculated to rule out any dysplasia or carcinoma. If no polyps are
n Average size is 1 to 1.5 cm (range, 0.2–4 cm)
identified, screening colonoscopy should be performed
n External surface is smooth or coarsely lobulated
n Cut surface shows grossly visible cystic spaces containing gray to

every 3 years. Colectomy is reserved for patients with
yellow mucoid material significant polyp burden, dysplasia, or malignant
transformation.
n Prominent lamina propria with a mixed inflammatory infiltrate
n Cystically dilated crypts in colon with cryptitis and crypt abscesses

■ COWDEN’S SYNDROME
n Eroded surface lined by inflamed granulation tissue
n Reactive epithelium commonly present underneath surface
ulceration and can mimic dysplasia Clinical Features

n Dysplastic change may be present, usually in large polyps,
and shows abrupt transition from surrounding epithelium and

is characterized by nuclear enlargement, hyperchromasia, Cowden’s syndrome, the most common subset of PTEN
pseudostratification, and mucin depletion
hamartoma tumor syndrome (PHTS), is an autoso-
Genetics
mal dominant syndrome caused by germline PTEN
n Germline mutation of either SMAD4 or BMPR1A gene in 50% of
gene mutation. PHTS also includes Bannayan-Riley-
cases Ruvalcaba syndrome, adult Lhermitte-Duclos disease,
and autism spectrum disorders associated with mac-
Differential Diagnosis rocephaly. CS is the most common manifestation of
n Non-syndromic juvenile polyp PHTS, and the two terms are often used interchange-
n Inflammatory polyp arising in inflammatory bowel disease
ably. CS is a multiorgan disorder characterized by
n Mucosal prolapse polyp
hamartomas involving not only the GI tract but also
n Peutz-Jeghers polyposis
n Cowden syndrome
the skin, thyroid, and breast, and an increased risk of
breast and thyroid malignancy. The facial lesions are
trichilemmomas (lichenoid and verrucous papules);
the oral mucosal lesions (gingiva and buccal mucosa)
as the cause of the polyp formation. Inflammatory pol- are often fibromas; and hyperkeratoses are seen on the
yps usually lack the cystically dilated glandular com- hands and feet. Breast lesions occur in almost half of all
ponent and the edematous character of lamina propria adult patients, ranging from fibrocystic disease to can-
typically seen in juvenile polyps. Mucosal prolapse pol- cer, commonly ductal carcinoma. Thyroid disease is the
yps also occur in the rectosigmoid region (a common most common abnormality, occurring in up to 68% of
site of involvement for juvenile polyps) but are usually patients. Recent studies have also shown an increased
seen in late adulthood. The lamina propria shows prom- risk of colorectal cancer in patients with CS. The major
inent fibromuscular hyperplasia, and a cystic glandular and minor diagnostic criteria for CS are summarized
component is lacking. Differentiation from PJ polyps in T able 11.2. Establishing a provisional diagnosis of
relies on recognition of the presence of an inflamed and CS requires presence of pathognomonic skin lesions,
prominent lamina propria and marked cystic change in two or more major criteria, one major and at least
juvenile polyps and presence of broad bands of smooth three minor criteria, or four or more minor criteria.
muscle dividing the epithelial component into discrete Positive germline mutations in P TEN gene confirm the
lobules in PJ polyps. Hamartomatous polyps in CS can diagnosis.
mimic juvenile polyps very closely, but inflammation
in the epithelium and stroma is less prominent in CS,
and other GI and extraintestinal manifestations are
necessary to make a distinction between these two Pathologic Features
conditions.
Gross Findings
Polyps associated with CS may occur anywhere from

the esophagus to the rectum (Fig. 11.16A), but the distal
large intestine is most commonly affected. The esoph-
Patients with JPS have a significant risk for adenocar- agus in patients with CS shows glycogen acanthosis,
cinoma of the colon, as well as increased risk for gas- which is endoscopically visible as yellow-white nodules
tric, duodenal, and pancreatic cancer. Upper endoscopy or plaques (Fig. 11.16B).
C D
FIGURE 11.12
In this colectomy specimen from a young patient with juvenile polyposis syndrome, multiple polyps are present that range from large sessile multilobulated
ones to small pedunculated ones on a slender stalk (A). Juvenile polyps have a rounded contour, and numerous cystically dilated glands can be appreciated
below the polyp surface (A). Another resection from a patient with juvenile polyposis syndrome with multiple sessile and pedunculated polyps with smooth
multilobulated surface (B). Some pedunculated lesions may undergo torsion and autoamputation. Typical juvenile polyps have expanded inflamed lamina
propria and cystically dilated glandular component with cryptitis and crypt abscesses (C). The lamina propria contains acute and chronic inflammatory cells, con-
gested vessels, and granulation tissue and cystically dilated glands (D). Large pedunculated juvenile polyps may mimic a mucosal prolapse polyp or a Peutz-
Jeghers (PJ)–type hamartomatous polyp
Continued
E F
FIGURE 11.12 cont'd (E). Extensive surface ulceration, cystically dilated crypts, lack of distinct smooth muscle arborization typical of a PJ polyp, and multiplicity of
polyps are useful features for diagnosis of juvenile polyp. The morphologically characteristic features of juvenile polyps are present in large lesions, but small
polyps are virtually indistinguishable from sporadic inflammatory polyps (F).
FIGURE 11.13
FIGURE 11.14
Gastric involvement in juvenile polyposis may be severe enough to warrant a
resection, as in this example. Microscopically, gastric syndromic juvenile polyps also resemble sporadic
hyperplastic polyps, and knowledge of the endoscopic findings is essential
for correct diagnosis. As in the colon, the lamina propria is expanded and
inflamed, and the glandular compartment shows marked cystic dilation.
A B
FIGURE 11.15
Reactive changes underneath the surface ulceration in juvenile polyps may be mistaken for dysplasia (A). True dysplastic change does occur in these lesions
and is characterized by abrupt transition, nuclear hyperchromasia, stratification, and pleomorphism (B).
by periodic acid–Schiff (PAS) and PAS with diastase his-

COWDEN’S SYNDROME—FACT SHEET tochemical stains. Gastric polyps in CS do not harbor
any distinctive features and may resemble prolapse-type
Definition polyps with fibromuscular proliferation in the lamina
n Multiple hamartomas of ectodermal, mesodermal, and propria (Fig. 11.17). Intestinal polyps in CS are also dif-
endodermal origin, including the gastrointestinal tract and ficult to diagnose and may resemble juvenile polyps. The
associated with increased risk of breast, thyroid, and colon cancer
presence of multiple hamartomatous polyps without any
Incidence and Location distinctive features, mucosal lipomas or fibromas, gangli-
n Rare; approximately 1 in 200,000 individuals
oneuromas, or benign lymphoid polyps should all raise
suspicion for a diagnosis of CS (Fig. 11.18). Distinctive
Morbidity and Mortality soft tissue vascular hamartomas (PTEN hamartoma
n Progressive macrocephaly and delayed mental development in of soft tissue) have also been described recently in CS.
children Colon adenomas and carcinomas may also occur at a
n 50% incidence of breast cancer among adult patients
young age in those with CS.
n 10% to 15% risk for papillary thyroid cancer

n Males and females equally affected
n Mean age at diagnosis in the fourth decade of life
Clinical Features Ganglioneuromatous polyps of the colon can occur in

n Hallmark of disease is multiple facial trichilemmomas around the CS and in a sporadic setting. Similar polyps are also
mouth, nose, and eyes known to occur in neurofibromatosis type 1. However,
n Café-au-lait spots, vitiligo, epidermoid cysts, skin carcinomas
n Benign soft tissue and visceral tumors also common

the distinctive extraintestinal manifestations of CS and
neurofibromatosis allow correct classification of the
Prognosis and Therapy patient’s disease. Hamartomas in CS are not distinctive
n 50% lifetime risk for breast carcinoma in appearance and are hard to distinguish from other
n 10% lifetime risk for thyroid cancer hamartomatous polyps, such as juvenile and PJ polyps,
n Ten times greater risk of colon cancer compared with the general
particularly when the latter are small in size and diag-
population
nostically characteristic features are not fully developed.
Correlation with upper GI tract findings and extraintes-
tinal manifestations is necessary to establish the correct
diagnosis.
TABLE 11.2
Criteria for Diagnosis of Cowden’s syndrome
Pathognomonic criteria Cowden’s Syndrome—Pathologic Features
Characteristic mucocutaneous or mucosal lesions
Cerebellar tumors (Lhermitte-Duclos disease) Gross Findings
Autism spectrum disorder n Polyps of variable size located throughout the gastrointestinal tract
Major criteria
Megalocephaly Microscopic Findings
Multiple gastrointestinal hamartomas or ganglioneuromas n Esophagus shows glycogen acanthosis
Mucocutaneous lesions (multiple trichilemmomas, n Gastric polyps in Cowden’s syndrome (CS) may resemble
palmoplantar keratoses, cutaneous facial papules, or hyperplastic polyps or prolapse-type polyps
macular pigmentation of glans penis) n Small intestinal and colon polyps in CS show a wide spectrum:
Thyroid (nonmedullary), breast, or endometrial cancer n Hamartomas that may resemble juvenile polyps
Minor criteria n Ganglioneuromatous polyps
Solitary gastrointestinal hamartoma or ganglioneuroma n Lipomas, fibromas
Lipomas, fibromas or uterine fibroids n Benign lymphoid polyps
Fibrocystic breast disease n Soft tissue vascular malformations have also been described
Autism spectrum disorder or delayed mental development in CS
(IQ <
75)
Genitourinary cysts or renal cell carcinoma
Genetics
n Autosomal dominant inheritance
n Germline PTEN gene mutation

On microscopy, the esophageal squamous mucosa shows n Sporadic polyps resembling hamartomas
increased mucosal thickness and ballooned squamous n Other hamartomatous polyposis syndromes
cells with abundant clear cytoplasm ( Fig. 11.16C
), n Neurofibromatosis
which is filled with glycogen that can be demonstrated

A B
C
FIGURE 11.16
Upper gastrointestinal tract involvement is often seen in patients with Cowden’s syndrome. This may manifest as numerous duodenal polyps (A) and glycogen
acanthosis of the esophagus, which presents as white-yellow nodules or plaques (B). Microscopically, these foci in the esophagus show thickened squamous
mucosa with large cells with abundant clear vacuolated cytoplasm filled with glycogen (C).
Patients with CS have a significantly higher risk for

breast tumors, including fibroadenomas and lipoma-
tosis. Breast carcinoma, the most common malignancy
in CS, affects up to 50% of female patients. Male
patients are also at increased risk for breast cancer,
and regular surveillance for breast cancer is indicated
in all patients. It was initially believed that CS does
not confer an increased risk of GI cancer, but recent
FIGURE 11.17
evidence suggests that the risk of colon cancer in
Gastric polyps in Cowden’s syndrome do not have a distinctive appearance
and may resemble mucosal prolapse polyps with haphazard proliferation of CS is increased more than 10 times over the general
smooth muscle in the lamina propria. population.
A B
C D
E F
FIGURE 11.18
Colonic involvement in Cowden’s syndrome (CS) may show multiple ganglioneuromatous polyps, which present as variably sized submucosal lesions (A) and
consist of a spindle-shaped neural proliferation with admixed ganglion cells (B). Submucosal lipomas (C) appear as distinct smooth yellow lesions that are eas-
ily recognized on colonoscopy. Lipomatous tissue in the mucosa along with fibrous bands in a polyp should raise suspicion for involvement by CS (D). Multiple
benign lymphoid polyps (E) and fibromas of the colon (F) are also lesions that should prompt evaluation for a possible diagnosis of CS.
■ CRONKHITE-CANADA SYNDROME malabsorption. In addition to GI polyposis, affected

patients show changes of the integumentary system,
Clinical Features including skin hyperpigmentation, vitiligo, alopecia,
and dystrophic changes of the nails.
The average age of onset is in the fifth to sixth
Cronkhite-Canada syndrome (CCS) is a nonheredi- decade of life. A slight male predominance is found. All
tary form of diffuse GI polyposis affecting adults and racial and ethnic groups are affected. The most com-
presenting with rapidly progressive diarrhea and mon presenting symptoms are diarrhea, protein-losing
CRONKHITE-CANADA SYNDROME—FACT SHEET Cronkhite-Canada Syndrome—Pathologic Features

n Diffuse gastrointestinal (GI) tract polyposis associated with n Diffuse polyposis affecting any portion of the gastrointestinal tract
protein-losing enteropathy, malabsorption, and cutaneous

manifestations, including hyperpigmentation and nail dystrophy Microscopic Findings
n Broad-based sessile polyp with prominent edema
Incidence and Location n Epithelial component shows cystic change with inflammation and
n Rare disorder that can involve any part of the GI tract crypt abscesses reminiscent of juvenile polyps
n Nonpolypoid mucosa also shows similar changes which is helpful
Morbidity and Mortality in making a diagnosis of Cronkhite-Canada syndrome

n 60% mortality rate if untreated
Gender, Race, and Age Distribution n Juvenile polyps
n Inflammatory polyps
n Male predominance
n Ménétrier’s disease
n Average age at diagnosis in sixth to seventh decades of life
Clinical Features and often show corkscrew-shaped glands, foveolar pits,

n Diarrhea, protein-losing enteropathy, weight loss, abdominal pain,
and smooth muscle fibers extending into the lamina
and anorexia propria (Figs. 11.19D–F). In the small intestine, the
n Laboratory findings notable for hypoalbuminemia, hypocalcemia, lesions are similar, although the degree of inflamma-
hypomagnesemia, and severe electrolyte deficiencies tion and edema tends to be greater, and the lesions may
involve the full thickness of the bowel wall. Sampling
of adjacent nonpolypoid mucosa often shows early cys-
n Rapidly progressive and fatal if untreated
n Management is largely supportive with aggressive nutritional

tic changes and is helpful in establishing a morphologic
support or antibiotics diagnosis of CCS.
enteropathy, weight loss, abdominal pain, and anorexia.
Laboratory findings are notable for hypoproteinemia,
particularly hypoalbuminemia, hypocalcemia, hypo- The distinction of the polyps of CCS from JPS can
magnesemia, anemia, guaiac-positive stool, and severe be difficult and often relies on the clinical history.
electrolyte deficiency. Microscopic features that support a diagnosis of CCS are
sessile appearance, abnormal intervening mucosa, and
stromal edema that is typically much more severe than
Pathologic Features seen in juvenile polyps. In the stomach, the confluence
of polyps may simulate the giant mucosal folds charac-
Gross Findings teristic of Ménétrier’s disease. The latter is restricted
to the gastric corpus and shows diffuse enlargement of
Polyps can be found anywhere in the GI tract but are gastric rugal folds rather than discrete polypoid lesions
most frequent in the stomach and colon. In severe seen in CCS.
cases, the entire mucosal surface of affected sites is
involved. Grossly, the polyps of CCS vary from a subtle
nodularity of the mucosal surface to large, edematous
fronds of mucosa resulting from the presence of large
cystically dilated glands within an edematous stroma
(Fig. 11.19A). The malabsorption syndrome is progressive and may
be fatal without specific therapy. The mortality rate is
Microscopic Findings 60% and results from severe protein and electrolyte
losses from the intestinal tract. A variety of medical and
In all sites, polyps are typically broad-based sessile surgical measures have been used to treat patients with
lesions with no recognizable stalk. In the colon, CCS this syndrome, including corticosteroids, antibiotics,
polyps are histologically similar to juvenile polyps and surgical resection. However, aggressive nutritional
with cystically dilated glands within an inflamed and support in the form of calories, nitrogen, lipids, fluids,
edematous stroma (Figs. 11.19Band C). In the stom- electrolytes, vitamins, and minerals appears the most
ach, gastric CCS polyps resemble hyperplastic polyps important factor associated with a favorable outcome.
A B
C D
E F
FIGURE 11.19
Cronkhite-Canada syndrome (CCS) shows diffuse nodularity of the colon (A), and the polypoid areas show an appearance resembling sporadic inflammatory
polyps (B). Sections from intervening macroscopically normal mucosa also show cystically dilated crypts surrounded by an edematous lamina propria, a find-
ing which is helpful in diagnosis (C). Gastric polyps in CCS are broad based and characterized by large, edematous fronds of mucosa (D). The lamina propria
shows marked edema (E). The epithelial component shows hyperplastic and reactive changes, and the intervening nonpolypoid mucosa shows prominent
lamina propria edema (F).
Multiple endocrine neoplasia (MEN) type 2, also

called multiple neuroma syndrome, is characterized by
the presence of medullary thyroid carcinoma, pheo-
chromocytoma, parathyroid adenomas, a marfanoid
habitus, and ganglioneuromatosis of the GI tract. The
ganglioneuromas of MEN type 2 can occur anywhere
throughout the GI tract from the lips to the anus but
are most commonly found in the colon and rectum.
This syndrome is a result of mutations of the RET proto-
oncogene on chromosome 10q11.2.
Devon family syndrome refers to multiple and
recurrent inflammatory fibroid polyps of the stomach
and intestine. These lesions are histologically dis-
tinct from juvenile polyps. Patients within this family
presented in their adult years, often with intestinal
obstruction.
Lymphomatosis polyposis is used to describe the
polyposis that results from malignant lymphomas that
retain homing receptors for gut-associated lymphoid
tissue. It can occur throughout the GI tract but tends
FIGURE 11.20
to be more prominent in areas normally containing
Hereditary mixed polyposis syndrome resembles juvenile polyposis on mac-
lymphoid follicles such as the terminal ileum and right
roscopic examination. A spectrum of sessile, pedunculated, and multilobu- colon. The intervening mucosa in areas of polyposis
lated polyps is present in this colectomy specimen A germline GREM1 gene may be normal. Histologic examination of polypoid tis-
mutation was present..
sue indicates the presence of the abnormal lymphoid
infiltrate, often with obliteration of the muscularis
■ HEREDITARY MIXED POLYPOSIS mucosa and involvement of mucosal and submucosal
SYNDROME tissue.
Hereditary mixed polyposis is characterized by a mix- SUGGESTED READINGS

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12
Epithelial Neoplasms of the Colorectum
■ Deepa T. Patil, MD
A large variety of neoplasms may occur in the colorec- studies. The prevalence increases with age such that
tum, reflecting the complexity of this organ and its cel- nearly 50% of the adult US population will develop
lular components. This chapter focuses primarily on an adenoma by age 50 years. Adenomas are of clinical
those neoplasms arising from the epithelial and neuro- importance because they can develop into an infiltrating
endocrine cells of the colorectum. Epithelial neoplasms adenocarcinoma, a notion supported by extensive epi-
that arise as a component of a polyposis syndrome are demiologic data. The incidence of adenomas parallels
discussed in Chapter 11. the incidence of CRC, and countries with high rates of
CRC also have high rates of colorectal adenoma. Clinical
data in support of the neoplastic potential of adenomas
COLORECTAL POLYPS relate to adenoma size, adenoma type, and the presence
of high-grade dysplasia. Infiltrating carcinoma is found
in 5% of all adenomas and is more commonly found in
Given the widespread use of colonoscopy as a screen- adenomas larger than 1.0 cm in diameter, with villous
ing tool for detecting colorectal cancer (CRC), colorec- morphology, and with coexistent areas of high-grade
tal polyps constitute some of the most common types of dysplasia.
specimens in gastrointestinal (GI) pathology practice. Four factors have been described in association with
Colorectal polyps can be broadly classified into inflamma- the formation of colorectal adenomas: environment,
tory polyps, hamartomatous polyps, mesenchymal pol- genetics, diet, and host factors. Colorectal adenomas
yps, and epithelial polyps. Inflammatory polyps usually show wide geographic variations in frequency among
occur in a background of mucosal injury, for example, industrialized nations. They are most common in North
idiopathic inflammatory bowel disease (IBD), drug-in- America, Western Europe, New Zealand, and Australia.
duced injury, or infections. Hamartomatous polyps are Variations in incidence are also found within industri-
typically associated with GI polyposis syndromes (see alized nations. Patients with a high risk for developing
Chapter 11). Occasionally, one may find mucosal polyps CRC are those with an inherited predisposition to col-
composed entirely of stromal elements. Most mesenchy- orectal adenoma formation (i.e., familial adenomatous
mal lesions that present as mucosal polyps tend to be polyposis [FAP]), patients with chronic IBD (partic-
benign in nature (leiomyoma, lipoma, ganglioneuroma, ularly ulcerative colitis), and patients with a family
perineurioma or fibroblastic polyps, glomus tumor, and history of colon cancer (as in hereditary nonpolyposis
inflammatory fibroid polyps). Epithelial polyps are the colon cancer).
most common types of polyps seen in daily practice. These The relationship of diet to CRC risk is a topic of
can be categorized into adenomatous polyps and serrated enormous interest and debate. Nonetheless, the role of
polyps and are discussed in the following section. dietary factors in the development of colorectal adeno-
mas and carcinoma is generally accepted and thought to
relate to diets that are high in animal fat and protein and
■ ADENOMATOUS POLYPS low in fiber or vegetables.
A variety of host factors related to CRC risk include
obesity, smoking history, and occupational exposures.
Clinical Features Bile acid turnover in association with gut microflora
metabolism is also related to tumor incidence. For exam-
The prevalence of adenomas varies in different parts ple, fecapentaenes, a product of the gut microflora, are
of the world. Adenomas are common in Western coun- potent mutagenic compounds found in human feces
tries and present in up to 60% of individuals in autopsy that are correlated with colorectal carcinogenesis.
363
commonly found in the sigmoid colon and rectum. In

ADENOMATOUS POLYPS—FACT SHEET general, the polyp size is correlated with the histologic
type—tubular, tubulovillous, or villous. Among adeno-
Definition mas smaller than 1 cm in diameter, more than 90% are
n Dysplastic neoplasms of intestinal epithelium with the potential tubular adenomas, 7% are tubulovillous, and 2% are
for transformation to invasive adenocarcinoma villous. In contrast, only 50% of adenomas larger than
2 cm are tubular, whereas 38% are tubulovillous and
Incidence And Location
12% villous. Grossly, colorectal adenomas may appear
n Common finding in patients living in industrialized countries
pedunculated, sessile, or flat. Tubular adenomas range in
Morbidity And Mortality size from individual crypt adenomas to large exophytic
n Related to risk for malignant progression lesions several centimeters in diameter. Larger tubular
n Infiltrating adenocarcinoma more common in high-risk adenomas adenomas may become polypoid with a lobulated surface
(adenomas >1 cm in diameter with villous morphology and high- and a stalk at the base of the lesion. In addition to the
grade dysplasia) surface lobulations, areas of hemorrhage may be present
resulting from erosion of the surface epithelium. In con-
Gender, Race, And Age Distribution
trast, villous adenomas are commonly sessile lesions with
n Males more than females
n More common in developed countries

a broad base and grossly evident papillary architecture.
n Average age at diagnosis in sixth decade of life Flat adenomas are a morphologic type of adenoma
that appear as flat or slightly raised plaques on the muco-
Clinical Features sal surface. By definition, they usually show a concave
n Associated with high-fat, low-fiber diet surface that does not exceed twice the thickness of the
n More common in patients with prior adenomas or positive family
adjacent non-neoplastic mucosa.
history
Prognosis And Therapy Microscopic Findings

n Left-sided adenomas are a biomarker for elevated colorectal
cancer risk Similar to the rest of the GI tract, adenomas are graded
n Routine surveillance is indicated to remove metachronous using the two-tiered system—low-grade and high-grade
adenomas dysplasia. By definition, adenomas harbor at least low-
grade dysplasia. Low-grade dysplasia is characterized
by atypical glands lined by cells with cigar-shaped
or penicillate, pseudostratified, and hyperchromatic
Pathologic Features nuclei (Fig. 12.1). These cytologic changes involve both
the crypts and the surface epithelium. The individual
Gross Findings cells have increased nuclear-to-cytoplasmic ratio and
frequent mitotic activity. High-grade dysplasia encom-
Adenomas smaller than 1 cm in diameter tend to be passes additional architectural and cytologic changes
evenly distributed throughout the colorectum. In con- (Fig. 12.2). Architecturally, the crypts show irregular
trast, adenomas 1 cm or larger in diameter are more branching, gland crowding, and cribriform architecture.
A B
FIGURE 12.1
Adenomatous polyp: tubular adenoma. Low-grade dysplasia characterized by atypical glands lined by cells with cigar-shaped, pseudostratified, and hyperchro-
matic nuclei (A). The nuclei maintain their polarity (the long axis of the nuclei is perpendicular to the basement membrane) (B). These cytologic changes
involve both the crypts and the surface epithelium.
CHAPTER 12 Epithelial Neoplasms of the Colorectum 365
A B
FIGURE 12.2
Tubulovillous adenoma with high-grade dysplasia. Adenomatous polyp with architectural atypia characterized by irregular branching, gland budding, and cribri-
form architecture (A). Cytologically, the nuclei show increased atypia with enlarged, hyperchromatic, vesicular nuclei; prominent nucleoli; and loss of nuclear
polarity (the basement membrane of the cell is no longer perpendicular to the long axis of the nucleus) (B).
Cytologically, the nuclei show increased atypia with

enlarged, hyperchromatic, vesicular nuclei; prominent
nucleoli; and loss of nuclear polarity (basement mem-
brane of the cell is no longer perpendicular to the long
axis of the nucleus). Mitoses, including atypical mitotic
figures, are prominent.
Flat adenomas are in essence tubular adenomas that
lack a polypoid growth or an exophytic growth pattern.
Rather than the complex branching of adenomatous
glands, villous adenomas show tall, fingerlike projec-
tions of adenomatous epithelium with a central fibro-
vascular core that extends from the polyp base to the
surface.
A variety of cell types may be encountered in adeno-
mas, including Paneth cells, goblet cells, and endocrine
cells. The finding of these cell types in an adenomatous FIGURE 12.3
polyp reflect the ability of the neoplastic cells to partially Adenomatous polyp with squamous morular metaplasia. The basal aspect
differentiate into a variety of cell types. Goblet cells of the polyp shows nests of cells with abundant eosinophilic cytoplasm and
within adenomatous polyps are often dystrophic, seen oval to spindle cells arranged in a whorled pattern (arrows). These foci can
be misinterpreted as high-grade dysplasia and have no clinical significance.
as cells or goblet cells with atypical nuclei oriented away
from the basement membrane of the gland. Endocrine
cells are present in at least half of adenomas and can best base of the lamina propria (Fig. 12.4). There are various
be discerned with the use of special stains. Paneth cells theories of histogenesis for this finding, including stem
are present in 10% of adenomas, recognized for their cells with divergent differentiation, collision tumor, or
characteristic eosinophilic granules. Excessive Paneth metaplastic phenomenon related to polyp trauma. These
cells may be seen in patients with polyposis syndrome, clusters are often surrounded by fibromyxoid stroma
especially FAP. Some adenomas may contain foci of and mimic invasive adenocarcinoma. They are most
squamous morular metaplasia (Fig. 12.3), osseous meta- common in adenomas that are 1 cm or larger in size, har-
plasia, melanocytes, or even gastric type epithelium. bor high-grade dysplasia, and show villous morphology.
They have been referred to as neuroendocrine prolifer-
ation or composite intestinal adenoma–microcarcinoid.
The latter term is less preferred because the word car-
Neuroendocrine Proliferation In Adenomatous
cinoid may result in unnecessary surgical treatment
Polyps
because of the implied malignant potential. In fact, stud-
ies have shown that these lesions are not associated with
In large adenomatous polyps, there may be small, mul- any lymph node or distant metastasis. Therefore, most
tifocal clusters of neuroendocrine cells located at the pathologists do not report this finding in daily practice.
be followed by a comment that clearly states the biologic

potential of the lesion.
The use of the term carcinoma in situ is no longer rec-
ommended in the GI tract because the word carcinoma
has the potential to be misinterpreted as malignancy and
can result in unnecessary colectomy for a lesion that is
confined to the basement membrane of the neoplastic
glands. These lesions are therefore diagnosed as high-
grade dysplasia.
Molecular Features Of Adenomatous Polyps
Most conventional adenomas progress toward carci-

FIGURE 12.4
noma via the chromosomal instability pathway char-
Neuroendocrine proliferation in an adenomatous polyp. The deep aspect
acterized by acquisition of several mutations during
of lamina propria shows nests and cords of uniform cells with abundant cancer development. Inactivation of APC/β-catenin/
granular eosinophilic cytoplasm, centrally located round to oval nuclei, and Wnt signaling pathway by germline or somatic muta-
stippled chromatin pattern. These nests are often surrounded by loose fibro-
myxoid stroma.
tion of one copy of the adenomatous polyposis coli
(APC) gene is one of the early molecular events.
Inactivation of the second allele and accumulation of
additional mutations, such as in KRAS, DCC, and p53,
In contrast, the presence of high-grade neuroendo- drives carcinogenesis.
crine proliferation or high-grade neuroendocrine carci-
noma (large cell or small cell type) is a significant finding
that needs to be reported. These foci are often unifocal
and associated with conventional invasive adenocarci-
noma. However, rarely, the high-grade neuroendocrine
component is seen in association with a tubular or tub- Adenomatous Polyps—Pathologic Features
ulovillous adenoma.
Gross Findings
n Pedunculated or sessile growth pattern
n Pancolonic distribution
Intramucosal Adenocarcinoma And “Carcinoma n Larger adenomas (>1 cm), more often left sided
In Situ”
n Tubular adenomas consist of branching dysplastic glands
Adenomas that show invasion of the lamina propria or n Villous adenomas contain dysplastic glands growing in long,
the muscularis mucosae (but not beyond) are considered fingerlike projections
n Low-grade dysplasia
intramucosal adenocarcinomas. The neoplastic prolifer-
n Nuclear hyperchromasia, enlargement, and pseudostratification
ation may either show single-cell infiltration by atypi- involving crypts as well as surface epithelium
cal cells or marked expansion of the lamina propria or n Individual nuclei show elongated or penicillate morphology
muscularis mucosae by closely packed glands without but maintain their nuclear polarity (long axis of the nucleus is
intervening lamina propria. However, compared with perpendicular to the basement membrane of the gland)
n High-grade dysplasia
the other parts of the GI tract (esophagus, stomach,
n Complex architecture composed of crowded glands with
small bowel), which harbor a rich lymphatic plexus that glandular budding and cribriform arrangement
facilitates metastatic spread, the colonic mucosa lacks n Cytologic atypia consists of marked nuclear enlargement,
lymphatic spaces, and therefore, in theory, intramucosal pleomorphism, vesicular nuclei, prominent nucleoli, and loss of
adenocarcinoma of the colon and rectum does not have nuclear polarity
n Mitotic figures are quite prominent
any propensity to metastasize. Therefore, some authori-
ties prefer not to use this term. Instead, these lesions are
Genetics
classified as adenoma with extensive high-grade dyspla-
n Complex genetic alterations
sia. The only situations when one might consider using n Frequent alterations of APC, KRAS, and p53
this term is in the setting of biopsy obtained from a large
mass or an incompletely resected polyp that shows the Differential Diagnosis
aforementioned cytoarchitectural features. However, n Reactive epithelial changes
when this term is used in a pathology report, it should

TABLE 12.1
Surveillance Guidelines for Colorectal Adenomas
Any pathologic entity in the colorectum in which the
epithelium undergoes reactive changes can mimic ade- New
nomatous dysplasia, including hyperplastic polyp (HP), Baseline Surveillance Quality of Evidence
mucosal prolapse, and inflammatory polyp. Reactive Colonoscopy: Most Interval Supporting Stronger
Advanced Findings (years) evidence than 2006
epithelial changes are often associated with ongoing or
resolving mucosal injury. The cells show slight nuclear No polyps 10 Moderate Yes
hyperchromasia, enlargement, and mucin loss. However, 1–2 small 5–10 Moderate Yes
these changes are often restricted to the epithelium adja- (<10 mm) tubular
adenomas
cent to mucosal injury. The cells maintain their overall
3–10 tubular 3 Moderate Yes
nuclear-to-cytoplasmic ratio, and there is surface epithelial adenomas
maturation. All of these features indicate reactive atypia. >10 adenomas <3 Moderate No
Adenoma ≥10 mm 3 High Yes
≥1 villous 3 Moderate Yes
adenomas
Prognosis and Therapy Adenoma with high- 3 Moderate No
grade dysplasia
Adapted from Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for
Per consensus update by the United States Multi-Society colonoscopy surveillance after screening and polypectomy: a consensus update
Task Force on Colorectal Cancer, low-risk adenomas refer by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology.
to one to adenomas smaller than 10 mm in diameter at 2012;143:844-857.
baseline colonoscopy. High-risk adenomas are defined

as adenomas that are 10 mm in size or larger, the pres-
ence of three or more adenomas, adenoma with villous small risk of lymph node metastasis. Studies have sug-
histology, or adenomas with high-grade dysplasia (HGD). gested that the prevalence of invasive adenocarcinoma
Advanced adenomas are adenomas that are large (>1 cm) in an endoscopically resected adenoma is around 2% to
and contain a villous architecture or at least HGD. 5%. In most cases, a good endoscopist recognizes the
Advanced adenomas are at a much higher risk for the presence of a malignant polyp by the “non-lifting” sign
development of HGD and invasive adenocarcinoma. In in which the endoscopist is unable to elevate a sessile
a meta-analysis, the relative risk for recurrent advanced polyp following submucosal saline injection. Newer
adenomas was 1.84 times in advanced adenomas com- techniques such as endoscopic submucosal dissection (a
pared with patients with low-grade dysplasia at baseline technique similar to endoscopic mucosal resection) offer
colonoscopy. In the National Cancer Institute pooling the advantage of en bloc resection with more accurate
project, patients with baseline polyps larger than 2 cm in histologic assessment of large or sessile polyps that are
size had a 19.3% risk of advanced neoplasia at follow-up. more likely to harbor foci of invasive adenocarcinoma.
Whereas patients with adenomas that measured 1 to 2 cm
in size had a 15.9% risk, those with adenomas smaller
than 5 mm in size had a 7.7% risk of advanced neopla-
Risk Assessment Of Malignant Polyps
sia. These data support different surveillance intervals
for adenomatous polyps based on the size and degree of
dysplasia (Table 12.1). The appropriate treatment for all Gross Evaluation
conventional adenomas (regardless of type, size, or degree
of dysplasia) is complete removal. The current guidelines Gross description of a polyp should include size, pres-
support the use of colonoscopy starting at age 45 years, ence or absence of a stalk, and intactness of specimen.
given the rising incidence of CRC in young patients, or at Pathologists should avoid using the terms pedunculated,
a time 10 years earlier than the age of cancer development sessile, and semi-pedunculated because these terms refer
in a first-degree family member. to in vivo endoscopic assessment of these lesions. It is
a common practice to ink the polyp base margin which
is cauterized during polyp removal. The benefit of this
process is that it allows for easy identification of margin
Malignant Polyps
on microscopic examination. However, improper iden-
tification of the polyp base and inaccurate inking can
A malignant polyp is defined as a polyp that shows neo- contribute to inaccuracy in assessment of the margin
plastic glands invading through the muscularis mucosae status. Therefore, cauterized tissue visualized under the
into the submucosa (pT1) (Fig. 12.5). These lesions microscope is the best guide for assessing the distance of
represent the vast majority of early CRCs and carry a invasive adenocarcinoma from the margin.
A B
FIGURE 12.5
Invasive adenocarcinoma arising in a tubulovillous adenoma with high-grade dysplasia (malignant polyp). This sigmoid colon polyp shows a proliferation of
neoplastic glands with irregular, angulated profiles infiltrating the muscularis mucosae and submucosa (A). The resection margin is indicated by the arrow. The
neoplastic glands are surrounded by stromal desmoplasia that is diagnostic of submucosal invasion (B).
Histologic Reporting Parameters is defined by the presence of tumor emboli within

endothelial-lined channels surrounded by smooth mus-
Risk assessment of malignant polyp (low or high risk of cle. There is a significant interobserver variability in
adverse outcome) is performed using histologic param- assessing lymphovascular invasion. Lymphatic invasion
eters that include margin status, lymphovascular inva- should be distinguished from retraction artifact and
sion, and tumor grade. Unfavorable histologic features micropapillary differentiation. Additional serial levels
that predict recurrent cancer or lymph node metastasis or ancillary stains such as D2-40 (Fig. 12.6B) and Movat
include tumor at or near the margin (≤1 mm), grade 3 stain may be used to confirm lymphovascular space
(poorly differentiated adenocarcinoma), or lymphovas- invasion. Extramural venous invasion (tumor emboli
cular invasion. In theory, the presence of any of these within veins beyond the muscle layer), characterized by
features is an indication for surgery. In the absence of the “orphan artery sign” and “protruding tongue sign,”
these features, the polypectomy procedure is considered represent a poor prognostic factor.
to be completely curative.
Margin Status
Tumor Grade
Cancer at or near the margin of resection is associated
Similar to colorectal resection specimens, the grade of with an adverse outcome. The status of margin can only
invasive adenocarcinoma is assessed using the American be assessed in intact polypectomy specimens. The resec-
Joint Committee on Cancer (AJCC) eighth edition clas- tion margin is the actual free edge of submucosal con-
sification system. It is based on the degree of glandular nective tissue showing thermal artifact (see Fig. 12.5B,
differentiation: black arrow). There is no consensus as to the definition
Grade 1: well-differentiated adenocarcinoma, greater of what constitutes a positive margin of resection. The
than 95% glandular differentiation or with well-formed National Comprehensive Cancer Network 2018 Colon
glands with open lumina Cancer Guidelines define positive margin as follows: (1)
Grade 2: moderately differentiated adenocarcinoma; tumor less than 1 mm from the transected margin, (2)
50% to 95% glandular differentiation tumor less than 2 mm from the transected margin, and
Grade 3: poorly differentiated adenocarcinoma, signet (3) tumor cells present within the diathermy of the tran-
ring cell or mucinous adenocarcinoma, less than 50% glan- sected margin. It is therefore recommended that when
dular differentiation or solid sheets of neoplastic glands the tumor is very close but not at the transected margin,
Grade 4: undifferentiated; no gland formation or the exact distance of the tumor from the cauterized mar-
mucin; no squamous or neuroendocrine differentiation gin be included in the report.
Grade 1 and 2 are considered low-grade tumors. When invasive adenocarcinoma is present at or near
the margin of resection (≤1 mm), the risk of relapse is
Lymphovascular Invasion
between 21% and 33%. However, studies have shown
Lymphatic space invasion requires the presence of that even in cases with “doubtfully complete” resec-
tumor cells within endothelial-lined channels without tions, the clinical outcome is favorable. This is because
significant red blood cells (Fig. 12.6A). Venous invasion of the assumption that diathermy coagulation destroys
A B
FIGURE 12.6
Lymphovascular invasion in a malignant colon polyp. A, Tumor cells within lymphatic space admixed with inflammatory cells. B, A D2-40 immunohistochemical
stain highlights the lymphatic spaces and can be helpful in differentiating lymphatic invasion from retraction artifact.
an additional 3 to 5 mm of submucosal tissue beyond between level 1 and level 2 invasion, and lack of muscu-
what is visualized by microscopy. Occasionally, the spec- laris propria in these specimens are some of the inherent
imen orientation and processing make it difficult, if not issues that make it difficult to apply this system in rou-
impossible, to accurately assess the resection margin. tine practice. Therefore, many practices do not report
In these cases, the report should clearly state the lim- Haggitt levels on pedunculated polyps.
itations of histologic assessment and encourage the cli- The Kudo or Kikuchi method is used for assessing
nician to assess completeness of excision by correlating depth of invasion in sessile malignant colorectal pol-
with in vivo endoscopic findings of resection. yps. Histologic assessment is performed by creating an
imaginary division of the submucosal region into thirds
Tumor Budding
(sm1, sm2, and sm3) and then determining the depth of
Tumor budding is considered as an independent invasion. However, accurate division of the submucosal
adverse prognostic factor in CRC. It is associated with space requires the presence of muscularis propria, and
a higher TNM (tumor, node, metastasis) stage, high therefore this classification is most commonly employed
tumor grade, and presence of lymphovascular invasion only in transanal endoscopy microsurgery resections,
and therefore, ultimately, with lymph node and distant which usually sample superficial layer of muscularis
metastasis. In malignant polyps, the presence of high propria. Studies have shown that the incidence of lymph
tumor budding is associated with an increased risk of node metastasis increases from 1% to 3% in sm1 can-
lymph node metastasis. Therefore, it has been suggested cers to 8% and 23% in sm2 and sm3 cancers, respec-
that the finding of high tumor budding may be an indi- tively. Newer studies suggest that submucosal invasion
cation for surgical resection. A recent International greater than 1 mm represents an adverse prognostic fac-
Tumor Budding Consensus Conference (ITBCC) tor and needs to be reported.
defined tumor budding as a single tumor cell or a cluster
of up to four tumor cells (see section on tumor budding
later). This finding is variably reported by pathologists.
Invasive Adenocarcinoma Versus Misplaced
Level or Depth of Invasion of Adenocarcinoma in Epithelium (Pseudoinvasion)
a Polyp
It is not a routine practice to report depth of inva- Pseudoinvasion or misplaced epithelium is a common
sion in malignant polypectomy specimens. The Haggitt phenomenon that occurs in large pedunculated col-
system is advocated for assessing depth of invasion in orectal polyps. It is most commonly observed in pol-
pedunculated malignant polyps. Per the Haggitt system yps located within the sigmoid or rectosigmoid colon.
for pedunculated malignant polyps, level 1 is defined as Repeated mucosal trauma related to the size of the polyp
invasion into the polyp head, level 2 is invasion into the results in mechanical displacement of the adenomatous
polyp neck, level 3 is carcinoma invading any part of epithelium into deep lamina propria or submucosa of
polyp stalk, and level 4 is invasion beyond the stalk but the polyp, mimicking invasive adenocarcinoma. Some
above the muscularis propria. Specimen orientation, tis- features that can be helpful in identifying misplaced
sue shrinkage after fixation, interobserver disagreement epithelium are listed in Table 12.2. Misplaced glands
are always accompanied by the surrounding lamina

TABLE 12.2 propria. In contrast, invasive adenocarcinoma is diag-
nosed in the presence of stromal desmoplastic response
Pseudoinvasion (Misplaced Epithelium) versus
Invasive Adenocarcinoma (Malignant Polyp) that surrounds the neoplastic glands. Misplaced glands
retain their lobular arrangement, are often surrounded
Pseudoinvasion or Misplaced Invasive Adenocarcinoma in by hemorrhage or hemosiderin (related to trauma), and
Epithelium a Polyp harbor the same degree of dysplasia as compared with
Rounded glandular contours Infiltrative, angulated glands the overlying dysplastic epithelium (Figs. 12.7 and 12.8).
of variable size In some instances, misplaced epithelium may be associ-
Dysplastic glands invested Dysplastic glands surrounded ated with cystically dilated dysplastic glands, which may
by lamina propria by stromal desmoplasia rupture and present as pools of acellular mucin within
Acellular mucin pools or Clusters of dysplastic cells
the stalk of the polyp. In these cases, the adenomatous
mucin pools lined by within mucin pools
attenuated epithelium epithelium may be seen partially lining the mucin pools.
Hemorrhage or hemosiderin- Hemorrhage or hemosiderin- In contrast, the presence of free-floating clusters of dys-
laden macrophages laden macrophages may be plastic glands within the center of mucin pools is an
surrounding the dysplastic present ominous finding and indicates the presence of mucinous
glands
adenocarcinoma (Fig. 12.9).
Degree of dysplasia usually Degree of dysplasia
resembles the overlying usually exceeds that of
dysplastic epithelium the overlying dysplastic
epithelium
FIGURE 12.8
Polyp with pseudoinvasion or misplaced epithelium. Higher magnifica-
FIGURE 12.7
tion shows that the glands maintain a rounded configuration and are sur-
Polyp with pseudoinvasion or misplaced epithelium. A sigmoid colon polyp rounded by lamina propria and hemosiderin-laden histiocytes. Hemorrhage
showing tubulovillous adenoma with aggregates of dysplastic glands within and mucin pools partially lined by epithelium are also present (lower right
the stalk of the polyp. corner).
A B
FIGURE 12.9
Invasive mucinous adenocarcinoma in a polyp. The trisected pedunculated polyp shows a tubulovillous adenoma with pools of mucin within the stalk of the
polyp (A). In one of the three fragments (far right), the mucinous pools reach the cauterized base of excision. Higher magnification shows that these dissecting
pools of mucin contain free-floating clusters of dysplastic cells, consistent with an invasive mucinous adenocarcinoma (B).
■ SERRATED POLYPS
Pathologic Features
Serrated colorectal polyps are characterized histologi- Gross Findings

cally by serrated appearance of the crypts. The current
World Health Organization (WHO) edition classifies Grossly, HPs are dome-shaped nodules that are usually
these polyps as smaller than 5 mm in diameter. They are often multiple
and are most frequently found in the sigmoid colon and
1. HP rectum. HPs are most commonly found on the crest of
2. Sessile serrated polyp/adenoma (SSP/A; also referred mucosal folds and are similar in color to the surround-
as sessile serrated lesion in the latest WHO edition) ing normal mucosa.
3. Traditional serrated adenoma (TSA)
Hyperplastic polyps contain serrated colonic crypts lined

Hyperplastic Polyps
by goblet and absorptive cells. The crypt serrations are
usually restricted to the upper half or two-thirds of the
Clinical Features crypt epithelium, resulting in the characteristic “saw-
toothed” or serrated appearance (Fig. 12.10). The basal
Hyperplastic polyps are the most commonly encountered aspect of the crypts is normal. The number of absorptive
polyps in the adult colorectum. They are found with cells lining the crypts is greater than the number of gob-
increasing frequency in individuals older than 40 years of let cells. Mitoses are common but are confined to the bot-
age and are more common in men than in women. HPs tom half of crypts (proliferative zone of the crypt). The
develop nearly a decade earlier than conventional adeno- basement membrane is often thickened, and this finding
mas and affect patients in the fifth and sixth decades of life is best appreciated at the polyp surface (Fig. 12.11). The
but do not show a significant association with increasing epithelial cells typically show basally located small and
age. They have an estimated prevalence of 10% to 15% hyperchromatic nuclei with only slight enlargement.
among adult patients in Western populations and constitute Scattered Paneth or endocrine cells may also be seen
approximately one-fourth of all endoscopically removed within the crypt bases. Larger HPs often show changes
polyps but 80% to 90% of all serrated polyps. Because of of mucosal prolapse. This is characterized by splaying of
their small size, HPs are asymptomatic and often detected the muscularis mucosae fibers at the crypt bases, with
incidentally at sigmoidoscopy or colonoscopy. extension of the smooth muscle fibers into the lamina
propria and around individual crypts (Fig. 12.12). This
often results in dilation of the crypt bases and can cause
HYPERPLASTIC POLYPS—FACT SHEET diagnostic confusion with SSP/A.
Definition
n Nondysplastic serrated polyp with low malignant potential

n Most common neoplastic polyp
n 10% to 20% of asymptomatic patients
Morbidity And Mortality

n Risk for neoplasia related to size and number

n Usually affects individuals in fifth or sixth decade of life
n Incidence does not increase with age
n Male more than female
n No racial or ethnic associations
Clinical Features
n Asymptomatic
n Incidental finding at endoscopy
FIGURE 12.10
Prognosis And Therapy
Hyperplastic polyp. A 0.5 mm diminutive polyp located in the sigmoid colon
n Polypectomy
showing serrated crypts. The crypt serrations are restricted to the upper half
to upper two-thirds of the crypt.

Hyperplastic polyp with thickened basement membrane. Hyperplastic polyp Microvesicular type hyperplastic polyp (HP). This variant of HP shows
often shows variable thickening of the basement membrane. This finding is microvesicular mucin within the cytoplasm of the cells lining the serrated
more commonly seen toward the surface of the polyp. crypts. Goblet cells are interspersed between these cells.
Hyperplastic Polyps—Pathologic Features
Gross Findings
n Small (diminutive) sessile polyp (<5 mm)
n Rectosigmoid colon most common location
n Crypt elongation with serrated crypt epithelium
n Crypt serrations are restricted to the upper third or two-thirds of
the crypt epithelium

n Well-differentiated goblet and absorptive cells
n Mitoses restricted to crypt bases
n Mucosal prolapse polyp with hyperplastic epithelial changes
n Inflammatory polyp with hyperplastic epithelial changes
n Tubular adenoma
FIGURE 12.12
Hyperplastic polyp with prolapse changes. The image shows a hyperplastic
polyp with basal dilation of some of the serrated crypts, mimicking a sessile
serrated polyp/adenoma. However, the lamina propria shows splaying of the
muscularis mucosae along with extension of the smooth muscle fibers into
the lamina propria and around individual crypts, consistent with prolapse.
Hyperplastic polyps are composed of three histologic Other lesions with serrated epithelial features can mimic
subtypes: microvesicular type, goblet cell–rich type, HP, including inflammatory cloacogenic polyps or pol-
and mucin-depleted type. Microvesicular type HPs are ypoid mucosal prolapse, which often show prominent
the most common subtype and are characterized by serrations of the crypt and surface epithelium. Features
microvesicular mucin with few goblet cells, including that are helpful in distinguishing mucosal prolapse or
some dystrophic goblet cells (Fig. 12.13). Goblet cell– inflammatory cloacogenic polyps from HPs include the
rich HPs show prominent goblet cells and subtle serra- polyp location at the anal verge, presence of smooth
tions of the crypts (Fig. 12.14). Mucin-depleted HPs are muscle ingrowth between the dilated colonic crypts, and
the least common subtype of HP and show reactive epi- lamina propria hemorrhage and fibrosis (Fig. 12.16).
thelial mucin loss with minimal cytoplasm (Fig. 12.15). In some instances, HPs may show reactive mucin loss,
Currently, there is no evidence to support subtyping especially, the mucin-depleted variant. These lesions can
HPs for prognostic purposes. mimic tubular adenoma. However, presence of surface
epithelial maturation in HPs and lack of significant cyto-

logic atypia help support a HP.
Because they may be endoscopically similar in appear-

ance to small adenomatous polyps, HPs are often removed
by polypectomy solely to distinguish them on histologic
grounds from adenomatous polyps. Based on the American
College of Gastroenterology recommendations, surveil-
lance for HPs ranges from 5 to 10 years and depends on
the size, number, and location of the polyps (Table 12.3).
FIGURE 12.14
Goblet cell–rich hyperplastic polyp (HP). This variant of HP shows numerous
goblet cells with subtle serrations within the crypts.
FIGURE 12.16
Polypoid mucosal prolapse. An example of a rectal polyp showing dilation
FIGURE 12.15 and branching of the crypts. The crypts also show serrated architecture and
Mucin-depleted hyperplastic polyp. In this morphologic variant, the serrated are lined by cells with abundant mucinous cytoplasm. These findings can
epithelium lining the crypts is composed of cells with minimal intracytoplas- mimic a serrated polyp. However, there is fibromuscular replacement of the
mic mucin and rare goblet cells. Mild nuclear atypia is present. The epithelial lamina propria along with extension of smooth muscle fibers alongside dis-
changes are reminiscent of regenerative changes after mucosal injury. torted crypts.
TABLE 12.3
Surveillance Guidelines for Serrated Polyps: Expert Panel Recommendations
Type of Polyp Size Number Location Interval (years)
HP <10 mm Any Rectosigmoid colon 10

HP ≤5 mm ≤3 Proximal to sigmoid colon 10
HP Any ≥4 Proximal to sigmoid colon 5
HP >5 mm ≥1 Proximal to sigmoid colon 5
SSP/A or TSA <10 mm <3 Any 5
SSP/A or TSA ≥10 mm 1 Any 3
SSP/A or TSA <10 mm ≥3 Any 3
SSP/A ≥10 mm ≥2 Any 1-3
SSP/A with dysplasia Any Any Any 1-3
Adapted from Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol.
2012;107:1315-1329.
HP, Hyperplastic polyp; SSP/A, sessile serrated polyp/adenoma; TSA, traditional serrated adenoma.
■ SESSILE SERRATED POLYP/ADENOMA Clinical Features

n Usually asymptomatic
Clinical Features Prognosis And Therapy

n Routine surveillance is indicated because of the risk for colorectal
neoplasia
Sessile serrated polyp/adenoma (also referred as sessile
serrated lesion) constitute approximately 10% of all ser-
rated colorectal polyps. They are difficult to recognize
endoscopically and therefore are often underreported. Pathologic Features
SSP/As are the precursor lesions that progress to colorec-
tal carcinoma via the serrated pathway of carcinogen- Gross Findings
esis. Recognition of these lesions has largely stemmed
from the observations that (1) patients with hyperplas- As their name indicates, SSP/As are generally sessile
tic polyposis, a disorder characterized by numerous HPs, lesions. They can arise anywhere within the colorectum
have an increased risk for colorectal neoplasia, and (2) but are predominantly located in the proximal colon.
sporadic right-sided HPs more commonly contain a vari- They show a wide size range and may reach several cen-
ety of genetic alterations, including microsatellite insta- timeters in diameter, hence the former designation giant
bility (MSI) and increased gene methylation compared hyperplastic polyps. Most lesions resemble thickened
with their left-sided counterparts. Part of the reason for mucosal folds with indiscrete borders that can be diffi-
discrepancies in the literature is that these lesions have cult to recognize endoscopically (Fig. 12.17). Adherent
been called by a variety of names, including serrated mucus or “mucin cap” is a frequent finding.
polyp with atypical proliferation, giant hyperplastic pol-
yps, large hyperplastic polyps, mixed hyperplastic/adeno-
matous polyps, sessile serrated polyps, serrated adenomas, Sessile Serrated Polyp/Adenoma—Pathologic Features
and inverted hyperplastic polyps. Given the potential
confusion with an adenomatous polyp, the 2017 British Gross Findings
Society of Gastroenterology guidelines and the current n Generally sessile
n Broad size range (millimeters to centimeters)

WHO fifth edition recommend using the terminology
n Proximal distribution
sessile serrated lesions for SSA/Ps. The term has not
been widely used. The most common age at diagnosis is Microscopic Findings
in the sixth to seventh decade of life, similar to that for n Serrated crypts with serrations involving the entire length of the
classic adenomatous polyps. Most patients are clinically crypt
asymptomatic, and the fecal occult test result is usually n Dilatation of crypt bases
n Horizontally arranged crypt bases with an L- or T- shaped

negative.
configuration
n May have an inverted growth pattern
n Irregularly branching of crypts
n Individual cells show microvesicular cytoplasm
n May show prominent submucosal adipose tissue and perineurial-
like stromal proliferation within the lamina propria

SESSILE SERRATED POLYP/ADENOMAS—FACT SHEET n Only one unequivocal abnormal shaped crypt is required to
diagnose sessile serrated polyp/adenoma

Definition
n Epithelial neoplasms with distinctive serrated epithelial
architecture and associated risk for colorectal neoplasia n Hyperplastic polyp
n Traditional serrated adenoma
Incidence And Location n Inflammatory polyp
n Polypoid mucosal prolapse

n 10% of all serrated polyps encountered at endoscopy

n Related to risk for progression to carcinoma
n 6% of colon cancers occur in association with a sessile serrated
polyp/adenoma
The two major morphologic features distinguish SSP/
Gender, Race, And Age Distribution As from conventional HPs are architectural distortion
n Females more than males and abnormal proliferation. Architectural features that
n No known racial predominance are characteristic of SSP/As include crypt dilation, hor-
n Average age at diagnosis in seventh decade of life izontal orientation of deep crypts, serrations extending
to the crypt bases, and “boot-shaped”, L- or inverted
FIGURE 12.17
FIGURE 12.19
Endoscopic appearance of a sessile serrated polyp/adenoma. This ascending
colon lesion consists of subtle thickening of the colonic mucosal fold with Sessile serrated polyp/adenoma (SSP/A). Higher magnification of the ser-
indiscrete borders. Saline-lift technique is often applied to delineate and rated crypts in a SSP/A shows that the individual cells harbor microvesicular
resect sessile polyps. mucin.
with distinct microvesicular mucin interspersed with

goblet cells (Fig. 12.19). Dystrophic goblet cells are also
common. Regardless of the size or location of the polyp,
the presence of at least one unequivocal, architecturally
distorted, dilated, or horizontally branched crypt is suf-
ficient for a diagnosis of SSP/A.
Another unique histologic finding that may be seen
in SSP/As is a bland spindle cell proliferation that sur-
rounds the serrated crypts (Fig. 12.20). Studies have
shown that these cells are of perineural origin, and these
polyps harbor BRAF mutations similar to other serrated
polyps and have no clinical significance with regards to
neoplastic progression. An epithelial membrane antigen
(EMA) immunohistochemical stain can be performed to
highlight these cells. SSP/As can also show prominent
FIGURE 12.18 submucosal adipose tissue that can be clinically mis-
Sessile serrated polyp/adenoma (SSP/A). This 2-cm ascending colon polyp taken for a lipoma (Fig. 12.21).
shows crypt dilation, horizontal orientation of deep crypts, and serrations Sessile serrated polyps/adenomas may harbor foci
extending to the crypt bases resulting in “boot-shaped” or “inverted T”–
shaped crypts, characteristic of SSP/A. of low- or high-grade dysplasia. In one large study, the
incidence of dysplasia in SSP/As was reported to be
5%. These cases were previously diagnosed as mixed
hyperplastic/adenomatous polyps. Although in most
T–shaped crypts (Fig. 12.18). Compared with conven- instances, the type of dysplasia resembles conven-
tional HPs in which atypia is confined to the crypt bases tional adenomatous dysplasia (tubular or tubulovil-
(proliferative zone of the crypt), in SSP/As, the prolif- lous adenoma) characterized by nuclear enlargement,
erative zone of the crypt shifts to the midportion of the hyperchromasia, and pseudostratified nuclei, other
crypts. This results in epithelial proliferation toward morphologic variants of dysplasia, such as serrated and
the lumen as well as the crypts. As the neoplastic pro- traditional serrated adenoma–like dysplasia have also
liferation extends to the basal aspects of the crypts, the been described. To diagnose dysplasia in an SSP/A, the
muscularis mucosae restricts further downward prolif- dysplastic focus should be seen in continuity with the
eration, and therefore, the crypts start proliferating later- nondysplastic areas (Fig. 12.22). Because of the high
ally, resulting in dilation and branching as well as lateral interobserver variability, the current WHO edition does
extensions of the crypts. The basement membrane of not specifically indicate classifying the grade of dys-
the surface epithelial cells is not thickened. The serrated plasia in these lesions. However, most practices report
crypts show decreased to near-complete absence of neu- the degree of dysplasia as either low- or high-grade
roendocrine cells. The serrated crypts are lined by cells dysplasia.
A B
FIGURE 12.20
Sessile serrated polyp/adenoma (SSP/A) with perineurial-like stromal proliferation. A transverse colon sessile SSP/A showing two biopsy fragments (A). The
fragment on the right shows expansion of the lamina propria by a bland spindle cell proliferation surrounding the crypts. This proliferation is a reactive process
seen in serrated polyps. Higher magnification shows that the cells lack atypia or mitotic activity (B). Immunohistochemically, the cells express epithelial mem-
brane antigen, a marker of perineurial differentiation.
FIGURE 12.21
Sessile serrated polyp/adenoma (SSP/A) with prominent submucosal adi-
pose tissue. An example of a cecal polypoid lesion that was clinically diag-
nosed as “lipoma.” The image shows a SSP/A overlying submucosal adipose FIGURE 12.22
tissue, a finding that is frequently seen in large right-sided serrated polyps. Sessile serrated polyp/adenoma (epithelial membrane antigen) with low-
grade dysplasia. An example of a SSP/A that shows atypical glands lined
by cells with enlarged, hyperchromatic, and stratified nuclei, consistent with
low-grade dysplasia. The dysplastic foci are seen in continuity with the non-
Ancillary Studies And Molecular Alterations dysplastic SSP/A (left half of the image). In most cases, the dysplastic foci
resemble conventional adenomatous polyps. In this case, there is cytoplas-
mic eosinophilia, resulting in a traditional serrated adenoma–like appearance.
Because none of the markers have demonstrated appro-
priate sensitivity to discriminate small SSP/A from HPs,
immunohistochemical labeling does not have a routine As mentioned earlier, transition to dysplasia corresponds
role in the diagnosis of SSP/As. Some markers, including to methylation-induced silencing of tumor suppressor
MUC6, annexin A10, and MUC5AC, have been reported genes, of which MLH1 is the most commonly gene.
to be markers of SSP/As; however, these markers have
not been validated by independent studies.
More recently, it was shown that some SSP/As show
loss of hMLH1 protein expression, consistent with
the increased rate of methylation-induced silencing of
MLH1 tumor suppressor genes with neoplastic progres- Several interobserver agreement studies have high-
sion. In about 70% of cases, loss of hMLH1 expression lighted the challenges in distinguishing SSP/As from
occurs in the setting of cytologic dysplasia. HPs, especially when these polyps are smaller than 1 cm
The majority of SSP/As harbor a somatic BRAF in size. The presence of abnormal crypt architecture and
mutation and show CpG island methylator phenotype. lack of thickened basement membrane are helpful in
distinguishing SSP/A from HP. Mucosal prolapse in large

HPs can lead to diagnostic confusion (see Fig. 12.12) TRADITIONAL SERRATED ADENOMAS—FACT SHEET
and mimic SSP/A. Recognizing the features of prolapse,
such as dilation of crypts, fibromuscular replacement of Definition
lamina propria, and vascular congestion, can be helpful n Epithelial neoplasms with serrated crypts, slitlike spaces; villiform
to separate SSP/A from a large HP with prolapse. growth pattern; ectopic crypt foci; and tall columnar cells with
prominent eosinophilic cytoplasm and minimally pseudostratified
Although traditional serrated adenoma is one of the nuclei
subtypes of serrated polyps, the left-sided location, vil- n Associated with an increased risk for colorectal neoplasia
liform growth pattern, distinct eosinophilic cytoplasm,
and ectopic crypt formation are all helpful in distin- Incidence And Location
guishing TSA from SSP/A. n Approximately 2% to 5% of serrated polyps and fewer than 1%
Last, inflammatory polyps or polypoid mucosal proof all colorectal polyps

lapse can show serrated epithelial changes in some of
the crypts (see Fig. 12.16), especially toward the surface
n Actual risk for progression to carcinoma unknown
of the polyp. However, the pedunculated nature of these
lesions, an edematous and inflamed stroma, fibromuscu- Gender, Race, And Age Distribution
lar replacement of lamina propria in polypoid mucosal n Slight male predominance
prolapse, and lack of the characteristic crypt architec- n No known racial predominance
tural changes of an SSP/A are helpful in this distinction. n Average age at diagnosis is seventh decade of life
Clinical Features
n Usually asymptomatic
Prognosis and Therapy n Symptoms related to larger polyp size
n Associated with sporadic microsatellite instability
Distinguishing SSP/A from HP is of clinical importance Prognosis And Therapy

because SSP/As are associated with an increased risk n Routine surveillance (1–3 years depending on the size and
for colorectal neoplasia, but HPs are not. The absolute number of polyps) because they have an increased risk for
risk for neoplastic transformation in an SSP/A remains colorectal neoplasia
unclear. However, an association is recognized between
CRCs and serrated polyps, with up to 25% of CRCs
found in association with the serrated neoplasia path-
way (see details later). The surveillance guidelines for Pathologic Features
SSP/As are outlined in Table 12.3.
Patients with SSP/As are at an increased risk for devel- Gross Findings
opment of adenomatous and metachronous serrated pol-
yps. Studies have also shown that patients with SSP/As Traditional serrated adenomas most commonly arise in
and synchronous high-risk adenomas (adenomas ≥1 cm the left colon. Their gross appearance is that of a polyp-
in size, villous architecture, and high-grade dysplasia) are oid growth that may or may not have villiform features.
at an increased risk of developing metachronous high- The lesions range in size from 0.5 to 2 cm in diameter.
risk adenomas, independent of the size of the lesion. In some instances, TSAs may present as sessile lesions.
These are usually located within the proximal colon.
Grossly, small TSAs are indistinguishable from conven-
tional HPs, and large TSAs may be difficult to distin-
■ TRADITIONAL SERRATED ADENOMAS
guish from a classic adenomatous polyp.
Clinical Features Microscopic Findings
Traditional serrated adenomas show a complex polyp-

Traditional serrated adenomas are a subset of serrated oid or villiform growth pattern composed of glands with
colorectal polyps characterized histologically by the serrated architecture. They often harbor slitlike spaces
presence of a villiform growth pattern, ectopic crypt foci within the proliferation. In many cases, the villi are
and tall columnar cells with distinct eosinophilic cyto- elongated and may show bulbous tips (filiform TSAs).
plasm and minimal pseudostratification. TSAs are less A characteristic feature of TSAs is the finding of ecto-
prevalent than SSP/As, comprising approximately 2% pic crypt foci, which are proliferative crypts located per-
to 5% of all serrated polyps and fewer than 1% of all pendicular to the long axis of the villous structures (Fig.
colorectal polyps. The average age at diagnosis is during 12.23). The individual cells show prominent eosinophilic
the seventh decade of life. They are slightly more com- cytoplasm, basally located slightly elongated nuclei,
mon in men, and there is no racial predominance. and open chromatin pattern. There is minimal nuclear

Traditional serrated adenoma. A rectosigmoid polyp showing polypoid or vil- Traditional serrated adenoma. Higher magnification of traditional serrated
liform growth pattern with slit-like spaces composed of glands with serrated adenoma showing prominent cytoplasmic eosinophilia, ectopic crypts (black
crypts. The arrow highlights the native colonic crypts. Even at this magnifica- arrows) and minimal nuclear atypia and pseudostratification. Mitotic activity
tion, the lesion is characterized by cytoplasmic eosinophilia. and apoptotic activity is rare.
pseudostratification without significant mitotic or apop-

totic activity (Fig. 12.24). Some examples may show
an abundance of goblet cells. Up to 50% of TSAs may
show a nondysplastic serrated precursor, either an HP or The main entities in the differential diagnosis of a TSA
SSP/A in the background. A subset of TSAs may develop are SSP/A and conventional tubular or tubulovillous
conventional adenomatous dysplasia (low or high grade). adenomas. SSP/As can be recognized by their sessile
These foci resemble tubular or tubulovillous adenomas. growth pattern and the presence of crypt dilation, hor-
izontal orientation of deep crypts, serrations of crypt
epithelium extending to the crypt bases, and inverted
crypts. SSP/As are also more commonly located in the
Molecular Alterations
right colon. Occasionally, large tubular or tubulovillous
adenomas may harbor serrated crypts, raising the pos-
At a molecular level, TSAs are far more diverse compared sibility of a TSA with conventional dysplasia. While
to SSP/As. They may either have BRAF or KRAS muta- there are no guidelines regarding the nomenclature for
tions and low or high levels of CpG island methylation. these large adenomatous polyps with serrated crypts, in
They do not show MLH1 methylation or develop MSI. most practices, if the predominant portion of the lesion
However, most cases show MGMT promoter methylation. is composed of a conventional tubular or tubulovillous
adenoma, these lesions are designated as tubular or tub-
ulovillous adenomas with serrated crypt architecture
Traditional Serrated Adenomas—Pathologic Features
or with TSA-like areas. Regardless, in these cases, the
lesions are clinically managed as conventional adeno-
Gross Findings matous polyps.
n Polypoid or villiform growth; rarely sessile lesions
n Size ranges up to 2 cm
n Common in left colon

n Villiform or polypoid growth
The absolute risk for neoplastic transformation in a
n Ectopic crypt foci
n Slitlike spaces
TSA is unknown. The AGA guidelines recommend rou-
n Eosinophilic cytoplasm tine surveillance at an interval of 1 to 3 years depending
n Minimal nuclear pseudostratification; rare mitotic or apoptotic on the size and the number of polyps (see Table 12.3). In
activity a large case-control study from Korea that consisted of
n May harbor foci of conventional low- or high-grade adenomatous
420 patients with TSA, it was shown that in comparison
dysplasia
with patients with conventional adenomatous polyps,
Differential Diagnosis patients with TSAs have a higher metachronous occur-
n Sessile serrated polyp/adenoma
rence rate of all polyp subtypes (adenomas, SSP/As, and
n Tubular or tubulovillous adenoma with serrated crypt architecture HPs), and the presence of TSA was found to be an inde-
pendent predictor of a high-risk polyp recurrence.
most frequently diagnosed cancer in the United States

■ SERRATED POLYPOSIS SYNDROME
among both men and women, with an estimated 135,430
new cases of CRC diagnosed in the United States in
Serrated polyposis syndrome (SPS) (formerly “hyper- 2017. Colorectal carcinoma is also the third most com-
plastic polyposis syndrome”) is characterized by multiple mon cause of cancer deaths in the United States among
serrated colorectal polyps (typically SSP/As and/or HPs) men and women, with an estimated 50,260 patients
and is associated with a more than 50% cumulative risk dying of colorectal carcinoma in the year 2017.
for developing CRC. Because a definite genetic basis for The lifetime risk for developing CRC is approxi-
SPS has not been established and patients cases do not mately 6% and is greater for men than women. It is
have a family history of SPS or even CRC, endoscopic more common in individuals of African American
and histologic findings remain essential in establishing a descent. The risk for development of CRC increases
diagnosis of SPS. Mutations in MUTYH have been doc- significantly after the age of 40 years in both men
umented in some patients with SPS, and therefore it has and women, with the median age of diagnosis being
been suggested that genetic testing for MUTYH mutations 67 years. In contrast to the decreasing incidence rate
may be performed in patients with SPS, especially if the among screening-aged individuals, CRC incidence rates
patients is found to have concurrent adenomas. Another in adults younger than 50 years rose by 1.6% from
study proposed germline mutations in oncogene-induced 2000 to 2013, for an overall increase of 22%. The cause
senescence pathways as a predisposing factor. of this increase is yet to be elucidated; however, factors
The updated WHO criteria for SPS include (1) at least such as excess body weight, unhealthy dietary patterns,
five serrated polyps proximal to the rectum, all at least and sedentary lifestyle have been implicated. CRC risk
5 mm in size, with at least two more 10 mm or larger also varies by location within the colorectum. In low-
or 2) more than 20 serrated polyps of any size detected risk countries, right-sided cancers are more common,
throughout the colon, with at least five being proximal whereas in high-risk countries, left-sided cancers are
to the rectum. All serrated polyp types—HP, SSP/A, and common. These statistics largely reflect the incidence
TSA—are included in the polyp counts when making this of colon cancer because the incidence of rectal cancer
diagnosis. It is also important to remember that the counts is fairly constant among high- and low-risk countries.
can be cumulative over multiple examinations and do not Right-sided cancers are more common in women, and
have to be fulfilled at a single colonoscopy. In screening the incidence increases with age.
populations, prevalence rates of up to 1 in 127 have been The cause of CRC is multifactorial, with envi-
reported. SPS is reported to occur more commonly in ronment and inheritance playing variable roles.
individuals with northern European ancestry and shows Approximately 70% to 80% of patients with CRC
a positive correlation with smoking, specifically with have sporadic disease; in the remaining 20% to 30% of
regard to the number of serrated polyps. SPS occurs both patients, an inherited component, which may be iden-
in male and female patients with age at diagnosis ranging tified, especially in patients younger than 50 years.
widely from 17 to 69 years (mean, 48 years). The estimated time for development of an infiltrating
It has been suggested that there are three phenotypes carcinoma from a small adenoma is approximately 10
of SPS: (1) large SSP/As in the proximal colon with a high to 15 years. Thus, most patients do not have specific
risk of CRC, (2) numerous small HPs throughout the col- clinical symptoms to alert the clinician to the pres-
orectum with a lower risk of CRC, and (3) many small left- ence of a lesion. Initial symptoms may be vague and
sided serrated polyps. In addition to serrated polyps, up nonspecific, such as weight loss or malaise, whereas
to 80% of patients may show a concurrent conventional up to 12% of patients are entirely asymptomatic at
adenoma, which confers an increased risk for CRC. At the time of diagnosis. Of patients who are symptom-
present, patients diagnosed with SPS are subjected to colo- atic, clinical presentation may be related to location
noscopic surveillance every 1 to 3 years with attempted of the carcinoma within the colorectum. Because the
removal of all polyps larger than 5 mm in diameter. proximal bowel can accommodate large, bulky tumors,
Indications for surgery include an inability to control the cancers of the cecum and right colon are often pol-
growth of serrated polyps or the development of cancer. ypoid, may remain clinically silent, and rarely cause
obstruction or bleeding. In contrast, left colon can-
cers may present with changes in bowel habits such
as diarrhea, tenesmus, incontinence, or a decrease in
■ COLORECTAL ADENOCARCINOMA
stool caliber as the carcinoma grows and obstructs the
lumen. Regardless of location, half of all patients pres-
Clinical Features ent with rectal bleeding, which may be the result of
frank hemorrhage or occult bleeding. Abdominal pain
may be a presenting symptom in up to 50% of patients
Colorectal carcinoma is among the most common neo- and appears to be more common in colon cancers than
plasms affecting industrialized nations. It is the fourth rectal cancers.
Lynch syndrome is not associated with increased col-

■ MOLECULAR PATHWAYS FOR COLORECTAL
orectal adenoma formation. It is caused by a deleterious
CARCINOGENESIS
germline mutation in a DNA mismatch repair (MMR)
gene, most commonly MLH1 and MSH2, and less com-
Three molecular carcinogenesis pathways that have monly PMS2 and MSH6. The designation of Lynch syn-
been identified for CRCs include (1) chromosomal insta- drome is also applied to families and patients with loss
bility (CIN), (2) microsatellite instability (MSI), and (3) of expression of the MSH2 gene caused by deletion in
CpG island methylator phenotype (CIMP) or epigenetic the EPCAM gene. These mutations result in deficient
instability pathways. The CIN pathway is characterized MMR function.
by alterations in the number and structure of chromo- The Amsterdam II criteria for a diagnosis of Lynch
somes and accompanying genetic mutations of proto-on- syndrome have a 22% sensitivity and 98% specificity
cogenes and tumor suppressor genes. The MSI pathway for diagnosis of Lynch syndrome (Table 12.4) Revised
features alterations in the number of nucleotide repeats Bethesda guidelines are clinicopathologic criteria that
(microsatellite sequences) located in the exons and sub- have a sensitivity and specificity of 82% and 77%,
sequent frameshift mutations in tumor suppressor genes respectively, for a diagnosis of Lynch syndrome (see
or tumor-related genes. The CIMP pathway is charac- Table 12.4). These guidelines work best in detecting
terized by widespread hypermethylation of numerous patients with MLH and MSH2 abnormalities compared
promoter CpG island loci and consequent inactivation
of tumor suppressor genes or tumor-related genes.
The morphologic multistep pathways include the
classical pathway and the serrated neoplasia pathway. TABLE 12.4
The classical adenoma–carcinoma sequence accounts Amsterdam Criteria and Revised Bethesda
for nearly 80% of sporadic CRCs. It is characterized Guidelines for Diagnosis of Hereditary
by early APC mutation and subsequent mutations of Nonpolyposis Colorectal Cancer (HNPCC)
KRAS, SMAD2, SMAD4, and TP53 and can be driven
AMSTERDAM I CRITERIA
by CIN or MSI. The precursor lesions consist of conven-
1. Three or more relatives with histologically verified CRC,
tional adenomas. The serrated neoplasia pathway has one of whom is a first-degree relative of the other two.
epigenetic instability as its driving force and MSI as an FAP should be excluded.
optional event. 2. Two or more generations with CRC
Microsatellite instability high (MSI-H) tumors
3. 3. One or more CRC cases diagnosed before the age of 50
can either result from sporadic or germline alter- years
ations (Lynch syndrome) of microsatellite sequences. AMSTERDAM II CRITERIA
However, the precursor lesions for sporadic MSI-H can- 1. Three or more relatives with histologically verified HNPCC-
cers are serrated in nature, but those in Lynch syndrome associated cancer (CRC or cancer of the endometrium,
are tubular or tubulovillous adenomas. The Cancer small bowel, ureter, or renal pelvis), one of whom is
a first-degree relative of the other two. FAP should be
Genome Atlas study results show that the CIN and MSI
excluded.
pathways are mutually exclusive. The CIMP pathway
2. Cancer involving at least two generations
overlaps with the MSI pathway because of the presence
of sporadic MSI-H CRCs, which are also usually CIMP- 3. 3. One or more cancer cases diagnosed before the age of
50 years
high (CIMP-H). However, the CIMP pathway does not
REVISED BETHESDA GUIDELINES
appear to be in an exclusive relationship with the CIN
1. CRC diagnosed at younger than 50 years
pathway. CIMP-H or non–MSI-H CRCs show some copy
2. Presence of synchronous or metachronous colorectal
number variations across the genome, although the
cancer or other Lynch syndrome–associated tumors a
degree of CIN is less pronounced than that of CIMP-
3. Colorectal cancer with MSI-H pathologic-associated
negative or -low or non–MSI-H CRCs.
features (Crohn’s-like lymphocytic reaction, mucinous or
signet cell differentiation, or medullary growth pattern)
diagnosed in an individual younger than 60 years old
■ LYNCH SYNDROME 4. Patient with colorectal cancer and colorectal cancer or

Lynch syndrome–associated tumor a diagnosed in at least
one first-degree relative younger than 50 years old
Lynch syndrome (formerly known as hereditary non- 5. 5. Patient with colorectal cancer and CRC or colorectal
polyposis CRC syndrome), the prototype of an autoso- cancer or Lynch syndrome–associated tumor a diagnosed at
mal dominant inherited colon cancer family syndrome, any age in two first- or second-degree relatives
is the most common cause of inherited CRC, accounting CRC, Colorectal cancer; FAP, familial adenomatous polyposis; MSI-H,
for 3% of newly diagnosed cases of CRC. In contrast to microsatellite instability high.
a
Lynch syndrome–associated tumors include tumors of the colorectum,
GI polyposis syndromes in which risk of carcinoma is endometrium, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract,
related to the development of innumerable adenomas, brain, small bowel, sebaceous glands, and keratoacanthomas.
with those with MSH6 and PMS2 abnormalities, which polyposis, serrated polyposis, hereditary mixed polyp-
are likely to have low penetrant phenotypes and thus osis syndrome, Peutz-Jeghers syndrome, juvenile pol-
likely to be missed on family history. Lynch-like syn- yposis, and PTEN hamartoma syndrome (Cowden’s
drome describes patients or families in which molecular syndrome). The polyposis disorders are discussed in
testing demonstrates the presence of MSI or abnormal- Chapter 11. Chronic ulcerative colitis and Crohn’s dis-
ities in the expression of MMR gene proteins on immu- ease are also associated with an increased risk for colon
nohistochemistry (IHC) testing of tumor tissue but cancer, typically beginning after 8 to 10 years of disease,
no pathogenic germline mutation can be found in the especially in patients with pancolitis.
patient (e.g., in the absence of a BRAF mutation and/or
MLH1 promoter hypermethylation when there is loss of
tumor expression of the MLH1 protein). More recently, COLORECTAL ADENOCARCINOMA—FACT SHEET
it has been shown that about half of Lynch-like syn-
drome patients had biallelic somatic mutations of MLH1 Definition
or MSH2 to explain the MMR deficient tumors without n Malignant neoplasm of colorectal epithelium
having causal germline or promotor mutations.

Muir-Torre syndrome, a rare variant of Lynch syn- Incidence And Location
drome, is diagnosed in patients or families with Lynch n Fourth most common cancer in industrialized nations
syndrome and skin sebaceous gland neoplasms (seba-

ceous adenomas and carcinomas) or neoplasms of
n Responsible for 8.4% of cancer deaths
the hair follicle (keratoacanthomas). MSH2 mutation n 5-year survival rate is 64.9%
appears most common in these patients, and MSI can be
identified in the skin neoplasms and colorectal tumors Gender, Race, And Age Distribution
of affected patients. n Males more than females
Turcot’s syndrome is defined as patients or families n More common among African American populations
with colorectal neoplasia and brain tumors. However, n Average age at diagnosis in sixth decade of life (fifth decade for
hereditary nonpolyposis colorectal cancer)

these families can be cases of Lynch syndrome (asso-
ciated with glioblastomas) or FAP (associated with Clinical Features
medulloblastomas), so Turcot’s syndrome is not an inde- n High-risk populations include patients with positive family history,
pendent entity. Last, patients or families with biallelic history of inflammatory bowel disease, polyposis syndromes
mutations of the DNA MMR genes are categorized as n 3% of colorectal cancers resulting from Lynch syndrome
having constitutional MMR deficiency syndrome. These n Proximal and mucinous carcinomas associated with younger age,
patients are characterized by café au lait spots, early (in female gender, and microsatellite instability (MSI)
childhood and teenage years) onset of colorectal neopla-
sia or other Lynch syndrome cancers, oligopolyposis in
n Prognosis related to clinical stage, tumor differentiation, MSI
the small bowel or colon, brain tumors, and hematologic status
malignancies. n Adjuvant therapy recommended for advanced-stage carcinomas
The average age at diagnosis of cancer in patients with

Lynch syndrome is 45 years, compared with 69 years
for sporadic cases of CRC. Synchronous and metachro-
nous colon cancers are common among patients with Pathologic Features
Lynch syndrome and affect up to 25% of patients with
this syndrome. About 60% to 80% of CRCs occur in the Gross Findings
right colon. The number of adenomas in patients with
Lynch syndrome is not more than those with attenuated Grossly, CRCs may be polypoid, exophytic, ulcerative,
polyposis syndrome, although the time for progression diffusely infiltrating, or obstructing, producing a cir-
from adenoma to carcinoma appears to be accelerated cumferential narrowing of the bowel lumen. Polypoid
in Lynch syndrome (estimated at 35 months compared cancers that protrude into the lumen and are more
with 10–15 years for sporadic cancer). These patients common in the cecum and right colon (Fig. 12.25). In
have an increased risk for a wide variety of extracolonic contrast, ulcerated carcinomas are more common in the
malignancies, most notably endometrial cancer; tran- left colon or rectum and show an edge that is barely dis-
sitional cell carcinoma of the ureter, renal pelvis, and cernable from the adjacent mucosa (Fig. 12.26). These
bladder,; adenocarcinomas of the ovary, stomach, hepa- tumors often involve the entire circumference of the
tobiliary tract, and small bowel; brain cancer (glioblas- bowel wall and result in constriction. Fungating tumors
toma); and cutaneous sebaceous neoplasms. Testing for show a mixture of these two patterns, characteristically
Lynch syndrome is discussed in Chapter 13. seen as a central ulcerated crater with raised edges.
Other inherited syndromes associated with an On cut surface, infiltrating carcinomas are tan-
increased risk of CRC include FAP, MUTYH-associated white in color with indistinct edges, owing to the host
FIGURE 12.25
Gross appearance of an adenocarcinoma arising in the ascending colon
showing an exophytic lesion with raised edges and central area of ulceration.
FIGURE 12.27
Low anterior resection specimen with total mesorectal excision for rectal can-
cer. Total mesorectal excision is a technique used for resecting rectal can-
cers. This procedure entails sharp dissection within the areolar plane outside
(lateral to) the visceral mesorectal fascia to remove the rectum along with
all regional nodes and mesorectal tissue. The image shows anterior and
posterior view of a low anterior resection specimen with intact mesorectal
surface. The peritonealized surface (shiny surface with taenia coli and fat)
is demarcated from the nonperitonealized surface by a white line. The ante-
rior peritoneal reflection is much lower on the anterior side than the poste-
rior peritoneal reflection. The American Joint Committee on Cancer (AJCC)
eighth edition and College of American Pathologists guidelines recommend
assessing the mesorectal surface into three categories: incomplete, nearly
complete, and complete.
typically glistening as a result of the prominent extra-

cellular mucin and may show a gelatinous cut surface.
Total mesorectal excision is a specific surgical tech-
nique used to resect rectal cancers. This technique
entails precise sharp dissection within the areolar plane
outside (lateral to) the visceral mesorectal fascia to
remove the rectum along with all regional nodes (Fig.
FIGURE 12.26
12.27). This procedure prevents development of local
Gross appearance of an ulcerated adenocarcinoma arising in the sigmoid
colon. The edges of the lesion blend with the surrounding mucosa. recurrence and improves the corresponding survival rate
by as much as 20%. Gross evaluation of the complete-
ness of the mesorectum is critical in these specimens
desmoplastic response. Involvement of the muscularis because this finding predicts both local recurrence and
propria usually results in thickening of the bowel wall. distant metastasis. The nonperitonealized surface of the
Invasion through the bowel wall may lead to perforation fresh specimen is examined circumferentially, and the
or foci of puckering on the serosal surface. These foci completeness of the mesorectum is scored as described
should be inked and thoroughly sampled for accurate in Table 12.5. Based on the AJCC eighth edition and
staging. Continued invasion through the bowel wall may CAP guidelines, the mesorectal surface is scored accord-
involve contiguous structures, including loops of small ing to the worst area into three categories: incomplete,
bowel, bladder, or stomach. Mucinous carcinomas are nearly complete, and complete mesorectum. In addition
with glandular fusion, budding, and cribriforming (Fig.

TABLE 12.5 12.28B). Poorly differentiated adenocarcinomas show
minimal gland formation, often seen as sheets of cyto-
Scoring Intactness of Mesorectal Surface in Total
Mesorectal Excision Specimens logically malignant cells (Fig. 12.28C). More than 80%
of colorectal adenocarcinomas are moderately differenti-
Incomplete mesorectum ated and are associated with foci of partial to near com-
• Little bulk to the mesorectum
plete destruction of the glandular walls and intraluminal
• Defects in the mesorectum down to the muscularis propria
• After transverse sectioning, the circumferential margin necrosis, referred to as “dirty necrosis” (Fig. 12.29).
appears very irregular Mucinous (colloid) adenocarcinomas account for
Nearly complete mesorectum 10% of all colon cancers and 30% of rectal cancers and
• Moderate bulk to the mesorectum are characterized by abundant extracellular mucin pools
• Irregularity of the mesorectal surface with defects greater
(by definition >50% of the tumor) (Fig. 12.30). Signet
than 5 mm, but none extending to the muscularis propria
• No areas of visibility of the muscularis propria except at ring carcinomas are composed of diffuse, infiltrative
the insertion site of the levator ani muscles nests, sheets of cells with abundant intracytoplasmic
Complete mesorectum mucin, and eccentrically located hyperchromatic nuclei
• Intact bulky mesorectum with a smooth surface (Fig. 12.31). By definition, more than 50% of the tumor
• Only minor irregularities of the mesorectal surface
should be composed of signet ring cells to be designated
• No surface defects >5 mm in depth
• No coning towards the distal margin of the specimen as a signet ring cell adenocarcinoma. Both mucinous
• After transverse sectioning, the circumferential margin and signet ring cell carcinomas commonly show neo-
appears smooth plastic cells floating within pools of mucin. If the ade-
nocarcinoma does not meet the requisite criteria for
mucinous or signet ring cell adenocarcinoma, the pres-
to the proximal and distal margins of resection, the cir- ence of mucinous or signet ring cell component should
cumferential (radial) margin should be assessed in all be documented in the report because this histologic find-
rectal carcinomas as well as colonic segments with non- ing serves as prognostic and predictive marker of MSI.
peritonealized surfaces. Serrated adenocarcinomas represent 10% to 15% of
The vast majority of rectal cancers are treated with all colorectal adenocarcinomas and are defined by glan-
adjuvant radiation therapy prior to resection, and dular serration reminiscent of serrated polyps and can
depending on the response to therapy, the mucosal be accompanied by mucinous features. Adenoma-like
surface may show very minimal to no definite residual adenocarcinomas (previously known as “villous ade-
tumor. In these cases, any mucosal abnormality that nocarcinoma” or “invasive papillary adenocarcinoma”)
potentially represents the tumor bed (ulcer, hemorrhage, represent fewer than 10% of all CRCs and are character-
tattoo site, puckering, or scarring) should be thoroughly ized by minimal desmoplasia, pushing growth pattern
sampled in addition to the adjacent colonic mucosa to and 50% or less low-grade adenoma-like areas in the
ensure complete histologic assessment of the lesion. invasive component.
■ UNCOMMON VARIANTS OF COLORECTAL
The vast majority of CRCs are adenocarcinomas. The
CARCINOMAS
current edition of AJCC recommends grading adenocar-
cinomas according to the degree of gland formation into
4 grades: Squamous carcinomas and adenosquamous carcino-
Grade 1: well-differentiated adenocarcinomas show- mas of the colorectum are exceedingly rare. A diagnosis
ing greater than 95% gland formation of squamous cell carcinoma (SCC) is typically accom-
Grade 2: moderately differentiated adenocarcinomas plished in the absence of a known primary SCC in any
showing 50% to 95% gland formation other organ, absence of squamous-lined fistula tracts,
Grade 3: poorly differentiated adenocarcinomas and a distinct demarcation of the tumor from the anal
showing less than 50% gland formation squamous epithelium. Chronic inflammation caused by
Grade 4: undifferentiated adenocarcinomas that do ulcerative colitis or chronic infection, chronic schisto-
not show any evidence of glands formation, mucin, squa- somiasis, pelvic radiation, smoking, human immuno-
mous differentiation, or neuroendocrine differentiation deficiency virus, and human papillomavirus are factors
In well-differentiated adenocarcinomas, the tumor associated with SCC. SCCs are associated with a higher
is usually composed of small glands or tubules that mortality rate compared with conventional adenocar-
are lined by cells with cytologic atypia (Fig. 12.28A). cinomas. Adenosquamous carcinoma consists of both
Moderately differentiated adenocarcinomas retain the squamous and glandular components. It is more com-
ability to make glands, but architecturally, they may be monly located in the cecum. Recent reports indicate that
composed of a mixture of simple and complex glands this morphology is associated with MSI-H status.
A B
C
FIGURE 12.28
Colorectal adenocarcinoma. An example of a well-differentiated adenocarcinoma showing glands or tubules lined by atypical cells (A). The vast majority of the
lesion (>95%) showed this morphology. An example of moderately differentiated adenocarcinoma showing architectural complexity with fusion, budding, and
cribriform arrangement of the glands (B). Moderately differentiated adenocarcinoma account for majority of the colorectal adenocarcinoma, and gland forma-
tion is seen in 50% to 95% of the lesion. Poorly differentiated adenocarcinoma (C) showing sheets of atypical cells with abundant eosinophilic cytoplasm,
pleomorphic nuclei, vesicular chromatin, and prominent nucleoli. By definition, there is minimal gland formation in these lesions.

Colonic adenocarcinoma with “dirty necrosis.” The image shows a colonic Mucinous adenocarcinoma. The neoplastic glands produce copious extracel-
adenocarcinoma with characteristic “dirty necrosis” where there is partial to lular mucin that results in glandular rupture and extrusion into the surround-
near complete destruction of the glandular lining and intraluminal eosino- ing stromal tissue. By definition, at least 50% of the tumor should show
philic necrotic debris. mucinous differentiation to be designated as a mucinous adenocarcinoma.

Signet ring cell adenocarcinoma. The image shows a neoplasm composed of Micropapillary carcinoma. This is an uncommon variant of colorectal carci-
diffuse, infiltrative nests and sheets of cells with abundant intracytoplasmic noma with a poor prognosis. The image shows small clusters of tumor cells
mucin and eccentrically located hyperchromatic nuclei. By definition, at least located within clear lacunar spaces lacking true fibrovascular cores. These
50% of the tumor should show signet ring cell differentiation to be desig- spaces can be mistaken for lymphatic channels.
nated as a signet ring cell adenocarcinoma.
Rare cases of carcinosarcoma, spindle cell carcinoma,

adenocarcinoma with areas of choriocarcinoma, hepa-
toid adenocarcinoma, and clear cell carcinoma have
been reported in the colorectum.
Micropapillary carcinoma is an uncommon variant of
colorectal carcinoma that is associated with aggressive
histological features such as lymphovascular invasion,
perineurial invasion, frequent lymph node and distant
metastasis, and higher TNM stages. Histologically, it is
characterized by small clusters of tumor cells located
within clear lacunar spaces lacking true fibrovascular
cores (Fig. 12.32). Given the poor clinical prognosis, the
presence of a micropapillary component (at least 5% of
the tumor) should be mentioned in pathology reports.
Small cell and large cell neuroendocrine carcinomas FIGURE 12.33
are categorized as high-grade neuroendocrine carcino- Colonic adenocarcinoma with microsatellite instability showing tumor het-
mas and are now staged as CRCs instead of neuroendo- erogeneity. This cecal adenocarcinoma showed morphologic heterogeneity
crine tumors (NETs; see section on NETs later). within the same lesion. The upper half of the image shows well-differenti-
ated areas. In addition, there were areas of poorly differentiated (lower left)
and signet ring cell phenotype (lower right). Some cases may show a combi-
nation of mucinous and well-differentiated morphology.
■ MORPHOLOGIC FEATURES ASSOCIATED

WITH MICROSATELLITE INSTABILITY
The individual tumor nests show increased density of
intraepithelial lymphocytes, often referred to as tumor
Regardless of whether adenocarcinomas are sporadic in infiltrating lymphocytes (Fig. 12.34). The advancing
nature or associated with Lynch syndrome, those that edge of the tumor may show a prominent Crohn’s-like
show MSI are frequently right-sided, show a mucinous reaction with lymphoid aggregates (Fig. 12.35). The
phenotype, and are either well-differentiated or poorly molecular work-up of CRC is discussed in Chapter 13.
differentiated. In addition, the presence of signet ring Undifferentiated carcinoma is another rare form of
cells and medullary phenotype is also a common phe- colorectal carcinoma, accounting for fewer than 1% of
notype. Tumors often show intratumoral heteroge- all colorectal neoplasms. They are characterized by the
neity characterized by an admixture of conventional, complete lack of glandular structures or other features
mucinous, and poorly differentiated carcinoma (Fig. (morphologic, immunohistochemical, or molecular) to
12.33). The “dirty necrosis” that is seen in association indicate cellular differentiation. Only occasional are MSI-
with microsatellite stable cancers is frequently absent. H. These cells are fairly round, with regular nuclei and
FIGURE 12.36
Medullary carcinoma. An example of a rare form of colorectal carcinoma
that shows complete lack of glandular structures. The images shows a lesion
FIGURE 12.34 composed of solid sheets of tumor cells with syncytial growth pattern with
Tumor infiltrating lymphocytes in colonic adenocarcinoma with microsatel- a lymphoplasmacytic infiltrate. These cells are round, with vesicular nuclei,
lite instability. An example of an ascending colon adenocarcinoma showing prominent nucleoli, and abundant eosinophilic to amphophilic cytoplasm.
sheets of neoplastic cells admixed with lymphocytes.
pT4a), distinguishing tumor deposits from lymph nodes,

reporting isolated tumor cells (ITCs) and micrometasta-
sis, assessment of tumor stage after neoadjuvant ther-
apy, and tumor budding.
Assessing Serosal Penetration (pT3 vs pT4a)
pT4a classification only pertains to carcinomas that occur

in close proximity to the peritoneal surface. The AJCC
eighth edition defines invasion of the visceral peritoneum
as gross perforation through the tumor; tumor cells at, or
on, the peritoneal surface; or continuous invasion of tumor
through areas of inflammation that extend to the peritoneal
surface. Although it is easy to understand this definition,
FIGURE 12.35 the practical application can be challenging and controver-
Crohn’s-like lymphoid response in colonic adenocarcinoma with microsat- sial because of the fibroinflammatory response that is often
ellite instability (MSI). The image shows tumor heterogeneity with foci of
well-differentiated and mucinous features (upper right). The advancing front present when tumor is close to the serosal surface. Serosal
of the tumor and the bowel wall is characterized by nodular lymphoid aggre- penetration always induces a tissue reaction that may be
gates, a feature that is commonly associated with the MSI high phenotype. in the form of fibrin plaques, fibrinous adhesions, creeping
fat on serosal surface overlying tumor, mesothelial hyper-
abundant eosinophilic cytoplasm, raising the question of plasia, mesothelial cells admixed with inflammation near
a neuroendocrine carcinoma. However, IHC stains for serosa, inflamed septa in subserosal fat at the advancing
neuroendocrine markers are negative. Undifferentiated edge of tumor, or peritumoral abscesses tracking to serosal
carcinomas are composed of solid sheets of tumor cells, surface. Because of these histologic changes, assessing can-
but in contrast to medullary carcinomas (Fig. 12.36), cers that are close to but not at the serosal surface can be
they lack syncytial growth pattern, accompanying problematic (Fig. 12.37). Although some pathologists clas-
lymphoplasmacytic infiltrate, and pushing borders. sify these as pT4a, others stage them as pT3 with a com-
ment indicating that the significance of tumors that are less
than 1 mm from the serosal surface and accompanied by
serosal reaction is unclear, with some but not all studies
■ STAGING COLORECTAL CANCERS
indicating a higher risk of peritoneal recurrence. Multiple
level sections or additional section of the tumor (or both)
Colorectal cancer staging is performed using AJCC should be examined in these cases. If the serosal involve-
staging system. Some of the challenges related to stag- ment is not present after additional evaluation, the tumor
ing include assessment of serosal penetration (pT3 vs should be assigned to the pT3 category.
A B
FIGURE 12.37
Serosal penetration in colon cancer (pT3 and pT4). The image shows transmural involvement of a colonic adenocarcinoma with penetration of the serosal
surface (inked black). This tumor is staged as pT4a (A). In contrast, image B shows neoplastic glands that are very close to the serosal surface (inked green)
and separated by fibroinflammatory debris. This constitutes serosal reaction to tumor. While some pathologists would interpret this as a pT3 cancer (because
the neoplastic glands are not present at the inked serosal surface), others may interpret this as a pT4a cancer. In tumors that reach close to but are not at the
serosal surface, a comment indicating that the significance of tumors that are less than 1 mm from the serosal surface and accompanied by serosal reaction is
unclear, with some but not all studies indicating a higher risk of peritoneal recurrence, is helpful.
is surrounded by lymphocytes or lymphoid follicles. A

capsule or subcapsular sinus is usually present.
Tumor deposits are associated with poor prognosis
among patients with CRC even in the presence of numer-
ous lymph node metastases. When they are noted in asso-
ciation with positive lymph nodes, they should be reported
as a separate count in the synoptic summary and should
not be counted as lymph nodes. In the absence of regional
lymph node metastasis, they are categorized as pN1c.
Isolated Tumor Cells and Micrometastasis
The clinical outcome, especially in patients with stage II

cancers, is directly linked to lymph node harvest. Although
FIGURE 12.38
12 lymph nodes is the minimum number of lymph nodes
Tumor deposit. A discrete tumor nodules within the pericolonic adipose tis-
sue without any identifiable lymph node tissue or vascular or neural struc- required for staging untreated carcinomas, all possible
ture. There is no distinct capsule or lymphoid cuff around this nodule. lymph nodes should be retrieved and examined.
In some cases, lymph nodes harbor individual tumor
cells in the subcapsular or marginal sinus. These repre-
Tumor Deposits
sent ITCs, the definition of which remains controversial.
In some studies, clumps of up to 20 tumor cells are clas-
The AJCC eighth edition defines tumor deposits as dis- sified as ITCs. The most widely used definition includes
crete tumor nodules within the lymphatic drainage area presence of tumor cell clusters that are less than 0.2 mm
of the primary carcinoma without identifiable lymph in greatest dimension (Fig. 12.40). They are designated
node tissue or identifiable vascular structure or neu- as “N0i+.” Although one prospective trial showed that
ral structure (Fig. 12.38). It is important to distinguish pN0i- patients are less likely to show disease recurrence
them from foci of venous invasion or perineurial inva- compared with pN0i+ patients, its clinical significance
sion. A Movat or elastic stain is very helpful to highlight remains unclear. These lymph nodes are staged as N0
vascular structures (Fig. 12.39). Tumor deposits tend with a note indicating the presence of ITCs. In cases in
to be irregular in contour and may have a thin rim of which there are other positive lymph nodes, there are
lymphocytes around the periphery. They do not show no guidelines on how to report these cases. In our prac-
organized lymphoid tissue or a distinct capsule. An tice, we categorize them as positive lymph nodes. The
effaced lymph node usually retains its round shape and ITC designation does not apply to treated CRCs. In a
A B
FIGURE 12.39
Venous invasion. An example of extramural venous invasion mimicking tumor deposit (A). This rounded aggregate of tumor nodule is present adjacent to an
artery (“orphan artery” sign). A corresponding Movat stain (B) highlights the internal elastic lamina and media of the vein (left) and artery (right).
FIGURE 12.41
Treated rectal cancer with therapy effect. This image shows a full-thickness
section of a tumor bed obtained from treated rectal cancer specimen. The
FIGURE 12.40 entire wall shows pools of acellular mucin surrounded by fibrosis. Because
Lymph node with isolated tumor cells. This lymph nodes shows small clus- no viable tumor cells are present in this section, the depth of acellular mucin
ters of tumor cells that measure less than 0.2 mm in greatest. Isolated tumor or fibrosis does not contribute to the final stage of cancer. Similarly, acellular
cells are designated as pN0i+, and the final nodal stage (in the absence of mucin in lymph nodes from treated cancers are considered as negative.
any other positive lymph nodes) is pN0.
of dystrophic calcification (Fig. 12.41). Assessment of

posttreatment setting, a lymph node is considered posi- pT and pN stage is based on the extent of viable tumor.
tive regardless of the size of the tumor cells. Acellular mucin or fibrosis does not change the stage
Micrometastasis are defined as clumps of tumor of cancer. Similarly, lymph nodes with acellular mucin
measuring 0.2 mm or greater in diameter. Their pres- are considered as negative. The pathology report should
ence indicates replication of tumor cells rather than include the extent of tumor regression because exten-
mere presence of isolated dormant tumor cells. Because sive therapeutic response with minimal residual tumor
micrometastases are a significant poor prognostic factor, has been associated with a favorable clinical prognosis.
they are best considered as positive nodes. Although there are numerous scoring systems, the AJCC
and CAP recommend using the modified Ryan system
(Table 12.6) for scoring the primary tumor.
Assessing Tumor Stage Following Neoadjuvant
Therapy Tumor Budding
Several studies have shown that tumor budding is a sig-

Following therapy for rectal cancer, the tumor shows nificant risk factor for nodal involvement in patients
therapy-related changes that include tumor regres- with malignant polyps and indicates an adverse progno-
sion with fibrosis, pools of acellular mucin, and foci sis in patients with stage II cancers. A recent ITBCC in
TABLE 12.6
Modified Ryan Scheme for Tumor Regression
Score in Treated Rectal Cancers
Tumor
Regression
Category Description Score
Complete No viable cancer cells 0

response
Near complete Single cells or rare small 1
response groups of cancers cells
Partial Residual cancer with evident 2
response tumor response but more
than single cells or rare
small groups of cancer cells
Poor or no Extensive residual cancer with 3
response no evident tumor regression FIGURE 12.42
Tumor budding. The image shows advancing edge of colonic adenocarci-
noma with tumor buds composed of single cells as well as small clusters of
less than five cells (arrows). Tumor buds count is performed on hematoxylin
and eosin–stained sections and scored using recommendations from 2016
international Tumor Budding Consensus Conference.
TABLE 12.7
Conversion Table for Scoring Tumor Budding
In tumors that show prominent inflammation at their
Eyepiece Diameter Specimen Area Normalization
advancing edge, IHC for keratin can be obtained to iden-
(mm) (mm 2) Factor
tify tumor buds, but the scoring should be done on H&E
18 0.636 0.810 sections. Tumor budding counts should not be reported
19 0.709 0.903 in cases of treated rectal adenocarcinoma, mucinous or
20 0.785 1.000
signet ring cell adenocarcinomas, medullary carcinoma,
21 0.866 1.103
22 0.950 1.210 micropapillary carcinoma, or tumors that show glandu-
23 1.039 1.323 lar fragmentation secondary to inflammation.
24 1.131 1.440
25 1.227 1.563
26 1.327 1.690 Colorectal Adenocarcinoma—Pathologic Features
Gross Findings
n Polypoid, fungating, or ulcerated appearance
2016 defined tumor budding as presence of single cells n Larger tumors more common in proximal colon
or small clusters of fewer than five cells at the advancing n Circumferential growth (apple-core lesions) more common in left
front of the tumor. They recommended the following colon
criteria for evaluating tumor budding:
n Adenocarcinomas are graded as well-differentiated, moderately
1. Tumor budding counts should be done on hematoxy-
differentiated, poorly differentiated, or undifferentiated
lin and eosin (H&E) sections.
n Abundant eosinophilic necrotic debris within gland lumens (“dirty
2. Tumor budding should be reported by selecting a necrosis”)
“hotspot” chosen after review of all available slides n Mucinous carcinomas associated with extracellular mucin
with invasive tumor. The total number of buds production and mucin pools comprising greater than 50% of tumor
n Other variants: signet ring cell adenocarcinoma, medullary,
should be reported in an area measuring 0.785 mm2,
serrated, adenoma-like, carcinomas with sarcomatoid
which corresponds to 20× field in some microscopes
components, squamous, adenosquamous, micropapillary,
(use appropriate conversion for other microscopes; undifferentiated
see Table 12.7) n Morphologic subtypes associated with an microsatellite instability
3. Both the total number of buds and a three-tier score high phenotype: mucinous, signet ring cell, medullary, tumors
(based on 0.785 mm2 field area) should be reported: with morphologic heterogeneity (e.g., admixture of conventional,
mucinous as well as poorly differentiated carcinoma)
low (0–4 buds), intermediate (5–9 buds) and high
(≥10 buds) (Fig. 12.42). Although this is not a Genetics
required element in CAP cancer staging template, n Sporadic carcinomas associated with APC, KRAS, and TP53
it is recommended that this feature be reported for alterations
cancers arising in polyps as well as for stage I and II n 3% of carcinomas caused by Lynch syndrome
cancers.
also indicate the primary tumor of origin, whereas the

Immunohistochemistry vast majority of the colorectal carcinomas are positive
n Strong cytokeratin (AE1/AE3, CK20, and CAM5.2) positivity in
for CK20, CDX-2, and SATB2.
sporadic carcinomas; variably positive for CK7
n Variable CK20 and CDX-2 positivity in MSI-high carcinomas
Involvement of the colorectum by endometriosis is
n SATB2 positive common among women of childbearing age (≤20% of
patients with endometriosis). Endometriomas involving
Differential Diagnosis the colon form ill-defined masses involving the subse-
n Metastatic carcinomas rosal tissue and muscularis propria, although polypoid
n Endometriosis and carcinomas arising in endometriosis
lesions have also been reported. Sigmoid colon and rec-
tosigmoid region are the most common location within
the GI tract. Histologic examination reveals the presence
of normal mucosa overlying endometrial glands and
Ancillary Studies
stroma, which should be differentiated from adenocarci-
noma glands with desmoplasia (Fig. 12.43).
Immunohistochemically, colorectal adenocarcinomas are
virtually always positive for broad-spectrum and low-
molecular-weight cytokeratins (AE1/AE3, CAM5.2),
EMA, and carcinoembryonic antigen (CEA). They are
consistently positive for cytokeratin (CK) 20 and variably
positive for CK7. CDX-2 and SATB2 are usually expressed Pathologists play a major role in the management of col-
by more than 90% of CRCs. In tumors that show MSI, orectal carcinoma by proper staging, which provides the
there may be variable loss of both CK20 and CDX-2. clinician with critical information regarding prognosis
and choice of adjuvant therapy. In addition to the TNM
stage, features that should be addressed in pathology
reports include histologic type and grade, presence or
absence of lymphovascular invasion, perineurial inva-
sion, tumor deposits, and resection margins. Adjuvant
A variety of metastatic neoplasms may involve the therapy significantly improves survival of patients with
colorectum, including prostate, breast, stomach, and stage III colon cancer, particularly adjuvant 5-fluoroura-
ovarian cancers and melanoma. The lack of associated cil (5-FU) and levamisole. However, adjuvant therapy
adenomatous epithelium combined with the gross find- can also be considered for patients with high-risk stage
ings and the growth pattern of the tumor (centered on II disease, defined as those with poor prognostic fea-
the external or serosal aspect of the bowel wall) supports tures, including T4 tumors (stage IIB/IIC); poorly dif-
a metastatic lesion. Immunohistochemical stains for ferentiated histology (exclusive of those cancers that are
appropriate markers (prostatic-specific acid phospha- MSI-H); lymphovascular invasion; perineurial invasion;
tase [PSAP], NKX3.1 for prostate; CK7, GATA-3, estro- bowel obstruction; lesions with localized perforation or
gen receptor for breast; CK7, WT-1, or PAX8 for ovary; close, indeterminate, or positive margins; and cases with
CK7 for stomach; S-100 or SOX-10 for melanoma) may inadequately sampled lymph nodes (<12 lymph nodes).
A B
FIGURE 12.43
Colonic endometriosis. A section from thickened sigmoid colon wall showing numerous, variably sized cystically dilated glands surrounded by stromal cells (A).
The angulated glandular profiles and mural thickening mimic colon cancer clinically and histologically. Higher magnification shows that the glands demonstrate
endometrial phenotype with low columnar cells and are surrounded by endometrial stroma with spiral arterioles, diagnostic of endometriosis (B).
Radiation therapy may be used to treat rectal cancers

preoperatively or postoperatively or to treat recurrent NEUROENDOCRINE NEOPLASMS—FACT SHEET
disease. Reductions in local recurrence and death have
also been shown for stage II and III rectal cancers using Definition
a combination of 5-FU and radiation therapy. n Neoplasms of the diffuse neuroendocrine system of the
In addition to TNM stage, MSI provides additional gastrointestinal tract

information when deciding about adjuvant chemother-
apy in patients with stage II cancers. Studies have shown
n Colorectal neuroendocrine tumors (NETs) represent 10% of all
that MSI-H tumors show a favorable outcome among NETs
patients with stage II cancers. The favorable impact does
not seem apply to stage III cancers and may vary with Morbidity And Mortality
tumor location. MSI-H status also appears to be pre- n Overall survival rate is 42% to 72%
dictor of poor response to 5-FU–based therapy in stage n One-third of patients have regional nodal or distant metastases at
II but not stage III cancers. Furthermore, it has been diagnosis

recently shown that MMR deficient tumors may be sen-
sitive to programmed death-ligand 1 (PD-L1) inhibitors
n Female more than males
in patients with metastatic disease. Therefore, univer- n Slight predominance in African American population
sal testing of MMR or MSI is recommended to identify n Average age at diagnosis in sixth to seventh decades of life
individuals with Lynch syndrome, predict response to

immune therapy, and select therapy for stage II cancers. Clinical Features
Additional details on molecular testing and rationale for n Usually asymptomatic
n Symptoms such as obstruction, weight loss, and anorexia related

therapy are detailed in Chapter 13.
to large bulky lesions
n Fecal occult blood test is usually negative because these are
submucosal lesions
■ NEUROENDOCRINE NEOPLASMS
n Surgical resection effective for small lesions
Clinical Features n Rectal NETs should be staged by endoscopic ultrasonography or
magnetic resonance imaging

n Rectal neoplasms larger than 2 cm or with muscularis propria
invasion are treated surgically with low anterior resection or

Neuroendocrine neoplasms can arise anywhere through- abdominoperineal resection
out the colorectum. They constitute a range of clinico- n Neuroendocrine carcinomas
pathologic entities ranging from well-differentiated NETs n Aggressive clinical behavior; 85% show metastasis at
presentation
(“carcinoid tumors”) to aggressive neuroendocrine car-
n Treated with platinum-based chemotherapy with or without
cinomas. Because neuroendocrine neoplasms arise from radiation therapy
cells of the diffuse neuroendocrine system, they are related
to medullary carcinoma of the thyroid, pheochromocy-
toma, and pancreatic NETs. They occur in 9% of patients
with multiple endocrine neoplasia syndrome type 1. Pathologic Features
Well-differentiated NETs of the GI tract account for
up to 95% of all NETs. Within the GI tract, well-differ- Gross Findings
entiated NETs comprise 20% of all GI neoplasms and
6% of colorectal neoplasms. The incidence is estimated Of the neuroendocrine neoplasms that occur in the
to be up to 8 per 100,000 individuals. The average age at large intestine, the most commonly affected site is the
diagnosis is in the sixth to seventh decade of life. They rectum followed by the cecum. This distribution paral-
are more common in women than men and are more lels the distribution and density of endocrine cells in the
common in African Americans than other races. large intestine. They usually occur singly, although in a
At least half of all NETs are discovered as an inci- minority of patients multiple tumors may occur, partic-
dental finding. The clinical presentation depends on the ularly within the rectum. Grossly, they present as a sub-
location of the tumor. Clinical symptoms associated with mucosal lesions with normal overlying mucosa. Their
colonic NETs are usually vague (weight loss, abdominal size can range from small nodules measuring 2 to 3 mm
pain) or related to the mass effect from bulky aggressive in diameter to large lesions in excess of 5 cm. Larger
lesions. Symptoms related to rectal neoplasms include tumors are more commonly encountered in the proxi-
pain, rectal bleeding, and diarrhea, usually resulting mal colon. On cut surface, they are yellow to tan-white
from mechanical trauma associated with a polypoid in color with a homogeneous cut surface. Large lesions
lesion. Carcinoid syndrome is uncommon even in the (especially neuroendocrine carcinomas) often show ero-
presence of liver metastases. sion and ulceration of the overlying mucosa.
Microscopic Findings Well-differentiated NET (G1): mitotic rate less than

2 per 2 mm2 and/or Ki-67 index less than 3%
The morphologic features of large intestinal neuroendo- Well-differentiated NET (G2): mitotic rate 2 to 20
crine neoplasms are similar to those arising in other loca- per mm2 and/or Ki-67 index 3% to 20%
tions. Well-differentiated NETs are composed of round Well-differentiated NET (G3): mitotic rate greater
or polygonal cells with uniform, round to oval nuclei, than 20 per 2 mm2 and/or Ki-67 index less than 20%
amphophilic or eosinophilic granular cytoplasm, and a Poorly differentiated neuroendocrine carcinomas
speckled chromatin pattern (“salt and pepper” nuclei). (large cell and small cell type) are now staged as col-
Necrosis is absent. The tumor may show a variety of orectal carcinomas (Fig. 12.45). Mixed neuroendo-
growth patterns, including a solid (Fig. 12.44A), nested, crine–non-neuroendocrine neoplasms (MiNENs,
trabecular, ribbonlike (Fig. 12.44B), or acinar pattern. previously known as mixed adenoneuroendocrine
Similar to rest of the NET in the GI tract, the CAP carcinoma [MANEC]) comprise a neuroendocrine
and AJCC eighth edition recommend the following grad- component (≥30%) and a non-neuroendocrine com-
ing system for well-differentiated NETs: ponent (≥30%).
A B
FIGURE 12.44
Well-differentiated neuroendocrine tumor. Well-differentiated neuroendocrine neoplasm with solid growth pattern (A). The tumor is composed of small uniform
cells with abundant eosinophilic cytoplasm, centrally located round nuclei with finely dispersed chromatin. Delicate vessels are present within the tumor. These
lesions may show a variety of growth patterns. An example of ribbonlike or trabecular pattern is shown in B.
A B
FIGURE 12.45
High-grade neuroendocrine carcinoma, large cell type. In this example, the tumor cells are arranged in solid sheets and show vesicular chromatin, prominent
nucleoli, and marked atypia and pleomorphism (A). Mitoses and apoptotic debris are abundant. Immunohistochemical stain chromogranin shows diffuse cyto-
plasmic immunoreactivity, confirming the neuroendocrine origin (B).
adenocarcinoma. Immunohistochemical staining for

Neuroendocrine Neoplasms—Pathologic Features prostate-specific antigen (PSA), NKX 3.1, and PSAP can
be helpful, although 80% of rectal carcinoids express
Gross Findings PSAP. Furthermore, rectal NET may lack chromogranin
n (Well-differentiated) neuroendocrine tumor (NET) expression. Therefore, performing two neuroendocrine
n Submucosal mass with yellow-tan cut surface
markers is helpful for rectal NETs. The uniform appear-
n Most commonly found in right colon or rectum
n (Poorly differentiated) neuroendocrine carcinoma (NEC)

ance of the neuroendocrine cells can mimic a lymphoid
n Ulcerated mass-forming lesions neoplasm, whereas the solid growth pattern can be sug-
gestive of a poorly differentiated carcinoma. In all cases,
Microscopic Findings performing neuroendocrine markers is very helpful in
n (Well-differentiated) NET this differential diagnosis.
n Uniform small round to oval cells with rare mitotic figures
n Fine, speckled chromatin pattern and granular eosinophilic to
amphophilic cytoplasm
n Solid, ribbonlike, trabecular or nested growth patterns
n (Poorly differentiated) NEC
n Small cell or large cell NEC
n Sheets, nests, or trabecular growth

Rectal NETs typically tend to be small and of lower grade
n High mitotic activity
than colonic NETs, which often present as masses and
Immunohistochemistry are associated with poor prognosis. For small (<1 cm)
n Positive for synaptophysin, CD56 and variably positive for
incidental lesions, complete endoscopic resection is
chromogranin usually considered sufficient. Rectal NETs should be
n Rectal lesions frequently positive for prostatic-specific acid staged with endoscopic ultrasonography or magnetic
phosphatase (>80%) and lack chromogranin expression resonance imaging. Rectal tumors that are larger than
n Grading is performed based on mitotic activity (per 10 hpf) and
2 cm or those the demonstrate invasion of muscularis
Ki-67 index (per College of American Pathologists and American
Joint Committee on Cancer (AJCC) eighth edition) propria are treated with low anterior resection, or in
n NET rare cases, abdominoperineal resection. Although fac-
n Grade 1 (well-differentiated NET): <2 mitoses/10 hpf and/ tors that would predict lymph node and distant metasta-
or <3% Ki-67 index sis are evolving, it appears that tumor size and depth are
n Grade 2 (well-differentiated NET): 2–20 mitoses/10 hpf
the strongest predictors of clinical behavior.
and/or 3–20% Ki-67 index
n Grade G3 (well-differentiated NET): >20 mitoses/10 hpf
Neuroendocrine carcinomas have an aggressive
and/or >20% Ki-67 index clinical behavior. Approximately 85% of tumors have
n NEC metastasis at the time of diagnosis. For localized disease,
n G3: >20 mitoses/10 hpf and/or >20% Ki-67 index curative surgery is usually followed by platinum-based
therapy with or without radiotherapy. Systemic chemo-
therapy is indicated for patients with advanced inoper-
n Poorly differentiated colorectal carcinoma
n Lymphoid neoplasms (particularly in small biopsy specimens)

able disease.
n Metastatic carcinomas
n Prostatic adenocarcinoma (especially in rectum)

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13
Molecular Testing of Gastrointestinal
Neoplasms
■ Daniela S. Allende, MD, MBA and Amitabh Srivastava, MD
■ MOLECULAR TESTING OF COLORECTAL Prevention, and the US Multi-Society Task Force have, in
CARCINOMA an evidence-based manner, supported tissue-based screen-
ing methods (MSI testing by PCR or IHC for MMR protein
expression) on a universal or near-universal basis.
Although there are numerous esoteric tests that a molec- Microsatellites are short, repetitive sequences of DNA,
ular pathology laboratory may use on colorectal cancer usually in noncoding regions of the genome, that are prone
(CRC) specimens, there are two tests that are the most to mismatch errors during the process of DNA replication.
common and important—assessment of mismatch repair A normally functioning MMR complex fixes these mis-
(MMR) integrity and RAS/RAF mutational analysis matches before they integrate into the genome. However,
(Tables 13.1 and 13.2). Assessment of MMR status serves upon silencing of the MMR genes, usually through muta-
two main functions. First, MMR testing is used to screen tion or promoter methylation, these mismatches are not
for Lynch syndrome. Second, it is used to aid oncologists in repaired and may perpetuate as mutations through DNA
predicting response to certain chemotherapy drugs. MMR replication. In cells with high turnover, such as the gut
testing is accomplished in two complementary ways— epithelium, serial oncogenic mutations may occur, lead-
microsatellite instability (MSI) testing by polymerase ing to neoplasia (i.e., the “mutator phenotype”).
chain reaction (PCR) and immunohistochemistry (IHC)
to assess protein expression of the key proteins involved
in the MMR complex (MLH1, PMS2, MSH2, and MSH6).
Polymerase Chain Reaction–Based Microsatellite
RAS/RAF mutational analysis is mainly used to help pre-
Instability Testing
dict responsiveness to monoclonal anti–epidermal growth
factor receptor (anti-EGFR) therapies (cetuximab and
panitumumab) in the presence of distant metastases. Microsatellite instability testing uses surrogate loci to iden-
tify the mutator phenotype, or high-frequency MSI (MSI-
H), in a highly sensitive manner. An unstable locus is
defined as one in which the tumor DNA contains a new, or
■ ASSESSMENT OF MISMATCH REPAIR
mutant, allele compared with the host germline DNA. MSI
FUNCTION
testing is accomplished by performing the MSI assay on
normal tissue and a relatively pure sample of tumor DNA
Lynch syndrome is the most common heritable CRC syn- (generally from formalin-fixed, paraffin-embedded tissue
drome, accounting for 3% to 4% of colorectal carcinomas. with ideally >50% tumor cellularity) and comparing the
In addition, patients with Lynch syndrome are at risk for an electropherograms of allele sizes (Fig. 13.1). The original
ever-expanding list of extracolonic malignancies, including “official” panel of microsatellites, known as the National
endometrial, ovarian, urothelial, sebaceous, and upper gas- Cancer Institute, or Bethesda, panel, recommended three
trointestinal (GI), among others. So far, deleterious muta- dinucleotide repeats (D2S123, D5S346, and D17S250) and
tions have been identified in MLH1, PMS2, MSH2, and two mononucleotide repeats (BAT25 and BAT26); how-
MSH6 as well as deletion in EPCAM, which is upstream of ever, dinucleotide (e.g., CACACACACA…) repeats lead to a
MSH2. Rarely, Lynch syndrome is secondary to germline 5% to 10% rate of low-frequency MSI (MSI-L). MSI-L has
MLH1 hypermethylation. All mutations are inherited in been studied extensively, and currently, MSI-L CRCs have
an autosomal dominant manner, and MLH1 and MSH2 no different risk of Lynch syndrome and no different che-
mutations make up the vast majority of Lynch syndrome motherapy implications than microsatellite stable (MSS)
mutations. Consensus guidelines from organizations such tumors. A panel of mononucleotide repeats (e.g., poly-A)
as the National Comprehensive Cancer Network (NCCN), is preferred by most laboratories because it has virtually
Evaluation of Genomic Applications in Practice and eliminated MSI-L phenotype and is likely more sensitive
395
TABLE 13.1
Mismatch Repair Function Terminology and Definitions
Mismatch Repair Function Definition
MSI Microsatellites are short, repetitive sequence of DNA, and MSI testing is typically reported as
MSS, MSI-L, or MSI-H. Arbitrarily, MSI-H is defined as ≥30% of microsatellites tested showing
instability, which is defined as generation of a new allele compared with normal.
MMR IHC MMR IHC. Antibodies targeted at MLH1, MSH2, PMS2, and MSH6 are commercially available.
Biologically, PMS2 expression requires intact MLH1 such that loss of PMS2 expression indicates
either loss of PMS2 or, much more commonly, loss of MLH1. The same holds true for MSH6
expression depending on intact MSH2.
MLH1 promoter The cause of the vast majority of sporadic (non-Lynch) MSI-H carcinomas. The MLH1 gene is
hypermethylation silenced by epigenetic methylation. Used as a test to exclude Lynch syndrome in patients with
MSI-H MLH1 loss carcinoma; however, up to 5% of Lynch-associated colorectal cancers may
harbor MLH1 promoter hypermethylation.
BRAF V600E Almost never mutated in Lynch syndrome–associated carcinomas and mutated in ≤75% of
sporadic MLH1 loss MSI-H carcinomas. Therefore, finding BRAF mutation in MSI-H MLH1 loss
carcinoma essentially excludes Lynch syndrome.
Lynch syndrome Deleterious germline mutation in MMR genes MLH1, MSH2, MSH6, PMS2, or EPCAM. Rare cases
of germline MLH1 promoter hypermethylation also exist. Patients are most commonly affected by
CRC and endometrial carcinoma (if female), but a minority also may have sebaceous (e.g., Muir-
Torre), ovarian, upper, biliary, CNS, and genitourinary or urothelial neoplasia.
HNPCC HNPCC is a clinical term for patients who fulfill Amsterdam criteria but germline mutation in Lynch
syndrome gene is not detected.
Lynch-like syndrome MMR-deficient tumors in which patients lack features of sporadic cancer (MLH1 promoter
hypermethylation or BRAF V600E mutation) and there is no demonstrable germline MMR
mutation.
Familial colorectal cancer, Patients fulfill Amsterdam criteria, but carcinomas are MMR proficient.
type X
CNS, Central nervous system; CRC, colorectal cancer; GI, gastrointestinal; HNPCC, hereditary nonpolyposis colorectal carcinoma; IHC, immunohistochemistry;
MMR, mismatch repair; MSI, microsatellite instability; MSI-H, high-frequency microsatellite instability; MSI-L, low-frequency microsatellite instability.
hypermethylation, or tumor-acquired somatic muta-

tions in an MMR gene. Most commonly, an MSI-H
TABLE 13.2
carcinoma occurs because of epigenetic silencing of
Mismatch Repair Immunohistochemistry MLH1 promoter. MLH1 promoter hypermethylation is
Interpretation
associated with the CpG island methylator phenotype
Protein Loss Interpretation (CIMP), the serrated pathway of colorectal carcinogen-
esis, and BRAF V600E mutations (∼75% of cases), not
MLH1 MLH1 loss; probably sporadic methylation;
less likely germline mutation or somatic
Lynch syndrome. Therefore, assessment of MLH1 pro-
inactivation/mutation moter hypermethylation and/or BRAF mutation status
PMS2 PMS2 or MLH1 loss; rule out MLH1 (even is invaluable in helping determine whether a carcinoma
when isolated PMS2 loss) with loss of MLH1 protein is sporadic or not. One must
MSH2 MSH2 loss; rule out germline MSH2 mutation be aware, however, that MLH1 promoter hypermethyla-
or somatic inactivation or mutation
MSH6 MSH6 or MSH2 loss; rule out MSH2 (even
tion can occur in Lynch syndrome as the “second hit” of
when isolated MSH6) or germline/somatic MMR gene silencing, more rarely, in the setting of ger-
MSH6 mutation mline MLH1 methylation. BRAF V600E mutations are
also reported in Lynch syndrome cancers but are about
1/10 as frequently as MLH1 methylation. Thus, BRAF
for detecting MSI-H, particularly those caused by MSH6 V600E mutations are more specific for sporadic carci-
mutations. nomas with MLH1 loss but less sensitive than MLH1
promoter hypermethylation. Last, up to 50% of non-
hypermethylated MSI-H carcinomas harbor tumor-ac-
quired, rather than germline, MMR mutations. These
Microsatellite Instability High Carcinoma:
“Lynch-like” or “tumor Lynch” carcinomas are difficult
Sporadic versus Lynch Syndrome
to identify. As few centers are testing tumors for somatic
mutations in the MMR genes, Lynch-like carcinomas
Microsatellite instability high almost always occurs as are usually a diagnosis of exclusion when no germline
a result of one of three processes—Lynch syndrome mutation is identified. However, a percentage of germ-
(and constitutional MMR deficiency), MLH1 promoter line mutations are not detected with current methods.
CHAPTER 13 Molecular Testing of Gastrointestinal Neoplasms 397
FIGURE 13.1
Electropherogram of a patient’s three unstable alleles. An unstable allele is most readily recognized when comparing carcinoma microsatellite loci (bottom)
with normal or non-neoplastic loci (top). Mononucleotide microsatellites are characterized by groups of peaks, or stutter peaks, in which the tallest peak is
assumed to be the patient’s true allele size.
Therefore, these “Lynch-like” cases are almost certainly be followed by IHC to determine the defected protein
a mixture of undetected Lynch syndrome cancers and and help guide further testing.
sporadic tumor-acquired mutations. The MMR stains may be difficult to interpret. Several
studies have catalogued the relatively high observer vari-
ability in interpreting the DNA MMR immunostains.
These studies usually conclude that some amount of
Mismatch Repair Immunohistochemistry
experience is required to accurately interpret these stains
or that all abnormal stains should be followed up by con-
Most laboratories choose to screen for Lynch syn- firmatory MSI testing. In a perfect world, these IHC stains
drome via IHC, mainly for logistical reasons: most are “all or none,” with no shades of gray, but the interpre-
have IHC capabilities, and most do not have PCR tation may be challenging in some cases. Some pearls to
capabilities. Clinically, the tests are essentially equiva- prevent misinterpreting DNA MMR IHC are as follows:
lent such that an MSI-H by PCR is analogous to MMR
protein loss of expression by IHC. In reality, the tests 1. Gain experience and some background knowledge of
are complementary, and laboratories are best served the stains. Experience clearly plays a role in interpret-
when they can perform both assays because each has ing these stains such that “experts” are more reliable
its strengths and weaknesses. In short, we prefer IHC than those without experience. These are nuclear
when tissue is limited (e.g., biopsies, neoadjuvant stains; no other cytologic location of immunoreactiv-
therapy) and when rapid turnaround time is neces- ity counts as positive (Figs. 13.2 and 13.3). Biopsies
sary. The immunostains are nuclear and essentially are easier to interpret than resection material, proba-
always have a built-in internal positive control. We bly because of more consistent formalin fixation.
prefer MSI testing on large, relatively pure samples 2. Understanding the protein pairings is quite helpful
of carcinoma (e.g., resections) because of its slightly because the finding of one IHC stain may help confirm
better overall sensitivity and, counterintuitively, it is the result in its respective binding partner (Table 13.3).
easier interpretation (see later). MSI-H results should MMR proteins function as heterodimers. PMS2 requires
TABLE 13.3
Colorectal Cancer Biomarkers and Therapeutic
Implications
Actionable Frequency
Result (%) Implication
MMR MSI-H or 15–20 Lack of benefit

status loss of IHC with 5-FU–
expression based chemo-
therapy
Benefit from
PD-1 blockade
KRAS/ Activating 50–60 Lack of benefit
FIGURE 13.2 NRAS mutations from anti-
MLH1 immunostain that is positive in carcinoma and non-neoplastic nuclei. in exon 2 EGFR antibody
(codons 12 therapy
and 13), exon
3 (codons
59 and 61),
and exon 4
(codons 117
and 146)
BRAF V600E 8–10 Lack of benefit
mutation from anti-
EGFR antibody
therapy
CDX2 Loss of IHC <5 Benefit from
expression conventional
chemotherapy
EGFR, epidermal growth factor receptor; 5-FU, 5-Fluorouracil; IHC,
immunohistochemistry; MSI-H, high-frequency microsatellite instability; PD-1,
programmed death 1.
FIGURE 13.3 5. The stains may be patchy, especially MSH6 and after
MSH2 immunostain that is lost in carcinoma nuclei but retained in tumor radiation therapy (Fig. 13.5). Remember, the vast
infiltrating lymphocytes as well as background non-neoplastic stromal cells. majority of true loss of expression occurs in every
tumor cell.
6. Do not interpret IHC stains as “positive” or “nega-
binding by MLH1 for its stability within the nucleus, tive” because these terms can lead to confusion or
and MSH6 requires MSH2 as its binding partner such misinterpretation. “Intact” expression and “loss” of
that loss of MLH1 shows concomitant loss of PMS2, expression are more clear and accurate terms.
and loss of MSH2 shows loss of MSH6. However, “iso- 7. Lynch syndrome–associated carcinomas, rarely, if
lated” loss of PMS2 and MSH6 are valid results. Thus, ever, arise from sessile serrated polyps/adenomas;
intact IHC results for PMS2 and MSH6 alone confirm therefore, testing of these lesions is extremely low
that all four MMR proteins are intact in nearly all cases yield when screening for Lynch syndrome.
while reducing testing costs. We often screen with
only these two IHC stains on small biopsies when MSI Much rarer than Lynch syndrome is so-called consti-
results would be of uncertain reliability. tutional MMR deficiency in which an individual inherits
3. Do not interpret the staining in tumor cells without adja- two mutations in an MMR gene rather than one muta-
cent positive internal control results. False interpretation tion in conventional Lynch syndrome. These patients
of lost protein expression may occur if one examines are characterized by early-onset malignancies, including
areas without positive internal controls (e.g., stromal hematologic and central nervous system tumors as well
cells, lymphocytes, endothelial cells. A rare exception is as Lynch syndrome–associated neoplasms. Because both
constitutional MMR deficiency (discussed later). alleles of a particular MMR gene are affected, immunos-
4. Beware of overly aggressive antigen retrieval. tains for the particular gene product protein are likely
Overstained slides may give the impression of falsely to be lost in both the neoplasm and the background
retained protein expression. In our hands and oth- non-neoplastic tissue, and one always should consider
ers’, this often manifests as cytoplasmic staining with constitutional MMR deficiency before deciding that the
a perinuclear “rim” of staining (Fig. 13.4). immunostain was technically unsatisfactory (Fig. 13.6).
FIGURE 13.6
PMS2 immunostain that was originally interpreted as technically unsatisfac-
tory because internal control tissue failed to stain. However, the patient had
biallelic PMS2 mutation such that internal control also did not express the
protein product.
FIGURE 13.4
MLH1 immunostain with artifactual nuclear membrane staining in a cancer
with MLH1 promoter hypermethylation. Intact protein expression is most reli-
ably determined when diffuse nuclear staining is identified. therapies, nearly half of whom had Lynch syndrome. Of
these 86 patients, 46 (53%) had an objective response
to pembrolizumab, including 18 (21%) with a complete
response. These results, published in Science, led to the
Food and Drug Administration (FDA) approval of pem-
brolizumab for MMR-deficient solid tumors (not just col-
orectal carcinoma) in May 2017. Type of testing—MSI
versus IHC—is not specified by the FDA; therefore, the
two methods should be viewed as equivalent, and prin-
ciples in test selection and interpretation outlined in the
preceding paragraphs still apply. Given that about 5% of
solid tumors are MMR deficient, MMR testing is expected
to play an expanded role in cancer care in the future. Last,
FIGURE 13.5 preliminary data have shown that stage II CDX2-negative
MSH6 immunostain is notoriously patchy, particularly after chemoradio- (by IHC) CRCs, although quite uncommon at about 5%
therapy. If there is even focal staining, as in this case, the mismatch repair of cases, may be another group of stage II carcinomas that
expression should not be interpreted as lost.
would benefit from chemotherapy.
Microsatellite instability testing also has clinical rel-

evance in helping oncologists predict chemoresponsive-
RAS, Extended RAS, and BRAF Testing
ness. Initially, oncologists used MMR status to help with
stage II carcinomas in which there is only a marginal
(~5%) benefit with adjuvant chemotherapy. For years, it Anti-EGFR medications, cetuximab and panitumumab,
has been known that MSI-H carcinomas do not respond are FDA approved for the treatment of patients with
to 5-fluorouracil (5-FU) chemotherapy, and oncologists colorectal carcinoma with distant metastasis (i.e., stage
often forgo 5-FU–based chemotherapy in “high-risk” IV). Although the original trials discovered that EGFR
stage II colon cancers (i.e., those with poor differenti- immunohistochemical detection did not predict response
ation, angiolymphatic invasion, perineural invasion, to therapy, the investigators quickly found that activating
invasion of serosa or another organ, perforation) that mutations in KRAS codons 12/13 (exon 2) were excel-
are MMR deficient. More recently, in a phase 2 study lent predictors of nonresponse, prompting consensus
of patients with metastatic carcinoma, led by research- recommendations that KRAS 12/13 should be tested and
ers at Johns Hopkins University, it was reported that wild-type before initiating costly (~$80,000) and poten-
clinical benefit of pembrolizumab, an anti–programmed tially toxic (skin rash) anti-EGFR therapies. Cetuximab
death 1 (anti–PD-1) immune checkpoint inhibitor, was and panitumumab work as competitive inhibitors of
predicted by the tumor’s MMR status; the reported data ligand binding and prevent receptor activation. It there-
supported the hypothesis that MMR deficient tumors are fore stands to reason that activating mutations in RAS
more responsive to PD-1 blockade than MMR proficient gene would not be affected by attempts at ligand-based
tumors. These results were followed-up in 2017 with inhibition. Interestingly, other EGFR inhibitors, aimed
a report of 86 patients with 12 different types of solid at the tyrosine kinase domain, are not effective against
tumor malignancies that had progressed on conventional colorectal carcinoma, even those that are RAS wild type.
KRAS codon 12/13 mutations occur in about 40% “polyposis” panel that searches for germline mutations
of colorectal carcinomas. More recently, additional in key polyposis genes such as APC, MUTYH, PTEN,
activating mutations in KRAS and NRAS have been SMAD4, BMPR1A, and STK11.
shown to predict nonresponse to anti-EGFR monoclo-
nal antibodies. These mutations, collectively known
as extended RAS mutations, account for an additional
■ HER-2 IN COLORECTAL CARCINOMA
10% to 20% of patients. Current guidelines (American
Society of Clinical Oncology, NCCN) call for extended
RAS testing before anti-EGFR therapy with cetuximab HER2 molecular alterations are observed in up 2 %
or panitumumab. Codons 12, 13, 59, 61, 117, and 146 on of colorectal cancers and up to 5 % the K ras wild-type
both KRAS and NRAS genes are recommended on all tumors (1). FDA has not yet approved anti-HER2 ther-
stage IV tumors. Further, emerging data have suggested apy for colorectal carcinoma and most cases patholo-
that patients with exon 2– or non–exon 2–activating gists order the test in the metastatic setting and at the
mutations in KRAS or NRAS may be harmed by treat- request of the clinician. That said, NCCN guidelines
ment with cetuximab or panitumumab, making timely (2021) colon cancer recommend testing all metastatic
extended RAS testing all the more important. colon cancers for HER2 (with the exception of those
The utility of BRAF V600E mutation testing in terms that are known to be RAS/RAF Mutant) (2). Testing
of prediction of response to anti-EGFR therapy continues the primary tumor or metastases is appropriate. To keep
to evolve. BRAF-mutated tumors, particularly those that in mind when interpreting the studies, landmark stud-
are MSS are difficult to study for two reasons: (1) BRAF ies in the field (HERACLES, MyPathway and Destiny)
mutations are uncommon in metastatic colorectal carci- have used different definitions of Her 2 positivity add-
noma, accounting for fewer than 10% of tumors, and (2) ing to the complexity of interpreting the stain (4–6).
BRAF V600E mutation in combination with MSS phe-
notype engenders a significantly worse prognosis than
BRAF wild-type tumors, so statistical survival benefit ■ HER2 TESTING IN UPPER
often translate to little or no clinical benefit. All that said, GASTROINTESTINAL TRACT (ESOPHAGEAL,
the pendulum appears to be swinging in the oncology GASTRIC, AND GASTROESOPHAGEAL
community to use the identification of a BRAF V600E JUNCTION) ADENOCARCINOMA
mutation in a similar manner as RAS testing (i.e., a
BRAF mutation precludes anti-EGFR antibody therapy).
Background and Rationale
For unknown reasons, BRAF inhibitor–based therapies
are not effective against BRAF-mutated carcinomas.
Human epidermal growth factor receptor 2 (HER2),
also known as CerbB-2 and ERBB2 is a proto-oncogene
located on chromosome 17q21 that encodes for a trans-
Future Directions of Molecular Testing in
membrane protein with tyrosine kinase activity. The
Colorectal Carcinoma
receptor has an extracellular ligand-binding site, a trans-
membrane segment, and an intracellular domain. With
Molecular oncology testing in colorectal carcinoma will binding of the ligands to the extracellular domains,
become increasingly important in the future, particu- HER2 protein undergoes dimerization and transphos-
larly as cost per test decreases and throughput increases. phorylation of the intracellular domain. This initiates
Companion diagnostics (i.e., biomarker testing to pre- a variety of signaling pathways, especially mitogen-
dict response to chemotherapy) is expected to bear the activated protein kinase (MAPK), phosphatidylinosi-
brunt of the expanded testing focus. Next-generation tol-4,5-biphosphate 3-kinase (PI3K), and protein kinase
sequencing (NGS), also known as deep sequencing or C (PKC) pathways, leading to cell proliferation, differen-
massive parallel sequencing, is the technology leading tiation, angiogenesis, and invasion. Although amplifica-
the charge. It allows for the relatively rapid and relation of HER2 and overexpression of its product has been
tively low cost sequencing of multiple clinically relevant extensively investigated in breast cancer, many studies
genes that may guide therapy or aid in diagnosis. For have now demonstrated role of HER2 in other malig-
example, our institution performs NGS on all metastatic nancies, especially gastric and gastroesophageal junction
colorectal carcinomas to assess for KRAS and NRAS 12, (GEJ) cancers.
13, 61, 117, and 146 as well as BRAF codon 600 as a The frequency of HER2 overexpression in gastric and
single multiplex assay rather than nine separate tests by gastroesophageal adenocarcinoma ranges from 4.4% to
Sanger sequencing, and this is just the tip of the iceberg. 53.4%, with a mean of 17.9%. A recent meta-analysis
Similar technology is being applied to hereditary cancer confirmed that HER2-positive status is associated with
syndrome diagnostics such as in patients with heredi- decreased survival and adverse clinicopathologic fea-
tary polyposis. A patient with a clinically determined tures, such as serosal invasion, metastases, and higher
polyposis can undergo testing for peripheral blood-based stage of disease. As a result, analogous to HER2-positive
breast cancer, upper GI adenocarcinomas can also be tar- overexpression as defined by IHC2+ and a confirmatory
geted with trastuzumab, a monoclonal antibody directed FISH result or by an IHC3+ result.
against HER2. Trastuzumab prevents dimerization of
HER2, stimulates endocytosis, and cell-mediated immu
nity, and inhibits angiogenesis. In the trastuzumab for
HER2 Testing Methods and Scoring
Gastric Cancer (ToGA) trial, 594 patients with HER2-
positive (defined as 3+ expression by IHC or amplifi-
cation by fluorescence in situ hybridization [FISH]) or National Comprehensive Cancer Network Clinical Practice
HER2 (ERBB2):CEP17 ratio ≥2) advanced gastric and Guidelines in Oncology recommend assessment of HER2
GEJ adenocarcinoma were randomized to standard che- expression by IHC and/or gene amplification using FISH
motherapy and trastuzumab or chemotherapy alone. or other in situ hybridization assays (silver-enhanced in
Patients receiving trastuzumab had a significantly longer situ hybridization or chromogenic in situ hybridization).
median overall survival (13.8 vs 11.1 months), progres- FISH is considered as the gold standard; however, given the
sion-free survival (6.7 vs 5.5 months), and response rate cost-effectiveness of IHC and high concordance between
(47% vs 35%), when the tumors were either 3+ by IHC FISH and IHC-positive result, IHC is the preferred method
or 2+ by IHC and positive FISH results (HER2:Chr17 in most laboratories. To standardize the testing method-
ratio >2). Based on these results, the FDA has approved ology and scoring, the College of American Pathologists
the use of trastuzumab for the treatment of patients with (CAP), American Society for Clinical Pathology, and
metastatic gastric, esophageal, and GEJ adenocarcinomas American Society of Clinical Oncology recently published
that meet the ToGA inclusion criteria. The European HER2 testing guideline for gastroesophageal adenocarci-
Medicines Agency has approved trastuzumab for HER2 noma (see Fig. 13.7).
A B
C D
FIGURE 13.7
HER2 immunohistochemistry (IHC). A, HER2-negative (IHC 0) staining with complete lack of staining within the tumor cells. (400× magnification). B, HER2-
negative (IHC 1+) staining wherein the tumor cells show faint or barely perceptible membranous reactivity (400× magnification). C, Equivocal HER2 (IHC 2+)
staining with weak to moderate, complete, basolateral, and lateral membranous reactivity within the tumor cells (100× magnification). D, Positive (IHC 3+) IHC
with strong, complete basolateral and lateral membranous reactivity in the tumor cells (100× magnification).
Specimen Type
The specimen of choice is formalin-fixed paraffin-

embedded biopsy or resection specimen that has been
obtained from the primary or metastatic site before ini-
tiation of therapy. In a series of 115 tumors tested for
HER2, there was 92.9% concordance between results of
biopsy and resection specimens. Studies testing HER2
status in paired samples from primary tumor and met-
astatic organs and synchronous metastatic sites have
reported concordance rates ranging from 87.5% to
98.5%, suggesting that tissue from metastatic tumor is
an acceptable alternative for HER2 status evaluation.
Although there are no data on the impact of cold
ischemia time (time between procurement of biopsy or
resection and tissue fixation) and fixation time on HER2 FIGURE 13.8
status in GI cancers, based on information derived from False-positive HER2 staining by immunohistochemistry. The tumor cells
breast cancer literature, it has been suggested that the show luminal staining, which should not be interpreted for HER2 scoring.
specimen should be rapidly (ideally within 1 hour)
placed in a fixative solution (10% neutral buffered for-
malin), and the fixation time should be 6 to 72 hours.
The thickness of the section can affect accurate interpre-
tation. Thicker sections can lead to the presence of over-
lapping nuclei and difficulties in probe hybridization.
Thinner sections can lead to fewer cells with adequate
signals, thus resulting in undersampling of the tumor.
Four-micron-thick paraffin sections are preferred unless
specified differently by commercially available kits.
The two FDA-approved kits that are routinely used in

most laboratories include HercepTest kit (Dako) and
PATHWAY anti-HER2/neu rabbit monoclonal antibody
(clone 4B5, Ventana Medical Systems). Both these anti-
bodies target the intracellular domain of HER2 protein. FIGURE 13.9
The scoring system proposed by Hofmann et al has HER2 fluorescence in situ hybridization. An example of amplified HER2 with
been approved by the CAPs and FDA. Figure 13.7 out- HER2:CEP17 ratio of 2.9. HER2 signals are represented in red, and CEP17
signals are represented in green.
lines the HER2 IHC scoring criteria for upper GI can-
cers. Cases with membranous staining in fewer than
10% of tumor cells (resection), weak or barely discern- circumferential membranous staining. In a biopsy spec-
ible staining requiring high magnification (40× objec- imen, strong staining in at least a single tumor cluster
tive) to visualize the staining (IHC 1+), or complete (defined as five or more cells) is scored as positive. The
lack of staining (IHC 0), are scored as HER2 negative prevalence of IHC-positive HER2 cases is quite variable
(Figs. 13.8A and 13.8B). Cases with weak to moderate and depends on the morphologic subtype and location of
complete, basolateral to lateral membranous staining in adenocarcinoma. The rate of HER2 positivity is higher for
at least 10% of cells (resections) or in at least a single intestinal-type adenocarcinomas (3%–23.5%) than dif-
tumor cluster (biopsies) are scored as IHC 2+ or equiv- fuse type gastric cancers (0%–6%). GEJ adenocarcinomas
ocal (Fig. 13.8C). In most instances, these cases require are more frequently positive than distal gastric cancers.
an intermediate magnification (10× or 20× objective) to False-positive staining can be seen in areas with
confirm membranous immunoreactivity. intestinal metaplasia, adjacent to mucosal ulcers, and in
Positive staining (IHC 3+) is usually readily visible at dysplastic foci. Luminal surface staining in the absence
low magnification (2× to 4× objective) and requires strong, of lateral or basal staining should be interpreted as neg-
complete basolateral or lateral membranous staining in at ative (IHC 0). Care should be taken when interpreting
least 10% of invasive adenocarcinoma cells in resection tissue with thermal or crush artifact, areas of necrosis,
specimens (Fig. 13.8D). This is in contrast to breast carci- and staining restricted to the edges of biopsy fragments
noma in which HER2 positivity is in the form of complete, (edge artifact; Fig. 13.9).
Tissue sample from patient diagnosed with gastroesophageal

adenocarcinoma
Perform HER2 test by IHC
Surgical specimen Surgical specimen Surgical specimen Surgical specimen

Strong, complete basolateral or Weak to moderate, complete Faint or barely perceptible, No reactivity or
lateral membranous reactivity in basolateral or lateral membranous reactivity in ≥10% of membranous
≥10% of tumor cells membranous reactivity in ≥10% tumor cells; cells reactive only in reactivity in <10%
of tumor cells part of their membrane of tumor cells
Biopsy specimen
Tumor cell cluster* with strong, Biopsy specimen Biopsy specimen Biopsy specimen
complete basolateral or lateral Tumor cell cluster* with weak to Tumor cell cluster* with faint or No reactivity in any
membranous activity irrespective moderate, complete basolateral barely membranous reactivity tumor cells
of percentage of tumor cells or lateral membranous activity irrespective of percentage of
stained irrespective of percentage of tumor cells stained
tumor cells stained
IHC 3+ IHC 2+ IHC 1+ IHC 0

Positive Equivocal Negative Negative
No further No further
ISH testing Perform ISH ISH testing
required testing required
FIGURE 13.10
HER2 testing algorithm based on recommendations by College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and American
Society of Clinical Oncology (ASCO). * Tumor cell clusters is defined as ≥ 5 neoplastic cells. IHC, Immunohistochemistry; ISH, in situ hybridization. (Adapted
with permission from CAP, ASCP, and ASCO guidelines.)
In Situ Hybridization but other investigators have found this in up to 16% of

gastric cancers. In these cases, HER2 gene copy num-
Fluorescence in situ hybridization is considered as the ber can be used to determine trastuzumab eligibility:
gold standard test for evaluating HER2 amplification. It presence of more than 6 HER2 signals/nuclei is inter-
is indicated in all cases with a 2+ HER2 IHC score. The preted as positive for HER2 amplification, fewer than
test can be performed either by using a HER2 probe or four HER2 signals/nuclei is interpreted as negative
dual HER2 and centromere (CEP17) probes. At least 20 for HER2 amplification, and four to six HER2 signals/
nonoverlapping tumor cell nuclei are evaluated at 20× nuclei are interpreted as an equivocal result.
magnification for HER2 and CEP17 probe signal enumer-
ation. A ratio of HER2 signal to CEP17 of 2.0 or greater PD-1/PDL-1 In Esophageal And Gastric Carcinomas
is considered positive (Fig. 13.10), and a ratio of HER2
signal to CEP17 less than 2.0 is considered negative. Bases on published data (1), FDA granted approval
Other in situ hybridization techniques that use bright- for the use of Pembrolizumab in patients with locally
field microscopy include chromogenic in situ hybridization advanced, recurrent or metastatic squamous cell carci-
and silver-enhanced in situ hybridization. These tech- noma of the esophagus or adenocarcinoma of the gastro-
niques allow for better visualization of tumor morphology esophageal junction or gastric. Subsequent KEYNOTE
and easy enumeration in cases with tumor heterogeneity. studies also supported this practice. The drug is indi-
One of the pitfalls regarding FISH interpretation cated if the tumors expresses PDL-1 on immunohisto-
is that chromosome 17 polysomy (defined in ToGA chemistry (clone 22C3) with a combine positive score
trial as three or more signals per nuclei) or amplifica- (CPS) equal or greater than 10 for squamous carcinoma
tion of the centromeric region of chromosome 17 can and equal or greater than 1 for adenocarcinomas (2).
lead to increased CEP17 signals. In patients who have The CPS is calculated based on the number of PDL-1
increased HER2 signals, this phenomenon can result positive cells (tumor, lymphocytes, histiocytes) divided
in a HER2:CEP17 ratio of less than 2 and misclassifica- by total number of viable tumor cells, then multiplied
tion of HER2 status as nonamplified. In the ToGA trial, by 100%. Studies have shown conflicting results on the
chromosome 17 polysomy was observed in 4.1% cases, concordance between biopsy and resection results when
using different clones (3–5). Recent publications sug- 17. Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4
treatment and RAS mutations in colorectal cancer. N Engl J Med.
gest that EBV+or MSI gastric cancers are more likely 2013;369:1023–1034.
to express PD-L1 (6). Pathologists should be aware that 18. National Comprehensive Cancer Network. Colon Cancer (version
chemotherapy and radiation may decrease PDL-1 immu- 2. 2016). https://www.nccn.org/professionals/physician_gls/pdf/
colon.pdf
nohistochemical expression (7). 19. Le DT, Durham J, Smith KN, et al. Mismatch-repair deficiency
predicts response of solid tumors to PD-1 blockade. Science. 2017
28;357(6349):409–413.
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14
Pathology of the Anal Canal
■ Mikhail Lisovsky
■ ANAL ANATOMIC AND HISTOLOGIC or islands of colorectal mucosa in the transition zone
LANDMARKS can give rise to adenocarcinoma of colorectal type, intra-
mural adenocarcinoma without a luminal component
may originate in anal glands or fistulae. Anal transition
The anal canal encompasses the distal most 3 to 4 cm of zone and the squamous zone are the source of several
the most distal intestinal tract. It is defined proximally by histologic subtypes of squamous cell carcinoma (SCC)
the palpable upper border of the internal sphincter mus- and of melanoma.
cle, which is a continuation of the muscularis propria of
the rectum. Distally, the anal canal is limited by the anal
verge, an imaginary line where the squamous mucosa ■ INFLAMMATORY AND NON-NEOPLASTIC
of the anal canal meets the perianal skin. The perianus
extends 5 cm laterally from the anal verge and is char-
acterized by the presence of adnexal structures, such as A number of inflammatory and infectious processes
hair and sebaceous glands. The horizontal circular den- may affect the anal canal; however, the histologic find-
tate line, located equidistant from the anal canal borders, ings of anal fissures, ulcers, abscesses, and fistulas are
is the main anal canal landmark and is formed by the nonspecific and are discussed only briefly. Infectious
bases of vertical mucosal folds called anal columns and agents that can affect the anal canal include human pap-
by anal valves that connect the bases of anal columns. illomavirus (HPV), herpes simplex virus, Treponema
Behind the valves are small spaces called anal sinuses. pallidum, Chlamydia spp., Neisseria spp., and Enterobius
Anal papillae are seen as small excrescences of squamous vermicularis. These infections are described in detail in
mucosa at the dentate line starting from the base of anal Chapter 9.
columns or valves. Below the dentate line, the anal canal Anal fissure is a vertical tear or defect in the squamous
is lined by nonkeratinizing squamous mucosa. Above the mucosa of the anal canal distal to the dentate line. The
dentate line lies the anal transition zone, measuring a few vast majority of fissures are primary, with 90% located
millimeters to 1 cm in width and lined by stratified epi- in the posterior midline and 10% in the anterior midline.
thelium similar to the urothelial mucosa of the bladder. The tear is thought to result from local trauma caused by
The anal transition zone may be covered by squamous passage of hard stools, prolonged diarrhea, vaginal deliv-
epithelium in some cases and may have islands of col- ery, and other injuries, that trigger spasm of the internal
orectal crypts. The most proximal part of the anal canal anal sphincter, leading to ischemia, necrosis, and poor
has colorectal mucosa. Melanocytes are an integral part healing. Secondary fissures are seen in fewer than 1%
of the transition zone mucosa and of the squamous zone of patients and are located laterally or are multiple. They
of the anal canal. The anal sinuses of the transition zone are seen in patients with Crohn’s disease other granu-
serve as openings for anal glands, which are formed by lomatous diseases, such as tuberculosis and sarcoidosis,
simple or branching ducts, ramifying in the submucosa. infections and malignancy. The typical symptoms of anal
Anal glands may extend into or through the internal anal fissure include severe pain during defecation and pas-
sphincter and are lined by urothelium-like epithelium at sage of small amount of bright red blood. An acute anal
the point of origin and by two cell thick epithelium dis- fissure is a fresh laceration, which usually heals within 6
tally. In both locations, the luminal cell layer is cytokera- to 8 weeks of conservative treatment with sitz baths and
tin (CK) 7–positive and mucin-producing cells. The basal diet modification to increase fiber consumption. Some
and intermediate cell layers are p63 and CK5/6 positive, fissures persist and progress to chronic stage, sometimes
similar to squamous epithelium. called anal ulcer. Typical features of chronic anal fissure
The anal canal is the source of multiple types of pri- include exposure of the internal anal sphincter muscle,
mary malignant neoplasms. Whereas the colorectal zone indurated and raised fissure edges, and development of
407
an external skin tag (sentinel pile) at the distal end of the or minimizing recurrence, and retaining continence.
fissure and of a hypertrophied anal papilla (fibroepithe- Long-standing (decades) fistulas are associated with an
lial polyp) at the proximal end. The treatment of patients increased risk of perianal mucinous adenocarcinomas.
with chronic fissure is surgical and is aimed at reducing
spasm of the internal anal sphincter. This may be accom-
plished by lateral internal sphincterotomy or pneumatic
■ CROHN’S DISEASE
balloon dilation.
Biopsies are rarely used in the assessment of acute
anal fissures; however, in chronic lesions to exclude Inflammatory bowel disease is discussed in detail in
inflammatory bowel disease (IBD) or underlying malig- Chapter 10. However, anal involvement by Crohn’s
nancy. Histopathology of a chronic fissure is poorly disease is described in more detail next.
studied. Scarce studies paucicellular scar at the base
of the ulcer and surprisingly minimal inflammation.
Secondary fissures warrant a high degree of suspicion
of associated.
Suppurative disease of the anal canal is thought to
derive from nonspecific infection of an anal duct or Perianal Crohn’s disease may manifest at any age, but
gland, beginning as an abscess, with infection following most patients are diagnosed in the third or fourth decade
the least resistant path, determining the location of the of life. Anal involvement in Crohn’s disease is seen in
abscess (perianal, ischiorectal, or intersphincteric). Less 14% to 38% of the patients. It is present in approxi-
frequently, perianal abscess is associated with Crohn’s mately 15% of patients with ileocolic disease and in
disease; or with infections such as actinomycosis, tuber- 90% of patients with Crohn’s disease involving the colon
culosis, or lymphogranuloma venereum; and in other
instances with incontinence, chronic diarrhea, irradia-
tion, and malignancy. The formation of fistula tract lead- CROHN’S DISEASE—FACT SHEET
ing to the surface of the perianal skin is the chronic phase
of suppurative disease. Histologic features of the perianal Definition
abscess and fistula are nonspecific and include acute and n A chronic idiopathic inflammatory process that may involve any
chronic inflammation, granulation tissue, fibrosis, and portion of the gastrointestinal tract, along with extraintestinal
foreign body giant cell granulomas (Fig. 14.1). The lat- manifestations
ter should be distinguished from the compact epithelioid
granulomas of Crohn’s disease. The presence of multiple
n Anal involvement in 14% to 38% of patients with Crohn’s
lymphoid aggregates and more typical sarcoid-type gran-
disease
ulomas should raise suspicion for Crohn’s disease. n In 15% of patients with ileocolic disease
The treatment of patients with the suppurative disease n In 92% of patients with Crohn’s disease involving the colon
is surgical and focuses on curing the fistula, preventing and rectum

n Location in anal canal and perianal skin

n High morbidity with high relapse rate after therapy

n No gender predominance
n Whites of Anglo-Saxon descent most often affected
n Most common in third and fourth decades of life, but individuals
of any age may be affected
Clinical Features
n Perianal pain, blood in stool, sepsis, incontinence

n Anal lesions are poorly responsive to usual medical therapy for
intestinal Crohn’s disease, such as steroids and aminosalicylates

n Antibiotics and immunomodulators (e.g., cyclosporin A,
azathioprine) are useful in managing fistulas

n Surgery: drainage of abscesses, fistulotomy, flap or graft repair of
fistulas, proctectomy
FIGURE 14.1 n Prognosis is guarded; high relapse rate regardless of therapeutic
Anal fistula tract. Necrosis, acute and chronic inflammation, and granulation modality
tissue are present.
CHAPTER1 14 Pathology of the Anal Canal 409
CROHN’S DISEASE—PATHOLOGIC FEATURES
Gross Findings
n Spectrum of lesions include fissure, ulcer, abscess, fistula, stricture
n Thickened perianal skin; may have fistulous openings
n Anal tag (a fibroepithelial polyp)
n Abscesses and fistulas show acute and chronic inflammation with
granulation tissue
n Sarcoid-like granuloma are characteristic
n Idiopathic abscess and fistula
n Tuberculosis
n Granuloma inguinale
A
n Sarcoidosis
and rectum. Although intestinal inflammation precedes

perianal involvement in the majority of cases, perianal
disease maybe the first manifestation of Crohn’s disease.
The lesions in perianal Crohn’s disease include fissures,
deep anal ulcers, abscesses, fistulas, anal tags, strictures,
SCC, and adenocarcinoma. The clinical presentation
depends on the type of perianal lesion and may include
perianal pain, blood admixed with stool, incontinence,
and sepsis. Patients with perianal disease also have more
extraintestinal manifestations and increased resistance
to steroids.
B
Pathologic Features
Gross Findings
Gross findings include ulcers and fissures, fistulous

openings in or around the anal canal, thickened and
discolored perianal skin, and prominent anal tags.
Multiplicity of lesions is common (Fig. 14.2A).
Acute and chronic inflammation, necrosis, presence

of granulation tissue, and fibrosis are usually pres-
ent, but are nonspecific. However, the presence of C
well-defined sarcoid-like granulomas with associated
FIGURE 14.2
multinucleated giant cells, particularly in close proxi
Anal Crohn’s disease. A, Gross photograph of the inflamed anal canal and
mity to the anal mucosa, is suggestive of Crohn’s dis- rectum. Mucosal inflammation, edema, and ulcers are present in the anal
ease (Figs. 14.2B and C). In many patients with perianal canal. Rectum is involved by the same process. B, At low power, multiple
Crohn’s disease, the histologic findings are nonspecific. granulomas are seen in the anal wall. C, At high power, granulomas with
multinucleated giant cells are located in close proximity to the surface epi-
thelium, which is typical of Crohn’s disease.
of granulomatous inflammation includes foreign body
Idiopathic anal abscesses, fistulas, and primary fissures reaction, tuberculosis, sarcoidosis, and granuloma
may be difficult to distinguish from anal Crohn’s dis- inguinale. Perianal tuberculosis is rare but should be
ease if granulomas are not present and the diagnosis suspected in high-risk populations, such as HIV-infected
of IBD is not established. The differential diagnosis individuals, low-income patients, homeless people, and
people with alcoholism. Tuberculous granulomas are aging, the supportive connective tissue of the cushions
usually characterized by caseation, acid-fast bacilli, and may weaken, causing distal displacement of the cush-
positive mycobacterial cultures. The diagnosis of gran- ions, which in turn leads to venous distention, erosion,
uloma inguinale is supported by identification of intra- bleeding, and thrombosis. “Internal” hemorrhoids arise
cellular Donovan bodies using silver-based stains (e.g., above the dentate line and are subclassified on the basis
Warthin-Starry stain). Sarcoidosis is another potential of whether they prolapse out of the canal and on the
cause of perianal granulomatous inflammation, but is persistence of the prolapse. Hemorrhoids that are per-
extremely rare. manently prolapsed are prone to thrombosis and infarc-
tion. External hemorrhoids, arising below the dentate
line, are prone to thrombosis.
Medical treatment of patients with perianal Crohn’s
disease includes antibiotics; steroids and immuno- The main complaint is minor painless bleeding, which
modulators, such as mercaptopurine, azathioprine, or is associated mostly with internal hemorrhoids. They
methotrexate; anti–tumor necrosis factor-α agents; and rarely show thrombosis and are not painful. In contrast,
cyclosporin A. Relapse is common after cessation of pain is usually associated with thrombosed external
therapy. Fistulas may require placement of drains or hemorrhoids.
diversion of the fecal stream to allow clearing of the
underlying infection. Operative procedures include
fistulotomy, placement of flaps or grafts to repair the Pathologic Features
defect, resection of proximal intestinal disease, a per-
manent diverting colostomy, and as a measure of last Gross Findings
resort, proctectomy. The prognosis for patients with
perianal Crohn’s disease is guarded because of the Hemorrhoids are fragments of dark purple connective
high incidence of recurrence. Approximately 20% of tissue covered by mucosa. They may be firm when
patients eventually require proctectomy. In addition, thrombosed, and sectioning typically reveals dilated vas-
the incidence of anal SCC and adenocarcinoma is sig- cular spaces.
nificantly increased in patients with perianal Crohn’s
disease. Microscopic Findings
The overlying mucosa of hemorrhoid specimens may be

columnar, transitional, or nonkeratinizing squamous.
■ HEMORRHOIDS AND ANAL TAGS
The submucosa contains dilated thick-walled vessels
and thin sinusoidal spaces in a loose and often edem-
Symptomatic hemorrhoids have a prevalence of 4.4% atous fibrous tissue, which may show variable chronic
to 12.8% in the general population. In a recent study inflammation (Fig. 14.3A). Thrombosis is common,
of screening colonoscopy, weighted toward individ- and hemosiderin deposits indicate previous trauma and
uals older than 50 years of age, hemorrhoids were hemorrhage. Organization of intravascular thrombi may
found in 39% with approximately half having symp- produce cellular masses of granulation tissue that may
toms. In both sexes, peak prevalence of symptomatic obliterate the vascular lumen. Excised hemorrhoidal
hemorrhoids appears to be between the ages of 45 tissue should always be carefully examined microscop-
and 65 years. Whites are affected more frequently ically to exclude an inflammatory or infectious condi-
than Blacks, and increased prevalence rates are asso- tion, or associated squamous neoplasia or melanoma.
ciated with higher socioeconomic status. Pregnancy
is also associated with an increased risk of hemor-
rhoids. There is no established association between
hemorrhoids and chronic constipation or portal
hypertension.
Current evidence suggests that hemorrhoids repre- The most common differential diagnosis is with an anal
sent “sagging” or “slippage” of the thickened submuco- skin tag. If an organizing thrombus results in florid
sal tissue of the anal canal called cushions. The cushions intravascular granulation tissue, a question of a vascular
carry the superior (above the dentate line) and inferior neoplasm can be raised, but the intravascular distribu-
(below the dentate line) hemorrhoidal vascular plexus tion and residual thrombus with recanalization allow
that have direct arteriovenous communication. With easy distinction in most cases.
HEMORRHOIDS—FACT SHEET
Definition
n Enlarged and edematous soft tissue lesions associated with the
anal mucosa that result from slippage or sagging of the normal

soft tissue in this region

n Reported incidence varies from 4.4% to 12.8%
n Location above and below the dentate line

n Not a significant cause of mortality but a common cause of
discomfort and morbidity

A
n Males equal to females; males more likely to seek medical
attention
n Wide age and ethnicity range, peaking in middle age and
declining thereafter
Clinical Features
n Painless bleeding most common symptom; also anal discomfort
on defecation
n Acute pain exacerbations with thrombosis and infarction
n Commonly symptomatic during pregnancy

n Medical therapy is mainstay of therapy: increases in dietary
fiber, injection sclerotherapy, banding, ablative photocoagulation,

electrocoagulation, laser ablation, and cryotherapy
n Surgical therapy is reserved for the 5% to 10% of those who fail
conservative measures B
n Surgical excision should include only symptomatic hemorrhoidal
tissue to protect continence FIGURE 14.3

n Recurrence rate is high A, Low-power view demonstrating a typical hemorrhoid, in this case cov-
ered by squamous epithelium. The submucosa contains thick-walled dilated
blood vessels in a loose fibroconnective tissue. B, Anal fibroepithelial polyp
or tag demonstrating loose fibrovascular stroma covered by squamous epi-
thelium. The fibroblastic cells are widely spaced and have no mitotic activity.
HEMORRHOIDS—PATHOLOGIC FEATURES The vasculature is delicate.
Gross Findings
n Usually 1 to 3 cm in diameter and stool softeners. In those with more severe symp-
n Pale connective tissue covered by thin gray to tan mucosa toms or failed therapy, sclerotherapy and banding to
n Infarcted or thrombosed hemorrhoids are dark purple and firm induce fibrosis and fixation of the sagging tissue is used.
n Cut surface with dilated vascular spaces, some with thrombi
Surgical excision or ablative techniques such as photo-
coagulation, electrocoagulation, laser ablation, and cryo-
n Epithelium: columnar, transitional, or squamous
therapy are also widely used in patient management.
n Submucosa with edematous stroma and dilated vessels
n Vessels may contain thrombi, with intravascular and perivascular
hemosiderin deposits, often with marked reactive changes

■ ANAL TAGS
n Gross differential diagnosis includes melanoma and carcinoma
Anal tag, also known as hypertrophied anal papilla or
n Histologic differential diagnosis of a thrombosed hemorrhoid with
organization includes angiosarcoma and Kaposi’s sarcoma anal fibroepithelial polyp, is a polypoid excrescence of
anal squamous mucosa and underlying tissue caused by
enlargement of an anal papilla. Anal tags can be idiopathic,
Prognosis and Therapy associated with fissures or fistulas, or associated with
Crohn’s disease. The gross appearance may be similar to
hemorrhoids, but the dilated blood vessels of hemorrhoidal
Treatment options for patients with mild symptoms tissue are lacking. Anal tags resemble cutaneous fibroepi-
include analgesics, sitz baths, increased dietary fiber, thelial polyps, with a squamous epithelial lining over loose
fibrovascular tissue (Fig. 14.3B). The stroma contains

a variably cellular fibroblastic proliferation, which may TABLE 14.1
show small spindle cells or, if the tissue was traumatized,
Terminology for Intraepithelial Neoplasia
enlarged stellate multinucleated cells with bizarre nuclei. (Dysplasia) of the Anal Canal and Perianal Skin
Such stellate cells are evenly distributed within the collag-
enous stroma and are of no clinical significance. Anal tags AIN (Three-Tiered ASIN (Two-Tiered
are easily removed by a snare or snip excision. System) System, WHO) Anal SIL (LAST)
I ASIN-L LSIL (AIN 1 or

ASIN-L)
II ASIN-H HSIL (AIN 2 or
■ ANAL AND PERIANAL SQUAMOUS ASIN-H)
NEOPLASIA TERMINOLOGY III ASIN-H HSIL (AIN 3 or
ASIN-H)
Condyloma Condyloma LSIL (condyloma
A unified lower anogenital squamous terminology acuminatum acuminatum acuminatum)
(LAST) for HPV-associated lesions was proposed by Bowen’s disease Bowen’s disease/ HSIL (PAIN 3,
the College of American Pathologists and the American PSIN PSIN-H)
Society for Colposcopy and Cervical Pathology in 2012 AIN, anal intraepithelial neoplasia; ASIN-H, high-grade anal squamous
and includes updated nomenclature for squamous neo- intraepithelial neoplasia; ASIN-L, low-grade anal squamous intraepithelial
neoplasia; LSIL, low-grade squamous intraepithelial lesion; PAIN,
plasia of both the anal canal and perianal skin. LAST perianal intraepithelial neoplasia; PSIN-H, high-grade perianal squamous
is based on the assumption of similar biology and mor- intraepithelial neoplasia.
phologic equivalence of HPV-related squamous lesions
across lower anogenital sites is an attempt to standardize
diagnostic categories to improve interdisciplinary com- ■ ANAL CANAL SQUAMOUS
munication and patient management. The recommended INTRAEPITHELIAL LESION
nomenclature uses a two-tiered system for premalignant
squamous lesions: low-grade squamous intraepithelial
lesion (LSIL) and high-grade SIL (HSIL). Reported repro- Clinical Features
ducibility is superior to prior three-tiered systems, and in
addition, a two-tiered classification system is supported Anal canal SIL (ASIL) has been also termed anal (canal)
by our current understanding of the biology of HPV intraepithelial neoplasia (AIN), anal squamous intraep-
infection. LSIL is usually associated with transient ext- ithelial neoplasia, and anal squamous dysplasia. It is
rachromosomal HPV replication, whereas HSIL is asso- considered to be a precursor of SCC of the anal canal
ciated with genomically integrated HPV DNA. Because and frequently accompanies SIL of the perianal skin,
LSIL and HSIL terminology does not distinguish between cervix, and vulvar and other lower genital sites. There is
different anogenital sites, a site-specific classification a strong association of ASIL with HPV infection. Low-
using two-tiered intraepithelial neoplasia (IN) terminol- grade lesions, in general, are associated with low-risk
ogy (e.g., AIN; see later) has been proposed for clarity HPV genotypes, whereas high-grade lesions occur in
of communication. It was acknowledged, however, that association with high-risk HPV genotypes, particularly
currently used clinical guidelines may stratify manage- 16 and 18. ASIL is most common in HIV-positive homo-
ment of HPV-related lesion according to a three-tiered sexual men and is rare in heterosexual men. About 5%
(AIN1–3) classification. The latter can therefore be used to 20% of ASIL cases occur in HIV-negative homosex-
in parenthesis when necessary. Comparison of the LAST ual men. In women, ASIL is also linked to anal inter-
terminology with the three- and two-tiered anal and peri- course and HIV-positive status. Immunosuppression
anal IN terminology is presented in Table 14.1. from causes other than HIV, such as solid organ trans-
plantation, also increases the risk for high-grade ASIL.
ASIL is more likely to occur in the transition zone and
■ TUMORS AND PRECURSOR LESIONS OF can be identified as acetowhite epithelium similar to
THE ANAL CANAL lesions of cervical SIL.
Low-Grade Squamous Intraepithelial Lesion Pathologic Features

(Condyloma Acuminatum) of the Anal Canal
Gross Findings
Condyloma acuminatum is more common in the peri-
anal skin and is associated with low-risk HPV genotypes Anal precursor lesions may be macroscopically invisi-
6 and 11. This is described in greater detail in the section ble or present as plaque-like or warty lesions or as mass
on perianal lesions. lesions mimicking malignancy.
ANAL SQUAMOUS INTRAEPITHELIAL LESION—FACT ANAL SQUAMOUS INTRAEPITHELIAL

SHEET LESION—PATHOLOGIC FEATURES

n A precursor of invasive squamous cell carcinoma, also known as n No distinctive features
anal intraepithelial neoplasia

Incidence and Location n Nuclear atypia, delayed maturation, and abrupt transition from
n True incidence of anal squamous intraepithelial lesion in the uninvolved epithelium to squamous intraepithelial lesion
general public is unknown because only high-risk populations are n Low-grade squamous intraepithelial lesion (LSIL): lack of
screened for dysplasia maturation involves the lower third of the epithelium
n The incidence of high-grade squamous intraepithelial lesion n High-grade squamous intraepithelial lesion (HSIL): lack of
(HSIL)in HIV-negative men who have sex with men (MSM) is maturation in at least the lower two-thirds or the epithelium;
17% to 21%, whereas HIV-infected MSM have a rate of 29% to prominent nuclear atypia
52% n Koilocytotic change is common in upper epithelial layers,
n The prevalences of anal HSIL are 0% to 3% and 0% to 9% especially in LSIL but can also be seen in HSIL
in HIV-negative women without and with known HPV-related n Mitotic figures are limited to basal layers in LSIL and throughout
pathology of the lower genital tract, respectively, and in 3% to the full thickness of the epithelium in HSIL
26% of HIV-positive women
Molecular Studies
Morbidity and Mortality n Polymerase chain reaction and fluorescent in situ hybridization
n Little or no morbidity and no mortality are frequently positive for human papillomavirus (HPV) types 6
and 11 in LSIL and 16 and 18 in HSIL
Gender, Race, and Age Distribution n Risk for developing invasive carcinoma is higher with HPV 16
n Males more than females

and 18
n Men who have sex with men (MSM) have a higher incidence of
anal SIL Immunohistochemistry

n The rate of anal SIL does not decrease with age in MSM n p16 immunohistochemistry is helpful in selected situations
Clinical Features Differential Diagnosis

n Anal SIL is asymptomatic n Reactive epithelial proliferation
n Detection by anal cytology and by anoscopy with biopsy

n Progression rates of HSIL to anal cancer are 0.17% per year for
perinuclear clear halo and may show binucleation (Fig.
HIV-positive MSM and 0.03% for HIV-negative MSM
n Topical treatment: fluorouracil, imiquimod, cidofovir, trichloroacetic
14.4A). HSIL is characterized by prominent nuclear
acid and lopinavir atypia and lack of maturation involving more than
n Ablative treatment: laser, infrared coagulation, and electrocautery one-third of the epithelium. Mitotic figures, including
n High recurrence rate in high-risk populations
atypical forms, may be present (Figs. 14.4B and C). In
the previous three-tiered grading system, AIN I (mild
dysplasia) is characterized by nuclear atypia and lack of
maturation in the lower third of the epithelium; AIN II
Microscopic Findings (moderate dysplasia) involves the lower two-thirds of the
epithelium; and AIN III (severe dysplasia) is diagnosed
ASIL is characterized by nuclear atypia, abnormal when dysmaturation involves the full thickness of the
maturation, and abrupt transition from uninvolved epithelium.
epithelium to SIL. Nuclear atypia is characterized by
hyperchromasia, pleomorphism, irregular nuclear bor-
ders, coarse chromatin, and loss of nuclear polarity.
Abnormal maturation refers to a delay in cytoplasm ■ ANCILLARY STUDIES
accumulation, which normally begins from the second
or third basal cell layer. LSIL is defined by mild cytologic Immunohistochemistry
atypia and minimal maturation in the lower third of the
epithelium. Cells appear basaloid and immature because A broad array of biomarkers that includes p16, Ki-67
of high nuclear-to-cytoplasmic ratio, and mitotic figures (Mib1), ProEx C, telomerase/TERC, HPV genotyp-
are increased but limited to the lower third of the epi- ing, and HPV16/18 mRNA levels is available for
thelium. Koilocytic change may be seen in the superfi- ancillary testing in anal neoplasia. However, LAST
cial epithelial layers and is diagnostic of HPV cytopathic guidelines recommend only p16 immunohistochem-
effect. Koilocytes characteristically have enlarged hyper- istry (IHC) as a surrogate assay for HPV infection in
chromatic nuclei with irregular nuclear borders and biopsies. Positive p16 IHC is defined as continuous
A B
C D
FIGURE 14.4
A, Anal low-grade squamous intraepithelial lesion (anal intraepithelial neoplasia AIN I) has expansion of the basal layer with delayed maturation in the lower
third of the epithelial thickness. Cell crowding and some loss of cellular polarity are present in the basal layers. Note the koilocytotic change in the superficial
layers of the epithelium consisting of irregular, enlarged, and hyperchromatic nuclei, binucleation, and perinuclear halo. Mitoses are limited to the lower third of
the epithelium. B and C, Anal high-grade squamous intraepithelial lesion (AIN II and AIN III) is characterized by nuclear crowding and lack of maturation in the
lower two-thirds (AIN II) or greater (AIN III) of the epithelial thickness. There is prominent nuclear crowding and atypia. Mitotic figures may extend to the very
top. Atypical mitoses may be present (C). D, Two examples of positive p16 immunohistochemistry showing continuous and strong nuclear and cytoplasmic
staining that involves at least the basal third of the epithelial thickness.
and strong nuclear or nuclear and cytoplasmic stain- Molecular Pathology

ing involving at least the basal third of the epithe-
lial thickness (Fig. 14.4D). Focal or patchy nuclear
staining can be seen in both reactive squamous Although not necessary for histologic diagnosis of ASIL,
metaplasia and in LSIL and is therefore nonspecific. in situ hybridization and polymerase chain reaction
Other staining patterns, such as cytoplasmic only, (PCR) techniques have been used in epidemiologic stud-
single cell, and blob-like positivity, are considered ies. In one systematic meta-analysis, crude prevalences
negative. LAST guidelines propose to limit p16 IHC of HPV in LSIL and HSIL were 88% and 91%, respec-
to the following scenarios: (1) differential diagno- tively. In order of prevalence, HPV genotypes 11, 6, 16,
sis between HSIL and a neoplastic mimic, such as 70, and 31 were detected in LSIL and genotypes 16, 18,
immature squamous metaplasia, atrophy, repara- 6, 33, 31, and 11 in HSIL. The combined prevalences
tive change, or tangential cutting; (2) differentia- of genotypes 16 and 18 were 27% in LSIL and 69% in
tion of HSIL from LSIL when it is not clear whether HSIL, supporting the view that LSIL and HSIL are asso-
hematoxylin and eosin morphology is that of AIN ciated with different HPV subtypes.
2 or AIN 1 in the older three-tiered nomenclature.
(block-positive strong staining supports the diagno-
sis of HSIL); or (3) there is a difference of opinion
regarding the presence of HSIL. P16 IHC is currently
not recommended for the diagnosis of LSIL, which
should be definitely established morphologically, or One of the main challenges in the diagnosis of ASIL is its
for the differential diagnosis of LSIL versus non– distinction from reactive squamous proliferation. There
HPV-associated abnormalities. is significant interobserver variability in the diagnosis
of LSIL because of mild cytologic abnormalities and of the disease, although still rare at 0.2 to 4.4 per
because delayed maturation in regenerative epithelium 100,000, has increased dramatically in recent decades.
is difficult to distinguish from the dysmaturation seen in There has been also a demographic shift of the affected
LSIL. An abrupt transition from normal epithelium to individuals with an increase in young adults, particu-
an atypical area and koilocytes in the upper epithelium larly in patients with HIV and other immune deficien-
are the hallmarks of LSIL. Even though a subset of LSIL cies, and in transplant patients on immunosuppression.
cases show strong diffuse p16 immunostaining, the use The average age of diagnosis in HIV-infected individu-
of p16 IHC is not recommended for diagnosis. Positive als is in the fourth decade of life. The risk is higher in
staining may lead to overinterpretation and inappropri- urban populations and in Blacks. In contrast, the risk
ate upgrade to HSIL. Similarly, negative p16 in an other- is particularly low among Asians and Pacific Islanders.
wise unequivocal HSIL should not be used to downgrade The incidence in MSM is 35 per 100,000, which dou-
the lesion to LSIL. ASIL can be encountered in speci- bles in those infected with HIV to approximately 70 per
mens from benign anal disease, such as hemorrhoids, fis- 100,000. Other associated risk factors include multiple
sures, and fistulas. The prevalence of incidental HSIL in sexual partners, receptive anal intercourse, and presence
surgical specimens varies from 0.25% to 2.5%. of other sexually transmitted diseases. HPV is detected
in the majority of anal SCCs. A strong link to tobacco
smoking has been noted in women but is less definitive
in men. Hemorrhoids, fissures, fistulas, abscesses, and
IBD are not associated with increased incidence of SCC.
The initial presentation of SCC may be nonspecific,
Low-grade squamous intraepithelial lesion is mainly resulting in delayed diagnosis. Minor anal bleeding,
caused by transient HPV infection and is self-limited. pain, discharge, altered bowel habits, pelvic pain, dis-
The estimates from a meta-analysis showed that pro- comfort in the sitting position, anal fissure or fistula, and
gression rate from HSIL to anal cancer in men who have incontinence from the involvement of the anal sphinc-
sex with men (MSM) is 0.17% per year for HIV-positive ter may be noted. A mass lesion is often evident on dig-
MSM and 0.03% for HIV-negative MSM, suggesting ital examination. Clinical evaluation typically includes
that immunologic status plays an important role in pro- rigid proctoscopy for biopsy, assessment for inguinal
gression to cancer. lymphadenopathy, computed tomography or magnetic
Cytopathologic techniques similar to those used for resonance imaging to evaluate other lymph node groups
the cervix have been used for screening high-risk pop- (inferior mesenteric, inferior rectal, and internal iliac),
ulations for anal SIL. Reflex testing for HPV is often colonoscopy to exclude extension from a primary rectal
performed on specimens with atypical cytology, and tumor, and ultrasonography to assess depth of invasion.
patients with positive results are referred for high-reso-
lution anoscopy and biopsy.
The quadrivalent HPV vaccine, now administered to
Pathologic Features
prevent cervical cancer, offers protection against HPV 6,
11, 16, and 18 and has demonstrated high efficacy against
Gross Findings
anogenital warts and may also prevent anal SIL.
Options available for treatment of anal SIL can be Anal canal SCCs are typically ulcerated, with raised bor-
divided into topical and ablative. Topically applied agents ders and may extend into the distal rectum and perianal
include fluorouracil, imiquimod, cidofovir, trichloroace- skin (Fig. 14.5A). It is uncommon to see an intact lesion
tic acid, and lopinavir. Ablation methods include laser, from the anal canal because most patients are treated
infrared coagulation, and electrocautery. Ablative meth- with neoadjuvant therapy. In such specimens, the tumor
ods are more effective than self-applied topical treat- may not be grossly evident. Careful and extensive sam-
ments, but the recurrence rates are high. One recent pling may be necessary to demonstrate the lesion; areas
study of HSIL ablation in MSM demonstrated recur- of induration or mucosal thickening are of particular con-
rence rate of 68% at 2 years for HIV-positive patients cern and should be selected for histologic examination.
and 57% for HIV-negative patients.
Although SCC of the anal canal may demonstrate one

■ SQUAMOUS CELL CARCINOMA
predominant pattern, the majority of tumors are char-
acterized by a varied histologic appearance. The tumors
Clinical Features above the dentate line often show basaloid pattern, char-
acterized by small cells with high nuclear-to-cytoplasmic
Squamous cell carcinoma comprises 75% to 80% of all ratio and nuclear palisading at the periphery of tumor
malignant tumors of the anal canal. The overall incidence islands. The tumor islands may have necrotic centers
SQUAMOUS CELL CARCINOMA OF THE ANAL SQUAMOUS CELL CARCINOMA OF THE ANAL
CANAL—FACT SHEET CANAL—PATHOLOGIC FEATURES

n Invasive malignant neoplasm demonstrating squamous n Mass, ulcer, or stricture may be seen
differentiation n In salvage surgery cases, carcinoma may not be grossly evident;
diagnosed by biopsy of the area of induration or mucosal

Incidence and Location thickening
n 75% to 80% of anal cancers
n Incidence: 3400 new cases annually Microscopic Findings

n Worldwide incidence is increasing, especially among HIV-positive n Varied histologic patterns and two predominant cell types: (1)
individuals large cells with or without evidence of keratinization and (2)

basaloid cells. One cell type may predominate, or an admixture of
Morbidity and Mortality patterns may be seen
n Irregular infiltration with desmoplasia or rounded pushing margin
n Anal canal lesions: 5-year survival rate is 60% to 86%
n Two more aggressive patterns: small cell (anaplastic) carcinoma
n Survival has increased with the advent of combined
chemoradiation, eliminating the need for abdominoperineal and squamous cell carcinoma with mucinous microcysts
resection
Molecular Studies
Gender, Race, and Age Distribution n Human papillomavirus (HPV) DNA is identified in most anal
n Females more than males, 2 to 1

squamous cell carcinomas
n Polymerase chain reaction is most sensitive; HPV types 16 and
n Increase in young males over past two decades, especially HIV-
positive men who have sex with men 18 are most often identified
n Gains in chromosomes 3q, 17, and 19; losses in 4p, 11q, and
n Higher incidence among urban populations
n More common in Blacks than in Whites; very low incidence in

18q
n Expression of p53, RB, and HER2 has no prognostic significance
Asians and Pacific Islanders
n Demographic shift in progress from older women to young men
Clinical Features n Basal cell carcinoma: a basaloid-predominant pattern may require
n Symptoms include pain, itching, bleeding, nonhealing ulcer,

immunohistochemistry to exclude melanoma, undifferentiated
anal discharge, altered bowel habits, anal fissure, fistula, and carcinoma and lymphoma
incontinence
n Risk factors: multiple sexual partners, anal-receptive intercourse,
presence of other sexually transmitted diseases, tobacco smoking

in women, immunosuppression, HIV seropositivity
Therefore, the current World Health Organization (WHO)
classification suggests that the broader term SCC be used
Prognosis and Therapy for these tumors. It may be accompanied by a comment
n May metastasize to perirectal, iliac, or inguinal lymph nodes describing additional histologic features, such as basaloid
n Chemoradiation therapy usually eliminates the need for radical features, degree of keratinization, presence of mucinous
resection and yields 5-year survival rates of 60% to 86% microcysts, or adjacent SIL.
n Abdominoperineal resection is used as salvage procedure for
The LAST guidelines also define a category of superfi-
recurrence or persistence after chemoradiation therapy; the 3– to
5-year survival rates are 44% to 100% cially invasive SCC of the anal canal, which can be man-
aged by local surgical excision with lower morbidity than
chemoradiation. SCC with an invasive depth of 3 mm or
less from the basement membrane at the point of origin
and small mucinous microcysts (Figs. 14.5B and C). The and horizontal spread of 7 mm or less in maximal extent
tumors below the dentate line may have predominance can be safely treated with surgical excision alone.
of large cells with pale eosinophilic cytoplasm without Verrucous SCCs are considered a subtype of SCC and
keratinization or keratinization of lamellar or single-cell represent bulky exophytic tumors with a bulbous acan-
type or (Figs. 14.5D and E). There is frequently a tran- thotic basal component with a pushing interface. HPV-
sition from one pattern to another with a spectrum of associated cytopathic changes are absent, and these
intermediate variations. tumors show only mild atypia. Diagnosing these lesions
In the past, anal canal tumors were subclassified into on a small biopsy is challenging.
large-cell keratinizing, large-cell nonkeratinizing, and
basaloid types. However, the majority of tumors demon-
strate a mixture of histologic patterns, and no definite ■ ANCILLARY STUDIES
association between histologic patterns and prognosis
has been established. In addition, the diagnosis is usually
based on a small biopsy specimen that may not be repre- Immunohistochemistry
sentative of the entire tumor. Therapy has also shifted
from radical surgery to combined modality chemoradia- Immunohistochemical stains are usually not needed,
tion, which is not dependent on the histologic subtype. except in poorly differentiated cases. Coexpression of a
FIGURE 14.5
A, Squamous cell carcinoma (SCC) arising above the dentate line, with the typical ulcerated appearance. B, A low-power view of SCC with basaloid features
showing large lobulated nests of cells with central necrosis. C, At higher power, cells are small, with a high nuclear-to-cytoplasmic ratio and scant amphophilic to
clear cytoplasm. D, A low-power view of keratinizing SCC producing a prominent desmoplastic reaction. E, At higher power, the polygonal cells have pale eosin-
ophilic cytoplasm; markedly atypical nuclei, scattered dyskeratotic cells; and lamellar keratinization. A brisk mitotic rate is noted.
high-molecular-weight keratin CK5 and of p63 or p40 genotypes 16 and 18 are most frequently found. HPV
supports the diagnosis of SCC. The surrogate marker increases the risk of anal carcinoma by inactivating
p16 may be used to suggest association with high-risk the tumor suppressor gene P53. Genetic alterations
types of HPV. Chromogranin and synaptophysin immu- include point mutations or deletions in chromosome
nostains are also helpful in poorly differentiated tumors 17p, which harbors the P53 gene. Another pathway of
to rule out the possibility of a poorly differentiated P53 inactivation involves viral protein E6, produced by
(small or large cell) neuroendocrine carcinoma. high-risk types of HPV. E6, when bound to a specific
cellular protein, causes proteolytic degradation of p53.
In addition to alterations in p53 activity, the E7 protein
of high-risk HPV binds to the product of retinoblastoma
Molecular Pathology
gene Rb, which normally restricts proliferative activity
in the basal layers of squamous epithelium, leading to
Human papillomavirus DNA is identified in the increased epithelial proliferation. The increased prolif-
vast majority of anal canal SCCs, and high-risk HPV eration and decreased apoptosis in response to DNA
injury are important in HPV-related squamous carcino-

genesis. Mutations in the PIK3CA are quite prevalent,
and c-myc amplification has been reported in one-third
of anal SCCs. Genomic hybridization studies have also
demonstrated gains in chromosomes 3q, 17, and 19 and
losses in chromosomes 4p, 11q, and 18q. Expression of
the p53, Rb, and HER2 proteins does not appear to have
prognostic significance.
A
A small biopsy specimen with tumor exhibiting a pre-

dominantly basaloid pattern may require further inves-
tigation to exclude neuroendocrine carcinoma of small
cell type, melanoma, lymphoma, or basal cell carcinoma
(BCC) of the perianal skin. In such cases, neuroendo-
crine markers (e.g., chromogranin and synaptophysin),
markers of melanocytic differentiation (e.g., S-100 pro-
tein, Melan-A, human melanoma black [HMB-45], and
microphthalmia transcription factor [MiTF]), or lym-
phoid markers are helpful. Poorly differentiated meta-
static tumors from the prostate or colorectal primary can
also mimic a primary anal SCC but can easily be distin-
guished based on clinical history, imaging findings, and B
immunostaining with PSA (prostate-specific antigen) FIGURE 14.6
and CDX2 (caudal type homeobox 2), respectively. The Basal cell carcinoma of perianal skin. A, Tumor nests with peripheral pali-
giant condyloma of Buschke-Lowenstein was thought sading, the classic retraction artifact and myxoid stroma that help differenti-
to be synonymous with verrucous carcinoma, but it is ate this tumor from basaloid squamous cell carcinoma. B, Diffuse Ber-EP 4
expression within the tumor supports this diagnosis.
actually associated with low-risk HPV genotypes and
shows viral cytopathic changes and is now regarded as a
separate entity. Pseudoepitheliomatous hyperplasia may
also mimic an invasive SCC, but is typically associated
either with an underlying granular cell tumor or with to the perirectal, iliac, and inguinal lymph nodes. The
syphilis. BCC of the perianal skin may also enter the current therapy of choice is combined modality therapy
differential diagnosis with basaloid SCC but is seldom (radiation + 5-flouracil [5-FU] + mitomycin C or cispla-
a challenging distinction. Basaloid SCC present as bulky tin), which achieves complete pathologic response in the
anal tumors with large nests of tumor cells with cen- majority of patients. For local disease, 5-year survival
tral necrosis and peripheral palisading, marked nuclear rates range from approximately 40% to 70% depend-
atypia, and proliferative activity. An in situ component ing on the stage. Up to 25% of patients relapse and
is usually discernable. In contrast, BCCs present as nod- undergo salvage abdominoperineal resection, which is
ular lesions involving perianal skin and show nests of also performed in patients with persistent disease after
monomorphic basaloid cells with peripheral palisading chemoradiation. Abdominoperineal resection results in
and a characteristic retraction artifact, along with myx- 5-year survival rate in the range of 40% to 60%. The
oid stroma. Central necrosis, atypical mitoses, and an in primary prognostic factors are tumor stage, which is
situ squamous neoplasia component are not character- based on size rather than depth of invasion, and nodal
istic of BCC of the skin (Fig. 14.6A). The diagnosis of status. Small tumors that conform to the definition of
BCC of the skin may be supported by diffuse Ber-EP4 superficially invasive SCC (≤3 mm depth of invasion
(Fig. 14.6B) and Bcl2 staining. and ≤7 mm horizontal spread) are treated with local
excision. Verrucous carcinomas recur locally but do not
metastasize, and surgical excision is the treatment of
choice. Recent studies have also shown PD-L1 expres-
sion in nearly 50% of SCCs, raising hopes that a signifi-
cant proportion of advanced staged tumors may respond
The tumor spreads by direct invasion into the anal sphinc- well to anti–programmed cell death protein-1(PD-1)–
ter muscle and adjacent soft tissue, and metastasizes targeted therapy.
■ ADENOCARCINOMA
Adenocarcinomas of the anal canal are uncommon, con-

stituting up to 10% of all anal canal cancers. The WHO
classification recognizes two groups of adenocarcino-
mas. A majority involving the anal rectal-type mucosa
with features essentially identical to colorectal adeno-
carcinoma and a second rare extramucosal (intramural)
group of adenocarcinomas, also called perianal adeno-
carcinomas, defined by the lack of a luminal component.
Extramucosal adenocarcinomas include tumors arising
in anal glands or anal fistulas and those arising in mal-
formations or embryologic remnants.
■ CLINICAL FEATURES FIGURE 14.7

Anal gland adenocarcinoma. This perianal adenocarcinoma lacks surface
mucosal abnormalities grossly and histologically. The tumor is characterized
The clinical features of adenocarcinomas of the anal by haphazardly arranged small glands with scant mucin production in the
perianal stroma.
canal include bleeding, pain, a palpable mass, inconti-
nence, and change in bowel habits. Anal adenocarcino-
mas characteristically grow slowly, and their diagnosis (Fig. 14.7). Some carcinomas have mucinous phenotype
may be delayed because of the lack of luminal compo- in the absence of an identifiable fistula and have been
nent. Adenocarcinomas arise in fistulas of typically of 20 tracked to normal anal glands, suggesting that anal gland
and more years of duration. The average age at diagnosis carcinomas may also have a mucinous phenotype.
is approximately 60 years with a male predominance.
Pathologic Features
Gross Findings
Adenocarcinomas of the colorectal type arise in the The adenocarcinoma of the colorectal-type is typically
uppermost mucosa of the anal canal. More often, they CK7−/CK20+/CDX2+, whereas the mucinous adeno-
are an extension of a low rectal adenocarcinomas. Anal carcinomas are generally CK7+/CK20+, and the anal
extramucosal adenocarcinomas present as a submucosal gland carcinomas are CK7+/CK20−. In addition, anal
mass; the surface mucosa may be ulcerated. The cut sur- gland carcinomas lose basal cell layer with associated
face is tan and firm or may demonstrate abundant muci- CK5/6 and p63 expression of normal anal glands and are
nous material. There may be evidence of a fistula in the negative for CDX2. The reported immunophenotype of
vicinity of the tumor. fistula tract-associated and nonanal gland, non–fistula-
associated anal adenocarcinomas is heterogeneous and
Microscopic Findings cannot be used to define a specific subtype.
Adenocarcinomas arising in anal colorectal mucosa are

histologically identical to adenocarcinomas elsewhere in
the colorectum. Adenocarcinomas associated with fis-
tulas are usually of the mucinous type, with abundant
extracellular mucin containing islands of atypical glandu- Adenocarcinoma of colorectal type cannot be separated
lar epithelium; these tumors have also been referred to from its lower rectal counterpart based on microscopic
as colloid carcinoma. Historically, the diagnosis of anal features alone. Differential diagnosis of poorly differ-
gland carcinoma was made when continuity of the tumor entiated carcinoma of the anal canal includes adeno-
with normal anal glands could be demonstrated. However, carcinoma, SCC, and neuroendocrine carcinoma. IHC
the continuity can be rarely established. The currently is helpful, and the algorithm is summarized in Table
favored definition describes anal gland carcinoma as 14.2. Melanoma can be distinguished using melanocytic
haphazardly dispersed small glands with cuboidal epi- markers S100, Sox10, Melan-A, and HMB-45. Anal
thelium and scant mucin production invading the wall gland carcinoma is a diagnosis of exclusion, and the ori-
of the anorectal area without an intraluminal component gin of a carcinoma in anal luminal mucosa or a fistula
TABLE 14.2
Immunohistochemical Panel for Discrimination Between Poorly Differentiated Anal Carcinomas
CK7 CK20 Synaptophysin Chromogranin CK5/6 P63/p40
Squamous cell carcinoma + − − − + +

Adenocarcinoma +/− +/− − − − −
Neuroendocrine carcinoma +/− − + + − −
CK, Cytokeratin.
ADENOCARCINOMA—FACT SHEET ADENOCARCINOMA—PATHOLOGIC FEATURES

n Malignant neoplasm with glandular differentiation n Adenocarcinoma arising in the anal mucosa is an exophytic or
n May arise either in the anal colorectal-type mucosa or ulcerated mass similar to usual colorectal adenocarcinoma
extramucosally in deeper anal structures with no involvement of n Extramucosal perianal adenocarcinoma is a submucosal mass
luminal mucosa with no surface epithelial involvement. Mucosal ulceration may

n Extramucosal adenocarcinomas include anal gland carcinoma and be present
adenocarcinoma arising in a fistula
Incidence and Location n Adenocarcinoma arising in anal mucosa: epithelial dysplasia
n 3% to 4% of all anal carcinomas adjacent to invasive component. Tubulovillous pattern with “dirty
n The majority of adenocarcinomas are extensions from a rectal necrosis” is common, similar to colorectal adenocarcinoma
primary cancer n Extramucosal perianal adenocarcinomas
n Colorectal-type adenocarcinomas localize to the upper anal canal; n Anal gland carcinoma: haphazardly arranged small tubular
anal gland carcinomas localize to the transitional zone glands with scant mucin production and no surface mucosal
component
Morbidity and Mortality n Adenocarcinoma associated with anal fistula: mucinous type,
n High level of morbidity because of locally destructive disease

with no surface mucosal component
n Stage is primary prognostic indicator; prognosis is less favorable
than in squamous cell carcinoma of the anal canal Immunohistochemistry

n Adenocarcinomas of colorectal type are usually cytokeratin (CK)
Gender, Race, and Age Distribution 7-/CK20+, CDX2+

n Anal gland carcinomas are CK7+/CK20-, CDX2-
n Perianal adenocarcinomas are male predominant
n Mucinous adenocarcinomas associated with anal fistula are most
n No clear racial or geographic predominance
n Average age is approximately 60 years

often CK7-/CK20+, CDX2+
Clinical Features Differential Diagnosis

n Colorectal adenocarcinoma extending from the lower rectum;
n Symptoms include bleeding, pain, a palpable mass, incontinence,
and other changes in bowel habits adenocarcinoma arising in the duplication of terminal hindgut;
n Perianal adenocarcinomas may grow slowly and present with a
adenocarcinoma of the prostate; metastasis
soft tissue mass in the buttock

n The rarity of perianal adenocarcinomas makes prognostication
difficult
n Treatment includes abdominoperineal resection with preoperative
or postoperative combined chemotherapy and radiation

n The prognosis is highly stage dependent
The rarity of perianal adenocarcinomas makes general-

izations with regard to prognosis and optimal therapy
and a metastatic tumor should be excluded. Negative of patients with these cancers difficult. Tumor stage,
staining of anal gland carcinoma for CDX2 is helpful lymph node status, and the degree of differentiation are
in differentiation from a colorectal adenocarcinoma. primary prognostic indicators. Stage for stage, adenocar-
Secondary involvement of anal squamous mucosa may cinoma of the anal canal has a less favorable prognosis
mimic Paget’s disease. Primary Paget’s disease typically than SCC with a 5-year survival rate of approximately
arises in perianal skin as a plaque-like lesion, shows 30%. Treatment may include abdominoperineal resec-
CK7 and GCDFP-15 positivity, and is negative for CK20 tion with preoperative or postoperative radiation and
and CDX2. chemotherapy, depending on stage at presentation.
■ MELANOMA
ANAL MELANOMA—FACT SHEET
Clinical Features Definition

n Primary anal malignant tumor of melanocytic origin
Anal melanoma is a rare mucosal malignancy account- Incidence and Location

ing for 0.05% of all colorectal tumors. The median age n Fewer than 0.1% of colorectal malignancies
at diagnosis is 71 years. It is 1.6 times more common in n Vicinity of the dentate line
women than men and 1.7 times more common among

Whites than Blacks. The most common presenting Morbidity and Mortality
symptoms are rectal bleeding and anal discomfort, and n Death usually caused by disseminated disease rather than local
patients are often misdiagnosed as having hemorrhoidal recurrence

disease. Others may present with inguinal lymphade-
nopathy, and up to 26% of patients have metastatic dis-
n Women more than men, 1.6 to 1
ease at the time of diagnosis. n Median age at diagnosis is 71 years
n 1.7-fold higher among Whites than Blacks
Clinical Features
Pathologic Features n Most common symptom is rectal bleeding
n Other symptoms include pain, change in bowel habits, and

Gross Findings inguinal lymphadenopathy
Anal melanomas are polypoid lesions arising in the Prognosis and Therapy
vicinity of the dentate line and thus may be mistaken n Virtually uniformly fatal, with few long-term survivors
for anal tags or hemorrhoids. The presence of brown n 26% of patients have metastatic disease at the time of
or black tumor discoloration may point to a melanoma. presentation

n Wide local excision is the treatment of choice
Small lesions may be covered by intact mucosa, and
n Abdominoperineal resection is reserved for those in whom
larger lesions are often ulcerated.
transanal excision is not technically feasible
n Tyrosine kinase inhibitors have provided symptomatic relief in a
Microscopic Findings subset of patients with mucosal melanoma and KIT mutations
Microscopically, anal melanomas are similar to cuta-

neous melanomas (Fig. 14.8A). An in situ component
demonstrating junctional nests indicates an anal pri-
mary (Fig. 14.8B). Pagetoid spread is common. The
invasive component may contain epithelioid, polygonal ANAL MELANOMA—PATHOLOGIC FEATURES
cells, spindle cells, or an admixture of both. The epi-
thelioid cells often have eosinophilic granular cyto- Gross Findings
n Frequently polypoid; can be mistaken for hemorrhoids or anal
plasm, variably pleomorphic nuclei, frequent mitotic
tags
figures, and prominent nucleoli. Pigmented tumors n Presence of brown or black pigment suggests melanoma
may demonstrate intracellular brown-to-black melanin
(Fig. 14.8C). Approximately 30% of tumors are amel- Microscopic Findings
anotic. Tumor depth or thickness (Breslow’s level) is n Similar to cutaneous counterpart
measured from the top of overlying mucosa or ulcer n In situ component with junctional nests and pagetoid
using an ocular micrometer. A depth of more than intraepithelial spread is common

n Cell types: epithelioid, with eosinophilic granular cytoplasm and
2 mm is associated with significantly more aggressive
large nuclei with prominent nucleoli; spindle cell type, or mixed
disease. n Intracellular melanin may be visible in tumor cells
■ ANCILLARY STUDIES n S-100 and SOX10 positive in most cases
n Melan-A is positive, sensitive, and specific
n HMB-45 (human melanoma black) is positive but often very

focal
S-100, Sox10, HMB-45, Melan-A, and MiTF are useful Differential Diagnosis
markers of melanocytic differentiation. Even though n Poorly differentiated carcinoma
S-100 is the least specific, it is the most sensitive marker, n Lymphoma
making it a mainstay in the differential diagnostic n Metastatic melanoma
workup of a potential anal melanoma. HMB-45 and

Molecular Pathology
A recent targeted exon sequencing analysis of 467 can-

cer-related genes demonstrated that oncogenic muta-
tional driver events could be identified in 14 of 15 anal
melanomas. Among the most common were activating
mutations in C-KIT, accounting for 30% of cases. Forty
percent of tumors had mutations suggestive of mito-
gen-activated protein kinase (MAPK) pathway activa-
tion, which included loss-of-function NF1 mutations in
20% of all cases, a novel finding in mucosal melanomas.
Activating mutations of BRAF or RAS isoforms are rare
in primary anal malignant melanomas.
A
Differentiation of anal melanoma from poorly differ-

entiated carcinoma and lymphoma is straightforward
with use of ancillary immunostains when the diagnosis
is suspected. Absence of junctional component raises
the possibility of a metastatic melanoma. However,
junctional component may be destroyed by the invasive
tumor, making distinction between primary and sec-
ondary melanoma difficult. A prior history of cutaneous
melanoma is helpful in establishing the diagnosis.
B
The prognosis of anal melanoma is poor. The 5-year

survival rate for stage I (clinically localized) disease is
approximately 27%; for stage II (regional lymph node
metastasis) disease is 10%; and for stage III (distant
metastases) disease, the rate is 0%. Patients with anal
melanoma are treated surgically, but the extent of sur-
gical intervention does not correlate with survival.
Therefore, the surgery of choice is transanal wide local
excision. Abdominoperineal resection is reserved for
cases in which transanal excision is not technically
feasible.
C Several studies have shown survival benefit from the
use of tyrosine kinase inhibitor imatinib in a subset of
FIGURE 14.8
patients with metastatic mucosal melanoma and acti-
A, Anal melanoma growing in a nested pattern. B, Junctional nest of in situ
melanoma indicating primary site in the anal canal. C, Higher power view
vating KIT mutations. Molecular testing to determine
illustrates epithelioid-type cells with abundant pale eosinophilic or clear cyto- the site of activating mutation is required to identify
plasm and large nuclei with prominent nucleoli. Deposits of fine brown mel- the patients likely to respond to treatment with imati-
anin pigment are seen.
nib. Patients carrying mutations in exons 11 or 13 are
usually sensitive. Eventual development of resistance
to imatinib is common. The utility of chemotherapy,
MiTF are specific, but less sensitive markers, and the radiation therapy, and immunotherapy has not been
staining may be focal. Melan-A generally provides more demonstrated in the treatment of patients with anal
diffuse staining of tumor cells. melanoma.
■ TUMORS AND PRECURSOR LESIONS OF

THE PERIANAL SKIN HIDRADENOMA PAPILLIFERUM—FACT SHEET
Definition
Hidradenoma Papilliferum n Benign cutaneous neoplasm originating in adnexal mammary-like
glands
Hidradenoma papilliferum is an uncommon benign Incidence and Location

cutaneous neoplasm that is almost exclusively seen in n Incidence uncertain; uncommon at any site
the vulvar and perianal regions. Although traditionally n Occur in vulvar, perineum, and perianal skin
considered a tumor of adnexal apocrine glands, convinc-

ing morphologic and immunohistochemical evidence Morbidity and Mortality
n Benign lesion with limited morbidity
supports its development from mammary-like glands,
a recently described normal adnexal structure previ-
ously thought to represent ectopic mammary tissue.
n Exclusively in women
Mammary-like glands are found in both sexes and are n Fourth to seventh decades of life
believed to be a source of a spectrum of neoplastic and n Most occur in whites
reactive lesions with striking resemblance to tumors of

the breast. Clinical Features
n Dermal nodule covered by intact skin in most cases
n Occasionally skin is eroded or ulcerated
Clinical Features Prognosis and Therapy

n Benign lesion; conservative excision is usually curative
n Extremely rare reports of possible malignant change

Hidradenoma papilliferum occurs predominantly in the
anogenital skin of white women in the fourth to seventh
decades of life. The most commonly involved sites are
the vulva and perineum. Perianal tumors are rare. The HIDRADENOMA PAPILLIFERUM—PATHOLOGIC
typical lesion manifests as a painless mass of a few mil- FEATURES
limeters in diameter. Rare cases of up to 2 cm in great-
est dimension have been described. Surface erosion or Gross Findings
ulceration may sometimes be present. Malignant trans- n Firm, ill-defined mass within dermis, with normal or ulcerated
formation to adenocarcinoma or adenosquamous carci- overlying skin

n Cut surface yellow-tan to brown
noma is exceedingly rare.
n Size ranges from a few millimeters (typical) to 2 cm (rare)
Pathologic Features n Complex papillary pattern with arborizing fibrovascular cores
n Double epithelial cell layer with outer layer of low columnar
cells with apocrine snouts; inner layer consists of flattened

Gross Findings myoepithelial cells
n Chronic inflammation with prominent plasma cells is common/
n No connection with overlying epidermis

A typical excisional biopsy specimen demonstrates a
small well-circumscribed dermal nodule without a cap- Differential Diagnosis
sule, and the overlying skin may be ulcerated. The cut n Gross differential diagnosis includes cutaneous cyst, hemorrhoids,
surface of the lesion is usually tan to brown and may polyps, carcinoma
have a papillary appearance in larger tumors. n Histologic differential diagnosis includes adenocarcinoma
Microscopically, the lesion has a complex papillary pat-

tern of growth (Fig. 14.9) The papillae have a fibrovas-
cular core and are lined by a double layer of luminal
cuboidal to low columnar cells with pale eosinophilic An erroneous diagnosis of SCC may be made on a small
cytoplasm and occasional apical snouts (decapitation biopsy. The presence of a distinctive double epithelial–
secretion) and a deeper layer of myoepithelial cells. The myoepithelial cell layer favors the diagnosis of hidra-
luminal cells may be slightly pleomorphic and strati- denoma papilliferum. Other adnexal tumors, such as
fied. Lymphoplasmacytic infiltration within stroma is apocrine gland adenoma and trichoepithelioma should
common. also be considered.
LSIL with an optional designation of condyloma within

parentheses.
Clinical Features
Condyloma acuminatum is the most common manifes-

tation of sexually transmitted HPV infection occurring
both in women and men. It affects the perianal skin
more commonly than the anal canal and can also involve
other genital organs. The incidence and demographics
of anal condyloma parallel the recent increase in anal
cancers, particularly among young men who practice
A anal intercourse.
Other conditions associated with increased incidence
of anal condyloma include HIV-affected individuals,
other sexually transmitted diseases, organ transplan-
tation, cigarette smoking, alcohol use, and low socio-
economic status. Most patients present with visible or
palpable polypoid perianal lesions.
Pathologic Features
Gross Findings
Condyloma acuminatum is a tan to gray lobulated polyp-

B oid mass ranging in size from a few millimeters to sev-
FIGURE 14.9
eral centimeters. It commonly grows in clusters and is
Hidradenoma papilliferum. A, A low-power view demonstrates an intracystic
reminiscent of cauliflower florets (Fig. 14.10A). Large
complex papillary proliferation with a lobulated appearance. B, The lesion is lesions should prompt a thorough assessment to exclude
characterized by fibrovascular cores with two-cell layers. The luminal secre- verrucous carcinoma.
tory cells are columnar, with eosinophilic cytoplasm and apical snouts. The
layer of flattened myoepithelial cells is visible between the secretory cells
and the fibrovascular cores. Microscopic Findings
The lesion typically shows epidermal papillomatous

architecture with prominent acanthosis and variable sur-
face parakeratosis (Fig. 14.10B). Koilocytes, a marker of
Prognosis and Therapy HPV infection, can be present in the superficial epithe-
lial layers. Expansion of basal layers with delayed mat-
Hidradenoma papilliferum is a benign lesion treated by uration in the lower third of the epithelium is common
surgical excision with no risk of local recurrence. (Fig. 14.10C). Mitotic figures, if present, are restricted
to the basal zone. These features are essentially those
of LSIL. In lesions treated with podophyllin, there may
be more atypia, along with individual cell keratinization
■ CONDYLOMA ACUMINATUM
and mitotic figures above the basal zone. These features
do not imply a more aggressive lesion and are a response
Condyloma acuminatum is a papillary epithelial prolif- to the topical treatment.
eration of the anogenital skin and, more rarely, of the Foci of HSIL (Fig.14.11) or even of microinvasive
squamous mucosa of the anal canal. It is usually caused carcinoma may be seen in up to 15% of condylomatas
by low-risk HPV types 6 and 11. In previous classifica- smaller than 5 cm in size. These lesions tend to harbor
tions, condyloma acuminatum was not equivalent to high-risk HPV genotypes 16 and 18. High-grade dyspla-
low-grade intraepithelial dysplasia or neoplasia; how- sia arising within a condyloma should be reported as
ever, LAST recommends to designate this lesion as “perianal HSIL (condyloma with high-grade dysplasia).”
A A
B B
FIGURE 14.11
A, Low power view of a condyloma acuminatum with high-grade dyspla-
sia. B, High-power view demonstrating high-grade squamous intraepithelial
lesion in the left part of the condyloma.
Routine use of p16 immunostain is not recommended

for diagnosis. Block positivity for p16 is usually seen in
foci of HSIL arising within a condyloma but is not neces-
sary for diagnosis. Serial sections to rule out foci of HSIL
C and invasive tumor are more useful than ancillary stains.
FIGURE 14.10
Condyloma acuminatum. A, Exophytic rubbery to firm lobulated or warty
cutaneous nodules. They are often light gray to white, bearing a striking Molecular Pathology
resemblance to cauliflower florets. B, At low power, the warty papillomatous
pattern of condyloma is readily apparent. Note the overlying hyperkeratosis.
C, A high-power view reveals low-grade squamous intraepithelial lesion (anal The detection of HPV DNA is currently performed using
intraepithelial neoplasia I) in the lower third of the epithelium.
either real-time PCR-based techniques (for genotypes 16
and 18) or multiplex PCR with line-probe hybridization
(all genotypes). Whereas the majority of condyloma har-
bor HPV types 6 and 11, those with high-grade dysplasia
demonstrate genotypes 16 and 18, underscoring the link
between HPV types 16 and 18 and malignancy.
CONDYLOMA—FACT SHEET CONDYLOMA—PATHOLOGIC FEATURES

n Exophytic papillomatous human papillomavirus–related lesion n Polypoid, exophytic, cauliflower-like lesions
of squamous epithelium with low propensity for progression to n Frequently multiple
malignancy n Few millimeters to 2 cm or larger in size

n High incidence in general population; particularly common in n Papillomatous proliferation of squamous epithelium with
men who have sex with men (MSM) acanthosis and parakeratosis
n Most commonly develop in the perianal skin; may be also seen n Koilocytes with perinuclear halo and enlarged, hyperchromatic,
in the anal canal irregularly shaped nuclei in the upper epithelial layers
n Binucleated koilocytes are common
Morbidity and Mortality n Epithelium demonstrates orderly maturation, with possible atypia
n Most are benign; some may progress to cancer

in the basal two to three layers
n Mitoses limited to the basal zone
n High-grade squamous intraepithelial lesion (HSIL) within a

condyloma should be reported
n Formerly more prevalent in females; now more in MSM
n Low socioeconomic status is linked to a higher incidence

Molecular Pathology
n The age range is broad, encompassing sexually active men and
n Low-risk human papillomavirus (HPV) types 6 and 11 are found
women
in the majority of condyloma cases
n High-risk HPV types 16 and 18 may be found in condyloma with HSIL
Clinical Features
n Most patients present with visible or palpable polypoid lesions
n Coexisting lesions of the vulva are common in women; penile
n Verrucous carcinoma
lesions are frequently encountered in men
n Hemorrhoid, fibroepithelial polyp, mucosal prolapse polyp

n Most pursue a benign clinical course
n Immunosuppressed individuals, including organ transplant
patients, HIV-positive patients, particularly those with a low CD4 related to multiple causes including HIV and organ
count, have a higher risk for recurrence and progression to high- transplantation.
grade squamous intraepithelial lesion
n Treatment includes topical agents, such as podophyllin and
ablative procedures, such as local excision, cryotherapy, and

electrocoagulation ■ PERIANAL HIGH-GRADE SQUAMOUS
INTRAEPITHELIAL LESION (BOWEN’S
DISEASE)
Perianal SIL is similarly subdivided into LSIL and HSIL
by LAST terminology. The term Bowen’s disease is typ-
Condyloma acuminatum should be distinguished from a ically applied to high-grade squamous intraepithelial
verrucous carcinoma. Any large condylomatous lesion neoplasia occurring in the perianal (marginal) skin, sim-
should be scrutinized for subtle evidence of invasion, ilar to Bowen’s disease in other cutaneous sites, where
which may manifest as endophytic growth with “push- it is synonymous with SCC in situ. Bowen’s disease is
ing” border extending into the underlying stroma. The similar to anal HSIL (AIN-3), being associated with
histologic similarity between a condyloma and verru- high-risk HPV genotypes 16 and 18. However, the treat-
cous carcinoma can make distinction virtually impossi- ment and prognosis of these two conditions are differ-
ble on a biopsy. Benign lesions to be distinguished from ent, making the distinction important.
condyloma include fibroepithelial polyp, hemorrhoids,
and mucosal prolapse polyps.
Clinical Features

Bowen’s disease occurs in middle-aged and older individ-
uals with female predominance. It is roughly four times
Treatment of anal condyloma includes topical agents more common in whites than in African Americans. The
such as podophyllin or ablative techniques, including dominant complaint is perianal itching; other symptoms
local excision, electrocautery, or cryotherapy. The recur- include slight bleeding or induration. Other synchronous
rence rate is high because of field effect of HPV infection HPV-associated lesions, such as condyloma acuminatum,
and is further increased because of immunosuppression vulvar SIL, and cervical SIL, are also commonly present.
PAGET’S DISEASE—FACT SHEET PAGET’S DISEASE—PATHOLOGIC FEATURES

n Intraepithelial form of adenocarcinoma that may or may not have n Erythematous patches, irregular in shape and variable in extent
an underlying component of invasive adenocarcinoma n If invasive component is present, the dermis may be indurated or
may contain pools of mucin

n Most cases of primary perianal Paget’s disease represent Microscopic Findings
extension of Paget’s disease of the vulva n The squamous epithelium is infiltrated by large cells with pale
n Secondary perianal Paget’s disease is associated with internal cytoplasm, a central vesicular nucleus, and prominent nucleolus
malignancy, most commonly rectal adenocarcinoma n Secondary Paget cells may have signet ring morphology
n Secondary Paget’s disease constitutes approximately 50% of all n Paget cells may form clusters or intraepithelial glands
cases n Paget cells may infiltrate the dermis and may extend into the
cutaneous adnexal structures

Morbidity and Mortality n Mucin stains such as mucicarmine, Alcian blue, and periodic
n Significant morbidity because of wide local excision for primary

acid–Schiff–diastase are helpful
Paget’s disease and by the complications of radical surgery for the
underlying rectal adenocarcinoma Immunohistochemistry
n Cytokeratin (CK) 7-/CK20+/GCDFP-/CDX2+: secondary Paget’s
Gender, Race, and Age Distribution disease with associated colorectal adenocarcinoma
n CK7+/CK20-/GCDFP+/CDX2-: primary Paget’s disease
n Majority of cases of primary Paget’s disease occur in
postmenopausal white women

n Men and women are affected equally in secondary Paget’s Differential Diagnosis
disease n Squamous hyperplasia with koilocytes
n Pagetoid high-grade squamous intraepithelial lesion or Bowen’s
Clinical Features disease

n Melanoma
n Pruritic erythematous, scaly patches; lesion may extend beyond
visible borders
n Vulvar lesions often present
Prognosis and Therapy Prognosis and Therapy

n For primary Paget’s disease, wide local excision is indicated
n Recurrences are frequent and are addressed by reexcision
n Primary Paget’s disease with dermal invasion may metastasize

The rate of progression of Bowen’s disease to invasive
and has a less favorable prognosis
SCC is approximately 2% to 5% per year. Wide local
n If Paget’s disease is associated with distal rectal adenocarcinoma,
the stage of the rectal tumor determines the prognosis excision remains the gold standard for therapy. Other
n Paget’s disease is often a marker of soft tissue extension of rectal modalities used in the management of perianal Bowen’s
adenocarcinoma. The prognosis is often poor disease include cryotherapy, CO2 laser ablation, top-
ical 5-FU, argon laser therapy, and photodynamic
therapy.
Pathologic Features
■ BOWENOID PAPULOSIS
Grossly, a reddish scaly patch or plaque can be seen on
the skin surface (Fig. 14.12A). Microscopically, there
are features of HSIL with lack of maturation and nuclear Bowenoid papulosis, also an HPV-associated lesion, is
atypia involving the full epithelial thickness. Mitotic seen primarily in young adults and is characterized by
figures, sometimes atypical, are seen in the middle or red-violaceous skin papules. It is more common in the
upper third of the epidermis (Figs. 14.12B and C). penis or scrotum but can occur in the perianal region
and can be seen synchronously with condyloma acum-
inatum. The natural history of bowenoid papulosis is
usually innocuous, with resolution spontaneously or
a benign outcome after local excision. The histologic
features of bowenoid papulosis resemble those of anal
Differential diagnosis includes bowenoid papulosis, HSIL (Fig. 14.13) and Bowen’s disease, with highly
Paget’s disease, and malignant melanoma. Whereas atypical nuclei scattered throughout the epithelial thick-
Paget’s disease can be distinguished by mucicarmine or ness. Closer examination, however, reveals orderly
periodic acid–Schiff (PAS) positivity, melanoma shows background maturation in contrast to crowded dis-
positive immunostaining for S-100, Sox10, HMB-45, tribution of nuclei in anal HSIL and Bowen’s disease.
MiTF, and Melan-A. Sparing of the pilosebaceous units and involvement of
A A
B
B
FIGURE 14.13
Bowenoid papulosis is similar to anal intraepithelial neoplasia (anal intraepi-
thelial neoplasia), grade III (A), with positive immunostaining for p16, a sur-
rogate marker for high-risk human papillomavirus infection (B).
■ SQUAMOUS CELL CARCINOMA OF THE

PERIANAL SKIN
Tumors that cannot be visualized on gentle traction to

the buttocks and are within 5 cm of the mucocutaneous
junction are categorized as perianal. The distinction
C between anal and perianal tumors has therapeutic impli-
cations. SCC of the perianal skin is less common than
FIGURE 14.12 SCC of the anal canal and has a better prognosis. It usu-
Perianal high-grade squamous intraepithelial lesion (HSIL) or Bowen’s dis- ally occurs in the sixth and seventh decade of life, has no
ease. A, Excisional specimen showing thin reddish patches on the perianal clear gender predominance, and is associated with high-
skin; these represent areas of HSIL microscopically. B and C, High-power
view of two different examples of Bowen’s disease. Note the lack of epithe-
risk genotypes of HPV, similar to SCC of the anal canal.
lial maturation with nuclear pleiomorphism (B) and multiple, including atyp- Perianal SCC may present with a painful mass, itching,
ical, mitoses (C). tenesmus, or bleeding and usually has raised rolled bor-
ders with central ulceration (Fig. 14.14A). Advanced
tumors may invade anal canal. Any nonhealing ulcer
the upper zone of the eccrine glands by dysplastic cells of the perianal skin should be examined via biopsy to
is typical of bowenoid papulosis, whereas the opposite exclude malignancy.
pattern is generally seen in anal HSIL and Bowen’s The typical histology is that of well- or moderately
disease. differentiated keratinizing SCC (Figs. 14.14B and C).
and occasional bleeding and crusting. Nodular growth

of basophilic basaloid cells and distinct palisading of the
peripheral row of cells is typical for BCC. Strong immu-
noreactivity for Ber-EP4 is seen in BCCs and is absent
in SCC.
The preferred treatment is surgery, contrasting sharply
with combined modality chemoradiation used for SCC
of the anal canal, which underscores the importance of
correct site designation for these tumors. Small lesions
(<3 cm) are managed by local excision with wide (1-cm)
negative margins. Larger and more invasive lesions may
require abdominoperineal resection and radiation with
or without chemotherapy. The tumor may metastasize to
inguinal lymph nodes; therefore, prophylactic radiation
A to the nodal region is given for T2 to T4 lesions. The
5-year survival rate ranges from 70% to 89%. Local con-
trol for the same period is between 69% and 87%.
■ VERRUCOUS CARCINOMA
Verrucous carcinoma differs from a usual condyloma

acuminatum by larger size and distinctive endophytic
growth. Cases harboring areas of infiltrative or destruc-
tive invasion and/or marked cytologic atypia are classi-
fied as a subtype of SCC.
B
Verrucous carcinoma is more common in men, with a

male-to-female ratio of 2.7 to 1. The average age of pre-
sentation is approximately 44 years. The most common
symptom is perianal mass; other complaints include
pain, abscess, fistula, bleeding, weight loss, and pruritus.
The tumor presents as a slowly growing lesion, poorly
responsive to topical therapy. When fully formed, it is a
large fungating mass that deeply invades perirectal tis-
sue with fistula formation.
Pathologic Features
C
Gross Findings
FIGURE 14.14
Squamous cell carcinoma (SCC) of the perianal skin (anal margin). Tumors Verrucous carcinomas are firm, warty, white to gray
in this location are usually of the keratinizing type, identical to cutaneous
SCC. B, A well-differentiated area of SCC. C, An area of poor differentiation
cauliflower-like masses, measuring up to 30 cm in size.
in the same tumor. Although the exophytic nature of the lesion is most
obvious, the endophytic component may also be appre-
Tumor staging follows the criteria used in other cuta- ciated grossly.
neous SCCs. The tumor may metastasize to inguinal
lymph nodes, which is an adverse prognostic factor. Microscopic Findings
Differential diagnosis includes cutaneous BCC and
melanoma. BCC of perianal skin is rare and presents as The epithelium shows prominent acanthosis and pap-
pearly nodules with raised borders, central ulceration, illomatosis with blunt, broad epithelial extensions
and often shows a lymphoplasmacytic inflammation.

VERRUCOUS CARCINOMA—FACT SHEET Keratin-filled cysts may be present in the endophytic
portion of the lesion, and surface keratinization may be
Definition
prominent. The cytologic atypia is minimal, if any, and
n A well-differentiated, locally aggressive squamous cell carcinoma
with no potential for metastasis

neoplastic epithelium appears benign, with orderly mat-
uration, basal mitoses, and retention of cellular polarity
Incidence and Location (Fig. 14.15B). The diagnosis may be difficult because
n Rare of limited sampling, especially in biopsies, and requires
n Perianal skin but may involve any part of the anogenital region awareness of a possibility of verrucous carcinoma. As
mentioned earlier under the discussion of anal tumors,
Morbidity and Mortality verrucous carcinoma is distinct from the giant condy-
n High morbidity and 20% mortality rate
loma of Buschke-Lowenstein. The latter is associated
with low-risk HPV DNA genotypes, shows viral cyto-
pathic changes, and only has an exophytic component.
n Males more than females, 2.7 to 1
n Average age of presentation is 44 years
n No racial predominance
Clinical Features
Ancillary Studies
n Cauliflower-like exophytic mass
n Resembles condyloma; large size suspicious

Ancillary testing is of limited value in the diagnosis of
n Complaints include mass lesion, pain, bleeding, abscess, fistula,
pruritus, and weight loss

anal or perianal verrucous carcinoma.

n Treatment of choice is wide local excision, which is potentially
curative
n Larger lesions with extensive locally destructive growth are treated
with abdominoperineal resection or combined radiation and

chemotherapy
VERRUCOUS CARCINOMA— PATHOLOGIC FEATURES
Gross Findings
n Firm, tan-white, cauliflower-like polypoid mass; also shows an
endophytic component on sectioning
A
n Squamous mucosa shows acanthosis, papillomatosis and virtually
no cytologic atypia
n Blunt epithelial extensions push into underlying stroma, with no
desmoplastic reaction
n Lymphoplasmacytic inflammation is common at the base of
lesion
Molecular Pathology
n Limited utility in diagnosis
n Not required for diagnosis
n Condyloma, particularly Giant condyloma of Buschke-Lowenstein
(which is associated with low-risk human papillomavirus and

does not show an endophytic components) B
n Squamous cell carcinoma
FIGURE 14.15
Verrucous carcinoma. A, At low power, the papillomatous pattern with abun-
dant surface keratinization and innocuous-appearing cytologic features are
“pushing” downward into the underlying stroma evident. Note the downward projections of the neoplasm into the submu-
cosal connective tissue. B, Typical “pushing” invasion of verrucous carcinoma
(Fig. 14.15A). The epithelial–stromal interface may cor- without desmoplastic reaction. There is no significant nuclear atypia or dys-
respond to an area of destruction of native structures maturation in this tumor. Mitotic activity is not present above this basal zone.
■ MOLECULAR PATHOLOGY and women, and the majority of cases are diagnosed in
the sixth to eighth decades of life. Early Paget’s lesions
The diagnosis of verrucous carcinoma is based on histol- appear as erythematous, scaly patches and are typi-
ogy and molecular testing has limited utility. The pres- cally pruritic; erosions or ulcers may also develop. The
ence of high-risk HPV genotype in biopsy samples from lesions may look small; however, neoplastic cells expand
perianal mass lesions should raise suspicion against a far beyond the visible abnormality within the epithe-
diagnosis of verrucous carcinoma. lium and may involve the anal canal. The rarity of the
disease and its resemblance to a variety of benign der-
matologic disorders may result in delayed diagnosis and
treatment.
Verrucous carcinoma can be distinguished from con-

Pathologic Features
dyloma acuminatum by larger size (>10 cm), presence
of endophytic growth with a broad pushing interface, a
thicker keratinized layer, and more prominent papillo- Gross Findings
matosis. If a lesion contains areas with irregular infil-
trating tumor interface, desmoplastic stromal response, A typical specimen is a punch biopsy. Excision speci-
or areas with marked cytologic atypia, it should be clas- mens may demonstrate scaly, erythematous patches or
sified as SCC. plaques or, less commonly, erosion or ulcer. If an inva-
sive component is present, the dermal or submucosal
tissue may appear indurated or nodular or may contain
mucinous material.
Perianal verrucous carcinomas are locally destructive
but do not metastasize. The treatment of choice is wide The squamous epithelium is infiltrated by scattered large
local excision, which is curative in early phases of the cells with abundant pale or amphophilic mucin-con-
disease. For particularly large and destructive lesions, taining cytoplasm, a centrally placed nucleus, vesicular
more aggressive surgery, such as abdominoperineal chromatin, and a conspicuous nucleolus (Fig. 14.16A).
resection and (neo)adjuvant radiation and chemother- In addition to the classic Paget cell, a signet ring cell–
apy, may be necessary. Local recurrences are common, type cell may also be seen in secondary Paget’s disease.
and approximately 20% of patients eventually succumb Paget cells may infiltrate the epithelium as single cells
to the disease. or as clusters or even form intraepithelial glandular
structures with intraluminal necrosis. Paget cells may
also involve cutaneous adnexal pilosebaceous units and
eccrine and apocrine ducts. Rarely, Paget cells appear
■ PAGET’S DISEASE
to directly infiltrate the perianal stromal tissue, a con-
dition called invasive Paget’s disease. In some cases, an
Paget’s disease of the perianal region is a form of ade- underlying eccrine or apocrine adenocarcinoma of the
nocarcinoma localized within the squamous epithe- skin or synchronous anorectal adenocarcinoma may be
lium. In the primary form of the disease, Paget cells are identified. In addition, the epidermis may demonstrate
thought to originate from the apocrine glands of cuta- a spectrum of proliferative changes, such as simple
neous adnexal structures. The secondary form of the hyperplasia or papillomatous hyperplasia. Parakeratosis,
disease represents approximately half of all cases and is hyperkeratosis, erosion, or ulceration may be
caused by pagetoid extension of the primary colorectal also seen.
or anal adenocarcinoma into the overlying squamous
epithelium.
Histochemistry
The majority of cases of primary perianal Paget’s dis-

ease occur in postmenopausal white women with Because Paget cells contain acid mucopolysaccharides,
Paget’s disease of the vulva extending to the perianal they stain with mucicarmine, Alcian blue (pH, 2.5), and
skin. Secondary Paget’s disease equally affects men PAS–diastase.
positive for CK7 and gross cystic disease fluid protein

(GCDFP) and are negative for CK20, consistent with
apocrine gland differentiation. In secondary Paget’s
disease, Paget cells are most commonly CK7−/CK20+/
CDX2+, consistent with the origin from a colorectal
adenocarcinoma (Fig. 14.16B and C). A CK7+/CK20+/
GCDFP− profile may be seen in secondary Paget’s dis-
ease associated with a urothelial carcinoma.
When perianal Paget’s disease is associated with papil-

A
lomatous squamous hyperplasia, Paget cells can show
small, pyknotic nuclei and perinuclear halo mimicking
koilocytes. Pagetoid Bowen disease may also exhibit
a nested growth pattern mimicking Paget’s disease.
However, mucin stains and immunopositivity for CK7,
as well as negativity for p63 and CK5/6 are helpful
in confirming the diagnosis of Paget’s disease. The
presence of melanin in neoplastic cells is not a proof
of melanoma because both Paget cells and dysplastic
cells of Bowen’s disease may contain melanin pigment.
Melanocytic immunomarkers, such as S-100, SOX10,
HMB-45, and MART-1 (melanoma antigen recognized
by T cells 1), are positive in melanoma and negative in
Paget’s disease.
Patients with primary perianal Paget’s disease are

treated with wide local excision. Local recurrence is
frequent and is treated with reexcision. The prognosis
is favorable with normal life expectancy. If Paget cells
invade the dermis, which may occur in primary Paget’s
disease, the risk of metastasis adversely affects the prog-
nosis. Secondary Paget’s disease has a poor prognosis,
defined by the primary visceral tumor, most commonly
a distal rectal adenocarcinoma.
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15
Pathology of the Gallbladder
and Extrahepatic Bile Ducts
■ James Conner, MD, PhD and Amitabh Srivastava, MD
The gallbladder and extrahepatic bile ducts show a lim- In 0.5% to 1% of cases, a porcelain gallbladder, char-
ited spectrum of inflammatory and neoplastic disorders, acterized by diffuse calcification of the wall, is seen
but these disorders are significant because they affect radiographically and intraoperatively. This finding cor-
a large proportion of the world’s population. The most relates with the pathologic diagnosis of hyalinizing cho-
common (>95%) is cholelithiasis. Inflammation in the lecystitis (HC) and has classically been associated with
gallbladder secondary to stones presents either as acute or an increased risk of gallbladder carcinoma. This risk
chronic cholecystitis and may lead to significant complica- has traditionally been considered sufficient to warrant
tions such as empyema, perforation, or fistula. Carcinomas prophylactic cholecystectomy, but recent studies have
of the gallbladder are uncommon and arise from flat, pol- shown the risk to be lower than previously reported.
ypoid or cystic precursor lesions and may sometimes be Sterile acalculous cholecystitis is much less common,
detected incidentally in patients undergoing a routine and most patients present with multiple other comor-
cholecystectomy. The recent World Health Organization bidities, especially in the hospital setting. It is most
(WHO) classification has proposed a new nomenclature commonly associated with ischemia and dysmotility.
for these precursor lesions to align them with precursors Infectious cholecystitis is rare, occurring predominantly
seen elsewhere in the pancreaticobiliary tree. Stage is the in immunocompromised patients. The most common
most important prognostic factor, and the 5-year survival infections are Cryptosporidium parvum and cytomeg-
rate is dismal because most cases are at an advanced stage alovirus. Rare cases of cholecystitis represent mani-
at initial presentation or have multifocal biliary dysplasia. festations of systemic diseases, including eosinophilic
cholecystitis, presenting as a component of eosinophilic
gastroenteritis, primary sclerosing cholangitis (PSC)–
associated cholecystitis, and immunoglobulin (Ig) G4–
GALLBLADDER associated sclerosing cholecystitis, which is present in
almost all patients with IgG4 sclerosing cholangitis of
the bile duct.
■ CHOLECYSTITIS
Clinical Features Pathologic Features
Cholecystitis presents with intermittent postprandial Gross Findings

epigastric or right upper quadrant pain. By far the most
common underlying cause is cholelithiasis, which in Acute cholecystitis is characterized by mucosal ery-
some cases may also lead to obstruction of the bile duct thema, friability, and ulceration. The gallbladder wall
(choledocholithiasis). Acute cholecystitis is also asso- may be thickened and edematous. In severe cases, serosi-
ciated with fever and leukocytosis. Clinical examina- tis may be present with a fibrinous exudate on the serosal
tion is supported by a positive “Murphy sign” in which surface. Chronic cholecystitis most often exhibits mural
pain is elicited when the inflamed gallbladder descends fibrosis with a thick and firm gallbladder wall. Extensive
during inspiration. The clinical impression may be con- hyalinization and calcification (>80% of the circum-
firmed by ultrasound, which demonstrates choleliths, ferential wall) is classified as porcelain gallbladder.
gallbladder wall thickening, and pericholecystic fluid. Xanthogranulomatous cholecystitis may be associated
Xanthogranulomatous cholecystitis may show mural with mural nodules that can grossly mimic malignancy
nodularity and dense adhesions to adjacent organs, (Fig. 15.1A). Cholesterolosis, which is found in approx-
which may cause clinical concern for malignancy. imately 20% of cholecystectomy specimens, results in a
435
In cases of both acute and chronic cholecystitis, these

Cholecystitis—Fact Sheet polyps may have associated reactive epithelial changes
and must be distinguished from the polypoid dysplastic
Definition lesions. Pyloric gland and intestinal metaplasia may also
n Acute or chronic inflammatory injury to the gallbladder, usually as be present as a consequence of chronic injury and repair
a consequence of cholelithiasis (Fig. 15.5). Less frequently, squamous metaplasia may
be seen. Xanthogranulomatous cholecystitis is caused
by extravasation of bile into the gallbladder wall, elic-
n 10% to 20% of adult population in the United States and
Western Europe with cholelithiasis iting a florid histiocytic response (Fig. 15.6). Reactive
n 80% to 90% are calculous cholecystitis; rest are acalculous fibroblasts are present, which can be so cellular as to
n 1000 to 4000 per 100,000 individuals present with symptomatic mimic a mesenchymal neoplasm. Clues to a benign diag-
disease nosis include bland histology, abundant foamy macro-
phages, and admixed cholesterol clefts and bile pigment.
Cholesterolosis is characterized by clusters of cholester-
n Complications include sepsis, abscess, perforation, peritonitis, and
fistulas
ol-laden macrophages that accumulate under the epi-
thelial surface. It is generally considered an incidental
Gender, Race, and Age Distribution finding and does not necessitate further work-up.
n Risk increases with age Hyalinizing cholecystitis is defined by paucicellular
n Female predominance for calculous cholecystitis hyaline sclerosis that obliterates all of the layers of the
n Males affected more frequently for acalculous cholecystitis gallbladder wall (Fig. 15.7). It is typically seen, on aver-
North American Indians affected more commonly than White
n
age, in patients one decade older than other variants of
Americans, African Americans, and Asians
cholecystitis and in those with long-standing gallbladder
Clinical Features inflammation. Focal or diffuse dystrophic calcification
n Right upper quadrant or epigastric pain with tenderness may be present in the gallbladder wall. HC cases with
(“Murphy sign”) diffuse (>80%) calcification correlate with porcelain
n Fever, nausea, vomiting gallbladder, but all cases of radiographically identified
n Mild jaundice may be present
porcelain gallbladder show HC histologically. However,
the converse is not always true. Paucicellular hyalin-
izing sclerosis of HC may be present in some patients
n Peptic ulcer, pancreatitis, kidney stones
n Appendicitis or intestinal obstruction

with only minimal or no mural calcification. HC, and
in particular cases with minimal or no calcification, is
associated with an increased (10%–20%) risk for gall-
bladder carcinoma. Given this risk, complete histologic
stippled mucosal surface, often described as “strawberry
gallbladder” (Figs. 15.1B and C). Choleliths or choledo-
choliths may be present. Cholesterol gallstones, the most
common type, are yellow-green, whereas gallstones Cholecystitis—Pathologic Features
composed of abundant bilirubin (“pigment stones”)
Gross Findings
are black or brown. Black pigment stones are some-
n Acute cholecystitis: mucosal erythema, friability, and ulceration or
times associated with hereditary hemolytic conditions,
frank necrosis
although the majority of cases are sporadic. n Chronic cholecystitis: mural fibrosis with thick, firm wall
n Xanthogranulomatous cholecystitis: mural nodules and extension
Microscopic Findings into adjacent organs may mimic malignancy

n Choleliths may be present
n Thick wall with calcification in porcelain gallbladder

Features of acute cholecystitis include neutrophilic or
eosinophilic infiltration, mucosal erosion or ulceration, Microscopic Findings
hemorrhage, gangrenous necrosis, and reactive epi- n Mucosal erosion, ulcer, or hemorrhage with neutrophilic infiltrate
thelial changes (Fig. 15.2). The predominant findings in acute cholecystitis
in chronic cholecystitis are mural fibrosis, muscular n Transmural necrosis in gangrenous cholecystitis
hypertrophy, and a variable degree of mononuclear cell n Chronic inflammation with mural thickening, pyloric gland, and
infiltration (Fig. 15.3). Mucosal invaginations through intestinal metaplasia in chronic cholecystitis
n Foamy histiocytes with a reactive spindle cell proliferation in
the muscularis propria, known as Rokitansky-Aschoff xanthogranulomatous cholecystitis
sinuses, are frequently seen in chronic cholecystitis and n Hyalinized wall with calcification in porcelain gallbladder
are usually associated with muscular hypertrophy. The
sinuses may undergo striking cystic change because of Genetics
outflow obstruction and can mimic a neoplastic process n Not relevant
(Fig. 15.4). Inflammatory polyps may also be present.

CHAPTER 15 Pathology of the Gallbladder and Extrahepatic Bile Ducts 437
A B
FIGURE 15.1
Xanthogranulomatous cholecystitis with a thickened gallbladder wall and gray-yellow nodules (A), which can mimic malignancy on radiologic examination.
Cholesterolosis is a frequent finding in cholecystectomy specimens and shows a yellow stippled mucosal appearance (B), which corresponds to foamy lip-
id-laden macrophages in lamina propria on microscopy (C). At times, this deposition may be exuberant and form a discrete polypoid lesion (“cholesterol
polyp”).
examination of gallbladder specimens with HC is war- carcinoma may be an incidental diagnosis in a gall-
ranted. Carcinomas associated with HC are generally bladder removed for acute or chronic cholecystitis. In
very well differentiated and may be paucicellular with other instances, cholecystectomy is performed for a
only scattered neoplastic glands present in the wall. An preoperative finding of a mass lesion suspicious for
overt desmoplastic response is not always present. cancer. Not surprisingly, the clinical presentation and
morphologic differential diagnosis are quite different
in these two situations. For this reason, early and
advanced gallbladder carcinomas are discussed under
Gallbladder Dysplasia and Carcinoma
separate headers later. However, it must be empha-
sized that early and advanced cancers are not distinct
Neoplasia involving the gallbladder is diagnosed in entities and represent two stages of the same neoplas-
two distinct clinical scenarios. Dysplasia or early tic process.
A A
B B
FIGURE 15.4
FIGURE 15.2
Adenomyoma. A, At low power, the presence of epithelium in the perimus-
Acute cholecystitis presents microscopically with marked acute inflammation, cular connective tissue raises the possibility of invasive carcinoma, but the
edema, hemorrhage, or necrosis and any one of these features can predom- lining epithelium is benign and does not show any atypia. B, In some cases,
inate. Acute gangrenous cholecystitis shows striking transmural necrosis (A), deeper levels can demonstrate communication with the surface mucosa.
but in other examples, a marked acute inflammatory infiltrate composed of Note the marked cystic dilation that may appear radiologically as a mass
neutrophils and eosinophils may be present (B). worrisome for neoplasia.
DYSPLASIA AND EARLY GALLBLADDER

CARCINOMA
Many cases of early gallbladder neoplasia are found

unexpectedly at the time of pathologic evaluation of a
routine cholecystectomy rather than by symptomatic
presentation or radiographic imaging. Gallbladder dys-
plasia can be divided into flat (or micropapillary) lesions
(biliary intraepithelial neoplasia [BilIN]) and exophytic
FIGURE 15.3 lesions (intracholecystic papillary neoplasm [ICPN]).
The typical features of chronic cholecystitis include marked expansion of Exophytic lesions may be suspected on preoperative
the lamina propria by a lymphoplasmacytic inflammatory infiltrate or meta-
plastic features of chronicity such as pyloric gland and intestinal metaplasia.
imaging, but BilIN is usually clinically occult. Early
Deep invaginations of the mucosa into and beyond the muscularis propria invasive gallbladder carcinoma with invasion into the
(Rokitansky-Aschoff sinuses) are often present. lamina propria (T1a) or into the muscular layer (T1b)
A B
FIGURE 15.5
Common forms of metaplasia in the gallbladder include pyloric gland metaplasia (A), where small tubular gastric-type pyloric glands replace the native pancre-
aticobiliary type epithelium. These foci are MUC6 positive, similar to glandular epithelium in the gastric antrum. Intestinal metaplasia is often present adjacent
to neoplasia in the gallbladder and is characterized by goblet cells (B). Paneth cells or intestinal-type neuroendocrine cells with basal red granules may also be
seen in some cases as part of the metaplastic process.
FIGURE 15.7
FIGURE 15.6
Hyalinizing chronic cholecystitis, also known as “porcelain gallbladder,” shows
Xanthogranulomatous cholecystitis can mimic malignancy on imaging and massive thickening of the gallbladder wall with fibrosis and calcification. A
extend into adjacent hepatic parenchyma. The inflammatory infiltrate is char- meticulous gross and microscopic examination is essential to rule out the
acterized by foamy histiocytes, often around extruded bile; variable acute possibility of malignancy in these cases.
inflammation; and dense fibrosis.
arising from BilIN cannot be identified preoperatively Pathologic Features

with certainty. ICPNs are present in 0.5% of all chole-
cystectomies and about 6% of all gallbladder carcinomas Gross Findings
arising in an ICPN.
Risk factors for BilIN and early gallbladder carcino- As expected, flat dysplasia or BilIN is invisible on gross
mas include cholelithiasis, chronic cholecystitis, history examination and is detected in random sections from
of gallbladder polyps, PSC, anomalous union of pan- a cholecystectomy. However, ICPN, by definition, is a
creatobiliary ducts, and familial adenomatous polypo- grossly visible lesion, typically 1 cm or larger, with a
sis. In contrast to flat dysplasia, ICPN is not strongly median size around 2 cm. Some ICPNs are friable and
associated with cholelithiasis. Both types of dysplasia may be present as detached fragments within the gall-
are associated with advanced age. There appears to be bladder lumen. They can be mistaken for luminal debris
geographic variance in the incidence of early gallbladder if this possibility is not considered. Mild thickening of
carcinoma. Asia and South America have two to three the gallbladder wall may be seen in early invasive car-
times the incidence in North America and Europe. cinomas, but this is often too subtle to be of practical
Dysplasia and Early Gallbladder Carcinoma—Fact Sheet
Biliary intraepithelial neoplasia used to be graded using
Definition
a three-tiered system (BilIN 1–3), but a two-tiered
n Neoplasia confined to the gallbladder epithelium (dysplasia) or
carcinoma confined to the lamina propria (T1a) or the muscular

scheme is now preferred. BilIN 1–2 is now classified as
wall (T1b) low grade and BilIN-3 as high grade. Low-grade BilIN
is characterized by mild to moderate cytologic atypia
Incidence and Location characterized by nuclear enlargement, hyperchroma-
n Approximately 2% to 5% of patients undergoing cholecystectomy sia, and mildly irregular contours (Fig. 15.8). Nuclear
in North America and Europe polarity toward the basement membrane is maintained.
n Higher incidence in South America and Asia
Architecturally, the epithelium may be completely flat
n Risk factors: cholelithiasis, primary sclerosing cholangitis,
advanced age, gallbladder polyps, familial adenomatous or form small simple papillae, but complex architec-
polyposis, anomalous union of pancreatobiliary ducts tural abnormalities are not seen. In contrast, high-grade
n 6% of all cancers arise in an intracholecystic papillary neoplasm BilIN is characterized by marked nuclear atypia, pleo-
morphism, and loss of polarity. Significant architectural
Morbidity and Mortality complexity is often present with papillary fronds, cribri-
n Dysplasia: cholecystectomy with negative margins is curative
forming, tufting, and intraluminal bridging (Fig. 15.9).
n Early carcinoma: favorable prognosis (∼90% 5-year survival) if
gallbladder is examined entirely to exclude deeply invasive tumor

Because architectural complexity, including forma-
tion of papillae, may also be seen in BilIN, a macroscopic
Gender, Race, and Age Distribution criterion of a grossly visible lesion, typically 1 cm or
n Female predominance larger, is required for a diagnosis of ICPN (Fig. 15.10).
n Mostly affects adults Gland architecture in ICPN may be papillary or tubular
but is most commonly a mixture of both. Extensive pap-
Clinical Features illary architecture is associated with a higher risk for
n Often asymptomatic
invasive carcinoma. ICPNs are also subclassified accord-
n Cholecystitis and cholelithiasis are usual indications for
cholecystectomy
ing to the predominant cytologic type: biliary, gastric,
intestinal, and oncocytic. Gastric-type ICPNs may be
Differential Diagnosis further subdivided into foveolar and pyloric subtypes,
n Reactive epithelial atypia
n Dysplasia involving Rokitansky-Aschoff sinuses versus invasive
carcinoma
A
utility, especially because most inflamed gallbladders

are edematous. Adequate sampling is key to ensure an
accurate diagnosis. Although there is some variation in
“optimal practice” based on expert opinion, most agree
on the general principle that more sections should
be taken with increasing degrees of atypia or dyspla-
sia. The cystic duct margin and one to three sections B
of representative mucosa are sampled routinely in all
cholecystectomy specimens. When low-grade dysplasia
or epithelial atypia insufficient for a definite diagno-
sis of dysplasia is found, submission of extra random
sections is useful to exclude high-grade dysplasia or to
detect more easily diagnosed foci of neoplasia, respec-
tively. When high-grade dysplasia is seen, thorough
sampling is mandatory to rule out an invasive carci-
noma. Similarly, multiple additional sections should be
submitted in T1a or T1b carcinomas to exclude a more
FIGURE 15.8
advanced tumor. Areas grossly suspicious for invasive
Low-grade dysplasia (biliary intraepithelial neoplasia) of the gallbladder. The
carcinoma should be entirely examined. ICPNs should dysplastic epithelium’s cytology is identical to that of a colonic adenoma and
be submitted entirely along with generous sampling of shows abrupt transition from the normal epithelium on the right (A). Higher
adjacent mucosa because they are commonly associ- magnification (B) shows typical features with hyperchromatic penicillate
nuclei with stratification, dense chromatin, and inconspicuous nucleoli. The
ated with high-grade dysplasia or invasive carcinoma architecture is still tubular and does not show complex branching or papillary
away from the grossly apparent lesion. fronds.
A A
FIGURE 15.10
Intracholecystic papillary tubular neoplasm of the gallbladder is defined as
a grossly visible neoplastic mass (A). The microscopic spectrum of these
lesions is broad and most commonly resembles colonic-type tubular, tubu-
lovillous, and villous adenomas (B). Rarely, gastric pyloric gland adenoma–
FIGURE 15.9 type lesions may also occur in the gallbladder.
High-grade dysplasia (biliary intraepithelial neoplasia) of the gallbladder. A,
Markedly hyperchromatic pleomorphic round nuclei with loss of polarity,
vesicular chromatin, and prominent nucleoli. B, Another example with similar
nuclear features, which also shows marked architectural complexity. When
this is an incidental finding in a cholecystectomy, deeper levels and exam-
ination of the entire gallbladder may be necessary to rule out an invasive Overall, KRAS mutations are likely present in approxi-
adenocarcinoma depending on the multifocality of the lesion. mately one-third of cases of preinvasive gallbladder neo-
plasia. Carcinomas arising in patients with anomalous
union of pancreatobiliary ducts are consistently reported
to have a higher frequency of KRAS alterations. More
the latter often resembling pyloric gland adenomas of advanced neoplasia (BilIN3 and invasive carcinoma) is
the gastrointestinal (GI) tract. MUC5 lines the surface associated with TP53, CDKN2A/B, and PIK3CA alter-
epithelium in these lesions, and the glandular compo- ations. Unlike intraductal papillary mucinous neoplasms
nent is strongly MUC6 positive (Fig. 15.11). of the pancreas, ICPN is not classically associated with
Invasive adenocarcinoma is defined by the presence GNAS alterations. EGFR, ERBB3, PTEN, ARID2, and
of small, tubular glands with an infiltrating pattern sur- TERT promoter mutations are more prevalent in the gall-
rounded by desmoplastic stroma. Approximately half bladder than in the intra- and extrahepatic bile ducts.
of gallbladder carcinomas are either well or moderately
differentiated, are incidentally diagnosed, and present at
late stages.
Molecular Findings
Awareness of the spectrum of reactive epithelial changes
There is a wide range of reported frequencies of KRAS is critical because severe changes may closely mimic dys-
alterations in gallbladder dysplasia and carcinoma. plasia or invasive carcinoma.
A
Dysplasia and Early Gallbladder Carcinoma —
Pathologic Features
Gross Findings
n Biliary intraepithelial neoplasia (BilIN) and early invasive
carcinomas may be grossly normal

n Intracholecystic papillary neoplasm (ICPN) is a grossly visible
lesion, usually 1 cm or larger

n Invasive carcinoma may be associated with wall thickening and
mimic chronic cholecystitis
n Low-grade (previously BilIN 1 and 2) have relatively simple
architecture with mild to moderate cytologic atypia

n High-grade BilIN (previously BilIN 3) has an in situ carcinoma-
like appearance with marked cytologic atypia and complex

architecture
n ICPNs may be classified as biliary, gastric (foveolar or pyloric),
B intestinal, and oncocytic types; architecture may be tubular,
papillary, or usually mixed
n Early invasive carcinoma has an infiltrative pattern and often
desmoplastic stroma
n Dysplasia extending into Rokitansky-Aschoff sinuses may mimic
invasive adenocarcinoma
Genetics
n KRAS alterations occur in approximately one-third of BilIN lesions
and carcinomas; there is a higher frequency in patients with

anomalous union of pancreatobiliary ducts
n Alterations in TP53, SMAD4, PIK3CA, and p16 inactivation occur
in high-grade BilIN and invasive carcinoma

n GNAS mutations are not frequent
Although there is substantial morphologic overlap,

C several useful histologic features distinguish between
benign reactive changes and neoplastic atypia, and
these are summarized in Table 15.1. Unfortunately,
none of these features are entirely sensitive or spe-
cific. They must be considered in combination and in
context of the clinical and radiographic features. In
general, reactive cytologic atypia often shows vesicu-
lar nuclei with mild to moderate enlargement, smooth
nuclear contours, and at most mild pleomorphism and
hyperchromasia (Fig. 15.12). Surface maturation and
the presence of an adjacent ulcer, often with mucin-de-
pleted “restituting” epithelium, are helpful features
when present. Architectural complexity, such as sim-
ple papillary growth at the mucosal surface, is accept-
able within the realm of reactive changes. However,
FIGURE 15.11
complex papillary architecture, cribriforming, or copi-
Pyloric gland adenoma of gallbladder with crowded small tubular glands with
ous tufting should prompt consideration of dysplasia
abundant mucin and mild nuclear atypia (A). Similar to their more com- or malignancy.
mon gastric counterparts, these lesions show positive MUC5 staining in the Early invasive lesions in the gallbladder can be
surface epithelium (B) and diffuse strong MUC6 positivity (C) in the small
tubular glands that make up bulk of the lesion.
extremely difficult to distinguish from dysplasia
involving Rokitansky-Aschoff sinuses (Fig. 15.13).
In extremely well-differentiated cases, non-neoplastic
Rokitansky-Aschoff sinuses may also enter the differen-
tial diagnosis. The distinction is often best made at low
TABLE 15.1
Features of Benign Reactive Atypia and Dysplasia and Malignancy in Gallbladder and Biliary Epithelium
Feature Benign or Reactive Dysplasia or Malignancy
Chromatin Vesicular, less commonly hyperchromatic Coarse, hyperchromatic

Nuclear size Increased, sometimes with Increased with increased nuclear-to-
accompanying increase in cytoplasm cytoplasmic ratios
Nuclear contours Smooth Smooth or irregular
Nucleoli Small to moderately sized Absent to very large “cherry nucleoli”
Pleomorphism Not marked Mild to marked, depending on grade
Surface maturation Usually present Usually absent
Background inflammation, ulceration, Often present Occasionally present
and restituting epithelium
Surface architecture Flat, simple papillary Flat, complex papillary, cribiforming, tufting
Mural architecture Lobulated, perpendicular orientation to Irregular or infiltrative, parallel orientation to
surface (Rokitansky-Aschoff sinuses) surface
A B
FIGURE 15.12
Reactive changes in the gallbladder and extrahepatic bile ducts can mimic neoplasia. The nuclei may be round with prominent nucleoli, similar to neoplastic
glands, but the contours are smooth, and the background mucosa shows acute or chronic inflammation (A) or erosions and ulcers, which are all helpful in
making the correct diagnosis. A history of stented bile duct is also useful in this differential diagnosis and should raise the threshold for a neoplastic diagnosis.
Dense chronic inflammatory infiltrate and patchy acute inflammation in the setting of primary sclerosing cholangitis, in another example, suggests that the epi-
thelial changes seen here are best considered reactive (B).
power, where native sinuses appear as organized, flask- cholecystectomy specimen have shown 5-year survival
shaped invaginations with a long axis perpendicular to rates in the order of 90%. The lower survival rates
the epithelial surface. Invasive carcinomas have an infil- from earlier studies are likely due to pathologic under-
trative, disorganized appearance, with glands invading staging when the entire gallbladder was not submitted
both perpendicular and parallel to the surface. for evaluation. Pathologic stage is critical for predicting
risk of residual disease and to guide subsequent therapy
in incidentally detected gallbladder adenocarcinomas.
Tumors invading into the lamina propria (T1a) are con-
sidered appropriately treated by cholecystectomy alone.
Invasion into the muscular wall (T1b) is associated with
Like other preneoplastic lesions of the GI tract, gall- a higher risk of recurrence. Although management of
bladder dysplasia, of either low or high grade, is cured T1b gallbladder carcinoma remains somewhat contro-
by cholecystectomy with negative margins. Although versial, most data suggest that en bloc resection of the
some studies have reported the 5-year survival rate as adjacent liver parenchyma is associated with better out-
low as 50% for early invasive carcinoma, more recent comes. Other important pathologic prognostic parame-
data restricted to patients with tumors considered ters include the status of cystic duct resection margin
T1a or T1b after histologic examination of the entire and nodal metastasis.
Advanced Gallbladder Carcinoma—Fact Sheet
Definition
n Carcinoma invading through the muscular wall of the gallbladder
Epidemiology
n Rare: fewer than 5000 new cases each year in the United States
n Constitutes majority of biliary tract malignancies
n Higher incidence in South America and Asia
n Females > males; increasing incidence with age
n Risk factors: cholelithiasis, anomalous union of the
pancreatobiliary ducts, hyalinizing cholecystitis

n Five-year survival rates are approximately 5%
Clinical Features
n Vague presenting symptoms: abdominal pain, anorexia, and
weight loss
FIGURE 15.13 n Some cases may be asymptomatic
Biliary intraepithelial neoplasia–type changes extending into preexisting n Ultrasound can detect some case preoperatively
Rokitansky-Aschoff sinuses can mimic an invasive adenocarcinoma. These

foci are cystically dilated and sharply circumscribed, and the typical architec-
ture of an invasive adenocarcinoma with small, angulated glands in a hap-
hazard distribution is not present in these cases. A desmoplastic stromal
response is also missing.
Pathologic Features
Gross Findings
ADVANCED GALLBLADDER CARCINOMA
Unlike early gallbladder neoplasia, advanced carcinomas
most often present with mass lesions on gross examina-
tion. In most cases, a fibrotic, infiltrative mass is present
in the gallbladder wall. Occasionally, mural involvement
by carcinoma can be difficult to distinguish from the
Advanced gallbladder carcinoma, defined as tumor inflammatory changes and fibrosis of acute and chronic
invasion beyond the muscular wall, is relatively rare, cholecystitis. Less commonly, a polypoid lesion may pro-
with fewer than 5000 new cases reported in the United trude into the lumen. The fundus is the most common site
States each year. However, it is by far the most com- of involvement, followed by the body and neck regions.
mon advanced malignancy of the biliary tract, consti- Carcinomas arising in the setting of hyalinizing cholecys-
tuting at least 80% of these lesions. The risk factors titis are not grossly apparent. Areas of serosal puckering
are generally the same as those for early neoplasia, in or distortion and induration around adherent hepatic
particular gallstones, long-standing chronic inflamma- parenchyma should raise suspicion for an advanced stage
tion, hyalinizing cholecystitis, PSC, and anomalous tumor. Tumor location should be specified as either on
union of the pancreatobiliary ducts. The geographic the hepatic side of the gallbladder or the serosal side of
distribution is also similar, with increased incidence the gallbladder. Carcinomas located on the hepatic side
in South America and Asia compared with North of the gallbladder are associated with worse prognosis
America and Europe. Women are at slightly higher than those on the serosal side. The eighth edition of the
risk than men, likely because of an increased incidence American Joint Commission on Cancer (AJCC) staging
of gallstones. The incidence of advanced gallbladder guidelines subclassifies T2 lesions as T2a (serosal side of
carcinomas increases with increasing age. Most series the gallbladder) or T2b (hepatic side of the gallbladder).
report median ages in the seventh or eighth decades.
Gallbladder carcinomas are often high stage at pre- Microscopic Findings
sentation, which is a major contributor to the overall
poor outcomes. Symptoms, when present, are typi- Most invasive gallbladder carcinomas arise in a back-
cally vague and include abdominal pain, anorexia, and ground of high-grade dysplasia and are of the pancre-
occasionally weight loss. Many cases, especially those atobiliary type with small tubular glands that are lined
associated with polypoid dysplasia, can be suspected by cuboidal cells with eosinophilic or amphophilic
by ultrasound. If the diagnosis can be made preopera- cytoplasm (Fig. 15.14). Although the degree of differ-
tively, endoscopic ultrasound is considered the modal- entiation is variable, most cases have well-formed glan-
ity of choice for clinical staging. dular architecture and abundant desmoplastic stroma.
A C
B D
FIGURE 15.14
Invasive adenocarcinoma of the gallbladder arising in the background of extensive high-grade dysplasia (A). The neoplastic glands are small and show an irreg-
ular infiltrative pattern that is in sharp contrast to the changes seen in Fig. 15.13. Well-differentiated adenocarcinoma can be difficult to diagnose because glan-
dular atypia may be minimal in some cases. The haphazard architecture of infiltrating glands and the surrounding desmoplastic stroma is helpful in this example
(B) to establish the diagnosis. Identification of small clusters of neoplastic cells adjacent to well-formed neoplastic glands (C), perineural or vascular invasion, or
single cell infiltration deep into the perimuscular tissue on a pankeratin immunostain (D) can also be helpful in making a diagnosis of invasive adenocarcinoma
in challenging cases.
Intestinal and/or gastric differentiation, either focally

or diffusely, is fairly common. Unusual subtypes of car-
cinoma include mucinous (>50% extracellular mucin),
colloid (predominantly mucin with occasional strips
or clusters of tumor cells), poorly cohesive carcinoma
with or without signet ring cells, adenosquamous or
squamous cell, clear cell, sarcomatoid, hepatoid, and
undifferentiated. The latter may resemble medullary
carcinomas of the GI tract or lymphoepithelioma-like
carcinoma (Fig. 15.15) of the aerodigestive tract but are
not positive for Epstein-Barr virus (EBV). Poorly differ-
entiated neuroendocrine carcinomas (small cell or large
cell) comprise approximately 5% of cases.
Pathologic stage is the most important prognostic
feature in the evaluation of malignant cholecystectomy
specimens. Extensive fibrosis and distortion of the gall-
bladder wall often precludes precise identification of the
point of deepest invasion grossly, and extensive micro- FIGURE 15.15
scopic evaluation is warranted to determine the T stage Undifferentiated gallbladder carcinoma with abundant intratumoral lym-
accurately. Important prognostic features include degree phocytes resembles lymphoepithelioma-like carcinoma of the head and
neck region but does not show any association with Epstein-Barr virus.
of differentiation, lymphovascular invasion, and nodal Programmed death-ligand 1 can be positive in such cases and offer a thera-
status. peutic option to these patients, who otherwise have a dismal prognosis.
Immunohistochemistry (IHC) has a limited role sinus is involved by dysplastic epithelium. Rokitansky-
in gallbladder carcinoma because there are no reliable Aschoff sinuses are typically oriented in a perpendicu-
markers to distinguish a benign from malignant prolif- lar fashion relative to the surface epithelium and have
eration. It may be useful when the differential diagnosis a lobulated rather than an infiltrative advancing front.
includes a metastasis. Primary gallbladder carcinomas Occasionally, ducts of Luschka, native subserosal or
are usually positive for cytokeratin (CK) 7 with patchy subhepatic ducts, can mimic well-differentiated carci-
CK20 and CDX2 reactivity. However, because this pro- noma. However, they lack cytologic atypia or infiltra-
file is not entirely specific for the gallbladder, the overall tive growth. The absence of carcinoma in the mucosa
morphology is more often helpful in excluding metasta- or muscular wall usually prevents any confusion with
ses, which are usually centered around the serosa or the malignancy.
middle of the wall rather than the mucosa. The presence
of flat or polypoid dysplasia in the background epithe-
lium favors a gallbladder primary.
Treatment and Prognosis
The genetic landscape of gallbladder carcinomas
appears complex and is more heterogenous than that of
pancreatic ductal adenocarcinoma. Common molecular The extent of resection depends on the depth of inva-
alterations typically associated with advanced gallblad- sion. T2 carcinomas are often managed by radical chole-
der carcinoma include mutations in MAP kinase genes, cystectomy with resection of liver segments IVb and V.
KRAS, TP53, CDKN2A/B, and PIK3CA. Loss of SMAD4 T3 lesions usually require more radical resections that
occasionally occurs, but like KRAS alterations, this is can include extended right hepatectomy, lobectomy, and
not as frequent as in pancreatic ductal adenocarcinoma. regional lymph node dissection. The prognosis is poor
with overall 5-year survival rates of around 5%.
Gallbladder Carcinoma—Pathologic Features

EXTRAHEPATIC BILE DUCTS
Gross Findings
n Most often fibrotic, infiltrative mass in the gallbladder wall
n Can be difficult to distinguish from fibrosis secondary to chronic
cholecystitis ■ INFLAMMATORY DISORDERS OF

n The most frequent location is the fundus followed by the body EXTRAHEPATIC BILE DUCTS
n The most common phenotype is pancreatobiliary with well-
Clinical Features
spaced glands separated by abundant desmoplastic stroma
n Intestinal and gastric differentiation is common
n Other variants include mucinous, colloid, adenosquamous,

Choledocholithiasis, the presence of entrapped gall-
squamous, clear cell, sarcomatoid, poorly cohesive carcinoma stones in the common bile duct (CBD), is the most
with or without signet ring cells, hepatoid and undifferentiated common cause of benign bile duct obstruction. Stones
carcinoma (including medullary and lymphoepithelioma-like may be classified as primary, arising within the CBD or
carcinomas)
intrahepatic bile ducts, or secondary, migrating from
Genetics
the gallbladder. Secondary stones are far more common
n Genetic landscape is complex and heterogeneous
than primary stones, especially in Western countries.
n KRAS, TP53, CDKN2A/B, PIK3CA mutations
Primary stones occur more frequently in Asian patients
and are thought to be related to biliary stasis and
Immunohistochemistry chronic bacterial infection (recurrent pyogenic cholan-
n Typically cytokeratin (CK) 7 positive; CK20 and CDX2 variable gitis). Choledocholithiasis secondary to cholelithiasis
occurs in up to 10% of patients who undergo chole-
cystectomy. Risk factors include a cystic duct diame-
ter larger than 4 mm, female gender, age older than 40
years, and obesity. Imaging modalities that may detect
choledocholithiasis include abdominal ultrasound,
computed tomography, endoscopic retrograde cholan-
Unlike early neoplasia, most advanced invasive gallblad- giopancreatography (ERCP), and magnetic resonance
der carcinomas are overtly malignant and are not often cholangiopancreatography (MRCP). A large majority of
confused with reactive changes. One exception is the patients are successfully treated by ERCP.
extension of Rokitansky-Aschoff sinuses deep into the Primary sclerosing cholangitis may involve the extra-
muscular layer, which can sometimes be difficult to dis- hepatic bile ducts with or without concurrent involve-
tinguish from invasive carcinoma, especially when the ment of smaller intrahepatic ducts. The diagnosis of
extrahepatic PSC is most often radiographic. MRCP is

the preferred modality. ERCP is also highly sensitive Inflammatory Disorders Of Extrahepatic Bile
and specific but has a higher rate of complications. In Ducts—Fact Sheet
most cases, a diffuse, strictured, and beaded appear-
ance is characteristic. The pathogenesis of PSC is not Definition
n Primary sclerosing cholangitis (PSC): autoimmune disease
well understood, although it is clearly an immune-me-
targeting intrahepatic and extrahepatic bile ducts
diated disease given its association with specific human n Immunoglobulin (Ig) G4 sclerosing cholangitis: part of a systemic
leukocyte antigen haplotypes (B8, DR3, and DQ2) disease of increased IgG4 production
and its close relationship with inflammatory bowel
disease (IBD). Approximately 50% of patients have Epidemiology
IBD at the time of presentation with PSC, and another n PSC typically associated with younger age (males > females) and
roughly 30% develop IBD within 10 years of diagnosis. is strongly associated with inflammatory bowel disease
n IgG4 sclerosing cholangitis is associated with older age (males
Although patients with PSC are at increased risk for
> females), and most patients have manifestations of systemic
both ulcerative colitis and Crohn’s disease, most patients IgG4 disease in other organs
have ulcerative colitis. Patients with PSC are at high risk n Both diseases are associated with increased risk for
for both biliary and colorectal dysplasia and malignancy. cholangiocarcinoma, though the risk appears to be higher in PSC
The cumulative 30-year risk of cholangiocarcinoma
(CC) is approximately 20% and of colorectal carcinoma Clinical Features
n Patients with PSC may be asymptomatic at presentation or
is 10% to 15%. In addition to malignancy, benign bile
present with abdominal pain, fatigue, pruritis, or jaundice
duct strictures are a common complication. Treatment n IgG4 sclerosing cholangitis patients may be asymptomatic or
options for PSC are quite limited and are mostly targeted present with obstructive symptoms (jaundice, pruritis)
toward alleviating or preventing complications rather n Diagnostic imaging includes endoscopic retrograde
than cure. Endoscopic dilation and stenting are used cholangiopancreatography and magnetic resonance
to treat benign strictures. Liver transplantation may be cholangiopancreatography, which most often show stricture; some
cases of IgG4 sclerosing cholangitis may present with a mass
indicated in patients with advanced disease. All patients n Systemic IgG4 levels are typically increased in patients with IgG4
with PSC should be screened for IBD and colorectal sclerosing cholangitis
carcinoma.
IgG4 sclerosing cholangitis is part of the emerging
class of IgG4-related diseases and is now considered an
important consideration in the differential diagnosis of in patients with end-stage disease. Biopsies of the extra-
benign bile duct strictures. It is critical to distinguish hepatic ducts are generally not specific for PSC and are
IgG4-related sclerosing cholangitis from PSC because usually only performed to rule out a CC in a stricture or
the former often responds to steroid therapy. Imaging less commonly to exclude IgG4 sclerosing cholangitis.
of the bile ducts shows stricturing, either single or mul- Most cases of PSC show some degree of chronic inflam-
tiple, which may mimic PSC or CC. The disease is most mation and fibrosis (Fig. 15.16) along with foci of duct
common in older men, although any age group may be stenosis and dilation. The inflammation is predominantly
affected. Most patients with IgG4 sclerosing cholangi- lymphocytic with some admixed plasma cells. Neutrophils
tis also have IgG4-related (type 1) autoimmune pancre- may be seen but are usually not prominent. The overlying
atitis. Accordingly, IgG4 sclerosing disease should be epithelium is often ulcerated. Dense fibrosis, usually cir-
strongly considered in patients with bile duct strictures cumferential around the duct (“onion-skin” appearance),
who have associated findings suggestive of autoimmune is a hallmark feature. The fibrosis results in luminal nar-
pancreatitis. An increase in serum IgG4 is often suffi- rowing, and in advanced cases, the lumen may appear
cient for diagnosis, and biopsy is not generally required slitlike or contain inspissated bile. The lining epithelium
to initiate therapy. However, because of the increased shows evidence of injury with cytoplasmic eosinophilia,
awareness and implications for therapy, bile duct biopsy nuclear disarray, and attenuation.
is often performed in cases with equivocal imaging In characteristic cases, IgG4 sclerosing cholangitis
and laboratory features to evaluate for IgG4 sclerosing consists of increased numbers of IgG4-positive plasma
cholangitis. cells, storiform fibrosis of the bile duct, and obliterative
phlebitis. Unlike PSC, in which the inflammation pri-
marily targets the bile duct mucosa, in IgG4 sclerosing
cholangitis, the inflammation is more often transmural.
Pathologic Features
Although plasma cell inflammation is usually prominent
on hematoxylin and eosin morphology, demonstration
Pathologic examination of extrahepatic bile ducts of an elevated ratio of IgG4-positive plasma cells to total
involved by PSC may be performed on segmental bile IgG-positive plasma cells (>40%) and finding at least 10
duct excisions for obstruction, resection specimens per- IgG4-positive plasma cells per high-power field by IHC is
formed for an associated CC, or liver explant specimens needed for histologic diagnosis.
Inflammatory Disorders of Extrahepatic Bile Ducts—

Pathologic Features
Gross Findings
n Primary sclerosing cholangitis (PSC) shows multiple strictures
separated by segments of bile duct of normal or dilated caliber

(“beads on a string” appearance)
n Immunoglobulin (Ig) G4 sclerosing cholangitis most commonly
shows strictures, but some cases present as a mass
n PSC invariably shows dense hyaline fibrosis, often concentric
around bile duct

n PSC consists of a predominantly mucosal infiltrate of
mononuclear cells with great variability in degree

n Ulceration of epithelium and hyperplasia of intramural glands is
common
n IgG4 sclerosing cholangitis has three hallmarks:
FIGURE 15.16
n Increased IgG4-positive plasma cells
Primary sclerosing cholangitis with duct ectasia and tortuosity, periductal scar- n >10 IgG4 positive cells in a single high-power field
ring, and marked chronic inflammation. Correlation with clinical and imaging
n IgG4 to IgG positive plasma cell ratio >40%
findings is often necessary to render a definite diagnosis.
n Storiform fibrosis
n Obliterative phlebitis
n In contrast to PSC, IgG4 sclerosing cholangitis is more often
transmural; occasionally, there is relative sparing of the bile duct

mucosa
As noted earlier biopsies to rule out IgG4 scleros-
ing cholangitis are becoming increasingly common Differential Diagnosis
because of the steroid-responsive nature of this dis- n Cholangiocarcinoma, which typically shows irregular, infiltrative
ease in contrast to PSC. Small biopsies have limited glands in desmoplastic stroma in contrast to the lobulated
sensitivity, and even when some diagnostic features configuration of hyperplastic intramural glands
are present, a definitive diagnosis can be difficult. All
three diagnostic features (increased IgG4 plasma cells,
storiform fibrosis, and obliterative phlebitis) are rarely
sampled in a single biopsy sample, so distinction from data to suggest significant geographic variation are less
PSC can be difficult. In these cases, documenting some clear for CC than for adenocarcinoma of the gallbladder.
of these histologic features in a patient with increased PSC is the best-known risk factor for CC. Other associa-
serum IgG4 levels may be helpful even if a definitive tions include choledochal cysts and parasite infections,
diagnosis is not possible. Caution is especially war- such as Clonorchis sinensis or Opisthorchis viverrine.
ranted in the setting of a mass lesion. Although IgG4 The mean age at presentation in most Western series
sclerosing cholangitis can cause mass formation, CCs is around 70 years. There appears to be a slight male
may also be associated with increased IgG4-to-IgG predominance.
ratios. Accordingly, demonstration of increased IgG4- The most common symptoms are caused by duct
positive plasma cells alone is not sufficient to entirely obstruction and include jaundice, pruritis, pale stools,
exclude malignancy. and dark urine. Imaging modalities (ultrasonography,
computed tomography, ERCP, MRCP) overall have
high sensitivity and specificity but malignant stric-
tures may occasionally be difficult to distinguish on
CARCINOMA OF EXTRAHEPATIC BILE imaging from benign ones in the absence of a mass
DUCTS lesion. CC is classified into three subtypes according to
anatomic location: intrahepatic (proximal to second-
ary branches of left and right hepatic ducts), perihilar
■ CLINICAL FEATURES (proximal to the origin of the cystic duct and distal
to the secondary branches of left and right hepatic
ducts), and distal extrahepatic (distal to the cystic
Cholangiocarcinoma is by far the most common malig- duct origin and proximal to the ampulla). Perihilar
nancy of the extrahepatic bile ducts, but it remains a rel- CC, also commonly referred to as Klatskin tumor, may
atively rare tumor. The incidence in the United States is be further subdivided into one of five categories based
estimated to be 0.6 to 1.0 per 100,000 persons yearly. By on the precise anatomic location (Bismuth-Corlette
some estimates, the rate is higher in Asia, although the classification).
A
Carcinoma of Extrahepatic Bile Ducts—Fact Sheet
Definition
n Carcinoma arising from the epithelial lining of the bile ducts

n Rare: incidence fewer than 1 per 100,000 persons per year in
the United States

n Risk factors include primary sclerosing cholangitis, choledochal
cyst, and parasite infection (Clonorchis sinensis, Opisthorchis

viverrine)
n Subclassified based on location. Extrahepatic carcinomas include
perihilar (Klatskin tumors) and distal extrahepatic lesions (distal to

the insertion of the cystic duct)
n Males slightly more affected than females (male-to-female ratio,
∼1.5 to 1) B
n Predominantly affects older adults (average age ∼70 years)

n Poor prognosis: overall 5-year survival less than 10%
n Better outcomes in patients who have curative surgical resection
(5-year survival rate, 30%–67%)
Clinical Features
n Obstructive symptoms common at presentation: jaundice, pruritis,
pale stools, and dark urine
Therapy
n Surgery is the only curative treatment
n Procedure is highly location dependent:
n Perihilar tumors treated with bile duct resection or right or left

FIGURE 15.17
partial hepatectomy Intraductal papillary neoplasm of the bile duct (IPNB). IPNBs show a mor-
n Distal tumors treated with pancreaticoduodenectomy phologic spectrum similar to their more common pancreatic counterparts,
and gastric, intestinal, pancreaticobiliary, or oncocytic differentiation may be
seen in the lining epithelium. This IPNB, at low power, shows circumferen-
tial involvement by an intraductal neoplastic papillary proliferation (A). The
nuclear atypia is striking, consistent with high-grade IPNB, but there is no
invasion into adjacent stroma (B).
Pathologic Features
Gross Findings
be found in association with invasive carcinoma or in
patients with strictures (often in the setting of PSC) that
Cholangiocarcinoma may present grossly in one of three are undergoing examination.
ways: mass forming, periductal, or intraductal. The Intraductal papillary neoplasm of the bile duct
most common finding is an ill-defined sclerotic mass or (IPNB; Figs. 15.17 and 15.18) and the related lesion
stricture. Some periductal cases may be extremely subtle, intraductal tubulopapillary neoplasm of the bile duct
with a thickened bile duct being the only notable finding are similar to their counterparts in the gallbladder
on gross examination. Exophytic intraductal cases are and pancreas. These tumors are, by definition, grossly
less common. They are typically associated with intra- and radiographically visible and usually larger than
ductal papillary neoplasms of the bile ducts, similar to 1 cm in size, although size is not a mandatory feature.
their more common pancreatic counterparts. Resection is indicated given their premalignant poten-
tial and frequent association with invasive carcinoma.
Microscopic Findings IPNBs, similar to ICPN (and IPMN of the pancreas), can
be classified based on predominant cell type as biliary,
Precursor Neoplasia intestinal, gastric, or oncocytic. The criteria for grade of
The same preinvasive neoplastic lesions that occur in dysplasia are the same as those described in the gallblad-
the gallbladder can be found in the extrahepatic biliary der. Intraductal tubulopapillary neoplasm are often high
tree. Isolated cases of flat dysplasia (low- and high-grade grade and distinguished from IPNB based on the pres-
BilIN) are rare because they are asymptomatic and, ence of greater than 70% nonmucinous tubular archi-
unlike with the gallbladder, bile duct resection is rarely tecture and negative MUC5AC. Extensive microscopic
performed for benign indications. However, BilIN may evaluation is appropriate for both because these lesions
Distinction of distal CBD carcinomas arising within

the intrapancreatic portion of the duct from a pancreatic
ductal adenocarcinoma in the head of the pancreas or
ampullary adenocarcinoma can be challenging in some
cases. Generally, carcinomas of the bile duct are circum-
ferential around the duct, which is more or less centered
in the middle of the lesion. Presence of an in situ com-
ponent facilitates the diagnosis, but this helpful feature
is not always present.
Pathologic risk factors associated with prognosis that
are considered while deciding on the need for adjuvant
therapy include T stage, lymph node and margin status,
small vessel invasion, portal vein invasion, and perineu-
ral invasion.
The molecular genetics of extrahepatic bile duct
carcinomas is complex. Alterations in KRAS occur in
approximately 20% to 30% of extrahepatic CCs, which
is significantly lower than pancreatic ductal adenocar-
cinoma. MDM2 amplifications occur in roughly 10%
of perihilar CC but are rare in distal CC. Other com-
monly altered genes include TP53, CDKN2A, SMAD4,
ARID1A, and GNAS. Genetic aberrations specific for
extrahepatic CCs include PRKACA/PRKACB fusion,
Carcinoma of Extrahepatic Bile Ducts—Pathologic

Features
Gross Findings
n Most often an ill-defined fibrous mass
FIGURE 15.18 n In some cases, subtle bile duct thickening is the only abnormality
Intraductal papillary neoplasms of the bile duct are precursor lesions that n Intraductal papillary neoplasm of the bile duct is (IPNB)
can give rise to invasive cholangiocarcinomas and must be examined in their characterized by an exophytic intraluminal mass
entirety to rule out this possibility. The exophytic intraductal papillary compo-
nent projects into the lumen, in this case, and the invasive carcinoma forms
cords within the underlying stroma.
n Most tumors are composed of infiltrative, well0 to moderately
differentiated biliary-type glands surrounded by a desmoplastic

are often associated with small, grossly invisible areas of stroma. Less commonly, intestinal type or gastric type
n Other types include mucinous (colloid), signet ring cell, clear cell,
invasive carcinoma. adenosquamous, squamous, lymphoepithelioma-like, hepatoid,
micropapillary, undifferentiated, and sarcomatoid carcinoma
Invasive Carcinoma n Dysplasia of background epithelium is often present in
association with invasive tumors

n Flat dysplasia graded as low- and high-grade biliary intraepithelial
Cholangiocarcinoma is an adenocarcinoma with the same
neoplasia
spectrum of morphologic features as the gallbladder (Fig. n IPNB and intraductal tubulopapillary neoplasms are grossly visible
15.19). Marked stromal desmoplasia is a characteristic find- dysplastic lesions, frequently associated with invasive carcinoma
ing that surrounds infiltrating well to moderately differenti-
ated neoplastic glands. Cytologic features are variable. Most Genetics
cases consist of biliary-type cuboidal epithelium, although n KRAS alterations occur in approximately 20% to 30% of cases
intestinal, gastric (foveolar or pyloric gland), and oncocytic n Other recurring alterations include TP53, SMAD4, ARID1A, GNAS,
and CDKN2A/B
variants occur. In some poorly differentiated cases, marked
nuclear atypia and pleomorphism can be present. Less com- Immunohistochemistry
mon subtypes include mucinous (colloid), signet ring cell, n Usually cytokeratin (CK) 7 positive; CK20 and CDX-2 variable
clear cell, adenosquamous, squamous, lymphoepithelio-
ma-like (which may be EBV associated), hepatoid, micro- Differential Diagnosis
papillary, undifferentiated, and sarcomatoid carcinoma. n Reactive atypia caused by a bile duct stent, stricture, or primary
Neuroendocrine differentiation may be present in some sclerosing cholangitis

poorly differentiated carcinomas.
A C
B D
FIGURE 15.19
Cholangiocarcinomas can also arise from grossly invisible (flat) precursor lesions. A distal extrahepatic invasive cholangiocarcinoma with an intestinal phenotype
arising from high-grade biliary intraepithelial neoplasia (A). Invasive adenocarcinoma involving the extrahepatic bile ducts can also show a bland pancreaticobili-
ary phenotype (B), striking perineural invasion (C), or an undifferentiated morphology with hardly any gland formation (D).
ELF3 and ARID1B mutation. FGFR2 fusion and allow distinction of reactive changes from true neo-
IDH1/2 and BAP1 mutations are specific for intrahe- plasia are similar to those described in the gallbladder
patic CC and are not detected in extrahepatic tumors. neoplasia section earlier.
Differential Diagnosis Treatment and Prognosis
Inflammation of any cause, either acute or chronic, Extrahepatic CC (both perihilar and distal subtypes)
may lead to marked reactive epithelial changes. is associated with a poor prognosis. The overall 5-year
Cholecystitis, extrahepatic primary sclerosing chol- survival rate is less than 10%. However, this is because
angitis, and IgG4 sclerosing cholangitis are the most most patients present at an advanced stage, preventing
common underlying causes of florid reactive atypia in curative-intent surgical resection. Five-year survival
the setting of severe inflammation. Choledocholithiasis rates between 30% and 67% have been reported in
and iatrogenic causes for reactive biliary atypia should patients after an R0 resection. The surgical approach
also be considered, especially in patients who have had depends on the tumor location. Some patients of peri-
biliary stents or those who had a recent ERCP. Acute hilar CC can be treated with cholecystectomy com-
conditions such as cholecystitis and bacterial cholan- bined with extrahepatic bile duct resection and regional
gitis present with fever, leukocytosis, and abdominal lymph node dissection, whereas others require right or
pain. More chronic conditions such as PSC are typi- left hepatectomy with an en bloc caudate lobectomy.
cally associated with strictures and, less commonly, Patients with PSC and perihilar CC are sometimes con-
obstructive symptoms. The morphologic features that sidered for liver transplantation because of the high risk
of subsequent PSC-associated carcinomas throughout A

the intrahepatic and extrahepatic biliary tree. Patients
with distal CC are typically treated with standard
pancreaticoduodenectomy.
■ OTHER LESIONS OF THE GALLBLADDER

AND EXTRAHEPATIC BILE DUCTS
Unilocular cystic dilations of the bile duct, known as

choledochal cysts, are rare lesions occurring most often
in female infants and children, though they have been
reported in adults as well. They are more common in
East Asia than in Western populations. Although they B
are generally considered to be congenital, their close
association with anomalous pancreatobiliary duct union
has led some to hypothesize that many choledochal cysts
are secondary reactive lesions arising because of bile and
pancreatic juice reflux. They are classified into five types
based on anatomic location. Histologically, they con-
sist of a fibrous wall with variable amounts of chronic
inflammation often lined by simple or papillary biliary
epithelium with reactive changes. Choledochal cysts are
benign, but patients with these lesions are at increased
risk for extrahepatic CC.
Primary well-differentiated neuroendocrine (“car-
cinoid”) tumors of the gallbladder and extrahepatic C
bile ducts are exceptionally rare. They most likely
originate from intestinal metaplasia because normal
biliary mucosa lacks endocrine cells. Typically, these
tumors are composed of nests of endocrine cells with
round nuclei, stippled chromatin, and moderately
abundant cytoplasm (Fig. 15.20). Expression of a
wide variety of peptide hormones, including gastrin,
serotonin, pancreatic polypeptide, and somatostatin,
has been reported. The WHO grading system is the
same as that used in other GI neuroendocrine tumors.
Because of their rarity, the AJCC eighth edition guide-
lines do not have a specific category for staging neuro-
endocrine neoplasms of the gallbladder and bile duct, FIGURE 15.20
so in clinical practice, such cases are often staged Well-differentiated neuroendocrine tumor involving the bile duct. Tumor cells
using the respective carcinoma templates. The mor- arranged in a trabecular pattern within the bile duct wall (A) with uniform
phologic differential diagnosis includes metastasis round nuclei (B) and diffuse positivity for chromogranin (C).
from another primary site and paragangliomas, which
may occur in the gallbladder or in close anatomic
vicinity to the bile ducts. Poorly differentiated neuro- the gallbladder or the extrahepatic biliary system, though
endocrine carcinomas, with either small cell or large most cases outside of the pancreas are intrahepatic. The
cell morphology, may also rarely arise as primary clinical and pathologic features of these lesions are sim-
lesions of the gallbladder or extrahepatic bile ducts. ilar to their counterparts in the pancreas. Specifically,
Like neuroendocrine carcinomas of other sites, these they are found almost exclusively in women. Most
tumors are associated with aggressive behavior and patients are between 30 and 60 years old. These lesions
poor prognosis. Although some are “pure” neuroen- are often multiloculated and lined by mucinous epithe-
docrine carcinomas, others arise as divergent differ- lium. Characteristic ovarian-type stroma is required for
entiation in poorly differentiated adenocarcinomas. the diagnosis (Fig. 15.21). The epithelial lining is, by
Mucinous cystic neoplasms, referred to as hepatobi- definition, dysplastic and usually consists of low-grade
liary cystadenomas in the past, may also occur in either simple mucinous columnar cells with minimal cytologic
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16
Non-Neoplastic and Neoplastic Pathology of
the Pancreas
■ L
odewijk A.A.Brosens, MD, PhD, MariMino-Kenudson, MDand
Laura D.Wood, MD, PhD
■ NON-NEOPLASTIC DISEASES forming a ring of pancreatic parenchyma around the

duodenum. This ring can cause duodenal obstruction
later in life. Most patients present clinically at a young
Developmental Anomalies age (∼1 year), but some do not develop symptoms until
adulthood. Children with annular pancreas can present
The three most commonly encountered developmental with vomiting after meals and abdominal distention.
anomalies of the pancreas in routine surgical pathology Abdominal radiographs may show a classic “double-
practice are pancreas divisum, annular pancreas, and bubble” sign of intestinal obstruction.
ectopic pancreas. A careful dissection of the resected specimen and
clinical correlation with preoperative imaging studies
Pancreas Divisum and findings at surgery is the best way to establish the
diagnosis. The differential diagnosis includes other
Pancreas divisum occurs in 3% to 7% of the population causes of obstruction such as pyloric stenosis, ectopic
as a result of failure of the embryonic dorsal and ventral pancreas, and duodenal atresia. Surgical resection of the
pancreatic buds to fuse properly. The duct of Santorini obstruction is the treatment of choice, with an excellent
becomes the major ductal system of the pancreas, and it prognosis after surgery.
drains into the duodenum through the diminutive minor
papilla. The small size of the minor papilla relative to Ectopic Pancreas
the substantial flow through the major duct impedes the
flow of pancreatic secretions and, in some patients, pro- Pancreatic parenchyma located outside of the normal pan-
duces pancreatitis. Endoscopic retrograde cholangiopan- creas is referred to as ectopic pancreas. Ectopic pancreas is
creatography can be used to demonstrate the abnormal found in 2% of the population. Although ectopic pancreas
ductal anatomy and to exclude other causes of the is usually an incidental finding, it can cause bleeding and,
patient’s symptoms. in rare instances, intestinal obstruction. Ectopic pancreas
Pancreas divisum is best appreciated through careful only rarely forms a mass large enough to be detected radio-
gross dissection of the duct system. Imaging of a resected graphically. The upper gastrointestinal tract (stomach,
pancreas after the injection of a radiopaque dye into the duodenum, jejunum) is the most common location of ecto-
duct system can also be used to establish the diagnosis. pic pancreas. Other sites include ileum and Meckel’s diver-
It is often associated with chronic pancreatitis, but the ticulum (Fig. 16.1). These foci are composed of collections
microscopic appearance is etiologically nonspecific. The of normal acini and ducts and frequently islets of
differential diagnosis includes other causes of pancreati- Langerhans. Surgical resection is the treatment of choice in
tis. Sphincterotomy of the minor papilla has been used symptomatic patients and is usually curative.
to treat some patients with mixed results. The prognosis
is dependent on the severity of pancreatitis.
Pancreatic Hamartoma
Annular Pancreas
Annular pancreas is a rare malformation in which the Pancreatic hamartoma presents at a mean age of 60
dorsal and ventral buds of the pancreas abnormally fuse, years, and men and women are equally affected.
455
between 60 and 70 years of age. It is usually asymptom-

atic and detected incidentally on imaging studies per-
formed for other reasons. Lymphoepithelial cyst is
typically a uni- or multiloculated cyst that is commonly
located within the pancreas. Rarely, it may present as a
cyst protruding over the pancreatic surface. The mean
size of these cysts is about 5 cm, and they are lined by
squamous epithelium with or without prominent kerati-
nization. The cyst wall also contains abundant mature T
lymphocytes and lymphoid aggregates with germinal
centers (Fig. 16.3). Cyst content varies from serous to
caseous, depending on the degree of keratin formation.
The differential diagnosis includes other cystic
lesions such as mucinous cystic neoplasm (MCN), intra-
ductal papillary mucinous neoplasm (IPMN), pseudo-
cyst, dermoid cyst, and epidermoid cyst in intrapancreatic
accessory spleen. Both dermoid cyst and epidermoid
cyst in intrapancreatic accessory spleen occur in a
younger age group. The large amount of organized lym-
phoid tissue and the lack of adnexal structures help to
FIGURE 16.1
distinguish these lesions from dermoid cyst.
Ectopic pancreatic tissue in Meckel’s diverticulum showing collections of nor-
mal acini and ducts and islets of Langerhans underneath gastric-type mucosa
Intrapancreatic Spleen and Epidermoid Cyst
Most patients are asymptomatic, but some may com-
plain of abdominal pain and weight loss. Preoperative Accessory spleens exist in up to 10% of the general pop-
diagnosis is based on imaging, and in most cases, a pan- ulation. Presence of an epidermoid cyst in an intrapan-
creatic neoplasm such as pancreatic ductal adenocarci- creatic accessory spleen (ECIPAS) is remarkably rare.
noma (PDAC) or neuroendocrine tumor (NET) is Intrapancreatic spleen is usually asymptomatic and an
suspected. Endoscopic ultrasound-guided fine-needle incidental finding, although it may cause vague abdomi-
aspiration typically contains normal-looking pancreatic nal pain. On imaging studies, intrapancreatic spleen
tissue and does not help to make a definite preoperative forms a well-demarcated mass that may resemble a small
diagnosis. These lesions show nonspecific heteroge- solid or cystic pancreatic neoplasm. The density of the
neous contrast enhancement on computed tomography tumor’s solid component matches splenic tissue on post-
(CT) and magnetic resonance imaging (MRI), and the contrast CT and MRI.
radiologic differential diagnosis is broad. Grossly, intrapancreatic spleen forms a well-circum-
Pancreatic hamartoma forms a well-demarcated lesion scribed dark red mass. In the case of ECIPAS, a unilocular
composed of mature acini and ducts with distorted archi- cyst with serous or keratinaceous contents is present and
tecture embedded in fibroblastic and collagenized stroma. is surrounded by splenic tissue. ECIPAS is lined by a
There are no discrete islets of Langerhans, but scattered benign multilayered squamous or urothelial-like epithe-
neuroendocrine cells are seen when immunohistochem- lium surrounded by splenic tissue. The differential diag-
istry (IHC) is applied. Ducts show variable amount of nosis includes solid-pseudopapillary neoplasm (SPN),
cystic dilation, which may be prominent in some cases. NET, lymphoepithelial cyst, and other cystic lesions.
Adjacent pancreatic parenchyma is usually normal (Fig. When the diagnosis can be made preoperatively using
16.2). Localized chronic pancreatitis is the main histo- fine-needle aspiration cytology and the patient is asymp-
pathologic differential diagnosis, but this typically is not tomatic, no further treatment or follow-up is needed. In
as well demarcated as a pancreatic hamartoma and con- all other instances, conservative resection is curative.
tains islets of Langerhans. Pancreatic hamartoma is a
benign lesion with an excellent prognosis.
Other Benign Cystic Lesions in the Pancreas
Lymphoepithelial Cyst Simple Mucinous Cyst
Lymphoepithelial cysts account for approximately 0.5% Simple mucinous cysts are larger than 1 cm in size, lined
of pancreatic cysts, predominantly occurring in men by flat mucinous gastric type epithelium with minimal
CHAPTER 16 Non-Neoplastic and Neoplastic Pathology of the Pancreas 457
B
FIGURE 16.2
A, Pancreatic hamartoma showing a well-demarcated lesion surrounded by normal pancreatic parenchyma (hematoxylin and eosin [H&E]). B , Microscopically,
pancreatic hamartoma is composed of mature acini and ducts with distorted architecture embedded in fibroblastic and collagenized stroma (H&E).
atypia, and lack ovarian-type stroma ( Fig. 16.4 ). Congenital Cyst

Depending on the features of the surrounding pancreatic
tissue, different terms have been used to address these Congenital cysts are usually 1 to 2 cm in diameter and do not
cysts. In case of an obstruction of the pancreatic duct, communicate with the duct system. These cysts have a pauci-
these cysts have been interpreted as retention cysts with cellular fibrous wall and are lined by cuboidal epithelium
partial pancreatic intraepithelial neoplasia 1 (PanIN-1) resembling the lining of normal ducts. The epithelium can be
lining. Terms such as m ucinous non-neoplastic cyst and flattened and atrophic, and squamous epithelium is some-
cystic mucinous duct lesion have been used for lesions not times present. These cysts are mostly solitary but may be mul-
associated with an obstructive process. Simple mucinous tiple when associated with cysts of the kidney and liver.
cysts can carry Kras mutations and even high-grade dys- Congenital cysts are most often found in children. In adults,
plasia in keeping with a neoplastic process. congenital cysts are indistinguishable from retention cysts.
Most cases are caused by alcohol abuse or biliary tract

disease. Other risk factors are smoking and genetic pre-
disposition. Patients present with epigastric pain that
radiates to the back and elevated serum amylase levels.
Local complications are peripancreatic fluid collections,
pancreatic and peripancreatic necrosis, infections, and
pseudocyst.
Radiologic Features
Ultrasonography and CT reveal diffuse enlargement of

the gland.
FIGURE 16.3
Pathologic Features
Multilocular lymphoepithelial cyst composed of lymphoid stroma and a cyst
wall lined by squamous epithelium with some keratinization (hematoxylin
and eosin).
The pancreas is usually enlarged and soft, and the pan-
creatic and peripancreatic fat contains chalky white foci
of fat necrosis. Severe cases may show hemorrhage into
the gland. Microscopic findings range from mild edema
with scattered inflammatory cells to extensive necrosis
and hemorrhage (Fig. 16.6).
FIGURE 16.4
Simple mucinous cyst lined by flat nonpapillary mucinous gastric-type epi-
thelium without and without ovarian-type stroma (hematoxylin and eosin).
Duodenal Diverticulum
FIGURE 16.5
Duodenal diverticula showing intestinal mucosa with reactive changes sur-
A duodenal diverticulum on the pancreatic side of the rounded by pancreatic tissue (hematoxylin and eosin).
duodenum can appear as a unilocular intrapancreatic or
peripancreatic cyst and mimic a pancreatic cyst.
Duodenal diverticula communicate with the duodenal
lumen, in contrast to enteric duplication cysts, which do
not communicate with the duodenal lumen and are
most often lined by gastric mucosa. Duodenal divertic-
ula are composed of small intestinal mucosa, which may
cause confusion with intestinal-type IPMN (Fig. 16.5).
PANCREATITIS
Acute Pancreatitis
Clinical Features
Acute pancreatitis affects approximately 20 individuals FIGURE 16.6

per 100,000 population each year in Western nations. Acute pancreatitis with associated fat necrosis (hematoxylin and eosin).
Ancillary Studies
Elevated serum amylase levels support the diagnosis.
The differential diagnosis for acute pancreatitis is nar-

row and includes recurrent chronic pancreatitis. Clinical
history is essential for making this distinction.
Acute pancreatitis has an overall low mortality rate of

approximately 1%, but this varies with the severity.
Several scoring systems (Ranson’s criteria, APACHE-II,
BiSAP, Marshall score) are used to predict the prognosis
FIGURE 16.7
of patients with pancreatitis. The treatment of patients
Chronic pancreatitis. Fibrosis, loss of exocrine parenchyma, and a relative
with acute pancreatitis primarily consists of “resting” enlargement of residual islets of Langerhans are seen (hematoxylin and
the pancreas and supportive care. Approximately 20% eosin).
to 30% of patients with acute pancreatitis have a recur-
rence, and approximately 10% develop chronic pancre-
atitis. Progression from acute to chronic pancreatitis associated with dilation of the pancreatic ducts and
occurs more frequently in patients with continued alco- intraductal inspissated secretions. The islets of
hol and tobacco use and in patients with hereditary Langerhans are relatively spared, with evidence of islet
pancreatitis. cell aggregation in some cases. The inflammatory cell
infiltrate is usually composed of a mixture of lympho-
cytes, plasma cells, and scattered neutrophils.
Chronic Pancreatitis
Ancillary Studies
Clinical Features None are needed.
Patients with chronic pancreatitis present with abdomi- Differential Diagnosis

nal pain; exocrine and endocrine insufficiency, includ-
ing diabetes mellitus and malabsorption with The atrophic glands of chronic pancreatitis can mimic a
steatorrhea; and weight loss. Most cases in Western well-differentiated infiltrating adenocarcinoma. Features
countries are caused by chronic alcohol abuse. In addi- that favor a reactive process over a neoplastic process
tion, obstruction of the pancreatic duct from ductal include retention of normal lobular architecture of the
stones, tumors, strictures, or anatomical anomalies such acini, glands with complete lumina, absence of luminal
as pancreas divisum can also cause chronic pancreatitis. necrosis, and only mild nuclear pleomorphism. Perineural
A minority of patients have an inherited syndrome, and vascular invasion, when present, are diagnostic of
including familial pancreatitis caused by mutations in invasive adenocarcinoma.
PRSS1 or S PINK1 or cystic fibrosis.
Radiologic Features
Patients with chronic pancreatitis have shorter survival
Calcifications within the pancreas can be visualized on times than the general population, but most die from non-
plain abdominal radiographs. Ultrasonography demon- pancreatic causes, such as other chronic diseases, can-
strates ductal dilation; CT shows an atrophic pancreas cers, or infections. Chronic pancreatitis, particularly
with calcifications and small cysts. young onset and hereditary pancreatitis, also increases
risk of pancreatic cancer. Treatment is mostly supportive,
Pathologic Features with pancreatic exocrine enzyme replacement and care-
ful management of diabetes and pain. Endoscopic inter-
Chronic pancreatitis is characterized by an inflamma- vention is indicated for ductal stones, main pancreatic
tory cell infiltrate associated with replacement of the duct strictures, and symptomatic pseudocysts. Indications
normal pancreatic parenchyma with fibrous connective for surgical intervention include poorly controlled pain,
tissue (
Fig. 16.7 ). This loss of acinar tissue can be symptomatic pseudocysts, and suspicion of malignancy.
conventional risk factors for pancreatitis such as alco-

CHRONIC PANCREATITIS—FACT SHEET holism are lacking. Two subtypes of AIP with different
histopathologic and clinical characteristics are recog-
Definition nized. Type 1 AIP, also called lymphoplasmacytic scle-
n An inflammatory process of the pancreas characterized by an rosing pancreatitis, is a disorder in the spectrum of
irreversible loss of exocrine and endocrine function immunoglobulin (Ig) G4–related diseases. Type 1 AIP
most often affects men, with a male-to-female ratio of
approximately 3 to 1. The mean age of diagnosis is 60
n 4–12 cases per 100,000 per year
years or older. Serum IgG4 levels are elevated in most
Gender, Race, and Age Distribution patients, and extrapancreatic involvement, such as prox-
n Males >
females imal bile duct strictures, retroperitoneal fibrosis, or
n 30–50 years of age bilateral salivary gland enlargement, is seen in about
n Alcoholism most common cause in Western countries half of these patients. IgG4 elevation is variably defined
depending on the laboratory, and levels greater than
Clinical Features
135 mg/dL, greater than 121 mg/dL, or greater than
n Abdominal pain
86 mg/dL have all been reported as cutoffs in the litera-
n Diabetes mellitus
n Malabsorption with steatorrhea

ture. Type 2 AIP, also called idiopathic duct-centric
n Weight loss chronic pancreatitis, occurs in patients between 40 and
50 years of age. Men and women are equally affected.
Radiologic Features About 25% of patients have concurrent inflammatory
n Calcifications within the pancreas bowel disease, and patients typically do not have ele-
n Ductal dilation
vated serum IgG4 levels.
n Small cysts
Prognosis and Therapy Radiologic Features

n Shorter survival than the general population
n Increased risk of pancreatic cancer Type 1 and type 2 AIP are radiologically indistinguish-
n Mostly supportive therapy; management of pain, exocrine and able. About 30% to 50% of patients show the classic
endocrine enzyme insufficiency, and complications radiologic appearance of a diffuse enlargement of the
gland with loss of the normal lobulated contour, the
so-called “sausage-shaped pancreas.” Alternatively,
focal or multifocal enlargement of the pancreas can be
Chronic Pancreatitis—Pathologic Features seen.
Gross Findings Pathologic Features

n Firm, atrophic gland
n Calcifications Type 1 and type 2 AIP are indistinguishable on gross

n Ductal dilation examination. Most cases show diffuse enlargement of
the pancreas, although localized “pseudotumor” or dis-
crete nodules can also be seen (Fig. 16.8). International
n Inflammatory infiltrate (predominantly chronic inflammation)
n Scattered foci of acute neutrophilic infiltrate may be present

consensus histopathologic diagnostic criteria have been
n Fibrosis
formulated that distinguish AIP from other forms of
n Loss of acinar tissue chronic pancreatitis and distinguish type 1 AIP from
n Relative sparing of the islets of Langerhans type 2. Periductal lymphoplasmacytic infiltrate and an
inflammatory cellular stroma are the key diagnostic fea-
tures of both types of AIP that distinguish AIP from
n Well-differentiated ductal adenocarcinoma
other types of chronic pancreatitis. Storiform fibrosis,
n Retention of lobular architecture favors reactive proliferation
n Marked atypia or perineural or vascular invasion favors malignancy

obliterative phlebitis, and lymphoid follicles are also typ-
ically seen in type 1 AIP. Obliterative phlebitis is often
best seen at the interface between diseased and normal
tissues (Fig. 16.9A). Marked pancreatic acinar atrophy
Autoimmune Pancreatitis is often associated with a brisk myofibroblastic prolifer-
ation in a storiform pattern (Fig. 16.9B). Importantly,
Clinical Features although type 1 AIP typically shows marked infiltration
by IgG4+plasma cells of greater than 10 per hpf, this is
Autoimmune pancreatitis (AIP) is a rare form of chronic not a specific finding for type 1 AIP and should only be
pancreatitis in which patients present with obstructive used as an adjunct to support the diagnosis (Fig. 16.9C).
jaundice, imaging findings mimic pancreatic cancer, and Granulocytic epithelial lesions are pathognomonic for
fibrosis, and obliterative phlebitis are features that favor

a diagnosis of AIP. In contrast, ectatic ducts with inspis-
sated secretions, marked acute inflammation within aci-
nar or interlobular stroma, fat necrosis, and dense
hyaline fibrosis involving intra- and interlobular stroma
are suggestive of chronic obstructive pancreatitis rather
than AIP. Differentiating type 2 AIP from acute on
chronic pancreatitis not otherwise specified can be chal-
lenging and should be done in correlation with clinical
findings.
Autoimmune pancreatitis is important to recognize

because it can clinically mimic pancreatic cancer. Both
type 1 and type 2 AIP respond well to steroid therapy,
and type 1 AIP also responds to rituximab. Type 1 AIP
frequently relapses, whereas relapses are uncommon in
type 2. Both types of AIP have excellent long-term sur-
vival rates.
AUTOIMMUNE PANCREATITIS—FACT SHEET
Definition
n Type 1: disorder in the spectrum of IgG4-related diseases
FIGURE 16.8 characterized by a dense periductal lymphoplasmacytic infiltrate,

storiform fibrosis, and marked immunoglobulin (Ig) G4–positive
Autoimmune pancreatitis showing diffuse enlargement of the pancreas with
effacement of the normal pancreatic lobular architecture. plasma cell infiltration
n Type 2: characterized by granulocyte epithelial lesions without
prominence of IgG4-positive plasma cells

type 2 AIP and are characterized by aggregates of neu- ■ Estimated prevalence of fewer than 1 per 100,000
trophils within the ductal epithelium and lumen (Fig. ■ Recognized with increasing frequency
16.10). In addition, neutrophilic infiltration in sur-

rounding acinar tissue may be present. Gender, Race, and Age Distribution
■ Type 1: more common in men than in women. Most patients are
60 years of age or older

Ancillary Studies ■ Type 2: affects men and women equally. Most patients between
40 and 50 years of age

International consensus diagnostic criteria for AIP and
to differentiate between type 1 and type 2 include five Clinical Features
cardinal features of AIP, which are imaging, serology, ■ Can mimic pancreatic cancer with abdominal pain, weight loss,
other organ involvement, histology of the pancreas, and and jaundice

■ Type 1 is a disorder in spectrum of immunoglobulin (Ig)
response to steroid therapy. A diagnostic steroid trial
G-related disease, and 50% have extrapancreatic involvement
can be considered to confirm a strong suspicion of AIP. and elevated serum IgG4 levels
Serum IgG4 levels are elevated in most patients with ■ Type 2 is associated with inflammatory bowel disease in 25% of
type 1 AIP, and this finding can be used to support a patients
preoperative diagnosis.
Radiologic Features
■ Similar for type 1 and type 2: diffuse, focal, or multifocal
Differential Diagnosis enlargement of the pancreas
The differential diagnosis includes other forms of pan- Prognosis and Therapy
creatitis and pancreatic cancer in cases of focal mass on ■ Steroid therapy
imaging. Duct-centric lymphoplasmacytic infiltrates, ■ Type 1 frequently relapses, whereas type 2 does not
with or without granulocytic lesions, increased IgG4 ■ Both types have excellent long-term survival
positive plasma cells, inflamed stroma with storiform

A B
C D
FIGURE 16.9
A, Type 1 autoimmune pancreatitis (AIP) showing inflammatory cellular stroma, storiform fibrosis, and obliterative phlebitis (hematoxylin and eosin [H&E]).
B, Brisk myofibroblastic proliferation in a storiform pattern seen in a case of AIP (H&E). C, Type 1 AIP showing many immunoglobulin G4+plasma cells D,
Periductal mononuclear cell infiltrate, rich in plasma cells, is characteristic of type 1 AIP.
Autoimmune Pancreatitis—Pathologic Features
Gross Findings
■ Diffuse or segmental enlargement of the pancreas (“pseudotumor”)
■ Both types: periductal lymphoplasmacytic infiltrate and an
inflammatory cellular stroma

■ Type 1: storiform fibrosis, obliterative phlebitis, lymphoid follicles,
and infiltration by immunoglobulin (Ig) G4+plasma cells

■ Type 2: granulocytic epithelial lesions
■ Type 1: increased numbers of IgG4-positive plasma cells (>10
FIGURE 16.10
IgG4-positive plasma cells per hpf)
Granulocytic epithelial lesion in type 2 autoimmune pancreatitis, character-
■ Type 2: scant to absent IgG4-positive plasma cells
ized by periductal lymphoplasmacytic infiltrate and neutrophils in the ductal
epithelium and lumen (hematoxylin and eosin).
■ Other forms of chronic pancreatitis
Paraduodenal (Groove) Pancreatitis ■ Pancreatic adenocarcinoma
Clinical Features. Paraduodenal or “groove” pan-

creatitis is a distinctive form of pancreatitis that occurs in
the “groove” region demarcated by the superior aspect of and m yoadenomatosis. Most patients are young to mid-
the pancreas, the common bile duct, and the minor papil- dle-aged men with a history of alcohol abuse.
la. Alternative names that have been used for this lesion Radiologic Features. Computed tomography usu-
are cystic dystrophy of heterotopic pancreas, paraduo- ally reveals a thickened duodenum associated with cyst
denal wall cyst, pancreatic hamartoma of duodenum, formation in the duodenal wall or subjacent pancreas.
Pathologic Features. Paraduodenal pancreatitis,

in addition to arising in a very specific region, has a
characteristic microscopic appearance. The cysts, which
may contain inspissated secretions and degenerated
polymorphonuclear cells, are lined by partially or com-
pletely denuded ductal epithelium and are often sur-
rounded by granulation tissue (Fig. 16.11). In addition,
pseudocysts can be present. A reactive spindle cell pro-
liferation is often present, which may be very promi-
nent, raising suspicion of leiomyoma or gastrointestinal
stromal tumor. Almost all cases show Brunner’s gland
hyperplasia, which is largely responsible for the thicken-
ing and polypoid appearance of the duodenal mucosa. A
Differential Diagnosis. The differential diagnosis
includes cystic neoplasms of the pancreas, as well as
mesenchymal neoplasms in cases that show marked re-
active myofibroblastic proliferation. The characteristic
location of the lesion, and the presence of a partially de-
nuded but otherwise unremarkable epithelium lining
the cyst helps establish the diagnosis.
Prognosis and Therapy. These are benign lesions
that have an excellent outcome but may need surgical inter-
vention.
PARADUODENAL (GROOVE) PANCREATITIS—FACT SHEET

B
Definition
FIGURE 16.11
■ Distinctive form of pancreatitis, often with cystic changes, occurring
in the “groove region” demarcated by the superior aspect of the A, Paraduodenal pancreatitis showing a solid and cystic mass in the groove
region of the pancreas. B
, Microscopically, paraduodenal pancreatitis is char-
pancreatic head, the common bile duct, and the duodenum
acterized by cysts, which may contain inspissated secretions and degener-
ated polymorphonuclear cells, are lined by partially or completely denuded
Incidence and Location ductal epithelium, and are often surrounded by granulation tissue (hematox-
■ Rare ylin and eosin).
■ By definition, located in the “groove” region

Groove Pancreatitis or Paraduodenal Wall Cyst—
■ Strong male predominance
Pathologic Features
■ Most patients are in their 50 s
Gross Findings
Clinical Features
■ Cystic or solid mass lesion located in the groove region of the
■ A history of alcohol abuse is common
pancreas
■ Common symptoms include abdominal pain and weight loss
Radiologic Features
■ Cysts lined by partially or completely denuded ductal epithelium
■ May produce a solid or a cystic mass lesion in the head of the
and pseudocysts
pancreas or duodenum
■ Associated inflammatory cell infiltrate
■ A prominent reactive spindle cell proliferation is present in some

cases
■ Prognosis is excellent because these are non-neoplastic lesions;
they may require surgery Differential Diagnosis

■ Cystic neoplasms of the pancreas
■ Leiomyoma or gastrointestinal stromal tumor
Pseudocysts
Clinical Features that account for 75% of all pancreatic “cysts.” They
usually develop after an episode of acute pancreatitis or
Pseudocysts are localized collections, usually extrapan- after trauma to the pancreas. Patients often have a severe
creatic, of necrotic material rich in pancreatic enzymes epigastric pain that radiates to the back. In the United
States, most patients have a history of heavy alcohol pancreatic neoplasm. The absence of an epithelial lining
consumption. combined with necrotic or hemorrhagic cyst contents
rich in lipase and amylase establish the diagnosis of a
Radiologic Features pseudocyst.
Abdominal imaging shows a unilocular cystic mass. Prognosis and Therapy
Pathologic Features Most pseudocysts resolve with supportive care, but some
require surgical drainage. Superinfection of a pseudo-
Pseudocysts are usually solitary and extrapancreatic and cyst is a serious complication.
filled with necrotic or hemorrhagic material. They do not
have an epithelial lining and are lined by variably inflamed
granulation tissue and necrotic debris (Fig. 16.12).
■ NEOPLASTIC DISEASES
Ancillary Studies
Ductal Neoplasms
Aspirates of pseudocysts show abundant thin and
watery, turbid, and sometimes hemorrhagic fluid, which
is rich in lipase and amylase and low in carcinoembry- Neoplastic pancreatic ductal lesions may present as a
onic antigen (CEA) levels. solid or cystic mass. In the latter scenario, the neoplastic
proliferation can be confined within the duct (intra-
Differential Diagnosis ductal) or infiltrate into periductal tissues (invasive).
The lining epithelium of neoplastic glands may resemble
The differential diagnosis of a pseudocyst includes gastric, intestinal, or pancreaticobiliary type epithelium.
retention cyst, serous cystadenomas (SCAs), MCN, Ductal neoplasms are therefore categorized into distinct
IPMN, SPN, and cystic change in a usually solid groups based on their macroscopic appearance (invisi-
ble, cystic, solid), type of lining epithelium, presence or
absence of an invasive component, and predominant
genetic alterations found in each group.
Precursor Lesions
The following lesions are currently considered to be precur-

sors to ductal carcinoma of the pancreas and its variants:
PanIN, IPMN, intraductal oncocytic papillary neoplasm,
MCN, and intraductal tubulopapillary neoplasm (ITPN).
Pancreatic Intraepithelial Neoplasia
A Clinical Features. Most ductal carcinomas of the

pancreas are associated with noninvasive epithelial pro-
liferations within the smaller pancreatic ducts, called
PanIN, which are classified into low and high grade. Low-
grade PanIN lesions are quite common, and their preva-
lence correlates with age, increasing sharply after the age
of 40 years. Whereas low-grade PanIN has a low malig-
nant potential, high-grade PanIN is associated with a sig-
nificant risk of progression to PCAC and is rarely (<5%)
seen in resections for benign cysts or chronic pancreatitis.
Radiologic Features. PanIN lesions are micro-
scopic and undetectable radiologically.
Pathological Features. Pancreatic intraepithelial
B neoplasia typically involves the epithelium of intra- and in-
terlobular ducts that are smaller than 5 mm in diameter,
FIGURE 16.12
but the main pancreatic duct may also be involved in some
A, Pseudocyst filled with necrotic or hemorrhagic material rich in pancreatic
exocrine enzymes. B , Pseudocyst lined by granulation and fibrous tissue cases. By definition, the lesions are not visible grossly un-
(hematoxylin and eosin). less the ducts get dilated because of obstruction or some
other mechanisms. PanIN is classified into low (previous inactivating mutations in the p16/CDKN2A gene tend
PanIN-1 and PanIN-2 categories) and high grade (previous to be seen in low-grade PanIN with more significant
PanIN-3 category). Low-grade PanIN is characterized by a cytomorphologic atypia. S MAD4 and TP53 mutations
flat or papillary or micropapillary proliferation of tall co- usually occur in high-grade lesions. In addition, hyper-
lumnar epithelial cells with abundant intracytoplasmic methylation of several genes, including p16, has been
mucin and basally located round to oval nuclei. Nuclear reported, and the prevalence of hypermethylation
atypia varies from none to mild nuclear crowding, enlarge- increases from low- to high-grade PanIN.
ment, pseudostratification, and hyperchromasia. Mitoses Ancillary Studies. Ancillary studies are usually
are rare, and when present, they are not atypical (Fig. not required for the diagnosis of PanIN. PanIN exhibits a
16.13A). Conversely, high-grade PanIN is usually papil- gastric type immunoprofile including positive MUC5AC,
lary/micropapillary and is characterized by cribriforming, +/– MUC6, and negative MUC2 and CDX2. A lthough
budding, luminal necrosis, and irregular nuclei with visible MUC1 is negative in low-grade PanIN, high-grade PanIN
nucleoli and frequent mitoses (Fig. 16.13B). may express MUC1.
Importantly, PanIN harbors many of the same genetic Differential Diagnosis. The differential diagnosis
alterations seen in PDAC. Although the genetic alter- includes IPMN, in particular the branch-duct type. The
ations do not occur in a specific sequence, their preva- latter is usually larger than 1.0 cm in diameter and gross-
lence tends to increase from low to high grade. Whereas ly visible. Other lesions that may mimic PanIN include
telomere shortening and activating mutations in codon reactive ductal epithelial changes associated with in-
12 of the KRAS gene occur early in low-grade PanIN, flammation and cancerization of ducts. The latter is
spread of invasive carcinoma along preexisting ducts
and may be difficult to distinguish from high-grade
PanIN. Abrupt transition from normal to markedly
atypical epithelium or the close proximity of invasive
carcinoma with the involved duct favors cancerization.
Prognosis and Therapy. Although some PanIN
lesions progress to invasive adenocarcinoma, it is not
known how often and how rapidly they progress. The
presence of even high-grade PanIN at a surgical resec-
tion margin does not appear to affect survival in patients
who undergo complete (R0) resection for PDAC, al-
though anecdotal case reports have described high-grade
PanIN lesions progressing to invasive adenocarcinoma.
However, in the setting of hereditary pancreatic cancer,
the presence of high-grade PanIN in a distal pancreatec-
tomy specimen obtained as part of a surveillance proto-
A
col is an indication for total pancreatectomy.
PANCREATIC INTRAEPITHELIAL NEOPLASIA—FACT

SHEET
Definition
■ Noninvasive neoplastic pancreatic ductal epithelial proliferations
that typically involve smaller pancreatic ducts

■ The incidence is unknown
■ Low-grade pancreatic intraepithelial neoplasia (PanIN) often seen
in pancreatic resections for benign cysts or chronic pancreatitis

■ High-grade PanIN rarely (<5%) seen rarely in surgical resections
without cancer; can occur throughout the pancreas

B
FIGURE 16.13
■ Increasing frequency of low-grade PanIN with age; common after
A, Low-grade pancreatic intraepithelial neoplasia (PanIN) lesion exhibiting age 40 years
papillary proliferation of tall columnar epithelial cells with abundant intracyto-
plasmic mucin, basally located round to oval nuclei, and no mitosis (hema-
toxylin and eosin [H&E]). B , High-grade PanIN demonstrating micropapillary
Clinical Features
proliferation of unequivocally atypical cells with irregular nuclei, visible nucle- ■ No association with clinical symptoms
oli, and frequent and often abnormal mitoses (H&E).
Radiologic Features
■ Typically not detectable by imaging studies

■ The frequency and rate of progression to invasive ductal
carcinoma are unknown

■ The presence of high-grade PanIN may be an indication for
further intervention depending on the clinical scenario
Pancreatic Intraepithelial Neoplasia—Pathologic Features
Gross Findings
■ Typically invisible on gross examination
■ Ductal epithelial proliferations typically seen in smaller pancreatic FIGURE 16.14
ducts with various degrees of cytologic and architectural atypia;
A gross photograph of intraductal papillary mucinous neoplasm, main-duct
classified into low and high grade type.
■ Positive for gastric-type markers (MUC5AC and MUC6) Pathological Features. The majority of IPMNs
arise in the head of the pancreas. Duct involvement
Differential Diagnosis may be unifocal, multifocal, or diffuse. IPMNs are usu-
■ Other epithelial proliferation involving smaller pancreatic ducts:
ally localized on gross examination but can involve the
branch-duct intraductal papillary mucinous neoplasm, reactive
entire length of the main duct. Histologically, IPMNs
ductal epithelial changes, cancerization of ducts
are characterized by cysts of variable size lined by tall
columnar mucinous cells with a flat, undulating or
papillary architecture. IPMNs exhibit varying degrees
Intraductal Papillary Mucinous Neoplasm of epithelial atypia and are classified accordingly into
low-grade dysplasia, high-grade dysplasia, and invasive
Clinical Features. Intraductal papillary mucinous carcinoma. They are also classified into various sub-
neoplasm is a grossly visible, mucin-producing epithelial types based on the epithelial morphology of the intra-
neoplasm that predominantly grows within the main ductal components: gastric, intestinal, pancreato-bili-
pancreatic duct or its major branches and exhibits a pap- ary, or oncocytic. The gastric type IPMN is typically
illary architecture (Fig. 16.14). IPMNs make up 3% to low grade and characterized by abundant, slightly eo-
5% of all pancreatic neoplasms and are usually diag- sinophilic cytoplasmic mucin and basally located nu-
nosed in the sixth to seventh decade of life with a mean clei (Fig. 16.15A). Whereas most branch-duct IPMNs
age of 63 years. They are slightly more common in men are of gastric type, main-duct and mixed-type IPMN
(male-to-female ratio, 3 to 2). The majority are found often contain epithelia of multiple subtypes. The intes-
incidentally in asymptomatic patients during imaging tinal type exhibits villous papillae with basophilic cyto-
for another indication. Symptoms are typically caused plasm and enlarged, oval, hyperchromatic nuclei with
by intermittent pancreatic duct obstruction and mani- pseudostratification (Fig. 16.15B). The pancreatobili-
fest as abdominal pain, back pain, anorexia and weight ary type consists of thin, branching papillae with
loss, and recurrent symptoms of pancreatitis. Jaundice amphophilic cytoplasm and enlarged hyperchromatic
often indicates the presence of more advanced lesions, nuclei (Fig. 16.15C). The oncocytic type is character-
including invasive carcinoma arising in IPMN. ized by thick branching papillae with intracellular and/
Radiologic Features. Intraductal papillary muci- or intercellular lumina, abundant eosinophilic cyto-
nous neoplasm lesions are classified into main-duct, plasm, and large round nuclei with prominent nucleoli
mixed, and branch-duct types based on the pattern of (Fig. 16.15D). The oncocytic subtype is genetically dis-
involvement of the pancreatic duct system. Whereas tinct from the remaining three subtypes and is now re-
main-duct and mixed-type IPMNs are characterized by a garded as a separate entity (intraductal oncocytic pap-
markedly dilated main pancreatic duct, often with con- illary neoplasm) in the latest World Health Organization
currently dilated branch ducts, branch-duct IPMNs ex- (WHO) classification (fifth edition). Various grades of
hibit single or numerous cysts that represent dilated dysplasia are often mixed in a single IPMN, and multi-
branch ducts. ple epithelial subtypes may also be seen in a single
A B
C D
FIGURE 16.15
A, Gastric-type intraductal papillary mucinous neoplasm (IPMN) characterized by gastric foveolar-type epithelium with basally located nuclei and abundant
apical cytoplasmic mucin (hematoxylin and eosin [H&E]). B, Intestinal-type IPMN exhibiting villous papillae with basophilic cytoplasm and enlarged, oval, hyper-
chromatic nuclei with pseudostratification (H&E). C, Pancreatobiliary-type IPMN consisting of thin, branching papillae and/or micropapillae with large nuclei
(H&E). D, Oncocytic-type IPMN characterized by thick branching papillae with intracellular and/or intercellular lumina, abundant eosinophilic cytoplasm, and
large round nuclei with prominent nucleoli (H&E).
lesion. Invasive carcinoma is found up to one-third of genetically distinct from other subtypes and does not
cases and is often small (<2 cm) and can be multifocal. show mutations in K RAS, GNAS, and R NF43.
The histology of invasive carcinoma is classified into Ancillary Studies. Expression of MUC5AC is a
three types: tubular adenocarcinoma that resembles hallmark of IPMN. Other immunomarkers are variably
conventional PDAC (Fig. 16.16A), colloid carcinoma expressed based on the epithelial morphology: the gastric
(Fig. 16.16B), and oncocytic carcinoma. Interestingly, type are MUC6 +/MUC1–/MUC2–/CDX2–, intestinal
the histology of invasive components usually cor- type are MUC6–/MUC1–/MUC2+/CDX2+, pancreatobi-
relates with the epithelial morphology of intraductal liary type are MUC6+ (weak)/MUC1+/MUC2–/CDX2–,
components. Gastric- and pancreatobiliary-type and oncocytic type are MUC6+/MUC1 variable/MUC2
IPMNs are associated with tubular adenocarcinoma, variable/CDX2 variable. Loss of SMAD4 and aberrant
intestinal-type IPMN with colloid carcinoma, and the TP53 expression can be seen in high-grade lesions.
oncocytic type with oncocytic carcinoma. Differential Diagnosis. The differential diagnosis
The vast majority (80%) of IPMNs harbor activating is mainly with other cystic lesions of the pancreas, in-
mutations in codon 12 of the K RAS gene. In addition, cluding MCN, simple mucinous cyst (cystic mucinous
hotspot GNAS codon 201 mutations are found in two- duct lesion), PanIN, and SCA (oligocystic variant), re-
thirds of the lesions, irrespective of grade of dysplasia. tention cyst, cancerization of ducts, and large duct-type
Inactivating mutations in the tumor suppressor gene invasive adenocarcinoma. IPMNs can usually be differ-
RNF43 are also common in IPMNs. Mutations in other entiated from these entities based on clinical features
genes such as TP53, SMAD4, p16, and B RAF are seen and cytomorphology. Differentiation of branch-duct
only in IPMNs with high-grade dysplasia and/or carci- IPMN from PanIN is dependent on the size of the lesion
noma. As mentioned earlier, the oncocytic subtype is but could be subjective in lesions between 0.5 cm and
INTRADUCTAL PAPILLARY MUCINOUS

NEOPLASM—FACT SHEET
Definition
■ Grossly visible, mucin-producing epithelial neoplasm that primarily
grows within the main pancreatic duct and/or its branches

■ Most common cystic neoplasm of the pancreas; comprises 8%
to 20% of all resected pancreatectomy specimens

■ Most common in the pancreatic head

■ Slightly more common in men
■ Mean age is 63 years (range, 25–94 years)

A
Clinical Features
■ The majority found incidentally
■ Can present with abdominal or back pain, anorexia, weight loss,
and recurrent episodes of pancreatitis

■ The presence of jaundice is suggestive for high-grade lesions or
invasive carcinoma
Radiologic Features
■ Markedly dilated main pancreatic duct with or without cysts (main-duct
or mixed type) and single or numerous cysts (branch-duct type)

■ Excellent prognosis for noninvasive intraductal papillary mucinous
neoplasm (IPMN)
■ 40% 5-year survival rate for invasive carcinomas arising in IPMN
■ Curative resection at the preinvasive stage has best prognosis

B
FIGURE 16.16
A, Tubular adenocarcinoma arising in a high-grade gastric-type intraductal
papillary mucinous neoplasm (IPMN) that resembles conventional pancre-
atic ductal adenocarcinoma (hematoxylin and eosin [H&E]). B, Colloid carci- Intraductal Papillary Mucinous Neoplasm—Pathologic
noma arising in the background of an intestinal-type IPMN exhibiting mucin Features
pools with atypical glands (H&E).
Gross Findings
1.0 cm in diameter. Similarly, discrimination of IPMN ■ Dilated main or branch ducts with peripheral cysts often
with invasive carcinoma from conventional PDAC with connecting to the main pancreatic duct; cyst lining smooth or
cancerization of ducts and/or retention cysts with muci- with florid papillary projections
■ Solid areas in cases associated with invasive carcinoma
nous epithelial changes may be challenging and requires
correlation with imaging findings.
Prognosis and Therapy. The prognosis is excel-
■ Intraductal proliferation of mucin producing epithelium often with
lent in noninvasive tumors, and the 5-year survival rate papillary architecture and no ovarian-type stroma
is close to 100%, provided that appropriate sampling to ■ Four epithelial types of mucinous epithelium
rule out invasive carcinoma has been performed. How- ■ Varying degrees of dysplasia (low-grade and high-grade) with or
ever, at least 10% of patients with completely resected without invasive carcinoma
■ Oncocytic subtype now regarded as a separate entity
noninvasive IPMN experience a recurrence of IPMN.
The 5-year survival rate of invasive carcinoma arising Immunohistochemistry
in IPMN is significantly worse (40%) than that of non- ■ MUC5AC expression seen in all intraductal papillary mucinous
invasive IPMN, although it is better than that of con- neoplasm subtypes and various expressions of other markers (MUC6,
ventional ductal adenocarcinoma (5%). Thus, curative MUC1, MUC2, and CDX2) depending on the epithelial subtypes
resection preferably at the preinvasive stage (high-grade
dysplasia) is the most appropriate therapy. To identify Differential Diagnosis
high-risk lesions, the international consensus guide- ■ Other cystic lesions of the pancreas such as mucinous cystic
neoplasm, simple mucinous cyst, and serous cystadenoma, as well

lines for the management of IPMN and MCN of the
as pancreatic intraepithelial neoplasia, retention cyst, cancerization
pancreas have introduced high-risk stigmata and worri- of ducts, and large duct-type invasive adenocarcinoma
some features.
Mucinous Cystic Neoplasm strate the ovarian-type stroma. The prevalence of inva-
sive carcinoma arising in the background of MCN is less
Clinical Features. Mucinous cystic neoplasms than that of IPMN. Several distinct histologic types of
comprise 10% of cystic lesions of the pancreas and are invasive carcinoma may arise in MCNs, including undif-
almost exclusively diagnosed in women (average age at ferentiated carcinoma with osteoclast-like giant cells.
diagnosis, 40–50 years). Tumors may reach a large size Importantly, invasive components can be very focal, so
and rarely communicate with the pancreatic duct sys- submission of the entire lesion is recommended.
tem. MCN has a propensity to involve the body and/or Molecularly, activating mutations in codon 12 of the
tail of the pancreas. Patients with MCN typically pres- KRAS gene have been reported in up to 75% of MCNs,
ent with epigastric pain and/or abdominal fullness sec- but RNF43 mutations are found in up to 50% of the
ondary to compression of adjacent organs and tissues. lesions. G
NAS mutations are specific for IPMNs and do
Radiologic Features. Mucinous cystic neoplasm is not occur in MCNs. TP53 and SMAD4 mutations are
characterized by a large, well-demarcated, thick-walled seen only in high-grade dysplasia and/or associated
multilocular cystic mass. Peripheral calcification may be invasive carcinoma.
present (in 20% of cases). The main pancreatic duct Ancillary Studies. The ovarian-type stroma can
and interlobular ducts typically do not communicate be highlighted by estrogen receptor (ER) and/or proges-
with the cyst. Mural nodules may be seen but are more terone receptor (PR), and calretinin and inhibin expres-
common in MCN with invasive carcinoma. sions are seen in luteinized cells in the ovarian-like stro-
Pathological Features. Mucinous cystic neo- ma. CD10, ER, and PR immunostains may be useful in
plasms are usually solitary and large (mean diameter, highlighting the findings in cases of more hyalinized and
7–10 cm) cystic tumors located in the body or tail of the hypocellular ovarian-type stroma.
pancreas. They can be multiloculated and filled with vis- Differential Diagnosis. The differential diagnosis
cous mucoid material. Intracystic papillary excrescences is mainly with other cystic lesions of the pancreas in-
and/or mural nodules, when present, are indicative of cluding pseudocyst, simple mucinous cyst, branch-duct
high-grade dysplasia or invasive carcinoma. The cyst type IPMN, SCA (oligocystic variant), and SPN. MCN
wall lining is composed of tall or cuboidal mucin-secret- can usually be differentiated from those entities based
ing epithelium surrounded by a cellular ovarian-type on clinical features and the morphology on hematoxylin
stroma. The presence of ovarian-type stroma is a hall- and eosin (H&E), in particular the presence of ovari-
mark of MCN (Fig. 16.17). Similar to IPMNs, MCNs an-type stroma.
exhibit a varying degree of epithelial atypia and are clas- Prognosis and Therapy. The prognosis of MCN is
sified into low-grade dysplasia, high-grade dysplasia, excellent if it is noninvasive and completely removed.
and invasive carcinoma. The epithelium may be focally The 5-year survival rate of MCNs with invasive carcino-
denuded or consist of intact pancreaticobiliary type epi- ma is approximately 50% and correlates with the extent
thelium, and the ovarian-type stroma may be replaced of invasion and patient’s age (lower survival rate in
by broad areas of hyalinization, making the diagnosis those older than 50 years of age). The current standard
challenging. Multiple sections may be required to appro- clinical care is resection for all MCNs, given the relative-
priately determine the grade of dysplasia or to demon- ly young age at presentation and potential progression
to invasive carcinoma.
MUCINOUS CYSTIC NEOPLASM—FACT SHEET
Definition
■ Cystic neoplasm composed at least focally of mucin-producing
epithelial cells associated with ovarian-type stroma, typically

without communication with the pancreatic duct system

■ 10% of cystic lesions of the pancreas; usually involves body or
tail of the pancreas (90%)

■ Almost exclusively in women (average age, 40–50 years)
Clinical Features
FIGURE 16.17
■ Vague abdominal symptoms associated with compression of
Mucinous cystic neoplasm demonstrating tall or cuboidal mucin-secreting
epithelium supported by a cellular ovarian-like stroma (hematoxylin and adjacent organs and tissues
eosin).
compared with IPMNs, and mucinous secretions are not

Radiologic Features present in the dilated ducts. The intraductal location of
■ Large, well-demarcated thick-walled multilocular cystic mass
the tumor may need to be confirmed by a careful dissec-
without communication with the pancreatic duct system;
peripheral calcification in 20%; the presence of mural nodule
tion of the pancreatic duct system. Histologically, ITPNs
indicative of an invasive component are characterized by back-to-back tubular glands, result-
ing in a large cribriform pattern. The majority is pre-
Prognosis and Therapy dominantly or exclusively tubular, but papillae or solid
■ Excellent prognosis for noninvasive, completely removed lesions, areas may be present. Each neoplastic nodule appears
and 50% 5-year survival rate for invasive carcinomas arising in relatively homogeneous and consists of tightly packed
mucinous cystic neoplasm (MCN)
small acinar glands lined by cuboidal cells with modest
■ Complete resection is the current standard of care for all MCN
lesions amounts of eosinophilic or amphophilic cytoplasm and

round to oval, moderately to markedly atypical nuclei.
Mitotic figures are often evident, and necrosis may be
seen in some cases. Because of the architectural com-
plexity and cytologic atypia, ITPNs are essentially clas-
Mucinous Cystic Neoplasm—Pathologic Features sified as high-grade dysplasia (Fig. 16.18). Invasive car-
cinoma is found in 40% of reported cases. The invasive
Gross Findings
component is usually limited and is characterized by
Usually solitary and large (mean diameter, 7–10 cm) cystic
■
thin strands of tubules extending into the stroma sur-
lesions in the pancreatic body or tail of the pancreas
■ Often multiloculated and filled with viscous mucoid material rounding the neoplastic nodules. The cytology of the in-
■ Mural nodules indicative of high-grade dysplasia or invasive carcinoma vasive tubules is essentially the same as that of the intra-
ductal component, leading to difficulty in identifying
Microscopic Findings the invasive component. At the molecular level, ITPNs
■ Lined by tall columnar or cuboidal mucin-producing epithelium are distinct from IPMNs. PIK3CA mutations have been
surrounded by cellular ovarian-type stroma identified in one-fifth of ITPNs opposed to none of
■ The cyst lining may be focally denuded in large tumors, or intact
pancreatic epithelium may partially line the cyst, and the ovarian-
IPMNs; GNAS mutations have not been identified, and
type stroma may be replaced by hyalinized tissue in some areas KRAS mutations are rare in ITPNs. In addition, the pro-
tein expression of phosphorylated-AKT, a marker for
Immunohistochemistry PI3K-AKT pathway activation, is significantly more
■ Expression of estrogen and progesterone receptors is seen in the prominent in ITPNs than in IPMNs.
ovarian-like stroma Ancillary Studies. Intraductal tubulopapillary
■ Luteinized cells in the ovarian-like stroma are positive for
neoplasms commonly label for keratins 7 and 19, mark-
calretinin and inhibin
ers of pancreatic duct epithelium. Neither MUC5AC (a
Differential Diagnosis consistent marker for IPMN) nor MUC2 (a marker for
■ Other cystic lesions of the pancreas: pseudocyst, simple
intestinal-type IPMN) is expressed in ITPNs, but MUC1
mucinous cyst, branch-duct type intraductal papillary mucinous is expressed in 90% and MUC6 in 60%. ITPNs are
neoplasm, oligocystic serous cystadenoma, and solid-
pseudopapillary neoplasm
Intraductal Tubulopapillary Neoplasm
Clinical Features. Intraductal tubulopapillary

neoplasm is rare, accounting for only 3% of intraductal
neoplasms of the pancreas. A limited number of report-
ed cases indicate that ITPN occurs in both genders
equally, and the age ranges from 35 to 84 years. Clinical
presentations are similar to those of IPMN.
Radiologic Features. Most ITPNs resemble
IPMNs on imaging studies. About half of ITPNs develop
in the pancreatic head, one-third diffusely involve the
pancreas, and 15% are limited to the tail.
Pathological Features. Grossly, ITPNs form solid, FIGURE 16.18
large, nodular masses within dilated pancreatic ducts, Intraductal tubulopapillary neoplasm characterized by back-to-back tubular
glands resulting in a large cribriform pattern. The glands are lined by predom-
and the surrounding pancreatic parenchyma often inantly cuboidal cells with cytologic atypia and no intracytoplasmic mucin. A
shows marked sclerosis. Cyst formation is less evident large area of necrosis is also seen (hematoxylin and eosin).
essentially negative for markers of pancreatic exocrine normal acini. Perineural and vascular invasion, when
enzymes, and β-catenin nuclear expression has been represent, can help establish the diagnosis. Moderately dif-
ported in fewer than 10% of cases. ferentiated adenocarcinomas show the same haphazard
Differential Diagnosis. The main differential di- growth pattern but, in addition, are characterized by
agnosis of ITPNs is with IPMNs. Gastric- and intesti- greater architectural complexity and increased cytologic
nal-type IPMNs can be easily distinguished from ITPNs atypia (Fig. 16.20). The neoplastic cells may form incom-
on microscopic examination, but some pancreatobili- plete glands, cribriform structures, or papillae without fi-
ary-type IPMNs may resemble ITPNs. Discernible mu- brovascular cores. Significant nuclear pleomorphism can
cin, the presence of gastric-type epithelium in the back- be appreciated, and the nuclei in a single gland often vary
ground, and the expression of MUC5AC favor a diagnosis in size by more than 4 to 1. Nucleoli may be quite promi-
of IPMN. ITPNs, in particular those with predominant- nent, and mitoses, including abnormal mitoses, can be
ly tubular areas, may be difficult to distinguish from ac- seen. Poorly differentiated adenocarcinoma is character-
inar cell carcinomas (ACCs) with an intraductal growth. ized by solid sheets of neoplastic cells with very rare gland
The presence of apical acidophilic granules that can be formation as well as single-cell infiltration. Significant
highlighted by periodic acid–Schiff (PAS) stain and im- nuclear pleomorphism with brisk mitotic activity and
munohistochemical labeling for trypsin and/or chymo- atypical mitotic figures are common.
trypsin are consistent with the diagnosis of ACC. Several variants of ductal adenocarcinoma have been
Prognosis and Therapy. Given that ITPNs are es- described. A
denosquamous carcinoma is characterized by the
sentially high-grade dysplastic lesions with or without presence of both glandular and squamous differentiation
invasive components, resection is considered to be the and is associated with a poor prognosis (Fig. 16.21). Hepatoid
most appropriate therapy for all ITPNs. ITPNs appear carcinoma shows morphologic and immunophenotypic
to follow an indolent clinical course, although only lim-
ited clinical data are currently available. Recurrence and
metastases to lymph nodes and/or to the liver have been
reported in one-third of cases, but even these patients
may survive for more than 2 years.
Pancreatic Ductal Adenocarcinoma
Clinical Features. Pancreatic ductal adenocarci-

noma is a disease of older adults, with most patients be-
ing older than 60 years at presentation. Men are affected
slightly more frequently than women, and in the United
States, African Americans more often than Whites.
Common presenting signs and symptoms include pain-
less jaundice, unexplained weight loss, and epigastric
pain radiating to the back. New-onset diabetes mellitus FIGURE 16.19
may be the first manifestation of the disease. Infiltrating adenocarcinoma of the pancreas. An irregular firm white mass is
Radiologic Features. Pancreatic ductal adenocarcino- present in the head of the pancreas (hematoxylin and eosin).
mas typically produce a hypodense mass lesion that distorts
normal gland architecture. The pancreatic duct is often dilat-
ed secondary to duct obstruction by the infiltrating tumor.
Pathologic Features. Grossly, most tumors form
poorly defined, firm, white-yellow masses (Fig. 16.19).
Most arise in the head of the pancreas, but they can also
involve the body, the tail, or even the entire gland. Focal
cystic degeneration and areas of necrosis are common.
The pancreatic duct is often dilated upstream from the
neoplasm. Microscopically, varying degrees of differentia-
tion can be seen based on extent of gland formation, ex-
tracellular mucin pools, cytologic atypia, and mitotic ac-
tivity. Well-differentiated adenocarcinoma is characterized
by clearly formed neoplastic glands with an infiltrating,
haphazard growth pattern. This growth pattern, more
FIGURE 16.20
than any other feature, helps distinguish well-differenti-
Pancreatic ductal adenocarcinoma showing neoplastic glands arranged hap-
ated adenocarcinomas from non-neoplastic reactive hazardly and surrounded by desmoplastic stroma. Note the perineural growth
glands that retain the circumscribed architecture of (hematoxylin and eosin).
features of hepatocellular differentiation, and metastasis These carcinomas can have a significant spindle cell compo-
from a liver primary cancer should be ruled out clinically nent, or they can be composed of large polygonal cells.
before making this diagnosis. Colloid carcinoma is also Undifferentiated carcinoma with osteoclast-like giant cells
known as the mucinous noncystic adenocarcinoma and is (UCOGC) is composed of mononuclear cells with severe
characterized by well-differentiated, neoplastic, mucin-pro- cytologic atypia, admixed with large multinucleated osteo-
ducing epithelial cells “floating” in large pools of extracellu- clast-like giant cells with uniform nuclei (Fig. 16.23). Whereas
lar mucin (see F ig. 16.16B). This variant may have a slightly the mononuclear cells are malignant, the osteoclast-like giant
better prognosis than PDAC and almost always arises in cells are reactive. An in situ or invasive adenocarcinoma is
association with an IPMN, which may explain the better also frequently present. The prognosis for UCOGCs is better
prognosis. S ignet ring cell carcinoma is composed of nonco- than that of PDAC. Undifferentiated carcinomas with a rhab-
hesive neoplastic cells with abundant cytoplasmic mucin doid morphology and loss of SMARCA4 or INI-1 m ay also
that indents the nuclei pushing them toward the periphery. arise in the pancreas but are extremely rare.
Infiltration as single cells, small clusters, or cords is charac- Pancreatic adenocarcinomas are genetically very com-
teristic. Metastases from a breast or gastric primary cancer plex, with widespread chromosomal abnormalities,
should be considered before making this diagnosis. numerous losses and gains of large segments of DNA, and
Medullary carcinoma is characterized by poor differentia- on an average more than 60 exomic alterations per can-
tion, syncytial growth pattern, tumor-infiltrating lympho- cer. K
RAS, CDKN2A, TP53, and S MAD4 are the most
cytes, pushing borders, and microsatellite instability. frequently altered genes in PDAC. In addition, a number
Medullary carcinoma can occur sporadically or in patients of less commonly mutated genes have been identified,
with Lynch syndrome and has a better prognosis than ordi- including MLL3, ARID1A, and TGFBR2. Approximately
nary PDAC. (Fig. 16.22) U ndifferentiated (anaplastic) carci- 10% of pancreatic cancers are familial. Germline muta-
noma, as the name suggests, is an extremely aggressive tions in B RCA2 and C DKN2A and less frequently in
neoplasm composed of highly atypical cells, with significant BRCA1, PALB2, and ATM have been identified in a small
pleomorphism and frequent, often bizarre, mitoses. subset of patients with familial PDAC. In addition,
patients with Lynch syndrome, Peutz-Jeghers syndrome,
and hereditary chronic pancreatitis are also at increased
risk of PDAC. The genetic basis for the majority of famil-
ial pancreatic cancers still remains unknown.
Ancillary Studies. Immunohistochemical labeling
can be used to highlight epithelial and glandular differ-
entiation of ductal adenocarcinomas, as well as to
demonstrate some of the molecular alterations present
FIGURE 16.21
Adenosquamous carcinoma showing both glandular and squamous differen-
tiation (hematoxylin and eosin).
FIGURE 16.23
FIGURE 16.22 Undifferentiated carcinoma with osteoclast-like giant cells composed of atyp-
Medullary carcinoma showing poor differentiation, a syncytial growth pattern, ical mononuclear cells admixed with non-neoplastic multinucleated giant
and tumor-infiltrating lymphocytes (hematoxylin and eosin). cells. The nuclei in the giant cells are uniform (hematoxylin and eosin).
in the neoplastic cells. Immunolabeling for cytokeratin an ampullary primary cancer can be challenging in some
(CK) 7, CK8, CK18, and CK19 is positive, as is immuno- instances and is discussed in greater detail in the section
labeling for CEA, CA19-9, Dupan-2, MUC1, MUC4, and on ampullary tumors in Chapter 6. A careful gross ex-
MUC5AC. The vast majority of adenocarcinomas of the amination to assess bulk of tumor localization and a
pancreas also label for mesothelin, claudin 18, and fas- thorough microscopic evaluation to determine presence
cin. Colloid carcinomas label for MUC2; the squamous of any precursor lesions (ampullary adenoma or high-
component of adenosquamous carcinomas with anti- grade PanIN) can usually resolve this differential diag-
bodies to p63. Aberrant p53 expression and loss of ex- nosis in most cases.
pression of Smad4 is seen in 60% to 80% and 50% to Prognosis and Therapy. The prognosis of patients
60% of the cases, respectively, and correlates with TP53 with an infiltrating adenocarcinoma of the pancreas is ex-
and SMAD4 mutational status. (Fig. 16.24). Of all these tremely poor. Most patients die of their disease, often
markers, the most commonly one used in routine prac- within months of diagnosis. Even though surgery is the
tice is SMAD4 for work-up of metastatic carcinomas of treatment of choice, most patients (∼80%) have metastat-
unknown primary origin. Loss of nuclear SMAD4 stain- ic disease at diagnosis and are not candidates for surgery.
ing is often used to favor a pancreaticobiliary origin. Radiation and chemotherapy have a small impact on sur-
Differential Diagnosis. Reactive non-neoplastic vival. Colloid carcinoma and UCOGC have been associat-
glands of chronic pancreatitis top the differential diag- ed with a slightly better prognosis, whereas the adenos-
nosis. Features useful in establishing a diagnosis of infil- quamous and undifferentiated variants have a worse
trating adenocarcinomas in histologic sections are (1) prognosis.
haphazard infiltrative growth pattern; (2) variation in
the size of nuclei by more than 4:1 in a single gland; (3)
incomplete lumen formation; (4) glands adjacent to PANCREATIC DUCTAL ADENOCARCINOMA—FACT SHEET
muscular vessels; (5) perineural or vascular invasion;
(6) mitoses, especially abnormal mitoses; (7) glandular Definition
luminal necrotic debris; and (8) aberrant p53 or Smad4 ■ A malignant infiltrative epithelial neoplasm with ductal differentiation
immunolabeling. The distinction of a pancreatic from

■ 85% to 90% of all pancreatic neoplasms
■ Pancreatic head (>60%)

■ More often in men (male-to-female ratio, 2 to 1)
■ Increased risk with smoking and family history of pancreatic cancer
■ Older age group; usually older than 60 years
Clinical Features
■ Epigastric pain, often radiating to the back
■ Weight loss
■ Painless jaundice
■ Less often, migratory thrombophlebitis, pancreatitis, new-onset
diabetes mellitus
A
Radiologic Features
■ Ill-defined infiltrative nonenhancing pancreatic mass

■ Surgical resection
■ Palliative bypass procedures
■ Radiation and chemotherapy
■ Prognosis extremely poor (slightly better for colloid carcinoma)
■ 5-year survival rate around 5%
Pancreatic Ductal Adenocarcinoma—Pathologic Features

B
Gross Findings
FIGURE 16.24
■ Poorly defined, firm mass with irregular borders
A, Strong and diffuse p53 immunolabeling in pancreatic ductal adenocarci-
■ Cut surface: yellow-white microcystic areas, hemorrhage, and necrosis
noma (PDA). B , Loss of immunolabeling for the S MAD4/DPC4 gene prod-
uct in PDA. Note the positivity of the stromal cells.
often multicentric, occur in 60% to 70% of patients

Microscopic Findings with multiple endocrine neoplasia syndrome type 1.
■ Neoplastic glands in a haphazard infiltrative growth pattern
Pancreatic manifestations of von Hippel-Lindau (VHL)
■ Architectural atypia with incomplete glands and luminal necrosis
■ Cytologic atypia with nuclei in a single gland varying by more than 4 to 1

syndrome include SCA, PanNETs with or without clear
■ Vascular and perineural invasion
cell features, and mixed serous neuroendocrine lesions.
■ Glands adjacent to muscular vessels In addition, PanNETs may be associated with other
■ Brisk mitoses and necrosis genetic syndromes, including tuberous sclerosis com-
■ Solid sheets or single cell infiltration (poorly differentiated tumors)
plex and neurofibromatosis type 1.
■ Glandular and squamous differentiation (adenosquamous carcinoma)
■ Hepatocellular differentiation (hepatoid carcinoma)
■ Mucin-producing cells floating in pools of mucin (colloid carcinoma) Radiologic Features

■ Individual cells with eccentric mucin vacuoles (signet ring cell carcinoma)
■ Undifferentiated spindle cell component (undifferentiated or Pancreatic neuroendocrine tumors present as well-cir-
anaplastic carcinoma) cumscribed masses on CT scans.
■ Mixture of malignant mononuclear cells and reactive osteoclast-
like giant cells

Pathological Features
■ Positive for cytokeratin (CK) 7, CK8, CK18, and CK19 Grossly, PanNETs are typically solitary, well-demar-
■ Positive for carcinoembryonic antigen, CA19-9, Dupan-2, MUC1, cated tumors with a tan-white to yellow cut surface
MUC4, and MUC5AC (Fig. 16.25A). They can be fleshy or fibrotic, and larger
■ Most tumors also positive for mesothelin, claudin 18, prostate
tumors may show hemorrhage or necrosis. Cystic
stem cell antigen, and fascin
■ Aberrant p53 expression (60%–80%)
degeneration can occur but is not common.
■ Loss of Smad4 protein expression (50%–60%) Microscopically, PanNETs can show multiple growth
patterns, including nesting, trabecular, glandular, or
Differential Diagnosis pseudorosetting (Figs. 16.25B and C). Tumors showing
■ Chronic pancreatitis any of these growth patterns are classified as “well-dif-
■ Ampullary carcinoma
ferentiated.” In contrast, “poorly differentiated”
■ Other primary and metastatic pancreatic neoplasms
PanNETs typically show confluent aggregates or sheets
of tumor cells, often with tumor necrosis. Cytologically,
the neoplastic cells are uniform with round nuclei and
■ NEUROENDOCRINE TUMORS characteristic coarsely clumped “salt-and-pepper”
chromatin (Fig. 16.25D). The cytoplasm can be amph-
ophilic or eosinophilic and may contain fine granules.
Well-Differentiated Neuroendocrine Tumors Luminal mucin can be seen in rare instances. Several
(Grades 1–3) histologic features are suggestive of production of a
specific hormone, including amyloid deposition in
Clinical Features insulinomas and psammoma bodies in somatostatino-
mas. Molecularly, PanNETs are distinct from ductal
Pancreatic neuroendocrine tumors (PanNETs) are pancreatic neoplasms. Somatic mutations in M EN1 are
uncommon primary pancreatic neoplasms, accounting the most common alteration. Inactivating mutations in
for only 1% to 2% of all pancreatic neoplasms that pres- the tumor suppressor genes A TRX and D AXX, leading
ent mostly in adults. The clinical presentation of to the alternative lengthening of telomeres (ALT) phe-
PanNETs depends largely on whether the tumor secretes notype, are also common, as are mutations in compo-
a hormone that causes clinical symptoms (functional nents of the mTOR (mammalian target of rapamycin)
PanNETs) or does not secrete hormones (nonfunctional pathway. The latter may be important in determining
PanNETs). Patients with functional NETs often present response to targeted therapy.
with symptoms caused by hormone hypersecretion; char-
acteristic clinical syndromes have been described for the Ancillary Studies
commonly secreted hormones, such as insulin and gluca-
gon. Because of clinical symptoms, functional PanNETs Immunohistochemical staining for chromogranin and
are often diagnosed at smaller size than nonfunctional synaptophysin is typically diffusely positive in PanNETs.
PanNETs. However, with the increased use of abdominal They usually express cytokeratins, though CK7 is often
imaging, incidental nonfunctional PanNETs are being negative. PanNETs frequently label immunohistochem-
increasingly identified. Large nonfunctional tumors can ically with antibodies to hormones, but hormone expres-
present with vague abdominal symptoms caused by com- sion as defined by immunolabeling is insufficient to
pression of adjacent structures. classify a PanNET as functional in the absence of clini-
Pancreatic neuroendocrine tumors also occur as key cal symptoms. Only PanNETs in patients with symp-
features of multiple inherited syndromes. PanNETs, toms associated with hormone hypersecretion are
A B
C D
FIGURE 16.25
Well-differentiated pancreatic neuroendocrine tumor (PanNET). A, Grossly, PanNETs are solid, well-circumscribed, fleshy masses. Multiple growth patterns can
occur, including glandular (B) and trabecular (C). D, PanNETs have characteristic neuroendocrine cytologic features, including round nuclei with “salt-and-
pepper” chromatin.
classified as functional and labeled as an “-oma” of their PanNET are those with 2 to 20 mitoses per 2 mm2 or a
hormone (e.g., insulinoma, gastrinoma). nuclear Ki-67 labeling index of 3% to 20%. Rarely,
architecturally well-differentiated PanNET may show a
Differential Diagnosis mitotic count greater than 20 per 2 mm2 or a Ki-67 pro-
liferative index greater than 20%. These tumors are
The differential diagnosis is chiefly with other solid cel- now classified as grade 3 PanNET in the 2017 WHO
lular neoplasms of the pancreas, including ACC, pancre- classification, and although they do not respond well to
atoblastoma, and SPN. Although morphology on H&E platinum based chemotherapy, the outcome is better
can be strongly suggestive of PanNET, there is also con- than small cell or large cell pancreatic neuroendocrine
siderable morphologic overlap between these entities, carcinomas (NECs). Well-differentiated grade 3 PanNET
and IHC is often required for definitive diagnosis. typically show a proliferative index in the 30% to 60%
Importantly, PanNETs do not express pancreatic exo- range, although no upper limit is currently defined for
crine enzymes (e.g., trypsin, chymotrypsin), and β-cat- excluding tumors from this group. In contrast, small cell
enin is not nuclear. or large cell PanNECs are poorly differentiated, and the
proliferative index on a Ki-67 immunostain is typically
Prognosis and Therapy greater than 60%. Loss of Rb protein and abnormal p53
expression is almost never seen in grade 3 well-differen-
Pancreatic neuroendocrine tumors are graded based on tiated PanNET but is quite prevalent in poorly differen-
mitotic rate, as determined by mitotic count or Ki67 tiated NEC. Surgery is the treatment of choice for
labeling index, and tumor grade is the most significant PanNET. Although the prognosis is better than that for
prognostic factor. Low-grade (G1) PanNET have a patients with PDAC, tumor recurrence after resection is
mitotic count of 0 to 1 per 2mm2 and/or a nuclear Ki-67 common. Targeted therapies with mTOR inhibitors
labeling index of 0% to 2%. Intermediate-grade (G2) have shown promise in ongoing clinical trials.
Neuroendocrine Carcinomas
WELL-DIFFERENTIATED NEUROENDOCRINE
TUMOR—FACT SHEET Pancreatic neuroendocrine tumors that are poorly dif-
ferentiated with greater than 20 mitoses per 2 mm2 and/
Definition
or a Ki67 proliferation index of greater than 20% are
■ Primary pancreatic epithelial neoplasm with neuroendocrine
differentiation and well-differentiated architectural growth pattern

classified as NEC. Overall, these are considered to be
(nested, trabecular, glandular) aggressive neoplasms with poor prognosis. Tumors may
show a small cell or large cell NEC phenotype. Whereas
Incidence and Location small cell carcinoma, as at other sites, shows tumor cells
■ 1% to 2% of all primary pancreatic neoplasms; more common in with minimal cytoplasm and molded nuclei, large cell
the pancreatic head but can occur throughout the pancreas carcinomas show abundant cytoplasm, prominent
nucleoli, and marked pleomorphism. The latter appear
to be more common than small cell carcinomas in the
■ Men and women are equally affected
■ No racial predilection
pancreas. PanNEC are genetically similar to ductal ade-
■ Peak incidence between 30 and 60 years of age
nocarcinomas and harbor K RAS mutations.
Clinical Features
■ Functional pancreatic neuroendocrine tumors (PanNETs) present
with defined clinical syndromes because of hormone hypersecretion. ■ TUMORS WITH ACINAR DIFFERENTIATION
Nonfunctional PanNETs can be discovered incidentally on abdominal
imaging or present with vague abdominal symptoms caused by
compression of adjacent structures Acinar Cell Cystadenoma
Radiologic Features
■ Well-demarcated mass Acinar cell cystadenoma, also known as acinar cystic
transformation in the new WHO classification, is a rare
Prognosis and Therapy benign cystic lesion of the pancreas that may involve any
■ Prognosis largely defined by tumor grade, determined by portion of the pancreas but is most commonly found in
proliferation rate defined by mitotic count or proliferation index
the pancreatic head. They can be detected because of clin-
on Ki67 immunostain
■ Surgery is treatment of choice
ical symptoms, most commonly abdominal pain, or found
■ mTOR (mammalian target of rapamycin) inhibitors are promising incidentally on abdominal imaging studies. Grossly, aci-
for patients in whom surgery is not curative nar cell cystadenomas can range in size from smaller than
1 cm to larger than 10 cm and can be uni- or multilocular.
The cysts contain watery fluid, and the cyst lining is usu-
ally smooth. Microscopically, the cysts are lined by a com-
bination of well-differentiated, benign-appearing acinar
Well-Differentiated Neuroendocrine Tumor—Pathologic and ductal epithelium ( Fig. 16.26
). Whereas the aci-
Features nar-type cells have uniform basally oriented nuclei and
apical cytoplasmic granules, the ductal-type cells lack
Gross Findings cytoplasmic granules; these two cell types have been con-
■ Well-circumscribed, solitary, fleshy or fibrotic mass firmed by IHC studies of acinar cell cystadenomas by dual
labeling with chymotrypsin and BCL10 (acinar) and
Microscopic Findings CK19 (ductal). The neoplastic nature of these lesions
■ Variety of architectural patterns (trabecular, nested,
remains controversial, but current data suggest that aci-
pseudorosetting, glandular); round uniform nuclei with “salt-and-
pepper” chromatin; granular cytoplasm
nar cell cystadenomas represent non-neoplastic cystic
transformation rather than true neoplasms. Perhaps most
Ultrastructural Findings important, these lesions are clinically benign because
■ Neurosecretory granules are common there has never been a reported case of malignant trans-
formation or association with ACC.
■ Positive for chromogranin and synaptophysin
■ Frequently express pancreatic hormones
■ Clinical syndrome with defined symptoms and signs is required Acinar Cell Carcinoma
to classify tumors as “functional”

■ Other solid pancreatic neoplasms: acinar cell carcinoma,
pancreatoblastoma, solid-pseudopapillary tumor Acinar cell carcinoma is a rare pancreatic malignancy,

accounting for fewer than 2% of all exocrine pancreatic
throughout the pancreas but are slightly more common in

the pancreatic head. Microscopically, they are composed
of neoplastic cells with architectural, cytologic, and
immunohistochemical evidence of acinar differentiation.
The most common architectural patterns are acinar struc-
tures with pyramidal-shaped cells forming small lumina
(Fig. 16.27A) or solid with sheets of tumor cells without
any well-defined structures. Less commonly, glandular
and trabecular patterns can also occur. Extensive intra-
ductal growth can also occur but is uncommon. The cyto-
plasm typically contains amphophilic or eosinophilic
zymogen granules. However, these granules are also not a
diagnostic requirement because they can be poorly devel-
oped and difficult to appreciate on routine stains. The
A nuclei are round to oval, and there is usually a single
prominent nucleolus (Fig. 16.27B). Molecularly, ACCs
are characterized by striking genomic instability, either at
the base pair or chromosomal level. There are no muta-
tions prevalent in a majority of ACCs, but SMAD4,
CDKN2A, and CDKN2B mutations have been described
in a minor subset of cases.
Ancillary Studies
Immunolabeling for pancreatic exocrine enzymes is typ-

ically positive in ACC, including trypsin (Fig. 16.27C),
chymotrypsin, lipase, and elastase. In addition, a rela-
tively new marker BCL10 is strongly and diffusely posi-
tive in ACC. Chromogranin and synaptophysin can be
B focally positive, but if positive in more than 25% of the
cells, a diagnosis of mixed tumor should be considered.
FIG 16.26
Immunolabeling for β -catenin can be aberrantly nuclear
Acinar cell cystadenoma. A , The cyst is lined by cuboidal acinar cells and
patches of mucin-containing ductal cells. B, BCL10 is positive in the cuboi- in a minority of ACCs because these tumors can have
dal acinar cells but negative in the mucin-containing ductal cells. mutations in A PC or C TNNB1, leading to aberrant
nuclear localization of the β -catenin protein.
neoplasms. Most occur in older adults, but up to 10%
occur in children. They are more common in men (male- Differential Diagnosis
to-female ratio, 3.6 to 1) and present with nonspecific
symptoms caused by compression of adjacent structures, The histologic differential diagnosis lies chiefly between
including abdominal and back pain, nausea, and diar- other solid cellular neoplasms of the pancreas, including
rhea. Jaundice is rare because of the growth pattern of PanNET or PanNEC, SPN, and pancreatoblastoma.
the tumor. A minority of patients present with a constel- Metastasis to the pancreas, although uncommon, should
lation of symptoms caused by hypersecretion of lipase always be considered. ACCs with extensive intraductal
by the neoplastic cells, including subcutaneous fat and papillary growth patterns can mimic an intraductal
necrosis, polyarthralgia, and eosinophilia. neoplasm, such as ITPN or IPMN. Acinar architecture,
cytoplasmic granules, and single prominent nucleoli
Radiologic Features favor a diagnosis of ACC, though there is considerable
morphological overlap with other entities on routine
Acinar cell carcinomas are large, circumscribed, homo- morphology. Pancreatoblastomas typically have a signif-
geneously enhancing masses on CT scan. icant component with acinar differentiation, but squa-
moid nests are diagnostic of pancreatoblastoma and are
Pathological Features absent in ACC. As described earlier, IHC can confirm a
diagnosis of ACC through demonstration of expression
Acinar cell carcinomas form solitary, well-circumscribed of BCL10 or pancreatic exocrine enzymes. When inter-
masses with soft, fleshy, red-tan cut surfaces. They are preting β -catenin immunohistochemistry, it is import-
large tumors, with an average size of 10 cm, and can have ant to remember that a subset of ACCs can also have
central necrosis or cystic degeneration. ACCs can occur aberrant nuclear staining.
tumors. Chemotherapy is typically used for patients with

metastatic disease, but there are no prospective randomized
clinical trials to guide treatment for this rare malignancy.
Typical regimens are similar to those used in PDAC or col-
orectal cancer because of molecular similarities.
ACINAR CELL CARCINOMA—FACT SHEET
Definition
■ Malignant epithelial neoplasm with acinar differentiation similar to
pancreatic acinar cells

■ Rare (<2% of all pancreatic malignancies); can occur throughout
A pancreas but more common in head

■ More common in men (male-to-female ratio, 3.6 to 1)
■ Most common in older adults, but a significant minority may
occur in children
Clinical Features
■ Usually presents with nonspecific abdominal symptoms
■ Minority of patients may show subcutaneous fat necrosis,
polyarthralgia, and eosinophilia caused by lipase hypersecretion
Radiologic Features
■ Large, circumscribed, homogeneously enhancing mass

B ■ Poor prognosis with 5-year-survival of about 25%; treatment is
surgery for localized disease and chemotherapy for systemic

disease
Acinar Cell Carcinoma—Pathologic Features
Gross Findings
■ Solitary, circumscribed fleshy mass
■ Architecture: most commonly acinar but can also be solid,
glandular, or trabecular
■ Cytology: cytoplasm with zymogen granules, round polarized
nuclei with prominent nucleoli
Ultrastructural Findings
C
■ Electron-dense zymogen granules in cytoplasm
FIGURE 16.27
Acinar cell carcinoma (ACC). A , Acinar architecture, with pyramidal-shaped cells Immunohistochemistry
polarized around small lumina, is characteristic but not required for the diagno- ■ Diffuse expression of BCL10 and pancreatic exocrine enzymes
sis. B, Cytoplasmic granules are common, and single prominent nucleoli are a (trypsin, chymotrypsin, lipase, elastase)
characteristic feature. C
, Trypsin is diffusely and strongly positive in ACC.
■ Can have focal (<25%) expression of chromogranin and
synaptophysin
Prognosis and Therapy ■ Subset of cases can have nuclear β -catenin
Acinar cell carcinomas are aggressive cancers, with a 5-year Differential Diagnosis
survival rate of only 25%. Stage is the best predictor of out- ■ Other solid cellular pancreatic neoplasms: pancreatic
come, which is better than stage-matched PDAC. There is neuroendocrine tumor or carcinoma, solid-pseudopapillary tumor,
currently no accepted system for grading ACCs. Surgery is pancreatoblastoma; metastasis from another site
the treatment of choice for patients with organ-confined
Acinar Cell Cystadenocarcinoma Pathological Features
Pancreatoblastomas are not associated with a specific

Acinar cell cystadenocarcinoma is a very rare grossly cystic, location in the pancreas and are evenly distributed
malignant neoplasm with acinar differentiation. Most cases throughout the head, body, and tail. Grossly, they typi-
are very large with variably sized cysts lined by cytologically cally form solitary well-circumscribed fleshy masses and
malignant cells with acinar differentiation as demonstrated can be encapsulated. There is a wide size range, but on
by morphology and IHC. Although few cases have been average, pancreatoblastomas are large tumors (>10 cm
described in the literature, the clinical behavior does not in size). Microscopically, they can consist of multiple
seem to be significantly different from that of ACC. components, but a combination of cells with acinar dif-
ferentiation with round nuclei and prominent nucleoli,
granular cytoplasm, and architecturally polarized
around small lumina (Fig. 16.28A) and squamoid nests
Pancreatoblastoma
with whorled groups of plump squamoid cells with
eosinophilic cytoplasm and clear nuclei (Fig. 16.28B)
Clinical Features must be present for diagnosis. The squamoid nests are a
diagnostic requirement and can distinguish pancreato-
Pancreatoblastomais a very rare pancreatic malignancy blastoma from ACC. Other possible components include
that accounts for a very small proportion of adult malig- neuroendocrine cells; ductal cells, which can produce
nancies but for approximately 25% of pancreatic neo- mucin; and immature small round blue cells. These
plasms in the first decade of life. The majority occur in components are typically arranged in well-defined
children younger than 10 years of age. There is a slight islands separated by stromal bands. The stroma can
male predominance. In young patients, pancreatoblas- rarely have heterologous elements such as bone or carti-
toma can be diagnosed because of a palpable abdominal lage. Because of the rarity of these tumors, they have not
mass, or patients can present with nonspecific symptoms been as well characterized at the genetic level, though
such as abdominal pain and nausea. As with ACC, jaun- loss of chromosome 11p and mutations in the APC/
dice is uncommon. Approximately one-third of patients CTNNB1 pathway have been reported.
with pancreatoblastoma have elevated serum levels of
alpha-fetoprotein caused by production by the tumor. Ancillary Studies
Pancreatoblastoma has been reported in patients with
Beckwith-Wiedemann syndrome, a disorder associated The cells in each component have immunohistochemi-
with imprinting dysregulation on chromosome 11p, as cal profiles in keeping with their line of differentiation.
well as in patients with familial adenomatous polyposis. The acinar component expresses pancreatic exocrine
enzymes (trypsin, chymotrypsin, lipase), the neuroen-
Radiologic Features docrine component expresses chromogranin and synap-
tophysin, and the ductal component expresses CK7 and
Pancreatoblastomas form large, circumscribed, hetero- CK19. Of note, the squamoid nests are negative for most
geneous masses, which may have calcifications. markers, but the nuclei contain biotin and thus label
A B
FIGURE 16.28
Pancreatoblastoma. These tumors consist of multiple components. A
, Most tumors show predominantly acinar differentiation. B
, Squamoid nests are specific
for pancreatoblastoma and required to establish a diagnosis.
nonspecifically with a variety of antibodies. Nuclear β chemotherapy is often used for metastatic tumors. Even
-catenin labeling is typically restricted to the squamoid in patients with resectable disease, local recurrence and
nests and is a useful feature for diagnosis. metachronous metastasis are common. Pancreatoblastoma
is staged using the same system as PDAC, and stage is the
Differential Diagnosis best predictor of outcome.
The differential diagnosis lies mostly with the other

solid cellular neoplasms of the pancreas. Squamoid nests Pancreatoblastoma—Pathologic Features
are a truly unique feature of pancreatoblastoma and can
be used to establish this diagnosis. ACC similarly con- Gross Findings
sists of cells with acinar differentiation but does not ■ Large, circumscribed, fleshy mass
have squamoid nests. Importantly, CTNNB1 mutations

have been reported in pancreatoblastoma, and thus they
■ Multiple components arranged in islands separated by stromal bands
can have nuclear β-catenin immunolabeling, which is ■ Must have at least acinar component and squamoid nests but
characteristically restricted to the squamoid nests. As can also have neuroendocrine, ductal, and primitive components
such, this antibody cannot be used to distinguish pan-
creatoblastoma from SPN, which uniformly shows aber- Ultrastructural Findings
rant nuclear labeling for β-catenin throughout the ■ Findings vary by differentiation of components: electron-dense
tumor. The presence of acinar cell differentiation on granules in acinar and endocrine components; desmosomes in
squamoid nests
IHC and squamoid nests is helpful in distinguishing
these two tumors. Although uncommon, metastasis to Immunohistochemistry
the pancreas should always be considered in the differ- ■ Each component has labeling typical of its line of differentiation:
ential diagnosis. acinar (trypsin, chymotrypsin, BCL10), neuroendocrine
(chromogranin, synaptophysin), ductal (CK7, CK19)
■ Squamoid nests have nuclear biotin and thus show nonspecific
nuclear labeling, but nuclear β -catenin in these nests is
characteristic
The overall survival rate is approximately 50%. Surgery
is the treatment of choice in localized disease, and Differential Diagnosis
■ Other solid cellular pancreatic neoplasms: acinar cell carcinoma,
pancreatic neuroendocrine tumor or carcinoma, solid-

PANCREATOBLASTOMA—FACT SHEET pseudopapillary tumor; metastasis from another site
Definition
■ Malignant epithelial neoplasm with pancreatic acinar
differentiation and squamoid nests Serous Cystadenoma

Clinical Features
■ Rare primary pancreatic tumor; extremely rare in adults, but about
25% of pancreatic neoplasms are in children younger than 10

years old Serous cystadenomas are uncommon but account for
almost one-third of all cystic pancreatic neoplasms.
Gender, Race, and Age Distribution They occur primarily in adults and have a female pre-
■ Slight male predominance dominance (male-to-female ratio, 3 to 7). SCAs are fre-
quently discovered incidentally on abdominal imaging
■ Most common in children younger than 10 years old but can
occur in adults
but can also present with nonspecific abdominal symp-
toms. SCAs are frequently found in patients with VHL
Clinical Features syndrome, an autosomal dominant tumor predisposition
■ Usually diagnosed because of a palpable abdominal mass in syndrome characterized by clear cell neoplasms in mul-
children or nonspecific abdominal symptoms tiple organs. In patients with VHL syndrome, the pan-
creas can be diffusely involved by SCAs, and patients
Radiologic Features can have combined serous neuroendocrine neoplasms in
■ Large, circumscribed, heterogeneous mass
addition to typical SCAs.
■ Treated with surgery (localized disease) or chemotherapy
Radiologic Features
(systemic disease)
■ Overall survival rate is about 50% Serous cystadenomas present as well-circumscribed,
■ Recurrence common even in patients with complete resection multilocular cystic masses, often with central stellate
scars.
Pathological Features are lined by flattened endothelial cells that are positive for
CD31, CD34, or ERG. Metastatic renal cell carcinoma
Grossly, SCAs are well-circumscribed round lesions with (RCC) is in the differential diagnosis, particularly of solid
an average size of 6 cm. On cut section, the most common SCA, but this can be resolved by IHC for PAX8, which is
appearance is a spongelike aggregation of tiny cysts with positive in RCC and negative in SCA. This differential
a central stellate scar (Fig. 16.29A). SCAs do not commu- diagnosis is particularly important in patients with VHL
nicate with the pancreatic duct system. Microscopically, syndrome, who are at increased risk for both neoplasms.
the cysts are lined by a single layer of cuboidal cells with
uniform round nuclei and clear cytoplasm (Fig. 16.29B). Prognosis and Therapy
These findings are characteristic of a microcystic SCA,
which is the most common growth pattern. SCA variants Serous cystadenomas are benign neoplasms. Surgical resec-
include macrocystic or oligocystic SCAs, which are com- tion is curative but is only necessary when SCA causes
posed of a few large cysts and can even be unilocular, and symptoms because of compression of adjacent structures.
solid SCA, which has a solid gross appearance and is Otherwise, SCAs are resected when they cannot be distin-
microscopically composed of small acinar structures with guished preoperatively from IPMNs and MCNs.
minute central lumina. The cytology in these variants is
similar to typical microcystic SCA. Rarely, intracystic epi-
thelial papillae can also occur. Genetically, SCAs can be SEROUS CYSTADENOMA—FACT SHEET
distinguished from other cystic neoplasms by frequent
mutation and loss of the V HL locus on chromosome 3, as Definition
well as a lack of mutations in the key driver genes of duc- ■ Benign cystic pancreatic neoplasm
tal neoplasia, such as K RAS and G NAS.

■ Rare cystic neoplasm; more common in body and tail of pancreas
Ancillary Studies
The cytoplasm of the neoplastic cells is positive on PAS ■ Female predominance
stain because of abundant glycogen. On immunohisto- ■ No racial predilection
chemical stains, SCAs are positive for cytokeratin, ■ Usually occurs in adults with an average age of 65 years
including CK7 and CK19, and negative for neuroendo-

crine markers and pancreatic exocrine enzymes. Clinical Features
■ Can be incidental findings on imaging or present with nonspecific
abdominal symptoms
Radiologic Features
The differential diagnosis includes other cystic pancreatic ■ Well-circumscribed multilocular cystic mass, sometimes with a
neoplasms, such as IPMN and MCN. Unlike these entities, central scar
SCAs do not produce mucin, do not have ovarian-type
stroma, and do not communicate with the pancreatic duct Prognosis and Therapy
system. Other entities on the differential diagnosis include ■ Surgical resection is curative
lymphangiomas and hemangiomas, which, unlike SCAs,
A B
FIGURE 16.29
Serous cystadenoma (SCA). A , The characteristic gross appearance is of a spongelike aggregation of small cysts with a central stellate scar. B
, The cuboidal cells
of SCA have small, round nuclei and clear cytoplasm.
Radiologic Features
Serous Cystadenoma—Pathologic Features
Solid-pseudopapillary neoplasms are circumscribed, are
Gross Findings often solid and cystic, and demonstrate heterogeneous
■ Classic microcystic type shows a spongelike mass composed of enhancing on imaging.
tiny cysts with central stellate scar
■ Macrocystic and oligocystic variants show a small number of
smooth-walled cysts Pathological Features

■ Solid variant shows a fleshy solid mass
Grossly, SPNs are large, solitary, well-circumscribed or
Microscopic Findings even encapsulated tumors. On cut section, most have a
■ Single layer of uniform cuboidal cells lining the cyst wall combination of soft yellow-brown solid areas and cystic
■ Cells with clear cytoplasm and uniform central round degenerative areas with friable material and hemorrhage (
monomorphic nuclei
Fig. 16.30A). Microscopically, SPNs are cellular neoplasms
consisting of poorly cohesive cells supported by delicate
■ Abundant cytoplasmic glycogen
small vessels. The architecture is a mixture of solid and
■ Lack of zymogen or neurosecretory granules
cystic areas with characteristic pseudopapillae consisting
of thin layers of neoplastic cells clinging to small blood ves-
Immunohistochemistry sels (Fig. 16.30B). Although grossly well circumscribed,
■ Periodic acid–Schiff positive cytoplasm because of abundant the neoplastic cells often infiltrate into the adjacent
glycogen non-neoplastic pancreas. The cytoplasm is usually eosino-
■ Cytokeratin positive; negative for chromogranin, synaptophysin,
philic, sometimes with vacuoles or hyaline globules, which
pancreatic exocrine enzymes, and endothelial markers
are characteristic but not entirely specific (Fig. 16.30C).
Differential Diagnosis Nuclei are round to oval and frequently have prominent
■ Intraductal papillary mucinous neoplasm, mucinous cystic
nuclear grooves. Additional typical features include foamy
neoplasm, lymphangioma/hemangioma, metastatic renal cell macrophages, cholesterol clefts, and hemorrhage. SPNs are
carcinoma can mimic solid serous cystadenoma characterized by almost universal mutation of CTNNB1,
leading to aberrant nuclear localization of the β-catenin
protein, which is diagnostically useful.
Serous Cystadenocarcinoma
Ancillary Studies
Serous cystadenocarcinoma is an extremely rare malig- The most characteristic immunohistochemical finding in
nant pancreatic neoplasm composed of cuboidal epithe- SPN is aberrant nuclear accumulation of β -catenin caused
lial cells with clear cytoplasm. Grossly and microscopically, by somatic mutations in the CTNNB1 gene, which are
they are remarkably similar to benign SCAs: they typi- present in more than 95% of SPNs. SPNs also express
cally do not exhibit cytologic atypia or an elevated mitotic CD10, LEF1, transcription factor enhancer 3, androgen
rate. Metastatic disease is the only way to establish a diag- receptor, vimentin, PR, and α -1 antitrypsin. Depending
nosis of malignancy. Although only a small number of on the antibody used, E-cadherin IHC can show complete
cases have been reported, the prognosis seems good, with loss of expression (antibodies to extracellular domain) or
most patients still alive at a mean follow-up period of 36 abnormal nuclear/cytoplasmic staining (antibodies to
months. intracellular domain). Cytokeratin expression is variable.
SPNs do not express pancreatic exocrine enzymes, and
although synaptophysin can be focally positive, chro-
mogranin is typically negative.
Solid-Pseudopapillary Neoplasm
Clinical Features
The differential diagnosis lies chiefly with the other solid
Solid-pseudopapillary neoplasm (SPN) is a rare pancre- cellular neoplasms of the pancreas, including PanNET or
atic malignancy, accounting for fewer than 5% of all PanNEC, ACC, and pancreatoblastoma. Although uncom-
pancreatic cancers. They occur predominantly in young mon, metastases to the pancreas should also be consid-
women, with a mean age of 28 years and a male-to-fe- ered. Aberrant nuclear localization of β-catenin is very
male ratio of 1 to 9. SPNs can be found incidentally on helpful in establishing a diagnosis of SPN. However, it is
abdominal imaging or can present with symptoms important to note that nuclear β -catenin is not specific for
caused by compression of adjacent structures, including SPN because this aberrant staining can occur uncom-
abdominal pain, nausea, and early satiety. Jaundice is monly in both ACC and within squamoid morules in pan-
very rare. creatoblastoma. Because SPNs do not express pancreatic
A B
C
FIGURE 16.30
Solid-pseudopapillary neoplasm (SPN). A , Grossly, SPNs are solid masses but frequently show areas of hemorrhage and cystic degeneration. B
, Microscopically,
SPNs frequently have a solid component, but areas of degeneration in which the neoplastic cells cling to delicate blood vessels are also common. C, At high
power, the nuclei frequently contain grooves, and cytoplasmic hyaline globules are characteristic but not entirely specific.
exocrine enzymes, IHC for these proteins can exclude

ACC or pancreatoblastoma in difficult cases. SOLID-PSEUDOPAPILLARY NEOPLASM—FACT SHEET
Prognosis and Therapy Definition

■ Low-grade malignant epithelial neoplasm with uncertain line of
Although SPNs are considered low-grade malignant differentiation

neoplasms that can metastasize, the prognosis is quite
good compared with other pancreatic malignancies. Incidence and Location
■ Uncommon primary pancreatic tumor; occurs throughout the pancreas
Approximately 90% of patients can be cured with com-
plete surgical resection. Even recurrences and metasta-
ses can often be surgically resected, with only a few
■ Much more common in women
patients reportedly dying of this disease. Stage is the best ■ No racial predilection
predictor of outcome, and the current staging scheme is ■ Most common in the third decade of life
the same as that for PDAC.

Clinical Features
■ Can be found incidentally on imaging or diagnosed because of
vague abdominal symptoms
Mixed Tumors
Radiologic Features
■ Well-circumscribed heterogeneous mass with solid and cystic
Neoplasms containing cells with multiple lines of differ- components
entiation have been increasingly recognized in the pan-
creas. These carcinomas are rare, so there are insufficient Prognosis and Therapy
data to rigorously define the biology and clinical course. ■ Excellent prognosis; surgery usually curative
However, in reported cases, the clinical course is highly

Mixed Acinar–Neuroendocrine Carcinoma

Solid-Pseudopapillary Neoplasm—Pathologic Features
Mixed acinar–neuroendocrine carcinomas are com-
Gross Findings posed of malignant epithelial cells with both acinar and
■ Well-circumscribed and often encapsulated; mixture of solid areas neuroendocrine differentiation. Although the different
and necrosis or cystic degeneration components can sometimes be appreciated on H&E-
stained sections, in many cases, the divergent directions
of differentiation are most easily appreciated on immu-
■ Tumor shows a mixture of solid and discohesive areas with
pseudopapillae nohistochemical stains, which can show two different

■ Cytoplasm can be eosinophilic or vacuolated and display components, one labeling with neuroendocrine markers
characteristic hyaline globules and the other with acinar markers. A subset of cells that
■ Nuclei are round to oval with prominent nuclear grooves label with markers for both lineages may also be present.
■ Foam cells and cholesterol clefts within the tips of papillae are
Typically, the majority of the tumor shows acinar differ-
common
entiation, but the neuroendocrine component must
Ultrastructural Findings account for at least 30% of the neoplastic cells to diag-
■ Abundant mitochondria and zymogen-like granules
nose a mixed carcinoma.
■ Neurosecretory granules present less frequently
Mixed Acinar–Ductal and Mixed Acinar–Ductal–

Immunohistochemistry Neuroendocrine Carcinoma
■ Nuclear localization of β
-catenin is characteristic
■ Also positive for CD10, LEF1, transcription factor enhancer 3,
Mixed acinar–ductal carcinoma is a malignant epithelial
androgen receptor, vimentin, progesterone receptor, and α -1
antitrypsin neoplasm with components of both acinar and ductal
■ Cytokeratin and synaptophysin variably positive differentiation. Each component must account for at
■ Negative for chromogranin and pancreatic exocrine enzymes least 30% of the neoplasm to make a diagnosis of mixed
acinar-ductal carcinoma. Typically, the acinar compo-
Differential Diagnosis nent is more prominent. In addition to the acinar com-
■ Acinar cell carcinoma, pancreatic neuroendocrine tumor or
ponent, which resembles ACC, some tumors contain a
carcinoma, pancreatoblastoma, metastasis from another site
component morphologically similar to PDAC, but others
show intracellular and sometimes extracellular mucin in
cells that cytologically resemble ACC. Rare tumors also
have a neuroendocrine component and are best classi-
aggressive, and the prognosis is poor. These tumors fied as mixed acinar–endocrine–ductal carcinoma.
are now designated mixed neuroendocrine and
non-neuroendocrine neoplasms in the new WHO
classification. The non-neuroendocrine component
Other Neoplasms
may be ductal or acinar and must constitute at least
30% of the entire tumor.
Although much less common than the epithelial neo-
Mixed Ductal–Neuroendocrine Carcinoma plasms described in this chapter, a variety of mesenchy-
mal and hematopoietic neoplasms can involve the
Mixed ductal–neuroendocrine carcinoma consist of a pancreas either primarily or secondarily. The diagnostic
mixture of neoplastic ductal and neoplastic neuroendo- criteria and clinical features of these mesenchymal and
crine cells, each including at least 30% of the neoplastic hematopoietic neoplasms parallel those in other organs.
cells. Two growth patterns are recognized: (1) intermin- In addition, carcinomas originally in other sites can also
gled ductal and neuroendocrine cells forming glandular metastasize to the pancreas; thus, metastatic carcinoma
and solid structures and (2) neoplastic ductal elements from another organ should always be considered in the
embedded in a background of solid neoplastic neuroen- differential diagnosis, particularly of a morphologically
docrine cells. Whereas the ductal cells express CEA and unusual tumor.
mucins, the neuroendocrine cells express chromogranin
and synaptophysin. A key feature of this diagnosis is
that both the ductal and neuroendocrine components
■ FROZEN SECTION EVALUATION AND
are neoplastic. As such, it must be distinguished mor-
DIAGNOSIS
phologically from NETs that entrap normal non-
neoplastic ducts as well as ductal adenocarcinomas with
adjacent reactive non-neoplastic islets. Both of these The reasons for intraoperative consultations for pancre-
mimics are much more common than true mixed atic lesions are twofold: (1) to determine if a pancreatic
ductal–neuroendocrine carcinomas. mass is a PDAC or a benign inflammatory process and
(2) to evaluate pancreatic parenchymal and bile duct close proximity of ducts to medium-sized arteries or
margins for tumor. The uncinate margin is not usually large vessels are helpful features for the diagnosis of car-
examined by frozen section because additional tissue cinoma (Fig. 16.32). Other key features to keep in mind
cannot be resected; however, in the institution that has are islet cell proliferation and juxtaposition of benign
capability of intraoperative radiation therapy, frozen glands to nerves secondary to marked parenchymal atro-
section consultation on the uncinate margin status for phy in chronic pancreatitis because the former may
PDAC may be requested. Similarly, in the setting of mimic solid foci of carcinoma and the latter may be mis-
post–neoadjuvant therapy resection, tissue adjacent to taken for perineural invasion.
the superior mesenteric artery (SMA) or hepatic artery The differential diagnosis includes chronic alcoholic
may be submitted to determine the resectability of the or obstructive pancreatitis, AIP, or paraduodenal or
carcinoma. groove pancreatitis. PDAC can usually be differentiated
from these entities based on the aforementioned
features.
Diagnosis of Pancreatic Ductal Adenocarcinoma
on Frozen Section
Evaluation of Resection Margins
Definitive diagnosis of pancreatic adenocarcinoma usu-
ally depends on one of two features: (1) architectural Intraoperative consultation of the pancreatic parenchy-
and/or cytologic features of infiltrating ducts that are mal margin and/or bile duct margin may be requested in
unequivocal for carcinoma and (2) evidence of invasion a variety of entities of the pancreas. Understanding the
into other structures such as nerves, lymphatics, blood morphology of the tumor in question is necessary to
vessels, extrapancreatic soft tissue, duodenum, or lymph render an appropriate interpretation. Several issues are
nodes. The infiltrative haphazard growth pattern, glands worth discussing in this context.
adjacent to muscular vessels, four-to-one nuclear size
variation within one gland rule, huge irregular nucleoli, Parenchymal Margin
glandular necrotic debris, and mitoses (in particular
atypical mitoses) favor a diagnosis of carcinoma. 1. Gross evidence of tumor, in particular IPMN, at the
Importantly, benign lobular atrophy with acinar–ductal pancreatic parenchymal margin leads to additional
metaplasia often results in an aggregate of small ducts in resections, if feasible, regardless of the diagnosis and
an infiltrating pattern ( Fig. 16.31 ); thus, judgments grade of dysplasia.
based on constellation of features are warranted. When 2. If invasive carcinoma is present at the margin, it
tumor morphology is well differentiated, it mimics reac- should be reported.
tive ducts or low-grade PanIN. In this context, architec- 3. If a high-grade intraductal lesion (either IPMN of
tural criteria for malignancy, such as loss of lobular PanIN) is present at the margin, it should be reported.
configuration of proliferating ducts, angulated and fused In addition, PDAC may exhibit cancerization
glands, and the presence of desmoplastic stroma and
FIGURE 16.32
FIGURE 16.31 Close proximity of benign-appearing ducts to medium-sized arteries or large
Benign lobular atrophy with acinar–ductal metaplasia exhibiting an infiltrating vessels are helpful features for the diagnosis of carcinoma (hematoxylin and
pattern (hematoxylin and eosin, frozen section). eosin, frozen section).
A B
FIGURE 16.33
A frozen section of the pancreatic transection margin (A, hematoxylin and eosin H&E]) demonstrating the main pancreatic duct involved by cancerization
(arrows), confirmed by the corresponding permanent section (B, H&E).
involving the main pancreatic duct and/or interlobu-

lar ducts at the margin (Fig. 16.33) and resemble a
high-grade intraductal lesion. Thus, the presence of
high-grade intraductal lesion may sometimes lead to
additional surgery to achieve negative margin status.
4. If only a low-grade intraductal lesion (either IPMN or
PanIN) is present at the margin, the report of intraop-
erative consultation should indicate that no invasive
or in situ carcinoma is identified and that only intra-
ductal/intraepithelial neoplasm of low-grade dyspla-
sia, either IPMN or PanIN, is present. Low-grade
dysplasia at the margin is usually not an indication
for additional tissue resection. However, if intra-
ductal intestinal-type IPMN is identified at the mar-
gin, it may be a consideration for additional tissue
removal, regardless of the grade of dysplasia, because FIGURE 16.34
of a high risk of recurrence. The significance and A frozen section of the bile duct at the margin (hematoxylin and eosin).
management of low-grade IPMN at the margin is an Reactive changes secondary to stent insertion characterized by micropapil-
area of considerable controversy. lary architecture, cytologic atypia, and disruption of epithelial lining can mimic
high-grade dysplasia of the biliary epithelium and/or invasive carcinoma.
5. If the main pancreatic duct is denuded because of
inflammation at the margin, it may be indicative of
Bile Duct Margin
close proximity to the lesion, in particular IPMN.
The report of intraoperative consultation should add 1. In the setting of bile duct obstruction caused by pan-
the possibility that subsequent evaluation on perma- creatic cancer, a stent may be placed in the bile duct,
nent sections may reveal dysplasia. which can cause severe inflammation, mucosal
A B
FIG 16.35
A frozen section (A, hematoxylin and eosin [H&E]) demonstrates residual carcinoma after neoadjuvant therapy involving a perineural space in tissue adjacent
the superior mesenteric artery (arrow). Because of the degenerative appearance of the gland secondary to therapeutic effects, it may be difficult to confirm the
presence of carcinoma. The corresponding permanent section (B, H&E) reveals unequivocal gland formation (arrow) and additional degenerated glands in the
region ( arrowheads).
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tions may be helpful to show more convincing features
17. AbrahamSC, KlimstraDS, WilentzRE, et al. Solid-
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17
Non-Neoplastic Disorders of the Liver
■ Daniela S. Allende, MD, MBA and Lisa M. Yerian, MD
■ MAJOR HISTOLOGIC PATTERNS OF INJURY clinical picture in most patients with acute hepatitis
varies from asymptomatic to mild, vague gastrointes-
Because the liver presents with a relatively small repertoire tinal (GI) or flu-like symptoms, including nausea and
of responses to injury, there is significant histologic over- malaise. Laboratory testing demonstrates marked serum
lap among liver diseases, making specific diagnosis chal- aspartate aminotransferase (AST) and alanine amino-
lenging. A pattern-based approach enables the pathologist transferase (ALT) elevations, but serum bilirubin and
to generate a relatively short list of differential diagnoses, alkaline phosphatase (ALP) are normal or only mildly
which can then be distinguished based on histologic find- elevated. A subset of patients with clinical features of
ings and available clinical data to establish an informative acute hepatitis exhibit histologic features of an acute
diagnosis that guides clinical management. Some liver hepatitis pattern of injury on biopsy. A biopsy is not
diseases (e.g., autoimmune hepatitis [AIH] and Wilson’s indicated in most patients but may be performed to con-
disease) can present with more than one pattern of injury. firm acute hepatitis, exclude entities other that are clin-
The major histologic patterns of injury are as follows: ically similar but histologically distinct (e.g., Wilson’s
disease, ischemic hepatitis, or Budd-Chari syndrome
▪ Hepatitic pattern of injury [BCS]), assess for features of chronic liver disease, or
▪ Acute hepatitis (panlobular) evaluate for acute exacerbation of AIH.
▪ Chronic hepatitis (portal predominant) Histologically, an acute hepatitis pattern of injury
▪ Steatotic-steatohepatitic pattern of injury is characterized by a predominantly lobular pattern of
▪ Cholestatic pattern of injury injury that exhibits lobular inflammatory cell infiltrates
▪ Vascular pattern of injury accompanied by hepatocyte injury manifest as hepatocyte
▪ Miscellaneous patterns swelling and necrosis of individual hepatocytes (“aci-
▪ “Almost normal biopsy” dophil bodies”) or hepatocyte clusters (“spotty necro-
▪ Granulomatous hepatitis sis”). The resulting loss of the normal, orderly hepatocyte
▪ Massive or submassive hepatic necrosis cord arrangement (“lobular disarray”) (Figs. 17.1A–C).
▪ Metabolic and storage disorders Depending on the severity of injury, marked hepatocel-
▪ Iron storage disorder lular regenerative changes, including mitoses, multinu-
▪ Copper storage disorder (Wilson’s disease) cleation (“giant cell transformation”), and hepatocellular
▪ α1-Antitrypsin (α1AT) deficiency rosettes (Fig. 17.1D) may also be present. The lobular
▪ Glycogen storage disorder inflammation is lymphocyte predominant with Kupffer
▪ Lysosomal storage disorder (LSD) cell hyperplasia. Neutrophils are neither an important
finding nor a defining feature of this pattern. There is
no fibrosis in uncomplicated acute hepatitis, although
patients with chronic liver disease may develop super-
ACUTE HEPATITIS PATTERN imposed acute hepatitis or an acute exacerbation of the
chronic disease. Biopsies obtained after the acute phase of
OF INJURY the illness may be nearly normal, showing only residual
Kupffer cell hyperplasia or aggregates of ceroid-laden his-
tiocytes on periodic acid–Schiff (PAS) with diastase stain
Whereas clinically, the term acute hepatitis denotes (PAS-D; Fig. 17.1E). There is no formal grading scheme
a particular pattern of acute-onset liver disease in a for the acute hepatitis pattern of injury.
patient without preexisting liver disease, this pattern of The differential diagnosis for an acute hepatitis
injury is defined histologically by a lobular-predominant pattern of injury includes acute viral hepatitis caused
pattern of inflammation and hepatocyte injury. The by hepatotropic viruses (hepatitis A or E or the acute
489
A D
B E
C
FIGURE 17.1
A, Acute hepatitis pattern of injury on low magnification. B, Lobular infiltrates are composed of lymphocytes and Kupffer cells. C, Lobular hepatocellular disarray
and infiltrating inflammatory cells are typical. D, Rosettes and multinucleated hepatocytes are seen in more severe cases. E, Periodic acid–Schiff–diastase stain
can highlight Kupffer cells in more subtle cases.
phase of hepatitis B, C, or D infection), nonhepatotropic chapter. A nonspecific form of hepatic inflammation

viruses, or drug-induced liver injury (DILI). Acute exac- in the absence of clinical illness or hepatocyte injury
erbation of AIH is also in the clinical and histologic dif- can be seen in patients undergoing abdominal surgery
ferential diagnosis, although it is considered an a priori (so-called “surgical hepatitis”). This entity should not
chronic disease. DILI and AIH are discussed later in this be confused with acute hepatitis.
CHAPTER 17 Non-Neoplastic Disorders of the Liver 491
TABLE 17.1
Viral Hepatitis
Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Type of virus Single-stranded Partially double- Single-stranded Single-stranded Single-stranded

RNA stranded DNA RNA circular defective RNA
RNA
Viral family Hepatovirus; related Hepadnavirus Flaviviridae Subviral particle Calicivirus
to picornavirus in Deltaviridae
family
Route of Fecal–oral Parenteral (IV Parenteral; Parenteral Fecal–oral
transmission (contaminated drug use), intranasal
food or water) sexual contact, cocaine use is a
perinatal risk factor
Mean incubation 2–4 weeks 1–4 months 7–8 weeks Same as for HBV 4–5 weeks
period
Frequency of Never 10% >85% Never 5% (coinfection);
chronic liver ≤70% for
disease superinfection
Diagnosis Detection of serum Detection of PCR for HCV RNA; Detection of IgM and PCR for HEV RNA;
IgM antibodies HBsAg or third-generation IgG antibodies; detection of
antibody to ELISA for antibody HDV RNA in serum; serum IgM and
HBcAg detection HDAg in liver IgG antibodies
Treatment Supportive α-Interferon, Direct-actin antivirals, α-Interferon Supportive
lamivudine protease inhibitors,
polymerase
inhibitors
ELISA, Enzyme-linked immunosorbent assay; HBcAg, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDAg,
hepatitis D antigen; HEV, hepatitis E virus; IV, intravenous; PCR, polymerase chain reaction.
ACUTE VIRAL (HEPATOTROPIC) HEPATITIS Laboratory Values
Acute viral hepatitis represents the prototype acute hepa- Most patients show markedly elevated serum AST and
titis pattern of injury. It is caused by hepatotropic viruses ALT levels (often >15-fold normal levels). Bilirubin
A, B, C, D, and E (Table 17.1). Hepatitis A and E are trans- and ALP may also be elevated. Viral serologies may be
mitted through contaminated food and water. Hepatitis A negative during the early course of disease. Polymerase
is highly endemic in parts of Africa and Asia, and hep- chain reaction (PCR)–based testing is frequently used
atitis E is highly endemic in Mexico and parts of Africa as a confirmatory test.
and Asia. Pregnant women are more susceptible to hepa-
titis E infection and exhibit a more severe clinical course.
Hepatitis B and C are bloodborne pathogens that can also
be sexually transmitted. Hepatitis B infection may be fur-
ther complicated by coinfection or superinfection with ACUTE VIRAL (HEPATOTROPIC) HEPATITIS—FACT SHEET
hepatitis D, which follows the same route of transmission.
Definition
■ Acute hepatitis caused by hepatitis A, B, C, D or E virus infection
■ CLINICAL FEATURES Incidence and Location

■ The incidence is underestimated because many cases are
asymptomatic
Acute viral hepatitis is often asymptomatic or mildly ■ Hepatitis A, B, and C are common worldwide, with hepatitis B
symptomatic. Patients present with mild symptoms of sys- more common in Southeast Asia and sub-Saharan Africa
■ Hepatitis A is highly endemic in parts of Africa and Asia
temic disease, including malaise, fatigue, low-grade fever,
■ Hepatitis E is highly endemic in Mexico and parts of Africa and Asia
flu-like, or GI symptoms. Adults can develop a more com-
plicated clinical course with prominent cholestasis and Morbidity and Mortality
even fulminant hepatitis (1%–3% of cases) with massive ■ Mortality rate for acute hepatitis A is low, but up to 22% with
parenchymal necrosis necessitating liver transplantation. clinical apparent hepatitis require hospitalization; mortality rate is
Physical examination typically reveals jaundice, right higher (∼1.8%) in patients older than 50 years
upper quadrant tenderness, and hepatomegaly.
As part of parenchymal regeneration, there may be pro-

Mortality for hepatitis E is greater in pregnant women; death rate
■
nounced regenerative bile ductular reaction. Cholestasis
is approximately 5%
may be present, including in some cases of hepatitis E (Fig.
Gender, Race, and Age Distribution 17.3D). Portal inflammation may be present but is usually
■ Occurs equally in males and females less prominent than the lobular inflammation and injury.
■ All races and age groups are affected Biopsies taken after the initial illness may show only resid-
ual Kupffer cell hyperplasia. There is no fibrosis unless the
Clinical Features patient has preexisting chronic liver disease.
■ Asymptomatic or mild systemic symptoms, including malaise,
low-grade fever, and flulike or gastrointestinal complaints

■ Jaundice and pruritus if cholestatic
■ Transaminase levels elevated 5- to 10-fold normal Acute Viral (Hepatotropic) Hepatitis—Pathologic Features

■ Vaccines are available to prevent hepatitis A and B infection ■ Hepatomegaly
■ Treatment of patients with hepatitis A and E is usually supportive; ■ Congestion; possibly yellow or green discoloration if cholestasis
the infection is self-limited ■ In fulminant hepatitis, the liver is friable with hemorrhagic and
■ Acute hepatitis B virus infection in neonates carries a 90% risk necrosis areas and the capsule is flaccid
of progression to chronic liver disease, but only 5% to 10% of
adults will develop chronic hepatitis B Microscopic Findings
■ Untreated acute hepatitis C carries a 20% to 50% chance of
■ Lobular disarray caused by hepatocyte injury or necrosis,
spontaneous resolution of disease
regeneration, and Kupffer cell hyperplasia
■ Predominantly panlobular mononuclear inflammatory infiltrate
■ Cholestasis may be present

■ Bridging necrosis to submassive or massive necrosis only in
Pathologic Features severe cases
Gross Findings
■ Drug-induced liver injury
■ Nonhepatotropic viral hepatitis

The liver may be swollen and congested with a yel-
■ Acute exacerbation of autoimmune hepatitis
low or green discoloration or shrunken with a “loose”
capsule in extensive parenchymal injury or collapse. In
cases of submassive or massive hepatic necrosis (Fig.
17.2), the liver may be friable and hemorrhagic with Ancillary Studies
obvious areas of necrosis upon sectioning.
In cases with extensive necrosis, the trichrome
stain may be difficult to interpret. In contrast to the
bright blue staining collagen in fibrosis, areas of col-
Acute viral hepatitis represents the prototype acute lapsed parenchyma show pale, grayish-blue staining
hepatitis pattern of injury, exhibiting the diffuse lobular- of the collapsed reticulin framework. Reticulin stain
predominant inflammation and hepatocyte injury with lob- highlights the areas of collapse of the normal reticu-
ular disarray (see Figs. 17.3A and B). Acidophil bodies are lin framework. Immunohistochemistry (IHC) for viral
prominent, and in severe cases, portions of lobules or entire antigens is not applied in clinical practice because the
contiguous lobules may undergo necrosis (see Fig. 17.3C). diagnosis is established through serologic and PCR-
based testing.
The differential diagnoses include nonhepatotropic

viral infections, chronic viral hepatitis, DILI, and AIH.
Distinguishing these entities often requires clinical infor-
mation (e.g., history of travel, new drug or toxins) along
with viral serologies and serum autoantibody titers.
Nonhepatotropic viral infections may follow a vari-
able clinical course depending on the specific underly-
ing infection. Classic histologic clues to these diagnoses
FIGURE 17.2
are discussed in the following section. In chronic viral
Massive hepatic necrosis in acute viral hepatitis. The liver is shrunken and
soft; islands of regenerating hepatocytes (right) may be localized to one area hepatitis, the inflammatory cell infiltrates are cen-
and mimic a neoplasm. tered within the portal tracts and fibrosis is common.
Prominent lobular inflammation and hepatocyte injury The course of CMV hepatitis varies with the age and
can be seen in AIH; however, AIH is usually associ- immune status of the patient. In immunocompetent
ated with brisk interface activity, plasma cells, elevated hosts, the disease frequently follows a self-limited clin-
serum autoantibodies, and polyclonal hypergamma- ical course and is often asymptomatic. In immunosup-
globulinemia. Exclusion of drug- or toxin-induced pressed hosts, including neonates, older patients, and
injury may be difficult clinically and histologically. organ transplant recipients, the infection can manifest
Wilson’s disease can mimic any clinical or histologic with fever, jaundice, and hepatosplenomegaly. Rare ful-
pattern of injury, including acute hepatitis, and a low minant cases have been reported. Patients with CMV
threshold for performing serum ceruloplasmin and tis- hepatitis may show mild hyperbilirubinemia, increased
sue copper quantitation is warranted. The differential ALP, and increased transaminases (often not exceeding
diagnosis for submassive or massive necrosis includes fivefold upper limit of normal).
infections (e.g., herpes simplex virus [HSV]), vascular Herpes simplex virus hepatitis is rare and most often
injury, and DILI. seen in neonates and other immunocompromised patients.
The clinical symptoms include fever, mucosal ulcers, hep-
Prognosis and Therapy atomegaly, and systemic constitutional symptoms. AST
and ALT are markedly elevated as a reflection of the exten-
Viral hepatitis A and E are self-limited diseases sive parenchymal necrosis associated with this infection.
that are associated with full recovery within weeks in HSV hepatitis is rapidly progressive and usually fatal.
most patients; treatment is supportive. Most patients
with acute hepatitis B virus (HBV) and 20% to 50% of
patients with acute hepatitis C experience spontaneous NONHEPATOTROPIC VIRAL INFECTIONS—FACT SHEET
resolution of infection. Newer, highly successful inter-
feron-free antiviral therapies for hepatitis C are available Definition
for those who do not clear the virus. Fulminant hepatic ■ Nonprogressive forms of hepatitis caused by viruses that do not
failure is rare in patients with hepatitis C but may lead preferentially affect the liver, including Epstein Barr virus (EBV),
to organ failure and liver transplant. cytomegalovirus (CMV), and herpes simplex virus (HSV)

NONHEPATOTROPIC VIRAL INFECTIONS ■ EBV: clinically evident liver disease occurs in minority of patients
with infectious mononucleosis and can be seen in the absence of

infectious mononucleosis symptoms; worldwide distribution
Epstein-Barr virus (EBV), cytomegalovirus (CMV), and ■ CMV: low incidence of clinically evident disease; worldwide
HSV are the most common nonhepatotropic viruses that distribution

■ HSV: low incidence; worldwide distribution
cause an acute hepatitis pattern of injury. These infec-
tions are typically mild and self-limited except when Morbidity and Mortality
they occur in infants or immunocompromised patients, ■ EBV: low
in whom they may follow a complicated clinical course ■ CMV: low in immunocompetent patients
with parenchymal necrosis and even hepatic failure and ■ HSV: high
death (especially in HSV infection). The nonhepatotro-

pic viral infections do not progress to chronic hepatitis. Gender, Race, and Age Distribution
■ EBV: adolescents and young adults; both genders equally affected
■ CMV: clinically apparent hepatitis in immunosuppressed and rarely
■ CLINICAL FEATURES in immunocompetent patients; both genders equally affected

■ HSV: neonates and other immunosuppressed patients; both
genders equally affected

Epstein-Barr virus hepatitis is usually mild and self-lim-
ited and may occur in patients of any age as a complica- Clinical Features
tion of infectious mononucleosis or in patients without ■ EBV: often subclinical; anorexia, flulike symptoms, abdominal
a clinical picture of infectious mononucleosis. Although pain, jaundice, and splenomegaly

■ CMV: usually subclinical; fever and hepatosplenomegaly
most patients (≤80%) with infectious mononucleosis ■ HSV: severe acute hepatitis that often evolves into acute liver failure
exhibit liver enzyme abnormalities, symptomatic hepa-
titis is uncommon. Symptoms of EBV hepatitis include Prognosis and Therapy
anorexia, flu-like symptoms, nausea or vomiting, ■ Variable prognosis, depending on underlying infection and
abdominal pain, and weight loss. Jaundice may be seen. immune status of the host
■ Good prognosis in immunocompetent patients with CMV and
Laboratory testing reveals serum lymphocytosis with
EBV hepatitis
elevated bilirubin and ALP and ALT elevations that are
■ Worse prognosis for HSV hepatitis
usually more modest than those seen in patients with ■ Supportive treatment and antivirals (ganciclovir for CMV and
hepatotropic viral infections. EBV-associated acute liver acyclovir for HSV infection)
failure is rare but described in immunocompetent and ■ No propensity to develop chronic hepatitis or progressive fibrosis
immunocompromised patients.
FIGURE 17.4
Areas of geographic necrosis with hyperemic borders are seen in herpes
simplex hepatitis.
Pathologic Features
Gross Findings
B
Mild hepatomegaly and variable congestion are com-
mon in all nonhepatotropic viral infections. An HSV-
infected liver may show a hyperemic and mottled cut
surface with foci of geographic necrosis (Fig. 17.4).
In general, nonhepatotropic viral hepatitis exhibits

histologic features similar to those described in hepato-
tropic virus infections, including lobular-predominant
inflammation and hepatocyte injury.
C The most characteristic histologic feature of EBV hep-
atitis is “sinusoidal lymphocytosis” characterized by a
diffuse sinusoidal infiltrate typically composed of small
lymphocytes arranged in a single-file “string-of-beads” pat-
tern (Fig. 17.5A). Acidophil bodies are rare. Small lobular
Kupffer cell aggregates may be present. The portal tracts
demonstrate mild lymphocytic infiltrates but significant
interface hepatitis. Immunosuppressed patients may show
more pronounced necroinflammatory activity and even
bile duct injury. Extensive necrosis is only seen in those
with fulminant EBV hepatitis (Fig. 17.5B).
Cytomegalovirus hepatitis histologically mimics EBV
infection in immunocompetent hosts. The typical intra-
nuclear or intracytoplasmic viral inclusions that are
often present in immunocompromised patients may not
D be seen. As with other causes of acute hepatitis, lobular
inflammation and injury predominate. Acidophil bodies
FIGURE 17.3
and spotty necrosis are common. Neutrophilic microab-
A, Both portal and lobular inflammation are seen in acute hepatitis; the
inflammatory infiltrate is mixed, but mononuclear cells predominate. B, scesses may be seen but are neither sensitive nor spe-
Hepatocyte necrosis and regeneration, inflammation, and Kupffer cell hyper- cific for CMV hepatitis. Diagnostic viral inclusions can
plasia contribute to the busy appearance of the lobule (lobular disarray). C, be detected on hematoxylin and eosin (H&E) stain or
Portal-central bridging may be seen in more severe cases and may be an
adverse prognostic feature in older patients. D, Hepatitis E with classic lobu- IHC in infected endothelial cells, hepatocytes, or biliary
lar inflammation and cholestatic changes. epithelial cells (Fig. 17.6).
B
FIGURE 17.5
A, Prominent sinusoidal lymphocytosis with minimal hepatocellular injury is
characteristic of Epstein-Barr virus (EBV) hepatitis. B, In a small subset of
cases, EBV infection can lead to massive hepatic necrosis.
c
FIGURE 17.7
A, Herpes simplex hepatitis with areas of geographic necrosis. B, Infected
cells contain ground-glass nuclear inclusions. C, Multinucleated cells may be
seen in a background of extensive necrosis in this case.
Herpes simplex virus hepatitis has distinct histologic

features, which, when present, should promptly suggest
this diagnosis. The hepatic parenchyma typically shows
irregular foci of nonzonal or “geographic” necrosis
(Fig. 17.7A) with relatively mild lobular and por-
tal chronic inflammation. Diagnostic viral inclusions
(Cowdry type A) with multinucleation, margination,
FIGURE 17.6
and molding are usually present within viable hepato-
In immunocompromised hosts, enlarged cells with intranuclear inclusions
are found in variable numbers. Associated microabscesses are often seen in cytes adjacent to foci of necrosis (Figs. 17.7B and C).
liver transplant cases but are not specific for cytomegalovirus infection. IHC may be needed to confirm the diagnosis.
Nonhepatotropic Viral Infections—Pathologic Features
Gross Findings The differential diagnosis includes other causes of acute

■ Hepatomegaly hepatitis, including hepatotropic and other nonhepato-
■ Herpes simplex virus (HSV): geographic necrosis with hyperemic
tropic viral infections (adenovirus, human herpesvirus
borders
6 A, parvovirus), other hepatic infections, and DILI. In
Microscopic Findings cases of suspected EBV hepatitis, specimens showing
■ Epstein-Barr virus (EBV): sinusoidal lymphocytic infiltrate (“string
“atypical lymphocytes” should be investigated carefully
of pearls”) to exclude the involvement of a lymphoproliferative
■ Cytomegalovirus (CMV): neutrophilic microabscesses and disorder.
intranuclear or cytoplasmic inclusions In cases with extensive hepatic necrosis, ischemia
■ HSV: geographic necrosis and Cowdry A-type inclusions
and DILI should be considered. The zonal distribution
Ancillary Studies of necrosis (predominantly zone 3), clinical history, and
■ EBV: scattered positive lymphocytes on chromogenic in situ
absence of viral inclusions are helpful in distinguishing
hybridization these entities.
■ CMV: positive viral inclusions on immunohistochemistry
■ HSV: positive viral inclusions on immunohistochemistry

■ Other causes of acute hepatitis, including the hepatotropic viruses
(hepatitis A, B, C, D, E)
In immunocompetent patients, the disease course is
■ Other hepatic infections self-limited, and symptoms usually resolve in 4 to 6
weeks. In immunocompromised individuals, the disease
follows a more severe course and may result in acute liver
failure.
In most patients, antiviral therapy is not required.
Ganciclovir is administered to CMV-infected patients
who are at risk of severe or life-threatening illness. HSV
is often treated with acyclovir, but the outcome is gen-
erally poor.
CHRONIC HEPATITIS PATTERN OF INJURY
Chronic hepatitis is defined histologically as a pattern

of ongoing hepatitis with portal-based inflammation
and fibrosis in which hepatocytes are the primary site of
injury. Symptoms vary and are often vague or nonspe-
cific, consisting of constitutional symptoms, abdominal
FIGURE 17.8
pain, nausea, and malaise. Many patients are asymp-
Epstein-Barr virus (EBV)-encoded small RNA demonstrate occasional positive
cells in a case of Epstein-Barr virus hepatitis.
tomatic, and some may present with decompensated cir-
rhosis or acute liver failure. The histologic differential
diagnosis for this pattern of injury is broad and includes
Ancillary Studies causes of chronic hepatitis (chronic viral hepatitis [hep-
atitis B and hepatitis C], AIH, and DILI) in addition to
Serologic testing and PCR-based assay are used certain inherited diseases (Wilson’s disease and α1AT
clinically to establish the diagnosis and exclude other deficiency) and early stages of primary biliary disorders
causes of hepatitis. Immunohistochemical stains (espe- (primary sclerosing cholangitis [PSC], primary biliary
cially for CMV and HSV) and chromogenic in situ cholangitis [PBC]).
hybridization (CISH) for EBV-encoded RNA (EBER) A liver biopsy may be performed to confirm the over-
are widely available. EBER-positive lymphocytes are all pattern of injury, establish the diagnosis, grade and
rare in EBV-infected patients; most of the lymphocytes stage the disease, and assess for other superimposed
seen in EBV hepatitis do not show positive EBV stain- patterns of injury (e.g., steatosis) that may impact man-
ing (Fig. 17.8). agement and prognosis. The histologic hallmarks of
chronic hepatitis pattern of injury are the dense por- because the normal extension of the hepatic capsule a
tal inflammatory cell infiltrates and often fibrosis. The few millimeters into the subcapsular parenchyma may
portal infiltrates are predominantly lymphocytic and be interpreted as fibrosis and result in over-staging. The
may be admixed with other inflammatory cells, includ- limitations of subcapsular or suboptimal (small or frag-
ing plasma cells. Interface activity (piecemeal necrosis) mented biopsies) should be clearly stated in the pathol-
and variable necroinflammatory lobular activity are ogy report. If bridging necrosis is present, the trichrome
often also seen. Periods of disease flare typically show
more prominent interface activity and lobular necro-
inflammatory activity, including confluent necrosis in
severe cases. Some cases show mild bile duct injury, but
TABLE 17.2
destructive bile duct lesions are not a feature. Bile duct-
ular proliferation may be evident in advanced fibrosis or Batts and Ludwig Staging System
extensive necrosis. Grading Staging
Biopsies from patients with chronic hepatitis (hepa-
titis B or C; AIH) may be assigned a semiquantitative 0: portal inflammation only, no 0: none
interface activity, no lobular
“grade” and “stage” to indicate the degree of necroin- inflammation
flammatory activity and fibrosis, respectively. There are 1: portal inflammation, minimal 1: fibrous portal
several semiquantitative systems for grading and staging patchy interface activity, spotty expansion
chronic hepatitis, including the Ishak, Knodell, Scheuer, lobular necroinflammatory
Metavir, and Batts and Ludwig systems (Table 17.2). All activity
2: mild portal inflammation, mild 2: periportal fibrosis
have been clinically validated with good interobserver interface activity involving some (allows rare delicate
reproducibility. The choice of system is often made or all portal tracts, mild lobular thin septa)
in partnership with the clinical team to ensure clear necroinflammatory activity
and consistent communication. Many centers prefer 3: portal inflammation, moderate 3: bridging fibrosis
the Batts and Ludwig system, in which necroinflam- interface activity involving all
portal tracts, moderate lobular
matory activity (grade) (Fig. 17.9) and fibrosis (stage) necroinflammatory activity with
(Fig. 17.10) are assessed using a 0 to 4 scale. Specimen noticeable hepatocellular injury
adequacy is an important consideration. An adequate 4: portal inflammation, severe 4: cirrhosis
liver biopsy is at least 2 cm in length and contains at least interface activity, severe lobular
11 portal tracts. Subcapsular biopsy samples (including necroinflammatory activity with
bridging necrosis
subcapsular wedge biopsies) cannot be accurately staged
FIGURE 17.9
Grading chronic hepatitis based on Batts and Ludwig classification system. A, Minimal activity (grade 1): mild portal inflammation with scant piecemeal necrosis
and no lobular necrosis. B, Mild activity (grade 2): mild portal inflammation, piecemeal necrosis and scant lobular inflammation. C, Moderate activity (grade 3):
moderate portal inflammation, piecemeal necrosis and lobular spotty necrosis. D, Severe activity (grade 4): marked portal inflammation, brisk piecemeal necro-
sis, considerable spotty necrosis, and areas of confluent necrosis leading to bridging. (From Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and
reporting. Am J Surg Pathol. 1995;19:1409–1417.)
FIGURE 17.10
Staging chronic hepatitis based on Batts and Ludwig classification system. A, Portal fibrosis (stage 1): mild fibrous portal expansion of portal tracts. B, Periportal
fibrosis (stage 2): fine strands of connective tissue in zone 1 with only rare portal–portal septa. C, Bridging (septal) fibrosis (stage 3): connective tissue bridges
that link portal tracts to other portal tracts and central veins, minimally distorted architecture but no regenerative nodules. D, Cirrhosis (stage 4): bridging fibrosis
and nodular regeneration. (From Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417.)
stain may be difficult to interpret, and areas of reticulin

collapse may result in overestimation of the degree of CHRONIC VIRAL HEPATITIS—FACT SHEET
fibrosis.
Definition
■ Chronic viral (hepatitis B, C) infection
CHRONIC VIRAL HEPATITIS

■ Common worldwide
■ Approximately 3% of world population (∼184 million) has

■ CLINICAL FEATURES hepatitis C infection
■ Approximately 240 million people (3.7%) worldwide are
Chronic viral hepatitis has a wide spectrum of clin- chronically infected with hepatitis B (defined as hepatitis B
ical manifestations, ranging from asymptomatic surface antigen positive for at least 6 months)
■ Less than 1% of the population in Western Europe and
infection to decompensated cirrhosis. Symptomatic
North America is chronically infected with hepatitis B, but the
patients have mild, nonspecific symptoms such as prevalence in endemic regions is up to 10%
fatigue, anorexia, and weight loss. Patients with
cirrhosis may present with esophageal varices, hep- Morbidity and Mortality
atosplenomegaly, spider angiomata, ascites, periph- ■ Chronic viral hepatitis accounts for a significant number of deaths
eral edema, muscle wasting, and abdominal collateral per year worldwide (estimated as 786,000 cases caused by
blood vessels. hepatitis B and ∼500,000 cases caused by hepatitis C in 2010)
■ Risk of hepatocellular carcinoma is high in chronic viral hepatitis,
Serum transaminase levels are usually elevated in the particularly hepatitis B
2- to 10-fold range of normal, although patients with
mild chronic viral hepatitis may have normal transam- Gender, Race, and Age Distribution
inase levels. ALP and bilirubin levels are usually nor- ■ Both genders and all races are equally affected
mal to mildly elevated unless hepatic decompensation ■ Wide age range for both hepatitis B and hepatitis C; hepatitis B is
occurs. Low-titer nonspecific autoantibodies, especially commonly acquired perinatally in high-incidence areas
anti–liver/kidney microsomal 1 antibodies (anti-LKM1)
Clinical Features
and smooth muscle actin (SMA), have been reported in
■ Commonly asymptomatic at diagnosis or may present with mild
this setting. Fibrosing cholestatic hepatitis (FCH) is a nonspecific symptoms
severe, rapidly progressive form of hepatitis B or C that ■ Patients with late-stage disease exhibit signs of chronic liver
occurs in immunosuppressed or immunocompromised disease
patients.
Bridging fibrosis occurs as portal–portal or portal–

central fibrous septa. The end result is cirrhosis.
■ Treatment for chronic hepatitis B includes oral antiviral agents,
such as tenofovir or entecavir. Interferon injections may be

considered in certain cases. A vaccine is available to prevent Other Findings
infection
■ Newer, highly effective treatment options for hepatitis C include Steatosis in hepatitis C can occur in patients with
interferon-free regimens with direct antiviral agents concomitant nonalcoholic fatty liver disease (NAFLD)
The prognosis for hepatitis B is related to severity of liver disease
■
and as a direct effect of the virus in patients with hepati-
at presentation
■ The prognosis for hepatitis C is variable; risk factors for
tis C virus (HCV) genotype 3 infection. HCV infection is
progression of untreated or refractory disease include presence of also associated with greater insulin resistance and met-
fibrosis in liver biopsy, immune status, alcohol use, viral genotype, abolic syndrome, and, when present, both steatosis and
age older than 50 years at infection, and male gender insulin resistance predict rapid progression of fibrosis,
poor response rate to interferon therapy (even in HCV
genotype 3 infection), and an increased risk of hepato-
cellular carcinoma.
Pathologic Features
Fibrosing Cholestatic Hepatitis
Gross Findings
The FCH variant of HBV and HCV is an aggressive form
Early-stage chronic viral hepatitis shows no specific of hepatitis that typically occurs in immunosuppressed
macroscopic features of chronic viral hepatitis. The liver patients. FCH is characterized by prominent perisinu-
becomes firm as fibrosis progresses. Late-stage disease is soidal/pericellular fibrosis occurring in the periportal
grossly evident as cirrhosis. region, ductular reaction, hepatocellular injury includ-
ing hepatocyte swelling and ground-glass inclusions
Microscopic Findings (in HBV), and prominent intracellular and canalicular
cholestasis (Fig. 17.13). The biopsy usually lacks signif-
The microscopic findings include the characteristic icant inflammatory infiltrates.
features of chronic hepatitis pattern of injury: portal
inflammation with or without fibrosis and variable
degrees of interface hepatitis and lobular necroin- Chronic Viral Hepatitis—Pathologic Features
flammatory activity. The portal tracts are expanded
by inflammatory infiltrates composed of mostly lym- Gross Findings
phocytes with variable plasma cells and other inflam- ■ Firm consistency if increased fibrosis
matory cells. Lymphoid follicles with prominent ■ Cirrhotic livers with brown discoloration and greenish hue,
germinal centers may be seen (Fig. 17.11A). Mild bile particularly in cases with end-stage cholestasis
duct injury with intraepithelial lymphocytes may be
seen, but there are no destructive bile duct lesions.
■ Mononuclear portal-predominant inflammatory infiltrates
Interface activity, also known as “interface hepatitis”
■ Interface hepatitis is variable
or “piecemeal necrosis,” is a frequent feature (Fig. ■ Lobular activity is manifested by acidophilic bodies and scattered
17.11B). It is characterized by extension of the por- foci of lobular inflammatory infiltrates
tal inflammation beyond the “limiting plate” into the ■ Confluent necrosis may be seen in severe disease or with
periportal hepatic lobule and accompanying hepato- superimposed acute injury

■ Fibrosis is portal based and evolves to involve the periportal
cyte injury or necrosis.
areas, with eventual portal–portal and portal–central bridging and
In most cases, lobular inflammation consists of ran- cirrhosis
domly scattered lobular collections of mononuclear cells
associated with hepatocyte injury or acidophil bodies Differential Diagnosis
(Fig. 17.11C), but confluent and even bridging necrosis ■ Autoimmune hepatitis
can be seen (Fig. 17.11D). Ground-glass hepatocytes ■ Drug-induced liver injury
■ Early chronic cholestatic conditions (primary sclerosing cholangitis,

(Fig. 17.11E) are a characteristic feature of HBV infec-
primary biliary cholangitis)
tion but are only seen in patients with chronic HBV in ■ Lymphoma or leukemic infiltrate
the setting of active viral replication. ■ Wilson’s disease
Fibrosis in chronic viral hepatitis is portal-based and ■ α1-Antitrypsin
evolves to extend into the periportal region (Fig. 17.12).

A B
C D
E
FIGURE 17.11
A, Portal tracts are expanded by an exuberant inflammatory infiltrate with prominent germinal center in this case of chronic viral hepatitis. Interlobular bile ducts
show no significant injury. B, Lymphocytic inflammation extending into the lobular region (interface hepatitis, arrows), causing focal hepatocyte injury. C, Lobular
activity is variable; small collections of mononuclear inflammatory cells mark sites of lytic necrosis of hepatocytes. D, Massive hepatic necrosis in acute viral
hepatitis. Collapse of the parenchymal framework may be mistaken for cirrhosis. Bile ductular reaction is common. E, Ground glass cytoplasmic inclusions in
hepatitis B infection.
FIGURE 17.12
Portal-based fibrosis is the norm in chronic hepatitis, in this case, periportal
to early bridging fibrosis.
FIGURE 17.14
A, Core antigen (HBcAg) immunohistochemistry showing nuclear positivity
in approximately half of the nuclei in this biopsy, with only trace amounts of
core antigen seen in the cytoplasm. Cytoplasmic HBcAg staining correlates
with high necroinflammatory activity. B, Immunohistochemistry for hepatitis
B surface antigen shows accumulation of HBsAg in hepatocytes.

Diffuse swelling of hepatocytes with pale appearance and bile ductular prolif-
eration, characteristic of early stages of fibrosing cholestatic hepatitis C.
The histologic differential diagnosis of chronic viral

hepatitis primarily includes AIH, primary biliary dis-
Ancillary Studies orders, Wilson’s disease, α1AT deficiency, DILI, and
low-grade lymphoproliferative disorders. Serologic and
For chronic HBV and HBC infection, the diagnosis PCR-based testing are essential in distinguishing these
is based on serologic testing and confirmatory RNA or entities. Ground-glass hepatocytes are associated with
DNA by PCR to exclude false-positive serologies (as can chronic HBV infection but are only present in the set-
occur in the setting of AIH). Cytoplasmic and nuclear ting of active viral replication. Similar-appearing cyto-
accumulation of hepatitis B core antigen (HBcAg) plasmic inclusions (“pseudo-ground-glass change”)
(Fig. 17.14A) may be detected by IHC and correlates have been described in other conditions, such as cyan-
with active replication of the virus. However, immuno- amide toxicity, type IV glycogen storage disease (GSD).
histochemical stains for surface (Fig. 17.14B) and core Lafora disease, uremia, transplant recipients, patients
antigens (HBV and HCV) are rarely helpful or required taking numerous medications, and immunosuppressed
in daily practice. patients. Extensive plasma cell inflammatory infiltrates
and more extensive interface activity with concurrent of acute exacerbations. The presenting symptoms are
lobular necroinflammatory activity favor AIH. highly variable and include anorexia, jaundice, hepato-
Like chronic viral hepatitis, the early stages of PBC megaly, and abdominal pain. However, the diagnosis
and PSC show portal-based inflammation and fibrosis. should be considered in any patient with elevated trans-
Elevated serum ALP, positive antimitochondrial anti- aminases of any duration. Between 10% and 20% of
bodies (AMAs) (in PBC), or endoscopic retrograde patients present with acute liver failure, but presenta-
cholangiopancreatography (ERCP) (in the case of tion with clinical features of an acute or chronic hepati-
PSC) help distinguish these entities from chronic viral tis is far more common.
hepatitis. Transaminase elevation is a consistent feature of
Wilson’s disease usually affects young individu- AIH, and nearly all patients exhibit elevated serum
als and can be clinically excluded by the serum ceru- immunoglobulin (Ig) G levels at the time of diagnosis.
loplasmin level, 24-hour urine copper levels, and Autoantibodies including anti–smooth muscle antibod-
quantitative copper on liver tissue analysis. A1AT ies (ASMAs) and antinuclear antibodies (ANAs), can
deficiency is characterized by the accumulation of be detected in most patients but are not required for
PAS-positive, diastase-resistant cytoplasmic globules the diagnosis. Anti-LKM1 are most often seen in young
in hepatocytes. female patients (including adolescents and children).
Drug-induced liver injury (discussed later in this These autoantibodies are not specific and can be pres-
chapter) must also be considered; medication history ent in other conditions including alcoholic liver disease,
is key to diagnosis. Rarely, lymphoproliferative disor- NAFLD, PBC, and PSC, among others. Hepatitis C anti-
ders, in particular low-grade B-cell lymphomas, can bodies can also be falsely positive in patients with AIH
mimic chronic hepatitis. Monotonous or expansile lym- and remain positive after effective HCV treatment; for
phoid infiltrates should raise suspicion for lymphoma. this reason, confirmatory RNA testing is used to con-
Immunohistochemical stains and flow cytometry help firm or exclude HCV infection. Hyperbilirubinemia and
differentiate lymphoma from chronic hepatitis. ALP elevations may be seen in patients with severe hep-
atitis and extensive hepatocyte injury and in the setting
Prognosis and Therapy of AIH–PBC overlap.
Given the multiple elements (clinical, serologic, and
Patients with chronic hepatitis B infection can be histologic) that contribute to the diagnosis, a detailed
treated with oral antiviral agents. The treatment sup- scoring system for diagnosing AIH was established by
presses viral replication and thus slows the progression the International Autoimmune Hepatitis Group and
to cirrhosis and improves long-term survival. In general, later simplified by Hennes et al. (Table 17.3). Rapid
the regimens include a combination of interferon and response to immunosuppression is typical.
nucleos(t)ide analogues, including tenofovir or enteca-
vir. Vaccines are available.
The therapeutic map for hepatitis C is rapidly chang-
ing with the introduction of newer interferon-free reg-
imens that are highly effective in achieving sustained TABLE 17.3
serologic response. The newer antiviral drugs are more Parameters Included in the Simplified Scoring
effective and better tolerated than interferon-based System for the Diagnosis of Autoimmune
therapies. Hepatitis
Fibrosing cholestatic hepatitis C (hepatitis B or hep-
atitis C) has been linked to rapid disease progression, Parameters
liver failure, and poor prognosis, although newer antivi-
ANA or SMA titers ≥1:40 → 1 point
ral therapies for hepatitis C in particular may be respon- ANA or SMA titers ≥1:80 or LKM titer ≥1:40 or SLA positive
sible for better outcomes in this subset of cases. → 2 points
(The sum of both results was limited to 2 points)
IgG levels >UNL → 1 point
IgG levels >1.10 UNL (>10% above UNL) > 2 points
AUTOIMMUNE HEPATITIS Liver histology compatible or typical for AIH → 1, or 2 points
Exclusion of viral hepatitis → 2 points
Cumulative score interpretation:
• ≥6: probable AIH
• ≥7: definite AIH
Autoimmune hepatitis is an immune-mediated hep-
atitis characterized by a combination of clinical, AIH, Autoimmune hepatitis; ANA, antinuclear antibodies; Ig, immunoglobulin;
laboratory, and histologic findings of hepatitis that LKM, liver-kidney microsomal antibodies; SLA, SMA, smooth muscle actin;
UNL, upper normal limit.
predominantly affects young to middle-aged women. Based on Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the
It is an a priori chronic form of hepatitis with phases diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169–176.
including perivenular plasma cell–rich inflammatory

AUTOIMMUNE HEPATITIS—FACT SHEET cell infiltrates and hepatocyte necrosis. Acidophil bod-
ies may be frequent, and patients experiencing an acute
Definition exacerbation may show diffuse hepatocyte swelling with
■ Ongoing immune-mediated hepatitis lobular disarray (Fig. 17.15B). Kupffer cell hyperplasia
can be seen, but well-formed epithelioid granulomas
are not a feature of AIH. A panel of pathology experts
■ Incidence is approximately 0.1 to 1.9 per 100,000 per year in
recently published a set of criteria to aid in the histo-
Northern Europe and North American white populations
■ Rare in Asia and Africa
logic diagnosis of AIH. In this publication (Lohse et al.,
2022), portal or lobular lymphoplasmacytic infiltrates
Morbidity and Mortality along with more than mild interface activity and portal
■ High rate of complications (from cirrhosis to acute liver failure) if based fibrosis remain importan features in the diagnosis.
left untreated Bile duct injury, if present, tends to be patchy, mild,
■ 50% 5-year mortality rate if untreated
and most commonly associated with lymphocytic injury.
Destructive bile duct lesions or “florid duct lesions” are
not a feature of AIH and, if present, should raise con-
■ Predominantly young to middle-aged women
■ More common in patients of European descent

cern for an AIH–PBC overlap syndrome, DILI, or other
forms of liver disease. Portal-based fibrosis is often pres-
Clinical Features ent at initial presentation.
■ Often presents abruptly, similar to acute viral hepatitis In a subset of cases, an acute hepatitis or acute-on-
■ Anorexia, jaundice, hepatomegaly, abdominal pain chronic hepatitis pattern of injury predominates. In these
■ May present with arthralgia and skin rash
biopsies, the lobular inflammation and injury predomi-
■ Marked elevation of transaminases
■ Polyclonal hypergammaglobulinemia
nates, with prominent hepatocellular swelling, lobular dis-
■ Positive autoantibodies: antinuclear antibodies, SMA, and/or liver-
array, and regenerative changes, including hepatocellular
kidney microsomal antibodies rosettes (Fig. 17.15C) and bile ductular proliferation. In
severe cases, extensive necroinflammatory activity leads
Prognosis and Therapy to bridging necrosis and even massive hepatic necrosis
■ Ongoing and variable clinical course, often with flares with parenchymal collapse (Fig. 17.15D). Transformation
■ Corticosteroids and other immunosuppressants significantly
of hepatocytes into syncytial multinucleated giant cells
improve survival
(acute hepatitis with giant cell transformation) can also
be present. Hepatocanalicular cholestasis may be seen in
the acute phase of exacerbation and present as an acute
Pathologic Features cholestatic hepatitis pattern of injury.
Gross Findings
Autoimmune Hepatitis—Pathologic Features
The gross appearance of the liver in AIH is variable.
Gross Findings
For patients presenting with an acute fulminant course,
■ Cases of acute fulminant disease may show massive hepatic
massive hepatic necrosis results in a shrunken liver with necrosis
a flaccid capsule. Islands of regenerating or preserved ■ In end-stage disease, the liver shows evidence of cirrhosis
hepatic parenchyma often show greenish hue caused by
cholestasis. The liver is firm in advanced fibrosis and Microscopic Findings
diffusely nodular in cirrhosis. ■ Chronic hepatitis pattern of injury
■ Usually well-established interface hepatitis and lobular
necroinflammatory activity in untreated disease

Microscopic Findings ■ Plasma cells may be prominent in portal tracts and perivenular
locations
Autoimmune hepatitis most commonly presents a ■ Variable fibrosis, from portal expansion to portal–portal or portal–
chronic hepatitis pattern of injury followed by acute central bridging and cirrhosis
hepatitis and cholestatic hepatitis patterns. The clas-
sic histologic findings include a chronic hepatitis with Genetics
■ Genetic predisposition associated with human leukocyte antigen
well-developed interface hepatitis and lobular necro-
A1-B8-DR haplotype
inflammatory activity. Most cases reveal dense portal
lymphoplasmacytic infiltrates, often with plasma cell Differential Diagnosis
aggregates. Prominent plasma cells are a frequent but ■ Viral hepatitis (especially hepatitis B and C)
not required feature. Interface hepatitis is often prom- ■ Primary biliary cholangitis and primary sclerosing cholangitis
inent in untreated AIH (Fig. 17.15A). The lobules ■ Drug-induced liver injury
demonstrate several foci of necroinflammatory activity,

A B
C D
FIGURE 17.15
A, Interface hepatitis and lobular activity are often pronounced in autoimmune hepatitis; plasma cells in clusters in the inflammatory infiltrate are a helpful
but relatively nonspecific feature of AIH. B, Lobular disarray with scattered acidophil bodies. C, Hepatocyte regeneration may lead to formation of hepatocyte
rosettes (arrow). D, Cases with severe acute AIH can demonstrate extensive lobular necrosis and collapse.
These histologic changes may be significantly reduced associated with an AIH-like pattern of injury include
or even absent after immunosuppressive therapy. nitrofurantoin, minocycline, diclofenac, infliximab,
atorvastatin, and other statins and hydralazine, meth-
yldopa, and anti–tumor necrosis factor-α (anti–TNF-α)
agents, among others. DILI is a diagnosis of exclusion
and requires clinical correlation. The LiverTox website
is a helpful database to search for medications known to
The differential diagnosis for AIH includes chronic viral induce liver injury. Wilson’s disease can rarely present
hepatitis, DILI, and early stages of primary biliary dis- with features of AIH; however, clinical and laboratory
orders, among others. Viral serologies and PCR-based findings are helpful in separating these entities.
testing are used to exclude chronic viral hepatitis, which
often shows less extensive interface hepatitis and lobu- Prognosis and Therapy
lar necroinflammatory activity than AIH. As opposed to
PBC, AIH exhibits only minimal bile duct injury with- The goals of treatment are to induce or maintain
out duct destruction and a hepatitic rather than choles- remission and prevent progression of disease. Most
tatic pattern of liver enzyme abnormalities. patients experience a rapid response to immunosup-
Drugs can cause an AIH-like clinical and histologic pressive therapy, which typically includes steroids with
picture with autoantibodies and hypergammaglobulin- or without azathioprine. Treatment-refractory cases are
emia at any time after initiating the medication. Drugs well recognized. Relapse is common upon withdrawal of
immunosuppression, but most patients quickly recover NONALCOHOLIC FATTY LIVER DISEASE
after restarting therapy. Liver transplantation is indi-
cated for cirrhotic patients as well as for patients with
massive hepatic necrosis. ■ CLINICAL FEATURES
Nonalcoholic fatty liver disease refers to steatosis and

FATTY LIVER DISEASE OR STEATOHEPATITIS steatohepatitis occurring in the absence of significant
PATTERN OF INJURY alcohol use and attributed to metabolic factors that are
associated with increased risk of cardiovascular disease
and death known as the metabolic syndrome: abdominal
The term fatty liver disease is used to describe a histo- obesity, atherogenic dyslipidemia, hypertension, insu-
logic pattern of injury that characteristically includes lin resistance, and prothrombotic or proinflammatory
steatosis at least at some point during the course of states. NAFLD is common in developed countries and
disease. Steatosis is associated with a wide spectrum of has also been recognized as an emerging health problem
clinical disorders, such as obesity, hyperinsulinemia, in the pediatric population. Patients are usually asymp-
metabolic disorders, malnutrition, medications, and tomatic and often incidentally discovered because of
others (Table 17.4). Steatosis and steatohepatitis are mildly elevated transaminase levels. Many patients who
distinguished based on their histologic features and were previously diagnosed with “cryptogenic cirrhosis”
prognoses. Steatosis occurs in the absence of features likely had cirrhosis secondary to end-stage NAFLD.
of steatohepatitis and carries the lowest risk of progres-
sive disease. Alcoholic steatohepatitis (ASH) and nonal-
coholic steatohepatitis (NASH) are both characterized
NONALCOHOLIC FATTY LIVER DISEASE—FACT SHEET
by progressive fibrosis and common histologic features,
including steatosis, lobular inflammation, hepatocellu- Definition
lar injury, and pericellular or perisinusoidal fibrosis. ■ Steatosis, mostly macrovesicular, occurring in patients with
features of the metabolic syndrome

■ May also exhibit features of steatohepatitis (ballooning
hepatocyte degeneration, inflammation) and fibrosis
TABLE 17.4 Incidence and Location

Conditions That Cause Steatosis ■ More common in developed countries; estimated prevalence in
the US population is 20% to 40%

Causes of Macrovesicular Causes of Microvesicular
Steatosis Steatosis Morbidity and Mortality
■ May progress to cirrhosis
Obesity or metabolic Acute fatty liver of preg-
■ Patients with steatohepatitis and fibrosis are at greatest risk of
Total parental nutrition nancy
cirrhosis
Rapid starvation Inherited disorders of fatty
Hypothyroidism acid metabolism
Jejunoileal bypass Reye’s syndrome
■ Common in both men and women of all races
Wilson’s disease Mitochondrial cytopathies
■ Nonalcoholic fatty liver disease increasingly diagnosed in obese
Abetalipoproteinemia Medications
Weber-Christian disease • Amiodarone children, teenagers, and young adults
Infection (hepatitis C) • Valproate
Alcohol • Nucleoside analog Clinical Features
Medication reverse transcriptase ■ Mostly asymptomatic, slightly abnormal liver tests (and alanine
• Amiodarone inhibitors aminotransferase > aminotransferase) or hepatomegaly

• Tetracycline ■ Associated with obesity, insulin resistance or diabetes,
• Tamoxifen
• Steroids Wolman’s disease hypertriglyceridemia, and other dyslipidemias (metabolic
• Estrogen Acute iron toxicity syndrome)
• Antiretroviral agents Cholesterol ester storage
• Tetracycline disease Radiologic Features
• Minocycline Jamaican vomiting disease ■ Fatty liver infiltration on ultrasound on magnetic resonance
Labrea fever imaging

Multiple hornet stings
Bacillus cereus toxins Prognosis and Therapy
Alcoholic foamy ■ Fibrosis on index biopsy is associated with progressive disease
degeneration and poor outcome
Navajo neuropathy ■ Treatment includes lifestyle modifications that include weight loss
Inherited urea cycle and blood glucose control; antidiabetic drugs and bariatric surgery
disorders have shown to have significant benefit
Pearson’s syndrome
Pathologic Features Microscopic Findings
Nonalcoholic fatty liver disease encompasses a range of

Gross Findings histologic findings, including mild steatosis to steato-
hepatitis (NASH) and even end-stage cirrhosis.
In severe steatosis, the liver is grossly enlarged, yel- Steatosis is a key feature of NAFLD. A minimum of
low, and greasy (Fig. 17.16). 5% macrovesicular steatosis (large or small droplets)
(Fig. 17.17A), often exclusively or predominantly mac-
rovesicular (Fig. 17.17B) or mixed, should be present
for the diagnosis. Microvesicular steatosis is less com-
mon and is characterized by very small fat vacuoles that
impart a granular or “fluffy” appearance to the hepato-
cyte cytoplasm (Fig. 17.17C). Microvesicular steatosis
may be present as scattered cells or in contiguous patches
in NAFLD. Steatosis is classified as none (<5%), mild
(5%–33%), moderate (34%–66%), or severe (>66%).
Nonalcoholic steatohepatitis can be distinguished
from steatosis by the presence of ballooning hepatocyte
FIGURE 17.16 degeneration (a key diagnostic feature) and inflamma-
Accumulation of fat leads to an enlarged yellow liver in nonalcoholic fatty tion (Fig. 17.17D). Ballooned hepatocytes (Fig. 17.17E)
liver disease (NAFLD). stand out from the background hepatocytes because of
A B
C D
FIGURE 17.17
Steatohepatitis. A, Macrovesicular steatosis is readily identified on low power by the large rounded clear vacuoles that represent fat accumulation in hepato-
cytes. Note the conspicuous zones 2 and 3 distribution of steatosis commonly seen in NAFLD. B, Mainly large droplets of macrovesicular steatosis. C, A patch
of microvesicular steatosis (right of the photo) is seen admixed with areas of macrovesicular steatosis (left) in this case. D, Histologic features of steatohepatitis
E F
G H
I
FIGURE 17.17, Cont'd
include steatosis, ballooning, and lobular inflammation. E, Ballooning degeneration of hepatocytes with Mallory hyaline (arrow) and focal accumulation of
mononuclear inflammatory cells in the lobule are features of nonalcoholic steatohepatitis. Mallory’s hyaline, ropey eosinophilic cytoplasmic accumulation
of intermediate filaments is more common in alcoholic steatohepatitis. F, Lobular inflammation may include lymphocytes, Kupffer cells, and neutrophils. G,
Mallory hyaline is chemotactic for neutrophil and frequently associated with “satellitosis.” H, Fibrosis in steatohepatitis generally begins in centrilobular areas as
delicate pericellular fibrosis in a “chicken wire” pattern. I, As advanced fibrosis develops, central-central bridging may be prominent, as in this case.
their large size and pale, irregular wispy or clumpy cyto- injury termed type 2 pediatric NAFLD and characterized
plasm and disrupted cell membranes. They tend to be by zone 1–predominant steatosis, portal inflammation,
most prominent in zone 3, where they are associated and portal or periportal scarring. Some children may
with perisinusoidal fibrosis and steatotic hepatocytes. show a combination of these patterns. The minimal
Classic ballooned hepatocytes may contain Mallory- diagnostic criteria for recognizing children at greatest
Denk bodies, although this is not a required feature. risk of progressive disease are unclear, and some pathol-
Mallory-Denk bodies (also termed Mallory bodies or ogists have used the term borderline, zone 1, steatohepati-
Mallory hyaline) are abnormally folded intermediate tis to indicate potentially progressive disease in biopsies
filaments recognized histologically as eosinophilic ropy exhibiting zone 1–predominant or panacinar steatosis,
or globular structures in hepatocyte cytoplasm. Mallory- portal inflammation (usually mild) (Fig. 17.18A), and
Denk bodies are not specific to NASH and can be seen portal fibrosis (Fig. 17.18B) but little or no ballooning or
in a variety of settings, including alcoholic liver disease, Mallory bodies.
chronic cholestatic conditions, Wilson’s disease, and In 2005, the semiquantitative “NAFLD Activity
some tumors. Score” (NAS; Table 17.5) was published by the NASH
The inflammation seen in NASH includes a mix- Clinical Research Network (CRN). This score was
ture of neutrophils, lymphocytes, plasma cells, and intended for use in research trials to standardize report-
macrophages in the hepatic lobules and/or portal tracts ing and assess changes in component features that
(Figs. 17.17F and G). Whereas lobular inflammation is might be seen in serial biopsies. The NAS represents
usually more prominent in adults, children may exhibit the unweighted sum of steatosis, lobular inflammation,
predominantly or exclusively portal inflammation (see and hepatocyte ballooning scores. As in chronic hepa-
later discussion). Lobular neutrophils are often present titis, grade is reported separately from stage (extent of
but are not required for the diagnosis of steatohepati- fibrosis).
tis. Portal inflammation is inconspicuous in most cases
and is usually composed of mature lymphocytes and
rare plasma cells. Greater portal inflammation occur-
ring in the absence of chronic hepatitis (e.g., hepati-
tis C) has been linked to faster progression of disease,
especially in pediatric patients, and with more severe
disease in adults. If portal inflammation exceeds the
extent of lobular inflammation, the possibility of coex-
isting chronic hepatitis or other liver disease should be
considered, particularly when interface activity is seen.
Megamitochondria, patchy glycogenosis, glycogenated
nuclei, and lipogranulomas may also be seen in patients
with steatohepatitis, although these features are not
required for diagnosis.
Fibrosis in adult patients with NASH begins in the
centrilobular region (Fig. 17.17H). In the early stages, A
delicate pericellular fibrosis is best highlighted by the tri-
chrome stain. With progressive disease, portal and peri-
portal fibrosis develops, and fibrous septa form between
portal tracts and central veins or between portal tracts
with subsequent evolution to cirrhosis. “Burned-
out” steatohepatitis presenting in the cirrhotic stage
(Fig. 17.17I) often shows only focal residual features of
steatohepatitis and may be difficult to recognize histo-
logically. Many cases of “cryptogenic cirrhosis” likely
represent end-stage NAFLD.
Pediatric Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease is the leading cause of B

liver disease in children. Some children show a sim- FIGURE 17.18
ilar histologic picture as seen in adults (type 1 pediat- Pediatric steatohepatitis. A, As opposed to adult NASH, these cases may
ric NAFLD), whereas others have a distinct pattern of reveal more prominent portal inflammation and B, portal-based fibrosis.
these entities. For example, steatosis is an important fea-

TABLE 17.5 ture of NASH but is not always seen in alcoholic liver
disease. Furthermore, canalicular cholestasis, bile ductu-
Nonalcoholic Steatohepatitis Clinical Research
Network Nonalcoholic Fatty Liver Disease lar proliferation, veno-occlusive lesions, sclerosing hya-
Activity Score line necrosis, and alcoholic foamy degeneration (pure
microvesicular steatosis) are features of alcoholic liver
Activity Score (0–8) a Fibrosis Score (0–4) b disease and are not commonly seen in NAFLD.
Steatosis (0–3) 1a: zone 3 perisinusoidal fibrosis Drug reaction should also be considered in the
0: <5% requiring trichrome differential diagnosis. Many medications, including
1: 5%–33% 1b: zone 3 perisinusoidal fibrosis estrogens, tamoxifen, and glucocorticoids, can cause
2: 34%–66% on H&E steatosis, and amiodarone toxicity, for example, can
3: >66% 1c: portal fibrosis only
cause a pattern of injury similar to ASH with frequent
Lobular inflammation 2: zone 3 + portal or periportal
(0–3) Mallory bodies.
1: <2 foci per 20× field Autoimmune hepatitis is sometimes considered in the
2: 2–4 foci per 20× field clinical differential diagnosis of NAFLD, and nonspe-
3: >4 foci per 20× field cific elevation of autoantibodies (ANA, SMA, AMA) can
Ballooning (0–2) 3: bridging fibrosis
be identified in up to 20% of individuals with NAFLD.
0: none
1: few When autoantibodies are detected in the presence of
2: many prominent portal inflammation, a careful search for
4: Cirrhosis diagnostic features of coexisting chronic liver diseases
a
Overall pattern of nonalcoholic fatty liver disease. such as AIH or PBC is warranted. Chronic HBV or HCV
b
Using Masson’s trichrome. can coexist with NAFLD and should also be excluded
H&E, Hematoxylin and eosin.
Adapted from Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic
clinically.
Steatohepatitis Clinical Research Network. Design and validation of a histologic
scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:
Ancillary Studies
1313–1321.
Some studies have shown the utility of cytokeratin

(CK) 8/18, hsp70, p62, and ubiquitin immunohisto-
chemical stains in the identification of ballooned hepato-
cytes, but these stains are not used in clinical practice.
Nonalcoholic Fatty Liver Disease—Pathologic Features
Gross Findings
■ Liver is enlarged, yellow, and greasy Although there are ongoing clinical trials, diet and
exercise and, in select patients, bariatric surgery remain
Microscopic Findings the mainstay therapy for NASH. Steatosis appears to fol-
■ Steatosis, variable amount, predominantly macrovesicular
low a relatively stable course, but steatohepatitis shows
■ Ballooning hepatocyte degeneration in steatohepatitis
■ Lobular inflammation
a greater propensity to progress to significant fibrosis or
■ Mallory’s hyaline may be conspicuous cirrhosis (∼28% of patients progress to bridging fibrosis
■ Early stages of steatohepatitis show centrilobular, pericellular or cirrhosis over 5–10 years).
fibrosis that evolves to involve portal tracts and eventually
bridging fibrosis and cirrhosis
ALCOHOLIC LIVER DISEASE
■ Alcoholic liver disease
■ Hepatitis C ■ CLINICAL FEATURES

■ Other metabolic disorders, especially Wilson’s disease
Excess alcohol consumption is a leading cause of liver

failure in the United States and worldwide. Significant
alcohol use has been variably defined for research pur-
poses. The National Institutes of Health–funded NASH
CRN defined a limit of 20 g/day for men and 10 g/day for
women for inclusion in their studies on NAFLD. Risk
Because of the histologic similarities, NAFLD cannot be for severe hepatic injury correlates with daily intake,
reliably distinguished from alcoholic liver disease on the with 80 g/day of alcohol being a risk factor for severe
basis of biopsy findings alone; this distinction is made hepatic injury. However, only 10% to 15% of people
clinically. That said, there are some differences between with alcoholism develop cirrhosis.
Like NAFLD, alcoholic liver disease can present as Pathologic Features

steatosis, alcoholic hepatitis, or cirrhosis. Hepatic ste-
atosis presents with hepatomegaly and mild elevation of
serum liver test results (in particular AST > ALT in a Gross Findings
>2:1 ratio). Steatosis resolves with cessation of alcohol
intake. Acute alcoholic hepatitis (acute alcoholic intox- The liver in patients with steatosis and alcoholic hep-
ication) may be life threatening. Patients often pres- atitis is often enlarged, yellow, soft, and greasy. In alco-
ent with malaise, anorexia, weight loss, jaundice, and holic cirrhosis, the liver is enlarged initially, with a finely
altered sensorium. In this setting, hyperbilirubinemia granular capsular surface and firm texture (Fig. 17.19).
may be seen in addition to more pronounced elevation
of transaminases. The clinical presentation of alcoholic Microscopic Findings
cirrhosis is similar to other forms of cirrhosis.
Alcoholic steatosis is commonly macrovesicular and
zone 3 in distribution. With abstinence, steatosis may
ALCOHOLIC LIVER DISEASE—FACT SHEET rapidly disappear, but residual foci lobular inflammation
and lipogranulomas may be observed.
Definition The diagnosis of alcoholic hepatitis (also known as
■ Spectrum of liver disease caused by alcohol use, including alcoholic steatohepatitis has overlapping histologic fea-
steatosis, alcoholic hepatitis, and cirrhosis tures with NASH: steatosis with lobular inflammation
and liver cell injury (ballooned hepatocytes and aci-
Incidence and Location dophil bodies), often with Mallory-Denk bodies (Fig.
■ 10% to 15% of people with chronic alcoholism develop cirrhosis;
17.20A). The degree of steatosis is variable. The lobular
true incidence of milder forms of alcoholic liver disease is
unknown
inflammation may be neutrophil rich with neutrophils
■ Worldwide distribution
in clusters around ballooned hepatocytes containing
Mallory-Denk bodies (“satellitosis”) (Fig. 17.20B). In
Morbidity and Mortality cases with pronounced hepatocellular injury, there is
■ For hepatic steatosis, full recovery is expected with cessation of evidence of hepatocellular dropout, readily highlighted
alcohol intake by the reticulin stain. Most cases show only mild or
■ Severe acute alcoholic hepatitis is associated with up to 50%
complete absence of mononuclear cell inflammatory
mortality rate; it may progress to cirrhosis or occur in the setting
of cirrhosis infiltrate within the portal tracts.
■ For alcoholic cirrhosis, the 5-year survival rate is approximately
50% for those who continue to consume alcohol; hepatocellular

carcinoma is a common complication

■ More common in men
■ All races are equally affected
■ Alcoholic cirrhosis is more common in older adults

■ Hepatic steatosis and alcoholic hepatitis may be seen in younger
adults
A
Clinical Features
■ Steatosis presents with hepatomegaly; mild elevation
of transaminases (aspartate aminotransferase > alanine

aminotransferase in a >2:1 ratio)
■ Alcoholic hepatitis usually follows an episode of binge drinking
and is associated with systemic symptoms, such as malaise or

anorexia, with or without fever; liver enzymes can be markedly
elevated with or without hyperbilirubinemia
■ Alcoholic cirrhosis presents with typical signs of cirrhosis

■ Steatosis has an excellent prognosis with cessation of alcohol
consumption
■ Alcoholic hepatitis may slowly resolve or may progress to
cirrhosis; treatment is cessation of ethanol consumption and

supportive therapy B
■ Alcoholic cirrhosis has a poor prognosis in patients who continue FIGURE 17.19
to drink, with a 5-year survival rate of 50%; treatment is A, The liver with steatosis is enlarged, soft, and yellow. The fat may be irregu-
supportive or liver transplantation larly distributed. B, Cirrhosis due to excess alcohol consumption is micronod-
ular, with a uniform cut surface.
A B
C D
FIGURE 17.20
A, In alcoholic steatohepatitis, the amount of steatosis is variable; hepatocyte injury, Mallory’s hyaline accumulation (arrow), and a neutrophilic infiltrate are key
diagnostic features. B, Mallory hyaline is often present and associated with “satellitosis.” C, Pericellular fibrosis in alcoholic hepatitis has a chicken-wire appear-
ance and is most prominent in the centrilobular region, where ballooned hepatocytes are frequently present. D, Cholestatic steatohepatitis is almost always
seen in the setting of alcohol-induced injury.
Zone 3 pericellular and perisinusoidal fibrosis is a char- inflammation is usually absent. Sclerosing hyaline necro-
acteristic feature of alcoholic hepatitis. Collagen surrounds sis is characterized by marked centrilobular hepatocel-
individual hepatocytes in a “chicken wire” pattern (Fig. lular necrosis and dropout. These patients later develop
17.20C). As fibrosis progresses, central–central and central– confluent fibrosis that obliterates the central veins
portal fibrous bridges form, eventually resulting in micro- (veno-occlusive lesions).
nodular cirrhosis. Scoring systems specifically designed for
alcoholic liver disease (e.g., the system by Altamirano et al.,
2014) are not widely used in clinical practice. Alcoholic Liver Disease—Pathologic Features
Although similarity between ASH and NASH exists,
Gross Findings
some patterns of injury described in alcoholic liver dis-
■ Steatosis: liver is enlarged, yellow, and greasy because of lipid
ease do not occur in NASH: (1) cholestatic steatohepa-
accumulation
titis (Figs. 17.20D), (2) alcoholic foamy degeneration, ■ Alcoholic hepatitis: liver may be enlarged; yellow discoloration
and (3) sclerosing hyaline necrosis. Patients with choles- and firm consistency with progressive fibrosis
tatic disease are often jaundiced with elevated ALP
and gamma-glutamyl transferase (GGT). Biopsy shows Microscopic Findings
prominent canalicular and hepatocellular cholestasis ■ Steatosis: macrovesicular steatosis, predominantly centrilobular
with or without bile ductular proliferation, mimicking but can be panlobular

■ Alcoholic steatohepatitis: hepatocyte ballooning degeneration,
bile duct obstruction. Alcoholic foamy degeneration is Mallory-Denk bodies, variable steatosis, neutrophilic inflammation,
characterized by marked centrilobular microvesicular zone 3 pericellular and perisinusoidal fibrosis, progressing to
steatosis, often with prominent megamitochondria and central–portal bridging fibrosis
cholestasis. Macrovesicular steatosis and neutrophilic
in general, patients present with pruritus and fatigue,

Alcoholic cirrhosis: delicate central–portal fibrous septa in early
and laboratory testing reveals elevation of ALPH, bili-
■
stages form micronodules, later mixed macronodular and

micronodular cirrhosis pattern rubin, and GGT. Clinically, cholestasis is associated with
certain signs and symptoms that correspond, at least in
Differential Diagnosis part, to elevated serum levels of bilirubin, bile acids, and
■ Nonalcoholic fatty liver disease cholesterol. However, pathologically, it is defined by mor-
■ Drug-induced liver injury phologic consequences of biliary retention and injury to
Chronic cholestatic conditions
■
the biliary tree. It is important to note that cholestasis
■ Wilson’s disease
by itself is quite nonspecific and does not necessarily
indicate a primary cholestatic disorder. It can be seen
in many other conditions, including drug injury, viral
Differential Diagnosis hepatitis, Wilson’s disease, and alcoholic liver disease.
Cholestasis may be classified by time frame (acute
vs chronic cholestasis) or by the pattern and location
Nonalcoholic fatty liver disease is the major differen- of cholestasis: bland cholestasis, canalicular cholestasis,
tial diagnosis for alcoholic liver disease, and frequently ductular cholestasis, ductal cholestasis, or ductular reac-
NASH and ASH cannot be differentiated based on tion or proliferation.
histologic features alone. In general, neutrophilic-rich
infiltrates, prominent Mallory’s hyaline, cholestasis,
and conspicuous pericellular sinusoidal fibrosis should Acute Versus Chronic Cholestasis
favor the diagnosis of alcohol-induced injury over
NASH. Acute cholestasis often results from acute biliary
Drug-induced liver injury is an important consider- obstruction but can also occur in sepsis and DILI.
ation if a history of alcohol use cannot be established. Histologic features of acute biliary obstruction include
Amiodarone toxicity causes phospholipidosis and prom- portal stromal edema, bile ductular proliferation with
inent Mallory-Denk bodies, which can mimic alcoholic accompanying neutrophils. The lobules show canalic-
hepatitis. ular cholestasis and bile plugs. Portal edema is a more
Cholestatic ASH, large duct obstruction, and other specific histologic feature; however, it is uncommon
chronic cholestatic conditions can show overlapping and lacks sensitivity. Occasionally, bile infarcts and bile
histologic features; however, the clinical history of alco- lakes are identified, and their presence indicates large
hol use and clinical exclusion of large duct obstruction bile duct obstruction.
should be helpful in sorting this differential. In young Chronic cholestatic conditions such as chronic biliary
patients, Wilson’s disease should be also considered as a obstruction, PBC, PSC, drugs or toxins, total parenteral
potential cause and should be distinguished using clini- nutrition (TPN) toxicity, sarcoidosis, graft-versus-host
cal and ancillary laboratory tests. disease, bile transporter mutations, IgG4 cholangitis,
and ischemic cholangitis, among others, show histo-
logic features of chronic cholestasis. A key feature is
Prognosis and Therapy periportal “cholate stasis” caused by accumulation of
bile salts in hepatocytes, imparting a rarefied, feathery
The long-term prognosis depends on the severity of liver appearance to the cytoplasm of periportal hepatocytes.
injury and alcohol abstinence. Alcoholic steatosis tends Intracytoplasmic copper accumulation within peripor-
to resolve within 1 to 3 months of stopping alcohol con- tal hepatocytes can be highlighted by rhodanine and
sumption. On the other hand, alcoholic hepatitis can orcein stains, and periportal Mallory-Denk bodies are
progress to cirrhosis. Sclerosing hyaline necrosis carries often seen. Other features include feathery degenera-
a poor prognosis and often leads to portal hypertension tion of hepatocytes, hepatocyte rosette formation, and
and ascites. Treatment includes alcohol cessation and ductular proliferation. Over time, scarring progresses
nutritional interventions and, for patients with more to a biliary-type cirrhosis, which exhibits a character-
severe disease, prednisolone or pentoxifylline. Liver istic low-power appearance of irregular, serpiginous, or
transplantation is an option for patients who achieve “jigsaw-shaped” nodules and periportal cholate stasis.
abstinence.
Patterns and Manifestations of Cholestasis
Cholestatic Pattern of Injury
Bland cholestasis is defined by the presence of lobu-
A cholestatic pattern of injury can be seen in disease lar canalicular and hepatocellular cholestasis in the
processes that affect parts of the biliary tree. The clini- absence of inflammation and hepatocyte injury. Bland
cal presentation depends on the underlying disease, but cholestasis is typically related to DILI (Fig. 17.21A).
Canalicular cholestasis refers to bile within the

bile canaliculi, which are not visible on routine
H&E in the normal liver. Hepatocellular cholesta-
sis indicates bile accumulation within hepatocyte
cytoplasm. Hepatocellular and canalicular cholesta-
sis often coexist (hepatocanalicular cholestasis)
(see Fig. 17.19B).
Ductal cholestasis is uncommon and indicates the
presence of bile within the lumen of a native interlob-
ular bile duct. Ductular cholestasis indicates the pres-
ence of bile plugs within the lumens of proliferating bile
ductules (see later). Also termed cholangitis lenta (Fig.
A 17.21C), this finding can be seen in patients with sepsis.
Ductular reaction or proliferation is a nonspecific find-
ing that can be seen in a broad array of settings, includ-
ing biliary obstruction, as a regenerative phenomenon
in the setting of hepatocyte injury, with drug-induced
injury, sepsis, parenteral nutrition, advanced hepatic
fibrosis, and others.
DISORDERS OF THE BILE DUCTS.
LARGE DUCT OBSTRUCTION

B
The clinical diagnosis of large duct obstruction is based

on imaging studies. Mechanical blockage of extrahepatic
(large) intrahepatic ducts in the setting of biliary lithia-
sis is usually manifested by colicky right upper quadrant
abdominal pain and elevated ALP, GGT, and serum bili-
rubin levels. In cases of malignant obstruction, patients
often present with painless jaundice. Fever is only pres-
ent when there is superimposed ascending bacterial
cholangitis.
LARGE DUCT OBSTRUCTION—FACT SHEET

c
Definition
FIGURE 17.21
■ Obstruction of large bile ducts by any cause, such as biliary
A, Bland cholestasis associated with drug-induced liver injury. B, Most com- stones, fibrosis, impingement by external structures/lesions (e.g.,
monly, canalicular and hepatocellular cholestasis as a result of cholestatic hematoma, abscess, tumor), or intrinsic biliary lesions
liver injury. C, Ductular cholestasis involves the interlobular bile ducts, classi-
cally described in the setting of “cholangitis lenta.”
■ Common worldwide
Medications associated with bland cholestasis include Morbidity and Mortality

■ Histologic changes can be reversible upon resolution of the
androgenic steroids, estrogen, azathioprine, and oth-
underlying obstruction
ers. Less frequently, bland cholestasis occurs in benign ■ Long-standing biliary obstruction may progress to cirrhosis
recurring intrahepatic cholestasis, thyroid disorders, or ■ Severe secondary ascending (bacterial) cholangitis; can lead to
intrahepatic cholestasis of pregnancy and as a paraneo- abscesses and strictures
plastic syndrome.
characterized by irregular nodules and greenish discol-

oration of the liver parenchyma.
■ Men and women equally affected; obstruction secondary to
gallstones more common in women

■ All races affected; gallstones more common in some populations. Microscopic Findings
■ Wide age range, depending on cause of obstruction
Liver biopsy does not play a major role in the work-up

Clinical Features and diagnosis of large duct obstruction because the his-
■ Cholestatic pattern of liver enzymes tologic features are largely nonspecific, and the diagnosis
■ Colicky abdominal pain suggests biliary obstruction from stones
of large duct obstruction is generally based on imaging
■ Painless jaundice suggests obstruction from malignancy
■ Fever may be seen in the setting of superimposed bacterial
studies. Portal tract abnormalities appear as early as 4 to
cholangitis 5 days after obstruction and include mixed portal inflam-
mation, bile duct proliferation, and portal stromal edema
Radiologic Features (Fig. 17.22A). The portal inflammation consists of numer-
■ Ultrasonography may show dilated intrahepatic or extrahepatic ous neutrophils (secondary to bile ductular proliferation)
ducts and may identify the cause of obstruction and scattered lymphocytes and plasma cells (Fig. 17.22B).
■ Endoscopic ultrasonography and endoscopic retrograde
Canalicular cholestasis and bile plugs may be present.
cholangiopancreatography are very helpful in determining the site
of obstruction and diagnostic/therapeutic interventions When present, bile infarcts and bile lakes are very spe-
cific for large duct obstruction (Figs. 17.22C and D). Some
Prognosis and Therapy patients may develop superimposed ascending cholangi-
■ Treatment is relief of obstruction by surgery, endoscopic or tis with numerous intraluminal neutrophils within bile
percutaneous drain or stent placement, endoscopic removal of ducts, portal edema, and bile ductular proliferation.
stones, or endoscopic dilation of stricture With prolonged biliary obstruction, periportal
■ Prognosis depends on the underlying cause but is generally good
for nonmalignant causes of obstruction

hepatocytes show cholate stasis, copper accumulation,
and Mallory hyaline inclusions. Mild periductal fibro-
sis may occur but bile duct loss is unusual in large duct
obstruction. Advanced fibrosis with prominent bile
ductular proliferation may develop in the setting of
chronic biliary obstruction (Fig. 17.22E).
Radiologic Features
Imaging studies remain the gold standard for diag- Large Duct Obstruction—Pathologic Features
nosing of large duct obstruction. Ultrasonography
may show dilated intrahepatic and extrahepatic bile Gross Findings
■ Intrabiliary stones
ducts above the level of obstruction as well as bili-
■ Bile lakes and infarcts
ary stones. Endoscopic ultrasonography or ERCP is ■ Strictures or thickening of the bile duct wall
more helpful in the setting of malignant obstruction ■ Biliary-type cirrhosis with green discoloration
because this procedure provides information on the
exact site of obstruction and allows clinicians to obtain Microscopic Findings
biopsy samples to place stents or dilate strictures. Early Findings
Compared with ERCP, magnetic resonance cholan- ■ Canalicular and hepatocellular cholestasis
■ Portal tract edema, more pronounced around interlobular bile

giopancreatography (MRCP) is noninvasive; superior in
ducts
visualizing the bile ducts proximal to a site of obstruc-
■ Variable portal mixed inflammatory infiltrates
tion; and provides additional information regarding ■ Bile ductular reaction accompanied by neutrophils
hepatic parenchyma, vascular structures, and lymph
nodes. Late Findings
■ Bile infarcts and bile lakes
■ Periportal cholate stasis with Mallory bodies and copper
Pathologic Features accumulation

■ Periductal fibrosis and biliary type cirrhosis
Gross Findings Differential Diagnosis

■ Primary sclerosing cholangitis
Biliary sludge or stone material may be seen in the ■ Primary biliary cholangitis
obstructed biliary tree, and areas of extravasated bile ■ Ischemic cholangiopathy and other forms of secondary sclerosing
may form bile lakes or bile infarcts. Dilated extrahepatic cholangitis

■ Immunoglobulin G4–related cholangitis
and intrahepatic bile ducts, thickening of the bile duct
wall, and ulceration of the bile duct mucosa may be seen ■ Sepsis
with malignant obstruction. Advanced stages of chronic ■ Total parenteral nutrition toxicity
biliary obstruction can result in biliary-type cirrhosis

FIGURE 17.22
A, Early in biliary obstruction, the portal tracts are edematous, with only a modest increase in inflammatory cells. The edema is particularly pronounced around
interlobular bile ducts. B, If obstruction is not relieved, bile ductular reaction at the periphery of the portal tract develops. C, In later stages of biliary obstruction,
hepatocyte necrosis with release of accumulated bile (bile infarct) may be seen. Note canalicular cholestasis (arrow), more prominent in centrilobular regions.
D, Bile lakes are seen in late-stage large duct obstruction. E, In biliary cirrhosis due to large duct obstruction, bile ductular reaction is prominent at the periphery
of the regenerative nodules.
diagnosis. In addition to the classic clinical findings,

patients with PBC and IgG4-related cholangitis usually
exhibit more dense portal inflammatory infiltrates and
Imaging studies are required to exclude large duct more prominent bile duct injury. In PBC, bile duct injury
obstruction as a cause of cholestasis. If large duct is recognized as “florid duct lesions” (see later), and in
obstruction has been excluded, other entities, includ- IgG4-related cholangitis, IgG4-positive plasma cells are
ing drug reaction, sepsis, and TPN toxicity, should be prominent. PSC is usually detected on imaging studies,
excluded clinically. although biopsy may be required if the imaging findings
In later stages, PBC, PSC, ischemic cholangiopa- are lacking or equivocal. Early ischemic cholangiopa-
thy, and IgG4-related cholangitis enter the differential thy shows eosinophilia of bile duct epithelial cells and
formation of bile duct casts, whereas late disease can and follow an identical clinical course. ANA positivity
lead to scarring and duct loss. All of these entities can can be found in 90% of patients with AMA-negative
lead to bile duct loss, which is not a feature of bile duct PBC. Patients often present with fatigue and pruritus
obstruction. in early stages. Jaundice is only seen in later stages. The
diagnosis of PBC is based on the presence of any two of
the following three criteria: (1) biochemical evidence
Prognosis and Therapy of cholestasis (mainly ALP elevation), (2) detection
of AMAs, and (3) characteristic histology (nonsuppu-
rative destructive cholangitis of the interlobular bile
Identifying and removing the cause of obstruction ducts, or “florid duct lesions”). Accordingly, biopsy
typically restores normal biliary function. Cirrhosis is is typically only required to establish the diagnosis in
uncommon in this setting. patients who are AMA negative or in whom another
diagnosis is suspected.
PRIMARY BILIARY CHOLANGITIS

Pathologic Features
Gross Findings
Primary biliary cholangitis (formerly known as pri-
mary biliary cirrhosis) is a chronic, progressive Gross abnormalities are only present in the late stages
autoimmune disorder leading to destruction of the of PBC when the liver shows features of biliary-type cir-
intrahepatic bile ducts. It usually affects middle-aged rhosis (Fig. 17.23).
to older females. Most patients (~95%) show AMAs,
although AMA-negative cases are well documented Microscopic Findings
Histologic features of chronic nonsuppurative cholangi-

tis are typically seen in the interlobular bile ducts. In early
PBC, the portal tracts contain dense inflammatory infil-
PRIMARY BILIARY CHOLANGITIS—FACT SHEET
trates composed of lymphocytes, histiocytes, and plasma
Definition cells. There may be patchy spillover of the portal inflam-
■ Progressive chronic cholestatic liver disease characterized
mation beyond the limiting plate, but significant hepato-
by destruction of intrahepatic bile ducts and positive cyte injury or necrosis is not a feature of PBC. The portal
antimitochondrial antibodies (AMA) inflammation is characteristically centered around the
interlobular bile duct, which shows evidence of injury in
Incidence and Location the form of intraepithelial lymphocytosis, nuclear disarray,
■ Variable prevalence reported, from 3.7 to 65 per 100,000
cytoplasmic eosinophilia, and cytoplasmic vacuolization.
■ More common in Western countries

■ Progressive disease leading to cirrhosis
■ Morbidity related to cirrhosis and chronic cholestasis
■ Slight increased risk for hepatocellular carcinoma

■ 90% are female and white
■ Most patients are 40 to 60 years old at diagnosis
Clinical Features
■ Strongly associated with AMA
■ Asymptomatic in early stages; may be detected by elevated
alkaline phosphatase (may be normal in early-stage disease),

fatigue, pruritus
■ Late symptoms related to chronic cholestasis include jaundice

■ Ursodeoxycholic acid improves serum biochemical liver tests,
delays histologic progression, and improves survival FIGURE 17.23

■ Liver transplantation for patients with decompensated cirrhosis
Biliary cirrhosis with bile discoloration and vague nodularity on the cut sur-
face. Note area of biliary dilatation containing dark-colored calculi.
These changes are often accompanied by loose histiocyte and may include scattered foci of inflammation and/or
aggregates or granulomas, often poorly formed. This con- granulomas.
stellation of inflammation and bile duct injury is the char- Late-stage PBC shows features of chronic cholesta-
acteristic histologic finding of PBC, termed florid duct lesion sis (periportal cholate stasis with periportal Mallory
(Fig. 17.24A). Granulomas are not required for the diag- bodies), bile duct loss, and variable degrees of fibrosis
nosis of PBC. Lobular inflammation is typically minimal (Figs. 17.24B–D).
A B
C D
E F
FIGURE 17.24
Primary biliary cirrhosis: A, Granulomatous destruction of interlobular bile ducts and intraepithelial lymphocytosis (florid-duct lesion) is present in this case of
stage I primary biliary cirrhosis. Larger bile ducts (>80 μm) are typically preserved, as in this example. B, In cirrhosis due to PBC, the regenerating nodules have
an irregular “jigsaw puzzle piece” outline. C, Periseptal hepatocytes appear pale due to accumulation of bile salts (cholate stasis), a common feature in chronic
cholestasis. D, In late-stage PBC, ductopenia is common, with few or no residual bile ducts and little bile ductular reaction. B, Rhodanine stain reveals copper
deposition in periportal hepatocytes. F, CK7 can be helpful in highlighting the interlobular ducts if present along with staining periportal hepatocytes.
Several staging systems (e.g., Scheuer and Ludwig) from PBC may be difficult because the clinical features
have been proposed for staging PBC but are variably overlap, both are often ANA positive, patients with PBC
used in clinical practice. can be AMA negative, and PBC can be patchy in distri-
bution. Whereas PBC is associated with cholestatic liver
enzymes (ALP or GGT elevations), AIH is characterized
Primary Biliary Cholangitis—Pathologic Features by striking transaminase elevations. Although mild bile
duct injury can be seen in AIH, bile duct destruction is
Gross Findings not a feature of AIH. Interface hepatitis is a key feature
■ Biliary-type cirrhosis in late stages, with green discoloration of AIH, but significant lobular hepatocyte injury is not
a feature in PBC.
Microscopic Findings Compared with PBC, peripheral needle biopsy in
■ Dense portal inflammatory cell infiltrates, including large numbers
patients with PSC usually shows nonspecific histo-
of lymphocytes and often plasma cells
logic features with less prominent portal inflammation.
■ “Florid duct lesions”: lymphocyte-mediated bile duct injury with
nuclear disarray, cytoplasmic eosinophilia, and vacuolization Clinical and imaging findings are key in separating these
■ Granulomas or loose collections of histiocytes associated with entities (Table 17.6). Sarcoidosis is associated with
bile duct injury destruction of bile ducts, granulomas, cholestatic liver
■ Variable bile ductular proliferation serology, and an irregular pattern of fibrosis. However,
■ Late-stage primary biliary cholangitis (PBC) exhibits features of
sarcoidosis is usually associated with well-formed gran-
chronic cholestasis, duct loss and biliary-type cirrhosis
ulomas, includes scarring within and around foci of
Genetics granulomatous inflammation, lacks AMA positivity,
■ Increased prevalence among first-degree relatives; variety of and often shows other systemic manifestations of the
reported human leukocyte antigen haplotypes disease.
■ Primary sclerosing cholangitis
■ Autoimmune hepatitis (AIH)
■ AIH–PBC overlap syndrome TABLE 17.6

■ Chronic viral hepatitis, especially hepatitis C Clinicopathologic Features of Primary Biliary
■ Granulomatous diseases, including sarcoidosis Cholangitis and Primary Sclerosing Cholangitis
Primary Biliary Primary Sclerosing

Cholangitis Cholangitis
Age Median age, 50 Median age, 30 years

years (30–70
Ancillary Studies years)
Gender Predominantly Predominantly male
female (90%) (70%)
Rhodanine or orcein stains highlight copper deposits Clinical Progressive Unpredictable but
within periportal hepatocytes in the setting of chronic course progressive
cholestasis of any cause and can be helpful to confirm Associated Sjögren’s syndrome Inflammatory bowel
the presence of a chronic cholestatic condition (Fig. conditions (70%) disease (UC more
17.24E). Cytokeratins (CK7 or CK19) can be used to Scleroderma (5%) common than CD)
Rheumatoid Pancreatitis (≤25%)
identify and count interlobular bile ducts, especially arthritis Idiopathic fibrosing
when ductopenia is suspected. CK7 often stains peri- Thyroid disease diseases (retroperi-
portal hepatocytes (biliary metaplasia of hepatocytes) in (20%) toneal fibrosis)
chronic biliary disorders (Fig. 17.24F). Serology 95% AMA positive 0%–5% AMA positive
incidence 20% ANA positive (low titer)
60% ANCA positive 6% ANA positive
82% ANCA positive
Differential Diagnosis Radiology Normal Strictures and
beading of large
bile ducts; “pruning”
The differential diagnosis for PBC depends on the stage of smaller ducts
Duct lesion Florid duct lesion; Concentric periductal
of the disease. Given the prominent portal inflammation loss of small fibrosis with
seen in the early stages, PBC must be distinguished from ducts epithelial injury;
chronic viral hepatitis and AIH. Histologic clues, AMA loss of small ducts
status, and serologic and PCR-based assays for viral hep- AMA, Antimitochondrial antibody; ANA, antinuclear antibody; ANCA,
atitis are helpful in this distinction. Distinguishing AIH antineutrophil cytoplasmic antibody.
If untreated, PBC follows a progressive clinical course.

Most but not all asymptomatic patients develop signif-
icant liver disease. Survival is variable, ranging from
6 to 12 years after presentation for untreated symp-
tomatic patients to several decades for asymptomatic
patients. Ursodeoxycholic acid is an effective treat-
ment, especially when started early in the course of
the disease, and has been shown to reduce morbidity
(delays histologic progression and risk of developing
esophageal varices) and improve survival (≤84% at 10
years). Patients with “AMA-negative PBC” are treated
like AMA-positive patients and exhibit the same out-
comes as those with AMA positivity. Liver transplanta-
tion is the only effective therapy for late-stage disease.
PRIMARY SCLEROSING CHOLANGITIS
FIGURE 17.25
Primary sclerosing cholangitis is a chronic progres- Primary sclerosing cholangitis. Extrahepatic and large intrahepatic bile ducts
sive, fibroinflammatory condition of the bile ducts show alternating areas of beading and structuring.
that results in biliary cirrhosis and hepatic failure. It
can only be reliably diagnosed when all other causes
of secondary cholangitis, such as postoperative bile
duct injury, biliary lithiasis, ischemic cholangiopathy, PRIMARY SCLEROSING CHOLANGITIS—FACT SHEET
and IgG4-related cholangitis, among others, can be
Definition
excluded clinically.
■ Chronic biliary disease characterized by inflammation and fibrosis
In its classic form, PSC typically affects extrahepatic of biliary tree, involving both intra- and extrahepatic bile ducts
and large intrahepatic bile ducts. In a minority of patients
(5%), only small ducts are affected (“small duct PSC”). Incidence and Location
Males are more commonly affected (male-to-female ratio, ■ Up to 5% prevalence in patients with ulcerative colitis
2–3 to 1), and disease onset usually occurs before 50 years ■ Prevalence in US population ranges from 1 to over 16 per
of age. Patients with PSC show an increased prevalence of 100,000

human leukocyte antigen (HLA) B8 and DR3 antigens.
Most, if not all, patients with PSC have inflammatory
■ Progressive disease, with a median survival period from diagnosis
bowel disease; however, only 2.5% to 7.5% of patients 9 to 18 years if liver transplant is not an option
with ulcerative colitis have PSC. Patients with PSC and ■ Complications include bacterial cholangitis and biliary stones
ulcerative colitis are at increased risk for cholangiocarci- ■ Increased risk of neoplasia: adenocarcinoma bile ducts, colon,
noma and pancreatic adenocarcinoma. pancreas

■ LABORATORY FINDINGS ■ More common in young men (<70%) of northern European
descent; rare in Asia

■ Mean age at diagnosis is approximately 40 years
Serologic studies reveal cholestatic biochemistry (usu- ■ Also occurs in children
ally ALP elevations), often with normal bilirubin levels.

A diagnosis of PSC is established upon identification of Clinical Features
multifocal beading, stricturing and irregularity of the ■ Strongly associated with ulcerative colitis and other autoimmune
extrahepatic biliary system, and dilation of the intrahe- diseases

■ Presentation ranges from asymptomatic to cirrhosis
patic biliary tree on cholangiography (ERCP or MRCP) ■ Fluctuating jaundice, fatigue, and weight loss are common
(Fig. 17.25). Liver biopsy is only performed in patients presenting symptoms
lacking imaging findings and in those suspected to have ■ Elevated alkaline phosphatase
small duct PSC.

Radiologic Features Primary Sclerosing Cholangitis—Pathologic Features

■ Endoscopic retrograde cholangiopancreatography and magnetic
resonance cholangiopancreatography can identify multifocal Gross Findings

strictures and beading involving the extra- and intrahepatic biliary
■ Biliary-type cirrhosis in late stages
tree
■ Large intrahepatic and extrahepatic ducts may show dilation and
strictures
■ No effective medical treatment Microscopic Findings
■ Patients with dominant bile duct strictures may be treated with
■ Concentric (“onion skinning”) periductal fibrosis
balloon dilation, stent placement, or surgery
■ Bile duct injury that leads to ductopenia and “tombstone” lesion
■ Liver transplantation for end-stage disease results in a greater
(fibro-obliterative scars)
than 80% 5-year survival rate
■ Mild portal inflammatory infiltrates
■ Chronic cholestatic changes and biliary type cirrhosis in late
stages
Genetics
■ Strong association with human leukocyte antigen haplotypes B8
and DR3
Pathologic Features
■ Large bile duct obstruction
Gross Findings
■ Immunoglobulin G4 disease
■ Ischemic cholangiopathy (ischemic cholangitis)

In late-stage PSC, the liver is grossly cirrhotic and bile ■ Primary biliary cholangitis
stained. Hilar fibrosis may be prominent, as are extrahe- ■ Idiopathic adulthood ductopenia
patic biliary strictures. Dense hilar scarring may mimic

the appearance of cholangiocarcinoma.

Larger bile ducts are not sampled in peripheral liver
biopsies. As a result, liver biopsies from patients with The differential diagnosis for PSC includes large bile
PSC may be completely normal or only show nonspe- duct obstruction, IgG4-related cholangitis, ischemic
cific features. Thus, the absence of histologic findings cholangitis, and PBC.
on needle core biopsies does not exclude a diagnosis of Chronic large duct obstruction may be difficult to dis-
large duct PSC. tinguish from PSC because of overlapping clinical and
The classic histologic features of PSC include per- histologic findings. However, chronic large duct obstruc-
iductal, concentric onion-skinning fibrosis associated tion seldom leads to loss of interlobular bile ducts, a fea-
with mild portal inflammation and bile duct injury ture characteristic of PSC.
(Fig. 17.26A). The bile duct epithelium is often flat- In contrast to PSC, IgG4 cholangitis typically affects
tened and may show vacuolization or eosinophilia older men (mean age 60 years or older). Most patients
of the cytoplasm with pyknotic nuclei. As the injury have concomitant autoimmune (type I) pancreati-
progresses, bile ducts may disappear, leaving an area tis. Imaging findings mimic those of PSC and include
of scar (tombstone or “fibro-obliterative” lesions) segmental strictures in the distal extrahepatic biliary
(Fig. 17.26B). The portal inflammatory infiltrates tree. However, IgG4 cholangitis may show mass-form-
are usually sparse and primarily composed of lym- ing lesions. Whereas ductopenia and fibro-oblitera-
phocytes with scattered plasma cells and eosinophils. tive lesions are more common in PSC, IgG4-positive
The hepatic lobules are usually unremarkable in the plasma cell infiltration and perivenulitis are promi-
early stage of the disease. With progressive disease, the nent in IgG4 cholangitis and storiform fibrosis can be
parenchyma shows features of chronic cholestasis as seen. As a general rule, greater than 10 IgG4 positive
well as changes of large duct obstruction such as bile plasma cells/hpf in biopsy specimens and greater than
ductular proliferation, canalicular cholestasis, and 50/hpf in resection specimens support a diagnosis of
portal edema. In liver explant specimens, larger intra- IgG4 cholangitis, but the sensitivity and specificity of
hepatic bile ducts are often dilated and contain inspis- this finding is low. Unlike PSC, the pathologic findings
sated bile plugs and sludge (Fig. 17.26C). The walls of of IgG4 cholangitis, especially strictures, resolve with
large bile ducts are fibrotic and contain chronic inflam- steroid therapy.
matory cells (Fig. 17.26D). Reactive epithelial atypia Most causes of ischemic cholangitis are iatrogenic in
within injured ducts can be difficult to distinguish nature, including vascular injury at cholecystectomy,
from biliary dysplasia. hepatic artery infusion with chemotherapeutic agents,
A B
C D
E
FIGURE 17.26
A, Interlobular bile ducts in PSC show a characteristic periductal pattern of “onion-skin” fibrosis. Also note the biliary epithelial injury. B, Fibroobliterative lesion
mark the area of destroyed interlobular bile ducts in late-stage PSC. C, Large bile ducts in PSC often contain inspissated bile and biliary stones. D, The epithe-
lium of large bile ducts is heavily infiltrated by mononuclear inflammatory cells; the underlying wall is fibrotic. E, The end result of PSC is biliary cirrhosis with
ductopenia.
radiotherapy, and liver transplantation. However, Fibrosing strictures of the biliary tree dominate the
human immunodeficiency virus (HIV), hereditary chronic stage.
hemorrhagic telangiectasia, polyarteritis nodosa, and Last, histologic overlap with PBC is occasionally a
atherosclerosis are also associated with this entity. problem. However, knowledge of the clinical setting,
Unlike PSC, acute ischemic injury results in forma- serologic tests, and radiographic appearance generally
tion of biliary casts, bile duct necrosis, and bilomas. helps in this distinction.
Prognosis and Therapy with autoimmune liver disease. The two diseases may
occur concurrently but more commonly present sequen-
tially in adults, with AIH frequently presenting before
The natural history of PSC is variable. PSC is commonly PSC. Histologic features of AIH–PSC overlap syndrome
complicated by bacterial cholangitis, and cholangiocar- include those of AIH combined with periductal concen-
cinoma is a major complication seen in up to 13% of tric fibrosis and bile duct injury. However, the diagnosis
patients with PSC. Immunosuppression is ineffective, of PSC is often based on cholangiography rather than
and liver transplantation is the treatment of choice for biopsy findings.
late-stage disease. The mean duration of survival (with-
out transplantation) ranges between 9 and 18 years
from the time of diagnosis. VASCULAR PATTERN OF INJURY
Vascular pathology of the liver can manifest with a broad

OVERLAP SYNDROMES (AUTOIMMUNE spectrum of clinicopathologic findings, including abdom-
HEPATITIS, PRIMARY BILIARY inal pain, hepatomegaly, jaundice, portal hypertension,
CHOLANGITIS, AND PRIMARY SCLEROSING and mass-forming and diffuse nodular appearance of the
CHOLANGITIS) parenchyma, among others. Vascular compromise can be
secondary to reduced inflow (e.g., hepatic artery or por-
tal vein thrombosis, obstruction), outflow obstruction
A minority of patients with AIH exhibit clinical, sero- (BCS, congestive heart failure) or systemic hypotension
logic, and histologic features of one or more autoimmune or hypovolemia (Table 17.7). The dual blood supply of
liver diseases, such as PBC or PSC. These “overlap” syn- liver provides protection against ischemia. However, an
dromes may present as two concurrent or sequential acute ischemic event is often uncompensated and results
diseases. Standardized diagnostic criteria are lacking, so in hepatocyte necrosis. Because of the lower oxygen
the prevalence of overlap syndromes remains unclear. In availability and higher metabolic activity, zone 3 hepato-
general, a diagnosis of overlap syndrome requires clear, cytes are the first to be affected.
objective clinical and histologic features of AIH in com- The clinical presentation of arterial flow impair-
bination with those of PBC or PSC. ment depends on the nature and timing of injury.
The AIH–PBC overlap syndrome describes patients Patients with acute, marked ischemic injury (“shock
with clinical and histologic evidence of both AIH and
PBC. Delineation of an overlap syndrome is somewhat
challenging and controversial because overlap exists in
the clinical and histologic features of otherwise typical
AIH and PBC. For example, mild lymphocytic infiltra- TABLE 17.7
tion of bile ducts and cholestatic features can be seen Common Causes of Vascular Pattern of Injury
in patients with AIH, but autoantibodies (ANA and
Pathogenic Event Entities
ASMA) and plasma cells are detected in most patients
with PBC. The presence of any of these features in Ischemic injury Hepatic artery disease (thrombosis or
isolation does not indicate the presence of an overlap obstruction) discussed in Chapter 20 on
liver transplantation)
syndrome. • Ischemic cholangiopathy: affecting bile
Although diagnostic criteria for AIH–PBC over- ducts
lap syndrome are not standardized, the European • Ischemic lobular injury: affecting lobu-
Association for the Study of Liver Disease guidelines lar parenchyma
require the presence of at least two of three specific crite- Portal vein thrombosis (discussed later)
or shock liver in setting of systemic
ria for AIH and PBC independently along with interface hypotension
hepatitis. The criteria for AIH include (1) ALT levels at
• Ischemic injury affecting lobular pa-
least five times the upper limit of normal, (2) IgG lev- renchyma
els at least twice the upper limit of normal or positive Congestive Hepatic vein disease
ASMA, and (3) liver biopsy with moderate or severe injury • Budd-Chiari syndrome
periportal or periseptal lymphocytic piecemeal necrosis. • Congestive (cardiac) hepatopathy
The criteria for PBC are (1) ALP levels at least twice the Sinusoidal disease
• Sinusoidal obstruction syndrome
upper limit of normal or GGT levels at least five times • Peliosis
the upper limit of normal, (2) positive AMA, and (3) Portal Portal vein disease
liver biopsy showing a florid duct lesion. hypertensive • Portal vein thrombosis or obstruction
The AIH–PSC overlap syndrome is less common and injury • Nodular regenerative hyperplasia
usually occurs in children, adolescents, and young adults • Hepatoportal sclerosis
liver”) show marked transaminase elevations (typically and hepatic encephalopathy. Jaundice and portal hyper-
>5000 U/L) followed by a rapid decline. Hepatic arte- tension are uncommon. Superimposed features of portal
rial ischemia compromises blood flow to the peribiliary venous obstruction are common in patients with severe
arterial plexus. Therefore, patients with arterial isch- BCS. Hepatic venography is considered the gold stan-
emia may show features of acute biliary injury (like bile dard for establishing the diagnosis. Alternatively, less
duct epithelial cell necrosis and bile leaks) followed by invasive techniques, such as Doppler ultrasonography
progressive scarring, stricture formation, and loss of bile and magnetic resonance imaging (MRI) or computed
ducts. These changes are associated with marked eleva- tomography (CT) scan with contrast, are also helpful.
tion of serum ALP and bilirubin levels. Imaging studies often reveal caudate lobe hypertrophy
Acute and chronic venous outflow impairment in 75% of patients. Regenerative nodules are more com-
present with distinct clinical and histologic pictures. mon in patients with chronic BCS.
Patients with acute impairment may present with hep-
atomegaly with or without splenomegaly, followed by
jaundice in cases of severe injury. Progressive scarring Laboratory Findings
can develop in patients with chronic outflow impair-
ment. Laboratory findings are variable and may include Liver enzymes, including transaminases and ALP, can
elevated ALP elevations or ALT elevations reflecting be normal or variably increased.
hepatocellular injury.
Pathologic Features
BUDD-CHIARI SYNDROME
Macroscopic Findings
There is lack of agreement on the definition of BSC. In the acute setting, the liver may be enlarged with
Based on recommendations from the European Group congestion. Later stages may reveal evidence of fibrosis
for the Study of Vascular Disorders of the Liver, BCS and nodularity. The large hepatic veins may contain
should be used as an eponym for hepatic venous outflow organizing thrombi or obstructing membranes or webs.
tract obstruction independent of the level or mechanism
of obstruction. Obstruction of venous outflow can occur Microscopic Findings
at the level of hepatic veins (small or large branches),
inferior vena cava (IVC), or both. By definition, the term Thrombosis of large veins cannot be appreciated on
excludes venous outflow obstruction from the other biopsy specimens, but small vein thrombosis with inti-
major causes of hepatic venous outflow obstruction: mal thickening can be evident in some cases. The classic
sinusoidal obstruction syndrome/veno-occlusive dis- features in the acute phase include zone 3 congestion,
ease (SOS/VOD) and right-sided cardiac decompensa- sinusoidal dilation, liver plate atrophy, and red blood
tion. Several conditions such as hypercoagulable states, cells in spaces of Disse (Fig. 17.27). Zone 3 necrosis
membranous obstruction of IVC (especially in Asia and and parenchymal collapse may be present in rapidly
South Africa), and mechanical intrinsic or extrinsic
compression of veins have been associated with BCS. Up
to 30% of cases are idiopathic.
The prevalence of BCS is low, ranging from 0.2 to 2

cases per 1 million population. It is more common in
Asia than in Western countries. Most affected Western
patients tend to be young women, but in Asia, patients
are middle aged, and there is no specific gender predi-
lection. The clinical presentation ranges from complete
absence of symptoms to fulminant hepatic failure. In
most cases, the disease progresses through acute, sub-
acute, or chronic stages. Asymptomatic BCS accounts
for up to 20% of cases and is thought to be related to
FIGURE 17.27
formation of large hepatic vein collaterals. Classical
Budd Chiari reveals congestion and sinusoidal dilation in zone 3, the distinc-
symptoms of BCS include fever, abdominal pain, hep- tion from congestive hepatopathy is mainly made through correlation with
atomegaly, ascites, lower extremity edema, GI bleeding, clinical history.
progressive cases. Nodular regenerative hyperplasia ■ CLINICAL FEATURES

(NRH) and macroregenerative nodules are more typical
of chronic BCS. These findings are attributed to super- Patients with congestive hepatopathy present with dull
imposed obstruction of intrahepatic portal vein branches right upper quadrant pain, nausea, vomiting, anorexia,
and increased arterial flow in the affected areas. In and mild jaundice. A pulsatile liver or positive hepato-
cases of pure hepatic vein involvement, the specimen jugular reflux is often present. Ascites occurs in up to
may show central–central fibrous septa, a phenomenon 25% of patients. Most patients often have long-standing
known as reverse nodularity. If the cause of BCS cannot history of cardiovascular or pulmonary disease, which,
be reversed, patients may ultimately develop advanced if left untreated, leads to cirrhosis and complications of
irregular fibrosis or even cirrhosis. portal hypertension.
Laboratory findings may vary depending on the clin-
ical presentation. Transaminases can be increased two
Differential Diagnosis to three times the normal range in most cases, mainly in
patients with low cardiac output. Total bilirubin is often
The differential diagnosis for BCS includes conges- mildly elevated. In addition, abnormalities in GGT and
tive hepatopathy, biliary obstruction, and other causes ALP are associated with elevated vascular pressures.
of sinusoidal dilation and congestion. Congestive On imaging, classic features include hepatomegaly,
hepatopathy is distinguished based on the clinical cirrhosis, and variably ascites as well as features of por-
features and is discussed later in this chapter. BCS tal hypertension and its complications.
can mimic chronic biliary disorders because approx-
imately 50% of patients may show mild bile ductu-
lar proliferation and ALP elevations. In these cases,
Pathologic Features
the lack of portal or periportal fibrosis and bile duct
injury along with the presence of centrilobular injury
should favor BCS. Other causes of sinusoidal dilation Macroscopic Findings
and congestion in the differential diagnosis include
DILI (estrogen, azathioprine, oxaliplatin), collagen The liver is often enlarged, tense, and congested. The
vascular diseases, Crohn’s disease, HIV infection, cut surface is classically described as “nutmeg liver,” pre-
sickle cell anemia, and hemophagocytic syndrome, senting a variegated mottled discoloration that results
among others. from passive congestion and hypoperfusion. Extensive
fibrosis usually develops in the later stages of the disease.

The prognosis depends on the clinical presentation. In Early findings of congestive hepatopathy include centri-
acute BCS, the mortality rate is high. In chronic BCS, lobular sinusoidal dilation with hepatocellular atrophy
an overall 80% 5-year survival rate has been reported. (Fig. 17.28A). In severe cases, there are necrosis and
Hepatocellular carcinoma remains a rare complication dropout of centrilobular and accumulation of ceroid-
in this population. The treatment depends on the under- laden macrophages. Inflammation is typically absent
lying cause but in most cases includes a combination of or inconspicuous. Cholestasis, when present, is mild
anticoagulation, thrombolysis, portosystemic venous and only seen in severe cases. The iron stain may show
shunt, or angioplasty with stent. Ultimately, transplan- increased storage iron within Kupffer cells in the cen-
tation is required in some cases. trilobular areas (Fig. 17.28B). Another unique finding
is that the centrilobular hepatocytes may show intracy-
toplasmic eosinophilic hyaline globules (the so-called
CONGESTIVE (CARDIAC) HEPATOPATHY congestion-associated globules) composed of a combina-
tion of serum proteins that are PAS positive and diastase
resistant. These should not be confused with cytoplas-
Congestive hepatopathy, also known as cardiac-related mic globules found in α1AT deficiency, which are typi-
venous congestion or chronic passive venous congestion, cally located within the periportal hepatocytes.
refers to hepatic parenchymal changes resulting from In long-standing cases, perivenular or perisinusoidal
right ventricular failure. A diagnosis of congestive hepa- fibrosis develops and eventually progresses to bridging
topathy is established when there are (1) structural fibrosis between adjacent central veins (Fig. 17.28C).
heart disease impairing right heart function, (2) signs The distribution of fibrosis is quite variable within
and symptoms of right heart failure, (3) serology consis- the sampled hepatic parenchyma. At this stage, there
tent with cholestasis, and (4) exclusion of other possible may be evidence of variable compensatory hepatocyte
causes of liver damage. hyperplasia.
disorder. In patients with no history of a cardiac or

pulmonary disorder, the differential diagnosis for
histologic findings includes BCS, peliosis, and other
causes of sinusoidal dilation mentioned earlier in this
chapter.
Therapy is directed towards treating the underly-

ing cause and improving cardiac function through
lifestyle modifications and medications. Congestive
hepatopathy is reversible during early stages of the
A disease.
SINUSOIDAL OBSTRUCTION SYNDROME
Hepatic SOS (also known as VOD) is a potentially

life-threatening complication that is most commonly
observed in patients undergoing hematopoietic
stem cell transplantation (HSCT). It was originally
described nearly 100 years ago in Jamaican individuals
consuming pyrrolizidine alkaloid–containing African
bush tea and in those consuming inadequately win-
nowed wheat or herbal traditional remedies in India
and Egypt. Myeloablative high-dose chemoradiation
B treatment in the context of HSCT is the most com-
mon cause of SOS. Other causes include solid organ
transplant, systemic inflammatory conditions, and
chemotherapeutic agents (oxaliplatin, azathioprine,
and others). An autosomal recessive condition of SOS
with immunodeficiency has also been described. The
term veno-occlusive disease was used to denote the
fibrous obliteration of small hepatic vein branches,
including the terminal hepatic venules. However,
recent animal model experiments have shown that
the main injury in SOS occurs at the level of hepatic
sinusoids, and the centrilobular venous involvement
that occurs after this acute phase of sinusoidal injury
becomes less apparent. Thus, SOS is currently diag-
nosed even in the absence of the characteristic hepatic
c
venous lesions.
FIGURE 17.28
Congestive hepatopathy. A, Marked centrilobular sinusoidal congestion and
dilatation is often present with extravasated red blood cells, hepatocellu- ■ CLINICAL FEATURES
lar atrophy and drop out. B, Nonspecific iron accumulation can be seen in
Kupffer cells within the sinusoids. C, Fibrosis is mainly centrilobular with pro-
gression to obliteration of central veins. Sinusoidal obstruction syndrome is not associated with
a specific age or gender. Clinical features of SOS include
hepatomegaly, weight gain caused by fluid accumulation
Differential Diagnosis or ascites, and hyperbilirubinemia. A Doppler ultra-
sound study demonstrating hepatomegaly, ascites, rever-
The clinical presentation and history are usually suf- sal of portal venous flow, and attenuation of hepatic
ficient to indicate the correct diagnosis. A liver biopsy venous flow, in the absence of other causes, is highly
is only performed to exclude any concurrent hepatic suggestive of SOS.
Laboratory Findings
Liver function tests usually show hyperbilirubinemia

and elevated transaminase and serum ALP levels.
Pathologic Features
The liver may be enlarged and congested with foci of

hemorrhage. In severe SOS, the liver shows a bluish-red,
marbled appearance. There may be evidence of dilated
A
blood-filled spaces (peliosis hepatis) on cut section.
The liver biopsy findings may be patchy in distribu-

tion and vary over the course of the disease. In the acute
phase of SOS, there is prominent zone 3 sinusoidal dila-
tion along with sinusoidal congestion, hepatocellular
atrophy, and centrilobular necrosis. The endothelial
injury initially results in subendothelial edema and later
leads to obliteration of central veins (Fig. 17.29A). A
Movat stain may be required to identify the “obscured
veins.” In the chronic phase, congestion is minimal.
Instead, there is dense perivenular fibrosis radiating
into the parenchyma dominates, with complete obliter- B
ation of the central veins and hemosiderin deposition FIGURE 17.29
(Fig. 17.29B). Sinusoidal obstruction syndrome. A, Obliteration of a central vein chemo-
therapy induced. B, Trichrome stain shows fibrosis of the central vein, in
other instances, Movat stain can be helpful in highlighting the presence of
a vein wall.
The differential diagnosis for SOS includes other improve outcomes, SOS remains a serious complication
causes of zone 3 congestion and sinusoidal dilation. with a mortality rate of up to 30%.
BCS shows centrilobular parenchymal changes sim-
ilar to SOS; however, occlusion of the central veins
is diagnostic of SOS. Severe SOS may mimic drug-in-
PORTAL VEIN THROMBOSIS
duced liver injury by exhibiting hepatocyte necrosis, OR OBSTRUCTION
cholestasis, and inflammation. However, the occlusive
venous changes of SOS help in distinguishing the two
causes. ■ CLINICAL FEATURES
The clinical features of portal vein disease depend on

Prognosis and Therapy whether the process involves the large (extrahepatic)
portal vein or smaller intrahepatic branches. Large
Treatment is targeted toward preventing fluid overload portal vein thrombosis may present acutely as a cata-
and vascular compromise to the liver with anticoagulant strophic and potentially lethal event or follow an insid-
therapy and methylprednisolone. Proposed strategies ious clinical course, whereas obstruction of the smaller
for SOS prevention include reduced conditioning for branches is often asymptomatic. Whereas the more
HSCT, treatment with ursodeoxycholic acid, and using acute clinical course occurs in the setting of sepsis,
a combination of chemotherapeutic agents to lower drug abdominal trauma or surgical interventions, or intra-
toxicity. Although significant progress has been made to vascular tumor spread, a silent clinical course is often
associated with various causes, including cirrhosis, dropout, and hepatocellular necrosis as a result of isch-
systemic inflammatory disease, vasculitis, prothrom- emia. NRH may be seen in cases of chronic episodes of
botic states, medications, sarcoidosis, or schistosomi- suboptimal portal vein flow.
asis, among others. Occlusion of smaller portal veins
branches is linked to obstruction as well as inflamma-
tory and toxic injury of diverse nature. Differential Diagnosis
Occlusion of the main portal vein or its branches
produces abdominal pain, portal hypertension, ascites, In most cases, portal vein thrombosis or obstruction
and GI bleeding caused by esophageal varices. Severe occurs as a superimposed phenomenon in patients with
continuous and colicky abdominal pain with bloody cirrhosis and portal hypertension. Other causes of non-
diarrhea often signifies concomitant mesenteric vein cirrhotic portal hypertension, including hepatoportal
thrombosis and intestinal infarction. Imaging stud- sclerosis (HPS; see section on Hepatoportal Sclerosis),
ies can confirm obstruction of larger branches and should be considered.
assess possible causes such as extrinsic compression by
tumors.
■ PATHOLOGIC FEATURES Anticoagulation therapy for at least 3 months is the

mainstay therapy for acute portal vein thrombosis. In
patients with chronic portal vein thrombosis, variceal
Macroscopic Findings banding or sclerotherapy is used to control bleeding
resulting from portal hypertension.
The portal vein may show a partially obstructed lumen
with thickening of the vessel wall. For cases presenting
more acutely, fresh intraluminal thrombus may be evi- NODULAR REGENERATIVE HYPERPLASIA
dent in addition to areas of parenchymal congestion and
necrosis. In advanced cases, there may be scarring or
nodularity of the vein. Nodular regenerative hyperplasia develops in the set-
ting of abnormal blood flow to the liver and is charac-
terized by the presence of multiple 1- to 2-mm nodules
distributed diffusely throughout the parenchyma.
Microscopic Findings NRH is part of a spectrum of hepatic disorders that
cause noncirrhotic portal hypertension and manifest
Depending on the phase of the disease, the portal vein histologically as HPS, SOS, and incomplete septal cir-
and its branches may show organizing or recanalized rhosis. NRH has been associated with several condi-
thrombus (Fig. 17.30). More severe injury is associated tions, including drug-induced injury (e.g., oxaliplatin,
with centrilobular hepatocyte swelling, hepatocellular azathioprine), portal vein thrombosis, prothrombotic
states, immunologic disorders (e.g., HIV, collagen vas-
cular diseases, liver allograft, celiac disease, common
variable immunodeficiency), and multiple tumors in
the liver.
The clinical presentation varies depending on the

underlying cause, and patients may manifest signs of
portal hypertension or may be completely asymptom-
atic. Imaging may show only focal nodularity (nodular
transformation of the hilum) or diffuse nodularity of the
liver that raises suspicion for cirrhosis.
Laboratory Findings
FIGURE 17.30
A portal tract demonstrates thrombosis and recanalization of the portal vein Laboratory findings may reveal elevation of ALP and
in long standing cirrhosis. transaminase levels.
Pathologic Features should be paid to the vasculature and superimposed

findings that could serve as a clue to the underlying
cause.
Diffuse nodularity mimicking cirrhosis is seen
grossly, but palpation of the cut surface confirms the
lack of scarring associated with the nodules. The main clinical differential diagnosis is cirrhosis. The
lack of fibrosis on trichrome stain as well as typical find-
Microscopic Findings ings on reticulin stain is helpful in distinguishing NRH
from cirrhosis. In patients with portal hypertension and
The hepatic parenchyma has a vaguely nodular appear- no evidence of cirrhosis, other causes of noncirrhotic
ance at low magnification. However, there is no accom- portal hypertension (see later) should be excluded both
panying fibrosis. The parenchymal nodularity is caused clinically and histologically.
by atrophy of zone 3 hepatocytes and compensatory
enlargement of hepatocytes in zones 1 and 2 (Fig. 17.31A).
Reticulin stain is extremely helpful in highlighting the Prognosis and Therapy
vague nodularity and collapse of the reticulin frame-
work (within zone 3) in subtle cases (Fig. 17.31B). The treatment of patients with NRH is directed towards
Sinusoidal dilation is often present. Special attention treating the underlying cause. The prognosis largely
depends on the severity of underlying disease and
management of complications related to portal
hypertension.
HEPATOPORTAL SCLEROSIS
The term noncirrhotic portal hypertension encompasses

a variety of conditions that manifest as portal hyperten-
sion but do not show histologic evidence of cirrhosis.
The underlying causes can be divided into “primary
causes” in which the cause is unknown (idiopathic non-
cirrhotic portal hypertension) and “secondary causes”
caused by a variety of conditions such as SOS, hepatic
venous outflow impairment, extrahepatic portal venous
A thrombosis, schistosomiasis, or congenital hepatic
fibrosis, among others. HPS is a presinusoidal cause
of noncirrhotic portal hypertension. Other names for
this entity include Banti’s disease, noncirrhotic portal
fibrosis, obliterative portal venopathy, and noncirrhotic
intrahepatic portal hypertension. Although the exact
cause of HPS remains unclear, hypercoagulability, infec-
tion, and immunologic abnormalities have been sug-
gested to play a role.
Most cases have been reported in Asia (mostly young

B men in India and middle-aged women in Japan); this
FIGURE 17.31 disease is rare in Western countries. The clinical mani-
Nodular regenerative hyperplasia. A, A low power magnification reveals festations include anemia or pancytopenia and features
a vaguely nodular architecture due to the relative preservation of zone 1
hepatocytes and atrophy of zone 3-2 hepatocytes. B, Reticulin stain empha-
of portal hypertension (splenomegaly, varices with or
sizes the collapse of the reticulin framework, with accentuation of the nodu- without hematemesis, and elevated portal pressure) in
larity particularly useful in subtle cases. the absence of cirrhosis with patent large portal and
hepatic veins and normal to mildly elevated liver func-

tion tests. Encephalopathy is rare.
Pathologic Features
The liver may appear completely normal or may

show a wrinkled capsular surface. Gross nodularity is
uncommon.
The main goal of liver biopsy is to evaluate for any

potential cause of portal hypertension and confirm or
exclude cirrhosis. The histologic findings of HPS may
be patchy. Typical cases show portal fibrosis and abnor-
malities of the intrahepatic portal veins such as phle- A
bosclerosis, portal vein dilation or arterialization, and
herniation of the portal veins into the periportal tissue
(Fig. 17.32). There may be accompanying sinusoidal
dilation and perisinusoidal fibrosis. In addition, portal
tract remnants (portal tracts with an overall size smaller
than twice the diameter of their bile ducts) have been
associated with this entity. NRH and incomplete thin
septa are also described and can be highlighted on reticu-
lin and trichrome stains. In most cases, the bile ducts are
intact. The lobular parenchyma is generally unremark-
able except for patchy foci of hepatocellular atrophy. In
long-standing cases, the hepatic veins show obliteration
of the lumens and phlebosclerosis with marked paren-
chymal atrophy.
B
Hepatoportal sclerosis is a diagnosis of exclusion.

Compared with primary extrahepatic portal vein
thrombosis, HPS is more frequently seen in men and
often shows more portal tract remnants, phlebosclero-
sis, portal vein arterialization, and NRH. Portal vein
dilation is often more severe in primary extrahepatic
portal vein thrombosis. However, these histologic fea-
tures have a low overall specificity, and other clinical
findings, including vascular imaging studies for portal
vein thrombosis, are often required to separate these
entities.
Prognosis and Therapy c

FIGURE 17.32
The prognosis in Western countries has been regarded Hepatoportal sclerosis. A, Herniation of portal veins extending into the lob-
ule. B, Long-standing cases may show complete obliteration/loss of portal
as poor compared with Asian cohorts that demonstrate veins. C, Trichrome stain can aid identified the lack of portal veins in portal
a 100% 5-year survival rate. Treatment is symptomatic tracts.
and includes beta-blockers, endoscopic sclerotherapy,

and endoscopic band ligation of varices. In patients with
more severe variceal bleeding or symptomatic hyper-
splenism, portosystemic shunt surgery or splenectomy
may be required.
PELIOSIS HEPATIS
Peliosis hepatis is a rare entity characterized by the

presence of multiple blood-filled cysts that are randomly
distributed throughout the liver. These cystic lesions
are thought to be a consequence of ruptured sinusoids.
The disease may involve other organs such as the lungs,
FIGURE 17.33
spleen, and lymph nodes. Peliosis hepatis has been asso-
Peliosis. Dilated blood-filled spaces surrounded by hepatocytes and lacking
ciated with steroid use (anabolic, oral contraceptives), an endothelial lining.
danazol, tamoxifen, thorotrast, methotrexate, vinyl chlo-
ride exposure, azathioprine, leukemia and lymphoma,
and Bartonella henselae infection.
Ancillary Stains
Warthin-Starry stain highlights the organisms of B.

henselae.
The diagnosis is often incidental at the time of autopsy.

Patients can also present with intraabdominal bleeding
as a result of ruptured cysts. Bartonella infection can
be detected using serologic studies, cultures, and PCR- Extensive sinusoidal dilation may mimic peliosis
based assays. hepatic, but intact sinusoidal walls and well-maintained
reticulin framework in areas of sinusoidal dilation help
distinguish these entities.
Pathologic Features
The hepatic parenchyma shows multiple round, Most cases are incidentally found and require no specific
blood-filled spaces ranging from 0.2 to 5 cm in diameter. therapy. Erythromycin or doxycycline therapy is used
These spaces may be separated by foci of fibrosis. Long- to treat B. henselae infection, but relapses are known to
standing cases of peliosis may show foci of dystrophic occur.
calcification.
Microscopic Findings DRUG-INDUCED LIVER INJURY

The characteristic finding is the presence of blood
lakes surrounded by hepatic cords and lacking an Drug-induced liver injury results from deleterious
endothelial lining (Fig. 17.33). Reticulin stain is useful effects of compounds present in medications, toxins,
in demonstrating the absence of reticulin framework herbal products, and dietary supplements that are pri-
in areas of peliosis. Adjacent lobular parenchyma may marily metabolized in the liver. Because many cases
show sinusoidal dilation, fibrosis, organizing thrombo- are asymptomatic and DILI is largely underreported,
sis, and calcification. In bacillary peliosis, the organ- the true incidence is difficult to estimate. The mecha-
isms are usually extracellular or within Kupffer cells nism of injury is either “intrinsic” (dose dependent) or
and can be easily highlighted by Warthin-Starry stain. “idiosyncratic” (non–dose dependent). Acetaminophen
Bacillary peliosis may also be associated with vascu- toxicity is the prototype of intrinsic injury and one of
lar proliferation, similar to that observed in bacillary the leading causes of DILI. Idiosyncratic DILI accounts
angiomatosis. for approximately 15% of cases of acute liver failure
in the United States. Idiosyncratic DILI can be further associated with HDS is unknown. Weight loss supple-
subdivided into hypersensitivity (immune-mediated ments (e.g., Hydroxy cut and OxyElite) were among the
processes, one-third of cases) and metabolism-mediated most common type of HDS implicated in DILI and more
injury (two-thirds of cases). frequently induced hepatocellular injury.
Several risk factors have been proposed for idiosyncratic
reactions, including HLA genotypes (e.g., HLA-DRB1*15
and *6 in amoxicillin–clavulanate toxicity), mitochon-
Laboratory Findings
drial enzyme (cytochrome P450, N-acetyltransferase
2, UDP-glucuronosyltransferases, and glutathione
S-transferases) gene polymorphisms, and as gene vari- Given the heterogeneous clinical manifestation, there is no
ants (mitochondrial DNA polymerase c gene [POLG] in diagnostic test or histologic finding that can unequivocally
sodium valproate toxicity). Age may be a risk factor as confirm the diagnosis. Based on the liver enzyme profile,
well because children are at a greater risk for developing cholestatic, hepatitis, and mixed patterns can be recog-
DILI in the setting of valproate therapy and aspirin use, nized. Some patients may reveal autoantibodies including
but older individuals may be more susceptible to isonia- ANA and SMA, resulting in an AIH-like picture.
zid and toxicity induced by amoxicillin–clavulanate.
DRUG-INDUCED LIVER INJURY—FACT SHEET

Definition
Although most patients are asymptomatic and show ■ Hepatic injury secondary to exposure to a chemical compound
only mild elevation of liver enzymes (“biochemical hep-

atitis”), some develop symptoms related to cholestatic
■ Difficult to estimate with certainty; approximately 10% of cases of
or hepatitic injury. Hypersensitivity reactions are asso-
all “hepatitis” are suspected to be a drug reaction
ciated with fever, rash, edema, and peripheral eosino- ■ Up to 25% of acute liver failure cases
philia. Severe DILI can occasionally result in acute liver
failure, a complication more frequently encountered in Morbidity and Mortality
women than men. ■ Depends on severity of injury and offending agent
Temporal association between exposure to the agent ■ Low mortality for mild reactions and prompt withdrawal of
and onset of symptoms is useful in some cases, although injurious agent

■ High mortality rate with direct hepatotoxins
other agents may induce a delayed response after months
or years of use. Gender, Race, and Age Distribution
More recent antiretroviral drugs (etravirine, ralte- ■ Both genders; women more susceptible to acute liver failure
gravir, elvitegravir, dolutegravir) exhibit lower toxicity ■ All ages affected, although variations are noted among age
characterized by hepatocellular injury and hypersen- groups

sitivity reactions. Tyrosine kinase inhibitors (lapati-
nib, pazopanib, ponatinib, regorafenib, and sunitinib) Clinical Features
■ Range from asymptomatic to mild hepatitis, cholestasis, and
more frequently show transient elevation of transami-
hepatomegaly
nases caused by hepatocellular injury (≤50% of cases), ■ Severe liver injury can result in symptoms associated with acute
but severe hepatotoxicity has also been documented. liver failure
Monoclonal antibodies are widely used in today’s prac-
tice. Whereas rituximab and bevacizumab have not Prognosis and Therapy
shown significant hepatotoxicity, other agents such as ■ Primary treatment is withdrawal of the culprit
ipilimumab and trastuzumab have been associated with ■ Immunosuppressive therapy may be required in patients with an
autoimmune hepatitis–like pattern

hepatocellular injury and rarely with more severe hepa-
■ Supportive measures and liver transplantation in severe life
tocellular injury, especially when used in combination threatening cases of acute liver failure
with other chemotherapeutic drugs. Newer therapies ■ Prognosis depends on severity of injury, but most cases resolve
with check point inhibitors have shown to induce mul- without sequelae
tiple patterns of injury including hepatitic, cholangitic,
mixed, steatotic patterns as well as nonspecific changes.
Among anti–TNF-α agents, infliximab has been
reported as the most common implicated agent in DILI, Pathologic Features
with a hepatocellular pattern of injury in 75% of cases.
Herbal and dietary supplement (HDS) use has Gross Findings
increased significantly over the past several years in the
United States. Even though the US DILI Network has In acute severe DILI, the liver shows massive hepatic
been reporting anecdotal cases, the incidence of DILI necrosis and hemorrhage. In cholestatic DILI, the liver
is bile stained. Long-standing DILI can induce fibrosis, other causes and guide therapy. DILI can cause virtually
which may be evident grossly. any known pattern of injury (Fig. 17.34). More recently,
the DILI Network (United States) has described 18 dis-
Microscopic Findings tinct histologic patterns of DILI (Table 17.8). Among
these, acute (including acute resolving hepatitis) and
The purposes of the liver biopsy are to assess the chronic hepatitic, cholestatic, and mixed hepatitis–
severity of the injury (necrosis or fibrosis) and exclude cholestatic patterns are the most frequently encountered
FIGURE 17.34
Toxic injuries. A, Bland cholestasis, with accumulation of bile in canaliculi and hepatocytes without significant portal inflammation, is a pattern of injury some-
times associated with estrogen administration. B, Canalicular cholestasis is usually more prominent in zone 3 in drug-related hepatic injury. C, Bile duct injury
and destruction (arrow) result in prolonged cholestasis in some cases of drug reaction. Also note the markedly increased number of eosinophils in this exam-
ple. D, Massive hepatic necrosis has led to parenchymal collapse in this case of hepatic injury due to isoniazid; nests of regenerating hepatocytes are sep-
arated by collapsed stroma. E, Macrovesicular steatosis is a common but nonspecific pattern of toxic injury. F, Microvesicular steatosis is less common than
FIGURE 17.34, Cont'd

macrovesicular fatty change. This pattern is classically seen in Reye’s syndrome, associated with aspirin use in children, or in valproic acid and tetracycline tox-
icity. G, Granulomas are a common pattern of injury due to drugs and may feature a prominent eosinophilic infiltrate. H, Veno-occlusive disease, or sinusoidal
obstruction syndrome, affects central veins and is associated with high-dose chemotherapy used in bone marrow transplantation. The lumen of the central vein
is narrowed by edematous fibrous tissue. I, Some injurious agents, such as halothane, carbon tetrachloride, and acetaminophen, may cause prominent zonal
necrosis without significant inflammation. J, Resolving acute hepatitis of injury is among the most commonly seen in DILI and characterized by subtle collec-
tions of ceroid-laden Kupffer cells and lymphocytes sparse in the lobules that can be highlighted on PAS-D stain.
patterns. In fact, the inability to classify a biopsy into homogeneous pale cytoplasm), “two-tone” hepatocytes
one of these histologic patterns is a strong indicator of (areas of pale cytoplasm and others of eosinophilic gran-
DILI. Within the hepatitic pattern, most patients pres- ular cytoplasm), and PAS-positive pseudo-ground-glass
ent with portal tract and lobular inflammation. Many inclusions.
patients exhibit features of acute resolving hepatitis at Because of the broad range of offending agents and vary-
the time of biopsy with rare lymphocytes and PAS-D– ing patterns of injury, data on PubMed and the LiverTox
positive Kupffer cells in small aggregates around rare website (http://livertox.nlm.nih.gov) are extremely helpful
acidophil bodies or within portal tracts. Eosinophilic for finding associations with specific substances.
infiltrates may be prominent in cases of hypersensitiv- Fibrosis is uncommon because most patients recover
ity type DILI. Among the cases with cholestatic pattern from acute DILI. However, it can be seen with long-term
of injury, bland cholestasis is a frequent observation. amiodarone and methotrexate use. In the case of metho-
Nonspecific hepatocellular changes in DILI are well rec- trexate toxicity, Roenigk grade is often reported to assess
ognized and include “induced” hepatocytes (abundant (Table 17.9).
TABLE 17.8
Drug-Induced Liver Injury Patterns
Pattern of Injury Associated Drugs and Toxins
Acute hepatitis Fluoroquinolones; statins, minocycline, isoniazid, interferon, infliximab,

nitrofurantoin, diclofenac, cephalexin, and methyldopa
Autoimmune-like hepatitis Minocycline, nitrofurantoin, hydralazine, methyldopa, statins, fenofibrate,
α- and β-interferon, infliximab and etanercept
Chronic hepatitis Nitrofurantoin, methyldopa
Acute (bland) cholestasis Estrogens, androgenic steroids
Chronic cholestasis Floxuridine
Cholestatic hepatitis, ductopenia, vanishing bile Amoxicillin–clavulanate, fluoroquinolones, azithromycin, trimethoprim–
duct syndrome (paucity of bile ducts in <50% sulfamethoxazole, anabolic steroids, ibuprofen, valproic acid, total
of portal tracts) parental nutrition
Granulomas Phenytoin, interferon-α, allopurinol, diphenylhydantoin
Macrovesicular steatosis Methotrexate, tamoxifen, irinotecan, oxaliplatin, protease inhibitors
Microvesicular steatosis Valproic acid, tetracycline, nucleoside–nucleotide analogs
Steatohepatitis Amiodarone, tamoxifen, methotrexate, steroids
Zonal necrosis Acetaminophen, carbon tetrachloride
Massive or submassive necrosis Isoniazid, nitrofurantoin, methyldopa
Sinusoidal obstruction syndrome and other Chemotherapeutic agents, steroids, Jamaican bush tea
vascular injury patterns
Mixed or unclassifiable injury A combination of two or more other patterns or significant change that
does not qualify for another pattern
No specific drugs associated
Minimal nonspecific changes Minor changes such as minimal inflammation or steatosis that do not
qualify as normal or for another pattern; no specific drug associated
Adapted from Kleiner DE, Chalasani NP, Lee WM, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical
associations. Hepatology. 2014;59(2):661–670
Drug-Induced Liver Injury—Pathologic Features TABLE 17.9

Gross Findings Roenigk Scoring System for Methotrexate
■ Variable; dependent on severity of injury
Grade Histologic Findings Clinical Implications
■ Normal in minimal cases, to steatosis, hepatomegaly, and even
necrosis 1 Normal to mild Continue therapy

■ In cases of massive hepatic necrosis, liver is shrunken and flaccid steatosis, nuclear
with islands of residual viable or regenerating parenchyma variability, and/or
portal inflammation
Microscopic Findings 2 Moderate to marked Continue therapy
■ Variable; 18 different histologic patterns of drug-induced liver steatosis, nuclear
injury described variability, and/or
■ Acute and chronic hepatitis, cholestasis, and cholestatic hepatitis portal inflammation
among the most frequent patterns 3 A: mild fibrosis A: can continue therapy
B: moderate to but repeat biopsy in 6
Differential Diagnosis severe fibrosis months
B: should not be given
■ Viral hepatitis
methotrexate therapy un-
■ Autoimmune hepatitis
less there are exceptional
■ Biliary disorders, such as primary biliary cholangitis or large duct
circumstances
obstruction
4 Cirrhosis Should not be given
■ Sarcoidosis
methotrexate therapy
■ Fatty liver disease
unless there are
■ Vascular injury
exceptional circumstances
Adapted from Roenigk HH Jr. Auerbach R, Maibach HI, Weinstein GD.
Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol. 1988;19
(1 Pt 1):145–156.
Differential Diagnosis MISCELLANEOUS PATTERNS

OF INJURY.
The differential diagnosis for DILI is broad because
drug and toxic reactions can mimic other liver diseases.
Diagnosis relies on identification of an offending agent, “ALMOST NORMAL” BIOPSY OR
and other causes of hepatic injury must be excluded. NONSPECIFIC FINDINGS
Prognosis and Therapy In certain circumstances, marked elevation of liver

enzymes does not necessarily correlate with obvious
Treatment for patients with DILI includes withdrawal of histologic findings or a definitive diagnosis. Table 17.10
the offending agent followed by supportive therapy. For includes frequent differential diagnoses under this pat-
mild liver injury, the prognosis is excellent. More severe tern of injury.
liver injury, such as massive hepatic necrosis, may be life Scattered mononuclear infiltrates within portal tracts
threatening, in which case liver transplantation is indi- (Fig. 17.35A) are commonly seen in this differential
cated. Chronic DILI is often associated with cholestatic diagnosis. Biopsies reveal scant lymphocytes and occa-
pattern of injury and can ultimately lead to cirrhosis. sional plasma cells without significant lobular or interface
TABLE 17.10
Causes of “Almost Normal” Pattern of Injury
Histologic Finding Suspected Diagnosis Ancillary Stain
Slight nodularity (clinically suspected cirrhosis) Nodular regenerative hyperplasia Reticulin stain
Dilated sinusoids Sickle cell disease
Sinusoidal infiltration Tumor infiltrating sinusoids (including
lymphoma)
Collagen vascular diseases
Hemophagocytic syndrome
Systemic inflammatory conditions
Periportal eosinophilic cytoplasmic globules α1-Antitrypsin deficiency PAS-D stain
Eosinophilic amorphous deposits in sinusoids Amyloid Congo red stain
and/or vessels Mass spectrophotometry
Scattered mononuclear infiltrates in lobules Celiac disease PAS-D can highlight scattered
or portal tracts with Kupffer cell aggregates Common variable immunodeficiency Kupffer cells
Crohn’s disease
“Resolving acute hepatitis pattern of injury”
in DILI and self-limited infections
Collagen vascular diseases
Large pale hepatocytes (classic diabetic Glycogenic hepatopathy
patient in metabolic acidosis)
Prominent, herniated portal veins with Causes of noncirrhotic portal hypertension, Reticulin stain
or without nodular architecture (portal including hepatoportal sclerosis
hypertension, suspected cirrhosis of
unknown cause)
Reduced number of bile ducts with or Vanishing bile duct syndrome in drug reac- Orcein or rhodamine to high-
without bile ductular proliferation, minimal tion and others light copper deposition
cholestatic changes Primary sclerosing cholangitis PAS-D, CK7, or CK19 may aid
bile duct identification
Minimal cholestasis without inflammation or “Bland lobular cholestasis” in the setting
bile duct changes of sepsis, thyroid disease, or DILI
Enlarged hepatic stellate cells (Ito cells) with Hypervitaminosis A
lipid-filled vacuolated cytoplasm and indented
nuclei
Amphophilic cytoplasmic change in hepatocytes Hepatitis B infection PAS or PAS-D
(ground-glass or pseudo Polypharmacy
ground-glass inclusions) Cyanamide therapy
Type IV glycogen storage disease
Uremia
Lafora’s disease
CK, Cytokeratin; DILI, drug-induced liver injury; PAS, periodic acid–Schiff; PAS-D, periodic acid–Schiff–diastase.
A B
C D
E
FIGURE 17.35
Almost normal pattern: A, Sparse chronic inflammatory infiltrates within portal tracts, in this case associated with minimal bile ductular proliferation. B, CK7 stain
demonstrates the lack of an interlobular bile duct and highlights periportal hepatocytes in a case of primary sclerosing cholangitis with ductopenia. C, Ito cells
(hepatic stellate cells) are not visualized under normal conditions but become hyperplastic and hypertrophic in certain diseases such as hypervitaminosis A. The
picture demonstrates Ito cell hyperplasia with cells that exhibit vacuolated cytoplasm with septations. D, In comparison, a case of macrovesicular steatosis with
large vacuoles of fat within hepatocytes without septations. E, Globular eosinophilic and amorphous deposits within sinusoids and involving the portal tracts,
consistent with amyloidosis.
activity. These findings need to be correlated with the clin- resolving acute hepatitis in the setting of infections or
ical impression but raise the possibility of medication-in- even AIH. This could also represent a nonspecific finding
duced injury, chronic biliary obstruction (in particular without clinical significance in some cases.
if there is bile ductular reaction or cholestatic findings), Ductopenia (Fig. 17.35B) is defined as the loss of bile
early primary biliary disorders such as PBC and PSC, and ducts. In general, up to 10% to 20% of portal tracts
may lack an interlobular bile duct, particularly those

of smaller size. The diagnosis of ductopenia can be ren-
dered when 50% or more of portal tracts do not show
a bile duct, and in most cases, at least 20 portal tracts
are required for a more accurate diagnosis. In clinical
practice, the term bile duct loss can be used in cases that
do not fulfill the criteria for ductopenia but demon-
strate absence of bile ducts in more than 20% of portal
tracts. Ductopenia is typically associated with primary
biliary disorders (PBC and PSC), but it can also occur
in the setting of drug-induced injury (antibiotics, total
parental nutrition), can be idiopathic, and can occur
as a paraneoplastic syndrome. CK7 stain is helpful in
highlighting the native bile ducts. PAS-D stain reveals
positive staining of the basement membrane of the
interlobular bile ducts, so it should also be useful when A
assessing this.
Ito cell hyperplasia (Fig. 17.35C and D), also known
as hepatic stellate cells, is found in a sinusoidal dis-
tribution within the space of Disse but is not visi-
ble on routine H&E stain under normal conditions.
In pathologic states such as hypervitaminosis A, Ito
cells are the main sites for storage, and they become
hyperplastic and hypertrophic, compressing sinusoids,
which imparts a honeycomb appearance to the liver.
Ito cells exhibit cytoplasmic vacuolation and septa-
tions with indented dark nuclei, a characteristic that
can help in the differential diagnosis from steatosis in
hepatocytes.
Amyloidosis (Fig. 17.35E) in the liver is often not
a subtle diagnosis but can be an incidental finding. B
The characteristic eosinophilic amorphous depos- FIGURE 17.36
its in a sinusoidal distribution, involving the stroma A, Histoplasma capsulatum found in a case of granulomatous inflammation
in the liver on GMS stain. B, In cases of sarcoidosis, granulomas are well
of portal tracts or involving the wall of small arteri- formed and can be encountered in the portal tracts.
oles. In doubtful cases, Congo red stain or sulfated
Alcian blue can confirm the diagnosis. Mass spectro-
photometry is the gold standard for subtyping the vari-
ant of amyloid. ■ NECROSIS
Liver necrosis can result from several different causes

■ HEPATIC GRANULOMAS (Table 17.12). The distribution of necrosis and severity
are helpful in suggesting the possible etiology. A zonal
distribution of necrosis, especially zone 3, is associated
Granulomas are reported in 5% to 10% of all liver with certain drugs or toxins and vascular injury. In con-
biopsies. The most common causes of hepatic granu- trast, a geographic or “random” pattern of necrosis favors
lomas are infections (Fig. 17.36A), PBC, sarcoidosis an infectious cause. Interface activity with spotty necro-
(Fig. 17.36B), DILI, systemic inflammatory condi- sis and coexistence of a lobular inflammatory infiltrate
tions, immunologic deficiencies, lymphomas (especially suggests infection (commonly viral) or immune-medi-
Hodgkin lymphoma), and nonspecific reaction adjacent ated injury. Autoimmune hepatitis and DILI should be
to a mass lesion. In up to one-third of patients, gran- suspected if there is bridging necrosis and hepatocellular
ulomas are idiopathic in nature. Table 17.11 outlines collapse. Most cases of focal necrosis resolve; however,
the different forms of granulomatous injury and corre- significant necrosis may evolve to fibrosis in a subset
sponding causes. A definitive diagnosis often requires of cases.
a thorough review of the clinical history or medication Submassive or massive hepatic necrosis is a nonspe-
list, extensive serologic work-up, culture, and imaging cific pattern of injury in which large areas of the paren-
studies. The treatment and prognosis depend on the chyma or entire hepatic lobule are destroyed (Fig. 17.37).
underlying cause. The trichrome stain can be difficult to interpret in these
TABLE 17.11
Types of Granulomas in the Liver and Common Associations
Granulomas Type Description Causes
Epithelioid Well-formed aggregates of macrophages Infections (fungal, mycobacterial, others)

with abundant eosinophilic dense Sarcoidosis
cytoplasm DILI
May have necrosis and destroy liver CVID
architecture
Microgranulomas Small aggregates (less than 10 cells) of Nonspecific
Kupffer cells with admixed lymphocytes CVID
usually.
Fibrin ring granulomas Epithelioid granuloma with a central lipid Q fever
vacuole surrounded by a fibrin ring Leishmaniasis
Rickettsia typhus
Toxoplasmosis
CMV
EBV infection
Mycobacterium avium–intracellulare
Typhoid fever
Allopurinol
Hodgkin’s lymphoma
Lipogranulomas Histiocytes contain lipid vacuoles Fatty liver disease
Hepatitis C
Mineral oil
Nonspecific
Granulomatous bile duct injury Portal-based granulomas with associated PBC (granulomas often poorly formed)
bile duct injury; rarely cholestasis DILI
Foreign body granulomas Birefringent material upon polarization Beryllium
of H&E-stained slide; occasional Talc
multinucleated giant cells Drug abuse
CMV, Cytomegalovirus; CVID, common variable immunodeficiency; DILI, drug-induced liver disease; EBV, Epstein-Barr virus; H&E, hematoxylin and eosin; PBC,
primary biliary cholangitis.
Adapted from Lamps L. Hepatic granulomas: a review with emphasis on infectious causes. Arch Pathol Lab Med. 2015;139:867–875.
TABLE 17.12
Common Entities Associated With Liver Necrosis
Pattern of Necrosis Diagnosis
“Bland necrosis,” often zonal DILI or toxins

Ischemia
Spotty necrosis Viral infections

Autoimmune hepatitis
Bridging necrosis Autoimmune hepatitis

DILI or toxins
Confluent necrosis Infection (HSV, others)

DILI or toxins
• Random, geographic necrosis FIGURE 17.37
Ischemia
• Submassive or massive
Autoimmune hepatitis Submassive hepatic necrosis involving zones 2 and 3 mainly in a patient
necrosis
with drug toxicity.
DILI, Drug-induced liver disease; HSV, herpes simplex virus.

METABOLIC DISEASES.
cases. Reticulin stain is particularly useful in such cases
because they demonstrate areas of parenchymal collapse IRON OVERLOAD
that may be distinguished from fibrosis. Although this is
relatively uncommon, it may be life threating, and liver Excessive accumulation of iron in the liver may be
transplant may be indicated. a manifestation of mutations of iron-related genes
TABLE 17.13
Most Common Mutations in Iron-Related Genes Involved in Iron Overload
Iron Accumulation Predominantly in Hepatocytes IRON ACCUMULATION PREDOMINANTLY IN KUPFFER CELLS
Onset
Entity Gene Mutated Subtype Transmission (decade) Entity Gene Mutated Transmission Onset (decade)
Hemo- HAMP Type 2 A Recessive Second A(hypo)trans- Tf Recessive First to second

chromatosis (juvenile) to third ferrinemia
HJV Type 2B
(juvenile)
TFR2 Type 3 A(hypo)ceruo- CP Second to third
plasminemia
HFE Type 1 Third to Ferroportin 1SLC40A1 Dominant Forth to fifth
Ferroportin SLC40A1 Dominant fifth disease (hypo-
disease (type B) (hyper- (type A) functional)
functional)
Adapted from Torbenson M. Biopsy interpretation of the liver. In: Epstein, ed. Wolters Kluwer; 2015:303.
(primary) or secondary to other acquired or genetic (HAMP) genes. Other mutations related to the iron
disorders such as anemia of chronic disease, systemic metabolism are described in Table 17.13.
inflammatory conditions, tumors, and even fatty liver
disease. Although primary iron overload was thought
to be mainly hepatocellular in distribution, rare con-
ditions with primarily Kupffer iron accumulation
have been described in recent years (summarized in
Table 17.13). Clinical manifestations of HH depend on the specific
gene mutation and homozygous versus heterozygous
status. More severe forms usually present early in life
and are related to genes that play a critical role in hep-
HEREDITARY HEMOCHROMATOSIS cidin synthesis, such as HAMP and HJV. In such cases,
there is extensive organ involvement, and cardiac insuf-
ficiency and endocrine gland dysfunction are frequent
Hereditary hemochromatosis (HH) is an inherited symptoms at diagnosis. Other less severe forms, such as
disorder caused by a group of different gene muta- HFE mutations, have a more variable clinical presenta-
tions that result in excess iron storage. HH is the most tion and are often influenced by external factors such
common genetic disorder in whites, with a 1 in 200 as alcohol consumption, blood donation, and menstru-
prevalence rate of homozygous mutations. That said, ation, among others. Patients often present between 40
heterozygous mutations have been reported in up to and 60 years of age. Women present later because of the
15% of the overall population. All currently known protective effects of menstruation. Some patients are
forms of HH are caused by an abnormal production, discovered incidentally through abnormal iron studies,
regulation, or activity of hepcidin. Hepcidin regulates but others present with lethargy, hepatomegaly, arthrop-
iron metabolism, so a deficiency in hepcidin triggers athy, hypogonadism, abdominal pain, and skin pigmen-
increased iron absorption from duodenal enterocytes tation. Heart failure, diabetes mellitus, and cirrhosis are
and release of iron from macrophages because of over- late manifestations.
expression of ferroportin. High levels of iron in plasma
lead to transferrin saturation and increased nontrans-
ferrin bound iron that is rapidly accumulated in differ-
Laboratory Findings
ent tissues (liver, heart, endocrine glands). The most
common HFE mutation is C282Y missense mutation,
which prevents formation of a disulfide bond neces- Patients typically present with increased iron serum
sary for binding of HFE protein to β2-microglobulin. concentration, transferrin saturation, and/or serum fer-
Other less common mutations are H63D and S65C. ritin as well as total iron-binding capacity. In this set-
The juvenile variant of hemochromatosis is caused ting, molecular genetic testing for HFE and non-HFE
by mutations of the hemojuvelin (HJV) and hepcidin mutations is often indicated.
HEREDITARY HEMOCHROMATOSIS—FACT SHEET
Definition
■ Inherited disorders of iron overload leading to chronic organ injury
(including the liver, heart, and endocrine glands) and cirrhosis

■ Most common identified genetic disorder in white populations
■ Rare in patients of non-European descent

■ Deposition of iron in the liver, heart, joints, and endocrine tissues
leads to organ damage and dysfunction (cirrhosis, diabetes

mellitus, congestive heart failure, hypogonadism)
■ Increased risk for hepatocellular carcinoma
Gender, Race, and Age Distribution A

■ Both sexes affected
■ White populations
■ Earlier onset in juvenile hemochromatosis
Clinical Features
■ Common presenting symptoms are arthralgias, skin pigmentation,
diabetes mellitus, and hepatomegaly

■ Endocrine and cardiac manifestations may be presenting
symptoms in younger patients (juvenile hemochromatosis)

■ Phlebotomy is the treatment of choice; chelating agents are less
effective
■ 10-year survival rate of cirrhotic patients is 60%
■ Hepatocellular carcinoma occurs as a late complication in up to
one-third of cases
B
FIGURE 17.38
Pathologic Features A, In hereditary hemochromatosis, iron accumulates in hepatocytes before
spilling over to Kupffer cells. The iron deposition is in a zonal distribution,
with accumulation predominantly in periportal hepatocytes in early stages of
Gross Findings the disease. The iron deposition progresses and involves the entire lobule,
as seen in this case. B, Prussian blue stain for iron is helpful in highlighting
the increased iron storage in HH, which is primarily hepatocellular but also
Early stages of HH show grossly normal or slightly noted in stromal cells and biliary epithelium (arrow).
darkened liver parenchyma. As the disease progresses,
patients may develop hepatomegaly, and the liver may
show a characteristic rust discoloration. In cases compli-
cated by hepatocellular carcinoma, the tumor may lack Iron grading systems are used to provide a semiquan-
iron deposits (iron-free foci) and appear distinct com- titative assessment of the overall hepatic storage of iron.
pared with the darker background cirrhosis. The four—scale system that is most commonly used in
clinical practice is as follows: 1+, zone 1 iron storage
Microscopic Findings only; 2+, zones 1 and 2 involved; 3+, panlobular but not
intense iron deposition; and 4+, panzonal and intense
The defining histologic feature is the presence of finely iron deposits (Fig. 17.38B). In cases of nonhepatocellu-
granular yellow-brown iron deposits within the peripor- lar (reticuloendothelial cells) iron deposition, a three-
tal hepatocytes (Fig. 17.38A). These are easily confirmed tier scale is used: mild, moderate, and severe trace iron
by an iron stain. As iron continues to accumulate, the deposition. The modified Scheuer system also represents
deposits extend to involve the rest of the lobule. In late a popular alternative option for grading iron storage.
stages, there is a milder degree of iron deposition within This is a five-tier system that evaluates hepatocellular
Kupffer cells and bile duct epithelial cells. Lobular or and reticuloendothelial cells' iron storage separately as
portal inflammation is usually absent or inconspicuous. well. Detailed description of the different grades is pro-
Periportal fibrosis evolves to bridging and cirrhosis. vided in Table 17.14.
for the test have been validated for the adult population
TABLE 17.14 and not in the younger age group. MRI has an accept-
able accuracy for assessing liver iron concentration as
Modified Scheuer System for Grading Iron
Storage well as differentiating hepatocellular from Kupffer cell
iron deposition.
Grade Description
0 Iron granules absent or iron granules barely

seen at 400× Differential Diagnosis
1 Iron granules resolved at 250×
2 Iron granules resolved at 100× Besides identifying the specific mutation, HH must be
3 Iron granules resolved at 25× distinguished from secondary pattern of iron overload.
4 Iron granules resolved at 10× or iron granules
Whereas iron accumulation in hepatocytes is more pro-
visible without magnification
nounced in HH, secondary iron overload is character-
ized by a mixed hepatocellular and Kupffer cell iron
deposition. Additional studies (HHI and mutational sta-
tus) are helpful to distinguish these patterns.
Hereditary Hemochromatosis—Pathologic Features
Gross Findings Prognosis and Therapy

■ Hepatomegaly
■ Early cirrhosis is micronodular, evolving to macronodular cirrhosis
■ Rusty discoloration The prognosis is linked to the specific gene involved as

■ The pancreas, spleen, heart, and other organs may be involved it determines severity and onset of disease. The over-
all 10-year survival rate in patients with cirrhosis who
undergo treatment is approximately 70%. Dysplastic
■ Deposition of iron in zone 1 hepatocytes, with subsequent
nodules and hepatocellular carcinoma are late complica-
accumulation in zones 2 and 3 hepatocytes
■ Lesser degree of iron deposition in Kupffer cells and duct
tions. The goal of treatment is to reduce serum ferritin
epithelial cells levels through regular phlebotomy sessions. Iron chela-
tion agents may be indicated in patients in whom phle-
Genetics botomy is contraindicated.
■ Most are autosomal recessive inheritance (except juvenile
hemochromatosis—dominant)
■ Most common HFE hereditary hemochromatosis (HH) are SECONDARY IRON OVERLOAD
related to C282Y (80% of all HFE HH) and H63D mutations
■ Non-HFE HH include juvenile hemochromatosis (HJV and HAMP
gene mutations), transferrin receptor 2 hemochromatosis ■ CLINICAL FEATURES

(TRF2 gene mutations), and type B ferroportin disease (SLC40A1
mutation)
Secondary iron overload is more common than HH
and frequently associated with dietary factors (exces-
■ Secondary iron overload
■ Hemolytic anemias and other hematologic disorders
sive consumption of iron pills), transfusions, chronic
■ Blood transfusions liver disease (hepatitis C, alcoholism, fatty liver),
■ Hemosiderosis in alcoholic liver disease, hepatitis C, hemodialysis, chronic anemia (thalassemia, sideroblastic anemia,
and metabolic syndrome anemias associated with defective heme synthesis,
and sickle cell disease), porphyria, and chronic sys-
temic inflammatory diseases. Clinical features in sec-
ondary iron overload are related to the underlying
Ancillary Studies cause rather than liver parenchymal damage caused by
iron deposition.
Special stains for iron such as Prussian blue stain are
helpful in confirming accumulation of iron in hepato-
cytes and differentiating it from other brown pigments
Pathologic Features
such as bile and lipofuscin. The hepatic iron index (HII)
can be assessed in paraffin-embedded tissue, and a value
greater than 1.9 is consistent with HH. Increased HII Gross Findings
correlates with severity of iron deposition observed
on histochemical iron stains. However, in isolation, Even though macroscopic findings may be similar to
increased HHI is not diagnostic of HH. It also has lim- those seen in HH, secondary iron overload tends to be
ited utility in pediatric patients because reference values less severe; therefore cirrhosis is rare.
majority of affected individuals are compound heterozy-

gotes; no consistent correlation between genotype and
clinical manifestations has been observed.
Wilson’s disease presents with a wide range of clinical

features and histologic findings. A high level of suspi-
cion is warranted in young patients (younger than 40
years) with liver disease of unclear cause, especially if
neurologic or psychiatric symptoms are also present.
Hepatic manifestations dominate in early stage of the
disease and can be seen in up to 40% of patients at
diagnosis. As a result of the liver injury, transaminases
FIGURE 17.39
are elevated, and patients can have signs of cirrhosis.
Secondary iron overload often presents as mild increased iron deposits in
Kupffer cells and hepatocytes in Prussian blue stain.
Some patients present with acute liver failure in the
setting of significant hepatocellular necrosis, usually
Microscopic Findings accompanied by hemolytic anemia caused by abrupt
release of massive amounts of copper from the liver.
In secondary iron overload, the main site of iron accu- Liver disease is followed by neurologic and psychiat-
mulation is the reticuloendothelial cells (Fig. 17.39), with ric symptoms in teens and young adults that include
subsequent involvement of hepatocytes and biliary epi- dysphagia, dysarthria, tremor, involuntary movements,
thelial cells. As in HH, inflammation is not prominent, seizures, dementia, depression, and schizophrenia,
and the biopsy may reveal other features of an underlying among others. The well-known Kayser-Fleischer rings
chronic liver disease. Fibrosis is less common than in HH. are caused by the deposition of copper in the limbus of
the cornea and may be detected on slit-lamp examina-
tion but are not pathognomonic because they can also
Differential Diagnosis be seen in iatrogenic copper overload. Other organs
such as the heart, joints, and endocrine glands can be
Marked iron deposition in Kupffer cells as opposed to affected as well.
hepatocytes favors secondary iron overload rather than
HH. Clinical history, genetic testing for HFE mutations,
and quantitative iron determination are often necessary Laboratory Findings
for a definitive diagnosis.
Low serum ceruloplasmin and elevated 24-hour urinary
copper concentrations can be encountered. Quantitative
Prognosis and Therapy hepatic copper in tissue is elevated (>250 μg/g dry
weight).
The prognosis is determined by that of the underlying
disease. Therapeutic interventions have two goals: treat-
ment of the underlying disease and iron chelation to
WILSON’S DISEASE—FACT SHEET
reduce tissue injury.
Definition
COPPER ACCUMULATION ■ Inherited disorder of copper metabolism caused by decreased
copper excretion
DISORDER. Incidence and Location

■ Prevalence of 1 in 30,000 to 1 in 45,000 individuals
WILSON’S DISEASE Morbidity and Mortality

■ Progressive disorder with variable clinical presentation, leading to
cirrhosis if untreated
Wilson’s disease is an autosomal recessive disorder of
■ Copper deposition in brain, particularly in basal ganglia and
copper metabolism. The underlying defect is caused by cerebral cortex, leads to extrapyramidal motor disorders
mutations in the ATP7B gene located on chromosome ■ Fulminant hepatitis with nonimmune hemolytic anemia and
13. ATP7B encodes a protein responsible for transport- massive release of copper into the bloodstream
ing copper into hepatocyte secretory pathways. The
Gender, Race, and Age Distribution Pathologic Features

■ Occurs equally in males and females
■ All races
■ Most patients present before 40 years of age

Gross Findings
Clinical Features The macroscopic appearance depends on the stage and

■ Liver disease (acute hepatitis, chronic liver disease, cirrhosis) and clinical presentation. In early stages, the liver may be nor-
neurologic or psychiatric manifestations are the most frequent mal or mildly enlarged with steatosis. In cases of acute
presenting features liver failure, extensive parenchymal necrosis can be seen
■ Kayser-Fleischer rings can be seen in patients with neurologic
disease but are not pathognomonic with occasional islands of residual viable parenchyma. In
■ Low serum ceruloplasmin; increased serum copper and 24-hour late stages, there may be macronodular cirrhosis.
urinary copper
■ Increased quantitative hepatic copper in tissue (>250 μg/g)
Wilson’s disease can present with any of the com-
■ Copper chelating agents such as D-penicillamine prevent disease
mon patterns of liver injury such as a steatohepatitic,
progression
■ Liver transplantation for patients with end-stage liver disease or
cholestatic, or even chronic hepatitis pattern (Figs.
fulminant hepatic failure 17.40A and B). In a series of 110 patients, cirrhosis was
the most common form of liver disease (38%), followed
by acute liver failure (27%) and acute hepatitis (19%).
Early Wilson’s disease may reveal minimal nonspe-
cific changes, including glycogenated nuclei, minimal
A B
c
FIGURE 17.40
A, Wilson’s disease often shows a nonspecific chronic hepatitis pattern of injury, with portal chronic inflammation and focal interface hepatitis. B, Steatohepatitis
can be seen as part of the spectrum of Wilson’s disease with extensive ballooning degeneration and Mallory hyaline formation. C, Rhodanine (copper) stain
highlights increased copper binding protein in Wilson’s disease with cytoplasmic accumulation of copper.
mononuclear inflammation, and steatosis. Some patients Less common diseases of increased copper storage
may exhibit ballooned hepatocytes and Mallory hyaline (other than Wilson’s disease) include idiopathic cop-
along with previously described features; this pattern per toxicosis, Indian childhood cirrhosis, and endemic
can be mistaken for NASH. A chronic hepatitis pat- Tyrolean infantile cirrhosis. These can be distinguished
tern of injury is relatively common, and in some cases, from Wilson’s disease by clinical presentation in child-
a mixed hepatitis and cholestatic pattern can be seen. hood and greater level of copper accumulation than
Occasionally, patients may present with acute liver fail- Wilson’s disease.
ure, in which case the liver shows submassive or mas-
sive hepatic necrosis. With disease progression, fibrosis
begins in the periportal region and eventually evolves to Prognosis and Therapy
cirrhosis. Copper cannot be usually identified on H&E
stain but may be visualized with special stains such as Copper-chelating agents (e.g., D-penicillamine) in com-
rhodanine or orcein as granular cytoplasmic staining in bination with dietary restriction of copper is the treat-
periportal or periseptal hepatocytes and within the lob- ment of choice in preventing progression of disease.
ules (Fig. 17.40C). Liver transplantation is needed in cases of acute liver
failure or cirrhosis.
Rarely, hepatocellular carcinoma and cholangiocar-
cinoma have been reported in patients with chronic
Wilson’s Disease—Pathologic Features
Wilson’s disease.
Gross Findings
■ Early: normal or mildly enlarged, steatotic
α1-Antitrypsin Deficiency
■ Massive hepatic necrosis in acute liver failure
■ Late: macronodular cirrhosis
α1-Antitrypsin, a plasma serine protease inhibitor, plays

Microscopic Findings a key role in controlling tissue degradation by forming
■ Early: nonspecific, fatty liver disease, chronic hepatitis pattern of complexes with proteases, such as elastase, trypsin, chy-
injury, cholestatic liver disease motrypsin, and thrombin. This function is particularly
■ Hepatocellular necrosis, fibrosis leading to cirrhosis
■ Periportal or periseptal hepatocyte often show copper

critical in the lungs, where α1AT inhibits leukocyte
accumulation (rhodanine stain) elastase and prevents degradation of alveolar walls by
this enzyme. More than 100 genetic variants of α1AT
Genetics have been identified; most are associated with normal
■ Autosomal recessive disorder levels and function of the protein. The deficiency state
■ Multiple known mutations in ATP7B gene on chromosome 13 is most commonly caused by homozygosity for the PI*Z
allele, in which alanine is substituted for leucine at
amino acid 213, causing self-aggregation of the protein.
■ Acute or chronic viral hepatitis
■ Autoimmune hepatitis
This abnormal form of the protein is trapped within the
■ Nonalcoholic fatty liver disease
endoplasmic reticulum of hepatocytes and appears as
■ Cryptogenic cirrhosis intracytoplasmic eosinophilic globules.
■ Idiopathic copper toxicosis
■ Endemic Tyrolean infantile cirrhosis ■ CLINICAL FEATURES

■ Indian childhood cirrhosis
The most common clinical disorder associated with α1AT

deficiency is pulmonary emphysema. Approximately 10%
of patients with α1AT deficiency present with liver dis-
ease in infancy, manifested as neonatal cholestasis, and
up to 25% of affected individuals develop cirrhosis in
The histologic differential diagnosis of Wilson’s disease childhood. Some of the genetic variants may be mildly
includes a broad differential diagnosis because Wilson’s symptomatic, and others may not reveal clinical manifes-
disease can mimic any pattern of injury in the liver. tations until adulthood when patients present with signs
Because most cases are diagnosed in young patients, of cirrhosis.
other entities such as drug toxicity, viral hepatitis, and
AIH need to be excluded clinically. Laboratory findings
and viral serologies are helpful but may not be available Laboratory Findings
in cases with acute liver failure. Quantitative copper
analysis of dry hepatic tissue is useful in supporting a The diagnosis can be determined based on serum levels
presumptive diagnosis of Wilson’s disease. of α1AT, which are low (<100 mg/dL) in these patients.
This is followed by genotyping by PCR testing or gene

sequencing to assess the specific variant of the disease.
In addition, normal or mildly elevated transaminases
are often seen.
α1-ANTITRYPSIN DEFICIENCY—FACT SHEET
Definition
■ Autosomal recessive disorder leading to accumulation of
α1-antitrypsin (α1AT) in hepatocytes, with decreased

serum α1AT
A
■ Homozygous state occurs in 1 in 6700 to 1 in 2000 births in
North America
■ Geographic variation, with highest incidence in Northern Europe,
particularly Scandinavia

■ Increased risk for emphysema, hepatocellular carcinoma, and
glomerulonephritis
■ Increased risk for cirrhosis (roughly 20% older than age 50 years)

■ Both genders
■ All ages
■ More common among people of Northern European ancestry B

■ Persistent jaundice in neonates
A, Rounded eosinophilic cytoplasmic inclusions in periportal hepatocytes
represent accumulation of α1AT in endoplasmic reticulum in α1AT defi-
■ Hepatosplenomegaly or ascites in late childhood
ciency. B, The inclusions are PAS-positive, diastase resistant.
■ Cryptogenic cirrhosis in adults
■ Low serum α1AT levels
■ Abnormal protein identified by serum electrophoresis,
polymerase chain reaction assay, or gene sequencing

be uneven throughout the parenchyma. With increas-
Prognosis and Therapy ing age, there is an increase in the number as well as
■ Avoid or stop smoking and liver toxins such as alcohol
the size of inclusions. Importantly, the inclusions are
■ Supportive therapy
■ Liver transplantation for end-stage cirrhosis

not evident in infants younger than 12 weeks of age;
in this setting, the PAS stain is less helpful. When the
clinical presentation is that of cholestatic disease (often
in infants), other histologic findings include canalicu-
lar cholestasis, giant cell transformation of hepatocytes,
Pathologic Features
ductopenia, and ballooning of hepatocytes. There may
be granular accumulation of α1AT within the hepato-
Gross Findings cytes, which is only highlighted by IHC. In adults, the
α1AT globules are present often in a background of
There are no specific gross manifestations of this dis- chronic hepatitis pattern of injury (with or without
ease in the early phase. Cirrhosis caused by α1AT defi- cirrhosis).
ciency is typically macronodular in appearance.
Ancillary Studies
α1-Antitrypsin cytoplasmic inclusions are strongly posi-
The diagnostic histologic feature of α1AT deficiency tive on PAS and resistant to diastase digestion. Negative
is the presence of globular eosinophilic PAS-positive, dia- stains should not exclude the diagnosis in infants
stase-resistant cytoplasmic inclusions within periportal younger than 12 weeks of age. Both granular and globu-
hepatocytes (Figs. 17.41A and B). The distribution can lar forms can be highlighted by IHC.
and there is no rationale for replacement therapy with

α1-Antitrypsin Deficiency—Pathologic Features α1AT because the liver injury is caused by an inherent
defect in metabolism and accumulation of the protein
Gross Findings within hepatocytes.
■ Hepatomegaly with bile staining in young children
■ Cirrhosis in late stages
Microscopic Findings GLYCOGEN STORAGE DISEASES

■ Periodic acid–Schiff–positive, diastase-resistant eosinophilic
cytoplasmic globules in hepatocytes in patients older than 12

weeks (not present in young infants or neonates) Glycogen storage diseases are inherited disorders of
■ Globules are more prominent in periportal hepatocytes and glycogen metabolism that result in accumulation of
represent accumulation of α1-antitrypsin (α1AT) in endoplasmic excess or structurally abnormal glycogen in the liver
reticulum
■ In neonates, bile ducts may be decreased in number and other organs such as the heart, kidney, and skeletal
■ Chronic hepatitis pattern of injury with cirrhosis in adults muscle because of specific enzymatic defects in gly-
cogen metabolism pathways. Almost all GSDs are
Ultrastructural Findings autosomal recessive in nature, with the exception of
■ Amorphous proteinaceous material in endoplasmic reticulum GSD IX, which shows an X-linked mode of inheritance
(Table 17.15).
Genetics
■ Autosomal recessive disorder
■ Gene is located on chromosome 14q

■ α1AT is a single-chain protease inhibitor in the Serpin family
■ M form is the normal form; Z form is the abnormal form of the
protein resulting from a single base substitution Even though each entity has specific findings, there
is a significant overlap in clinical presentation. Many
Immunohistochemistry patients present in early infancy and childhood with
■ α1AT accumulation is more pronounced in periportal
hepatomegaly, hypoglycemia, and failure to thrive. Some
hepatocytes
GSD present in adulthood with muscle weakness and
■ Granular accumulation in neonates, without globule formation
hepatomegaly. Some patients are at risk for developing
Differential Diagnosis hepatic adenomas and hepatocellular carcinomas, docu-
■ Neonatal hepatitis mented in the literature mostly among those with GSD
■ Biliary atresia type Ia but also in types Ib, III, and VI.
■ Paucity of intrahepatic bile ducts
■ Chronic viral hepatitis
■ Cryptogenic cirrhosis
■ Nonspecific hyaline globules
■ Congestion associated globules

GLYCOGEN STORAGE DISEASE—FACT SHEET
Definition
Differential Diagnosis ■ Inherited disorders of glycogen metabolism leading to abnormal
accumulation of glycogen in the liver
In children, the main differential diagnosis is with other Incidence and Location
causes of neonatal cholestasis, and protein electropho- ■ Type I: 1 in 100,000
retic testing is needed for a definitive diagnosis. ■ Type II: fewer than 1 in 100,000 live births
In general, identification of characteristic cytoplas- ■ Other types: very rare
mic inclusions is highly suggestive of α1AT deficiency.

Occasionally, nonspecific cytoplasmic inclusions can be
■ Failure to thrive
noted in end-stage liver diseases that mimic α1AT glob-
■ Patients with type I survive into adulthood but may have focal
ules. However, these globules are usually much smaller segmental glomerulosclerosis and hepatic adenomas
in size. ■ Type II is variable in severity
■ Patients with type IV often die in the early perinatal period
■ Type VI is relatively benign; adults are asymptomatic

■ Males and females are equally affected, except for some
Older men are at a greater risk for cirrhosis and rarely subtypes of type IX, which are X linked
hepatocellular carcinomas. ■ Age at presentation is variable and depends on type, although
Interventions include smoking cessation and avoid- most cases present in infancy
ance of drugs or toxins in the liver. Therapy is supportive,
TABLE 17.15
Glycogen Storage Diseases With Hepatic Manifestations
Glycogen Storage
Disease Clinical Presentation Enzyme Deficiency Histopathologic Findings
Type 0 Hepatomegaly, hypoglycemia Glycogen synthetase Steatosis

Type Ia (von Growth retardation, hepatomegaly, lactic Glucose-6- Glycogenosis and macrovesicular
Gierke’s disease) acidemia, hyperlipidemia phosphatase steatosis; glycogenated nuclei,
possibly fibrosis; hepatic adenomas
Type Ib As for Ia; neutropenia and impaired Glucose-6-phosphatse As for Ia
PMN function, some with IBD
Type II (Pompe’s Variable; cardiomegaly, hypotonia Lysosomal acid Glycogenosis, intralysosomal glycogen
disease) (floppy baby syndrome), α-glucosidase accumulation (PAS-positive
hepatomegaly; adult presentation with cytoplasmic vacuoles); lacks fibrosis
only muscle weakness with breathing
complications
Type III (Cori’s Similar to type I but less severe Amylo-1, 6-glucosidase Glycogenosis, glycogenated nuclei;
disease) Type IIIa: liver and muscle involvement fibrosis with progression to cirrhosis,
Type IIIb: only liver involvement hepatic adenomas
Type IV Hepatosplenomegaly and failure to Amylo-1,4-1,6 Ground glass inclusions (PAS positive,
(Andersen’s thrive; hypoglycemia is uncommon transglucosidase partially diastase resistant)
disease) Two forms: nonprogressive and classic
hepatic form with cirrhosis before
age 5 years
Type VI (Hers’ Hepatomegaly, failure to thrive; variable Liver phosphorylase E Predominantly glycogenosis with
disease) hypoglycemia and hyperlipidemia, variable steatosis, fibrosis, hepatic
usually mild adenomas
Type IX As for type VI Liver phosphorylase Marked glycogenosis (PAS positive,
kinase diastase sensitive), fibrosis leading
to cirrhosis
Type XI (Fanconi Failure to thrive, hypoglycemia, moon GLUT2 transporter Glycogenosis and macrovesicular
Bickel syndrome) face, fat deposition in shoulders and steatosis
abdomen
IBD, Inflammatory bowel disease; PAS, periodic acid–Schiff; PMN, polymorphonuclear leukocytes.
genetic analysis by next-generation sequencing are

Clinical Features needed for further classification.
■ Definitive diagnosis requires biochemical determination of
enzyme defect
■ Patients present with variable hepatomegaly, hypoglycemia, and
Pathologic Features
failure to thrive

■ Treatment is dietary supplementation with glucose drip feedings
and uncooked cornstarch in type I, high-protein diets in types II The liver in most GSD types is enlarged and pale.
and III, and uncooked cornstarch in type VI Some forms of GSDs reveal advanced fibrosis or cirrho-
■ Prognosis depends on type: good for type VI, poor for type IV,
and intermediate for other types

sis. Distinct lesions can be seen in patients who develop
hepatocellular adenomas or carcinomas.
Laboratory Findings
Most patients demonstrate diffuse glycogen accumula-
Patients can present with hypoglycemia with hyper- tion in enlarged hepatocytes, which results in a pale appear-
lactatemia. Increased serum creatine kinase levels are ance on H&E stain with distinct cell membranes (described
described. Other laboratory abnormalities include as mosaic appearance) (Fig. 17.42A). PAS further supports
hyperuricemia, hyperlipidemia, hypercalciuria, and azo- the presence of cytoplasmic glycogen (Fig. 17.42B). In some
temia. Elevated biotinidase activity has been suggested forms, glycogenated nuclei and macrovesicular steatosis
as a useful biomarker for hepatic GSDs. In addition, may be prominent (see Fig. 17.42C). Ground-glass cyto-
determination of liver enzyme activities and molecular plasmic inclusions are classically described in GSD type IV.
FIGURE 17.42
A, Cytoplasmic accumulation of glycogen in hepatocytes leads to a clear appearance with distinct cell membranes on hematoxylin and eosin stain (mosaic
pattern). B, PAS stain highlights the glycogen accumulation (shown), with removal of glycogen with diastase digestion. C, Type II GSD does not show a mosaic
pattern; hepatocytes contain lipid vacuoles. D, Histologic findings of GSD type IX.
Fibrosis tends to develop in certain cases (typically in GSD

Mosaic pattern caused by compression of sinusoids and
types III, IV, VI, and IX) (see Fig. 17.42D) and can lead to ■
accentuation of hepatocyte cell membranes (type II lacks mosaic

cirrhosis. Although histologic findings may raise suspicion pattern)
for GSD, a definitive diagnosis often requires further met- ■ In type IV, hepatocytes contain rounded ground glass cytoplasmic
abolic work-up. The general approach when suspecting a inclusions
GSD should be to snap freeze a portion of the tissue, submit ■ Fibrosis leading to cirrhosis may be found in types
III, IV, VI, and IX
a sample in glutaraldehyde for electron microscopy, and
process the rest of the sample for routine stains. Ultrastructural Findings
■ Large pools of glycogen displace cytoplasmic organelles
■ In type I, double-contoured vesicles are seen in the endoplasmic
Glycogen Storage Disease—Pathologic Features reticulum

■ In type II, glycogen accumulates in lysosomes
■ In type IV, non–membrane-bound inclusions are seen

Gross Findings
■ Hepatomegaly
■ Pale discoloration
Genetics
■ Variable fibrosis, cirrhosis in certain cases ■ Autosomal recessive inheritance, except for some subtypes of
■ Liver masses: hepatocellular adenomas or carcinomas type IX, which are X linked

■ Hepatocytes are enlarged by glycogen accumulation, with pale ■ Glycogenic hepatopathy
cytoplasm ■ Type IV: Lafora’s disease

Ancillary Studies For most GSDs, no specific treatment is available.

Dietary manipulation can prevent hypoglycemia and
promote growth. Liver transplantation is considered in
Ultrastructural Findings patients with cirrhosis.
Lysosomal Storage Disorders. Lysosomal storage
By electron microscopy, monoparticulate glyco- disorders most commonly involve glycolipid, phospho-
gen fills the cytoplasm displacing normal organelles. lipid, or mucopolysaccharide metabolism and result in
Intranuclear glycogen may also be identified in some accumulation of storage products within cytoplasmic
types of GSD. In type IV GSD, fibrillar aggregates char- membrane-bound vesicles. The excessive undegraded
acteristic of amylopectin are present. substrate usually accumulates in reticuloendothelial
cells in the liver, nervous system, and muscle. There are
more than 50 LSDs described. Most are inherited in an
Differential Diagnosis autosomal recessive manner (Table 17.16).
One of the main differential diagnoses is glycogenic

hepatopathy (GH); however, a history of diabetes mel- ■ CLINICAL FEATURES
litus and overall clinical presentation of GH (hepato-
megaly, abdominal pain, and elevated transaminases
in a patient with poorly controlled diabetes) is helpful. The clinical presentation depends on the disorder.
GSDs may show considerable morphologic overlap with In severe cases, the substrate accumulation starts in
each other, and definitive diagnosis relies on biochem- utero and often results in hydrops fetalis. Most patients
ical testing of fresh, frozen, or other target liver tissue. exhibit multiorgan involvement with organomegaly (an
enlarged liver and spleen are most common) and neuro-
logic symptoms, including visual abnormalities, seizures,
Prognosis and Therapy and neurodegenerative signs. In addition, hematologic
and psychiatric manifestations can be encountered. The
The prognosis depends on the specific type because some diagnosis is confirmed through specific enzyme assays,
present in early infancy and carry a high mortality rate, but lysosomal enzyme activity in tissue cultures, and muta-
others present in adulthood and are mildly symptomatic. tional analysis.
TABLE 17.16
Clinical Features of Selected Lysosomal Storage Diseases
Disorder Inheritance Clinical Features Clinical Outcome
Mucopolysaccharidoses Autosomal recessive Multisystem involvement; organomegaly; Chronic progressive course;

(MPS) (seven distinct (six types); X-linked abnormal facies; mental retardation in survival depends on specific
types, most common: for MPS II some types disease type and severity and
Hunter, Hurler, and ranges from early childhood
Morquio diseases) to old age
Gaucher disease types 1, Autosomal recessive Hepatosplenomegaly, all types; CNS Type 1: 6–80 years
2, and 3 degeneration, types 2 and 3 Type 2: <2 years
Type 3: second to fourth
decades of life
Niemann-Pick disease Autosomal recessive Type A: failure to thrive; hepatospleno- Type A: fatal by age 3 years
types A, B, and C megaly; neurologic degeneration Types B and C: survival into
Type B: variable presentation, no adulthood
neurologic involvement
Type C: progressive neurologic degenera-
tion, hepatosplenomegaly
Acid lipase deficiency Autosomal recessive Hepatosplenomegaly; steatorrhea, adrenal Wolman’s disease is fatal by
(Wolman’s disease) calcification 1 year
Metachromatic Autosomal recessive Gait disturbances, mental regression, Variable; may be slowly
leukodystrophy dementia, seizures progressive over decades
Mucolipidoses (I cell Autosomal recessive Severe psychomotor retardation; Death in first decade for
disease and pseudo- abnormal facies, hepatomegaly in I-cell disease; survival into
Hurler polydystrophy) I-cell disease; joint abnormalities and adulthood for pseudo-Hurler
growth retardation in pseudo-Hurler polydystrophy
polydystrophy
CNS, Central nervous system.
LYSOSOMAL STORAGE DISORDERS—FACT SHEET TABLE 17.17

Histopathologic Features in Select Lysosomal
Definition
Storage Disorders
■ Inherited disorder of degradation of substances normally broken
down in lysosomes such as sphingolipidoses (e.g., Gaucher Disorder Microscopic Features

disease, Niemann-Pick disease), mucopolysaccharidoses
(e.g., Hurler’s disease, Hunter’s disease), mucolipidoses, Mucopolysaccharidoses Vacuolization of Kupffer
oligosaccharidosis, and acid lipase deficiency (Wolman’s disease, (liver involvement in types cells and hepatocytes, well
cholesterol ester storage disease) I, II, III, VI, and VII) demonstrated on colloidal
iron stain; liver fibrosis and
Incidence and Location cirrhosis may develop
■ Rare disorders but collectively represent 1 in 7000 to 1 in 10,000
Gaucher disease Accumulation of storage
births material in Kupffer cells;
■ Gaucher disease is most common
striated or wrinkled
cytoplasm (PAS negative);
progressive fibrosis in some
cases but rarely cirrhosis;
■ Depends on biochemical defect
hepatocytes not affected
Niemann-Pick disease Progressive increase in lipid-
Gender, Race, and Age Distribution laden foamy histiocytes
■ For most of these disorders, males and females are affected in hepatic sinusoids;
equally hepatocyte vacuolization;
■ Certain ethnic groups may be at a greater risk (e.g., Ashkenazi cirrhosis in some cases;
Jews: Gaucher disease; Irish descent: Tay-Sachs) cholestasis with giant cell
■ Most are diagnosed in infancy or childhood, but some may transformation in type C; oil
present in late adulthood (type I Gaucher disease) red O and Luxol fast blue
positive, but PAS is negative
Clinical Features Acid liposomal lipase Microvesicular steatosis;
■ Variable; hepatomegaly and neurologic symptoms are common deficiency (Wolman’s vacuolated and enlarged,
disease) pale-staining Kupffer cells
Prognosis and Therapy and hepatocytes; needle-
shaped birefringent crystals
■ Bone marrow transplantation has been performed for some of
in hepatocytes; fibrosis and
the lysosomal storage disorders
cirrhosis; oil red O stain
■ Liver transplantation is rarely indicated and is not curative
positive
■ Prognosis depends on the disease
Metachromatic Light brown granules in
leukodystrophy Kupffer cells, portal
macrophages, and biliary
epithelium; metachromatic
Laboratory Findings with cresyl violet staining of
frozen sections
Mucolipidoses Vacuolated hepatocytes,
Abnormal liver function ranges from a clinical picture Kupffer cells, and portal
of neonatal hepatitis with marked elevation of transam- fibroblasts
inases to established cirrhosis. Elevated excretion of oli-
PAS, Periodic acid–Schiff.
gosaccharides and glycosaminoglycans can be assessed
in urine. Enzymatic activity and DNA mutation analysis
in blood are useful in classifying the underlying disease. and Fig. 17.43). On a histologic basis, specific findings may
be a clue to the diagnosis. For example, enlarged Kupffer
cells with a “crinkled paper” appearance of the cytoplasm
Pathologic Features are present in Gaucher disease. Certain cases evolve to
fibrosis and cirrhosis, although the true incidence depends
Gross Findings on the underlying disease and medical interventions.
Similar to GSDs, hepatomegaly is common, but in

patients with LSD, the cut surface has a yellow to orange Ancillary Studies
discoloration. In advanced cases, there may be obvious
scarring or cirrhosis. Trichrome and PAS-D stains can highlight the striations
in the cytoplasm of Gaucher cells. In Niemann-Pick
Microscopic Findings disease, the cells storing sphingomyelin reveal a foamy
pale cytoplasm that can be easily identified on PAS stain
The characteristic finding in most LSDs is accumula- because of the dark staining of hepatocytes. Colloidal
tion of foamy material (“the substrate”) within reticulo- iron stain demonstrates mucosubstances in Kupffer cells
endothelial cells and sometimes hepatocytes (Table 17.17 and hepatocytes in mucopolysaccharidosis.
FIGURE 17.43
Lysosomal storage diseases. A, In Gaucher’s disease, Kupffer cells are markedly distended and accumulate in hepatic sinusoids; hepatocytes do not accumu-
late glucosylceramide and are thus uninvolved, although they may show atrophic changes. B, The Gaucher cells are characterized by striated or wrinkled cyto-
plasm. C, In Niemann-Pick disease, both Kupffer cells (top) and hepatocytes develop cytoplasmic vacuoles. Fibrosis is typically not prominent. D, In Wolman’s
disease, both hepatocytes and Kupffer cells are swollen and pale staining. Lipid droplets may be seen in hepatocytes. Needle-shaped birefringent crystals of
cholesterol may be inconspicuous (arrow).
Lysosomal Storage Disorders—Pathologic Features
Electron microscopy shows lysosomal inclusions,
Gross Findings usually granular or fibrillar. In Niemann-Pick disease,
■ Hepatomegaly with yellow-orange discoloration the inclusions resemble myelin. Lipid droplets and cho-
lesterol clefts are seen in Wolman’s disease and choles-
terol ester storage disease.
■ Reticuloendothelial cells are enlarged and may appear
vacuolated, foamy, or exhibit striated cytoplasm

■ Steatosis is present in cholesteryl ester storage disease
■ Lysosomal or lamellar inclusions Although some of the LSDs have characteristic liver
■ Membrane-bound vacuoles containing granular or fibrillar material findings, definitive diagnosis is based on demonstration
in some disorders of decreased enzyme activity in appropriate tissues or
with diagnostic molecular assays.
Genetics
■ Most are autosomal recessive
■ Some exhibit an X-linked pattern of inheritance

■ The specific diagnosis is established by biochemical or genetic Most cases are diagnosed in infancy. The reported sur-
testing vival is 5 to 10 years after diagnosis (see Table 17.16).
Whereas some LSDs are fatal in early childhood,
milder forms are compatible with a normal lifespan.

There is no cure for LSDs, and the treatment is symp-
tomatic. Enzyme replacement therapy can be bene-
ficial, if available. HSCT is performed as therapy for
some of the LSDs, including mucopolysaccharidosis
types I and VI and attenuated forms of metachromatic
leukodystrophy.
GLYCOGENIC HEPATOPATHY
Glycogenic hepatopathy is typically seen in adult and

pediatric patients with type I diabetes mellitus who
have poorly controlled blood glucose levels. Patients
with GH classically have a history of poorly controlled
blood glucose and present with hepatomegaly, abdom-
inal pain, and markedly elevated transaminases after
an episode of marked or prolonged hyperglycemia that
required intense insulin therapy. Mauriac’s syndrome,
originally described in children with type 1 diabetes,
consists of hepatic glycogenosis with associated growth
retardation, dwarfism, delayed puberty, and cushingoid
features.
Pathologic Features
The most striking feature is the prominent hepato-

cyte swelling with cytoplasmic rarefaction and accentu-
ation of cell membranes. Diffuse glycogenated nuclei are
common, as are giant megamitochondria. The overall
liver architecture remains intact, and there are absent to
minimal steatosis, inflammation, acidophil bodies, and
fibrosis. PAS stain is not needed for the diagnosis, but if
performed, it highlights the abundant cytoplasmic glyco-
gen (Fig. 17.44).
FIGURE 17.44
Glycogenic hepatopathy. A, Prominent cytoplasmic clearing is present
throughout this biopsy sample from a 14-year-old patient with poorly con-
The differential diagnosis of GH includes GSDs, as trolled type 1 diabetes and elevated transaminases. B, Hepatocytes show
well as other genetic disorders. The clinical setting in uniform cytoplasmic distention and glycogenated nuclei. C, PAS stain
which these occur is helpful in making this distinction. demonstrating abundant intracytoplasmic glycogen.
Cases with diffuse microvesicular steatosis can mimic
GH. Microvesicular steatosis occurs in a very limited
number of clinical situations (e.g., acute fatty liver of GH. Patchy or diffuse glycogenosis in the setting of
pregnancy, Reye syndrome) and the hepatocytes reveal NAFLD is common. That said, those patients have a
a pale, foamy appearance that differs from the rarefied different clinical presentation, and the biopsy often
cytoplasm with distinct nuclear membranes seen in shows steatosis or features of NASH.
Prognosis and Therapy Gender, Race, and Age Distribution

■ AIP: more common in women; peak in third decade
■ PCT: sporadic PCT (80%) occurs in male patients in fourth

Clinical findings and histologic features gradually decade of life; familial PCT is equally common in males and
resolve with adequate blood glucose control. females
■ EPP: males affected twice as often as females; peak in third
decade
PORPHYRIAS
Clinical Features
■ AIP: abdominal pain, sympathetic and neurologic symptoms
■ PCT presents with blisters on sun-exposed skin

■ EPP: acute photosensitivity on sun-exposed skin
The porphyrias are a group of eight inherited metabolic Prognosis and Therapy
disorders associated with abnormalities in the heme bio- ■ Treatment in general is supportive and symptomatic
synthetic pathway. Acute intermittent porphyria (AIP), ■ Patients with AIP are treated with intravenous lyophilized alkaline
heme; good prognosis

porphyria cutanea tarda (PCT), and erythropoietic pro-
■ PCT: approximately 65% develop cirrhosis; increased risk for
toporphyria (EPP) are inherited in an autosomal domi- hepatocellular carcinoma
nant fashion and can be associated with significant liver ■ Treatment for PCT is avoidance of sun exposure and alcohol;
disease. Based on the clinical presentation, porphyrias phlebotomy to decrease iron stores if increased; chloroquine is
are divided into acute and cutaneous forms. The acute effective in some cases
■ EPP: hematin is effective treatment; liver transplantation for
attacks often follow a prodrome and are timated because
patients with cirrhosis
many case triggered by several events such as hormonal
changes, drugs, smoking, or fasting, among others. AIP
usually presents after puberty with episodes of severe
abdominal pain, sympathetic symptoms, and motor
Pathologic Features
neuropathy. Life-threatening neurologic and adrener-
gic symptoms can develop. Patients with PCT present
with erosive photodermatosis and chronic blisters in Gross Findings
sun-exposed skin. Most cases coexist with hemochro-
matosis, alcoholic liver disease, hepatitis C or HIV infec- Gross findings are nonspecific, except in end-stage
tion, ethanol use, and estrogen administration. The liver disease when micro- or macronodular cirrhosis can
most common clinical manifestation of EPP is lifelong be evident. The liver may show a dark brown to black
acute photosensitivity in sun-exposed skin that starts in discoloration in some cases.
childhood and includes burning, stinging, and pruritus.
Cholelithiasis is common, and a minor subset of patients Microscopic Findings
develop cholestatic liver failure.
Microscopic changes in the liver in AIP are non-
specific and include cholestatic changes, steatosis, and
PORPHYRIAS—FACT SHEET accumulation of iron in Kupffer cells and hepatocytes.
In PCT, distinctive cytoplasmic uroporphyrins may
Definition be identified. These inclusions are autofluorescent nee-
■ Disorders of biosynthesis of porphyrins and heme dle-shaped structures in the cytoplasm of hepatocytes
■ Acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), and can be seen on light microscopy or fluorescent
and erythropoietic protoporphyria (EPP) often affect the liver microscope. They can be difficult to identify in routinely
processed sections and are best appreciated in unstained
Prevalence and Location
sections. Nonspecific histologic findings in PCT include
■ AIP prevalence is 1 to 2 in 100,000; it is more common in
European countries
variable hemosiderosis, mild chronic portal inflamma-
■ PCT is most common porphyria in the United States
tion, steatosis, and fibrosis (Figs. 17.45A and B).
■ EPP prevalence is 1 in 75,000 to 1 in 200,000 worldwide Erythropoietic protoporphyria is characterized by
the presence of dense dark brown pigment in Kupffer
Morbidity and Mortality cells, canaliculi, and bile ducts. This pigment is bire-
■ Most patients with AIP recover fully; it can be life threatening fringent and shows characteristic central, dark Maltese
during acute attacks
cross configuration under polarized light (Fig. 17.45C).
■ PCT is associated with collagen vascular diseases, acquired
immunodeficiency syndrome (AIDS), and hepatitis C, among Cholestasis is common.

others Cirrhosis occurs in a small subset of cases and may
■ Patients with EPP can develop cirrhosis be complicated by the development of hepatocellular
carcinoma.
Porphyrias—Pathologic Features
Gross Findings
■ Explanted livers show cirrhosis or marked green discoloration if
cholestatic liver failure

■ Black discoloration in particular in erythropoietic protoporphyria
(EPP)
■ Acute intermittent porphyria (AIP): nonspecific steatosis;
increased iron deposition in Kupffer cells and hepatocytes

■ Porphyria cutanea tarda (PCT): needle-shaped cytoplasmic
inclusions of uroporphyrin are birefringent, best seen in unstained

paraffin sections
■ Other findings in PCT are hepatic steatosis, iron deposition, and
fibrosis
■ EPP: cholestasis, dark autofluorescent-dense pigment in canaliculi,
bile ducts, and Kupffer cells that display central Maltese cross
upon polarization
■ Cirrhosis and hepatocellular carcinoma in a small subset
■ PCT: crystalline inclusions
■ EPP: protoporphyrin crystals have a “starburst” pattern
■ AIP: drug reaction, chronic viral hepatitis
■ PCT: chronic viral hepatitis, iron overload
■ EPP: cholestatic disorders, including extrahepatic biliary
obstruction
Ancillary Studies
Deposits of uroporphyrin in PCT and protoporphyrin
in EPP exhibit red autofluorescence in sections exam-
ined under ultraviolet light.
Microscopic findings of porphyrias are largely nonspe- FIGURE 17.45

cific. However, with an appropriate clinical history, A, The liver in porphyria cutanea tarda (PCT) may exhibit nonspe-
the finding of characteristic inclusions in PCT and in cific changes such as portal chronic inflammation and mild interface
hepatitis. B, Iron accumulation in periportal hepatocytes is a common fea-
EPP may be helpful. A definitive diagnosis requires cor- ture. C, In cases of EPP, a dark autofluorescent dense pigment within cana-
relation with porphyrin precursors in urine, feces, and liculi, bile ducts and/or Kupffer cells will display a central Maltese cross upon
plasma fluorescence emission spectroscopy in plasma. polarization.
DNA mutational analysis remains the gold standard for
diagnosing this group of disorders.
to treat acute crises in patients with AIP. Patients with
PCT may be treated with phlebotomy to reduce hepatic
Prognosis and Therapy iron stores and chloroquine. Patients with EPP are
treated with β-carotene and avoidance of sun exposure.
The treatment is mainly supportive and symptomatic. Liver transplant may be needed in some cases, but
Infusion of intravenous lyophilized alkaline heme is used EPP can recur in the allograft.
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18
Liver Neoplasms
■ Safia N.Salaria, MD, AmitabhSrivastava, MD, and Daniela S.Allende, MD, MBA
Primary hepatocellular neoplasms are much less common an overall prevalence of 0.9%. The majority (80%) of
than metastatic tumors to the liver. The former may arise cases are solitary, but patients with multiple FNHs who
from either the epithelial or mesenchymal component of also have one or more concurrent hepatic hemangioma,
the hepatic parenchyma and rarely may also show both berry aneurysms, and brain tumors (astrocytoma and
lines of differentiation. Hepatocellular neoplasms may be meningioma) have also been described and are consid-
benign or malignant (Table 18.1). The differential diag- ered to have the multiple FNH syndrome.
nosis of a well-differentiated hepatocellular proliferation
is typically between focal nodular hyperplasia (FNH),
hepatic adenoma (HA), and a well-differentiated hepato-
cellular carcinoma (HCC). These can usually be distin-
guished based on morphologic features and a small panel
of ancillary stains. HAs are now known to be composed Focal nodular hyperplasia is found mainly in women of
of distinct subsets of tumors with well-characterized reproductive age (80%–95%), but these tumors are not
genetic alterations that must be subclassified accurately hormone dependent and unaffected by oral contraceptive
because of varying risks of malignant transformation in use and pregnancy. Up to 15% of cases occur in children
these distinct categories. Rarely, the distinction between and may be associated with glycogen storage disease type Ia.
benign and malignant hepatocellular neoplasms may be FNH is usually an incidental finding and nonspecific abdom-
challenging, particularly in a biopsy specimen, and the inal pain is the most common complaint in symptomatic
terms a typical hepatic adenoma and w ell-differentiated patients. FNH may increase in size over time. The back-
hepatocellular neoplasm of uncertain malignant potential ground liver and the serum α-fetoprotein (AFP) level is nor-
have been used in such cases. Poorly differentiated tumors mal in almost all cases. Some lesions may occur in association
pose a greater challenge because they may represent a with portal vein thrombosis, Budd-Chiari syndrome, or
HCC or intrahepatic cholangiocarcinoma (CC) or a meta- hereditary hemorrhagic telangiectasia. The pathogenesis is
static carcinoma, sarcoma, or malignant melanoma. thought be outflow tract obstruction that leads to collapse,
Distinguishing primary versus metastatic tumor in this fibrosis, and nodular regeneration. Expression of angiopoie-
scenario often requires a larger panel of ancillary stains, tin 1 and 2 is altered compared with normal liver with an
and often correlation with imaging findings may be the increase in A
NGPT1-to-ANGPT2 ratio.
only way to render a definite diagnosis.
FOCAL NODULAR HYPERPLASIA—FACT SHEET
Definition
EPITHELIAL TUMORS HEPATOCELLULAR n Non-neoplastic mass lesion caused by nodular overgrowth of
TUMORS FOCAL NODULAR HYPERPLASIA hepatocytes in region of altered hepatic blood flow

Focal nodular hyperplasia is a localized disorganized n Up to 0.9%
n 2% of hepatic tumors in children

non-neoplastic proliferation of hepatocytes that is
n No geographic predilection
believed to be centered around a vascular anomaly, usu-
ally an arterial malformation, and may coexist with Morbidity and Mortality
hepatic cavernous hemangiomas (CHs) in about 20% of n Low morbidity
cases. Current theories propose outflow obstruction and n Rupture is rare
hepatic congestion as etiologic factors. It accounts for n No increase in mortality
approximately 10% of hepatocellular mass lesions with

557
show a centrifugal hypervascularity with numerous

Gender, Race, and Age Distribution enlarged peripheral vessels imparting a “wheel-spoke”
n More common in women than men (male-to-female ratio, 9 to 1)
appearance. A technetium-99 sulfur colloid scan shows
n Occurs in all age groups
n No race predilection
normal or increased uptake. Imaging studies are about
70% sensitive for a preoperative diagnosis of FNH, and
Clinical Features false-positive results are rare.
n Usually incidental finding
n Rarely associated with abdominal pain, hepatomegaly, or tenderness
n Associated with extrahepatic vascular lesions

Pathologic Features
Radiologic Features
n Central scar by ultrasonography, computed tomography (CT), or
Gross Findings
magnetic resonance imaging
n Doppler imaging may detect feeding artery
n Hypodense lesion on CT with enhancement during arterial phase Focal nodular hyperplasia is usually a subcapsular, well-cir-
cumscribed, bulging, tan, nodular mass. Size can vary
widely, but most lesions measure less than 5 cm in diame-
n Prognosis is excellent
n Observation is adequate for asymptomatic lesions

ter. The most characteristic finding is the presence of a cen-
n Surgical resection for symptomatic or enlarging lesions or lesions
tral stellate scar with radiating fibrous septa that subdivide
that cannot be diagnosed with certainty on imaging the mass into multiple smaller nodules (Fig. 18.1). The
central scar may be inconspicuous in smaller lesions.
Hemorrhage, necrosis, and bile staining are rare. The back-
ground liver is normal in most cases.
TABLE 18.1
Hepatic Mass Lesions Microscopic Findings
Epithelial Mass Lesions Nonepithelial Mass Lesions
Focal nodular hyperplasia is composed of nodules of
BENIGN Benign hepatocytes surrounded by fibrous septa that contain
Hepatocellular Hemangioma thick hepatic artery branches along with a variable
Focal fatty change Angiomyolipoma degree of bile ductular proliferation. Interlobular bile
Focal nodular hyperplasia Infantile
hemangioendothelioma
ducts and portal vein branches are markedly decreased
Hepatic adenoma Mesenchymal hamartoma or absent. The central scar is composed of dense colla-
Macroregenerative nodule Inflammatory “pseudotumor” gen (Fig. 18.2A) and contains numerous thick-walled
Dysplastic nodules dystrophic arteries and bile ductules (Fig. 18.2B). The
• Low grade histologic features of the lesion overall resemble biliary
• H igh grade
Biliary
type of cirrhosis with marked ductular proliferation, but
Biliary cyst the background liver is completely normal. The hepato-
Bile duct adenoma cytes in FNH lesions are similar to those in the sur-
Bile duct hamartoma rounding liver, although they may be somewhat larger
flat precursor (biliary and paler and may incorporate variable quantities of fat
intraepithelial neoplasia)
Mucinous cystic neoplasm
Intraductal papillary neoplasm of
the bile duct
MALIGNANT Malignant
Hepatocellular Carcinoma Epithelioid
hemangioendothelioma
Hepatoblastoma Angiosarcoma
Intrahepatic Undifferentiated
(embryonal) sarcoma
Intrahepatic Cholangiocarcinoma Lymphoma
• Mucinous cystic neoplasm with
associated invasive carcinoma
• Intraductal papillary neoplasm with
associated carcinoma
• Metastasis Other rare sarcomas
Radiologic Features
FIGURE 18.1
Typical features of FNH on computed tomography (CT)
Focal nodular hyperplasia is a sharply circumscribed mass in a background
or magnetic resonance imaging (MRI) include a central of normal liver and shows a multinodular cut surface with a characteristic
scar, and angiography or Doppler ultrasonography can central scar.
CHAPTER 18 Liver Neoplasms 559
C
FIGURE 18.2
The central stellate scar is composed of dense hyalinized collagen and thick arteries (A), and a variable degree of bile ductular proliferation is typically present
at the interface of the scar and hepatic parenchyma (B). A map-like staining pattern on glutamine synthetase immunostain (C) is diagnostic of focal nodular
hyperplasia but may be challenging to interpret in a small biopsy specimen.
or glycogen. Nuclear pleomorphism, prominent nucle- ductular proliferation, a central scar, and nodular archi-
oli, and mitotic figures are not found in FNH. Mild tecture distinguishes FNH from all subtypes of HA with
chronic inflammation may be present within the lesion. the exception of inflammatory HA, which still rep-
The variant formerly referred to as “telangiectatic FNH” resents a difficult differential diagnosis because of the
has been shown to be a form of HA by molecular analy- significant histologic overlap. Sinusoidal dilation, ste-
sis. Other variations on the typical appearance described atosis, and isolated arteries favor a diagnosis of inflam-
earlier include prominent steatosis, steatohepatitis, and matory HA. Whereas FNH shows a map-like pattern of
even large cell change. staining on GS, inflammatory HA can be negative,
patchy positive, or diffusely positive if β-catenin muta-
tions occurred. Inflammatory HAs are also diffusely
positive for serum amyloid A (SAA) or C-reactive pro-
Focal Nodular Hyperplasia—Pathologic Features tein (CRP). Well-differentiated HCC are typically not a
challenge in this differential because they show more
Gross Findings pronounced cellular atypia, thickened hepatic cords
n Single subcapsular lesion with loss of reticulin, and positivity for glypican-3 in a
n Variable size; average size is smaller than 5 cm subset of cases.
n Central stellate scar with radiating septa
n Nodular overgrowth of normal-appearing hepatocytes Prognosis and Therapy
n Large-caliber vessels in central stellate scar
n Bile ductular proliferation in scar
n Appears like “localized cirrhosis” The majority of FNH is stable, nonprogressive lesions
that do not undergo malignant transformation and can
Genetics therefore be followed safely by imaging without the
n Polyclonal proliferation need for surgical resection. Unlike HAs, FNHs rarely
n Increased angiopoietin (1:2 ratio)
rupture or cause intraperitoneal bleeding. Surgical man-
n β- Catenin pathway activated without mutations in C
TNNB1 or
AXIN1 agement is reserved for enlarging tumors, those that
cause symptoms, or cases in which the diagnosis cannot
Differential Diagnosis be established with certainty on imaging findings alone.
n Cirrhosis
n Hepatic adenoma
HEPATIC ADENOMA
Ancillary Studies ■ CLINICAL FEATURES
Immunohistochemistry Hepatic adenoma is a benign hepatocellular neoplasm

arising in normal livers. The overwhelming majority of
A characteristic “map-like” staining pattern is seen in these cases (90%) develop in women in their childbearing
lesions on a glutamine synthetase (GS) immunostain as a years, and long-term oral contraceptive steroid (OCS)
result of activation of the β-catenin pathway (Fig. 18.2C) use is a common risk factor. In men, use of anabolic or
and can be very helpful in establishing the diagnosis in androgenic steroids is a risk factor for HA. HAs are
lesions without the characteristic central scar. The positive rarely found in children and are usually associated with
areas of staining are markedly expanded anastomosing metabolic disorders such as glycogen storage disease
zones around hepatic veins, but this may not be easily iden- (especially types I and III), diabetes mellitus, and
tified in small biopsy samples. Hurler’s disease. Obesity and metabolic syndrome are
also risk factors for the development of HAs.
A majority of HAs are found incidentally and are
asymptomatic; however, patients with larger tumors can
present with a palpable mass or with acute abdominal
pain secondary to hemorrhage within the tumor.
Focal nodular hyperplasia may be confused on biopsy Intraperitoneal rupture produces hemoperitoneum and
with cirrhosis; with HA, especially the telangiectatic may lead to shock. Serum AFP levels are normal. The
variant; and less likely with well-differentiated HCC. lesions are usually solitary but may be multiple, and
The localized nature of the lesion and its origin in nor- when more than 10, the condition is described as hepatic
mal liver excludes cirrhosis. The presence of bile adenomatosis. There are distinctive subtypes of HA
(HNF1A-inactivated, inflammatory, β-catenin activated, Pathologic Features

GLI family zinc finger 1 [GLI-1] rearranged, unclassi-
fied). The overall risk of malignant transformation is
4% to 8% and linked to high-risk features such as male Gross Findings
gender, androgen use, and β -catenin mutations. Risk of
bleeding has been recently described as associated with Hepatic adenoma is a well-circumscribed, often subcapsular
HA with G LI-1 rearrangements. mass in the right lobe of an otherwise noncirrhotic liver.
Ruptured HAs may be obscured by blood clot and difficult to
recognize, but the tumor is usually pale or more yellow com-
HEPATIC ADENOMA—FACT SHEET pared with the adjacent liver (Fig. 18.3). Fibrous septa may be
present as a result of a previous infarct.
Definition
n Benign hepatocellular neoplasm with low risk of malignant
transformation Microscopic Findings
Incidence and Location On first glance, most HAs represent a nodular prolifera-
n 3.4 per 100,000 in long-term users of oral contraceptives (OCPs) tion of bland-appearing hepatocytes arranged in cords
n Approximately 1.3 per million in women who have never used that are one to two cells thick and separated by sinu-
OCPs soids lined by inconspicuous Kupffer cells. However, no
n Higher incidence in Western countries than in Asia
normal portal tracts are present, and there is a notable
lack of any biliary epithelium. Another key feature of
HA is the presence of haphazardly distributed arteries
n Hemorrhage in approximately 25% of patients; usually in tumors
larger than 5 cm and thin-walled veins (Fig. 18.4). Hepatocellular rosettes
n Mortality rate of 6% to 20% in patients with hemorrhage (pseudoglands) are rare in HA and should not be con-
fused with bile ducts. Extensive pseudoglandular prolif-
Gender, Race, and Age Distribution eration raises concern for a diagnosis of well-differentiated
n More common in young to middle-aged women (average age, HCC.
30 years) The hepatocytes of HA frequently display clear or
n Rare in men; increased in those with anabolic steroid use
n In children, seen mainly in setting of glycogen storage disease

vacuolated cytoplasm because of accumulation of glyco-
types I and III, in whom they occur before age 20 years (male-to- gen or fat. Cytoplasmic inclusions representing α1-anti-
female ratio, 2 to 1) trypsin ( α
1AT), megamitochondria, and Mallory’s
n No race predilection hyaline are occasionally found. Focal cellular pleomor-
phism and prominent nucleoli may be seen, especially in
Clinical Features
tumors associated with androgenic steroid use. Mitoses,
n More than 90% of patients have history of oral contraceptive use
vascular invasion, and stromal invasion are not seen in
for more than 5 years
n Most common complaint is right upper quadrant abdominal pain
HA and are suggestive of malignancy. Various degenera-
n Occasionally seen in patients taking anabolic steroids tive changes occur in HA and include dilated sinusoids
and larger blood-filled (peliosis-like) spaces, myxoid
Radiologic Features stroma, and areas of necrosis, infarct, and hematoma.
n Vascular lesion on computed tomography, with irregular
enhancement
n Magnetic resonance imaging shows well-defined mass, low signal
to slightly hyperintense on T1-weighted images

n Surgical resection (if >
5 cm or high-risk factors)
n Withdrawal of estrogens to reduce tumor size
n Liver transplantation is considered for adenomatosis
n Malignant transformation to hepatocellular carcinoma is
uncommon (4%–8%)
Radiologic Features
FIGURE 18.3
Hepatic adenoma is visualized as a vascular lesion on Hepatic adenomas are sharply circumscribed lesions of variable size that
CT scan, with irregular enhancement. MRI shows a also occur in a background of normal liver. Intralesional hemorrhage is com-
mon, as in this example, in adenomas that activate sonic hedgehog signal-
well-defined mass with low to slightly hyperintense sig- ing because of fusion of inhibin subunit beta E (INHBE) promoter with GLI
nal on T1-weighted images. family zinc finger 1 (Gli-1).
FIGURE 18.4
Hepatic adenomas show isolated arteries, and with the exception of the inflammatory variant, these tumors lack portal tracts and bile ductules. The hepatocytes
are monomorphic with cords of normal thickness, preserved reticulin, and minimal atypia. Nuclear abnormalities are more common in the β -catenin–mutated
adenomas.
TABLE 18.2
Classification of Hepatic Adenomas
Hepatic Adenoma β- Catenin Mutated Inflammatory Sonic Hedgehog

Type HNF1α (30%) (20%–25%) (35%–40%) (<5 %) Unclassified
Clinical features Females Males Females and Significant risk None

males, alcohol, of intralesional
obesity hemorrhage
Pathologic features Steatosis, ≥
Cytologic atypia, Inflammatory Bleeding even in No distinctive
10 adenomas pseudogland infiltrate in small lesions associations
(adenomatosis) formation portal tract–
like structures;
dilated sinusoids;
bile ductular
component
Genetics HNF1A, MODY3, CTNNB1 mutations IL6 signal INHBE-Gli-1 fusion None
CYP1B1 transducer, F RK,
mutations STAT3, GNAS,
JAK1 mutations
Progression to Rare Increased Rare; almost None None
HCC always in
‎β-catenin–
mutated subset
Diagnostic IHC Loss of LFABP Aberrant nuclear Positive SAA and/ Positive PTGDS None
findings ‎β-catenin or CRP or ASS1
ASS1, Argininosuccinate synthase 1; C RP, C-reactive protein; H CC, hepatocellular carcinoma; L FABP, liver fatty acid binding protein; P TGDS, prostaglandin D2 synthase;
SAA, serum amyloid A.
Includes inflammatory hepatic adenoma (HA) c β - catenin mutation.
The current World Health Organization (WHO) classi- CRP; (4) sonic hedgehog HA harboring somatic deletions
fication of HAs is based on genotype-phenotype correla- of inhibin subunit beta E (INHBE) leading to INHBE
tion. Based on presence of HNF1αor β -catenin mutation and GLI-1 fusions; and (5) unclassified HA, tumors that
and expression of SAA or CRP in tumors that show a con- do not fit any of these categories (Table 18.2). HNF1α-
spicuous inflammatory infiltrate, HAs can be subclassified inactivated tumors are the second most common (30%–
into four categories: (1) HAs with mutations of the 35% of HAs) and show prominent steatosis without
HNF1α gene; (2) HAs with β-catenin gene mutation; (3) cellular atypia or inflammation ( Figs. 18.5A and B ).
inflammatory HA positive for serum amyloid A (SAA) or β-catenin–activated HA (10%–15%) is more common in
male patients and tend to show cytologic and architectural dilation (telangiectatic areas) (Figs. 18.5 C and D). Lesions
atypia, overlapping features between HA and HCC. previously classified as “telangiectatic FNHs” are now
Inflammatory HAs are the most frequent (35%–40%) classified as inflammatory HA based on clonality studies
and show pseudoportal tracts, bile ductular proliferation, and expression of SAA and CRP. A new subtype has been
inflammatory infiltrates, and prominent sinusoidal described recently that shows activation of the sonic
A B
C D
E F
FIGURE 18.5
HNF1A-mutated adenomas (HAs) show prominent steatosis in the majority of cases (A). Loss of staining for liver fatty acid binding protein on immunohisto-
chemistry is diagnostic (B). Portal tract–like structures with lymphoid aggregates and dilated (telangiectatic) sinusoids are characteristic of inflammatory HAs (C)
that stain positively with serum amyloid A (D) or C-reactive protein. Malignant transformation to carcinoma occurs rarely in HAs and manifests as increased cell
density (E), cellular atypia, and loss of reticulin (F) in the malignant foci.
hedgehog pathway caused by I NHBE deletion and conse- have reported overexpression of ASS1 in sonic hedgehog
quent INHBE-GLI-1 fusion. This subtype confers an HAs, but this finding remains under investigation.
increased high risk of hemorrhage, even in small tumors.
The term a denomatosis is sometimes used for cases
with multiple (>10) adenomas. Because the etiologic
associations appear to be similar for multiple and soli-
tary adenomas, distinction between these two groups is
probably not warranted on clinicopathologic grounds. Focal nodular hyperplasia shows a central scar, promi-
HNF1A and inflammatory HA are the most common nent bile ductular proliferation at the interface of hepa-
subtypes that may present with adenomatosis. It is also tocellular nodules and stroma and a map-like staining
important to remember that different HA subtypes may pattern on GS. HA is characterized by isolated arteries,
occur in the same liver. lack of normal portal tracts, absence of bile duct prolifer-
ation (with the exception of the inflammatory subtype),
and hepatic cord architecture that is uniformly one to
Hepatic Adenoma—Pathologic Features two cells thick. Diffuse presence of pseudoglandular
architecture should raise suspicion for well-differenti-
Gross Findings ated HCC. A diagnosis of HCC is based on classic radio-
n Yellow, tan, or red-brown solitary nodule in noncirrhotic liver logic features, thickened hepatic cords with loss of
n Most measure 5 to 15 cm reticulin staining, prominent nuclear, and architectural
n May be hemorrhagic or multiple (>10 is labeled adenomatosis)
atypia (Figs. 18.5E and F) and in some cases, positivity
for glypican-3 or heat shock protein 70. Foci worrisome
for HCC in an otherwise typical HA can sometimes be
n Benign hepatocytes without acinar architecture or portal tracts
n Thin-walled vascular channels and isolated arteries scattered

seen. In small biopsy samples, these lesions are classified
throughout tumor as either hepatocellular neoplasm with uncertain malig-
n Tumor cells may show prominent steatosis (usually in the nant potential or as atypical hepatocellular neoplasm. In
HNF1α-inactivated subtype); loss of liver fatty acid–binding resection specimens, these tumors can be classified as
protein is diagnostic
HA as long as the atypical foci constitute less than 5%
n Bile ductular reaction is not present within the lesion (except in
inflammatory hepatic adenoma [HA]) of the tumor and do not fulfill the criteria for HCC.
n Prominent sinusoidal dilation (telangiectasia) and lymphoid
infiltrates in portal tract–like structures are seen in inflammatory

HA; serum amyloid A and C-reactive protein positive
n Nuclear atypia may be prominent in β -catenin–activated HA; Prognosis and Therapy
nuclear β -catenin and/or diffuse glutamine synthetase positivity
n Intralesional hemorrhage in sonic hedgehog subtype of HA
Rupture with subsequent massive bleeding into the perito-
Differential Diagnosis neal cavity is the most common cause of death related to
n Focal nodular hyperplasia HA. Because of this risk, HAs increasing in size on surveil-
n Well-differentiated hepatocellular carcinoma lance are often resected. In many institutions, patients
with lesions larger than 5 cm are treated surgically. This
management algorithm is likely to change with the recog-
nition of the specific sonic hedgehog subtype of HA associ-
Ancillary Studies
ated with hemorrhage. Liver transplantation is occasionally
performed for very large lesions or adenomatosis. There is
The most useful immunohistochemical stain in the dif- a low risk for transformation to HCC and is typically seen
ferential diagnosis from FNH is GS, map-like pattern of in the β -catenin activated HAs.
staining is diagnostic of FNH but can be challenging to
determine in small biopsy samples. A panel of immu-
nostains has been proposed to further classify HAs
■ MACROREGENERATIVE AND DYSPLASTIC
including β
-catenin, liver fatty acid–binding protein
NODULES
(LFABP), SAA, or CRP. Loss of LFABP is diagnostic of
HNF1α-mutated HA, positivity for SAA or CRP sup-
ports the diagnosis of inflammatory HA, and nuclear Numerous terms have been applied to grossly distinct
β-catenin expression is indicative of a β-catenin– large hepatocellular nodules arising in the setting of
activated HA. Diffuse homogenous GS positivity is con- cirrhosis. Macroregenerative nodules (MRNs) are
sidered a surrogate for β -catenin mutations, leading to larger than surrounding nodules but do not display any
strong activation of this pathway such as exon 3 muta- atypical features. Dysplastic nodules (DNs) exhibit
tions. Diffuse heterogenous GS expression is observed atypical architectural or cytologic features but do not
in other β -catenin mutations (exon 3 S45). Some authors meet histologic criteria for HCC.
MACROREGENERATIVE NODULES AND DYSPLASTIC

NODULES—FACT SHEET
Definition
n Macroregenerative nodule (MRN): large dominant nodule in
cirrhotic liver
n Dysplastic nodule (DN): putative precursor lesion to
hepatocellular carcinoma; does not meet definite histologic

criteria of malignancy

n Reflect the etiology of the underlying cirrhosis

n Related to the risk for development of hepatocellular carcinoma FIGURE 18.6
The macroregenerative nodule in this cirrhotic liver (arrow) is distinguishable
Gender, Race, and Age Distribution from the background cirrhosis by its larger size. The variegated nodule of
similar size in the same specimen is a small hepatocellular carcinoma.
n Similar to etiology of underlying cirrhosis
Clinical Features
n Arise in setting of cirrhosis normal) and are graded as low or high grade. Portal tracts
n Usually seen in explant specimens are preserved in low- and high-grade DNs, and the hepato-
cytes show a monomorphic appearance with increased cell
Radiologic Features
density or cytologic atypia (Fig. 18.7). Cytologic and archi-
n Indistinguishable from cirrhotic nodules
tectural abnormalities are minimal in low-grade DNs.
n Do not fulfill radiologic criteria for hepatocellular carcinoma (HCC)
There is often slight increase in nuclear density (<1.3
Prognosis and Therapy times compared with the adjacent parenchyma), large cell
n Excision for DNs, when possible, facilitates definite pathologic change (nuclear enlargement but preserved N/C ratio,
classification, but more commonly, these lesions are ablated, pleomorphism, hyperchromasia) and possibly multinucle-
given the risk of surgical intervention in cirrhotic patients ation. In contrast, high-grade DNs show small cell change
characterized by smaller size and a greater nuclear-to-cyto-
Prognosis depends on status of underlying cirrhosis
plasmic ratio than the surrounding hepatocytes (approxi-
n High risk for development of HCC
mately two times), nuclear hyperchromasia, cytoplasmic
basophilia, and mild nuclear pleomorphism. Architectural
and cytologic atypia, including pseudoglandular forma-
Pathologic Features tions, are common in high-grade DNs, but reticulin archi-
tecture is well preserved in both low- and high-grade DNs.
Gross Findings Loss of iron deposition when compared with the back-
ground cirrhotic liver is a useful feature of high-grade dys-
Macroregenerative nodules and DNs are usually similar to plasia arising in a DN. It is common to see an HCC in close
other cirrhotic nodules, although they may be paler, slightly proximity to a high-grade DN. The progression from MRN
larger in size, or more bile stained. A thick fibrous capsule to DN and ultimately HCC is noted by decreased ductular
or a variegated cut surface is more suggestive of a small reaction as demonstrated by loss of cytokeratin (CK) 19
HCC. MRNs are larger than other cirrhotic nodules and immunohistochemical labeling, but this is not necessary
are larger than 1 cm and may measure up to 5 cm or more for the diagnosis.
in diameter (Fig. 18.6). High-grade DNs resemble MRNs
grossly but may appear less well circumscribed.
Most of the MRNs in cirrhosis are multiple and contain Dysplastic nodules are considered an important precursor
portal tracts scattered throughout the nodule. The hepato- to HCC. Ablation or resection of the lesion is recom-
cytes within these nodules are identical to those in the mended because of the potential to develop into HCC.
surrounding liver. The hepatocellular plates are one or MRNs cannot always be reliably distinguished from low-
two cells thick. Prominent bile ductular reaction may be grade DNs on imaging grounds, and patients with appar-
seen in the adjacent fibrous tissue. The reticulin frame- ent MRNs on imaging studies are kept under surveillance
work is intact and similar to a typical cirrhotic nodule. by periodic imaging. Between 10% and 30% of high-grade
Dysplastic nodules are regarded as precursors to HCC. DNs are reported to progress to HCC within 3 years, but a
They demonstrate increased nuclear density (twice that of substantial proportion do not progress and can even
B
FIGURE 18.7
Dysplastic nodules (DNs) retain portal tracts and may exhibit small cell change (arrow) that is recognized by the presence of densely packed hepatocytes
smaller than those of the surrounding liver (A). Large cell change shows enlarged hepatocytes with atypical, irregular nuclei and large nucleoli (B). Abnormal
architectural features of hepatocellular carcinoma are not seen in DNs.
n Trabeculae are two cells thick, and reticulin framework is

Macroregenerative Nodules and Dysplastic Nodules—
preserved in dysplastic nodules
Pathologic Features
n Increased mitotic activity may be seen in high-grade DNs, but it is
more commonly associated with the diagnosis of hepatocellular
Gross Findings carcinoma (HCC)
n Macroregenerative nodule (MRNs) are larger than other nodules
in cirrhotic liver; there is no difference in color or texture

Genetics
n Dysplastic nodules (DNs) may be of any size; may be paler than
n MRNs are polyclonal
other cirrhotic nodules and bile stained
n Low- and high-grade DNs may be monoclonal or polyclonal, but
high-grade DNs tend to have a molecular profile more

reminiscent of HCC
n MRNs are similar to other nodules in the cirrhotic liver
n Low-grade DNs show minimal nuclear atypia and only slight

architectural abnormalities; large cell change may be seen; portal
n Hepatocellular adenoma
tracts could be present within nodule
n HCC
n High-grade DNs can show small cell change and focal
pseudoglandular formation
regress spontaneously. Imaging surveillance and biopsy

are key to guiding management in these patients. HEPATOCELLULAR CARCINOMA—FACT SHEET
Definition
n Malignant neoplasm of hepatocytes
n Most common primary liver malignancy in adults
Separation of low-grade DNs from MRNs, as well as high-
n In United States, incidence is 4 per 100,000
grade DNs from HCC, may be difficult on hematoxylin n Wide geographic variation in incidence, with high incidence in
and eosin (H&E) examination alone. Features more often Southeast Asia and sub-Saharan Africa and low incidence in
seen in HCC are diffuse architectural atypia (more than Western countries
three cell thick cords, pseudoglandular formation, reticu-
lin loss), marked cellular atypia with increased mitoses, Morbidity and Mortality
n High mortality rate; 5-year survival rate is less than 5%
and increased number of unpaired arteries or vascular
n Median survival for resectable tumors is up to 45 months; for
invasion, which is helpful but rarely seen in early lesions. unresectable tumors, less than 6 months
n Patients with cirrhosis are at risk for development of new tumors

HEPATOCELLULAR CARCINOMA n Male predominance (male-to-female ratio, 2:1 to 5:1)
n Predilection for Asian and African population probably because of
chronic viral hepatitis and aflatoxin exposure

■ CLINICAL FEATURES n Incidence increases with age in Western countries (peak
incidence, seventh decade), but mean age in South Africa is 35

years
Hepatocellular carcinoma is the most common type of
primary epithelial tumor in the liver. Although rela- Clinical Features
tively uncommon in Western countries, HCC is one of n Associated with chronic hepatitis C and hepatitis B infections and
the most prevalent malignant tumors worldwide, exposure to aflatoxins

n Commonly arises with a background of cirrhosis; obesity is
responsible for 20% to 40% of cancer deaths in regions increasingly associated with hepatocellular carcinoma
of high incidence, such as sub-Saharan Africa and n Presentation is variable, ranging from decompensated liver
Southeast Asia. In low-incidence areas, HCC is a tumor disease to malaise, weight loss, and hepatomegaly
of older men. In areas of higher incidence, HCC occurs n Serum α -fetoprotein is elevated in approximately 50% of cases
in the third or fourth decade of life because of the high
Radiologic Features
prevalence of perinatally acquired hepatitis B.
n Computed tomography or magnetic resonance imaging used for
Virtually any chronic liver disease may predispose
noninvasive diagnosis: based on arterial phase
toward HCC. The most common predisposing condition hyperenhancement and portal venous or delayed phase washout
is cirrhosis from any cause, with hepatitis B, hepatitis C, n Ultrasonography used for surveillance in patients with cirrhosis
and alcoholic liver disease being the most common causes.

Obesity-related liver disease is increasingly recognized as Prognosis and Therapy
a risk factor for HCC, and genetic hemochromatosis car- n Prognosis is heavily dependent on status of liver disease
n Treatment is surgical excision when feasible
ries a particularly high risk. The annual risk for HCC
n Liver transplantation may be indicated when tumors are small
developing in a cirrhotic liver is estimated at 1% to 6%. and low stage in the setting of cirrhosis
Patients may present with abdominal pain or fullness, a n Palliative treatments include ethanol injection, cryoablation, and
mass, or clinical signs and symptoms of cirrhosis. HCC rarely chemoembolization
presents with metastases. The most useful serum marker is n Chemotherapy has limited benefit
elevation of AFP, which may be highly elevated in patients

with large tumors. Of note, serum AFP levels may also be ele-
vated viral hepatitis and cirrhosis. High AFP levels are also useful in screening for HCC in cirrhotic livers; a mosaic
seen in hepatoid variants of gastric adenocarcinomas and pattern with peripheral sonolucent region is typical.
germ cell tumors containing a yolk sac component.
Pathologic Features
Radiologic Features
Gross Findings
Advanced HCC is generally easily detected by ultrasonog- Hepatocellular carcinoma arising in a noncirrhotic liver
raphy, CT, or MRI. HCC on CT is usually low attenuation usually grows as a single large mass with or without satellite
and may have daughter nodules. Ultrasonography is nodules (Fig. 18.8A) and may also exhibit this pattern in the
C
FIGURE 18.8
Variegated appearance and a bile-stained cut surface are characteristic of hepatocellular carcinoma (A). Satellite nodules are often present around large lesions.
Nodules of carcinoma may be small and diffusely scattered throughout the liver and difficult to distinguish from cirrhosis (B). Invasion of large veins is an
important prognostic feature to assess on gross examination (C).
setting of cirrhosis. However, tumors arising in cirrhosis may invasion are present in some cases (Fig. 18.8C). Involvement
grow as numerous small nodules (diffuse type) that may be of the inferior vena cava, sometimes with extension into the
difficult to distinguish from the background liver (Fig. 18.8B). right atrium, may be found.
Tumor nodules are soft, bile stained, or yellow to tan and
often variegated because of foci of hemorrhage and necrosis. Microscopic Findings
Separate tumor nodules may represent multicentric growth
or may represent tumor spread via intrahepatic vascular Hepatocellular carcinomas show a wide range of differ-
routes. Macroscopic portal vein, hepatic vein, or bile duct entiation, and several grades may be present within the
same tumor. Well-differentiated HCC shows obvious

hepatocellular differentiation with tumor cells Hepatocellular Carcinoma—Pathologic Features
arranged in a trabecular pattern lined by endothelial
cells. Stroma is typically scant, and bile production by Gross Findings
n Single large mass, with or without satellite nodules or multiple
neoplastic cells is pathognomonic of HCC but should
nodules diffusely involving the liver
not be confused with bile production by trapped n The tumor is soft, often variegated, and can be bile stained
non-neoplastic hepatocytes. Cytoplasmic inclusions n Vascular invasion is common, with involvement of portal or
such as Mallory’s hyaline, α 1AT inclusions, and fat hepatic veins
accumulation are frequently present, often in focal
areas of the tumor or in individual tumor nodules. Microscopic Findings
Vascular lakes may simulate peliosis hepatis. The WHO n Wide range of differentiation
n Most tumors have trabecular growth pattern; a pseudoglandular

classification divides HCC into well-, moderately, and
pattern is also common
poorly differentiated grades. Whereas well-differenti- n Stroma is sparse in most tumors
ated tumors show minimal atypia and resemble normal n Bile production, fat droplets, Mallory’s hyaline, and other
hepatocytes, poorly differentiated tumors resemble a cytoplasmic inclusions may be seen

variety of carcinomas and are not clearly recognizable
as hepatocellular on H&E stain. The moderately differ- Ultrastructural Findings
n Bile canaliculi may be demonstrated
entiated spectrum of tumors falls between the two
extremes. In the compact or solid areas, compression of
Genetics
broad trabeculae forms sheets with inconspicuous
n TP53 mutations associated with progression from early to
sinusoids (Fig. 18.9A). Pseudoglandular (acinar) for- advanced stage
mation with dilated rounded spaces rounded by cyto- n Frequent allelic losses on multiple chromosomes
logically malignant hepatocytes may be mistaken for n TERT promoter mutations in transformed hepatic adenoma (HA)
adenocarcinoma (Fig. 18.9B). The lumen of these acini

may contain bile. Immunohistochemistry
n Tumor cells are positive for HepPar-1 (granular cytoplasmic
Among the major histologic subtypes are steatohepa-
pattern), glypican 3, and nuclear/cytoplasmic expression of
titic, clear cell, macrotrabecular massive, scirrhous, arginase 1
chromophobe, neutrophil-rich, lymphocyte-rich, and n Fewer than 50% of tumors are positive for α -fetoprotein (AFP)
fibrolamellar hepatocellular carcinoma (FL-HCC). The n Polyclonal carcinoembryonic antigen (CEA) or CD10 demonstrate
steatohepatitic subtype (5%–20%) reveals steatosis and a canalicular staining pattern; monoclonal CEA is negative
n CAM 5.2 is positive; CK7 and CK20 can be focally expressed
ballooning as seen in steatohepatitis ( Fig. 18.9D).
Because of the fragmentation of the reticulin framework
in areas of fat, the differential diagnosis can be challeng-
n HA
ing. Clear cell HCC (3%–7%) demonstrates clear cell n Dysplastic nodule in cirrhosis
morphology in more than 80% of the tumor (Fig. 18.9E) n Metastatic tumors, especially neuroendocrine tumors
and carries better prognosis than conventional HCC. n Cholangiocarcinoma
Macrotrabecular massive HCC (5%) consists of thick-

ened trabeculae larger than 10 cells thick and has worse
prognosis than conventional HCC (Fig. 18.9F). The rare
scirrhous HCC (4%) displays prominent fibrous stroma
accounting for more than 50% of the tumor (Fig. 18.9G). with HepPar-1 and nuclear/cytoplasmic staining for
Neutrophil-rich ( <1%), chromophobe (3%), lympho- Arginase is present in HCC and normal hepatocytes.
cyte-rich (<1%) (Fig. 18.9H), sarcomatoid (Fig. 18.9I), Glypican 3 is expressed in HCC (with lower sensitivity
lipid-rich, HCC with syncytial giant cells (Fig. 18.9J), in well-differentiated HCC) and negative in nonmalig-
GCSFP producing HCC, and cirrhotomimetic are rare nant liver. Arginase-1 has been proposed as the hepato-
subtypes. cellular marker with greater sensitivity in poorly
differentiated HCC. In situ hybridization for albumin
messenger RNA appears to be highly sensitive but not
Ancillary Studies specific because it has been demonstrated in CCs and
adenocarcinomas of other sites.
Immunohistochemistry Even though CAM 5.2 is positive in HCC, other ker-
atins (CK7, CK20, CK19, AE1/AE3, Ker 903) area vari-
Hepatocellular carcinoma demonstrates canalicular able expressed and more commonly negative. CK19
staining pattern with antibodies to CD-10 and poly- expression has been associated with a poor prognosis.
clonal carcinoembryonic antigen (CEA) (Fig. 18.10), as MOC-31 and Ber-Ep4 are negative and can be use-
well as positivity for hepatocyte (HepPar-1), glypican 3, ful in the differential diagnosis with CC or other
and Arginase-1. Granular cytoplasmic staining pattern adenocarcinomas.
A B
C D
E F
FIGURE 18.9
Hepatocellular carcinomas (HCCs) show a variety of architectural and cytologic patterns. Certain areas of the tumor may reveal a more solid architecture (A)
or pseudoglandular pattern (B) that can mimic an adenocarcinoma. Typical areas of trabecular growth pattern are seen in most cases (C). The steatohepatitic
subtype of HCC (D) can be challenging to diagnosed because it is often cytologically bland and shares morphologic features with fatty liver disease. Ancillary
stains such as loss of reticulin in fat-poor areas or positive glypican-3 stain can be helpful. HCC clear cell can mimic other clear cell tumors such as metastatic
renal cell carcinoma, so immunostains are needed to sort out the differential diagnoses (E). Some HCCs demonstrate a macrotrabecular growth pattern with
trabecula of more than 10 cells thick (F). The rare scirrhous HCC (G) shows prominent collagen bands, but the cytologic features of fibrolamellar HCC are not
present. Uncommon subtypes also include lymphocytic-rich HCC (H), which shows an immune-rich stroma with greater than 100 tumor-infiltrating lympho-
cytes in 10 hfp. Sarcomatoid HCC (I) mimics an undifferentiated sarcoma and can only be diagnosed by demonstration of a conventional HCC component or
positivity for markers of hepatocellular differentiation and HCC with syncytial giant cells (J).
G H
I J
FIGURE 18.9
Continued
Dysplastic nodule and HA are in the differential diagno- The prognosis is determined primarily by HCC stage
sis of well-differentiated HCC (discussed earlier). and the functional status of the liver. Nonoperative
Neuroendocrine tumors metastatic to the liver, particu- palliative therapies include percutaneous ethanol
larly those with oncocytic features (Fig. 18.11A), may injection, cryoablation, and transcatheter arterial
be mistaken from HCC because of their trabecular archi- chemoembolization; chemotherapy has largely proven
tecture. Diffuse positivity for neuroendocrine markers ineffective. At autopsy, metastases, most commonly to
such as synaptophysin and chromogranin is helpful in the lung and porta hepatis lymph nodes, are found in
making this distinction. Similarly, metastatic breast car- up to 75% of patients. Bone, adrenal gland, and virtu-
cinoma (Fig. 18.11B), adrenocortical carcinoma, onco- ally any site in the body can be involved by metastatic
cytic renal tumors, hepatoid adenocarcinomas, and disease. Tumor size, number and location (one or both
melanoma may also mimic HCC but can be easily ruled lobes) of tumor nodules, presence of gross or micro-
out with a panel of immunostains. Distinction of poorly scopic vascular invasion, and disease status of the
differentiated and undifferentiated HCC from poorly uninvolved liver are the most important prognostic
differentiated CC (Figs. 18.11C and D), high-grade neu- variables. In carefully selected patients, hepatic resec-
roendocrine carcinoma, and certain sarcomas can be tion and/or liver transplantation may be performed
challenging and often requires a battery of ancillary with success. Small, low-stage, incidentally discovered
stains and correlation with clinical and imaging findings HCCs in a cirrhotic liver at transplantation do not
to arrive at the correct diagnosis. adversely affect outcome.
FIBROLAMELLAR CARCINOMA—FACT SHEET
Definition
n Rare variant of hepatocellular carcinoma (HCC) with characteristic
morphology occurring in a noncirrhotic liver

n Rare in Asian and African countries
n Age-adjusted incidence rate is approximately 0.02 per 100,000

n Overall, more indolent course than typical HCC but stage-
matched outcomes similar

A n Male to female ratio, 3:4
n No race predilection in US population
n Mean age, 23 years
Clinical Features
n Nausea, weight loss, abdominal pain, malaise
n Not associated with chronic liver disease or cirrhosis
n Normal or mild serum α -fetoprotein elevation
Radiologic Features
n Well-demarcated hypodense tumor on computed tomography
scan
n Central scar may mimic focal nodular hyperplasia

n Approximately 60% are surgically resectable
n Chemotherapy is reserved for patients with unresectable disease
and is not curative

B n The most significant determinant of survival is tumor stage
n 5-year survival rate is approximately 60%

FIGURE 18.10
Ancillary stains are often helpful in diagnosis of hepatocellular carcinoma.
Thickened hepatic cord architecture or loss of reticulin on a reticulin stain
is diagnostic of malignant transformation (A). The presence of a canalicu-
lar pattern of staining on a polyclonal carcinoembryonic antigen immunos- Pathologic Features
B). Arginase-1,
tain is helpful in confirming hepatocellular differentiation (
HepPar-1, and glypican-3 are other commonly used markers of hepatocel-
lular differentiation. Gross Findings
Most FL-HCCs arise in the left lobe, but large tumors

may affect both lobes. The tumors are usually solitary,
firm, and well circumscribed and may be bile stained,
FIBROLAMELLAR CARCINOMA necrotic, or hemorrhagic. They are typically large, mea-
suring up to 25 cm. A central stellate scar similar to that
seen in FNH may be present (Fig. 18.12). The adjacent
non-neoplastic liver is unremarkable.
Fibrolamellar HCC (is a rare HCC variant arising in Microscopic Findings

noncirrhotic liver in young patients, 80% between
ages of 10–35 years). It is associated with a better The tumor cells of FL-HCC are very large, display abun-
prognosis than typical HCC, likely because of the dant granular eosinophilic cytoplasm because of large
younger age of the patients and their lack of signifi- numbers of mitochondria and distinct cell borders, and
cant underlying liver disease. The outcome in stage- have a distinctive oncocytic appearance (Fig. 18.13A).
matched fibrolamellar and conventional HCC appears A defining feature of FL-HCC is the presence of parallel
to be similar. Clinical presentation is similar to typical bands of hyalinized fibrous tissue separating the tumor
HCC. In most cases, serum AFP levels are normal or cells into nests (Fig. 18.13B). Other patterns of fibrosis
only modestly elevated. include haphazard collagen deposition and tumors
A B
C D
FIGURE 18.11
The differential diagnosis of hepatocellular carcinoma (HCC) is broad and includes primary intrahepatic and metastatic tumors. Tumors with oncocytic change,
such as metastatic pancreatic endocrine tumors (A) and breast carcinoma (B), can mimic HCC but are easily distinguished by appropriate immunostains.
Poorly differentiated HCC with small cell undifferentiated morphology (C) can be challenging to separate from metastatic melanoma, carcinoma, or lymphoma.
Positive staining for HepPar-1 (D), glypican-3, or arginase-1 is essential for definitive diagnosis.
showing areas with little or no intratumoral fibrosis

(least common pattern). Cytoplasmic eosinophilic hya-
line globules, which may be Periodic Acid–Schiff (PAS)
positive and diastase resistant, may represent α1AT.
Cytoplasmic pale bodies contain fibrinogen and are pres-
ent in about 50% of cases (Fig. 18.13C). In a subset of
cases, pseudoglandular formation and mucin produc-
tion can be seen, but these findings do not constitute a
component of adenocarcinoma. Most FL-HCC are mod-
erately differentiated, but they can contain foci of carci-
noma that are poorly differentiated. In addition to
staining with HepPar-1, albumin in situ hybridization
(ISH), and arginase-1, FL-HCC is positive for CK7
(Fig. 18.13D) and CD68 (Fig. 18.13E). Polyclonal CEA
demonstrates a canalicular staining pattern.
Recent molecular data have shown that FL-HCC show
FIGURE 18.12 activation of protein kinase A, most commonly through a
Fibrolamellar hepatocellular carcinoma is usually a solitary mass arising in a DNAJB1-PRKACA fusion transcript, secondary to
noncirrhotic liver and may also show a central stellate scar. somatic intrachromosomal deletion on chromosome 19.
A B
C D
E
FIGURE 18.13
Fibrolamellar hepatocellular carcinoma is characterized by large and polygonal tumor cells with abundant granular pink cytoplasm and prominent nucleoli
(A) arranged in cords and nests separated by dense collagen bundles are arranged in parallel layers (B). The glassy pink cytoplasmic inclusions (C) are also a
characteristic feature. Coexpression of cytokeratin 7 (D) and CD68 (E) in the tumor cells helps support the diagnosis.
This genetic abnormality is diagnostic of FL-HCC in Ancillary Studies

the differential of hepatocellular malignancies. Interes
tingly, the DNAJB1-PRKACA fusion transcript has
been also demonstrated in other oncocytic pancreatic Ultrastructural Findings
and biliary neoplasms, but these are typically not in the The cytoplasm contains numerous mitochondria, as expec
differential of FL-HCC so do not constitute a diagnostic ted from the oncocytic appearance of the tumor cells. Dense
challenge. core neuroendocrine-like granules may also be rarely found.
presence of D
NAJB1-PRKACA translocation supports
Fibrolamellar Carcinoma—Pathologic Features the diagnosis of fibrolamellar HCC.
Gross Findings
n Two-thirds are located in left lobe Prognosis and Therapy
n Single mass in 56% of cases
n Firm tan or green circumscribed mass
n Central scar in many cases Fibrolamellar HCC is often resectable and is thus
n Surrounding liver is noncirrhotic associated with an overall better outcome than usual
HCC, but stage-matched outcomes are similar in both
Microscopic Findings groups. Hepatic transplantation may be considered for
n Large polygonal, granular oncocytic tumor cells in nests separated
nonresectable tumors confined to the liver. The most
by lamellar fibrous stroma
n Cytoplasmic inclusions contain pale bodies (accumulated
common metastatic sites are the abdominal lymph
fibrinogen), Mallory’s hyaline, α
1-antitrypsin nodes, peritoneum, and lung.
n Numerous densely packed mitochondria
HEPATOBLASTOMA
Genetics
n DNAJB1-PRKACA translocation is diagnostic of fibrolamellar
hepatocellular carcinoma (HCC) ■ CLINICAL FEATURES
n Positive for HepPar-1, albumin in situ hybridization (ISH),
Hepatoblastoma is the most common primary hepatic
arginase 1, CK7 and CD68 tumor in children, accounting for about 50% of all pri-
n Polyclonal carcinoembryonic antigen positive with a canalicular mary pediatric hepatic malignancies. The majority
distribution occur by 2 years of age, and there is a male predomi-
n α-Fetoprotein negative
nance (male-to-female ratio, 2 to 1). Patients generally
present with an abdominal mass noticed by the parent,
n Focal nodular hyperplasia
but some patients present with precocious puberty
n Conventional hepatocellular carcinoma (HCC) related to human chorionic gonadotropin production by
n Sclerosing or scirrhous variant of HCC the tumor. Approximately 5% of patients have an asso-
n Cholangiocarcinoma ciated congenital abnormality. Familial adenomatous
polyposis is associated with higher risk for hepatoblas-
toma, as are Beckwith-Wiedemann syndrome and tri-
somy 18. Although the etiologic factors of hepatoblastoma
Differential Diagnosis are unknown, an association with parental smoking
and low birth weight is recognized, although it is not
clear if an environmental cause is responsible. The
The most common lesions in the differential diagnosis serum AFP level is elevated in 90% of cases.
for FL-HCC are FNH, typical HCC, scirrhous HCC, and
metastatic tumors with extensive fibrosis. Although
FNH and FL-HCC may have central stellate scars,
Radiologic Features
microscopically, the lack of hepatocellular atypia, iso-
lated arteries, bile ductular proliferation, and lamellar
collagen distinguishes FNH from FL-HCC. Diffuse Hepatoblastoma is visualized as a solid or multifocal mass on
lamellar fibrosis combined with oncocytic cellular fea- CT, with calcification in more than half of cases. MRI shows
tures is not found in typical HCC. In metastatic carci- decreased signal relative to the normal liver on T1-weighted
nomas, the collagen is more haphazardly arranged and images and increased signal on T2-weighted images.
lacks the lamellar features characteristic of FL-HCC.
The tumor cells in scirrhous HCC are smaller, do not
display oncocytic features, and form glandular pat-
Pathologic Features
terns. Scirrhous HCC arises in liver with chronic liver
disease, and Hepar-1 expression is often weak or
absent; the opposite is true for FL-CC. Both FL-HCC Gross Findings
and scirrhous HCC can be CK7 positive, leading to
confusion with CC, which can be easily excluded based Hepatoblastoma is typically a solitary mass that may be
on typical morphologic characteristics and presence quite large, measuring up to 20 cm. Purely epithelial
of markers of hepatocellular differentiation. The hepatoblastoma is a soft, fleshy mass ( Fig. 18.14);
whereas the fetal type grossly appears similar to normal

HEPATOBLASTOMA—FACT SHEET liver, other patterns show a variegated appearance.
Tumors with a prominent mesenchymal component are
Definition often firm and may be calcified. Cystic degeneration,
n Malignant liver tumor occurring in children, mimicking fetal or necrosis, and hemorrhage may be seen.
embryonal liver and often containing heterologous cell types

n Rare; annual incidence in the United States is 0.2 per 100,000
children Hepatoblastomas may be classified as either epithelial or

n 47% of pediatric malignant liver tumors mixed epithelial–mesenchymal and are subclassified
into a variety of patterns that are usually present in vari-
Morbidity and Mortality able combinations (Figs. 18.15A-D).
n Overall survival is 65% to 70%
1. Fetal pattern (30%): Hepatocytes are uniform and

similar to normal hepatocytes, although they have a
n Male predominance (male-to-female ratio, 2:1)
slightly higher nuclear-to-cytoplasmic ratio. An alter-
n 90% occur within first 5 years of life

nating light and dark pattern is characteristic on low
power. Mitoses are rare and less than 2 per 10 hpf. The
Clinical Features tumor cells form cords two to three cells thick, sepa-
n More common in low-birth-weight infants rated by sinusoids, in a pattern reminiscent of normal
n Presenting symptom is enlarging abdomen noted by parent liver. However, normal structures such as portal tracts,
n Weight loss and anorexia are less common
bile ducts, and ductules are absent. A mitotically active
n 5% of children with hepatoblastoma have congenital anomalies;
known association with familial adenomatous polyposis,

aggressive variant of the fetal type is also recognized.
Beckwith-Wiedemann syndrome, and trisomy 18 2. Embryonal pattern (20%): The tumor cells in the
n Human chorionic gonadotropin production may lead to embryonal pattern are less differentiated and cohe-
presentation with precocious puberty sive than the fetal pattern and have a high nucle-
ar-to-cytoplasmic ratio and coarser chromatin. The
Radiologic Features
trabecular pattern is not well developed, and the
n Solid or multifocal mass on computed tomography
tumor cells may form sheets. Mitoses and necrosis
n Calcification in more than 50% of cases
n Magnetic resonance imaging shows decreased signal relative to

are more common than in the fetal pattern.
normal liver on T1-weighted images and increased signal on 3. Macrotrabecular pattern (3%): This pattern is char-
T2-weighted images acterized by broad trabeculae 10 or more cells thick.
Trabeculae may be composed of embryonal or fetal
Prognosis and Therapy cells.
n Tumor stage is the key prognostic factor
4. Small cell undifferentiated pattern (3%): This pat-
n The pure fetal type may have a better prognosis; the small cell
undifferentiated pattern has a worse prognosis

tern is the least differentiated pattern and resembles
n Treatment is surgical excision when possible
other small blue cell tumors of childhood. The tumor
n Preoperative chemotherapy allows many previously unresectable is composed of loosely cohesive sheets of uniform
cases to be completely resected small cells with scanty cytoplasm. The tumor cells are
positive for keratins.
5. Cholangioblastic pattern (rare): Small ducts are
dis
persed around or within a hepatocellular
component.
6. Mixed epithelial and mesenchymal pattern (44%).
Both epithelial and mesenchymal differentiation are
present. The primitive mesenchymal component may
be primitive, with spindle or stellate cells with little
cytoplasm, or display differentiation along chondroid
and rhabdomyoblastic lines. Osteoid is the most fre-
quent heterologous element and may be more promi-
nent after chemotherapy. The mesenchymal elements
may also be keratin positive, suggesting sarcomatoid
differentiation of the epithelial component.
7. A subtype of mixed pattern tumors displays teratoid
features and may contain elements of mature teratoma
FIGURE 18.14 such as keratinized squamous epithelium, intestinal
Hepatoblastoma typically presents as a single, large, soft, fleshy tumor mass. epithelium, and neuroectodermal structures.
A B
C D
FIGURE 18.15
The fetal pattern of hepatoblastoma exhibits alternating areas of light- and dark-staining tumor cells showing hepatocellular differentiation (A). Osteoid is the
most common mesenchymal element and may be abundant after chemotherapy (B). Some tumors may show rare clusters of differentiated hepatocytes
embedded in primitive mesenchymal cells (C), and others may show marked differentiation and resemble hepatocellular carcinomas (D).
n Glycogen accumulation and bile canaliculi may be seen in

Hepatoblastoma—Pathologic Features
epithelial components
Gross Findings
Genetics
n Single well-circumscribed mass in 80% of cases
n WNT/β-catenin abnormalities present in 80%
n Pure fetal tumors are soft, tan to brown, and coarsely lobulated
n Deletions or mutations in C TNNB1, AXIN, or APC
n Mixed epithelial and mesenchymal tumors have a variegated,
n Two subtypes on gene expression studies:
heterogeneous cut surface
1. Genomic instability with overexpression of α
-fetoprotein (AFP),
CK19, EpCAM, and Myc; these tumors are usually of an
Microscopic Findings immature embryonal phenotype
n Pure fetal epithelial pattern (∼30%) is composed of sheets of 2. Genomically stable with lack of above findings that is usually of
uniform cells resembling fetal hepatocytes fetal type
n Embryonal pattern consists of a mixture of fetal-type cells and smaller,
less differentiated cells with higher nuclear-to-cytoplasmic ratio Immunohistochemistry

n Macrotrabecular pattern: epithelial hepatoblastoma with
n Epithelial components are Hepar-1, AFP, and epithelial
trabeculae more than 10 cells thick
membrane antigenpositive; immature components may be
n Small cell undifferentiated pattern is composed of discohesive
Hepar-1 negative and glypican-3 positive
sheets of small cells indistinguishable from other small blue cell
n Glutamine synthetase positive in the fetal component
tumors of childhood
n Pankeratin are variably expressed
n Cholangioblastic pattern also shows small duct-like structures
n Cytokeratin (CK) 7 and CK19 are positive in the cholangioblastic
n Mixed epithelial and mesenchymal pattern contains fetal and
component
embryonal epithelial cells and primitive mesenchyme with various
n SWI/SNF related, matrix associated, actin dependent regulator of
mesenchymal tissues such as fibrous tissue, osteoid, and cartilage
chromatin, subfamily b, member 1 (SMARCB1) (INI-1) is usually
n Teratoid pattern contains a variety of tissue types in addition to
positive; exception is a subset that shows INI-1 loss in small cell
those found in the mixed pattern, such as skeletal muscle, bone,
undifferentiated component and carries a worse prognosis
or squamous epithelium
n Hepatocellular carcinoma
n Small cell tumors have relatively dense cytoplasm with
n Other small blue cell tumors of childhood
tonofilaments, intercellular junctions, and microvilli
Ancillary Studies BILIARY TUMORS

BILE DUCT HAMARTOMA
Immunohistochemistry ■ CLINICAL FEATURES
Positivity for keratins helpful in confirming epithelial

differentiation. Markers of hepatocellular differentia- Bile duct hamartomas (BDHs), also known as von
tion are useful in fetal, embryonal, and small cell undif- Meyenburg complexes, are small, incidental, clinically
ferentiated subtypes; the latter may be negative for asymptomatic lesions, reported in up to 27% of all autop-
HepPar-1 but may be positive for arginase 1 and glypi- sies. BDH is considered part of the spectrum of ductal plate
can 3. INI-1loss is seen in a subset of small cell undiffer- malformation and may be sporadic or related to autosomal
entiated subtype of tumors that are associated with a dominant polycystic kidney disease, congenital hepatic
worse prognosis. fibrosis, or other genetic disorders
BILE DUCT HAMARTOMA (VON MEYENBURG

COMPLEX)—FACT SHEET
Definition
Hepatoblastoma with a predominantly or exclusively n Bile duct malformation at the level of the interlobular bile duct
small cell component may be difficult to distinguish caused by failure of involution of the embryonic ductal plate
from the small, round cell tumors such as neuroblas-
toma, lymphoma, and rhabdomyosarcoma. The pres-
n Common incidental finding at autopsy or surgery
ence of more differentiated areas of hepatoblastoma and n No geographic predilection
the tumor cell immunophenotype (CK positive; leuko-
cyte common antigen, neurofilament, and desmin nega- Morbidity and Mortality
tive) can distinguish small cell hepatoblastoma from n Sporadic lesions are innocuous; not associated with increased
other neoplasms. The absence of a renal mass generally morbidity or mortality

excludes Wilms’ tumor. The macrotrabecular variant of n Increased risk for cholangiocarcinoma when present as part of
the spectrum of ductal plate malformations

hepatoblastoma closely resembles HCC; however, HCC
is exceedingly rare in the age group affected by hepato- Gender, Race, and Age Distribution
blastoma. Other diagnostic considerations include sar- n Equal gender distribution
comas, such as embryonal sarcoma, which can be n No race predilection
distinguished by the lack of an epithelial component. n All ages but more common in adults
Germ cell tumor must be considered in the differential

diagnosis but is generally excluded by the focal nature of Clinical Features
the teratoid areas in hepatoblastoma. n Most commonly sporadic asymptomatic incidental finding
n When multiple and numerous may be part of the spectrum of
ductal plate malformation and adult polycystic disease
Prognosis and Therapy Prognosis and Therapy

n Treatment is not indicated; lesion is excised for diagnostic
purposes when identified during surgery

The outcome is dependent on tumor resectability. Most n Prognosis is excellent—innocuous finding
patients are treated with neoadjuvant multiagent che-

motherapy, and the rate of resection is greater than
90%. More than 70% of patients have long-term sur-
Pathologic Features
vival. The most frequent metastatic sites are regional
lymph nodes and the lung. Liver transplantation may be
considered in some cases in which tumor is limited to Gross Findings
the liver but is unresectable.
Histologic pattern is generally not an independent Bile duct hamartomas appear as single or multiple sub-
predictor of prognosis, although the small cell undiffer- capsular, gray-white, or occasionally green nodules
entiated pattern with INI-1 loss does appear to cor- smaller than 0.5 cm in diameter.
relate with a poorer prognosis, and completely resected
pure fetal tumors may have a more favorable outcome. Microscopic Findings
Other unfavorable prognostic features are increased
mitotic activity, vascular invasion, incomplete tumor Bile duct hamartomas are found directly adjacent to portal
resection, and AFP levels of less than 100 ng/mL at tracts and consist of ectatic, branched bile ducts lined by a
diagnosis. single layer of bland, low columnar to cuboidal biliary
B
FIGURE 18.16
Bile duct hamartomas are well-circumscribed and frequently subcapsular lesions (A) characterized by dilated biliary channels (B) that may be filled with inspis-
sated bile.
epithelium (Fig. 18.16

). The lumen frequently contains the presence of intraluminal bile. It is distinguished
bile. The stroma is dense and hyalinized, with minimal from CC by its circumscribed lobular configuration and
inflammation. the lack of cellular atypia.
Bile Duct Hamartoma (von Meyenburg Complex)—

Pathologic Features Prognosis and Therapy
Gross Findings
n Small gray-white nodule, often subcapsular
Bile duct hamartomas are innocuous incidental find-
ings. Rarely, CC has been reported in association with
Microscopic Findings multiple BDHs, as with other ductal plate malformation
n Dilated biliary channels embedded in fibrous stroma disorders.
n Located at periphery of portal tract
n Channels may contain bile
Differential Diagnosis BILE DUCT ADENOMA

n Bile duct adenoma
n Metastatic adenocarcinoma or cholangiocarcinoma
A BDA is an innocuous lesion, usually an incidental finding
at autopsy or in the resected liver. It is not clear that a BDA
A BDH is distinguished from a bile duct adenoma (BDA) is a true neoplasm, and it is regarded by some investigators
by its dilated, rather than compact, biliary channels and as a hamartoma of peribiliary glands.
BILE DUCT ADENOMA—FACT SHEET Bile Duct Adenoma—Pathologic Features

n Small benign lesion composed of acini and tubules, regarded by n Usually solitary, subcapsular lesion
some as a peribiliary gland hamartoma n ≤1 cm, well-demarcated gray-white mass

n No geographic variation in incidence reported n Densely packed tubules and acini lined by single layer of cuboidal
n Considered rare but found in approximately 25% of livers at to columnar cells

autopsy when livers were closely examined n Fibrous stroma with variable inflammatory infiltrate
Morbidity and Mortality Immunohistochemistry

n No increase in morbidity or mortality n Immunophenotype is that of peribiliary glands: cytokeratin 19,
carcinoembryonic antigen, and epithelial membrane antigen

Gender, Race, and Age Distribution positive
n Male predominance (male-to-female ratio, 3 to 2)
n Older adults (mean age, 55 years) but all age ranges n Bile duct hamartoma (von Meyenburg complex)
n Cholangiocarcinoma
Clinical Features n Metastatic adenocarcinoma, especially pancreatic
n Incidental finding at surgery or autopsy

adenocarcinoma

n Excellent prognosis
with small lumina. It is distinguished from CC and met-
n Excised for diagnosis; no treatment indicated
astatic adenocarcinoma, especially pancreatic ductal
adenocarcinoma, by its circumscribed nature (lack of
infiltrative growth pattern), no mitoses, no intraluminal
debris, and the lack of cytologic atypia. Having said that,
Pathologic Features some BDAs can reveal clear cell and oncocytic change
and even harbor cytologic atypia that can lead to diag-
Gross Findings nostic challenges, especially during intraoperative con-
sultations for subcapsular liver lesion in a patient
Bile duct hamartomas are solitary, well-circumscribed, undergoing Whipple’s procedure for a pancreatic mass.
firm, gray-white or tan, subcapsular nodules. Most mea- On permanent sections, Ki67 stain can help in the dif-
sure 5 mm or less. ferential diagnosis because most BDA demonstrate a
low proliferative index (<10%) (Fig. 18.17C).
Bile duct hamartomas consist of a compact prolifera-

tion of simple tubular ducts embedded in a variable
amount of fibrous stroma. The tubules have small
lumen unlike the dilated channels of a BDH and do not A BDA is an innocuous incidental finding. However,
contain intraluminal secretions or bile. The cuboidal or some lesions, particularly larger BDAs, may carry a low
low columnar lining epithelium resembles that of inter- risk for malignant transformation.
lobular bile ducts (Figs. 18.17A and B). The cells of a
BDA are uniform and usually lack nuclear pleomor-
phism and hyperchromasia. Mitoses and vascular or
lymphatic invasion are not seen. The stromal inflam- SOLITARY BILIARY CYST
mation is variable. Some variants may be larger in size
and show a prominent stromal component (“biliary
adenofibroma”). ■ CLINICAL FEATURES
Solitary biliary cysts are found in up to 14% of autop-

sies but rarely come to clinical attention. They occur
predominantly in women and are usually asymptomatic.
A BDA is distinguished from a BDH by its lack of intra- Their origin is obscure, but many may develop from
luminal bile and the compact nature of the proliferation BDHs that become isolated from the biliary tree.
C
FIGURE 18.17
Bile duct adenomas (BDAs) are small, well-circumscribed lesions, similar to hamartomas (A) and composed of a tightly packed proliferation of bland biliary
glands with angulated profiles and a narrow lumen (B). Ki67 proliferative index is low, often less than 10% in BDAs (C).
SOLITARY BILIARY CYST—FACT SHEET
Definition
n Non-neoplastic unilocular cyst lined by single layer of cuboidal to
columnar epithelium

n Often incidental finding
n Up to 14% of autopsies
n No geographic variation in incidence reported

n Clinically insignificant unless large in size and causing symptoms
n Favorable outcome in most cases

A
n Female predominance (male-to-female ratio, 4 to 1)
n Rare in children; more common in 30- to 50-year-old age range
Clinical Features
n Smaller cysts are usually asymptomatic
n Abdominal fullness, mass, nausea, rarely jaundice in larger cysts
Radiologic Features
n Circumscribed lesion with water density on computed
tomography

n Surgical excision, laparoscopic fenestration, or aspiration with
sclerotherapy are treatment options
B
Pathologic Features FIGURE 18.18
Biliary cyst is a unilocular, smooth-walled cyst, usually found just under the
hepatic capsule (A) lined by low cuboidal or markedly attenuated biliary epi-
Gross Findings thelium. In contrast, ciliated foregut type cysts (B) are lined by a columnar
respiratory-type epithelium with cilia and surrounded by a variable cuff of
smooth muscle.
Most cysts are subcapsular (Fig. 18.18A) and of variable
size that ranges from a few centimeters in incidental
lesions to up to 40 cm. Biliary cysts usually contain thin
clear yellow fluid, and the cyst lining is flat and glisten- Solitary Biliary Cyst—Pathologic Features
ing. Connection to the biliary tree is not demonstrated.
Gross Findings
Microscopic Findings n More common in right lobe
n Round, with smooth lining
Biliary cysts are frequently lined by a single layer of cuboi- n Fluid is usually clear but may be bile stained; fluid may be
purulent if secondarily infected

dal, flattened, or columnar biliary-type epithelium. The
cyst wall is thin and fibrous and lacks the mesenchymal Microscopic Findings
ovarian-type stroma of biliary cystadenoma, better known n Single layer of biliary-type epithelium
as hepatic mucinous cystic neoplasm (MCN). A ciliated n Cyst wall is fibrous tissue and lacks ovarian-type mesenchymal
lining and smooth muscle in the cyst wall are characteris- stroma
tic of ciliated hepatic foregut cyst (Fig. 18.18B). n Ciliated foregut cyst lined ciliated cuboidal epithelium and
surrounded by smooth muscle and fibrous tissue

n Mucinous cystic neoplasm (formerly known as biliary
cystadenoma shows ovarian-type stroma)

Asymptomatic biliary cysts do not require treatment. n Polycystic liver disease (distinguished on gross examination by
Partial or complete surgical excision or cyst fenestration presence of numerous cysts)

may be performed in symptomatic cases.
POLYCYSTIC LIVER DISEASE Pathologic Features
Gross Findings
Multiple unilocular cysts resembling simple biliary cysts
Polycystic liver disease belongs to the family of fibrocys- and ranging in size from a few millimeters to over 10 cm
tic disorders of the liver and represents one of the ductal in diameter are scattered diffusely throughout the liver
plate malformation disorders, with the malformation or, more rarely, are limited to one lobe (Fig. 18.19).
occurring at the level of the interlobular bile duct.
Patients with polycystic liver disease usually have auto- Microscopic Findings
somal dominant polycystic kidney disease. The liver
cysts are not present at birth but develop over time as Cysts in polycystic liver disease resembled solitary bili-
fluid accumulates in the dilated biliary spaces of BDHs ary cysts microscopically. Origin from BDHs may be
(von Meyenburg complexes). Up to 30% of young adults seen (Fig. 18.20).
have liver cysts; this prevalence increases to 90% in
older patients. Polycystic Liver Disease—Pathologic Features
Gross Findings
n Numerous cysts of various sizes, sometimes involving one lobe
POLYCYSTIC LIVER DISEASE—FACT SHEET more than the other
n Cysts contain clear colorless or yellow fluid
Definition
n Multiple hepatic cysts associated with autosomal dominant Microscopic Findings
polycystic kidney disease n Cysts are lined by columnar to flat biliary epithelium
n Origin in von Meyenburg complex may be demonstrated in
Incidence and Location smaller cysts

n Incidence of autosomal dominant polycystic kidney disease is 1
in 1000 Genetics
n Numerous hepatic cysts are found in approximately 20% of n Associated with autosomal dominant polycystic kidney disease.
patients with polycystic kidney disease n Mutations in P
KD1 and P
KD2 have been implicated
n More common in patients of Northern European descent
Morbidity and Mortality n Solitary biliary cyst
n Morbidity is associated with infection of cysts and development of n Mucinous cystic neoplasm (formerly known as biliary
cholangiocarcinoma cystadenoma) shows ovarian-type stroma
n Death is usually caused by renal disease, not hepatic
involvement
Gender, Race, and Age Distribution Prognosis and Therapy

n Symptomatic hepatic cysts are more common in women, related
to number of pregnancies
The cysts usually do not compromise hepatic function but
n More common in whites
may produce hepatomegaly (sometimes massive) and abdom-
n Average age for manifestation of liver cysts is approximately inal discomfort. Women are more likely to be symptomatic
53 years; number and size of cysts increase with age
Clinical Features
n Hepatomegaly and upper abdominal pain
n Jaundice and portal hypertension are rare
n Hepatic outflow obstruction may be seen
n Manifestations in other organs include colonic diverticula, cardiac
valve abnormalities, and intracranial aneurysms
Radiologic Features
n Multiple circumscribed lesions with water density on computed
tomography

n Excision or fenestration of cysts is rarely indicated
n Liver transplantation has been performed in selected patients FIGURE 18.19

n Prognosis is related to underlying renal disease
Polycystic liver disease shows numerous cysts of varying sizes that com-
pletely distort the hepatic parenchyma.
MUCINOUS CYSTIC NEOPLASM—FACT SHEET
Definition
n Multilocular cystic neoplasm lined by biliary-type or mucinous
epithelium surrounded by an ovarian-type stroma

n Rare tumors
n Geographic variation in incidence not reported

n Survival is excellent for completely resected lesions
n Recurrence rate of approximately 13% for completely resected
carcinomas arising in mucinous cystic neoplasms

FIGURE 18.20
The cysts are lined by flattened or cuboidal biliary epithelium, and some Gender, Race, and Age Distribution
cysts can be seen in association with small bile duct hamartomas.
n Almost exclusively in women
n Mean age is 51 years
n More common in whites
from the cysts, and morbidity is related to number of pregnan- n Carcinomas occur in older patients (mean age, 59 years)
cies, use of oral contraceptives, and severity of renal involve-

ment. Hepatic complications include secondary infection Clinical Features
n Present with upper abdominal discomfort or pain
of cysts and development of cholangiocarcinoma (CC) .
Treatments include resection of more severely affected areas
Radiologic Features
of liver, and in some cases, liver transplantation.
n Solitary, multilocular cystic lesions
n Papillary areas, thickened internal septa, and enhancing mural
nodules suggest malignant transformation
MUCINOUS CYSTIC NEOPLASM Prognosis and Therapy

n Complete surgical excision is the treatment of choice
n Prognosis is excellent for completely resected lesions

The previous terms hepatobiliary cystadenoma and cysta-

denocarcinoma are no longer recommended. These lesions cyst fluid is usually clear and mucinous. The cyst lining
are similar to their pancreatic counterparts and are now is flat, with a few coarse trabeculations (Fig. 18.21A).
designated mucinous cystic neoplasms that are character- Solid areas suggest an invasive adenocarcinoma arising
ized by an ovarian-type stroma. The tumor occurs almost in mucinous cystic neoplasm (MCN) ( Fig. 18.21B ).
exclusively in women, with the mean age at diagnosis 45 MCNs show no communication to the biliary tree.
years. It is likely that lesions reported in the past as hepa-
tobiliary cystadenoma or cystadenocarcinoma in men Microscopic Features
were examples of intraductal papillary neoplasms (IPNs)
of the bile duct that lack an ovarian-type stroma. Patients The cyst epithelial lining of MCNs is composed of cuboi-
may present with abdominal pain or an abdominal mass. dal to columnar or flattened mucinous epithelium
Although most mucinous cystadenomas are intrahepatic, (Fig. 18.22A). Tall columnar mucinous epithelium sim-
these tumors may also be found in the common bile duct, ilar to pancreatic MCNs and intestinal metaplasia can be
hepatic duct, cystic duct, and gallbladder. Carcinomas seen in a subset of tumors (Fig. 18.22B). Neuroendocrine
arising in hepatic MCNs are rare and usually arise in cells, gastric-type epithelium, and squamous metaplasia
older patients. can also be identified occasionally. A characteristic
dense subepithelial mesenchymal spindle cell stroma
resembling ovarian stroma is found in almost all cases
from women and is not found in lesions occurring in
Pathologic Features
men. The characteristic stroma is usually diffusely noted
in the majority (75%) of patients but can be focal and is
Gross Findings immunoreactive for estrogen receptor, progesterone
receptor, and inhibin.
Intrahepatic MCNs are encapsulated and solitary multi- Mucinous cystic neoplasms typically show a flat
cystic lesions ranging from 2.5 to 28 cm in diameter. The lining or papillary intraluminal growth with low- or
A
A
B
FIGURE 18.21
Mucinous cystic neoplasms (formerly known as biliary cystadenomas) are B
multilocular lesions arising in a normal liver (A). The cyst walls are smooth,
FIGURE 18.22
without exophytic projections, and the presence of mural nodules is an indi-
cation of malignant transformation into a biliary cystadenocarcinoma (B). Mucinous cystic neoplasms are lined by a cuboidal pancreaticobiliary-type
epithelium in more than half of all cases that is surrounded by an ovari-
an-type stroma (A). An intestinal type lining epithelium, similar to their pan-
high-grade dysplasia (or both) (Fig. 18.23A). High-grade creatic counterparts, can also be seen in some cases (B).
dysplasia characterized by marked architectural and
cytologic atypia is rare in these tumors. An associated n Most cases show low-grade dysplasia; high-grade dysplasia is
invasive adenocarcinoma is present in about 6% of rare
tumors and is characterized by invasion into the adja- n Invasive adenocarcinoma is present in fewer than 10% of cases
cent stroma accompanied by a desmoplastic stromal
reaction (Fig. 18.23B).
n Epithelium is positive for cytokeratin (CK) 7, CK 8/18, CK 19,
epithelial membrane antigen, carcinoembryonic antigen, mucin 1

(MUC1), and/or mucin 5A (MUC5A)
n Ovarian-type stroma is positive for estrogen receptor,
progesterone receptor, and inhibin

Mucinous Cystic Neoplasm—Pathologic Features
Gross Findings n Simple biliary cyst
n Multilocular cystic mass, 2.5 to 28 cm n Metastatic mucinous adenocarcinoma
n Cyst fluid is usually clear but may be blood tinged in tumors
associated with carcinoma

n Papillary or solid areas suggest cystadenocarcinoma
n Extensive sampling is necessary to rule out associated carcinoma
Ancillary Studies
n Lined by cuboidal, flat, or columnar mucinous epithelium
n Others show nonmucinous epithelium; intestinal or squamous Molecular Studies

metaplasia may be present in a subset
n Ovarian-type stroma underlying the epithelium is characteristic KRAS mutations are present in about 20% of MCNs, but
these lesions lack mutations in G
NAS, RNF43, and P
IK3CA.
B
FIGURE 18.23
A majority of mucinous cystic neoplasms (MCNs) show low-grade dysplasia. However, cases with high-grade dysplasia also occur and show a complex papillary
proliferation (A) correspond to exophytic areas noted on gross examination. Demonstration of invasion into the surrounding stroma is necessary for a diagnosis
of invasive adenocarcinoma arising in an MCN (B).
Differential Diagnosis CHOLANGIOCARCINOMA
Mucinous cystic neoplasms are distinguished from sim- ■ CLINICAL FEATURES

ple biliary cysts by their multilocular nature, nature of
lining epithelium, and ovarian-type stroma.
Cholangiocarcinomas are generally subdivided into
peripheral (small duct) or hilar (large duct) types.
Peripheral small duct CC is defined as cholangiocarci-
noma arising in a segmental duct or a more peripheral
duct. Intrahepatic CC is the second most common pri-
Complete excision of a cystadenoma is the treatment of mary hepatic malignancy and accounts for nearly 15%
choice and is curative. Incomplete resection or cyst fen- of all primary hepatic carcinomas. The cause of CC is
estration usually results in persistent disease. The prog- usually unknown. However, large duct–type CC may be
nosis for patients with invasive adenocarcinoma arising associated with chronic inflammatory lesions of the bile
in an MCN carries a better prognosis than conventional ducts and conditions associated with bile stasis, includ-
intrahepatic CC. ing primary sclerosing cholangitis (PSC), parasitic
infections with liver flukes such as Clonorchis and

On magnetic resonance imaging, tumors are usually hypointense
Opisthorchis, and recurrent bacterial cholangitis with n
relative to liver on T1-weighted images and hyperintense on

hepatolithiasis. Large duct–type CCs have also been T2-weighted images
reported to occur in forms of fibropolycystic liver dis-
ease, including the presence of multiple BDHs. Small Prognosis and Therapy
duct–type CC tends to be associated with nonbiliary n Poor prognosis, with median survival period of approximately
type cirrhosis (viral, hemochromatosis, alcohol, obesity 6 months in patients with unresectable tumors
n Chemotherapy and radiation therapy are of little benefit
or diabetes), Thorotrast, and asbestos.
n Survival depends on tumor stage; tumor grade is less important
Cholangiocarcinoma generally occurs in older adults,
with most patients between 50 and 70 years of age.
Intrahepatic CC is often clinically silent until late in the Radiologic Features
course; patients typically complain of fever, weight loss,
anorexia, and vague abdominal pain. Patients with
intrahepatic CC rarely present with jaundice, in contrast CCs are visualized on CT as a homogeneous low-attenuation
to those with hilar CC. mass, with calcification in some cases. On MRI, the tumors
Elevated serum CA19-9 levels, if greatly elevated, are usually hypointense relative to liver on T1-weighted
may be of utility, although considerable overlap with images and hyperintense on T2-weighted images.
PSC without cancer is seen. Serum CEA is elevated in Cholangiography is useful in visualizing biliary strictures in
about 40% of PSC patients with CC but is less sensitive hilar CC, but distinction from benign lesions may be difficult.
and specific than CA19-9. The serum AFP level is not
typically elevated.
Pathologic Features
CHOLANGIOCARCINOMA—FACT SHEET Gross Findings
Definition On gross examination, intrahepatic CCs are generally

n Malignant hepatic neoplasm demonstrating biliary differentiation
gray-white to tan masses arising in a noncirrhotic liver
(Fig. 18.24A). Whereas hilar lesions grow as periductal
n Approximately 46,000 cases worldwide per year; 19% of primary
liver malignancies
n Incidence is rising
n Geographic variation, with higher incidence in Japan and East Asia
compared with the United States

n Most patients have unresectable tumors
n Patients undergoing resection have longer survival times (23
months median survival vs 6 months with unresectable tumors)

n More common in Asian population
n Affects older adults; mean age is 62 years A

Clinical Features
n Large duct–type cholangiocarcinoma (CC): associated with
inflammatory conditions involving the biliary tree (primary

sclerosing cholangitis, recurrent pyogenic cholangitis, parasitic liver
diseases, hepatolithiasis)
n Small duct–type CC: associated with risk factors of hepatocellular
carcinoma (nonbiliary-type cirrhosis)

n Patients with intrahepatic CC present with nonspecific symptoms
(upper abdominal pain, ascites, weight loss, anorexia)

n Patients with hilar CC present with obstructive jaundice
B
Radiologic Features
FIGURE 18.24
n The usual finding on computed tomography is homogeneous
Peripheral or intrahepatic cholangiocarcinoma arises as a single firm mass,
low-attenuation mass usually in a noncirrhotic liver (A). Hilar cholangiocarcinoma leads to biliary
n Calcification is present in some cases
obstruction, resulting in severe bile staining, and may be indistinguishable
from hilar scarring in primary sclerosing cholangitis (B).
and sclerosing mass lesions along the large ducts (lesions >2 cm), infiltrative growth pattern, mitotic figures,
(Fig. 18.24B), peripheral lesions appear as irregular gray- intraluminal necrosis, and vascular and perineural invasion
white mass-forming lesions in the hepatic parenchyma. are clues toward the diagnosis of carcinoma. Other variants
Large tumors may contain areas of central necrosis or of CCs include signet ring cell, squamous, adenosquamous,
hemorrhage. Central umbilication may be seen in subcap- sarcomatoid (spindle cell), mucinous or signet ring cell, clear
sular tumors. Intrahepatic CCs are grossly classifiable cell, neuroendocrine, and lymphoepithelioma-like variants.
into mass-forming (the most common pattern), periduc-
tal infiltrating, and intraductal growth pattern (least com-
mon) types. The mass-forming type is often seen in a Cholangiocarcinoma—Pathologic Features
background of chronic nonbiliary liver disease. The peri-
ductal infiltration type shows spreading along portal Gross Findings
n Intrahepatic cholangiocarcinomas (CCs) may form large single
tracts, resulting in bile duct strictures, but can also infil-
tumor masses or infiltrate diffusely
trate into the hepatic parenchyma. The intraductal n Tumors are firm and white to tan
growth type is the least common type, often presenting as n Satellite nodules are common
a papillary tumor within the dilated bile duct, and are n Hilar CCs grow as periductal growth and strictures along large
considered part of the spectrum of IPNs of the bile duct. ducts

n Peripheral CC appear as gray white mass-forming lesions in liver
Most CCs are firm because of the prominent desmo-
parenchyma
plastic stroma, which may be gritty because of dystro-
phic calcifications. Satellite lesions resulting from Microscopic Findings
intravascular or intraductal spread may be present. The n The most common pattern is adenocarcinoma
margins may be infiltrative or deceptively well circum- n Most are composed of small glands lined by cuboidal to
scribed on gross examination. Rarely, involvement of columnar mucin-producing epithelium in a dense fibrous stroma
n Perineural invasion is common
portal or hepatic veins may be seen.
n Other adenocarcinoma variants include a bland bile ductular (CC)
or ductal malformation-like pattern of CC

Microscopic Findings n Squamous, signet ring or mucinous, clear cell, neuroendocrine, or
sarcomatoid differentiation may also occur

Most CCs are adenocarcinomas with variable grades of
differentiation. The most common microscopic pattern Genetic
is a well- to moderately differentiated adenocarcinoma n Mutations in K
RAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, and
forming small tubular glands and duct-like structures EGFR are the most common genetic abnormalities
n GNAS mutations are reported in minor subset of fluke-associated
(Fig. 18.25A) in a background of abundant desmoplastic CC
or hyalinized fibrous stroma. The tumor cells are low n IDH1/2, BRAF, and FGFR2 fusions are seen in small duct CC
cuboidal to columnar, with clear to eosinophilic cyto-
plasm and round to oval nuclei. Intracellular mucin pro- Immunohistochemistry
duction may be scant but is usually demonstrable with n Most are cytokeratin (CK) 7 and CK19 positive
n Variable expression of CK20 (more common in hilar type)

special stains for mucin. Perineural and lymphovascular
n HepPar-1 and arginase 1 are negative
invasion is common (Fig. 18.25B). CCs often involve
n Albumin ISH is positive in intrahepatic CC
portal tracts, either by spread within portal vein radicals n MOC31 and Ber-EP4 positive
or by spread within the intrahepatic biliary tree. In cases n polyclonal CEA (pCEA)shows cytoplasmic expression
of large duct CC, adjacent bile ducts may demonstrate n Hepatoid variants of CC can show glypican 3 expression
n CDX-2 is usually negative but may show focal weak positivity in

varying degrees of epithelial dysplasia which is graded
some cases
as low- and high-grade biliary intraepithelial neoplasia.
n CD56 and epithelial membrane antigen in small duct–type CC
Small duct type CC is comprised of malignant tubules
that area bland appearing and mimic reactive bile ducts. Differential Diagnosis
The growth pattern is in the form of nodules encroach- n Metastatic adenocarcinoma
ing the hepatic parenchyma. n Hepatocellular carcinoma
The bile ductular or cholangiolocarcinoma type resem- n Benign lesions such as florid bile ductular proliferation or bile duct
bles a proliferation of primitive biliary ductules with cells adenoma

that are smaller in size than conventional intrahepatic CC
and embedded in a hyalinized stroma. More than 80% of
the tumor is composed of ductular structures. They can
Ancillary Studies
resemble small caliber tubular structures with slit-like cords,
spindled cell morphology with no discernible lumen-
like structures. Ductal plate malformation type of CC Immunohistochemistry
(Fig. 18.25C) is a deceptively bland-appearing variant that
mimics congenital hepatic malformation and is accompa- Cholangiocarcinomas are positive for CK7 and CK19.
nied by a fibrous stroma. The presence of a larger size Peripheral CCs are usually negative for CK-20, whereas
A B
C D
E
FIGURE 18.25
Cholangiocarcinomas are adenocarcinomas of varying grades that incite a striking desmoplastic response, which can be helpful in distinguishing it from
pseudoglandular hepatocellular carcinoma (A). Perineural invasion is an almost universal finding in cholangiocarcinomas (CCs) (B) but is hardly ever seen in
needle biopsies. Within the group of small duct cholangiocarcinomas, a subset can show a ductal plate malformation type of growth pattern (C). The small duct
cholangiocarcinomas are known to express CD56 (D), which can cause diagnostic confusion on some cases. Ki67 stain reveals a proliferation rate of approxi-
mately 50% supportive of the diagnosis of malignancy (E).
hilar CCs are commonly positive for this marker, partic- Differential Diagnosis
ularly carcinomas arising in IPNs. CDX-2 is usually neg-
ative in peripheral and hilar CC but may show focal
weak reactivity in some tumors. CCs show cytoplasmic The primary challenge in diagnosing most CCs is dis-
reactivity for CEA and usually are negative for AFP, tinction from metastatic adenocarcinoma, particularly
arginase 1, and HepPar-1 but may be positive for albu- of the pancreas, gastrointestinal tract, breast, and occa-
min in situ hybridization. Glypican 3 can be positive in sionally lung. Immunohistochemical stains are of lim-
intrahepatic CC with hepatoid features. MOC 31 and ited use in distinguishing CC from other primary tumors
Ber-Ep4 can be helpful in the differential diagnosis with and correlation with imaging findings to exclude a pri-
HCC. mary site elsewhere is usually needed for definite diag-
CD56 (Fig. 18.25D) and luminal expression of epithe- nosis. Colorectal and lung primary cancers can usually
lial membrane antigen is described in small duct–type CC. be excluded using a panel of CK7, CK20, CDX2, and
thyroid transcription factor 1 (TTF-1). Albumin in situ patients with unresectable intrahepatic tumors is only 6
hybridization has been reported as positive in intrahe- to 7 months, even with adjuvant therapy. Patients with
patic CC and HCC as well as in adenocarcinomas meta- carcinomas arising in IPNs and small duct CC have a
static to the liver with the exception of pancreatic better prognosis. At autopsy, 75% of patients have
adenocarcinoma. metastases, usually to porta hepatis lymph nodes, peri-
Among the most difficult differential are benign toneal surfaces, lung, bone, and adrenal gland. Vascular
BDAs because small duct–type CC can be extremely invasion and high tumor stage are important poor prog-
bland appearing. Histologic findings that support a diagnostic indicators.
nosis of CC are large size (>2 cm), infiltrative growth Adjuvant (or more recently neoadjuvant) therapy
pattern, cytologic atypia, mitoses, intraluminal necrosis, used in this setting includes chemotherapy, radiation,
and increased Ki67 (often > 30%) (Fig. 18.25E). chemoradiation, and transarterial chemoembolization.
The distinction between HCC and CC is usually more 5-Fluoracil–based regimens, as well as gemcitabine and
straightforward. HCCs display a trabecular architecture cisplatin are agents commonly used for the treatment of
with scant fibrous stroma, a distinctly different mor- intrahepatic CC. Newer therapeutic approaches encom-
phology from the usual CC. Polyclonal CEA and CD10 pass targeting molecular pathways activated in intrahe-
staining in CC usually show a cytoplasmic staining pat- patic CC (erlotinib is an epidermal growth factor
tern without the canalicular pattern typically seen in receptor–inhibiting drug and more recently pemigatinib,
HCC. Arginase-1 immunohistochemistry may also be which is a fibroblast growth factor receptor inhibitor).
useful in this setting, especially in cases of poorly differ-
entiated lesions. Glypican-3 can be problematic because
it is expressed in CC with hepatoid features and in germ
cell tumors such as yolk sac within can be in the differ- COMBINED HEPATOCELLULAR–
ential diagnosis.
Ultrastructural examination is seldom indicated, but
CHOLANGIOCARCINOMA
electron microscopy of CC cells shows typical features of
adenocarcinoma, such as microvilli and true lumen for-
mation. Epithelioid hemangioendothelioma (EHE) is
easily distinguished from CC by its immunophenotype
(ERG, CD31, and calmodulin binding transcription Hepatic neoplasms demonstrating morphologic features
activator 1 [CAMTA 1 ] positivity) and morphologic fea- of both CC and HCC within the same tumor are classi-
tures (discussed later). fied as combined HCC–CCs. They are rare and share
many epidemiologic characteristics with conventional
HCC and intrahepatic CC. Imaging features also overlap
and are not specific.
Molecular findings
Recent advances in the understanding of molecular path- COMBINED HEPATOCELLULAR-

ways leading to CC have described two main subtypes of CHOLANGIOCARCINOMA—FACT SHEET
intrahepatic CC: The first is inflammatory (38% of
cases), which is associated with alterations in P TGS2 Definition
(COX-2), GNAS, and S TAT3. Kras mutations have been n A tumor containing unequivocal morphologic evidence of both
described also as early events in CCs arising in PSC). The hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC)
second subtype is proliferative (62% of cases), which is
linked to activation of oncogene pathways, including
n Rare tumors
Ras, MAPK, c-Met, Braf, Kras, TP53, IDH mutations, and n Fewer than 5% of all liver carcinomas
chromosomal instability. IDH1/2, Braf and FGFR2 n Geographic variation similar to that of HCC
fusions are found only in small duct–type CC.
n Survival appears to be better than that of CC but worse than that
of HCC
Prognosis and Therapy n Overall 3- and 5-year survival rates of 30% and 18%, respectively

Complete resection of the tumor appears to be an import- n Reported frequently in Asian populations
ant factor in prognosis in CC. The median survival n Older adults (older than 60 years)
period for patients with resectable intrahepatic CC is n Male
around 30 months, and the 5-year survival rate ranges n Association with underling chronic liver disease is not clear
between 35% and 45%. The median survival period for

prominent CC component, the cut surface is often firm

Clinical Features
and fibrotic. Hemorrhagic and necrotic cut surfaces have
n Abdominal pain
also been noted.
n Elevation of α
-fetoprotein, CA19-9, and carcinoembryonic antigen
levels
Radiologic Features
n No specific radiologic features There are no data to support a minimum cut-off thresh-
old for the two components. Therefore, any extent of
Prognosis and Therapy each component is acceptable as long as the evidence is
n Resectability is a good prognostic factor unequivocal. The classical type of combined HCC–CC is
n Prognosis is worse than pure HCC
composed of conventional-appearing HCC and CC (Fig.
n Locoregional therapy is preferred over transplantation
18.26A). Both components range in their differentiation,
and immunohistochemical stains can aid in highlighting
both components. Intraluminal mucin can be present in
Pathologic Features the CC component. In clinical practice, hepatocellular
markers such as arginase-1 can be used to demonstrate
Gross Findings hepatocellular differentiation (Fig. 18.26B), and CK19 is
helpful in highlighting CC (Fig. 18.26C). A transitional
The gross findings are similar to those of HCC. Tumors morphology with stem cell–like features is often present
are usually solitary; however, multiple nodules can be at the interface of the HCC and CC. Positivity for CK19,
present. The size ranges from 3 to 15 cm. If there is a epithelial cellular adhesion molecule (EpCAM), CD56,
A B
C
FIGURE 18.26
Combined hepatocellular–cholangiocarcinomas (HCC–CCs) are rare tumors and require demonstration of two histologically distinct components, HCC and CC
(A). Tumor cells on the left reveal morphologic features of HCC and are positive for markers of arginase-1 (B), whereas the foci on the right clearly show a
gland forming adenocarcinoma component consistent with CC and expressing cytokeratin 19 supportive of the diagnosis (C).
CD117/c-kit stain, and CD133 has been used in the past Differential Diagnosis
as evidence of stem cell–like features, but none of these
markers are specific for hepatic or cancer stem cells and
can be expressed in both components (HCC and CC). Metastatic carcinomas can be challenging to distinguish
The use of the term c ombined hepatocellular and cholan- combined HCC–CC if the HCC component is minimal.
giocarcinoma with stem cell features is no longer recom- Immunohistochemical studies along with clinical and
mended in the latest WHO classification. Similarly, radiologic correlation can help in making this distinc-
mere CK19 positivity in an otherwise typical HCC tion. Undifferentiated carcinomas, by definition, do not
should not be classified as a combined HCC–CC. show any evidence of hepatocellular or glandular differ-
Primary liver carcinomas that show a uniform, mono- entiation but can be identified as epithelial based on ker-
morphic appearance that is intermediate between atin positivity. These can also be primary or metastatic
hepatocytes and cholangiocytes have been classified as tumors, and hence correlation with clinical and imaging
intermediate cell carcinoma of the liver. Immuno findings is necessary.
histochemical expression of both markers of hepatocel-
lular and cholangiolar differentiation are present within
the same cells uniformly throughout the tumor. It is
unclear whether these represent a unique tumor type or
a variant of combined HCC–CC. A CC component with
antler-like anastomosing cords of bile ductular profiles Long-term follow-up for these tumors is currently lim-
with a high nuclear-to-cytoplasmic ratio may be present ited and partly reflects changing diagnostic criteria for
as a component of combined HCC–CC. However, when various subtypes within the group. Patients with com-
this component is present alone or admixed with other bined tumors who underwent resection or liver trans-
adenocarcinoma variants, it is now classified as an intra- plantation have shown worse survival compared with
hepatic CC. patients with HCC alone. At present, locoregional ther-
apy (i.e., transarterial chemoembolization, radiofre-
quency ablation) is preferred.
Combined Hepatocellular-Cholangiocarcinoma—Pathologic
Features MESENCHYMAL TUMORS BENIGN
Gross Findings
HEMANGIOMA
n Solitary or multiple nodules
n 3 to 15 cm in size
n Firm cut surface with areas of necrosis and hemorrhage ■ CLINICAL FEATURES
n Variable; depends on proportion of hepatocellular carcinoma
Cavernous hemangioma, the most common primary
(HCC) and cholangiocarcinoma (CC) components hepatic tumor, is usually an incidental finding at autopsy.
n Either component can be well, moderately, or poorly It is more frequent in adults. Symptomatic CH is more
differentiated common in women, and abdominal pain is the most
n Typically, more fibrosis and desmoplasia compared with pure
common symptom. Most CHs are static over time, but
HCC
n Classic type demonstrates two distinct components
the lesions can rapidly increase in size in pregnancy or
morphologically; an intermediate zone of transition may be with estrogen therapy. CHs may occur in conjunction
present with FNH.
n Pure intermediate-cell tumors are classified as intermediate cell
carcinoma rather than mixed tumors

n CC may be present as the CC component in a mixed HCC–CC
but if present in pure form, it should be classified as an HEMANGIOMA—FACT SHEET

intrahepatic CC
Definition
Differential Diagnosis n Benign vascular tumor of the liver
n HCC with extensive pseudoglandular formation
n Metastatic carcinoma Incidence and Location

n Common; found in approximately 7% of autopsies
Immunohistochemistry n No geographic variation
n HepPar-1, Arginase-1, and/or glypican-3 in HCC areas
n Cytokeratin (CK) 19, CK7, or mucicarmine positivity in CC areas Morbidity and Mortality
n No marker is specific for liver stem cell phenotype other than n Usually incidental, innocuous finding
keratin expression n Rarely, hemangiomas increase rapidly in size and rupture

channels. As these thrombi undergo organization, the

Gender, Race, and Age Distribution CH may undergo sclerosis that begins centrally but may
n More frequent in women
sometimes spread to obscure the entire lesion, resulting
n More common in adults (mean age, 46 years)
in a fibrous nodule.
Clinical Features
n Most patients (>85%) are asymptomatic
Hemangioma—Pathologic Features
n Upper abdominal mass or pain is seen in approximately 50%
n Rupture may be spontaneous or related to trauma Gross Findings

n Single or multiple
Radiologic Features n Vary from smaller than 1 cm to larger than 30 cm
n Mass isodense to large blood vessels on computed tomography, n Spongy honeycombed surface on sectioning
with cloud-like peripheral enhancement

Prognosis and Therapy n Well-formed, blood-filled spaces lined by single layer of bland
n Excellent prognosis for incidental lesions endothelium

n Rarely, surgical excision is performed for symptomatic lesions n Extensive fibrosis may be seen
n Some vascular spaces may contain recent or organized thrombi
Pathologic Features n Hepatic lymphangioma
n Peliosis hepatis
Gross Findings
Most CHs are small (<4 cm) solitary lesions, and back-
ground liver is normal. They are soft, spongy, and well
circumscribed and may be subcapsular or deep within
the parenchyma. On sectioning, CH has an empty Major differential diagnostic considerations include heredi-
mesh-like appearance because of escape of blood from tary hemorrhagic telangiectasia, lymphangioma (extremely
the dilated vascular channels (Fig. 18.27). rare), and peliosis hepatis. In hereditary hemorrhagic telan-
giectasia (Rendu-Osler-Weber disease), hepatic involvement
Microscopic Findings is rarely symptomatic. Telangiectatic lesions, composed of
dilated veins and small capillaries, arise in portal tracts and
Cavernous hemangiomas consist of large variably sized are frequently found in fibrous septa. In peliosis hepatis,
vascular spaces lined by bland, flattened endothelial the blood-filled cavities are not lined by endothelium. CH
cells (Fig. 18.28). The intervening stroma consists of with sclerosis may be confused with other hepatic lesions
fibrocollagenous or myxoid tissue. Thrombi in various that may have prominent fibrosis; the relatively acellular
stages of organization are commonly found within the nature of the fibrosis should prevent confusion with malig-
nancy. CHs with superimposed thrombosis can reveal
areas of cytologic atypia and florid endothelial cell prolifer-
ation mimicking angiosarcoma.
Most CHs are not associated with any morbidity or increased

mortality rate. Asymptomatic CH is not treated and can be
followed up with imaging. Symptomatic lesions larger than
10 cm are often treated by resection or enucleation.
INFANTILE HEMANGIOMA
FIGURE 18.27
Cavernous hemangiomas are spongy red-brown lesions, usually incidentally Infantile hemangioma (IH, previously known as infan-
discovered at imaging examinations or at autopsy. tile hemangioendothelioma) is the most common
FIGURE 18.28
Large, ectatic blood-filled spaces lined by a single layer of bland endothelial cells are characteristic of cavernous hemangioma.
mesenchymal tumor of the liver in childhood, account-

90% are seen in first 6 months of life
ing for about 20% of all primary pediatric hepatic n
n Almost all cases present by 2 years of age

tumors. The vast majority (90%) of patients are younger
than 6 months of age at the time of diagnosis. Girls are Clinical Features
affected slightly more often than boys. Typical present- n Many patients are asymptomatic; symptoms are usually
ing signs include an abdominal mass and high-output nonspecific (nausea, gastrointestinal bleeding, lethargy, liver
cardiac failure, although a significant number of cases failure)
n Most present with hepatomegaly and diffuse enlarged abdomen
are asymptomatic and are discovered incidentally at
n 15% present with congestive heart failure
autopsy after rupture. Platelet sequestration within the n Associated with extrahepatic hemangiomas in approximately 10%
lesion may lead to severe thrombocytopenia and bleed- of cases
ing (Kasabach-Merritt syndrome). IH is associated with
hemangiomas of the skin and other organs in up to 40% Radiologic Features
of cases. The serum AFP level is usually normal. n Hypoechoic or complex mass on ultrasonography
n Low-attenuation mass on nonenhanced computed tomography
n Fine calcifications in 50% of cases

INFANTILE HEMANGIOMA—FACT SHEET n Magnetic resonance imaging is helpful in determining
multifocality
Definition n Enlarged tortuous feeding arteries on arteriography
n Low-grade vascular neoplasm occurring in the first year of life

Incidence and Location n Surgical resection is often curative for unifocal lesions
n Approximately 17% of all pediatric liver tumors n Transplantation is used for large or multifocal lesions
n 40% of benign liver tumors in first 21 years of life n Hepatic artery embolization is also used for large lesions
n Jaundice and multiple tumor nodules are poor prognostic features

n Spontaneous regression in up to 10% of cases
n Overall survival rate is 70% Pathologic Features

n Most deaths are associated with operative complications or
congestive heart failure

Gross Findings
n Female predominance (63%)
Infantile hemangiomas may be solitary or multiple. The
tumor nodules are variable in size and are well
circumscribed. Smaller lesions have a vascular appear- Differential Diagnosis

ance and are red to tan, soft, and spongy; larger nodules
are variegated and have a gray-white, scarred central
area with calcification. Infantile hemangioma should be differentiated from angio-
sarcoma. An infiltrative margin can be found in IH and is
Microscopic Findings not a discriminating feature. Mitotic activity is more pro-
nounced in angiosarcoma, there is higher KI67 proliferative
Infantile hemangioma is composed of a proliferation of index, and hypercellularity caused by densely packed tumor
small, capillary-like, or dilated vascular spaces lined by cells and marked cytologic atypia also favors angiosarcoma.
plump endothelial cells (Figs. 18.29A and B). Occlusion Of note, pediatric patients with angiosarcoma are typically
of the lumen by the endothelial cells may be seen, but older than 1.5 years. The presence of extrahepatic tumors in
mitoses are rare except for proliferative areas. Areas of patients with IH is not indicative of metastatic spread.
pseudopapillary architecture should not be interpreted as When considering benign vascular lesions and vas-
malignant. The vascular channels of IH are separated by cular malformations in the differential diagnosis,
loose connective tissue. Extramedullary hematopoiesis is GLUT-1 stain can be helpful because it is only positive
present in most cases. Portal tracts may be identified in IH. CH lacks the proliferation of numerous small
embedded within the lesion (Fig. 18.29C). Areas indistin- blood vessels found in IH.
guishable from CH are often present in the center of the Myxoid stroma in IH may be confused with mesen-
lesion. Degenerative changes such as thrombi, fibrosis, chymal hamartoma (MH), but the presence of calcifica-
and stroma calcification are common in larger lesions. tion suggests the possibility of IH.

Infantile Hemangioma—Pathologic Features
Gross Findings Roughly 70% of patients survive at least 7 years; most

n Single tumor in 55% deaths occur within 1 month of diagnosis. Congestive
n Spongy red-brown lesions; may have areas of hemorrhage, heart failure and jaundice are the factors most often
necrosis, calcification associated with death, but multiple nodules and the
absence of cavernous differentiation are also adverse
prognostic features. Solitary lesions may be resected.
n Thin vascular channels lined by single layer of plump endothelial cells
n Myxoid to dense fibrous stroma

Ablative therapies may be considered, and in some
n Margins may be well demarcated or infiltrative cases, liver transplantation has been performed.
n Solid areas with atypical endothelial cells should be diagnosed as Spontaneous regression may occur in some cases.
angiosarcoma
Genetics
n Most tumors are diploid; aneuploidy may be associated with a MESENCHYMAL HAMARTOMA
poor outcome
n Balanced translocations reported
n Endothelial cells are positive for vascular markers: ERG, CD31,
CD34, glucose transporter 1 (GLUT-1) Mesenchymal hamartoma is the second most common
n Pericytes surrounding vessels are positive for α
-smooth muscle actin
benign pediatric tumor. Most patients are male, and 75%
n Low Ki67 proliferation index
show symptoms by 1 year of age. Serum AFP levels are usu-
Differential Diagnosis ally normal but can be slightly elevated for age. The neoplastic
n Hemangioma
nature of MH has not been conclusively established; alterna-
n Mesenchymal hamartoma tive theories include aberrant development of primitive mes-
enchyme in portal tracts associated with ductal plate
malformation and localized ischemia during development.
Ancillary Studies
Pathologic Features
Gross Findings
The endothelial nature of the lining cells is easily
demonstrated by immunohistochemical stains for ERG, Mesenchymal hamartoma is solitary and well circum-
glucose transporter 1 (GLUT-1), CD31, and CD34. scribed, is usually large (≤23 cm), and is more common
C
FIGURE 18.29
Infantile hemangioma shows irregular vascular channels separated by loose edematous stroma (A) or densely cellular granulation tissue–like areas (B) that
may harbor entrapped portal tracts (C).
MESENCHYMAL HAMARTOMA—FACT SHEET
Definition
n Benign lesion occurring in young children; composed of large
fluid-filled cysts surrounded by mesenchymal stroma

n 8% of all pediatric liver tumors
n No geographic variation

n 90% survival rate
n Mortality and morbidity are primarily related to surgical
complications

n Median age, 10 months
Clinical Features
n Most common presentation is enlarging abdomen
n Physical examination reveals a nontender mass
Radiologic Features
FIGURE 18.30
n Ultrasonography shows complex multicystic mass
Mesenchymal hamartomas are large, well-circumscribed lesions with vari-
n May be detected in utero
able sized degenerative cystic spaces with smooth surfaces.
n Computed tomography shows variation in cyst size and septal
thickness

n Surgical excision is the preferred therapy
n Rare examples of embryonal sarcoma arising in conjunction with Mesenchymal Hamartoma—Pathologic Features
mesenchymal hamartoma have been reported
Gross Findings
n Involves right lobe in 75% of cases
n Pedunculated in up to 30% of cases

in the right lobe. In most cases, multiple cysts are pres- n Vary from a few centimeters to more than 30 cm
ent, imparting a multilocular appearance (Fig. 18.30). n Cysts in more than 85% of cases; cysts are filled with clear
The cysts contain clear or mucoid fluid, do not commu- amber fluid
n Hemorrhage and necrosis are rare and suggest undifferentiated
nicate with the bile duct, and are separated by solid
sarcoma
areas that become fibrotic with age.
Microscopic Findings n Mixture of bile ducts, hepatocytes, loose mesenchyme, and
vessels
Mesenchymal hamartoma is characterized by a mixture n Degenerative cystic changes lacking epithelial lining are common
of different cell types, including mesenchymal elements, n Loose edematous stroma with scattered bland stellate cells
n Dilated bile ducts at periphery of lesion may be surrounded by

bile ducts, nests of hepatocytes, and vessels. The cysts
dense collar of fibrosis
occur secondary to degenerative changes in the mesen- n Extramedullary hematopoiesis is common
chymal component but rarely represent dilated bile
ducts lined by attenuated biliary epithelium ( Fig. Genetics
18.31A). This stroma consists of bland stellate and spin- n Chromosome 19q13.4 alterations (MHLB1), translocations
dle cells embedded in a myxoid matrix that may show between chromosomes 15 and 19, 11 and 19 are consistently
variable fibrosis (Fig. 18.31B). Extramedullary hemato- reported and cases with germline DICER1 mutations have also
been described. Some authors have reported chromosome 19
poiesis is an almost universal finding. The bile ducts
inversions in a subset of cases
may show progressive dilation and an aberrant architec-
ture reminiscent of ductal plate malformation. The bili- Differential Diagnosis
ary epithelium is often flattened, with atrophic or n Myxoid change in infantile hemangioma
degenerative changes, and a periductal neutrophilic n Embryonal sarcoma
infiltrate may be present.

B
FIGURE 18.31
The bile ducts in mesenchymal hamartoma may undergo progressive cystic dilation (A), and the stroma is abundant, loose, edematous, and myxoid with bland
stellate stromal cells (B).
Ancillary Studies
the perivascular epithelioid cell tumor family. Although
usually detected incidentally, large tumors may cause
Ancillary work-up is not helpful except in ruling out a abdominal discomfort. Tumor rupture with intraab-
metastatic tumor or undifferentiated sarcoma. dominal bleeding is an uncommon complication.
Association of hepatic AML with tuberous sclerosis
occurs in only 6% to 10% of cases compared with 20%
to 40% of cases of renal AML. Tumors with a low-fat
content are often mistaken for other benign or malig-
The treatment of choice is total excision, which is cura- nant lesions on imaging studies.
tive. The perioperative mortality rate is relatively high
(≤17%) and is related to technical difficulties with sur-
gical resection. Recurrence of incompletely resected
Pathologic Features
lesions has not been reported. MH has rarely been
associated with embryonal sarcoma, raising the possi-
bility of malignant transformation of MH. Gross Findings
Hepatic AMLs are usually solitary, well-circumscribed,

ANGIOMYOLIPOMA
nonencapsulated lesions. Tumor size varies from a few
millimeters to larger than 36 cm. The gross appearance is
highly dependent on the tumor composition. Whereas the
fatty component may be evident as soft, yellow regions, the
vascular component may appear as hemorrhagic foci (Fig.
Hepatic angiomyolipomas (AMLs) are rare benign 18.32). Myomatous areas are soft, white-tan, and homoge-
tumors that predominantly affect women and belong to neous. Necrosis is not commonly present.
ANGIOMYOLIPOMA—FACT SHEET
Definition
n Rare benign lesion composed of a combination of abnormal
blood vessels, myoid cells, and adipocytes

n Rare
n No known geographic variation

n Generally benign
n Rare malignant examples reported

n Female predominance (1.4:1 to 9:1)
A
n No known race predilection
n Adult patients; no specific age group
Clinical Features
n Most lesions are asymptomatic and detected incidentally
n Large lesions may present with abdominal pain
Radiologic Features
n Heterogeneous, circumscribed, hyperechoic lesion on ultrasound
n Computed tomography shows a hypodense mass with marked
early contrast enhancement, as well as delayed enhancement in

the portal venous phase
n Magnetic resonance imaging is very sensitive for the detection of
the fatty component on T1-weighted images (high signal intensity)
Prognosis and Therapy B

n Surgical excision usually indicated; nonsurgical management may
be an option for selected patients

n Excellent prognosis
Hepatic AMLs are composed of three basic histologic ele-

ments: blood vessels, myoid cells, and adipocytes (Fig.
18.33A). Tumors have been classified as angiomatous,
C
FIGURE 18.33
Angiomyolipomas contain variable amounts of thick-walled vessels, spindle
or epithelioid myoid cells, and adipose tissue (A). Myoid cells with epitheli-
oid morphology can mimic a variety of epithelial and mesenchymal tumors
(B). Tumors with minimal or no adipose tissue also occur (C). The eccentric
nuclei with abundant eosinophilic cytoplasm, reminiscent of rhabdomyo-
blasts, should raise suspicion for a myomelanocytic tumor involving the liver.
myomatous, lipomatous, or mixed, depending on the pro-

portion of each element present in an individual lesion.
Although a lipomatous component is usually present in
FIGURE 18.32 hepatic AMLs, the fatty areas may be inconspicuous and
Hepatic angiomyolipoma is usually a well-circumscribed soft lesion with areas may not be represented in core biopsies. Myoid cells may
of hemorrhage and adipose tissue in a background of normal liver parenchyma. show different histologic appearances, including spindled,
epithelioid, and intermediate morphology. Epithelioid myoid factor [MiTF], tyrosinase) and smooth muscle markers
cells are commonly present in hepatic AMLs and may cause (desmin, SMA). Pancytokeratin, S100, SOX-10, Hep-Par
significant diagnostic difficulties. They are large, polygonal 1, and arginase-1 are negative and may be used to differ-
cells with abundant clear to eosinophilic cytoplasm and a entiate AMLs from metastatic carcinomas and hepatocel-
round nucleus with a single, often prominent nucleolus (Figs. lular lesions.
18.33B and C). Although mitoses are not numerous, the epi-
thelioid myoid component may show considerable cytologic
atypia. Hemosiderin and melanin pigment may be present.
The vascular component is comprised of tortuous, thick-
walled blood vessels. In addition, extramedullary hematopoie-
sis may also be present in hepatic AMLs, a feature not typically Hepatic AMLs with one predominant component may
seen in renal AMLs. An infiltrating growth pattern with pose diagnostic dilemmas. Angiomatous AMLs must be
tumor invasion of portal tracts and liver parenchyma has distinguished from hepatic hemangiomas and vascular
been reported in AMLs that had a benign clinical course upon malformations, whereas lipomatous AMLs may be con-
follow-up; these features, therefore, should not be regarded as fused with focal fatty change and hepatocellular lesions
an indication of malignant behavior. Malignant AMLs result- with prominent steatosis. The differential diagnosis of
ing in metastatic disease or death are very rare. myomatous AML is broader and includes hepatocellular
lesions (liver cell adenoma and HCC), metastatic carci-
nomas from various sites, and metastatic melanomas.
Angiomyolipoma—Pathologic Features
Recognition of the additional components of the lesions
is the key for a correct diagnosis, which may be con-
Gross Findings
firmed by demonstrating myomelanocytic differentia-
n Well-circumscribed lesion, variable size (0.1–36 cm)
n Gross appearance varies according to tumor composition—

tion on immunohistochemistry. Metastatic carcinomas
combination of hemorrhagic foci (vascular component), white- and hepatocellular lesions can be excluded with CKs
tan, solid, homogeneous areas (myomatous component), and and hepatocytic immunohistochemical markers. The
soft, yellow areas (lipomatous component) nonfatty component of hepatic AML is S-100 negative,
n Normal background liver
which is helpful in excluding metastatic melanomas.
n Angiomatous: abnormal, thick-walled vessels
n Myomatous: myoid cells, which may have a spindle cell,

epithelioid, or intermediate morphology
n Myoid cells with epithelioid morphology are common in hepatic
angiomyolipomas (AMLs) and may be misinterpreted as Most patients with hepatic AMLs are managed surgi-
neoplastic hepatocytes, or another epithelial malignancy
n A lipomatous component usually present but may be inconspicuous
cally, although observation may be appropriate in
n A subset of tumors may show significant atypia; the presence of
selected cases. Hepatic AMLs are generally benign
diffuse atypia, increased mitoses, or atypical mitoses is associated lesions and have an excellent prognosis. Only rare, anec-
with aggressive behavior dotal cases of malignant AMLs have been reported.
Genetics
n Most hepatic AMLs are monoclonal lesions, although no
characteristic molecular abnormalities have been described

n Similar gene expression profile as activated stellate cells by cDNA
MALIGNANT ANGIOSARCOMA
microarray
Differential Diagnosis ■ CLINICAL FEATURES

n Benign and malignant hepatocellular tumors (myomatous variant)
n Metastatic carcinomas and melanoma (myomatous variant)
n Focal fatty change, steatotic hepatocellular tumors (lipomatous variant)
n Hemangioma, vascular malformations (angiomatous variant)

Although hepatic angiosarcoma (HAS) is the most com-
mon primary malignant mesenchymal tumor of the liver
in adults, overall it is quite rare, with only about 200
cases of HAS diagnosed annually worldwide, for an esti-
Ancillary Studies
mated annual occurrence of 10 to 20 cases in the United
States. HAS usually occurs in older men and has been
Immunohistochemistry associated with vinyl chloride exposure and Thorotrast
administration. HAS caused by environmental exposure
Hepatic AMLs are myomelanocytic tumors (Fig. 18.34) is associated with a prolonged latency period. Patients
that are positive for melanocytic (human melanoma present with abdominal pain, fatigue, weight loss, or an
black [HMB-45], Melan-A, microphthalmia transcription abdominal mass.
FIGURE 18.34
Positive staining for myoid markers, desmin, or smooth muscle actin, along with strong human melanoma black reactivity (illustrated in this figure), is character-
istic of angiomyolipomas. Other markers of melanocytic differentiation (S100, MART1, Sox10) can also be variably positive.
ANGIOSARCOMA—FACT SHEET Prognosis and Therapy

n The prognosis is dismal
n Chemotherapy is ineffective
Definition
n Surgery and radiation have been used in rare cases
n High-grade malignant neoplasm of endothelial cells

n Most common primary hepatic sarcoma
Pathologic Features
n 200 cases diagnosed worldwide annually
Morbidity and Mortality Gross Findings

n Rapidly fatal tumor, with most patients dead within 6 months of
liver failure or hemorrhage Hepatic angiosarcoma is usually multicentric and

involves both lobes. The spleen is often involved at the
Gender, Race, and Age Distribution time of diagnosis. Individual tumor foci are infiltrative,
n Male predominance (male-to-female ratio, 3:1) variable in size, and heterogeneous, with solid areas
alternating with large blood-filled spaces.
n Peak age incidence is in the seventh decade of life
Clinical Features Microscopic Findings

n Patients may present with symptoms of liver disease,
hemoperitoneum caused by tumor ruptures, splenomegaly, or Hepatic angiosarcoma is composed of highly atypical,
symptoms related to metastasis large, plump, pleomorphic endothelial cells with hyper-
n The most important known etiologic factors are exposure to vinyl
chromatic nuclei (Fig. 18.35). Solid areas resembling fibro-
chloride, Thorotrast, or androgenic steroids
sarcoma and bizarre tumor giant cells may be seen. Mitotic
Radiologic Features
figures are easily identified. At the periphery of the lesion,
n Nonenhanced computed tomography shows hypodense masses
tumor cells of HAS display a characteristic growth pattern
that are isodense on delayed postcontrast scans of spread along preexisting sinusoids. Obliteration of sinu-
n Abnormal vascular pattern on angiography soids by tumor cells leads to hepatocyte atrophy. Tumor
invasion of portal or hepatic vein branches is common.
Epithelioid angiosarcomas, a minor subset (10%), may be

keratin positive, leading to confusion with a carcinoma.
Subtle foci, especially at the infiltrate edge of the lesion,

may be mistaken for inflammatory or benign vascular
disorders. The atypia of the sinusoidal lining cells dis-
tinguishes HAS from benign mimics. The pattern of
infiltration along sinusoids seen in HAS should not be
confused with HCC, in which the hepatocytes, not the
endothelial cells, are malignant. Kaposi’s sarcoma may
be confused with HAS; however, clinical history of
FIGURE 18.35 acquired immunodeficiency syndrome (AIDS) and posi-
Angiosarcomas show a cellular proliferation of highly atypical cells that are tive staining in endothelial cells for human herpesvirus
spindle or epithelioid in shape and may form narrow vascular channels. 8 facilitates the diagnosis.
Angiosarcoma—Pathologic Features
Gross Findings
n Gray-white tumor tissue alternates with hemorrhagic areas
n Entire liver is usually involved The prognosis for patients with HAS is dismal, with
most patients dying within months of diagnosis.
Microscopic Findings Available therapies are ineffective. Hepatic failure and
n Tumor cells grow along sinusoids and other preformed vascular
intraabdominal bleeding are the most common causes of
channels and replace normal endothelial cells
n Tumor cells are highly pleomorphic spindle cells and may grow as
death. At autopsy, most patients have metastases, most
solid nodules frequently to the lung.
n Areas of infarct, atrophy, and fibrosis are frequent
Molecular alterations
n TP53 mutations mTOR (mammalian target of rapamycin)
EPITHELIOID HEMANGIOENDOTHELIOMA
pathway alterations; PTEN deletions rare
Immunohistochemistry ■ CLINICAL FEATURES

n Tumor cells are positive for endothelial markers: ERG, CD31, and
CD34 (only in 50% of cases)

n Keratin expression can be seen in epithelioid angiosarcoma Epithelioid hemangioendothelioma is a malignant vas-
cular neoplasm most commonly developing in mid-
Differential Diagnosis dle-aged women. Common presenting symptoms are
n Other primary or metastatic sarcomas abdominal pain and weight loss and, rarely, hepatic rup-
n Hepatic metastases of angiosarcoma arising in other organs
ture or liver failure. Involvement of major hepatic vein
branches or terminal hepatic venules may produce
hepatic venous outflow obstruction. In about 40% of
Ancillary Studies cases, EHE may be an incidental finding. The cause of
EHE is unknown, although OCS use has been suggested
Electron Microscopy as an etiologic factor. Multicentricity is not uncommon
in these tumors.
Demonstration of Weibel-Palade bodies by electron
microscopy may confirm the diagnosis, but ultrastruc-
tural examination is rarely necessary.
Pathologic Features
Immunohistochemistry Gross Findings
Immunoreactivity for vascular markers (ERG, CD31, Grossly, EHE lesions are usually multiple ill-defined
CD34, FLI-1) confirms the vascular nature of the tumor. tumor nodules of variable size, with involvement of both
EPITHELIOID HEMANGIOENDOTHELIOMA—FACT SHEET
Definition
n Low-intermediate grade malignant neoplasm of endothelial cells

n Rare tumor
n No reported geographic variation

n Approximately 75% 5-year survival rate, independent of therapy
n Metastases in 25%, primarily to lung, abdominal lymph node,
omentum, and peritoneum; does not preclude long-term

survival

n Female predominance (62%) FIGURE 18.36
n No race predilection Neoplastic cells in epithelioid hemangioendothelioma are embedded in col-
n Wide age range (12–86 years) lagenous or myxoid stroma and show foci of intracytoplasmic lumen that
mimic carcinoma. A subset is also keratin positive and may lead to misdiag-
Clinical Features nosis (not shown).
n Incidental finding in many cases
n Weakness, anorexia, nausea, jaundice, hepatomegaly
n Two-thirds have elevated alkaline phosphatase levels at
presentation
cells are spindle shaped or stellate. Epithelioid cells are
rounded and display a greater amount of eosinophilic
Radiologic Features cytoplasm. A notable feature is the presence of one or
n On computed tomography, low-attenuation, peripheral tumor more well-defined intracytoplasmic vacuoles of vari-
nodules able size that represent vascular lumen formation may
n Signal halo around nodules on magnetic resonance imaging
contain erythrocytes.
n Outcome is unpredictable
n Approximately 30% metastasize or involve other organ
systems Epithelioid Hemangioendothelioma—Pathologic Features

n Treatment ranges from observation only to chemotherapy and
radiation to liver transplantation Gross Findings

n Multiple white to tan firm nodules involving the entire liver
n Margins of lesions appear hyperemic
n Nodules vary from a few millimeters to several centimeters
lobes. Tumor nodules are typically gray to white, firm,

and sometimes gritty. Vascular channels are not appreci-
n Ill-defined lesions
ated on gross examination. n In early stages, tumor spares portal areas
n Tumor cells grow along sinusoids and cause atrophy of liver cell
Microscopic Features plates

n Myxoid or collagenous stroma with epithelioid or spindle cells in
Epithelioid hemangioendothelioma often demon- clusters, nests or single cells

n Cytoplasmic vacuoles represent intracellular vascular lumina and
strates a zonal pattern. At the periphery, portal tracts may contain erythrocytes
are spared and are surrounded by a sinusoidal prolifer-
ation of tumor cells, with residual intact hepatocytes Immunohistochemistry
and scanty myxoid stroma. Progressive obliteration n Tumor cells are positive for vascular endothelial markers ERG,
of the sinusoids results in atrophic hepatocyte plates CD31, CD34

in the midzonal portion of the hepatic acinus. In n Keratin 8/18 expression in a subset of cases
n Positivity for calmodulin binding transcription activator 1

zone 3, the tumor stroma becomes progressively scle-
(CAMTA1) (85%–90%) on immunohistochemistry is diagnostic
rotic, and central veins may be partially or totally
obliterated by tumor cells. However, this feature can- Differential Diagnosis
not be evaluated in biopsies, and the diagnosis rests on n Angiosarcoma
demonstration of epithelioid tumor cells in cords, n Cholangiocarcinoma
small nests, or single cells embedded in a myxohyaline n Non-neoplastic diseases
or dense collagenous matrix (Fig. 18.36). Dendritic

are paucicellular and well circumscribed and do not

Ancillary Studies
invade veins. The distinction between primary hepatic
EHE and metastatic EHE, usually from the lung, is not
Electron Microscopy possible on morphologic grounds.
Ultrastructural examination reveals Weibel-Palade bod-

ies, characteristic of endothelial cells, and numerous
intermediate filaments, which are responsible for the
epithelioid histologic appearance.
The clinical course of EHE is variable and unpredictable.
Immunohistochemistry Some patients die within months of initial diagnosis, but
roughly 20% survive for at least 5 years. Resection is usu-
The tumor cells demonstrate immunoreactivity for ally performed if possible, and hepatic transplantation has
ERG, CD31, and CD34 but are negative for CEA. Nearly led to improved survival even in selected unresectable
15% of EHEs are positive for keratins. Positivity for cases showing signs of extrahepatic disease. Prolonged
CAMTA1 is diagnostic (Fig. 18.37). survival with metastatic disease has been reported.

Genetics. WWTR1-CAMTA1 fusion present in ap- Extrahepatic involvement (lung, omentum or mesentery,
proximately 90% of cases and involves chromosomal lymph nodes) is noted in 50% of patients and may reflect
regions 1p36.3 and 3q25. A minor subset has been multicentricity rather than metastatic spread.
shown to harbor a Y
AP1-TFE3 gene fusion.
EMBRYONAL SARCOMA OF THE LIVER
The differential diagnosis includes other neoplasms ■ CLINICAL FEATURES

such as metastatic adenocarcinoma (particularly the sig-
net ring cell carcinoma), CC, and neuroendocrine neo-
plasms. These tumors can be distinguished from EHE Embryonal sarcoma of the liver (ESL) (also previously
by their lack of zonal growth pattern, cytologic features, described as undifferentiated sarcoma, mesenchymal sar-
and negative staining for endothelial markers. Although coma, and malignant mesenchymoma) is a rare malig-
neuroendocrine tumors may contain dense sclerotic nancy occurring almost exclusively in the pediatric
stroma, their trabecular growth pattern and other char- population. Most patients with ESL are between 6 and 10
acteristic features make the diagnosis straightforward. years of age, and more than 90% are 21 years of age or
Non-neoplastic lesions such as sclerosed hemangi- younger. There is no gender predilection. Patients lack a
oma, fibrous scarring, granulation tissue, and cirrhosis history of chronic liver disease. An abdominal mass or
may also be confused with EHE. Sclerosed hemangiomas abdominal pain is the most common presentation.
EMBRYONAL SARCOMA OF THE LIVER—FACT SHEET
Definition
n Primitive primary sarcoma of liver; more common in children

n Approximately 6% of primary liver neoplasms in childhood

n Prolonged survival and cure possible with multiagent
chemotherapy followed by surgical resection

n Morbidity related to massive local tumor growth

n Equal distribution between sexes
FIGURE 18.37 n Most common between 6 and 10 years of age; rare in those
The neoplastic cells of epithelioid hemangioendothelioma mark strongly with older than 20 years of age
vascular markers, such as ERG, CD31, CD34, but positivity for CAMTA1 (as
shown in the figure) is diagnostic for these tumors.
Clinical Features
Embryonal Sarcoma of the Liver—Pathologic Features
n Most patients present with abdominal swelling, with or without a
palpable mass
Gross Findings
n Most occur in the right lobe and measure up to 20 cm in diameter
Radiologic Features
n Cut surface is gray-white, variegated, and glistening with cystic areas
n Computed tomography reveals a hypodense mass with solid and
cystic areas
n Tumor is usually hypovascular
n Tumor cells are stellate or spindle shaped and loosely arranged in
myxoid stroma
n Tumor cells are often bizarre, with numerous mitotic figures
n Multiagent chemotherapy followed by surgical resection
n Multiple eosinophilic periodic acid–Schiff–positive cytoplasmic
n Combined modality treatment has improved survival; previously
globules are a characteristic feature
reported as 15% 5-year survival rate
n Fibroblastic, smooth muscle, and skeletal muscle differentiation
may be demonstrated
Radiologic Features
Genetics
n No single characteristic abnormalities
Embryonal sarcoma of the liver is usually hypodense on n Multiple cytogenetic alterations reported
CT scan, with solid and cystic areas. The tumor is gen-

erally hypovascular. Immunohistochemistry
n Tumor cells may express cytokeratins, are usually positive for
vimentin, and may express α

1-antitrypsin and α
1-chymotrypsin
Pathologic Features Differential Diagnosis

n Mesenchymal hamartoma
n Mixed epithelial and mesenchymal hepatoblastoma

Gross Findings n Other hepatic sarcomas
Embryonal sarcoma of the liver is usually a large, bulky

solitary mass measuring up to 30 cm in diameter. Immunohistochemistry
On macroscopic examination, the tumor is a well-
circumscribed, soft, gray mass; degenerative changes are Immunohistochemical studies have indicated variable
common and include necrosis, hemorrhage, and cystic immunoreactivity with antibodies to desmin, mus-
degeneration. cle-specific actin, calponin, CD10, CD68, and cytokera-
tin. HepPar-1, myogenin, MyoD1, CD34, CD117, ALK-1,
S100, and β -catenin are usually negative. Areas of spe-
cific sarcomatous differentiation are positive for mark-
ers of their respective lineage.
Embryonal sarcomas of the liver are composed predom-

inantly of large, highly atypical spindle to stellate cells
with ill-defined cell borders embedded in abundant
fibromyxoid stroma (Fig. 18.38A). Cell density may be The sarcomatoid (spindle cell) variant of HCC is distin-
quite variable. Multinucleation, cellular anaplasia, and guished by identification of typical foci of HCC.
numerous mitotic figures are usually found. Cytoplasmic Hepatoblastoma should also demonstrate epithelial
hyaline globules that are PAS positive and diastase resis- areas with fetal or embryonal hepatocellular features;
tant are a characteristic finding and may represent α1AT despite the dissimilar immunohistochemical profile and
uptake by tumor cells (Fig. 18.38B). morphologic findings, glypican 3 can be expressed in
50% of ESL cases, creating confusion. MH is cytologi-
cally bland and paucicellular relative to ESL.
Ancillary Studies
Electron Microscopy Prognosis and Therapy
Ultrastructural features are consistent with mesenchy- Survival in patients with ESL has improved with modern
mal differentiation. therapy. Multiagent chemotherapy followed by complete
B
FIGURE 18.38
Embryonal sarcoma of the liver shows large, bizarre tumor cells in a cellular background of neoplastic spindle to stellate cells (A). Cytoplasmic globular inclu-
sions are common (B) and may be positive for α
1-antitrypsin.
resection has resulted in long-term disease-free survival A male predominance is seen among reported cases,
(>10 years) in some cases. The lung, pleura, and perito- which includes a wide age range. Patients may present with
neum are the most common sites of metastasis. abdominal pain with hepatomegaly; liver test results are
variably abnormal. Human immunodeficiency virus (HIV),
hepatitis B virus, hepatitis C virus, and autoimmune dis-
eases have been implicated in some cases. Please see C
hapter
PRIMARY HEPATIC LYMPHOMA 19for additional details on hepatic lymphomas.
Pathologic Features
Primary hepatic lymphoma is rare and represents fewer Gross Findings

than 0.5% of all extranodal non-Hodgkin’s lymphomas.
However, reported cases vary in lymph node, bone mar- In most cases, a single large mass or multiple bulky
row, and splenic involvement, resulting in difficulties in deposits are present in the liver (Fig. 18.39). A diffusely
comparing clinicopathologic features. In particular, the infiltrative pattern may also be seen, depending on the
spleen is often involved at the time of detection. type of lymphoma.
PRIMARY HEPATIC LYMPHOMA—FACT SHEET Primary Hepatic Lymphoma—Pathologic Features

n Malignant lymphoid neoplasm confined to the liver n Large cell lymphomas produce bulky white to yellow masses
n A discrete mass may not be evident

n Rare; only approximately 0.4% of extranodal non-Hodgkin’s Microscopic Findings
lymphomas n Most are diffuse large cell B-cell lymphomas
n No geographic predilection n T-cell lymphomas are more likely to infiltrate sinusoids diffusely
Gender, Race, and Age Distribution Immunohistochemistry

n Male predominance (male-to-female ratio, 2:1) n Depends on type of lymphoma; most hepatic lymphomas are
n No racial predilection CD20+(see C hapter 19for additional information)

n Usually occurs in adults (median age, 53 years) n Sinusoidal T-cell lymphomas are CD3+, CD45RO+(see C hapter
19for additional information)
Clinical Features
n Reported in setting of chronic viral hepatitis (hepatitis B and Differential Diagnosis
hepatitis C) and AIDS n Chronic hepatitis is distinguished by the mixed nature of the
n Patients present with abdominal pain, distension, and infiltrate and characteristic pattern of tissue damage and
hepatomegaly inflammation
n Epstein-Barr virus hepatitis is best distinguished by clinical
Radiologic Features findings

n Lesions are hypoechoic on ultrasonography
n Low-attenuation lesions with variable enhancement on computed
tomography

n Prognosis is poor for HIV-positive and cirrhotic patients
n Approximately 60% 2-year survival rate
n Combination chemotherapy is generally used The presence of a lymphoid infiltrate that does not fit a
recognized pattern of inflammatory disease in the liver
should prompt consideration of hepatic lymphoma.
Although immunohistochemical markers for various
lymphoid markers may be helpful, gene rearrangement
studies may be necessary. Lymphoma is not usually mis-
taken for carcinoma in the liver; immunostains for CK
and leukocyte common antigen are useful in making
this distinction.
FIGURE 18.39 In general, the prognosis depends on the specific type of

Hepatic lymphomas can present as multiple nodular masses mimicking a lymphoma and the presence or absence of underlying
metastatic carcinoma. liver disease. Treatment has included surgery, chemo-
therapy, and radiation therapy. Patients with HIV infec-
tion or cirrhosis have a poor prognosis.
Most cases are of B-cell lineage, with the diffuse large

cell type accounting for more than 75% of cases.
METASTASES
However, reported cases include many of the lymphoma
histologic subtypes, including primary extranodal mar-
ginal zone lymphoma and hepatosplenic T-cell lym-
phoma. Some B-cell lymphomas are manifested primarily
by the presence of a relatively monomorphic portal infil- Metastatic tumors account for the overwhelming major-
trate (Fig. 18.40). T-cell lymphomas tend to demon- ity of all hepatic malignancies in noncirrhotic livers in
strate a sinusoidal infiltrative pattern. Western countries. In cirrhotic livers, however, primary
FIGURE 18.40
Low-grade B-cell lymphomas involving the liver often present as a monomorphic portal infiltrates of small lymphocytes, a pattern that can mimic chronic hepati-
tis. The neoplastic infiltrate is typically dense and monomorphic and shows marked expansion of the portal tracts.
hepatic malignancies are more common than metastatic

tumors. Carcinomas of the lung, breast, colon, and pan- n Jaundice may be seen when tumors near the hilum cause large
duct obstruction
creas are the most common primary sites in adults; neu-
n Patients may present with acute liver failure from massive diffuse
roblastoma, Wilms’ tumor, and rhabdomyosarcoma are hepatic involvement
the most common primary sites in children.
Clinical features range from asymptomatic to fulmi- Radiologic Features
nant hepatic failure because of the diffuse replacement n Imaging studies show multiple hepatic lesions
of the liver. Obstructive jaundice may occur secondary n Solid, hypoechoic masses on ultrasonography
n Computed tomography appearance is variable, usually decreased

to tumor growth within large bile ducts or compression
attenuation
of the extrahepatic biliary tree by involved perihilar n Magnetic resonance imaging shows high lesion-to-liver contrast
lymph nodes.
n Treatment is usually palliative (systemic or intrahepatic artery
HEPATIC METASTASES—FACT SHEET chemotherapy; chemoembolization, or cryotherapy)
n Resection of isolated hepatic metastases from colorectal cancer
Definition produces an approximately 30% 5-year survival rate for carefully

n Malignant tumor that secondarily involves the liver
selected patients
n Prognosis is related to growth characteristics of tumor, extent of
Incidence and Location hepatic involvement, and comorbid conditions

n Most common malignant neoplasm involving liver
n 40% of patients dying from cancer have liver metastases
n No geographic variation
Morbidity and Mortality Pathologic Features

n High morbidity, with many patients having signs of liver failure
n High mortality rate, with most patients dying within 2 years of
diagnosis Gross Findings
Gender, Race, and Age Distribution In most cases, multiple tumor deposits of varying sizes
n Depends on primary site of cancer
are present (Fig. 18.41A), although in some cases, the
liver parenchyma is diffusely replaced, and nodules are
Clinical Features not apparent on gross examination (Fig. 18.41B). Large
n The most common primary sites are lung, breast, colon, and subcapsular nodules may demonstrate central necrosis
pancreas and fibrosis, producing umbilication. Highly vascular
n Hepatomegaly, anorexia, and weight loss are common
tumors such as choriocarcinoma, angiosarcoma, and
thyroid carcinoma appear hemorrhagic.
A B
FIGURE 18.41
Metastatic carcinoma is the most common malignancy involving the liver. Whereas metastatic colon cancer may be solitary or multicentric and typically shows
abundant necrosis (A), metastatic breast cancer may produce diffuse involvement without discrete mass formation (B).
B
FIGURE 18.42
Metastatic colon cancer resembles the primary tumor, and abundant central necrosis is characteristic (A). Small cell neuroendocrine carcinoma metastatic to
the liver may infiltrate the liver diffusely in a sinusoidal pattern (B) and result in fulminant hepatic failure.
origin from hepatocytes. Vascular invasion of portal
Metastases usually retain the histologic features of the vein radicals may be noted. Colon carcinoma may
primary tumor ( Fig. 18.42). Intrasinusoidal growth involve large bile ducts, with an intrabiliary growth pat-
should not be mistaken for a trabecular architecture or tern that mimics CC.
n Metastatic adenocarcinoma may grow within bile ducts and

Hepatic Metastases—Pathologic Features
simulate cholangiocarcinoma (CC)
Gross Findings
Fine-Needle Aspiration Biopsy Findings
n Usually multiple irregular nodules of varying sizes
n Features are similar to those of primary tumors
n Central necrosis with retraction produces an umbilicated
appearance
n Tumors are firm because of desmoplastic stromal response
n Hepatocellular carcinoma
n CC
n Primary hepatic sarcomas
n Features are similar to primary tumors
n Benign bile duct lesions
B
FIGURE 18.43
Metastatic well-differentiated neuroendocrine tumors from a pancreatic or gastrointestinal primary cancer also commonly spread to the liver. A trabecular or
nested growth pattern with monomorphic tumor cells that show fine nuclear chromatin is characteristic (A), and the diagnosis is easily established by positivity
for markers of neuroendocrine differentiation such as chromogranin (B) or synaptophysin.
5. AishimaS, OdaY. Pathogenesis and classification of intrahepatic

Differential Diagnosis cholangiocarcinoma: different characters of perihilar large duct
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19
Gastrointestinal Lymphoma
■ Michael Cruise, MD, PhD
The gastrointestinal (GI) tract is the most common site lymphomas (including hepatic lymphomas) and updates
of extranodal lymphoma, which should not be a surprise the proposed terminology from the 2017 update to the
as the GI system contains approximately 70% of the lym- fourth edition of the World Health Organization (WHO)
phoid tissue and 80% of the plasma cells (most of those Classification of Hematological malignancies Table 19.1.
being immunoglobulin [Ig] A expressing). Anywhere Several updates are pertinent to the GI lymphomas,
from 20% to 48% of primary extranodal lymphomas including the new category of indolent T-cell lymphop-
have been reported to occur in the GI tract. Additionally, roliferative disorder of the GI tract and duodenal-type
recent reports provide evidence of increasing incidence FL. There is also the reclassification of B-cell lymphoma
rates of primary GI lymphoma in North American popu- unclassifiable with features intermediate between
lation with 0.13 per 100,000 in 1999 up to 2.7 per 100,000 DLBCL and BL to high-grade lymphoma with or without
in 2007. A 2018 report from Japan also places the cur- MYC and BCL2 or BCL6 translocation. Additionally, the
rent incidence at around 2.97 per 100,000. Furthermore, accumulation of clinical and molecular data has shown
there appear to be specific populations such as those from that the two subtypes of enteropathy-associated T-cell
northern Italy, Asia, Native Americans, the Netherlands, lymphoma (EATL) are two distinct disease processes,
and Mexico with an increased incidence of GI lymphoma and their names have been changed to reflect this reali-
of up to 13.2 cases per 100,000. zation. Specifically, the entity formerly known as type I
The primary sites of involvement of the GI tract are EATL is now only designated as enteropathy-associated
the stomach and the small bowel. In developed coun- T-cell lymphoma, and the entity known as type II EATL
tries, most occur in the stomach; however, in developing will be designated as monomorphic epitheliotropic intes-
countries and the Middle East, the small bowel is the tinal T-cell lymphoma (MEITL). Additionally, other
most common site of involvement. In general, approx- entities that can affect the GI tract, Epstein-Barr virus
imately 50% to 75% of primary GI lymphomas occur (EBV)–positive DLBCL, EBV-positive mucocutaneous
in the stomach but only make up 1% to 7% of gastric ulcer, and indolent T- and natural killer (NK) cell pro-
malignancies. In the stomach, lymphomas are evenly liferation, have been added to the WHO classification.
divided between marginal zone lymphoma and diffuse
large B-cell lymphoma (DLBCL). The small bowel is the
primary site in 15% to 35% of GI lymphomas, and 25% ■ MATURE B-CELL NEOPLASMS
of small bowel neoplasms are GI lymphomas. DLBCL
represents the majority of cases (30%–50%) followed
by follicular lymphoma (FL), marginal zone lymphoma, ■ EXTRANODAL MARGINAL ZONE B-CELL
Burkitt lymphoma (BL), and primary intestinal T-cell LYMPHOMA OF MUCOSA ASSOCIATED
lymphomas. Approximately 10% to 20% of GI lym- LYMPHOID TISSUE (MALT LYMPHOMA)
phomas arise in the colon, but these account for only
between 0.2% and 1% of colorectal malignancies. Clinical Features
Overall, in the GI tract, the number of B-cell lym-
phomas greatly outnumber T-cell lymphomas, and in
the GI tract, aggressive lymphomas outnumber the The most common primary low-grade B-cell lymphoma
mature (low-grade) B-cell lymphomas. However, given of the GI tract is extranodal marginal zone B-cell lym-
the increased endoscopic evaluations and improved phoma of mucosa-associated lymphoid tissue (MALT
resolutions, an increased number of smaller lesions, of lymphoma). This lymphoma can develop in either
mature B-cell lymphoma, are being identified. primary or secondary MALT. Extranodal marginal
Although almost any lymphoma or leukemia can zone lymphomas primarily occur in the stomach with
involve the GI tract, this chapter focuses on primary GI decreasing incidences in the small bowel and colon.
613
TABLE 19.1
2017 World Health Organization Updated Classification of Mature Lymphoid, Histiocytic, and Dendritic
Neoplasms
MATURE B-CELL NEOPLASMS

Chronic lymphocytic leukemia/small lymphocytic lymphoma
Monoclonal B-cell lymphocytosisa
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma
Hairy cell leukemia
Splenic B-cell lymphoma/leukemia, unclassifiable
Splenic diffuse red pulp small B-cell lymphoma
Hairy cell leukemia-variant
Lymphoplasmacytic lymphoma
Waldenstrom macroglobulinemia
Monoclonal gammopathy of undetermined significance (MGUS), IgMa
Monoclonal gammopathy of undetermined significance (MGUS), IgG/Aa
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Monoclonal immunoglobulin deposition diseasesa
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
Nodal marginal zone lymphoma
Pediatric nodal marginal zone lymphoma
Follicular lymphoma
In situ follicular neoplasiaa
Duodenal-type follicular lymphomaa
Pediatric-type follicular lymphomaa
Large B-cell lymphoma with IRF4 rearrangementa
Primary cutaneous follicle center lymphoma
Mantle cell lymphoma
In situ mantle cell neoplasiaa
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
Germinal center B-cell typea
Activated B-cell typea
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the central nervous system
Primary cutaneous DLBCL, leg type
EBV-positive DLBCL, NOSa
EBV-positive mucocutaneous ulcera
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK1 large B-cell lymphoma
Plasmablastic lymphoma
Primary effusion lymphoma
Human herpesvirus 8–positive DLBCL, NOSa
Burkitt lymphoma
Burkitt-like lymphoma with 11q aberrationa
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangementsa
High-grade B-cell lymphoma, NOSa
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Approximately 75% to 85% of MALT lymphomas of are associated with Helicobacter pylori infection. The
the GI tract involve the gastric mucosa with the remain- inflammatory response to the infection leads to the for-
ing involving the small bowel and colon. mation of secondary lymphoid tissue in which the lym-
Compared with the distal GI tract, the stomach is phoma develops.
normally devoid of primary lymphoid tissue, and any In other sites in the GI tract, the extranodal marginal
lymphoid tissue present is secondary to inflammatory, zone lymphoma can develop in the normal primary lym-
infections, or autoimmune causes. So, it should not be phoid tissue, especially in the distal small bowel and the
surprising that the majority of gastric MALT lymphomas colon. Although extranodal marginal zone lymphoma of
CHAPTER 19 Gastrointestinal Lymphoma 615
TABLE 19.1
2017 World Health Organization Updated Classification of Mature Lymphoid, Histiocytic, and Dendritic
Neoplasms
MATURE T AND NATURAL KILLER NEOPLASMS

T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of natural killer (NK) cells
Aggressive NK cell leukemia
Systemic EBV-positive T-cell lymphoma of childhooda
Hydroa vacciniforme–like lymphoproliferative disordera
Adult T-cell leukemia/lymphoma
Extranodal NK-/T-cell lymphoma, nasal type
Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T-cell lymphomaa
Indolent T-cell lymphoproliferative disorder of the gastrointestinal tracta
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
Lymphomatoid papulosis
Primary cutaneous anaplastic large cell lymphoma
Primary cutaneous gamma delta T-cell lymphoma
Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
Primary cutaneous acral CD8-positive T-cell lymphomaa
Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disordera
Peripheral T-cell lymphoma, NOS
Angioimmunoblastic T-cell lymphoma
Follicular T-cell lymphomaa
Nodal peripheral T-cell lymphoma with TFH phenotypea
Anaplastic large-cell lymphoma, ALK1
Anaplastic large-cell lymphoma, ALK2a
Breast implant–associated anaplastic large-cell lymphomaa
HODGKIN LYMPHOMA
Nodular lymphocyte–predominant Hodgkin lymphoma (HL)
Classical Hodgkin lymphoma
Nodular sclerosis classical HL
Lymphocyte-rich classical HL
Mixed cellularity classical HL
Lymphocyte-depleted classical HL
POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS
Plasmacytic hyperplasia posttransplant lymphoproliferative disorder (PTLD)
Infectious mononucleosis PTLD
Florid follicular hyperplasia PTLDa
Polymorphic PTLD
Monomorphic PTLD (B- and T-/NK cell types)
Classical Hodgkin lymphoma PTLD
HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS
Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
Indeterminate dendritic cell tumor
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Fibroblastic reticular cell tumor
Disseminated juvenile xanthogranuloma
Erdheim-Chester disease+ a
Modified from Swerdlow SH, Campo E, Harris NL, et al, eds. W
HO Classification of Tumours: Pathology and Genetics. Tumours of Haematopoietic and
Lymphoid Tissues. Revised 4t. Lyon, France: IARC; 2017. h ttp://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Who-Classification-
Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017.
a
Changes from the 2008 classification.
MALT occurs less often in the small bowel, there is a The lymphoepithelial lesions are more prominent
unique form of MALT lymphoma that is primarily seen in the stomach than the small bowel and colon, where
in patients from the Mediterranean and Middle Eastern they can be quite rare. Unfortunately, MALT lymphoma
areas that is referred to as immunoproliferative small of the small bowel and colon can resemble expanded
intestinal disease (IPSID), which is discussed separately reactive MALT and Peyer’s patches. The marginal zone
in this chapter. lymphoma cells expand from the marginal zone but
can also infiltrate and colonize the reactive germinal
centers (Fig. 19.1F and G). Reportedly, up to one-third
of gastric cases demonstrates a component of plasma
Pathologic Features
cell differentiation. These can also lead to amyloid
deposition and light chain accumulation. There can
Gross Findings be scattered larger atypical cells, which are admixed
with the smaller neoplastic cells; however, if there are
Endoscopically, lymphomas generally have a nonspecific diffuse sheets of the larger neoplastic cells, the diag-
appearance. MALT lymphomas of the stomach generally nosis would be DLBCL. In the evaluation of cases for
have a benign appearance often mimicking multifocal MALT lymphoma, one can use the Wotherspoon crite-
gastritis with ulceration. However, the findings can vary ria (Table 19.2) as a useful framework to separate reac-
significantly and include multiple ulcerations, polypoid tive gastritis (Wotherspoon 1 and 2) from suspicious
masses (mucosal or submucosal), mucosa erythema or lesions (Wotherspoon 3 and 4) from MALT lymphoma
edema, granular or nodular mucosal changes, thick- (Wotherspoon 5).
ened or hypertrophic gastric folds, or a combination
of features. Endoscopic ultrasonography can be useful
and tends to yield a more details view of the lesion and
Ancillary Studies
pattern of involvement.
Our ability to detect small bowel lesions has increased
with the advent of capsule endoscopy and double-bal- Immunohistochemical stains are often an essential
loon push enteroscopy. Typically, the appearance in the part of rendering the diagnosis of MALT lymphoma.
small bowel is of an ulcerated or fibrotic area or polyp- However, unfortunately, unlike most other low-grade
oid mass, or it may have a stricture appearance. In the B-cell lymphomas, only a proportion of cases will
colon, MALT lymphomas are more likely to have a whit- have an aberrant immunophenotype. The neoplas-
ish or whitish-red polypoid lesion. Given the endoscopic tic cells are B cells and express B-cell lineage mark-
overlap with other common nonhematopoietic entities, ers, CD20, PAX5, and CD79a. Additionally, because
cases are only rarely submitted with a high suspicion for they are derived from marginal zone B cells, they also
lymphoma or are submitted fresh for ancillary testing express BCL-2 but are negative for germinal center
such as flow cytometry. markers CD10, BCL6, and LMO2. The germinal
center markers can highlight the residual germinal
Microscopic Findings centers and helps accentuate follicular colonization by
the lymphoma cells. There is no aberrant coexpression
As the name implies, the neoplastic cells are derived of CD5, cyclin D1, LEF1, SOX11, or CD23 on the neo-
from the marginal zone of the germinal centers and have plastic cells. Marginal zone lymphomas can demon-
a centrocyte to “monocytoid” appearance. They demonstrate aberrant coexpression of CD43 (Fig. 19.1C, D,
strate abundant pale to clear cytoplasm with slightly and E) but generally only in a minority of cases (up
irregular nuclei and inconspicuous nucleoli. Although to 25% of gastric cases and 30%–40% of the colon
the neoplastic cells are B cells, the lesions can contain a or small bowel cases). In cases with prominent plasma
prominent T cells, or plasma cell infiltrate. Typically in cell differentiation, immunohistochemistry (IHC) or in
GI MALT lymphomas, the lamina propria is expanded situ hybridization for κ and λlight chains can be used
by the neoplastic lymphocytes that infiltrate through to differentiate the clonal plasma cells from reactive
the muscularis mucosa as well as into the glandular epi- plasma cells that are present as part of the inflamma-
thelium with destructive lymphoepithelial lesions (Fig. tory background. Additionally, the presence or absence
19.1A and B). Lymphoepithelial lesions consist of at of H
elicobacter organisms should be documented in all
least three neoplastic B cells infiltrating the glands with gastric lymphoma or carcinoma cases either by hema-
distortion or destruction of the glands (see Fig. 19.1B). toxylin and eosin (H&E), Giemsa, or immunohisto-
Actual lymphoepithelial lesions are typically thought chemical stains (Fig. 19.1H).
to be pathognomonic for marginal zone lymphoma. In borderline cases (e.g., Wotherspoon 3 and 4), when
However, lymphoepithelial-like lesions can be seen in CD43 coexpression cannot be demonstrated, B-cell
multiple etiologies and in these cases, they consist of the gene rearrangement studies by polymerase chain reac-
epithelium infiltrated by T cells. tion (PCR) may be helpful. In the distal small intestine
A B
C D
E F
G H
FIGURE 19.1
Mucosa-associated lymphoid tissue (MALT) lymphoma. A, At low magnification, the lamina propria is markedly expanded by small lymphocytes. Residual oxyn-
tic glands are present within the neoplastic infiltrate. B
, The infiltrate is composed of monomorphic, monocytoid lymphocytes with abundant clear cytoplasm,
well-defined cell borders, and eccentric small nuclei. The lymphocytes invade the gastric glandular epithelium to form lymphoepithelial lesions. The lympho-
cytes are primarily CD20+B cells (C) admixed with a background of CD3 positive T cells (D). The B cells demonstrates aberrant CD43 expression (E). MALT
lymphomas can demonstrate colonized germinal centers. The lymphoma cells expressing BCL2 (G) can be seen infiltrating the BCL6-expressing germinal cen-
ter (F). As in all cases of possible lymphomas and gastric carcinoma, the presence or absence H elicobacter pylori (H) should be determined.
TABLE 19.2
Histological Differential Scoring of Lymphoid Infiltrations in the Stomach According to
Wotherspoon et al. (1993)
Score Diagnosis Histologic Features
0 Normal Scattered plasma cells in lamina propria; no lymphoid follicles

1 Chronic active gastritis Small clusters of lymphocytes in lamina propria; no lymphoid
follicles; no lymphoepithelial lesions
2 Chronic active gastritis with florid lymphoid Prominent lymphoid follicles with surrounding mantle zone and
follicle formation plasma cells; no lymphoepithelial lesions
3 Suspicious lymphoid infiltrate, probably reactive Lymphoid follicles surrounded by small lymphocytes that infiltrate
diffusely in lamina propria and occasionally into epithelium
4 Suspicious lymphoid infiltrate, probably Lymphoid follicles surrounded by marginal zone cells that infiltrate
lymphoma diffusely in lamina propria and into epithelium in small groups
5 MALT lymphoma Presence of dense infiltrate of marginal zone cells in lamina
propria with prominent lymphoepithelial lesions
Adapted from Wotherspoon A, Doglioni C, Diss T, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after
eradication of Helicobacter pylori. L ancet. 342:575-577, 1993.
MALT, Mucosa-associated lymphoid tissue.
TABLE 19.3
Groupe d’ Etude des Lymphomes de l’Adulte Histologic Grading System for Posttreatment Evaluation of
Gastric Mucosa-Associated Lymphoid Tissue
Interpretation Lymphoid Infiltrate Lymphoepithelial Lesions Stromal Changes
Complete histological remission Absent or scattered plasma cells Absent Normal or empty LP
and small lymphoid cells in the LP and/or fibrosis
Probable minimal residual Aggregates of lymphoid cells Or Absent Empty LP and/or
disease lymphoid nodules in the LP/MM fibrosis
and/or SM
Responding residual disease Dense, diffuse or nodular, extending Focal LEL or absent Focal empty LP and/or
around glands in the LP fibrosis
No change Dense diffuse or nodular Present but may be absent No changes
Adapted from Copie- Bergman C, Wotherspoon AC, Capella C, et al. Gela histological scoring system for posttreatment biopsies of patients with gastric MALT lymphoma
is feasible and reliable in routine practice. B
r J Haematol. 2013;160:47-52.
LEL, Lymphoepithelial lesions; L P, lamina propria; M M, muscularis mucosa; S M, submucosa.
where normal B cells can coexpress CD43, B-cell gene (q21;q21)/API2-MALT1, t(1;14)(p22;q32)/IgH-BCL10,
rearrangement studies are often necessary to establish t(14;18)(q34;q21)/IgH-MALT1, and t(3;14)(p14.1;q32)/
or confirm the diagnosis. Of note, B-cell clonality studies FOXP1-IGH. Only two are associated with GI MALT
have a use in the initial diagnosis but should not be used lymphoma, t(11;18) and t(1;14). The t(11;18) translo-
as a means to determine therapy response. Specifically, cation has been reportedly seen in 6% to 16% of gastric
B-cell clones may persist for an extended time after mor- and 12% to 56% of intestinal MALT lymphomas. Only
phologic resolution, and their presence does not affect rare gastric (0%–5%) or intestinal (0%–13%) MALT
outcomes. We typically utilize the Groupe d’ Etude des lymphoma cases have the t(1;14). The most common
Lymphomes de l’Adulte (GELA) histologic scoring sys- genetic abnormalities in MALT lymphoma are triso-
tem by Copie-Bergman et al. (2013) (Table 19.3) as a way mies involving chromosomes 3 and 18. Interestingly,
of reporting treatment effect. One should note that even although t(11;18) (API2/MALT1) lymphomas tend
in the absence of lymphoma that treated H elicobacter to be less responsive to Helicobacter eradication ther-
gastritis takes months to more than 1 year for histology apy, they also have little to no potential to progress
to become “normal.” to DLBCL.
Several cytogenetic abnormalities have been asso-
ciated with MALT lymphoma. There are four recur- CD43 Pitfall
rent chromosomal translocations associated with
MALT lymphoma, and they vary in their prominence The diagnosis of marginal zone lymphoma can be
at various anatomic sites. These include t(11;18) challenging because most cases lack an aberrant
immunophenotype. A minority of cases aberrantly SOX11 by the neoplastic B cells. MALT lymphomas can
expressed is CD43. CD43 is normally expressed by T have a nodular appearance overlapping with that of low-
cells and plasma cells but can be aberrantly expressed grade FL. However, FL has a distinctive immunophe-
by B-cell lymphomas. It is essential to remember that it notype with an expression of germinal center markers
is not specific for marginal zone lymphoma. Typically, CD10, BCL6, LMO2 with aberrance coexpression for
CD43 on the B cells in MALT lymphomas demon- BCL2. FL is negative for CD43. Another mature B-cell
strates a dimmer expression than T cells, and if the lymphoma that can mimic MALT lymphoma is SLL
CD43 expression on the B cells is as strong as or stron- or CLL. These can also have similar cytomorphologic
ger than the background T cells, other possible mature appearance (although typically with less cytoplasm).
B cells must be considered. Specifically, aberrant SLL and CLL lymphoma cells are typically B cell mark-
CD43 expression can be seen in mantle lymphoma, ers CD19, CD20, PAX5, and CD79a as well as aberrant
small lymphocytic lymphoma (SLL) and chronic lym- expression of CD43, CD5, CD23, and CD200. SLL and
phocytic leukemia (CLL), as well as BL. Additionally, CLL also demonstrate aberrant coexpression of LEF1 in
there are populations of normal B cells in the terminal the neoplastic B cells. The expression of LEF1 is typi-
ileum and proximal right colon that generally express cally seen in T cells and can be seen in aggressive B-cell
CD43. In certain situations, the lymphomas have a lymphomas.
prominent population of T cells and plasma cells, and
one must be cautious not to misinterpret these cells as
aberrant B cells.
Long-term remission is generally the rule, not the

exception, in low-grade MALT lymphomas, espe-
cially the gastric subtype. The continued prolifera-
Often the most challenging differential diagno- tion of gastric MALT lymphoma cells in patients with
sis is between chronic active Helicobacter gastri- H. pylori is dependent on the presence of H . pylori–
tis versus MALT lymphoma. The infection leads specific T cells and not caused by antigen and direct
to a reactive lymphoid infiltrate, creating acquired B-cell receptor interactions. The majority of patients
MALT with reactive germinal centers and surround- respond to H elicobacter eradication antibiotic therapy
ing mantle and marginal zones. During the transi- with long-term remissions seen in up to 70% to 80%
tion from gastritis to lymphoma, both the number of cases. Certain features are associated with failure
of H elicobacter organisms and the amount of acute of H elicobacter eradiation therapy. Specifically, the
inflammation typically decreases. Of note, although the presence of either the t(11;18) and t(1;14) transloca-
neoplastic B cells are not Helicobacter antigen depen- tion is associated with BCL10 expression, and these
dent, the reactive T cells appear to be Helicobacter anti- patients are more likely to fail Helicobacter eradication
gen driven. These activated T cells active or stimulate therapy. Approximately, 6 weeks after H elicobacter
B cells (both neoplastic and non-neoplastic) via CD40- eradication therapy, patients should be tested
CD40L interaction. for the continued presence of the organisms (either
This differential between gastritis and lymphoma by biopsy or another method, such H. pylori fecal
can at times be extremely challenging. Although strict antigen test). Specifically, with the rise in clarithro-
adherence and application of the Wotherspoon criteria mycin as well as metronidazole and levofloxacin anti-
are not typically required, it does provide a useful frame- biotic-resistant strains, more than 20% of patients
work for classifying reactive gastritis from cases that need a second round of antibiotic therapy to eliminate
are suspicious for or diagnostic for MALT lymphoma. the infection.
A differentiating point is the presence of epithelial inva- Additionally, when the lymphoma has extended
sion and glandular destruction by a B-cell process. As beyond the submucosa, the lesion tends to be more
outlined earlier, aberrant CD43 expression and detec- resistant to conservative therapy. Generally, MALT
tion of a clonal B cell process are useful in the differ- lymphomas are sensitive to radiation therapy with an
entiation between a reactive inflammatory process and excellent response rate. Additionally, some patients
lymphoma. may be managed with single-agent rituximab or ritux-
The other primary differential includes the other imab with additional chemotherapy. Transformation
mature B-cell lymphomas. Both mantle cell lymphoma to DLBCL may occur but typically in fewer than 10%
(MCL) and FL are discussed in further detail later. of cases. Interestingly, DLBCL cases that are associated
Briefly, MCL demonstrates an abnormal phenotype with Helicobacter may also respond to Helicobacter erad-
with aberrant expression of CD5, CD43, cyclin D1, and ication therapy only.
■ Prominent plasma cell differentiation in up to a third of gastric

MALT LYMPHOMA—FACT SHEET
cases
■ Reactive follicles occasionally present with the colonization of the
Definition follicles
■ Low-grade extranodal marginal zone B-cell lymphoma that arises ■ Presence of moderate nuclear atypia, Dutcher bodies, and
from mucosa-associated lymphoid tissue (MALT) prominent lymphoepithelial lesions are features highly suggestive
of lymphoma
■ Most common location is stomach (75%–85%), followed by the Immunohistochemistry
small bowel and colon/rectum ■ Positive B-cell markers (CD19, CD20, PAX5, CD79), BCL2+,
■ Account for fewer than 1% to 4% of primary gastric neoplasms CD3-, CD5-, LEF1-, Cyclin D1-, SOX11- BCL6-, LMO2-, CD10-,
and up to 50% of gastric lymphomas and low Ki-67 proliferation index
■ Associated with H
elicobacter pylori gastritis in the stomach ■ Minority of cases (20%–40%) are CD43+
Morbidity and Mortality Genetic Abnormalities

■ Indolent behavior in most low-grade lesions with excellent ■ t(11;18)(q21;q21) , API2/MALT1
prognosis ■ t(1;14) results in B
CL1 and IGH fusion leading to overexpression
■ Minority of lesions (<10%) show transformation to high-grade of BCL10
B-cell lymphoma ■ Trisomy of chromosomes 3 and 18
Gender, Age, and Race Distribution Differential Diagnosis

■ Slight female predominance in gastric MALT lymphoma and male ■ Reactive lymphoid hyperplasia such as chronic H elicobacter
predominance in small intestinal MALT lymphoma gastritis or autoimmune gastritis
■ Presents in the fifth and sixth decades of life ■ Mantle cell lymphoma (Cyclin D1+, SOX11+, CD5+, BCL2+,
CD43+, LEF1-, CD23-, CD10-, BCL6-, LMO2-)

Clinical Features ■ Follicular lymphoma (CD10+, BCL6+, LMO2+, BCL2+, CD43-,
■ Physical examination is normal in 55% to 60% CD5-, cyclin D1-, SOX11-, LEF1-, CD23-)
■ Abdominal pain ■ Small cell lymphoma/Chronic lymphocytic leukemia (CD5+,
■ Bleeding LEF1+, CD43+, CD23+, CD43+, BCL2+, SOX11-, CD10-, BCL6-,

■ Intestinal obstruction or perforation LMO2-, cyclin D1-)
■ Weakness, night sweats, or fever ■ DLBCL
■ Palpable abdominal mass
■ Hematemesis and melena are rare
Prognosis and Treatment ■ IMMUNOPROLIFERATIVE SMALL

■ Good prognosis associated with age younger than65 years, low-
INTESTINAL DISEASE (a HEAVY CHAIN
grade histology, and/or initial complete remission
■ 5-year survival rates for gastric MALT lymphoma: 50% to 90%
DISEASE)
■ 5-year survival rate for small intestinal MALT lymphoma: 50% to
80%
■ Progression to diffuse large B-cell lymphoma (DLBCL) may occur Immunoproliferative small intestinal disease (also
in 8% of MALT lymphomas known as α heavy chain disease, Mediterranean lym-
■ Adverse prognostic factors include extension beyond the bowel
phoma, and diffuse small intestinal lymphoma) is a
wall, nodal involvement, and transformation to DLBCL
subtype of extranodal marginal lymphoma of mucosa
associated lymphoid tissue. The production of α heavy
chains without associated light chains character-
izes this disease. IPSID occurs almost exclusively the
Mediterranean, Middle Eastern, and North African
Malt Lymphoma—Pathologic Features countries. However, the disease has also been reported
in places with a prominent population of migrants,
Gross, Endoscopic, and Radiology Findings
including Asia, Europe, and the United States. This
■ Ulcerated, polypoid, granular, nodular, or edematous and
lymphoma accounts for up to 75% of the GI lymphomas
hyperplastic mucosal folds
■ Single or multiple mucosal or submucosal masses
that occur in adolescents and adults in the Middle East.
■ Stricture (in small bowel or colon cases)
■ Most commonly found in the gastric body or the prepyloric area
Microscopic Findings Clinical Features

■ Infiltrate of small monocytoid lymphocytes often mixed with
immunoblasts and plasmacytoid cells

■ Lymphoepithelial lesions
Immunoproliferative small intestinal disease typically
■ Infiltrate expands interfollicular space and effaces normal
affects adolescent and younger adults with a median age
architecture of 25 years. Patients typically present with abdominal
pain with chronic diarrhea and malabsorption (often
severe), resulting in malnutrition and weight loss. In these similar morphologic features as those of stage A.
patients, the malnutrition can lead to peripheral edema, However, the infiltrate becomes nodular, imparting
muscle spasms, and digital clubbing. GI tract obstruction, an endoscopic appearance of thickened mucosal folds,
bleeding, and perforation is uncommon. However, these nodularity, flatting, or cobblestoning of the small bowel
patients can also present with enteroenteric fistula as mucosa. The infiltrate also extends beyond the mucosa
well as lactose intolerance, hypocalcemia, and organo- through the muscularis propria to involve the submu-
megaly. Common risk factors for IPSID include low cosa or muscularis propria. Stage C disease represents
socioeconomic status, poor sanitation, endemic parasitic large cell transformation in which large masses are seen
infestation, and history of infantile infectious enteritis. in the small bowel. The neoplastic cells often retain a
Importantly, in areas with improving sanitary condi- plasmacytoid appearance but are often quite pleomor-
tions, the frequency of the disease is decreasing. Similar phic and bizarre appearing. Additionally, the mesenteric
to the association of H . pylori infection and gastric mar- lymph nodes can be involved in any stage. Typically, in
ginal zone lymphoma, IPSID is thought to be associated early-stage disease, the lymph node sinuses are expanded
with an infectious etiology. Specifically, Campylobacter by plasma cells with progressive involvement of the mar-
jejuni has been shown to be associated with IPSID, ginal zone and colonization of the follicular centers.
although other possible infectious agents have also been
suggested. As mentioned earlier, patients with IPSID
produce an altered α heavy chain that can be secreted
Ancillary Studies
and then detected in body fluids. Up to 70% of patients
can have an αheavy chain paraprotein, which typically
is at its highest levels early in the disease course and may The neoplastic cells are positive for B-cell markers CD20,
diminish as the disease progresses. PAX5, and CD79a as well as BCL2. They can also aber-
rantly express CD43 but are negative for germinal cen-
ter markers CD10, BCL6, and LMO2. Additionally, the
neoplastic cells are negative for aberrant coexpression of
Pathologic Features
CD5, cyclin D1, LEF1, and CD23. The plasmacytic com-
ponent can be highlighted by plasma cell marker CD138.
Gross and Endoscopic Findings One of the distinctive features of IPSID is the pres-
ence of an aberrant αheavy-chain protein in which
Immunoproliferative small intestinal disease can be the Ig lacks the variable heavy chain domain as well
divided into three stages based on gross and micro- as the first constant domain producing a truncated Ig
scopic features and the extent of involvement. The lym- that cannot bind to the light chain. This protein can be
phoma typically involves the proximal portion of the detected in the plasma or serum. Additionally, the α Ig
small bowel but can involve any other part of the small heavy chains can be demonstrated in the cytoplasm of
bowel. Additionally, gastric and colonic lesions have the infiltrating B cells, plasma cells, and transformed
been reported. Stage A is confined to the small bowel large cells. The Ig heavy chain is clonally arranged.
and mesenteric lymph node. There are typically no gross However, other recurrent genetic abnormalities have
lesions. Stage B disease typically demonstrates a mildly not been described. Specifically, the t(11;18) transloca-
modular or cobblestone appearance. In stage C disease, tion described in other MALT lymphomas has not been
patients have can have single or multiple larger masses. demonstrated in IPSID.
Immunoproliferative small intestinal disease demon-
strates a histologic spectrum ranging from low-grade
histologic changes seen in stage A and B to high-grade The differential diagnosis for IPSID depends on the
histology seen in stage C. Because this is considered a stage of the disease. As described earlier, one of the most
specialized subtype of MALT lymphoma, most patients challenging differentials is between lymphoma and
demonstrate features typical of MALT lymphomas. reactive lymphoid process. In stage A, the initial con-
Specifically, IPSID tends to demonstrate marked plasma- sideration is often that of gluten-sensitive enteropathy
cytic differentiation. In stage A, there is a lymphoplas- (GSE) or celiac disease. However, in GSE, the intraep-
macytic infiltrate with lymphoepithelial lesions. Similar ithelial lymphocytes are significantly increased with
to typical MALT lymphomas, there are often reactive associated villous atrophy. Typically, patients with GSE
follicles surrounded by marginal zone with an expan- are from northern European ancestry and respond to
sion of the lamina propria. The changes are limited to a gluten-free diet. Also, the infiltrate in GSE is CD3+
the mucosa and often demonstrate widened or blunted T cells, whereas IPSID is populated by CD20+B cells.
villi. In stage B disease, the neoplastic cells demonstrate Additionally, other intestinal T-cell lymphomas often
present with a similar diffuse infiltrate like IPSID; how-

ever, these are easily differentiated by CD3 and CD20
■ Stage A: dense lymphoplasmacytic infiltrate with features of a
immunostains.
typical mucosa-associated lymphoid tissue (MALT lymphoma),
The nodular lymphoid aggregates of stage B disease including lymphoepithelial lesions, but is restricted to the mucosa
can mimic reactive lymphoid hyperplasia as well as FL ■ Stage B: similar features to stage A with prominent nodular
and MCL. Reactive follicular hyperplasia is common in infiltrate and germinal center colonization, infiltrate extends
the distal small bowel, but lymphoid aggregates in the through the muscularis mucosa into the submucosa, and no
evidence of large cell transformation
proximal small bowel necessitate additional work up. The
■ Stage C: large masses with a transformation to large cell
reactive processes also lack prominent lymphoepithelial lymphoma, plasmacytoid differentiation often evident along with
lesions that are typical of MALT-lymphoma or IPSID. centroblasts, immunoblasts, and pleomorphic cells
Compared with other low-grade lymphomas, IPSID
demonstrates a prominent plasma cell or plasmacytoid Immunohistochemistry
differentiation with lymphoepithelial lesions. The neo- ■ CD20+, CD19+ PAX5+, CD79a+, BCL2+, CD5-, CD10-,
plastic cells are not as monotonous as is typical of MCL BCL6- and CD23-; may be positive for CD43. The plasmacytic
component is positive for CD138
and do not demonstrate aberrant expression of cyclin D1 ■ α-Immunoglobulin heavy chains in the cytoplasm (typically
or SOX11. FL consists of centrocytes with germinal cen- without light chain expression) of the infiltrating plasma cells,
ter differentiation and aberrant BCL2 expression. centrocytes, and transformed blast cells
The differential diagnosis of stage C disease is that
of high-grade malignancies, including EATL, DLBCL Differential Diagnosis
malignancies, plasmablastic lymphoma (PBL), and even ■ Low-stage disease: reactive lymphoid hyperplasia, mantle
cell lymphoma, celiac disease, indolent T-cell lymphoma, and

poorly differentiated carcinoma or melanoma. Often
follicular lymphoma
among and between the pleomorphic neoplastic cells are ■ High-stage disease: large B-cell lymphoma, enteropathy-
residual low-grade neoplastic cells that can help with associated T-cell lymphoma, melanoma, and other poorly
these differentials differentiated malignancies

IMMUNOPROLIFERATIVE SMALL INTESTINAL
DISEASE—FACT SHEET
There are no treatment guidelines for patients with
Definition
IPSID; however, in patients with early-stage disease, the
■ IPSID and α
heavy-chain disease are considered subtypes of
use of broad-spectrum antibiotic therapy has led to remis-
MALT lymphoma that produces α heavy chain that can be either
sion, similar to H
elicobacter eradication for gastric MALT secreted or nonsecreted by the neoplastic cells
lymphoma. In more advanced cases with visible tumor
masses, chemotherapy with rituximab (e.g., R-CHOP [rit- Incidence and Location
uximab, cyclophosphamide, doxorubicin, vincristine, and ■ Primarily in Mediterranean, Middle East, and North Africa
prednisone]) is typically used, with reported remission ■ In these areas, immunoproliferative small intestinal disease
and long-term survival rate of up to 70%. Ultimately, in accounts for up to 20% of non-Hodgkin lymphomas and 75% of
all small bowel neoplasms
situations with obstructing tumors, treatment with radi-
ation, surgery, or both may be required. Gender, Race, and Age Distribution
■ Young adults with a median age of 25 to 30 years; no gender to
only a slight male predominance
Clinical Features
Immunoproliferative Small Intestinal Disease—Pathologic
■ Severe chronic intermittent diarrhea, abdominal pain, weight loss
Features
ultimately leading to severe carbohydrate and lipid malnutrition
■ Protein-losing enteropathy can be seen
■ Nearly half of patients have peripheral edema, tetany, and
■ May have normal macroscopic appearance
clubbing of digits
■ Thickened mucosal folds and nodularity or cobblestoning
■ Advanced disease presents with large masses

■ Typically involves the proximal small intestine but may also
■ Patients with early-stage disease respond to antibiotics
involve any part of the small intestine, and involvement of
■ Established disease: radiation therapy and/or combination
stomach and colon have been reported
■ Mesenteric lymph node involvement is a common finding in all
chemotherapy combined with nutritional support
■ Because intestinal involvement is generally diffuse, surgery is
stages of the disease
■ Direct extension into adjacent structures is a feature of advanced
rarely indicated
■ Prognosis is variable; it was previously poor, but the chance of
disease
5-year survival might be as high as 70%
■ FOLLICULAR LYMPHOMA (INCLUDING Centroblasts have one to three nucleoli, and the cells are
PRIMARY DUODENAL-TYPE FOLLICULAR typically greater than three times the size of normal lym-
LYMPHOMA) phocytes. The number of these large centroblasts in a
high-power field (hpf) determines the grade of the tumor
with up to 5 centroblasts being grade 1, 6 to 15 being
Although outside of the GI tract, the two most common grade 2, and greater than 15 being grade 3. The current
lymphomas are FL and DLBCL; FL is far less common in WHO combines grade 1 and 2 into a low-grade category.
the GI tract. Specifically, systemic FL makes up to 40% of There are two growth patterns, a nodular and a diffuse
all non-Hodgkin lymphomas (NHLs) and up to 70% of growth pattern. The diffuse pattern can have a promi-
mature B-cell lymphoma. However, FL only accounts for nent sclerotic component and on biopsies can lack any
1% to 6% of primary GI lymphomas. FL is a neoplasm nodular architecture.
of follicle (germinal) center cells and consists of smaller Typically, FL presents as nodules composed primarily
centrocytes admixed with larger centroblasts. There is of centrocytes. Compared with normal germinal centers,
a unique variant of FL that occurs in the GI tract and the neoplastic nodules lack tangible body macrophages
was initially referred to as primary intestinal FL in the and significant mitotic figures ( Fig. 19.2A and B).
2008 edition of the WHO Classification of Tumours of Occasionally, only the diffuse portion is biopsied, which
the Haematopoietic and Lymphoid Tissues. In the 2017 can mimic the other low-grade B-cell lymphomas. DTFL
update to the WHO classification, the lesion is referred almost exclusively consists of centrocytes in a predom-
to as duodenal-type follicular lymphoma (DTFL). These inantly follicular pattern (Fig. 19.2A) and is limited to
are unique and have a different course than systemic the mucosa or submucosa. If the lymphoma demon-
FL’s involvement of other locations in the GI tract. strates high-grade features, has extensive diffuse growth
DTFL primarily occurs in the second portion of the duo- pattern, extends into or beyond the muscularis propria,
denum or periampullary. DTFL is a localized polypoid or demonstrates extensive lymph node involvement, it
variant of this disease typically limited to a stage IE dis- be consistent with systemic FL involvement of the GI
ease and tends to have an indolent course. DTFL is rare lymphoma and should not be considered a DTFL.
with current estimates of occurring once in 3000 to 7000
endoscopic evaluations. In one recent review of 1109 GI
FL cases, 63.6% of cases involved the small bowel with
Ancillary Studies
18.2% involving the stomach and 18.2% in the colon.
The neoplastic cells are positive for B-cell markers CD19,

CD20, PAX5, and CD79a (Fig. 19.2C). The neoplastic cells
Pathologic Features
are derived from the germinal center and as such are typi-
cally positive for CD10, BCL6, and LMO2 (Fig. 19.2E and F).
Gross and Endoscopic findings However, in some cases, CD10 can be weak or lost. The
neoplastic cells demonstrate aberrant coexpression of BCL2
Follicular lymphomas can have a variety of appearances. (Fig. 19.2G). Most FLs will be positive for the standard
DTFL presents as small polyps in the duodenum (often BCL2 (clone 124); however, because mutations can occur
distal). Typical FLs can form obstructive lesions, espe- in the BCL2 gene, the use of an alternative BCL2 clone
cially when they involve the terminal ileum, as well (clone EP36/E17) is sometimes necessary to confirm the
as ulcerated lesions. Similar to MCL, they can have a diagnosis. The neoplastic cells are negative of CD3, CD43
multiple “lymphomatous polyposis”–like appearance. (Fig. 19.2D), CD5, Cyclin D1, Sox-11, and Lef1. Typically,
Increasing numbers of FLs are diagnosed incidentally whereas neoplastic follicles in low-grade lymphomas have
on screening colonoscopy or esophagogastroduodenos- a Ki-67 labeling index of less than 10%, normal reactive
copy. Capsule endoscopy, as well as barium studies and germinal centers have an elevated Ki-67 (>90%) label-
computed tomography scans, can assist in identifying ing index. The dendritic cell networks are highlighted by
multiple small polyps or intussusception. Imaging may immunostains for CD21, CD23, and CD35. Compared
also highlight involved mesenteric lymph nodes. with the nodal and extranodal types, the DTFLs tend to
have to a diminished follicular dendritic cell network,
Microscopic Findings often resulting in a “hollowed-out” appearance with the
stain restricted to the periphery (Fig. 19.2H). Additionally,
The neoplastic cells are composed of two B-cell types that unlike the systemic forms, the duodenal-type variant often
are found in follicle or germinal centers, centrocytes, and express IgA as well as the mucosal homing receptor α -β 7.
centroblasts. The centrocytes are small and have angu- Follicular lymphomas demonstrate clonal rearrange-
lated and cleaved nuclei with inconspicuous nucleoli. ments of the Ig heavy chain and light chains. Additionally,
The centroblasts are larger cells that have round to oval almost all FLs have cytogenetic abnormalities with the
nuclei that can occasionally appear indented or cleaved. most common involving translocation of the B CL2 gene,
A B
C D
E F
G H
FIGURE 19.2
Follicular lymphoma. A , At low magnification, the neoplastic infiltrate is composed of mixture of small centrocytes with nuclear irregularities and no nucleoli
and larger centroblasts with vesicular chromatin and prominent nucleoli (B). The lymphoid nodules are CD20+B cells (C) that are negative for aberrant coex-
pression for CD43 (D). These germinal center–derived cells expression CD10 (E) and BCL6 (F) with aberrant expression of BCL2 (G). In cases of duodenal
follicular lymphoma, the CD21 highlights diminished follicular dendritic cell network often resulting in a “hollowed-out” appearance with the stain restricted to
the periphery (H).
which can be identified in up to 90% of low-grade FLs. of lymphoma, DTFL has a particular indolent course.
The most common is the translocation involving the Specifically, DTFL is a localized disease to the mucosa and
BCL2 and I GH genes, t(14;18)(q32;q21), with rare cases submucosa with only rare cases demonstrating evidence
involving the B CL2 and light chain gene t(2;18)(p12;q21). of nodal disease, and none of these cases demonstrated
The majority of DTFLs tested to date only have a BCL2/ high-grade transformation. Patients with asymptomatic
IGH translocation. Outside of this variant, only 10% of DTFL can be treated with a watch-and-wait approach.
cases have only the t(14;18) with most demonstrating In general, therapy for patients with low-grade FL is
additional abnormalities. Other frequent abnormalities, directed at symptom relief and includes resection or exci-
which can be seen in non-DTFL forms, include B CL6 sion, single-agent chemotherapy (rituximab only), or
rearrangements or B CL6 5’ mutations, as well as + 7, radiation therapy. Low-grade FLs are typically considered
+12, +
18, 17p deletion, and 6q23-36 abnormalities. noncurative and are a chronic disease with a median sur-
A translocation involving IRF4 can rarely be seen in vival time of greater than 12 years. Follow-up is aimed at
cases of grade 3 FLs. Interestingly, DTFL (compared with evaluation for high-grade transformation or progression
systemic) demonstrates elevated expression of CCL20 to DLBCL or high-grade B-cell lymphoma (HGBL; dou-
and MADCAM1 similar to marginal zone lymphoma. ble-hit lymphomas). Grade 3a lesions tend to have a more
aggressive course than grade 1 and 2 lesions requiring
therapy. However, those treated with doxorubicin-con-
taining regiments demonstrate similar overall survival to
grade 1 and 2 lesions.
Patients with FL grade 3B are treated like those with
The differential diagnosis includes benign reactive lym- DLBCL.
phoid proliferation, such as follicular hyperplasia and
rectal tonsil, as well as other low-grade B-cell lympho-
mas. Specifically, many conditions in the GI tract can lead
FOLLICULAR LYMPHOMA—FACT SHEET
to nodular lymphoid hyperplasia, and the distal small
bowel usually demonstrates prominent lymphoid aggre- Definition
gates with well-defined germinal centers. Most reactive ■ Lymphoma that is derived from follicular or germinal center B
nodular FL hyperplasia can be differentiated from FL cells and consists of centrocytes and centroblasts often with a
on histology evaluation. Reactive lymphoid hyperplasia nodular or follicular growth pattern
demonstrates expanded polarized germinal centers with
intact marginal and mantle zones. The germinal centers Incidence and Location
■ Accounts for 1% to 6% of primary non-Hodgkin gastrointestinal
also demonstrate prominent mitotic activity with high
lymphomas
Ki-67 labeling index and multiple tingible body macro- ■ Accounts for 30-% to 40% of nodal non-Hodgkin lymphomas
phages. These reactive germinal centers express germinal
center markers BCL6, CD10, and LMO2 but are negative Morbidity and Mortality
for aberrant BCL2 expression. The reactive process typi- ■ Duodenal-type follicular lymphoma (DTFL) demonstrates indolent
cally demonstrates increased mitotic index with Ki-67 of behavior with an excellent prognosis
■ Low-grade (World Health Organization [WHO] grade 1 or 2)
greater than 90%; however, neoplastic follicles typically
lesions with an excellent prognosis
demonstrate less than 10% Ki-67 staining. Most of the
■ Grade 3 lesions have a more aggressive course
other mature B cells lymphomas (marginal zone, mantle,
and SLL) can have a nodular growth pattern, and immu- Gender, Age, and Race Distribution
nohistochemical features are often vital in the differen- ■ Equal male and female distribution
tial. BCL2 expression helps differentiate FL from benign ■ Median age is 55 to 59 years
germinal centers, but most other mature B-cell lympho- ■ Two to three times as prevalent in whites than blacks
mas also expression the antiapoptotic protein BCL2.

Clinical Features
■ Often is asymptomatic and found incidentally
■ May present with abdominal pain or obstructive type symptoms

■ Patients with DTFL have an excellent prognosis and are often
The prognosis of patients with FL can be variable treated with a watch-and-wait approach
depending on the grade and stage of the lesion. There is a ■ Low grade (WHO grade 1–2) lesions are incurable but may be
specific prognostic system for FL (Follicular Lymphoma treated with a watch-and-wait approach, chemotherapy (including
rituximab alone), or radiation
International Prognostic Index score), which includes ■ Grade 3 lesions are more aggressive, requiring therapy. With
age older than 60 years, serum lactate dehydrogenase, aggressive therapy, these patients have similar outcomes to grade
hemoglobin level, Ann Arbor stage, and number of 1 or 2 lesions and in some cases can become disease free
involved nodal areas. Compared with a systemic variant
Pathologic Features
Follicular Lymphoma—Pathologic Features
Gross, Endoscopic, and Radiology Findings Gross, Endoscopic, and Radiologic features
■ Nodularity or granularity of the mucosa
■ Can present as diffuse lesions with transmural involvement

When MCL involves the GI tract, it typically involves
occasionally with changes of obstruction or rarely perforation
multiple sites with a predilection for involvement of
Microscopic Findings the distal small bowel and colon. However, involvement
■ Follicular, diffuse, or combination of follicular and diffuse growth
of the stomach and duodenum can also be seen. MCL
patterns tends to present as either isolated polyps or masses or
■ Mixture of small-cleaved B cells (centrocytes) admixed with large multiple small nodules or polyps and can vary in size
B cells (centroblasts) from submillimeter to several centimeters. The numer-
ous small polyps of lymphoma are referred to as lym-
phomatous polyposis. MCL can also present as ulcerated
■ Positive B cell markers (CD19, CD20, PAX5, CD79), germinal cell
differentiation (CD10, BCL6, LMO2) lesions (more common in the stomach), increased bowel
■ Positive for aberrant coexpression of BCL2 (standard BCL2 wall thickness, or obstructive masses. Additionally, cap-
clone124 but might need an alternative clone, e.g., EP36/E17) sule endoscopy and barium radiography can demon-
■ CD21, CD23, and CD35 highlight follicular dendritic strate multiple small polyps in the small bowel or colon.
cell networks, which can appear “hollowed out” in the duodenal-
Alternatively, imaging may demonstrate bowel wall
type variant
■ Negative for CD3, CD5, Lef1, Cyclin D1, CD43, and MUM1
thickening or obstructive masses as well as mesenteric
■ Low Ki-67 proliferation index compared with reactive follicular and retroperitoneal lymphadenopathy or hepatic or
hyperplasia splenic enlargement.
Genetic Abnormalities
■ t(14;18) chromosomal rearrangement (IGH/BCL2)
■ Rearranged immunoglobulin H and light chains

Mantle cell lymphoma can grow in three architectural
Differential Diagnosis patterns, including mantle, nodular, and diffuse. In the
■ Benign follicular lymphoid hyperplasia
GI tract, the lesions tend to be nodular or diffuse; how-
■ Low-grade follicular lymphoma: other low-grade B-cell ever, mantle zone pattern and in situ disease can be
lymphomas such as marginal zone lymphoma, small lymphocytic seen. Typically, the lymphoma is centered in the mucosa
lymphoma, mantle cell lymphoma and submucosa with a diffuse or nodular pattern. The
■ High-grade follicular lymphoma: diffuse large B-cell lymphoma,
infiltrate often displaces the glands, and although there
high-grade lymphoma, and poorly differentiated carcinoma
can be glandular destruction, lymphoepithelial lesions
are not typically seen.
The lymphomatous infiltrate is composed of small
lymphocytes with scant cytoplasm and irregular nuclei.
■ ■ MANTLE CELL LYMPHOMA The classical variant cells are typically very mono-
morphic or monotonous compared with other mature
or low-grade lymphomas or reactive conditions ( Fig.
Clinical Features
19.3A and B). In the background, there are often scat-
tered epithelioid macrophages, which can give the sec-
Mantle cell lymphoma is a small cell lymphoma that tion a “starry-sky” appearance. There are only rare
morphologically resembles a mature or low-grade larger cells, which tend to be follicular dendritic cells
B-lymphoma but typically has an aggressive clini- and not large neoplastic cells. Another classic finding is
cal course. MCL is typically a disease of older adults the presence of hyalinized small vessels throughout the
(mean age, 60 years) with a male predominance (at lesion. Mitotic figures are easy to identify but are usu-
least 2:1). Unfortunately, almost 70% to 80% of ally less than 1 to 2/hpf. There are two aggressive vari-
patients have advanced disease (stage IV) at the time ants of MCL, the blastoid and the pleomorphic variants.
of diagnosis. In some series, greater than 80% of these The blastoid variant is typically monomorphic medium
patients have GI tract involvement. Although any part to large cells resembling lymphoblasts and can resem-
of the GI tract can be involved, the small bowel, specif- ble cells of acute leukemia or lymphoma. This variant
ically the ileum, is the most common site. MCL was the typically also contains tingible body macrophages and
first to be associated with lymphomatous polyposis. At increased mitotic index of greater than 3 mitoses/hpf.
the time of initial diagnosis of MCL in the GI tract, As the name suggests, pleomorphic MCL demonstrates
patients can be asymptomatic but may also present variable size from large anaplastic-looking cells to small
with abdominal pain, diarrhea, hematochezia, weight lymphocytes seen in the classic variant. The prolifera-
loss, and fatigue. tion index is between that of the blastoid variant and the
classic variant. Often the morphologic features overlap IRF4 in a minority of the lymphoma cells. Mantle cells
and are challenging to differentiate from DLBCL. typically express surface IgM or IgD heavy chain with
a restricted surface light chain expression, typically
lambda restricted.
Fluorescent in situ hybridization (FISH) and cyto-
Ancillary Studies
genetic studies typically demonstrate the classic
translocation associated with MCL, which is t(11;14)
The neoplastic cells are positive for B-cell markers CD20, (q13;q32), involving the cyclin D1 gene and the IGH
CD19, CD79a, and PAX5 (Fig. 19.3C). Additionally, the gene. The t(11;14) is seen in the vast majority of cases;
neoplastic B cells aberrantly expression CD5 and CD43 however, there is a minor population of MCL that does
and are negative for CD3 (Fig. 19.3Dand E). There is not have the cyclin D1 translocation. In these cases,
normal expression for BCL-2; however, the cells typi- t(2;12) (p12;p13) translocation, fusing cyclin D2 to the
cally lack expression of germinal center markers CD10, κlight-chain gene locus, or a t(6;14)(p21;q32) trans-
BCL6, and LMO2. The B cells are also typically neg- location, fusing IGH and cyclin D3, have been identi-
ative for aberrant coexpression for LEF1 and CD23 fied. Additionally, several other cytogenetic alterations
(Fig. 19.3H). By flow cytometry, MCL is typically posi- have been reported, including gains in 3q, 7p, 8q, 12q,
tive for the FMC7 (an epitope of CD20). MCL demon- and 18q and loss of 1p, 6q, 8p, 9p, 10p, 11q, 13, and
strates nuclear expression of cyclin D1 (BCL1) in the 17p. Additionally, tetraploidy and complex karyotypes
vast majority of cases (Fig. 19.3F). Fortunately, SOX11 are more often associated with pleomorphic or blastoid
is expressed in most cases of cyclin D1 positive and neg- variants. MYC (8q24) translocations can also be seen in
ative cases as well as the blastoid and pleomorphic vari- blastoid MCL and tend to predict an aggressive clinical
ants (Fig. 19.3G). There can be expression of MUM1/ course.
A B
C D
FIGURE 19.3
Mantle cell lymphoma. A , Mantle cell lymphoma often forms polypoid masses in the gastrointestinal tract (lymphomatous polyposis) and can be seen in the
biopsy of multiple polyps (low magnification). B, At high magnification, the infiltrate is composed of a monomorphic population of small lymphocytes with
minimally irregular nuclei and scattered epithelioid histocytes. These lymphocytes are B cells with expression of CD20 (C) and aberrant expression of CD5
E F
G H
(E). The background T cells is highlighted by CD3 (D). These neoplastic cells are positive for cyclin D1 (F) and SOX11 (G) expression. These neoplastic B cells
are negative for LEF1 (H) expression that is typically seen in small lymphocytic lymphoma and chronic lymphocytic leukemia.
Differential Diagnosis markers, BCL-2, CD5 and CD43. However, SLL is typ-
ically positive for LEF1, but the MCL is positive for
cyclin D1 and SOX11. A notable pitfall is that the prolif-
The primary diagnostic considerations are other low- eration centers of SLL or CLL can be cyclin D1 positive
grade lymphomas such as marginal zone lymphoma, FL, by immunohistochemical stains.
and SLL. Specifically, lymphomatous polyposis can be
caused by MCL, FL, or marginal zone lymphoma. From a
cytomorphologic perspective, MCL cells are very monot-
onous appearing with slight nuclear irregularities, but
they lack the typical cleaved morphology of FL cells
and the monocytoid appearance of marginal zone lym- Typically, at the time of diagnosis, the patient already
phoma cells. Given that many of the biopsies suffer from has systemic disease. Surgery generally has limited
extensive crush artifacts, increased importance is placed utility unless there are obstructive type symptoms or if
on immunohistochemical and cytogenetic findings. there was persistent hemorrhage. Survival is poor and
Specifically, although both FL and MCL are positive for worse in patients with blastoid or pleomorphic vari-
pan-B-cell markers and BCL2, FL cell also expresses ger- ants or classic type with a Ki-67 index of greater than
minal center markers CD10, BCL6, and LMO2, which 40% to 50%. The overall median survival period is 3
are negative in MCL. Conversely, MCL expresses CD5, to 5 years from the time of diagnosis. Unfortunately,
cyclin D1, SOX11, and CD43, and patients typically the majority of patients are not curable even
have systemic disease as well. SLL or CLL can also be with aggressive chemotherapy and newer therapeutic
a systemic disease, and like MCL, expresses pan-B-cell modalities.
MANTLE CELL LYMPHOMA—FACT SHEET
■ Small to medium sized with scant cytoplasm
■ Irregular nuclear outlines (but no deep clefts) and indistinct

Definition
nucleoli
■ Mature appearing B-cell lymphoma with often aggressive clinical
■ Mitotic figures can be easily identified
course ■ Most common architectural pattern is diffuse, but a nodular
■ Typically systemic disease with secondary involvement of the
pattern and true mantle zone pattern can be seen
gastrointestinal (GI) tract ■ Reactive follicles may be intermixed and compressed by the
■ Can present as lymphomatous polyposis
lymphoma
■ Some epithelial involvement, but no actual lymphoepithelial
Incidence lesions
■ Represents 3% to 10% of non-Hodgkin lymphomas
■ More than 80% of patient with systemic disease can also have GI Immunohistochemistry
involvement ■ Positive for B-cell markers (CD20, CD19, PAX5, CD79a) and BCL2
■ Aberrant positive expression of CD5, CD43, FMC7, Cyclin D1, and

Gender, Race, and Age Distribution SOX11
■ Mean age at presentation is 60 years ■ Negative for germinal center markers (CD10, BCL6, LMO2),
■ Male predominance (greater than 2:1, males to females) markers associated with small lymphocytic lymphoma and
chronic lymphocytic leukemia (CD23 and LEF1), and TdT
Clinical Features ■ Surface immunoglobulin expression (usually immunoglobulin [Ig]
■ Abdominal pain M or IgD) with light chain restriction, typically lambda restricted is
■ Diarrhea present
■ Hematochezia ■ Ki-67 important prognostic marker; greater than 40% to 50%
■ Weight loss associated with an adverse prognosis

■ Fatigue
■ Widespread disease (hepatosplenomegaly and ■Genetic Abnormalities
lymphadenopathy) ■ Typical genetic alteration - t(11;14)(q13;q32) chromosomal
■ Asymptomatic rearrangement cyclin D1 with Ig heavy chain (CCND1/IGH)
■ Cyclin D1 negative variant typically has rearrangements involving
Prognosis and Treatment CCND2 or CCND3

■ Generally considered an incurable disease ■ t(2;12) (p12;p13) translocation, fusing cyclin D2 to the κ
light-
■ Median survival of 3 to 5 years; patients with blastoid and chain gene locus or a t(6;14)(p21;q32) translocation, fusing IGH
pleomorphic types have a worse prognosis and CCND3
■ Mitotic index correlates with prognosis with greater than 50 ■ MYC (8q24) alterations, including the t(8;14)(q24;q32)
mitoses per mm2 corresponding to a worse prognosis translocation, have been seen in blastoid variant cases and tend
■ Systemic chemotherapy is the treatment of choice to correlate with aggressive clinical course
■ Aggressive chemotherapy followed by autologous stem cell ■ Clonally rearranged IgH and/or light chain
transplantation may benefit younger patients

■ Surgery has a role in cases with bowel obstruction or continuous Differential Diagnosis
bleeding ■ Reactive follicular hyperplasia (polarized germinal centers, without
aberrant expression of CD5, CD43, cyclin D1, SOX11, or LEF1 on

B cells)
■ Follicular lymphoma (CD10+, BCL6+, LMO2+, CD5-, Cyclin D1-,
SOX11-, CD43-)
■ Mucosa-associated lymphoid tissue (CD10-, CD5-, Cyclin D1-,
SOX11-, CD43+/-)
■ Small lymphocytic lymphoma (CD10-, CD5+, LEF1+, SOX11-,
Mantle Cell Lymphoma—Pathologic Features Cyclin D1 typically negative but can be positive in proliferation
centers, CD43+, CD23+, FMC7-)
■ Predilection for the colon and small intestine in nearly all cases,
but gastric and duodenal involvement are also common

■ An isolated mass or multiple polyps throughout the GI tract
■ Multiple polyps referred to as lymphomatous polyposis

■ LARGE CELL AND AGGRESSIVE B-CELL
■ Polyps range from 0.5 cm to 2 cm; larger polyps common in the
LYMPHOMAS
ileocecal region
■ Nodules or polypoid tumors may be ulcerated with or without
normal intervening mucosa In addition to mature B-cell lymphomas, the GI tract is

■ Involvement by and extension into regional fibroadipose commonly involved by diffuse and aggressive large B-cell
mesentery is common lymphoma. The entities that can commonly involve the
■ Barium radiographs can show numerous luminal round filling
GI tract and are discussed later include DLBCL, not
defects or tumor mass
■ Abdominal computed tomography reveals intestinal wall
otherwise specified (DLBCL, NOS); Epstein-Barr virus–
thickening, mass lesion, retroperitoneal lymphadenopathy, and positive DLBCL, NOS; high-grade B-cell lymphoma;
hepatic or splenic enlargement PBL; and BL. At the end of this section, EBV-positive
mucocutaneous ulcer is also discussed
■ ■ DIFFUSE LARGE B-CELL LYMPHOMA pattern. The large neoplastic cells form sheets of
neoplastic cells but may be intermixed with a low-
grade (mature) B-cell lymphoma or with the prom-
Clinical Features inent T-cell background. The neoplastic cells can be
morphologically heterogeneous and can be divided
This is the most common nodal and extranodal NHL. into three variants: centroblasts, immunoblasts, and
DLBCL is one of the most common lymphomas involv- anaplastic. Occasionally in these lesions, cell size can
ing the GI tract and can involve any portion of the be challenging to determine. A helpful way to deter-
GI tract. Unlike those with mature low-grade B-cell mine the cell size is to compare it with the nucleus
lymphomas, patients with DLBCL are more likely to of endothelial cells or benign histiocytes. The most
be symptomatic from ulcerations, GI bleed, obstruc- common variant and appearance of the neoplastic
tion, or perforation. However, some patients may be cells are the centroblasts. Centroblasts are large B cells
asymptomatic. DLBCL can either arise de novo or may with round to oval nuclei with multiple (two to four)
occur as progression or transformation of low-grade small nuclei that are typically attached to the nuclear
lesions. It is essential to make a note of any possible membrane. The cells show minimal amount of cyto-
existing or concurrent low-grade lymphoma. For exam- plasm. The immunoblasts are large cells typically
ple, DLBCL of the GI tract is most frequently encoun- with a single large nucleolus. These have more cyto-
tered in the stomach. Some patients show histologic plasm than centroblasts, and in some cases, acquire a
evidence of concurrent low-grade B-cell lymphoma more plasmablastic type appearance with ample baso-
(marginal zone lymphoma). For gastric DLBCLs, philic cytoplasm. The anaplastic variant has large to
Helicobacter infections have shown to be involved extremely large neoplastic cells with pleomorphic to
both in MALT lymphoma associated DLBCL and de bizarre nuclei.
novo DLBCL. The presence of H elicobacter organisms In the GI tract, DLBCLs can often also demonstrate
should be noted in any gastric carcinoma or lymphoma. lymphoepithelial lesions with the neoplastic cells invad-
In the revised 2017 WHO classification, EBV-infected ing and destroying the glandular epithelium.
lymphoma and double-hit lymphoma are classified
separately as EBV-positive DLBCL, NOS, and HGBL,
respectively
Ancillary Studies
The large neoplastic cells typically express B-cell mark-

Pathologic Features
ers, CD20, CD22, CD79a, PAX5, and CD19. In cases
of lymphoma treated with rituximab, the neoplastic
Gross Findings cells lack expression of CD20; therefore, alternative
B-cell markers are needed to confirm the diagnosis.
Grossly, DLBCL can have a variety of appearances. Additionally, in cases that are more plasmablastic, the
DLBCL of the stomach typically presents as solitary or neoplastic cells can express CD138. Importantly, as
multifocal ulceration and most commonly involves the part of the workup, the DLBCL should be classified
gastric body or fundus. Additionally, in the minority by cell of origin into either germinal center B-cell type
of cases, DLBCL can present as polypoid lesions or dif- or activated B-cell type (also known as nongerminal
fusely infiltrative lesion, leading to a “linitis plastica” center type). Most practices prefer to use the Hans cri-
appearance. In the small bowel, DLBCL also typically teria and use CD10, BCL6, and MUM1 immunostains
presents as an ulcerated lesion but can also occur as a in which expression by greater than or equal to 30%
single polypoid lesion or multiple polyps or polyposis. of neoplastic cells is considered positive. For the Hans
DLBCL can also have an infiltrative pattern that pres- criteria, the germinal center subtype is either positive
ents as a stricture or perforation. In the colon, DLBCL for CD10, or the cells are CD10-/BCL6+/MUM1-; the
typically presents as a bulky annular lesion that is nongerminal center type is CD10-/BCL6- or CD10-/
most often suspected to be a carcinoma. Typically, BCL6+/MUM1+ . Additionally, immunohistochemi-
regional lymph nodes are involved, especially in cal stains for MYC and BCL2 are typically performed
nongastric cases. with MYC considered positive if greater than 40% of
the neoplastic cells are positive and BCL2 is consid-
Microscopic Findings ered positive if 50% of the neoplastic cells are posi-
tive. Importantly, immunohistochemical stains cannot
The histologic features of DLBCL are the same in the be used as a surrogate for double hit rearrangement
GI tract as in other locations. The lesions are com- status, which requires FISH testing. Ki-67 prolifera-
posed of a proliferation of large to intermediate-sized tion rate typically ranges between 40% to greater than
lymphoid cells that typically have a diffuse growth 95%. There is a small number of CD5 + DLBCLs,
which represent de novo DLBCL, but cyclin D1 and

SOX11 are needed to exclude the pleomorphic or DIFFUSE LARGE B-CELL LYMPHOMA—FACT SHEET
blastoid variants.
Generally, Biomed B-cell clonality studies are not Definition
necessary. Typically, when the DLBCL occurs with a ■ High-grade B-cell neoplasm composed of large, pleomorphic B
low-grade B-cell lymphoma, these two entities are clon- cells with a diffuse growth pattern
ally related, both by light chain restriction and at the
DNA sequence level. FISH for BCL2, BCL6, and MYC
■ Most commonly involves the stomach but can involve any
are typically performed and will be discussed more in portion of the gastrointestinal tract
the section on HGBL.
■ Aggressive clinical behavior
■ Mortality varies with the extent of disease and other clinical

Differential Diagnosis parameters

The differential diagnosis includes other aggres-
■ Median age is in the sixth to seventh decade of life
sive lymphomas, including HGBL, BL, anaplastic ■ Slightly more common in males than in females
large cell lymphoma, EBV-positive DLBCL, PBL, and
acute leukemia/lymphoma as well as poorly differenti- Clinical Features
ated carcinomas. ■ Presents with pain, dyspepsia, sometimes asymptomatic
It is most important to distinguish primary DLBCL ■ Rapidly enlarging mass may cause site-specific symptoms
from secondary lymphoma and other aggressive

B-cell lymphomas as the treatments are quite differ-
■ Preliminary data suggest that gastric diffuse large B-cell
ent. The differentiation between DLBCL and HGBL
lymphoma with Helicobacter infection may be effectively treated
is further discussed in a later section on HGBL. with antibiotics
DLBCL can be differentiated from BL by the pro- ■ Aggressive but potentially curable with multiagent chemotherapy
totypical morphologic features of BL (as discussed (R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine,
later). One should keep in mind that not all cases of and prednisone])
■ Overall 5-year disease-free survival rate ranges from 50% to 80%
aggressive lymphoma with a high Ki-67 index are BLs
because DLBCL and HGBL can both have Ki-67 indices
that approach 100%.
Immunohistochemical stains for markers of
immaturity such as CD34 and CD117 may also be Diffuse Large B-Cell Lymphoma—Pathologic
useful in the differentiation of GI involvement by Features
acute leukemia/lymphoma. Occasionally, large cell
lymphoma can have a particularly cohesive appear- Gross, Endoscopic, and Radiology Findings
■ Ulcerative or mass-forming lesion
ance or an infiltrative pattern that may raise the
possibility of carcinoma. In these instances, immuno-
histochemical stains for keratins are helpful in exclud-
■ Diffuse infiltration by large lymphoid cells
ing this possibility. ■ Most commonly have oval to round vesicular nuclei with multiple
nucleoli and scant to moderate cytoplasm

■ Effacement of normal structures
Prognosis and Therapy Immunohistochemical

■ Positive for pan-B markers CD19, CD20, PAX5, CD79a
■ Occasional CD138 or CD30 expression

Standard therapy for patients with GI tract DLBCL ■ Hans criteria (considered positive if ≥
30% of lymphoma cells)
mirrors the approach to nodal DLBCL: chemotherapy CD10, BCL6, MUM1
with rituximab and CHOP. This may be followed by ■ Variable coexpression: CD10 (30%–50%), BCL6 (60%–90%),
radiation therapy. Surgery is typically reserved for MUM1 (35%–65%), CD5 (5%–10%)
■ BCL2 considered positive if 50% or greater of tumor cells are
cases with complications from obstruction, exten-
positive
sive hemorrhage, or perforation. Additionally, after ■ MYC considered positive if 40% or greater of tumor cells are
surgery, these patients require adjuvant chemother- positive
apy. The role of antibiotic therapy in DLBCL of the ■ Ki-67 proliferation index 40% to greater than 90%
stomach has not been extensively studied; however,

several groups report lasting regression of de novo Genetic Abnormalities
DLBCL and DLBCL with MALT lymphoma after anti- ■ Up to 30% have a BCL6 translocation
biotic therapy alone.

on morphologic grounds alone and require cytogenetic

20% to 30% have a BCL2 translocation
■
or FISH studies for classification. High-grade B-cell lym-
■ Up to 10% have an MYC translocation (single hit)
phoma, NOS, is a somewhat of wastebasket term in that
Differential Diagnosis it is used for lesions that do not fit into another mature
■ Aggressive B-cell lymphomas, including high-grade B-cell aggressive large B-cell lymphoma category. These can
lymphoma, Burkitt lymphoma, plasmablastic lymphoma, Epstein- resemble DLBCL or BL or may have a blastoid morphology.
Barr virus–positive large B-cell lymphoma
■ Blastic or pleomorphic mantle cell lymphoma
■ Acute leukemia/lymphoma
Ancillary Studies
■ Poorly differentiated carcinoma
These mature large B cells express B-cell markers CD20,
CD19, PAX5, and CD79a and lack TdTexpression. The
Ki-67 index can be quite variable and cannot be used to
■ ■ HIGH-GRADE B-CELL LYMPHOMA predict if the lymphoma has MYC, BCL2, or BCL6 trans-
locations. The majority of cases demonstrate a germinal
Clinical Features center phenotype with expression of CD10 and BCL6,
with a minority of these lymphomas expressing MUM1.
Those with a BCL2 translocation are diffusely positive for
This is a new entity in the 2017 update to the fourth edi- BCL2. cMYC protein expression can also be variable, and
tion of the WHO classification. There are two categories although 40% positivity in the lymphoma is interpreted
of HGBL. The first replaces the prior entity known as as positive, this cannot be used as a surrogate for MYC
B-cell lymphoma unclassifiable with features interme- translocation. FISH is an essential part of the workup
diate between DLBCL and BL or those HGBLs with a for these cases. The translocations can be complex, and
blastoid morphology that does not fit into another entity. break-apart probes are helpful in demonstrating these
The second category includes large B-cell lymphomas abnormalities. Specially, FISH for MYC, BCL2, and BCL6
with MYC and BCL2 and/or BCL6 translocation (dou- is recommended when working up cases of aggressive
ble- or triple-hit lymphomas.). This category should be B-cell lymphoma.
used for de novo cases and should not be used for the
progression of previously known lymphoma. These lym- Differential Diagnosis
phomas can present similarly to DLBCL of the GI tract
but are thought to have a more aggressive course. The differential diagnosis includes other aggressive
B-cell lymphomas. Specifically, the morphologic features
have extensive overlap with DLBCL, NOS, and molec-
Pathologic Features
ular studies for MYC, BCL2, and BCL6 are required.
Additionally, the lymphoma can mimic BL; however,
Gross Findings the lesion fails to meet the current definition of BL.
Specifically, cytologically, HGBL can be more pleomor-
The gross appearance is similar to that of other aggres- phic with various cell sizes. Additionally, Burritt lym-
sive lymphomas. The lesions can be polypoid or show a phoma usually does not express BCL2. Pleomorphic or
masslike growth. These typically have a high prolifera- blastic variants of MCL can demonstrate overlapping
tion rate that leads to bulky masses. Additionally, the morphologic features, but MCL can be excluded with
lymphoma tends to demonstrate transmural involvement cyclin D1 and SOX11 expression. Additionally, HGBL
with extension into the surrounding mesenteric tissue. can have a blastic morphology and cytologically resem-
This can lead to ulceration as well as stricture formation, ble acute lymphoblastic leukemia/lymphomas. The
bowel obstruction, or perforation. On cut sections, these acute lymphoblastic leukemias typically express mark-
lesions have a characteristic fish flesh appearance, often ers of immaturity such as TdT with variable expression
accompanied by areas of hemorrhage and tumor necrosis. of CD34. The B-lymphoblastic leukemia/lymphomas
express PAX5 and cytoplasmic CD22 and CD79a and
Microscopic Findings are typically CD10 positive while CD20 is variable to
absent. T-lymphoblastic leukemia/lymphomas are posi-
The entity covers two categories that can have various tive for CD3 (may be cytoplasmic only) and often posi-
morphologic and immunohistochemical profiles. The tive for CD1a and/or CD99.
high-grade B-cell lymphoma with MYC and BCL2 and/
or BCL6 rearrangements typically have the morphologic Prognosis and Therapy
appearance similar to DLBCL, NOS. Although the lesions
have a diffuse growth pattern, these can have a variable Overall, the prognosis is poor with reported median sur-
proliferation index ranging from low (<60%) to as high as vival time between 4.5 and 18.5 months. Unfortunately,
BL (>95%). As such, the entities cannot be distinguished these patients do not respond to standard R-CHOP
therapy that is the standard of care for patients with

DLBCL, NOS. Although this not standardized ther- ■ Variable morphology:50% to 85% have morphology of DLBCL,
not otherwise specified (NOS)
apy for these patients, they are often treated more ■ Can have morphology similar to Burkett lymphoma, although
aggressively with some variation of an EPOCH-R (rit- more pleomorphic nuclei
uximab, etoposide phosphate, prednisone, vincristine ■ Solid growth pattern with minimal small lymphocytes
sulfate [Oncovin], cyclophosphamide, and doxorubi- ■ Variable mitotic figures and apoptotic cells (occasional starry-
cin hydrochloride hydroxydaunorubicin]) therapy and sky pattern)

■ HGBL, NOS
require central nervous system (CNS) prophylaxis. ■ More closely resembles Burkitt lymphoma than diffuse large
Unfortunately, a significant proportion of cases are B-cell lymphoma (DLBCL); some have a blastic appearance
refractory to even aggressive therapy, and relapses are ■ Solid growth pattern of medium- to large-sized cells
common. ■ Often no stromal reaction
■ Prominent mitotic figures and prominent apoptosis
HIGH-GRADE B-CELL LYMPHOMA—FACT SHEET ■ Positive for pan-B markers CD19, CD20, PAX5, and CD79a
■ Typically, positive for BCL6 with variable expression of CD10
■ Minority of cases are MUM1 positive (20%)

Definition
■ Negative for CD5, cyclin D1, and TdT
■ Highly aggressive B-cell neoplasm, new 2016 World Health
■ Ki-67 is variable (between 30% and 100%)
Organization category replaces lymphomas previous known as
■ Those with MYC and B CL2 translocations typically demonstrates
B-cell lymphoma unclassifiable with features between diffuse
MYC and BCL2 protein expression
large B-cell lymphoma and Burkitt lymphoma as well as the
double- and triple-hit lymphomas
■ Two subtypes: high-grade B-cell lymphoma (HGBL) with
■ “Double hit” demonstrates translocations involving MYC, including
MYC and BCL2 and/or BCL6 rearrangements and HGBL, not
otherwise specified t(8;14) and BCL2
■ “Triple hit” demonstrates translocations involving MYC, BCL2, and
Incidence and Location BCL6

■ Complex cytogenetic abnormalities
■ Specific data are not available for HGBL involving the
gastrointestinal tract
■ Typically involves older patients sixth or seventh decade of life;
■ Diffuse large cell lymphoma
can involve younger patients
■ Burkitt lymphoma
■ Male predominance
■ Epstein-Barr virus–positive DLBCL
■ Typically present with widespread disease involving more than
■ Acute lymphoblastic leukemia/lymphoma
one extranodal site, and more than half have bone marrow or
central nervous system involvement

■ Typically, poor prognosis with median survivals time of 4.5 to
■ EPSTEIN-BARR VIRUS–POSITIVE DIFFUSE
18.5 months LARGE B-CELL LYMPHOMA, NOT
■ The mainstay of treatment is intensive combination OTHERWISE SPECIFIED
chemotherapy regimens, often resistant to R-CHOP (rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone)
therapy Clinical features
■ Surgical therapy has a role in the treatment of obstruction or
intussusception, debulking, and perforation

In the previous edition of the WHO classification, EBV-
positive DLBCL, NOS, was known as EBV-positive
DLBCL of the elderly. This entity had an age cut-off of
50 years; however, subsequent work demonstrated that
High-Grade B-Cell Lymphoma—Pathologic this lesion was not limited to this older patient popula-
Features tion. Although most commonly seen in patients older
than 50 years of age, it can occur at any age. In some
Gross Findings cases, this lesion is thought to be secondary to immu-
■ Solid tan-white cut surface (fish flesh appearing) often associated nosenescence secondary to aging.
with hemorrhage and necrosis This entity has a predilection for extranodal sites,
■ In the gastrointestinal tract, the lesions are often ulcerated, and
especially the GI tract. Up to 10% of patients may
mass forming, or transmural and in some cases can present as
obstructive mass or perforation have both nodal and extranodal disease. The percent
of DLBCL case that falls under this category increases
Microscopic Findings with age with a peak of 20% to 30% of DLBCL cases
■ High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or in patients older than 90 years old. Clinically, they can
BCL6 rearrangements present similar to other aggressive or large B-cell lym-
phoma as outlined previously.
Pathologic Features large neoplastic cells. These large neoplastic cells typi-
cally have a Reed-Sternberg or Hodgkin-like appearance
or transformed immunoblasts (Fig. 19.4E). The number
Gross Findings of neoplastic cells can be quite variable, occasionally have
a more monomorphic appearance forming solid sheets of
Grossly, EBV-positive DLBCL, NOS has similar features neoplastic cells (challenging to distinguish from conven-
as DLBCL (see the DLBCL section earlier). tional DLBCL) to those with only rare scattered neoplastic
B cells admixed with mature-appearing T cells and histio-
Microscopic Findings cytes. The background inflammatory cells may out-num-
ber the neoplastic cells and be reminiscent of a T-cell/
Morphologically, EBV-positive DLBCL, NOS, resembles histiocytic rich large B-cell lymphoma or classical mixed
other EBV-positive lesions. Specifically, this lymphoma can cellularity Hodgkin lymphoma. This lymphoma may have
have a polymorphic appearance with numerous scattered extensive tumor necrosis as well as angioinvasion.
A B
C D
E F
FIGURE 19.4
Aggressive B-cell lymphoma. A , At low magnification, this diffuse large B-cell lymphoma (DLBCL) can involve the gastric mucosa. A dense lymphoid infiltrate
with a pushing border is noted. B, The infiltrate is composed of sheets of pleomorphic large cells with prominent nucleoli and moderate amounts of cytoplasm
infiltrating into and destroying the overlying glandular epithelium. C , Immunohistochemical stain for CD20 shows a membranous staining pattern of the B cells
and emphasizes the pleomorphic nature of these cells. D , This lesion can have various Ki-67 labeling, including near 100% of cells as in this example. E, This
G H
I J
example of Epstein-Barr virus (EBV)–positive DLBCL demonstrates transmural infiltration with associated ulceration. This lesion demonstrates extensive expres-
sion of the B-cell marker CD20 (F). The in situ hybridization for Epstein-Barr encoding region (EBER) highlights the extensive number of EBV-infected cells (G).
This example of plasmablastic lymphoma (hematoxylin and eosin) demonstrates large neoplastic cells with eccentric nuclei with prominent. The neoplastic cells
have amble basophilic cytoplasm and often has paranuclear clearing (H). The neoplastic cells are positive for CD138 (I) as well as positive for EBV by in situ
hybridization (J).
Ancillary Studies The monomorphic variant of EBV-positive DLBCL can

appear identical to EBV-negative DLBCL but can be dif-
ferentiated by ISH-EBER. Additionally, EBV-positive
The large neoplastic cells are positive for pan-B-cell DLBCL lymphoma can be differentiated from HHV8-
markers CD20, PAX5, and CD79a (Fig. 19.4F). These positive DLBCL by the presence of HHV8 infected cells.
neoplastic B cells typically demonstrate a nongerminal After an organ transplant, patients can develop a lym-
center phenotype with expression of MUM1 and absence phoma that is morphologically similar to EBV-positive
of staining for LMO2, CD10, and BCL6. Additionally, DLBCL; however, the clinical history of transplantation
the neoplastic cells also express CD30, but only a small drives the diagnosis. PBLs lack expression of B-cell dif-
number of cases (15%) coexpress CD15. By definition, ferentiation markers CD20 and PAX5. EBV-positive
the majority of the neoplastic cells should be positive for mucocutaneous ulcers usually have a band of CD30+
EBV by in situ hybridization for Epstein-Barr encoding EBV-positive lymphocytes at the deepest leading edge,
region (ISH-EBER) (Fig. 19.4G). The neoplastic cells a finding that is absent in EBV-positive DLBCL. The
are also positive for PDL1. cases with a prominent background of T cells and his-
tiocytes can resemble T-cell/histiocyte-rich large B-cell
lymphoma. However, T-cell/histiocyte-rich large B-cell
lymphomas are negative for EBV-infected cells. In cases
in which there is associated necrosis and ulceration,
the diagnosis can be partially obscured by the mixed
The differential diagnosis for EBV-positive DLBCL inflammation and necrosis and resemble granulation
includes DLBCL, NOS; PBL; posttransplant lymphopro- tissue of ulcer exudate. Sometimes the neoplastic cells
liferative disorder; human herpesvirus 8 (HHV8)–posi- are b difficult to identify on H&E along, and often a
tive DLBCL; EBV-positive mucocutaneous ulcer as well PAX5 (and or CD20) along with ISH-EBER can be
as classical Hodgkin lymphoma and granulation tissue. extremely useful.
Prognosis and Therapy Immunohistochemistry

■ Positive for pan-B markers CD19, CD20, PAX5, and CD79a
■ Positive for MUM1 and negative for germinal center markers

The prognosis in these cases tends to be worse with age. CD10 and BCL6
Specifically, the presence of symptoms and age older ■ Negative for CD5, cyclin D1, and TdT
than 70 years are poor prognostic features. In older adult ■ Positive for CD30 with infrequent CD15 coexpression
■ Neoplastic cells are positive for EBV (in situ hybridization for
patients, a median survival period of 2 years is reported,
Epstein-Barr encoding region)
and if there are B symptoms, the median survival period
decreases to 9 months. In younger patients, the progno- Differential Diagnosis
sis is excellent with long-term remission seen in more ■ EBV negative diffuse large cell lymphoma
than 80% of cases. ■ Plasmablastic lymphoma
■ human herpesvirus 8–positive DLBCL, not otherwise specified
■ EBV-positive mucocutaneous ulcer
■ Classical Hodgkin lymphoma

EPSTEIN-BARR VIRUS–POSITIVE DIFFUSE LARGE ■ T-cell/histiocyte-rich large B-cell lymphomas
B-CELL LYMPHOMA, NOT OTHERWISE SPECIFIED— ■ Granulation tissue
FACT SHEET
Definition
■ Epstein-Barr virus (EBV)–positive clonal B-cell proliferation, a new
2017 World Health Organization category, replaces lymphoma ■ PLASMABLASTIC LYMPHOMA
previous known as EBV-positive diffuse large B cell lymphoma
of the elderly. The current diagnostic criteria removed the age
requirement. It excludes other EBV-positive lymphomas Clinical features
■ Most cases occur in patients after the age of 50 but can occur at Plasmablastic lymphomas is a clinically aggressive lym-
any age
phoma. The disease typically affects patients who are
■ Typically involves older patients sixth or seventh decade of life;
can involve younger patients immunosuppressed through immunosenescence, infec-

■ Male predominance (male-to-female ratio, 1.2–3.6:1) tious causes, after transplant, or medications. The typ-
■ Typically involves extranodal sites in older adults and nodal ical presentation is the oral cavity, but the GI tract is
disease in patients younger than 40 years of age the second most common site, and these two represent
the primary site in the vast majority of cases. In human
immunodeficiency virus (HIV)–positive patients, the
■ Prognosis is worse with older age
■ The presence of B symptoms and age older than 70 years are

lesions tend to occur in the anus or distal rectum. Patients
poor prognostic indicators with HIV tend to present with disseminated disease
■ Patients younger than 40 years of age have a better prognosis more often than patients in the posttransplant setting or
with most achieving long-term remission those that are immunocompetent. Those with dissemi-
■ Combined chemotherapy with rituximab
nated disease tend to have bone marrow involvement.
Typically, lymph nodes involvement is rare and affects
fewer than 10% of patients (slightly higher percentage of
nodal involvement in the posttransplant setting).
Epstein-Barr Virus–Positive Diffuse Large B-Cell
Similar to patients with other types of GI lymphomas
Lymphoma, Not Otherwise Specifiedpathologic
Features or malignancies, these patients typically present with
abdominal pain, weight loss, anorexia, melena, or painless
Gross Findings rectal bleeding. Additionally, many patients have diarrhea,
■ In younger patients, primary enlarged lymph nodes and only rarely have patients presented with obstruction.
■ Older patients with extranodal disease and in the gastrointestinal
tract present with ulceration or mass-forming lesion
Microscopic Findings Pathologic Features

■ Large neoplastic cells with a Reed-Sternberg or Hodgkin-like
appearance or transformed immunoblasts

■ Polymorphic variant with a background of mixed inflammatory Gross Findings
cells, neoplastic cells often the minority cell population
■ Monomorphic variant with increased under of neoplastic cells Plasmablastic lymphoma presents most commonly with
forming sheet; similar to Epstein-Barr virus (EBV)–negative an ulcerated mass lesion. Otherwise, the gross appear-
diffuse large B-cell lymphoma (DLBCL)
■ Often with ulceration and large areas of necrosis or granulation-
ance is similar to other aggressive lymphomas, appear-
type tissue ing as a bulky polypoid masslike lesion. This can lead to
strictures, obstructions, or perforation. On cut sections,
these lesions have a typical fish flesh appearance with lymphomas; however, PBL is negative for ALK expres-
areas of hemorrhage and necrosis. sion. Also, some DLBCLs can have a plasmablastic
appearance, but DLBCL is positive for CD20 and PAX5,
Microscopic Findings unlike PBL. HHV8-positive DLBCL often has a plas-
macytic/plasmablastic morphology, but the presence of
Plasmablastic lymphoma demonstrates a spectrum of HHV8-positive cells assists in the exclusion of this entity.
cytologic features ranging from cells with an immuno- The starry-sky pattern can resemble BL as well as
blastic appearance to those with plasmacytic/plasmacyt- acute leukemia/lymphoma; however, PBL is negative for
oid features and plasmablasts. The neoplastic cells have CD20 (and other B0cell markers) and TdT. Often the
a more solid or cohesive growth pattern. The nuclei more challenging differential is with plasma cell neo-
are enlarged and typically round and eccentric with plasm with plasmablastic differentiation. Unfortunately,
prominent single or multiple nucleoli. They have ample CD56 can also be expressed on PBL, limiting its useful-
amount of basophilic cytoplasm that often shows para- ness. Cyclin D1 is expressed in a proportion of plasma
nuclear clearing. The lymphoma typically has a high cell neoplasms and can be useful. However, often the
proliferation rate with scattered apoptosis giving it a differential can be solved with a patient’s history of
starry-sky pattern (Fig. 19.4H). The tumors also have plasma cell myeloma. Also, plasma cell myelomas (or
areas of geographic necrosis. Typically, there is only a plasmacytomas) occur in immunocompetent people and
minor component of infiltrating T cells. typically lack EBV-infected tumor cells. Additionally, the
presence of an M protein on serum electrophoresis or
symptoms of hypercalcemia, renal insufficiency anemia,
Ancillary Studies or bone lesions would support a plasma cell myeloma.
The neoplastic cells are positive for markers of plasma

cell differentiation, including CD138, CD38, VS38, and
MUM1 (Fig. 19.4I). Additionally, expression of CD79a
can be seen in up to 40% of cases. Importantly, the lym-
phoma lacks expression of other B-cell markers CD20 The prognosis of this lymphoma is dismal. The major-
and PAX5 and has variable expression of cytoplasmic ity of patients will succumb to this lymphoma with a
light chains. Although the tumor is negative for pan-ker- median survival time of 6 to 11 months. The presence of
atins, the lesion can express epithelial membrane antigen aM YC translocation is associated with worse outcomes.
(EMA; often weakly). This lymphoma lacks expression Unfortunately, there is no true standard of care therapy
of BCL6 and BCL2 with up to 20% expressing CD10. for these patients.
Expression for CD56 can be seen in up to 25% of cases,
which can make it challenging to differentiate from a
plasmablastic progression of myeloma. The neoplas-
tic cells are negative for CD3 and CD5 with only rare PLASMABLASTIC LYMPHOMA—FACT SHEET
cases expressing CD43. EBV (ISH-EBER) is positive
Definition
in around 70% of cases (Fig. 19.4J). By definition, this
■ Highly aggressive neoplasm composed of immunoblasts and
lesion is negative for HHV-8 expression. This lymphoma
plasmablasts
is typically positive for MYC by IHC with 50% to 75% ■ Excludes human herpesvirus and ALK-positive lymphomas
of patients demonstrating an M YC translocation.
■ Predominantly involves adults with immunodeficiency (human
Differential Diagnosis immunodeficiency virus, posttransplant, immunosenescence)
■ Primarily involved oral cavity and luminal gut
Often with the cohesively appearing neoplastic cells, this

Clinical Features
lesion can resemble nonhematopoietic malignancies such
■ Typically presents as an ulcerative mass
as carcinoma or melanoma. Immunohistochemical stains ■ Presents with abdominal pain, weight loss, anorexia, melena, or
for keratin (i.e., CAM5.2, AE1/3, OSCAR) can assist in painless rectal bleeding
excluding carcinoma, and melanoma can be excluded ■ Disseminated disease is found at presentation in 75% of
with immunostains for S100 or SOX10. A possible pitfall patients

is the use of EMA, which is expressed in carcinomas but
can often be expressed in plasmablastic or plasmacytic
■ Poor prognosis with median survivals of period of 6 to 11 months
lesions. Also remember that in addition to plasmablasts ■ No standard therapy
and plasma cells that CD138 is also a good epithelial ■ Rarely, surgical therapy has a role in treatment for obstruction or
and carcinoma marker. The differential also includes intussusception, debulking, and perforation
anaplastic large cell lymphoma and ALK-positive B-cell
orbit, or paraspinal lesions in 50% to 70% of cases. In

Plasmablastic Lymphoma—Pathologic Features some cases, it can present as an ileal or ileocecal mass
that serves as a leading point for intussusception or
Gross Findings intestinal obstruction. This form is strongly associated
■ Ulcerated (often circumscribed) mass with EBV infection with the EBV genome seen in more
■ Solid tan-white cut surface (fish flesh appearing) often associated
than 95% of the neoplastic cells.
with hemorrhage and necrosis
■ Lymph nodes involved in fewer than 10% of cases
Sporadic BL is seen throughout the world, where it
mainly occurs in children or younger adults. In nonen-
Microscopic Findings demic areas, BL accounts for 1% to 2% of lymphomas
■ Solid or cohesive growth pattern of immunoblasts or large but 30% to 50% of childhood lymphomas. Significantly
neoplastic cells with plasmablastic differentiation fewer cases are associated with EBV (20%–30% of
■ Cells with eccentric nuclei with abundant typically with abundant
cases). The majority of sporadic BL cases present as an
basophilic cytoplasm with prominent single or multiple nucleoli
abdominal mass with the ileocecal area being the pri-
■ Some demonstrate a paranuclear hof (clearing)
■ High proliferation rate, often with a starry-sky pattern and

mary site of involvement. However, any part of the GI
associated tumor necrosis tract may be involved because cases of gastric or rectal
BL are common. Patients can present with complaints of
Immunohistochemistry abdominal pain or obstructive-type symptoms.
■ Positive for plasma cell markers CD138, MUM1, CD38, VS38c, Immunodeficiency-associated BL is primarily seen
and EMA with HIV infection. Although BL can be the first man-
■ Negative for B-cell markers CD20 and PAX5 as well as CD45
■ Can be positive for CD79a; 40% of cases

ifestation of AIDS, BL often occurs when the patients
■ Positive for cMYC IHC expression still have relatively high CD4 counts. The risk of devel-
■ Epstein-Barr virus (EBV) (in situ hybridization for Epstein-Barr opment of BL in patients with HIV also appears to be
encoding region) in 70% of cases similar in the pre and post–highly active antiretroviral
■ Minority of cases positive for CD10 (20%) or CD56 (25%)
therapy era. Additionally, only 25% to 40% of immu-
■ Negative for BCL6, BCL2, CD5, cyclin D1, TdT, CD30, human
herpesvirus (HHV) 8, and ALK nodeficiency-associated BL are also associated with EBV
■ Ki-67 index greater than 95% infection. In addition to GI involvement, nodal localiza-
tion and bone marrow involvement are frequent.
■ 50% of cases demonstrate an MYC rearrangement
■ Complex karyotypes
Pathologic Features
■ DLBCL and Burkitt lymphoma
■ HHV8- or EBV-positive diffuse large B-cell lymphoma

Gross Findings
■ Poorly differentiated carcinoma or melanoma In GI BL cases, there exists a predilection for the involve-
ment of the ileocecal region and less often the rectum
and stomach. Given the high proliferation rate, they
typically present as large bulky masses that completely
■ ■ BURKITT LYMPHOMA replace the bowel wall. The lesions often infiltrate
transmurally into the surrounding mesenteric tissue
Clinical Features with areas of necrosis and hemorrhage. Similar to other
higher grade lymphomas, the lesion has a typical fish
flesh appearance. Interesting, the lymph nodes are not
Burkitt lymphoma is a highly aggressive B-cell neoplasm; involved by BL, but the tissue around the lymph may be
however, it is often a curable lymphoma. The disease typ- involved.
ically presents in extranodal sites or as acute leukemia.
There are three recognized epidemiologic variants of BL, Microscopic Findings
and they differ in their geographic distribution, clinical
presentation, and molecular and morphologic aspects. The tumor is characterized by the infiltration of mono-
These include endemic, sporadic, and immunodeficien- morphic medium-sized lymphocytes that often has a
cy-associated BL, and all these variants are seen in the GI cohesive appearance. The nuclei have clumped chro-
tract. Regardless of the variant, they present with bulky matin with multiple small nucleoli. The cytoplasm is
abdominal disease with a high tumor burden. densely basophilic with classic lipid vacuoles, which
The endemic form of BL is found primarily in equa- are seen best on touch preps or cytology specimens. The
torial Africa, where it is the most common childhood most recognized feature is the starry-sky background,
malignancy in children 4 to 7 years of age. This form which is composed of multiple tingible body macro-
typically presents in the head and neck region with jaw, phages with apoptotic debris (Fig. 19.5A and B). Given
the high proliferation rate, mitotic figures and apoptosis (Fig. 19.5D) and show aberrant expression of CD43.
are readily identified in all cases. Rarely, cases may show Importantly, BCL2 is either negative or there may be
a florid granulomatous reaction. In older adults and weak patchy staining (Fig19.5D). TdT is usually neg-
patients with the immunodeficiency-associated variant, ative. In addition, the cells are negative for cyclin D1,
the cells can show a greater degree of nuclear pleomor- CD23, and CD5. They also show aberrant coexpression
phism or harbor a plasmablastic morphology. of LEF1, and a subset are positive for SOX11. The neo-
plastic cells are strongly positive for surface IgM with
light chain restriction. Given the high mitotic rate, the
Ancillary Studies Ki-67 index is nearly 100% of cells (Fig19.5 F). (ISH-
EBER) highlights the EBV infected cells.
The neoplastic cells express pan-B-cell markers CD19, The tumor cells demonstrate Ig gene rearrange-
CD20, PAX5, and CD79a ( Fig. 19.5C). Additionally, ment. The prototypic cytogenetic abnormality BL is
they express germinal center markers BCL6 and CD10 translocations involving the MYC (8q24) loci. The
A B
C D
E F
FIGURE 19.5
Burkitt lymphoma. A , At low power, this lymphoma commonly involves the small bowel with transmural inflammation and obstruction or perforation B , At high
power, the neoplastic infiltrate is composed of a highly monotonous, monomorphic population of medium-sized lymphocytes with round nuclei, finely clumped
chromatin; several small nucleoli; and scant cytoplasm admixed with tangible-body macrophages containing apoptotic debris lead to a “starry-sky” appearance
within the dense infiltrate. C, The neoplastic cells are B cells as highlighted by CD20. The neoplastic cells are typically strongly positive for CD10 (D) but should
H I
be negative for BCL2 (E). An immunohistochemical stain for Ki-67 (F) shows nuclear positivity in virtually all neoplastic cells, corresponding to a high prolifera-
tive index. Burkitt lymphoma has MYC protein overexpression (G). Florescent in situ hybridization using break apart probes demonstrates rearrangement of the
MYC gene (H) and normal intact B CL2 gene (I).
most common MYC translocation is with the heavy can also be morphologic overlap between BL and lym-
chain gene t(8;14)(q24q32). However, less commonly, phoblastic lymphoma. Lymphoblastic lymphoma lacks
the MYC translocations can involve one of the light expression of mature B-cell markers (e.g., CD20) and is
chain genes IGK (2q11) or IGL (22q11), resulting positive for TdT.
in t(2;8) or t(8;22). The translocations involving
MYC result in increased MYC protein expression.
Immunohistochemical stains for MYC label the major-
ity of cells in BL cases (Fig. 19.5G). Up to 10% of clas-
sic BLs can lack detectable M YC rearrangements. The
presence of B CL2 and B CL6 rearrangements suggest Burkitt lymphoma is a highly aggressive tumor; how-
an alternative diagnosis such as high-grade B-cell lym- ever, with aggressive therapy, it can be potentially cur-
phoma (Fig. 19.5H and I). able in the majority of patients. Specifically, intense
chemotherapy leads to long-term survival in 70% to
90% of cases. The prognosis depends on clinical stage
and is generally is better in children than in adults.
Poor prognostic factors include involvement of bone
marrow and/or CNS by BL as well as high serum LDH
The differential diagnosis includes other high-grade or large (>10 cm) unresectable masses. In immunode-
lymphomas and acute leukemia. Typically, DLBCL is ficiency-associated BL, BL remains curable, and the
more pleomorphic than BL. Although other aggressive overall prognosis is related more to the underlying HIV
lymphomas can have increased proliferation index, or immunodeficiency pathology than to the lymphoma
few have 100% Ki-67 index that is so typical of BL. itself. Surgical resection or debulking is indicated in
Additionally, many of the aggressive lymphomas can patients with present with symptoms of obstruction or
have BCL2 expression, which is absent in BL. There perforation.
■ Round nuclei with finely clumped chromatin containing three to

BURKITT LYMPHOMA—FACT SHEET
four centrally located small basophilic nucleoli
■ Extremely high proliferation rate
Definition ■ Associated tingle-body macrophages creating a “starry-sky”
■ Highly aggressive B-cell neoplasm appearance
■ Occurs in three clinical forms: endemic, sporadic, and
immunodeficiency associated Immunohistochemistry

■ All three forms may present in the gastrointestinal (GI) tract
■ Positive for pan-B-cell markers CD19, CD20, PAX5, CD79a
■ Positive for CD10, BCL6, CD43, and LEF1

Incidence and Location ■ Negative for BCL2, CD5, and cyclin D1
■ Endemic, primarily in equatorial Africa and Papua New Guinea ■ Ki-67 index is nearly 100%
■ Associated with Epstein-Barr virus (EBV) infection more than ■ Positive for protein expression for MYC
95% of cases ■ Positive for surface immunoglobulin M expression with light chain
■ Most common childhood malignancy in endemic areas, with restriction
peak incident between 4 and 7 years of age
■ Sporadic: sen throughout the industrialized world affecting Genetic Abnormalities
primary children and young adults ■ Translocation involving M
YC, including t(8;14) M
YC/IGH, t(2;8)
■ Only 20% to 30% are associated with EBV infection
IGK/MYC, or t(8;22) M YC/IGL
■ Accounts for 1% to 2% of all lymphomas and 30% to 50%
■ Negative for B
CL2 and B CL6 rearrangements
childhood lymphomas
■ Immunodeficiency associated: Seen throughout the world and
associated with human immunodeficiency (HIV) infection
■ Diffuse large cell lymphoma
■ Up to 25% to 40% are associated with EBV infection
■ High-grade B-cell lymphoma

Clinical Features
■ All subtypes: bulky disease and frequently widespread with bone
marrow involvement and acute leukemia common

■ Endemic: mass in the jaw, orbit, or paraspinal lesion; GI tract
involvement less common, usually ileocecal ■ EPSTEIN-BARR VIRUS–POSITIVE

■ Sporadic: children present with abdominal mass, typically in MUCOCUTANEOUS ULCER
the ileocecal region; causes abdominal pain and obstructive
symptoms. Adults can have tumors in any part of the GI tract,
most commonly in the ileocecal region and the rectum Another recently described entity is termed EBV-
positive mucocutaneous ulcer and is an EBV-associated
lymphoproliferative process. These lesions are reported
■ Highly aggressive tumor but potentially curable in the majority of
patients to occur in the GI tract, oropharynx, and skin. The

■ Prognosis depends on the stage and is generally better in cases are reported in immunosuppressed individuals
children secondary to iatrogenic, primary immunodeficiency, or
■ The mainstay of treatment is intensive combination age-related immunosenescence.
chemotherapy regimens The lesions are typically ulcerated with a shallow
■ Surgical therapy has a role in the treatment of obstruction or
intussusception, debulking, and perforation punctate or well-demarcated lesion (Fig. 19.6A). There
are no associated systemic symptoms or involvement.
Histologically, the lesion demonstrates a polymorphic
infiltrate with a mixture of small mature-appearing
lymphocytes and plasma cells with scattered immu-
noblasts and large atypical lymphocytes (Fig. 19.6B).
Burkitt Lymphoma—Pathologic Features These large atypical cells can have Reed-Sternberg–like
morphology. In some cases, there may be evidence of
Gross Findings
angioinvasion. These large atypical lymphocytes are
■ Typically large bulky mass that in the GI tract has a predilection for
positive for B cell marker PAX5 with variable expres-
the ileocecal region and less often rectum and stomach
■ Solid tan-white cut surface (fish flesh appearing) often associated
sion of other B-cell markers (CD20 and CD79a) (Fig.
with hemorrhage and necrosis 19.6E). The neoplastic cells are positive for CD30 (Fig.
■ Lymph nodes typically not involved by tumor but instead are 19.6C), and about 50% of reported cases are CD15 posi-
surrounded by tumor tive. These large cells are also highlighted by ISH-EBER
■ In the GI tract, the lesions tend to be transmural and in some
(Fig. 19.6D). The lesional cells demonstrate an acti-
cases can present as an obstructive mass or perforation
vated or postgerminal center phenotype and typically
Microscopic Findings express MUM1 but are negative for BCL6 and CD10.
■ Intermediate-sized cells with scant cytoplasm with cytoplasmic
ISH-EBER highlights the large atypical cells. Most cases
vacuoles seen on touch and smear preparations that are positive are associated with an extensive background of CD3+
for Oil red O (usually frozen section preparation) and CD8+T cells, typically with a dense perilesional
infiltrate (Fig. 19.6F).
Even though the morphology is highly concerning, to be self-limited and spontaneously resolve, reduction
these lesions have been reported to have an indolent nat- of immunosuppression is the primary goal of treatment.
ural history. Local progression and tissue destruction can In cases when this is not an option, chemotherapy with
occur. Although a few of the lesions have been reported rituximab or local radiation has proven useful.
A
B
C D
E F
FIGURE 19.6
Epstein-Barr virus (EBV)–positive mucocutaneous ulcer. A, At low power, the lesion is ulcerated with a dense inflammatory infiltrate underlying the ulcer. B , At
high power, the lesion is composed of a polymorphic population of cells, including atypical Reed-Sternberg-like cells. The large atypical cells are typically most
prominent at the base of the lesion and strongly expression CD30 (C). Additionally, these large atypical cells and a background of small lymphocytes are EBV
infected, as highlighted by in situ hybridization for Epstein-Barr encoding region (D). There is only focal patchy expression of CD20 (E), and the extensive T-cell
infiltrate can be seen on CD3 immunostains (F).
■ MATURE T- AND NATURAL KILLER CELL for unknown underlying celiac disease. Although most
NEOPLASMS cases are localized disease, when the disease dissemi-
nates, it has a predilection to involve the liver, spleen,
Intestinal T-cell lymphomas are far less common than lung, testes, and skin but only rarely the bone marrow.
those of B-cell origin. Although these have a lower inci-
dence, there are subtypes of T-cell lymphomas that are
specific to the GI tract. Additionally, the most recent edi- Pathologic Features
tion of the WHO has reclassified these lesions and added
a few preliminary entities. Gross and Endoscopic Findings
The most common type of intestinal T-cell lym-
phoma occurs in the setting of GSE and is referred to Enteropathy-associated T-cell lymphoma typically
as EATL. The lymphoma previously referred to as type involves the jejunum (90% of cases) occurring as iso-
II EATL has now been reclassified as MEITL and is not lated or multifocal lesions, but it can also involve the
associated with GSE. An additional rare classification is stomach and large bowel. Typically, the segment of the
the indolent T-cell lymphoproliferative disorder of the GI tract involved by the lymphoma has an edematous
GI tract. Although other T-cell lymphomas only infre- appearance with large circumferential ulcers and occa-
quently involve the GI tract, the liver is more commonly sional plaques. The lesions can also look similar to celiac
affected. Hepatosplenic T-cell lymphoma (HTCL), in disease with loss of mucosal folds. Less commonly,
particular, frequently involves the liver and well as the EATL can present as bulky, exophytic, or infiltrating
spleen. Other T- and NK cell entities that can involve masses. It is common for the lymphoma to infiltrate the
the GI tract include peripheral T-cell lymphoma (PTCL, mesentery and involve mesenteric lymph nodes.
NOS), and extranodal NK/T-cell lymphoma, nasal type
(which is not discussed in this text). Microscopic Findings
The histologic appearance of EATL is variable between

■ ENTEROPATHY-ASSOCIATED T-CELL individual cases and between different sites in the
LYMPHOMA same patient. The tumor cells are relatively pleomor-
phic medium to large cells with round or angulated
vesicular nuclei, prominent nucleoli, and moderate
Clinical Features to abundant pale-staining cytoplasm (Fig. 19.7A and
B). Occasionally, the tumor exhibits marked pleomor-
Enteropathy-associated T-cell lymphoma is a rare lym- phism with multinucleated cells bearing a resemblance
phoma representing fewer than 1% of all lymphomas to anaplastic large cell lymphoma. An associated
and approximately 5% of all GI tract lymphomas. inflammatory infiltrate of histiocytes, eosinophils, and
However, EATL represents up to 60% to 80% of the plasma cells is often present. This inflammatory infil-
GI T-cell lymphomas. The vast majority of cases are trate can be so extensive that it may obscure the neo-
associated with GSE or celiac disease. Interestingly, plastic process.
it is common for the diagnosis of GSE to occur at the
same time as the lymphoma. Although lymphoma can
arise in patients with a long-standing history of GSE, Ancillary Studies
it is most commonly seen in adult-onset or presenta-
tion of celiac disease or patients who develop dermatitis The neoplastic cells are double-negative T cells, express-
herpetiformis. ing CD3 without expressing CD4 or CD8. The neoplastic
The most common presentation of EATL is a history cell typically loses expression of CD5 but retains expres-
of abdominal pain and weight loss. Additionally, many sion of T-cell associated antigens, CD7, CD2, and CD43.
patients have symptoms of celiac disease include mal- Additionally, the neoplastic cells demonstrate a cyto-
absorption or diarrhea. Patients can also present with toxic phenotype with expression of TIA1, granzyme B,
hemorrhage and symptoms of obstruction, and up to and perforin. The neoplastic cells also express CD103,
50% of patients present with intestinal perforation. In typically seen on mucosal homing or intraepithelial lym-
patients with a history of GSE, refractory changes and phocytes. The neoplastic cells are α-β T cells that lack
clinical deterioration, especially in the setting of com- expression of surface T-cell receptor (TCR) as well as
pliance with a gluten-free diet, should raise a concern CD56. The immunoprofile of the lymphocytes in EATL
for refractory type II celiac disease and the possibility is the same as that seen in the refractory celiac disease
of evolution to EATL. Unfortunately, many patients type II. The large cells in EATL usually express CD30
presenting with EATL appear to have unknown or sub- but are negative for ALK. ISH-EBER is usually negative.
clinical GSE, and as such, all patients with T-cell lym- Even though the neoplastic cells do not express
phoma of the intestinal tract should also be evaluated surface TCR, clonal TCR-βor -γrearrangements are
A B
C D
E F
FIGURE 19.7
Enteropathy-associated T-cell lymphoma (EATL). As seen from low power (A), EATL in the small bowel shows transmural involvement with marked architectural
effacement by a diffuse proliferation of neoplastic T cells. At higher magnification (B), the infiltrate is pleomorphic, including scattered anaplastic-appearing
cells admixed with small and larger lymphocytes with plasma cells and eosinophils. The infiltrate is negative for CD20 (C) but expresses CD3 (D). In addition
to the neoplastic cells an intraepithelial lymphocytosis can be seen in the small bowel villi. E, The neoplastic cells demonstrate loss of CD5 with patchy intact
expression of CD5 in the intraepithelial lymphocytes. F, The background histocytes are positive for CD4 as are the non-neoplastic T cells in the lamina propria;
G H
I J
however, the neoplastic cells are negative for CD4. G, The intraepithelial lymphocytes are positive for CD8; however, the neoplastic cells are negative for CD8
expression. There is retained expression of CD7 (H) and CD43 (I) in the neoplastic cells and the intraepithelial lymphocytes. The large pleomorphic neoplastic
cells express CD30 (J).
found in virtually all cases. Given the correlation with the mucosa and tends to show loss of folds or fissures
celiac disease, it is not surprising that greater than 90% and scalloped folds. Refectory celiac disease can have
of patients have HLA-DQA1*0501 or DQB1*0201. these same features but also can demonstrate erosions
Additionally, up to 90% of patients have amplifications and ulcerations. However, when there are obstructing
of chromosome 9q31 or deletions of 16q12 are preva- masses, ulcerated nodular mucosa, or stricture, these
lent. The lesions also tend to have gains of 1q and 5q. features suggest the likelihood of an EATL.
Enteropathy-associated T-cell lymphoma typically
presents as an infiltrative mass that can resemble an
Differential Diagnosis aggressive B-cell lymphoma, which can be distinguished
by IHC. Additionally, given the atypical or anaplastic mor-
In superficial biopsies, the histologic changes over- phology and strong CD30 expression within the large cells,
lap with celiac disease and refractory celiac disease. the differential diagnosis includes an anaplastic large cell
Specifically, they all demonstrate a dense intraepithelial lymphoma. EATL and anaplastic large cell lymphoma
infiltrate of CD3+T cells with associated villous blunt- can have similar immunohistochemical features including
ing. The infiltrate in celiac disease is composed of CD3+ features of cytotoxic T cells. However, EATL is negative
CD8+T cells with intact expression of T cell–associated for ALK and CD25. Other mature T and NK cells such
antigens CD2, CD5, and CD7. Both refractory type II as extranodal NK cell lymphoma and PTCL, NOS, also
celiac disease and EATL have T cells that have an aber- remain in the differential diagnosis. At times, these can be
rant phenotype, with double negative T cells (CD3+, more difficult to distinguish, especially in the absence of
CD4-, CD8-) along with loss of CD5 and TCR surface a history or clinical features of GSE. Poorly differentiated
expression with clonal TCR rearrangements. Grossly or malignancies (melanoma, carcinoma) can be sorted out by
endoscopically nonrefractory celiac disease is limited to morphologic features and immunohistochemical stains.

Enteropathy-Associated T-Cell Lymphoma—Pathologic
Features
The prognosis of EATL is unfavorable with a median
survival time of only 7 months with reported 1- and Gross and Endoscopic Findings
5-year survival rates of 31% to 39% and 0% to 59%, ■ Most common in the jejunum, either alone or in combination
respectively. Most patients succumb to malnutrition with other sites in the gastrointestinal tract
and disease progression with complications related to ■ Affected bowel segment is often dilated and edematous, with
perforation, infection, and peritonitis. Unfortunately, loss of normal mucosal folds
the malnutrition makes most patients intolerant of che- ■ Large circumferential ulcers, ulcerated plaques, and strictures with
intervening areas of normal mucosa
motherapy, and given the diffuse bowel involvement,
Bulky exophytic or infiltrating masses are not typical but can be
surgery is typically not useful except in cases of perfo-
■
seen in some cases

ration or obstruction. Factors associated with long-term
■ Mesenteric lymph node involvement is common
survival include the absence of a previous diagnosis of
GSE and completion of an entire course of chemother- Microscopic Findings
apy. Aggressive chemotherapy along with autologous ■ Variable cytologic appearance between cases and between
stem cell transplant has shown an overall survival of different sites in the same patient
60% and progression-free survival of 52%. ■ Pleomorphic medium-sized to large cells with round or angulated
vesicular nuclei, prominent nucleoli, and moderate to abundant
pale-staining cytoplasm
■ Up to half have marked pleomorphic or anaplastic appearance
ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA— with multinucleated cells
FACT SHEET ■ Dense inflammatory infiltrate of histiocytes, eosinophils, and
plasma cells
Definition ■ Destruction of the overlying epithelium by the lymphoma cells
■ An intestinal T-cell lymphoma associated with gluten-sensitive ■ Background mucosa shows changes of gluten-sensitive
enteropathy enteropathy (intraepithelial lymphocytosis, increased lamina
propria lymphocytes and plasma cells, villous blunting, and crypt
Incidence and Location hyperplasia)
■ Rare; approximately 5% of all gastrointestinal (GI) tract
lymphomas but 60% to 80% of GI T-cell lymphomas Immunohistochemistry

■ Geographic distribution is similar to that of celiac disease with the
highest incidence in people of Northern European ancestry ■ Most cases are CD3+, CD4-, CD8-, CD7+, CD5- and express
cytotoxic granule-associated protein TIA-1, often with granzyme B
Gender, Race, and Age Distribution ■ Large pleomorphic cells are typically CD30+but negative ALK
■ Typically occurs in the seventh decade of life expression
■ Slight male predominance with a male-to-female ratio of ■ Negative for surface TCR expression (only up to 25% have
1 to 2.8:1 cytoplasmic T-cell receptor [TCR] expression)
■ Negative for CD56 and CD57 expression
Clinical Features ■ Neoplastic cells are Epstein-Barr virus (in situ hybridization for
■ Typical presentation: several months to year history of abdominal Epstein-Barr encoding region) negative
pain and weight loss
■ May present acutely with acute bleeding, obstruction, or
perforation
■ Clonally rearranged TCR genes
■ Deterioration of celiac disease may herald the presence of
lymphoma ■ Segmental amplification of chromosome 9p31.3 or deletion at

■ Gluten-sensitive enteropathy (GSE) history, typically of recent 16q12.1 are seen in up to 80% of cases
onset ■ Other common cytogenetic findings are grains in 1q, 5q, and 7q
■ Subclinical GSE may be present or loss in 8p, 9p, or 13q
■ Most have localized intestinal disease with or without contiguous ■ Up to 69% demonstrate evidence of microsatellite instability.
lymph node involvement ■ Patients enriched for HLA-DQ2/DQ8
■ Disseminated disease has a predilection for the liver, spleen, lung,
testes, and skin

■ Malnutrition may result in finger clubbing and ichthyosis rash
■ Celiac disease
Prognosis and Treatment ■ Diffuse large B-cell lymphoma
■ Prognosis is poor (median survival time, 7 months) ■ Extranodal natural killer cell lymphoma
■ Patients have complications of peritonitis and malnutrition and ■ Peripheral T-cell lymphoma, not otherwise specified
later from progressive disease ■ Poorly differentiated malignancies (melanoma, carcinoma)
■ MONOMORPHIC EPITHELIOTROPIC neoplastic infiltrate expands the lamina propria and

INTESTINAL T-CELL LYMPHOMA involves the epithelium resulting in widening and blunt-
ing of the villi (Fig. 19.8A). Unlike EATL, MEITL does
not have significant background inflammation.
Clinical Features
The lymphoma previously referred to as type II EATL

Ancillary Studies
is now referred to as MEITL. The name change more
closely represents the morphologic appearance of the
lymphoma and more clearly delineates this form of The lesion is composed of T cells that express CD3,
lymphoma from EATL. Specifically, MEITL is not asso- CD8, and CD56 ( Fig. 19.8C, E, and F). The cells
ciated with GSE. This entity constitutes 34% of the pri- retain expression of CD7, CD43, and CD2 expression
mary intestinal T-cell lymphomas and has a slight male but are often negative for CD5 (Fig. 19.8D) and CD4.
prominence with a reported male-to-female ratio of 1.9 Interestingly, the majority of CD8 are CD8 α homodi-
to 2.6:1. Additionally, there is no association with spe- mers. The lymphoma cells are typically γ -δ T cells but
cific human leukocyte antigens. Although MEITL has may also be TCR silent. This lymphoma has a cytotoxic
a worldwide distribution, increased incidence has been phenotype with most expressing TIA-1 and fewer cases
documented in patients from an Asian or Hispanic or expressing granzyme B. More recently, a novel marker,
indigenous origin. megakaryocyte-associated tyrosine kinase (MATK), has
Patients present with symptoms similar to those been reported as being positive in up to 90% of cases.
of other intestinal lymphomas, such as abdominal Importantly, up to 65% of cases have different immu-
pain, weight loss, diarrhea, and GI bleeding. However, noprofiles between the mucosal lymphoma cells and the
patients usually do not have a history of malabsorption intraepithelial lymphocytes.
seen in patients with GSE. The lymphoma has clonal TCR gene rearrangements
and has some of the similar genomic changes as EATL.
MEITL also demonstrates amplification of 9q and dele-
tion of 16q. Additionally, MEITL can often demonstrate
Pathologic Features
gains in the CMYC gene with associated MYC expres-
sion seen by IHC. Similar to other γ-δ T cells, MEITL
Gross and Endoscopic Findings also typically demonstrates STAT5B mutation.
Grossly, MIETL resembles other lymphomas involving

the small bowel. The jejunum is preferentially involved,
but the colon can also be involved. Additionally, it is
common for the lymphomatous process to infiltrate
the mesentery and involve mesenteric lymph nodes. The monomorphic appearance of the mantle cells can be
Endoscopically, diffuse mucosal thickening and edema reminiscent of MEITL; however, MCL usually does not
with multiple shallow ulcerations and a nodular or show intraepithelial lymphocytosis. Although celiac
mosaic mucosal pattern are characteristic of the disease. disease can demonstrate a prominent intraepithelial
These changes can grossly resemble celiac disease with lymphocytosis and therefore can mimic MEITL, the
loss of normal mucosal folds. Occasionally, the lesion abnormal T cells in celiac disease are restricted to the
can be polypoid or masslike with or without ulceration. epithelium and do not expand the lamina propria.
Unfortunately, up to 69% of these patients present with The morphologic and immunohistochemical features
perforation or obstruction. Typically, loss of mucosal of MEITL can overlap with other γ-δT-cell lympho-
folds is only present at the site of the lesion. However, in mas as well as NK or T-cell lymphomas. Specifically,
some cases, there is patchy involvement of the mucosa, there can be overlap with extranodal NK or T-cell lym-
which can result in a plaque-like appearance. The lymphoma nasal type, and PTCL, NOS. Extranodal NK or
phoma commonly involves the abdominal, inguinal, or T-cell lymphoma, nasal type, can frequently involve
mesenteric lymph nodes. the GI tract and typically demonstrates villous atro-
phy. EBV is typically positive in the neoplastic cells,
Microscopic Findings which are positive for CD56 and negative for surface
CD3. Additionally, NK or T-cell lymphoma does not
Cytomorphologically, the neoplastic cells are intermedi- typically have an intraepithelial lymphocytosis or an
ate or medium in size. As the name implies, the cells adjacent associated enteropathy. The diagnosis of
are monomorphic with a uniformly round noncleaved PTCL, NOS, requires that the T-cell lymphoma does
appearance. These cells also demonstrate clear cyto- not meet diagnostic features of another defined T-cell
plasm (Fig. 19.8B) with inconspicuous nucleoli. The lymphoma.
B
A
D
C
E F
FIGURES 19.8
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formally known as enteropathy-associated T-cell lymphoma, type II. At low power (A), there
are a dense intraepithelial lymphocytosis and expansion of the lamina propria. At high power (B), the tumor has a very monomorphic population of interme-
diate-sized lymphocytes with inconspicuous nucleoli. The lymphoma cells are strongly positive for CD3 (C), CD8 (E), and CD56 (F) with loss of expression of
CD5 (D).
Prognosis and Therapy survival rates of 35% and 32%, respectively. There is
limited information in regards to prognostic factors and
useful treatment regimens. As is typical of lymphopro-
The prognosis is poor and similar to EATL with a liferative disorders, an initial response to therapy pre-
median survival time of only 7 months, and 1- and 5-year dicts a better outcome.
Hepatosplenic T-cell lymphoma occurs mainly in

Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma— adolescents and young adults with a male predilection
Pathologic Features and median age of 35 years. Additionally, up to 20% of
patients with HSTL have chronic immunosuppression,
Gross, Endoscopic, and Radiologic Findings
including those with a history of solid organ transplan-
■ Most common in the jejunum, either alone or in combination
tation, Hodgkin lymphoma, acute myelogenous leuke-
with other sites in the gastrointestinal tract
■ Affected bowel segment is often dilated and edematous with loss
mia, malaria infection, pregnancy, and inflammatory
of normal mucosal folds bowel disease treated with azathioprine or infliximab or
■ Large circumferential ulcers, ulcerated plaques, and strictures with biological agents.
intervening areas of normal mucosa
■ Bulky exophytic or infiltrating masses are rarely seen
■ Mesenteric and distal lymph node involvement is common
Pathologic Features
■ Uniform (monomorphic) medium-sized round nuclei with a rim
of pale cytoplasm Gross and Microscopic Findings

■ Florid infiltration of intestinal crypt epithelium with associated with
expansion of lamina propria and villous blunting Diffuse hepatic and splenic enlargement is noted with
■ Mixed inflammatory background is usually absent
■ Intraepithelial lymphocytosis is limited to the area of lymphoma

no discrete nodules or masses. The lymphoma predom-
involvement inantly involves the red pulp of the spleen. The liver
shows sinusoidal infiltration by tumor cells with rela-
Immunohistochemistry tive sparing of portal triads (Fig. 19.9A). The infiltrate
■ Most cases are CD3+, CD56+, CD8+, CD4-, CD7+, CD5-, and consists of a monotonous population of cells with medi-
express cytotoxic granule-associated protein TIA-1, often with um-sized nuclei, small inconspicuous nucleoli, and a
granzyme B
rim of pale cytoplasm (Fig. 19.9B). Occasional mitotic
■ Aberrant CD20 expression in up to 20% of cases
■ Megakaryocyte-associated tyrosine kinase reported as a novel

figures and single-cell necrosis may be noted. Cytologic
marker atypia with large cell changes may be seen, especially
■ Negative for CD30, ALK, and Epstein-Barr virus with disease progression.
■ Clonal T-cell receptor rearrangement
■ Amplified MYC Ancillary Studies

■ Activating mutations in STAT5B
■ Gains in 9q34.3
The commonly reported T-cell phenotype is CD2+, CD3+,
Differential Diagnosis CD4-, CD5-, CD7+/-, CD8-, with γ-δ TCR expression
■ Celiac disease (Fig. 19.9C&D). CD7 expression may be lost during
■ MCL treatment. NK cell markers CD56 ( Fig. 19.9E
) and
■ Extranodal natural killer cell lymphoma
CD16 are often expressed, but CD57 is usually negative.
■ Peripheral T-cell lymphoma, not otherwise specified
The cells also express the cytotoxic granule-associated
proteins, TIA1 (Fig. 19.9F) but are negative for gran-
zyme B and perforin. Although most cases are derived
from gamma-delta T-cells, a minority of cases of α β T
■ HEPATOSPLENIC T-CELL LYMPHOMA cells have also been reported. ISH-EBER is negative.
Most cases of HSTL have a specific recurrent chromo-
Clinical Features somal abnormality, isochromosome 7q, and frequently
have S TAT5 mutations. Additionally, trisomy 8 and loss
of the Y chromosome have also been reported.
Hepatosplenic T-cell lymphoma is a rare neoplasm of
gamma δ T cells. This T-cell lymphoma involves and
expands the sinusoids of the liver, spleen, and bone
marrow. The involvement leads to hepatosplenomeg-
aly without lymphadenopathy. Patients tend to present
with B symptoms and pronounced thrombocytopenia. The differential diagnosis of HTCL includes aggressive
Additionally, patients can present with anemia and NK leukemia/lymphoma, EBV hepatitis, and T-cell
often leukopenia along with fever, abdominal pain, and large granular lymphocyte leukemia. These other dis-
weakness. There can also be variable elevation in liver ease entities can also present with hepatomegaly or
function tests (aspartate transaminase, alanine transam- hepatosplenomegaly. NK leukemia/lymphoma has an
inase, and alkaline phosphatase). aggressive clinical course. The tumor cells in NK cell
lymphoproliferative disorders are immunophenotypi- among these malignancies. Morphologic overlap is also
cally similar to HSTL, but they lack expression of a seen, although the localization of the HSTL tumor
TCR and CD3. The tumor cells share many func- cells within sinusoids in spleen and bone marrow is
tional and phenotypic similarities with NK cells and a feature not seen in other large granular lymphocyte
NK-like cytotoxic T cells, resulting in clinical overlap disorders.
A B
C D
E F
FIGURE 19.9
Hepatosplenic T-cell lymphoma. A , A core biopsy of the liver shows a lymphocytic infiltrate involving the sinusoids with relative sparing of the portal triads. B
,
At higher power, the infiltrate is composed of a monotonous population of cells with medium-sized nuclei, small inconspicuous nucleoli, and a rim of pale
cytoplasm expanding the sinusoidal spaces. C , An immunohistochemical stain for CD3 highlights the predominantly sinusoidal pattern of infiltration by the neo-
plastic T-lymphocytes. These neoplastic cells demonstrate loss of CD5 expression (D) and aberrant expression of CD56 (E). These neoplastic cells are cytotoxic
and demonstrates expression of TIA1 (F).

Hepatosplenic T-Cell Lymphoma—Pathologic Features
The clinical course is aggressive with a dismal progno- Gross Findings

sis. Patients may initially respond to chemotherapy, but ■ Diffuse enlargement of spleen and liver
■ Generally, no specific mass-forming lesion

there is a high relapse rate and short median survival
time of 8 months. Microscopic Findings
■ Monotonous lymphocytes with medium-sized nuclei and a rim of
pale cytoplasm
■ Diffuse involvement of the cords and sinuses of the splenic red
HEPATOSPLENIC T-CELL LYMPHOMA—FACT SHEET
pulp
■ Splenic white pulp atrophy
Definition
■ Hepatic sinusoid involvement
■ Extranodal and systemic neoplasm of cytotoxic T cells
■ Cytologic atypia with large cell or blastic changes seen in disease
progression
■ Up to 20% arise in the setting of chronic immune suppression Immunohistochemistry
■ Involves the spleen, liver, and bone marrow
■ Usually γ -δT-cell receptor type, but a minority are α
-β type
■ CD3+, CD56+/-, CD4-, CD8-/+, and CD5-
Gender, Race, and Age Distribution ■ Express cytotoxic granule-associated proteins, TIA1
■ Peak incidence in adolescents and young adults ■ Negative for granzyme B and perforin
■ Male predominance ■ Epstein-Barr virus is usually negative
■ Median age of 35 years
Clinical Features ■ Isochromosome 7q present in most cases
■ Marked splenomegaly usually with hepatomegaly ■ STAT5B mutations
■ No lymphadenopathy
■ Thrombocytopenia often with anemia and leukopenia Differential Diagnosis

■ Systemic symptoms
■ Extranodal natural killer cell lymphoma
■ Peripheral T-cell lymphoma, not otherwise specified

■ Aggressive course
■ Initial response to chemotherapy
■ Median survival less than 2 years Generally, at the time of diagnosis, the disease is limited
to the GI tract with the majority of the patients demon-
strating small bowel involvement. However, in some
cases, these proliferations may involve the liver, bone
marrow, and lymph node. Morphologically, the lam-
■ INDOLENT T- AND NATURAL KILLER CELL
ina propria is expanded by a population of mature-ap-
LYMPHOPROLIFERATIVE DISORDERS
pearing small lymphocytes. The cells tend to have clear
cytoplasm with inconspicuous nuclei. Typically, there
As outlined earlier, T-cell lymphomas are generally con- is no significant intraepithelial lymphocytosis, but the
sidered aggressive neoplasms. However, over the past 2 infiltrate can often be seen involving the muscularis
decades, T and NK lymphomas and lymphoprolifera- mucosa and submucosa. As the name suggests, all cases
tive disorders with an indolent behavior have also been are positive for CD3 and CD4. These cells are α -β T cells,
reported. In the 2017 update to the WHO classification often with aberrant loss of CD5 and CD7. They are also
system, the provisional entity of indolent T-cell lymph- negative for CD56, CD30, cytotoxic markers, CD103,
oproliferative disorder of the GI tract was added. Based HHV8, and EBV and demonstrate a low Ki-67 index
on a published series and case reports, these T- and NK (<10%). The cases show clonal TCR rearrangements
cell lymphoproliferative disorders can be subdivided and often other genetic abnormalities; however, there
into CD4+, CD8+, CD4-/CD8-, and NK lymphoprolif- are no common or recurrent genetic abnormalities in
erative disorders. these patients. Many of these cases were found on ret-
Indolent CD4+lymphoproliferative disorder of the rospective review, and because clonal T-cell processes
GI tract was first described in 1994, and since then, a have generally be considered to be aggressive malignant
little more than 20 have been reported. Patients tend to processes, most of the patients had undergone aggres-
present clinically with diarrhea and often with associ- sive chemotherapy. Interestingly, even with aggressive
ated weight loss. Rarely, patients present with symptoms therapy, 83% of patients demonstrated continued per-
of bowel obstruction. Endoscopically, the mucosa may sistent disease at 5 years, with 22% showing continued
either appear completely normal or may show erosions involvement for longer than 10 years. Only 13% died of
or ulceration, nodularity, polyps, or a masslike lesion. disease or treatment-related complications.
Indolent CD8+T-cell lymphoproliferative disorder variable, presenting as mucosal nodularity, hyperemic

was first reported in 2000. The median age at the time or erythematous lesions, or focal superficial bleeding
of diagnosis is 45 years, and patients typically present ulcers. Histologically, the lamina propria is expanded by
with diarrhea along with abdominal pain and bloating. intermediate- to large-sized lymphocytes that can have
Morphologically, the lamina propria is expanded, and the a clear to pale eosinophilic cytoplasm, giving the cells
glands may be displaced; however, destructive lymphoe- a so-called histiocytoid appearance. Occasionally, there
pithelial lesions and changes of celiac disease (including is glandular destruction, but changes of more aggressive
intraepithelial lymphocytosis) are not seen. The lym- NK or T-cell lymphoma such as necrosis or angiocentric
phocytes are positive for CD3 and CD8 with only a small lesions are not seen.
proportion demonstrating aberrant loss of CD5 and CD7. Immunohistochemically, the lymphocytes demon-
The lymphocytes are α-β T cells and typically demonstrate an NK phenotype with expression of CD56, cyto-
strate expression of cytotoxic marker TIA1. They are plasmic (not surface) CD3, CD2, and CD7 and cytotoxic
positive for intraepithelial T-cell marker CD103 and markers TIA1, perforin, and granzyme B. The lympho-
are negative for CD30 and CD56. All reported patients cytes are negative for CD4 and CD5, and results of ISH-
are negative for EBV. The lymphocytes demonstrate EBER are negative. Because this is an NK process, no
clonal TCR rearrangements, but other recurrent genetic TCR rearrangements were identified. Additionally, no
rearrangements have not been documented. Although in recurrent genetic abnormalities were identified.
the reported cases the median follow-up period was only
2 years (range, 1–19.8), all patients have persistent dis-
ease, and no cases of transformation have been reported.
■ SUMMARY
Indolent NK cell lymphoproliferative disorders were
first described in 2006 and have been reported as NK cell
enteropathy as well as lymphomatoid gastropathy. The Although lymphoproliferative processes in the GI tract
disease was either found during asymptomatic gastric are still rare, they appear to be increasing in frequency.
screening in the Japanese cohort or in the US and Korea An awareness of the various entities is essential.
cohorts that presented with abdominal pain. This disease To assist in this, T able 19.4summarizes the immu-
process is often localized to the gastric mucosa but can nohistochemical profiles of lymphoma common to
involve multiple GI sites. The endoscopic appearance is the GI tract.
TABLE 19.4
Immunohistochemical Profiles of Gastrointestinal Lymphoma
Mature Low-Grade B-Cell Lymphoma Aggressive B-Cell Lymphoma T-Cell Lymphoma Other
Indolent
T-Cell
MALT Mantle CLL/SLL FL DLBCL, NOS EBV+ DLBCL BL HGBL PBL EATL MEITL HSTL EBVMCU Lymphoma
CD20 + + + + + + + + - - - (+ in - + -
20%)
CHAPTER 19 Gastrointestinal Lymphoma
PAX5 + + + + + + + + - - - - + -
CD79a + + + + + + + + + in 40% - - - + -
of cases
CD138 + in PC - - - +/ - (rarely) + - ND + - - - + -
CD10 - - - + + (in 30%–50%) - + Variable - (+ in - - - - -
20%)
BCL2 + + + + + (in 47%–84%) ND - +/ -a - - - - ND -
BCL6 - + - + + (in 60%–90%) - + + - - - - - -
LMO2 - - - + + (in 45%) - - +/ - ND - - - ND -
MUM1 - + - - + (in 35%–65%) + - - + - - - + -
Cyclin D1 - + - - - - - - - - - - - -
SOX11 - + - - - - - - - - - - - -
LEF1 - -/+ (in + - + (≤3 0%–40%) ND + ND - ND ND - - -
≤% )
CD30 - - - - + (in 10%–20%) + (in 40%) - +/ - - + - - + -
CD2 - - - - - - - - - + + + + +
CD3 - - - - - - - - - + cytoplasmic + + - +
CD4 - - - - - - - - - - - - - +/ -
CD5 - + + - + (≤10%) - - - - - - - - +
CD7 - - - - - - - - - + + +/ - - +
CD8 - - - - - - - - - + (20%– + -/+ - +/ -
30%)
CD43 + in + + - + (≤2 5%) -/+ + ND - + + + - +
40%
CD56 - - - - - - - - + - + + - -
Tia-1 - - - - - - - - - + + + - + (in CD8
+)
MYC - - - - + (≤4 0%) - + +/ -a + - - - ND -
EBER - - - - - + (required) + (25%– - - - - - + -
50%)
HHV8 - - - - - - - - - - - - - -
+, expressed; −, negative for expression, BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; EATL, enteropathy-associated T-celllymphoma; EBER, Epstein-Barr encoding region; EBV, Epstein-Barr virus;
EBVMCU, Epstein-Barr virus–positive mucocutaneous ulcer; F L, follicular lymphoma; H HV8, human herpesvirus 8; H STL, hepatosplenic T-cell lymphoma; M ALT, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; M
EITL,
monomorphic epitheliotropic intestinal T-cell lymphoma; N D, no or insufficient data; N
OS, not otherwise specified; P
BL, plasmablastic lymphoma P C, plasma cell; S
LL, small lymphocytic lymphoma.
a
In the high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements variant, these cases strongly express BCL2 and MYC.
653
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20
Pathology of Liver, Small Bowel, and
Pancreas Transplantation
■ DanielaS. Allende, MD, MBA, LisaM. Yerian, MD, and Deepa T.Patil, MD
■ LIVER TRANSPLANTATION organs with severe steatosis or prolonged warm or cold

ischemia times and organs from donors of advanced age,
Liver transplantation is performed in patients with elevated liver enzymes, hepatitis C virus infection, and
liver failure caused by acute or chronic liver disease, other factors.
selected hepatic tumors, and some metabolic diseases. Liver biopsy is a critical diagnostic tool in the care
Approximately 7000 liver transplants (LT) are per- of transplant recipients. It is used in the diagnosis or
formed annually in the United States. The graft survival exclusion of several forms of graft pathology ranging
rate at 5 years is greater than 70%, and the patient sur- from rejection to technical (biliary, vascular) and infec-
vival rate is even higher. The most common types of LT tious complications and is the “gold standard” test for
are cadaveric and living donor LT. Cadaveric LTs are diagnosis of rejection. Biopsy practice varies by center
by far the most common type performed in the United and with recipient factors. Liver biopsies are performed
States, accounting for 95% of all LTs. Most cadaveric when patients exhibit laboratory abnormalities or other
donor organs derive from brain-dead donors with stable signs or symptoms of graft dysfunction such as fever or
cardiopulmonary function. However, a small percentage abdominal pain. Some centers also perform “protocol”
of cadaveric donor organs (4%) are procured after cessa- biopsies at set time intervals in the absence of evidence
tion of cardiopulmonary function. These donation after of graft dysfunction.
cardiac death (DCD) organs are subject to complications
related to warm ischemia–induced injury and show
reduced graft survival. Cadaveric LT may be performed
■ PRETRANSPLANT DONOR EVALUATION
using a whole donor liver or using a split or reduced
size graft. Split grafts enable a donor organ of sufficient
size be transplanted into two recipients (often an adult Protocols for evaluating potential donor organs vary
and a child), whereas a reduced size graft is reduced in across transplant centers. Frozen sections are commonly
size to match a single recipient. Living donor LTs cur- used to assess deceased donor organs, although in many
rently account for about 5% of LT performed in the instances, no histologic evaluation of the donor organ is
United States. Far less common are domino LTs. In this performed before transplantation and other factors, such
case, an explanted liver from an LT recipient who has a as gross impression of the organ, are used to determine
metabolic disease of the liver that can potentially cause suitability of the graft. Frozen sections are not routinely
severe systemic disease but does not structurally dam- performed on DCD organs because doing so would pro-
age the liver (e.g., familial amyloidotic polyneuropathy) long the cold ischemia time and increase risk of intrahe-
is transplanted into another recipient whose condition patic bile duct strictures. In some centers, preperfusion
precludes a long time on the waiting list. or “time-zero” biopsies are used to assess for preexisting
The term e xtended criteria denotes donor organs donor organ pathology at the time of transplantation.
carrying risk factors associated with a greater risk of The histologic confirmation of greater than 30%
poor graft function than standard criteria donor organs. macrovesicular steatosis has long been associated with
These organs traditionally would not have been used poor early graft function. However, some studies have
for transplant but are now used in selected recipients shown that grafts with moderate to severe steatosis can
in an effort to increase the number of organs avail- be safely in select situations (Fig. 20.1). These appar-
able for transplantation. There is no consensus defini- ently conflicting findings are likely caused at least in part
tion of extended criteria organs, but examples include by the complex nature of donor selection and differing
657
ischemia-reperfusion injury (IRI). The mechanism of

injury is complex, multifactorial, and attributed to
warm and cold ischemic injury followed by reperfusion.
Warm ischemic injury occurs in situ and causes hepato-
cyte damage, whereas cold ischemia occurs after the har-
vested organ is flushed with cold preservation solution
and results in damage of sinusoidal endothelial cells and
biliary epithelium. Ischemia results in anaerobic metab-
olism, cell swelling, and cell death. Microcirculatory
damage ensues, and Kupffer cell activation drives a
local inflammatory response that is magnified by tissue
reperfusion and involves the formation of reactive oxy-
gen species, production of cytokines and chemokines,
and activation of the complement systems. These mech-
anisms further microvascular dysfunction and cellular
FIGURE 20.1
injury. The injury is exacerbated by preexisting donor
Frozen sections of a donor liver biopsy with steatosis.
pathology (e.g., donor steatosis) and by extended warm
or cold ischemia times, whereas the injury is minimal
organs with short ischemia times (as in living donors).
definitions and methods of assessing steatosis. In 2022, Some degree of IRI is expected in biopsies obtained in
The Banf Working Group published recommendation to the first 1 to 2 weeks after liver transplantation, and his-
standardize this assessment. Two forms of macrovesic- tologic evidence of IRI can persist beyond 2 weeks in
ular steatosis have since been delineated as “large drop- more severely injured grafts. When assessing a biopsy in
let” (a single fat vacuole occupying greater than half of the early posttransplant period, it is helpful to know if
the cell and displacing the nucleus to the periphery) or the biopsy was performed for clinical concern for rejec-
“small droplet” (one or several discrete vacuoles, each tion or other form of graft dysfunction because biopsies
occupying less than half of the cell and not displacing may be obtained during this interval in the absence
the nucleus). Both forms are distinguished from true of clinical concern for graft dysfunction if the patient
microvesicular steatosis (innumerable tiny lipid vacu- is taken back to operating room to address bleeding,
oles diffusely distributed in the cytoplasm and impart- intraabdominal infection, or fluid collections.
ing a foamy appearance to the cell), which may coexist
with macrovesicular steatosis but in its pure, diffuse
form is uncommon in potential liver donors. There is no
universal cutoff for an acceptable amount of steatosis. ■ LABORATORY FINDINGS
In most practices, the total amount of macrovesicular
steatosis is assessed as the percentage of the hepatocel- Ischemia-reperfusion injury is common and typically
lular component (area) of the biopsy that is involved. mild; laboratory findings indicative of this form of graft
Care should be taken not to interpret freeze artifact in injury are minor or absent in most patients. Elevated
frozen liver specimens as fat vacuoles. serum lactate levels and persistent serum transami-
In addition to steatosis, pretransplant donor biop- nases elevations in the early posttransplant period are
sies are used to assess other factors that may affect graft common.
function, including necrosis, inflammation, and fibrosis.
These findings are particularly relevant in the assess-
ment of extended criteria donors, who may exhibit fea-
tures of hepatitis C or other forms of pathology. Mild Pathologic Features
portal inflammation or bile ductular proliferation may
be seen in deceased donor organs and in isolation are
not contraindications for transplantation. Microscopic Features
The histologic findings include predominantly zone 3
hepatocellular injury, which is manifested as perivenular
hepatocyte swelling, necrosis, or dropout (Fig. 20.2A).
■ PRESERVATION OR ISCHEMIA-
This is usually accompanied by Kupffer cell hyperpla-
REPERFUSION INJURY
sia and regenerative hepatocellular changes such as
increased mitotic activity (Fig. 20.2B). Centrilobular
Donor organs are subject to injury related to the pro- perivenular cholestasis is common. Rarely, the degree
cess of organ procurement, preservation, and reim- of preservation or IRI is extensive with areas of conflu-
plantation that is referred to as p
reservation injury or ent or even bridging hepatocyte necrosis and marked
CHAPTER 20 Pathology of Liver, Small Bowel, and Pancreas Transplantation 659
A B
C
FIGURE 20.2
A, An example of marked preservation or reperfusion injury with hepatocellular dropout in centrizonal regions as well as congestion. B , In some cases, regen-
erative hepatocellular changes, including mitoses and hepatocyte multinucleation, can be seen. C , Bile ductular proliferation can be prominent in a subset of
cases, raising the differential diagnosis of biliary obstruction.
bile ductular reaction in response to parenchymal AMR shows microvascular changes that are not seen
collapse. Portal areas may exhibit mild bile ductular in IRI, and a diagnosis of AMR requires demonstration
proliferation (Fig. 20.2C) and portal neutrophils, and of C4d positivity and detection of serum donor-specific
scattered clusters of neutrophils may be seen in the antibodies. IRI demonstrates less perivenular and por-
hepatic lobules. tal inflammation than ACR, and the portal infiltrates of
early ACR are distinct from those seen in preservation
injury, including enlarged, activated-appearing lympho-
Differential Diagnosis cytes along with other inflammatory cells such as eosin-
ophils. If lobular collections of neutrophils are seen in
association with hepatocyte necrosis, a careful search
The major differential diagnosis for IRI includes biliary for viral inclusions is warranted.
obstruction, antibody-mediated rejection (AMR), acute
T cell–mediated rejection (ACR), and infection. In the
early posttransplant period, mild neutrophilic infiltra-
tion and ductular proliferation can be seen, but these
changes should not be overinterpreted as acute chol-
angitis. If there is concern for biliary obstruction, this Most patients with mild preservation or IRI show an
possibility should be excluded clinically with imaging initial delay in normalization of liver enzymes but even-
studies. Neutrophil collections within duct lumens and tually recover without significant complications. Severe
portal edema are required to diagnose acute ascending IRI often reflect preexisting donor disease or graft injury
cholangitis. Neutrophils, cholestasis, ductular reaction, that may lead to long-term complications, including
and hepatocyte necrosis are also features of AMR, but scarring and ischemic cholangiopathy.
ANTIBODY-MEDIATED REJECTION Microscopic Features
Severe, early (“hyperacute”) acute AMR is rarely biop-

■ CLINICAL FEATURES sied because of the severe coagulopathy that develops
in affected patients. Explanted, failed allografts show
Antibody-mediated rejection (formerly termed “humoral” widespread parenchymal necrosis with congestion and
rejection) is a pattern of allograft injury mediated by pre- hemorrhage (Fig. 20.3A). Neutrophilic infiltrates may
formed or de novo antidonor antibodies (“donor-specific be prominent, and vascular changes, including endothe-
antibodies” [DSAs]) that bind to antigens on endothelial cell hypertrophy and inflammation, fibrinoid necro-
lial cells, resulting in antibody-mediated endothelial cell sis, and thrombus formation, can be seen. Bile ducts may
injury and activation of the complement cascade. AMR also show ischemic injury caused by arterial thrombus.
occurs in recipients of ABO-incompatible grafts or in Early histologic evidence of acute AMR includes
recipients with preformed or de novo lymphocytotoxic centrilobular hepatocyte ballooning and cholestasis,
antibodies. Preformed antibodies are encountered in 10% sometimes accompanied by spotty or confluent hepato-
to 15% of LT recipients and are most commonly found in cyte necrosis (Fig. 20.3B). Portal edema, ductular reac-
women and patients with autoimmune diseases. De novo tion, and neutrophil-rich portal infiltrates are common
DSAs develop after LT in 8% to 15% of liver allograft yet nonspecific findings ( Fig. 20.3C). Microvascular
recipients. Risk factors for de novo DSA include low pathology is characteristic and includes endothelial cell
immunosuppression, young age, cyclosporine use, low hypertrophy or enlargement, capillary dilation, leuko-
Model For End-Stage Liver Disease (MELD) score, and cyte sludging or margination, and edema. Sinusoidal
previous transplants. DSAs represent a key diagnostic fea- infiltration by neutrophils and neutrophil-rich endothe-
ture of AMR, and because DSA can occur de novo in LT lial inflammation or “microvasculitis” affecting portal
recipients and may not persist, serum DSA testing should veins, portal capillaries, and central veins may be seen.
be performed during the posttransplant interval and at the More severe cases may show disruption of the microvas-
time of biopsy to confirm or exclude a diagnosis of AMR. culature with portal and periportal hemorrhage, lobu-
Severe, early acute AMR, or “hyperacute rejection,” lar inflammation, and hepatocyte necrosis. Necrotizing
is exceedingly rare, occurs within hours to a few days arteritis and lymphocytic intimal inflammation can be
after transplantation, and is largely limited to recip- seen but are rare findings. Focal bile duct necrosis may
ients of ABO-incompatible grafts. Affected patients also be seen because of thrombosis of the peribiliary
develop signs of rapid, acute graft failure within the first plexus. Many patients exhibit mixed features of acute
2 weeks after transplantation, including a rapid rise in AMR and ACR. Tables 20.1 to 20.3highlight scoring
serum aminotransferases and severe coagulopathy with system for AMR.
increased prothrombin times. A more common and The histologic features of chronic AMR are less well
less severe form of acute AMR (late-onset acute AMR) characterized. The vascular changes of acute AMR are
develops 1 to 4 weeks after transplant in patients with less evident in chronic AMR. Portal, periportal, and
detectable DSA. Patients present with hyperbilirubin- perivenular lymphoplasmacytic inflammation with
emia, posttransplant transaminasemia, thrombocytope- interface activity, perivenular necroinflammatory activ-
nia, and low serum complement levels. Most patients ity, and scarring are often present (Table 20.4). Portal
also have superimposed ACR. vein collagenization, biliary strictures, nodular regener-
Some patients develop a less well-defined, smolder- ative hyperplasia, and obliterative arteriopathy may also
ing, and, in some cases, subclinical form of “chronic be seen.
AMR” that persists over months or even years and may
be linked to persistent or de novo DSAs, late-onset ACR,
chronic rejection (CR), and decreased survival. Specific
clinical or biochemical features have not been identified. ■ ANCILLARY STUDIES
As with acute AMR, patients can develop mixed chronic
AMR and T cell–mediated rejection. Complement C4d deposition is an indicator of tis-
sue-based complement activation and can be detected by
immunohistochemistry (IHC) or immunofluorescence.
Diffuse linear or granular microvascular endothelial cell
Pathologic Features complement C4d deposition involving greater than 50%
of portal tracts in greater than 50% of the circumference
Gross Features
of portal microvascular endothelia (portal veins and
capillaries) is required to establish a diagnosis of defi-
In hyperacute AMR, the liver becomes enlarged with nite acute AMR (Fig. 20.3D; see Tables 20.1 and 20.3).
congestion, hemorrhage, and variable degrees of necro- C4d positivity may also extend into inlet venules or peri-
sis. Vascular thrombi may be identified. portal sinusoids. However, C4d staining is not specific
A B
C D
FIGURE 20.3
A, “Hyperacute” antibody-mediated rejection (AMR) demonstrating hepatocellular necrosis and hemorrhage. B, Bile duct changes in the setting of acute AMR,
including bile ductular proliferation with a neutrophilic-rich infiltrate. C, Occasional AMR can show lobular involvement with hepatocellular dropout or necrosis
and neutrophilic-rich infiltrates.
TABLE 20.1
Scoring of C4d Deposition
Score Description
1 No C4d deposition in portal microvasculature

2 Minimal (< 10% of portal tracts) C4d deposition in > 5 0% of the circumference of portal microvascular
endothelia (portal veins and capillaries)
3 Diffuse (> 5 0% portal tracts) C4d deposition in >
5 0% of the circumference of portal microvascular endothelia
(portal veins and capillaries), often with extension into inlet venules or periportal sinusoids
C4d-(immune)-score, formalin-fixed, paraffin-embedded tissue. (Adapted from Banff Working group, Am J Transplant. 2016;16:2816–2835).
for AMR. C4d staining has been described in a variety Differential Diagnosis
settings, including in native livers and in other forms
of allograft pathology, although usually less widespread Conditions that mimic hyperacute rejection include
and less intense than in acute AMR. Hence, C4d stain- severe ischemia or reperfusion injury and allograft isch-
ing in isolation is insufficient to establish a diagnosis emia. Clinical data, including risk factors for severe IRI
of AMR. C4d staining is a feature of chronic AMR (e.g., prolonged ischemia times or preexisting donor
but tends to be less diffuse and intense than in acute disease) and ABO compatibility, are helpful in distin-
AMR. Diagnostic criteria for chronic AMR require only guishing hyperacute rejection from severe IRI. In the
focal C4d-positivity (>10% portal tract microvascular appropriate clinical setting, the clinical history of an
endothelia). ABO-incompatible graft, documentation of preformed
TABLE 20.2
Scoring of Histopathologic Features for Diagnosis of Acute Antibody-Mediated Rejection
Score Description
1 Portal microvascular endothelial cell enlargement (portal veins, capillaries, and inlet venules) involving a majority
of portal tracts with sparse microvasculitis defined as three or four marginated and/or intraluminal monocytes,
neutrophils, or eosinophils in the maximally involved capillary with generally mild dilation
2 Monocytic, eosinophilic, or neutrophilic microvasculitis or capillaritis, defined as at least 5 to 10 leukocytes
marginated and/or intraluminal in the maximally involved capillary, prominent portal, and/or sinusoidal
microvascular endothelial cell enlargement involving a majority of portal tracts or sinusoids, with variable but
noticeable portal capillary and inlet venule dilation and variable portal edema
3 As above, with marked capillary dilation, marked microvascular inflammation (≥ 10 marginated and/or intraluminal
leukocytes in the most severely affected vessels), at least focal microvascular disruption with fibrin deposition, and
extravasation of red blood cells into the portal stroma and/or space of Disse (subsinusoidal space)
h-score (Adapted from Banff Working group, Am J Transplant. 2016;16:2816–2835).
TABLE 20.3
Criteria for Diagnosis of Acute Antibody-Mediated Rejection
Definite for Acute AMR (All Four Criteria Required)
1 Histologic pattern of injury consistent with acute AMR, usually including portal microvascular endothelial cell
hypertrophy; portal capillary and inlet venule dilation; monocytic, eosinophilic, and neutrophilic portal microvasculitis;
portal edema; ductular reaction; cholestasis is usually present but variable; edema and periportal hepatocyte necrosis
are more common or prominent in ABO-incompatible allografts; variable active lymphocytic and/or necrotizing arteritis
2 Positive serum DSA
3 Diffuse (C4d score = 3 ) microvascular C4d deposition on frozen or formalin-fixed, paraffin-embedded tissue in ABO
compatible tissues or portal stromal C4d deposition in ABO-incompatible allografts
4 Reasonable exclusion of other insults that might cause a similar pattern of injury; most patients have C4d scores: 3+
h-score = 5 or 6
SUSPICIOUS FOR AMR (BOTH CRITERIA REQUIRED)
1 Positive serum DSA
2 Nonzero h-score with C4d-score + h-score of 3 or 4
INDETERMINATE FOR AMR (REQUIRES 1 + 2 AND 3 OR 4)
1 C4d score + h-score is ≥
2
2 DSA not available, equivocal, or negative
3 C4d staining not available, equivocal, or negative
4 Coexisting insult might be contributing to the injury
Adapted from Banff Working group, Am J Transplant. 2016;16:2816–2835.
AMR, Antibody-mediated rejection; DSA, donor-specific antibodies.
TABLE 20.4
Criteria for Diagnosis of Chronic Active Liver Allograft Antibody-Mediated Rejection
Probable Chronic Active AMR (All Four Criteria Required)
1 Histologic pattern of injury consistent with chronic AMR
a.Otherwise unexplained at least mild mononuclear portal and/or perivenular inflammation with interface and/or
perivenular necroinflammatory activity
b.At least moderate portal or periportal, sinusoidal, and/or perivenular fibrosis
2 Recent (within 3 months of biopsy) circulating HLA DSA in serum samples
3 At least focal C4d-positive (> 10% portal tract microvascular endothelia)
4 Reasonable exclusion of other insults that might cause a similar pattern of injury
POSSIBLE CHRONIC ACTIVE AMR
1 As above, but C4d staining minimal or absent
AMR, Antibody-mediated rejection; DSA, donor-specific antibodies; HLA, human leukocyte antigen.
DSAs, and the vascular changes described earlier all features of ACR described in the 1997 Banff clas-
support a diagnosis of hyperacute rejection. sification are those of “early” ACR, and most often
Acute AMR can mimic a variety of conditions, includ- occur within the first 6 months after transplanta-
ing IRI, ACR, biliary obstruction, ischemia, and sepsis. tion. Late ACR is often clinically, biologically, and
The vascular features of acute AMR are more helpful histologically distinct and is most often seen after
in establishing the correct diagnosis than the cholestatic 6 months after transplantation, although there is no
or hepatocellular changes. Clinical information (includ- strict timeline delineating early versus late ACR. Patients
ing imaging studies) is often needed to distinguish these with late ACR often have a history of inadequate immu-
entities, and evaluation of the biopsy for C4d deposition nosuppression or prior autoimmune disease.
and patient serum for DSAs is warranted in any patient The clinical features of ACR range from completely
with compatible histology and no clear alternative asymptomatic patients to those with fever or abdominal
explanation for their biopsy findings or graft dysfunc- pain caused by graft swelling or tenderness. Liver enzyme
tion. In particular, acute AMR should be considered in abnormalities, including elevations of total bilirubin,
patients with histologic features of biliary obstruction alkaline phosphatase (ALP), γ-glutamyl transpeptidase
in whom there is no clinical evidence of biliary obstruc- (GGT), and serum transaminases, are common in most
tion. In contrast to ACR in which the inflammation is patients. There may be leukocytosis and eosinophilia.
lymphocyte-rich, the portal venous endothelial inflam-
mation seen in acute AMR is more neutrophilic. That
said, acute AMR frequently occurs in association with
Pathologic Features
ACR; these diagnoses are not mutually exclusive.
The classic histologic triad characteristic of ACR con-
The prognosis for AMR is highly variable. Patients with sists of (1) mixed but predominantly mononuclear
DSAs are at increased risk of CR, chronic inflammation, portal inflammatory cell infiltrates, (2) bile duct inflam-
and progressive fibrosis compared with those without. mation or damage, and (3) subendothelial inflam-
Most patients with severe, early AMR develop progres- mation of portal veins or terminal hepatic venules
sive hemorrhagic infarction and graft failure requiring (“endotheliitis”) (Fig. 20.4A). At least two of these fea-
retransplantation, even if the patient survives the acute tures should be present to establish a diagnosis of ACR.
episode. Late biliary or vascular complications, includ- This classic histologic picture most closely reflects the
ing ischemic cholangiopathy with biliary strictures, nod- findings seen in patients with ACR occurring within
ular regenerative hyperplasia, or progressive fibrosis, the first 6 months after transplantation and is now
may develop with acute AMR. often referred to as e arly ACR. The portal inflamma-
Antibody-mediated rejection prevention is prefera- tory infiltrates of early ACR include an admixture of
ble to treatment, and AMR can be prevented in most enlarged (usually medium or large lymphocytes), “acti-
patients by maintaining immunosuppression levels with vated-appearing” lymphocytes, neutrophils and often
tacrolimus and in recipients of ABO-incompatible grafts, eosinophils (Fig. 20.4B). The bile duct inflammation
total plasma exchange, rituximab, and other therapies. and damage seen in ACR include intraepithelial lym-
Other prevention strategies including avoiding sensiti- phocytes and cytologic changes that include cytoplas-
zation by reducing blood product usage and administra- mic vacuolization, eosinophilia, and uneven spacing
tion of antibody-based induction therapy. Therapy for of nuclei. Subendothelial inflammation with associ-
mild acute AMR typically includes immunosuppressive ated endothelial cell injury and lifting of endothelial
therapy in the form of steroids and tacrolimus, and thy- cells (“endotheliitis”) affects portal veins or terminal
moglobulin. Plasmapheresis, intravenous immunoglob- hepatic veins (Fig. 20.4C). Hepatic arterial involve-
ulin (IVIg), rituximab, and other agents may be required ment is rare. Recently, isolated “v” lesions (inflam-
in patients with moderate to severe acute AMR. matory, necrotizing, and/or obliterative arteriopathy)
have been recognized and associated with impending
ACR and/or chronic antibody-mediated rejection.
(ACUTE) T CELL–MEDIATED REJECTION Late ACR most commonly shows similar features
to early ACR, including predominantly mononuclear
portal inflammation, inflammatory bile duct damage,
Clinical Features
and subendothelial inflammation. However, compared
with early ACR, the inflammatory infiltrates are more
T cell–mediated rejection (Banff 2016), previously homogenous and mononuclear, and there is less prom-
referred to as acute cellular rejection (ACR), affects inent endotheliitis and bile duct damage (Fig. 20.4D).
around 20% to 40% of all LT recipients. The classical Parenchymal injury in the form of low-grade interface
A B
C D
FIGURE 20.4
A, Acute cellular rejection (ACR, T-cell mediated rejection) is characterized by bile duct injury, endotheliitis, and the classic “rejection” type infiltrate. B, The typ-
ical infiltrate seen in ACR includes enlarged “activated” lymphocytes, numerous eosinophils, and scattered plasma cells. C , Endotheliitis is often seen, defined
by rejection-type infiltrates involving a vein with associated endothelial injury such as swelling of endothelial cells and possibly lifting of the endothelial lining. D,
The inflammatory infiltrate seen in late ACR is slightly different and commonly comprises smaller lymphocytes and more prominent plasma cells.
activity, perivenular necroinflammatory activity, or are less activated than those seen in typical ACR. Most
patchy lobular activity is usually present. cases do not show significant bile duct injury or endo-
Additional patterns of late ACR have been described theliitis. Lobular necroinflammatory activity is com-
under a variety of terms, including c entral perivenulitis, mon and most prominent in the perivenular regions.
posttransplant chronic hepatitis, and plasma cell–rich Plasma cell–rich rejection encompasses a histologic
rejection (also known as plasma cell hepatitis or de novo pattern of immune-mediated graft injury previously
autoimmune hepatitis [AIH]). Central perivenulitis is described as de novo AIH and posttransplant plasma
characterized by centrilobular perivenular inflamma- cell hepatitis. It occurs in patients who lack a history
tion with or without hepatocyte dropout, which may of AIH. The histologic features include dense, plasma
occur in combination with portal inflammatory infil- cell–rich portal and perivenular infiltrates, often with
trates or in isolation (“isolated central perivenulitis”) prominent interface activity and confluent necrosis, and
(Fig. 20.5). It may or may not be accompanied by C4d deposits can be demonstrated in the portal micro-
portal vein or central vein endotheliitis, and this feature vasculature. The diagnostic criteria for plasma cell–rich
is not required for a diagnosis of ACR in this setting. rejection are outlined in T
able 20.5.
Posttransplant chronic hepatitis (also known as Recently, a pattern of rejection with “hepatitis-like
idiopathic posttransplant chronic hepatitis) shows his- features” was described in patients who completely
tologic features that mimic chronic hepatitis, including stop taking immunosuppressive agents. In this pattern,
mild chronic portal inflammatory infiltrates accompa- the lobular parenchyma shows activated lymphocytes
nied by minimal or focal interface activity. The portal within the sinusoids (“sinusoidal pattern”) or prom-
infiltrates are more monotonous and the lymphocytes inent necroinflammatory activity that is randomly
A
FIGURE 20.6
Hepatitic variant of acute T cell–mediated rejection revealing lobular necro-
inflammatory activity, mimicking a “hepatitis pattern of injury.” In such cases,
exclusion of viral infections and medication-induced injury is critical.
distributed throughout the parenchyma (Fig. 20.6). All

of these findings may be seen in conjunction with por-
tal-based ACR findings. In early stages, a lesser compo-
nent of typical ACR involving the portal tracts is noted
in close to 50% of cases but later in the posttransplant
course that is less often seen.
Grading Acute T Cell–Mediated Rejection
B After a diagnosis of ACR is established, the extent of

injury is graded using the Banff global assessment as
FIGURE 20.5
mild, moderate, or severe rejection. According to the
A, Central perivenulitis, defined as rejection type infiltrates damaging the
central veins with associated endothelial injury, can be seen in isolation or 2016 Banff schema, the term indeterminate for rejec-
associated with more typical portal-based findings. B, Delicate perivenular tion is used for cases that have portal or perivenular
fibrosis highlighted on trichrome stain after recurrent episodes of acute cen-
inflammatory infiltrates that could represent rejection
tral perivenulitis.
but show insufficient tissue damage to meet criteria
for a diagnosis of rejection. Mild ACR denotes cases
in which rejection-type infiltrates are generally mild,
seen in a minority of portal triads or perivenular areas.
In portal-based rejection, the infiltrates remain con-
TABLE 20.5 fined within the portal spaces. In patients with isolated
Diagnostic Criteria for Plasma Cell–Rich perivenular infiltrates, there is no confluent necrosis or
Rejection hepatocyte dropout in mild ACR. In moderate rejection,
the infiltrate expands most or all of the portal triads or
CRITERIA 1 AND 3 ARE REQUIRED FOR DIAGNOSIS.
perivenular areas with confluent necrosis or hepato-
CRITERION 2 IS DESIRABLE BUT NOT STRICTLY REQUIRED
FOR DIAGNOSIS. cyte dropout limited to a minority of perivenular areas
1. Portal and/or perivenular plasma cell–rich (Fig. 20.7A). Severe ACR shows the features described
(estimated > 3 0%) infiltrates with easily for moderate ACR and exhibits spillover of the inflam-
recognizable periportal/interface a nd/or matory infiltrate into periportal areas or moderate to
perivenular necroinflammatory activity usually
severe perivenular inflammation that extends into the
involving a majority of portal tracts and/or
central veins hepatic parenchyma and is associated with perivenular
2. Lymphocytic cholangitis hepatocyte necrosis involving a majority of perivenu-
3. Original disease other than autoimmune lar areas (Fig. 20.7B). The findings may also be semi-
hepatitis quantitatively scored to yield a “Rejection Activity
Adapted from Banff Working group, Am J Transplant. 2016;16:2816–2835. Index” (Table 20.6). The Rejection Activity Index is a
TABLE 20.6
Rejection Activity Index for Grading Acute T
Cell–Mediated Rejection
Portal 1. Mostly lymphocytic inflammation
inflammation involving, but not noticeably
expanding, a minority of the triads
2. Expansion of most or all portal triads
by a mixed infiltrate containing
lymphocytes with occasional blasts,
neutrophils, and eosinophils
3. M arked expansion of most or all of
the portal triads by a mixed infiltrate
containing blasts and eosinophils
with inflammatory spillover into the
periportal parenchyma
Venous 1. Subendothelial lymphocytic infiltration
A
endotheliitis involving some but not a majority of
the portal and/or hepatic venules
2. Subendothelial infiltration involving
most or all of the portal and/or
hepatic venules with or without
confluent hepatocyte necrosis or
dropout involving a minority of
perivenular regions
3. As for 2 above, with moderate or
severe perivenular inflammation
that extends into the perivenular
parenchyma and is associated with
perivenular hepatocyte necrosis
involving a majority of perivenular
regions
Bile duct 1. A minority of the ducts are cuffed and
damage infiltrated by inflammatory cells and
B show only mild reactive changes such
as increased epithelial cell nuclear-to-
FIGURE 20.7 cytoplasmic ratios
A, A case of moderate acute T cell–mediated rejection (ACR). By defini-
tion, the majority of portal tracts need to be affected by classic features of 2. M ost or all ducts infiltrated by
rejection. B
, Severe ACR demonstrates not only involvement of the major- inflammatory cells; more than an
ity of portal tracts but also areas of parenchymal necrosis and often central occasional duct shows degenerative
perivenulitis. changes such as nuclear
pleomorphism, disordered polarity,
and cytoplasmic vacuolization of the
epithelium
3. Inflammation affecting the majority
numerical score intended to indicate severity of ACR of the bile ducts with most ducts
based on the severity of the three features of ACR: por- showing marked bile duct injury or
tal inflammation, bile duct inflammation or damage, and duct necrosis
Total Of possible score of 9:
venous endotheliitis. These grading schemas should
only be applied after a diagnosis of ACR is established RAI 3–4: mild ACR
RAI 5–6: moderate ACR
and should not be used to establish or refute a diagnosis RAI 7–9: severe ACR
of ACR.
ACR, acute T cell–mediated rejection; RAI, rejection activity index.
and vascular complications, and recurrent disease. In
Depending on the clinical and histologic picture, many cases, the clinical history of reduced immuno-
ACR may need to be differentiated from IRI, AMR, suppression (through patient history or drug levels)
infections, drug-induced liver injury (DILI), biliary is helpful in establishing the correct diagnosis. IRI is
only a diagnostic consideration in the first few weeks Many recurrent diseases can mimic ACR, and fea-
after transplantation and usually lacks the prominent tures of recurrent disease and ACR can coexist in the
portal and perivenular lymphocyte-rich infiltrates same biopsy. Knowledge of the patient’s native liver
seen in ACR. disease is critical to accurate posttransplant biopsy
Biliary obstruction can coexist with ACR and can also interpretation. Recurrent viral hepatitis and AIH
mimic the portal inflammatory infiltrates and bile duct have already been addressed; both are most likely to
injury of ACR, although biliary obstruction may exhibit mimic late ACR because the features of early ACR are
more neutrophil-rich infiltrates and can be excluded somewhat distinctive with its characteristic mixed and
with imaging studies. Neutrophil-rich infiltrates and activated portal infiltrates. Primary biliary cholangitis
cholestasis also raise the possibility of AMR; patients (PBC) can cause bile duct injury and portal inflam-
with these findings who are not found to have biliary mation, but the bile duct injury of PBC is often more
obstruction should be investigated for AMR with serum histiocytic, forming vague granulomas and florid-duct
DSA testing and C4d immunostaining. Prominent lesions.
eosinophilic or neutrophilic infiltrates and the vascu-
lar features of AMR described earlier also warrant fur-
ther evaluation with C4d staining and serum testing for
DSAs. Of note, AMR may coexist with ACR, so estab-
lishing a diagnosis of AMR does not exclude additional
T cell–mediated rejection. All patterns of ACR respond to increased immunosup-
Both recurrent and de novo hepatotropic viral infec- pression, but if left untreated, they may result in pro-
tions and nonhepatotropic infections can mimic ACR. gressive graft injury and, in some cases, graft failure.
In early ACR, the mixed “rejection-type” portal infil- About 10% of patients with ACR develop CR, and
trate helps distinguish ACR from other causes of portal patients with moderate or severe ACR and repeated or
inflammation (e.g., chronic viral hepatitis). However, untreated episodes of ACR are more likely to develop
this distinction can be more difficult in late ACR in CR, which can lead to graft failure. Patients with late
which the portal infiltrates may be more monotonous ACR may respond to immunosuppression less well than
and both interface activity and lobular hepatocyte injury those with early ACR and may have a higher risk of CR,
can be seen, and the overall histologic picture may be fibrosis, and graft loss. Up to 27% of adults with post-
that of a posttransplant chronic hepatitis. Depending on transplant chronic hepatitis develop progressive fibrosis
the histologic picture, the findings may mimic chronic with bridging fibrosis or cirrhosis.
hepatitis (hepatitis C, hepatitis B, and AIH), other In most cases of ACR, patients are first treated with
infections (e.g., cytomegalovirus [CMV] or Epstein-Barr adjustment to their baseline immunosuppression reg-
virus [EBV]), or DILI. These other causes should be imen, corticosteroids, or both. In patients who do not
carefully excluded based on clinical history, laboratory respond to heightened immunosuppression and initial
testing, and special stains (CMV and EBV) before initi- steroid therapy, antithymocyte globulin with or without
ating heightened immunosuppression. The distinction rituximab may be used.
between ACR and recurrent viral hepatitis C can be
challenging but is now a less frequent diagnostic prob-
lem with the use of direct-acting antiviral therapies (see
later). In the setting of chronic viral hepatitis C, at least
50% of bile ducts or central veins should demonstrate Liver Acute Cellular Rejection—Fact Sheet
features of ACR to establish a diagnosis of ACR in a
Incidence
patient with chronic hepatitis C to avoid overdiagnosis
■ 20% to 40% of all liver transplant recipients, most during the first
of ACR and steroid therapy. 6 months
The centrilobular hepatocyte dropout and inflam-
mation of central perivenulitis raise a differential diag- Demographics
nosis that includes ischemia, viral hepatitis, AIH, and ■ No gender or race predilection
drug toxicities. Ischemic tends to be less inflamed, and

clinical risk factor for ischemia and Doppler studies Clinical Features
can be helpful in evaluating the hepatic vasculature. ■ Variable, from asymptomatic to abdominal pain or tenderness,
Viral hepatitis and drug toxicities should be excluded fever

■ Elevated transaminases and/or alkaline phosphatase
as noted earlier. Plasma cell–rich rejection closely mim-
ics AIH. If the patient has no history of AIH before Therapy and Prognosis
transplantation, a diagnosis of plasma cell–rich rejec- ■ Respond to immunosuppression
tion should be considered. There is no clear diagnos- ■ If untreated, progressive injury leading to graft failure
tic distinction between plasma cell–rich rejection and ■ 10% evolve to chronic rejection
recurrent AIH.
and can be applied when the majority of ducts exhibit

Liver Acute Cellular Rejection—Pathologic Features degenerative, atrophic, or senescent changes character-
ized by cytoplasmic eosinophilia, irregular nuclear spac-
Gross Findings ing, nuclear enlargement, nuclear hyperchromasia, and
■ Congestion to hemorrhagic changes and necrosis epithelial attenuation (Fig. 20.8A). Bile duct loss affects
fewer than 50% of portal tracts in early CR. Mild por-
tal inflammation and features of ACR, including central
■ Classic portal based acute T cell–mediated rejection: rejection-
perivenulitis and perivenular hepatocyte dropout, are
type infiltrates, endotheliitis, and bile duct injury (at least two of
the three features required) (grading based on T able 20.6) often seen in early CR. These diagnoses are not mutu-
■ Plasma cell–rich rejection (see T able 20.5) ally exclusive, and evidence of both may be present
■ Lobular (“hepatitis-like”) rejection: lobular rejection–type infiltrates simultaneously. Other changes, including spotty hepato-
(“sinusoidal pattern”) and necroinflammatory injury cyte necrosis, centrilobular cholestasis, and perivenu-
lar fibrosis, may be seen. Hepatic arteriole loss (portal
tracts lacking an arteriole) may be found in occasional
• Opportunistic infections
■ Recurrent disease (e.g., hepatitis C)

(<25%) portal tracts.
■ Ischemia or reperfusion injury In “late” CR, bile duct loss affects a least 50%
■ Antibody-mediated rejection of the portal tracts in a biopsy containing at least
■ Drug-induced injury 10 portal tracts. Bile duct counting can be facili-
■ Biliary and/or vascular complications
tated by cytokeratin (CK) 7 or CK19 staining. In
late CR, there are also more extensive degenerative
bile duct changes, marked centrilobular hepatocel-
lular swelling and hepatocanalicular cholestasis,
and prominent perivenular hepatocyte dropout with
CHRONIC (DUCTOPENIC) REJECTION more severe perivenular (bridging) fibrosis. Central
veins may show luminal obliteration. Late CR may
eventually show cirrhosis as well as parenchymal
Clinical Features extinction.
Although only rarely identified in needle biopsies,
Unlike ACR, CR (or ductopenic rejection) is uncom- obliterative “foam cell” arteriopathy denotes the accu-
mon; fewer than 1% to 2% of allografts fail because mulation of foamy macrophages within arterial walls,
of CR. Most cases occur more than 12 months after resulting in luminal narrowing and impeding arterial
transplant, although cases have been reported as early blood flow (Fig. 20.8B). Although this is a very specific
3 months after transplant. CR is often related to inad- feature of CR, it primarily affects medium-sized and
equate immunosuppression and recurrent, untreated, large-caliber perihilar arteries not sampled in needle
refractory, severe, or persistent ACR. Other risk fac- biopsies. In the appropriate clinical context, a diagnosis
tors include active CMV infection in the recipient, of CR can be rendered on a needle biopsy if any one of
long cold ischemia time, and older donors. Patients the following features is present: (1) biliary epithelial
often present with persistent jaundice or persistently atrophic changes affecting a majority of the bile ducts
elevated bilirubin, elevated ALP, and elevated trans- with or without bile duct loss, (2) foam cell obliterative
aminase. Evidence of arteriopathy and ischemic arteriopathy, or (3) bile duct loss affecting 50% of the
bile duct injury may be evident on imaging studies as portal tracts.
irregular narrowing of the hepatic arterial and biliary
trees.
Pathologic Features Biliary complications usually show histologic features of

cholestasis and a ductular reaction; however, a ductular
reaction is less common in CR and its presence favor
another cause. Hepatic artery stricture and thrombosis
Chronic rejection is characterized by obliterative arte- can also cause bile duct injury and duct loss but can be
riopathy and bile duct injury with progressive loss of excluded via imaging and vascular studies. Ischemic
small interlobular bile ducts. The histologic features cholangiopathy caused by microvascular injury is dif-
can be divided into those of “early” and “late” stages, ficult to exclude based on biopsy findings alone; the
although there is no consistent time frame over which clinical history is helpful in identifying risk factors of
patients progress from early to late CR. A diagnosis of ischemic injury (DCD donor, long ischemia time) versus
early CR suggests the changes are potentially reversible risk factors for CR.
A B
FIGURE 20.8
Chronic rejection (CR). A, Bile duct injury is an early feature of CR showing cytoplasmic vacuolization, nuclear disarray and hyperchromasia, attenuated cyto-
plasm and cytoplasmic eosinophilia. B, Foam cell arteriopathy is a well know feature of CR but uncommonly seen, in particular in biopsy specimens.
Given the cholestatic features, recurrent sclerosing

cholangitis (primary sclerosing cholangitis [PSC]) and Chronic Ductopenic Rejection—Pathologic Features
PBC are a common differential. The presence of arte-
rial changes (arterial “pruning”) on imaging studies Gross Features
favors CR over PSC. Perivenular fibrosis is a feature of ■ Parenchymal scarring, sometimes with biliary type pattern, leading
to cirrhosis
CR not seen in PSC. As seen in PBC in the native liver,
recurrent PBC usually shows patchy but, in some por- Microscopic Features
tal areas, dense mononuclear inflammatory cell infil- ■ Bile duct injury or loss (≥50% portal tracts)
trates with lymphocytic or granulomatous cholangitis ■ Obliterative “foam cell” arteriopathy or arteriole loss
that is histologically distinct from the bile duct injury ■ Inflammatory infiltrates (typical less pronounced than in acute T
seen in CR. cell–mediated rejection)
■ Recurrent disease (e.g., primary sclerosing cholangitis)
Prognosis and Therapy ■ Vascular complications
■ Biliary complications
Increased immunosuppression is the mainstay therapy.

A lack of response to immunosuppression ultimately
leads to retransplantation or death.
■ COMPLICATIONS OF TRANSPLANTATION
Liver Chronic Ductopenic Rejection—Fact Sheet
Incidence
■ 1% to 2% allografts fail because of chronic rejection (CR)
Hepatic Artery Thrombosis or Stenosis
Demographics Hepatic artery thrombosis (HAT) and hepatic artery

■ No race predilection stenosis (HAS) are the major arterial complications
occurring after liver transplantation. HAT occurs in
Clinical Features up to 9% of adult LT recipients, and reported rates
■ History of prior episodes of acute T cell–mediated rejection of HAS range from 3.5% to 11% among LT recipients.
■ Inadequate immunosuppression
Whereas HAT can present at any time after transplan-
■ Persistent jaundice
tation, HAS tends to be a later complication, occurring
■ Elevated bilirubin, alkaline phosphatase, and transaminases
several months to several years after transplantation.
Therapy and Prognosis Because the bile ducts are perfused by hepatic arterial
■ Increase immunosuppression blood flow, patients with HAT and HAS often present
■ Ductopenia can be reversible in some cases with complications of biliary ischemia, leading to bili-
■ CR may lead to graft loss, need for retransplantation, or death ary leaks and abscess formation, ischemic biliary stric-
tures, or cholangitis. Patients with early HAT (within
A B
C
FIGURE 20.9
Hepatic artery thrombosis. A
, In the acute setting, hemorrhagic changes with focal hepatocellular necrosis accompanied by regenerative hepatocellular changes
and increased mitotic activity are seen. B, In severe cases, necrosis may be more prominent. C, Bile ducts can be injured, leading to bile extravasation and
bilomas.
21 days of transplantation) commonly present with revascularization through arterial reconstruction, sur-
fever, abdominal pain, and signs of graft dysfunction gical thrombectomy, and radiologically guided throm-
or fulminant hepatic failure. Late HAT (at >21 days bolysis. Patients with HAS are treated with surgical
posttransplantation) exhibits a more insidious onset reanastomosis or interventional vascular procedures
characterized by more ischemic biliary lesions. Elevated such as dilation and vascular stenting. Restenosis is
serum transaminases, bilirubin, ALP, and GGT is seen common, occurring after stent placement in about 25%
in most patients. Vascular imaging studies are used to of patients.
assess arterial patency.
Early findings of hepatic arterial compromise include
nonspecific centrilobular hemorrhage and hepatocyte ■ PORTAL HYPERPERFUSION INJURY OR
dropout or spotty hepatocyte necrosis with increased SMALL-for-SIZE GRAFT SYNDROME
mitoses and cholestasis (Fig. 20.9A). In severe cases,
extensive necrosis of hepatocytes and portal connective
tissue is evident (Fig. 20.9B). Ischemic bile ducts with Portal hyperperfusion (PHP) or small-for-size graft
intraluminal biliary casts composed of sloughed necrotic syndrome (SFSS) is a graft complication that primarily
biliary epithelial cells may be seen, with or without bile occurs in recipients of reduced size grafts (including liv-
leaks. These changes are usually more evident in larger ing donor LT recipients) and in those with adequately
segmental bile ducts (Fig. 20.9C). Late changes include sized grafts but with severe portal hypertension.
those of ischemic cholangiopathy with progressive scar- A graft is considered “small for size” if the graft-to-re-
ring and biliary strictures. cipient-weight ratio is less than 0.8 or when the ratio of
Hepatic artery thrombosis and HAS are serious graft volume to standard liver volume is less than 40%.
complications associated with significant morbidity The spectrum of graft injury seen in PHP or SFSS is the
and mortality. Retransplantation represents the main result of high portal flows subjected to the reduced vas-
therapy for HAT. Other therapeutic options include cular bed of a smaller graft liver, a reciprocal decrease in
arterial flow, and downstream effects, including bile duct Portal hyperperfusion or SFSS is associated with
ischemia. Although the pathogenesis is not well under- increased morbidity and mortality and remains an import-
stood, the increased portal blood flow impairs hepatic ant limiting factor for use of reduced size grafts. Treatment
regeneration and induces hepatic dysfunction. The high and prevention strategies are largely aimed at reducing por-
portal flows cause a reciprocal decrease in hepatic arte- tal flows and portal pressure while maintaining adequate
rial blood flow through accelerated adenosine washout portal flows to support liver regeneration. This may be
and resultant hepatic artery constriction mediated via achieved through techniques that reduce portal blood flow
the hepatic arterial buffer response, which serves to reg- or divert a portion of the portal blood supply from the liver
ulate total hepatic blood flow within an acceptable range. to the systemic circulation, including portal vein banding;
Hepatic artery constriction results in bile duct ischemia splenectomy; splenic artery ligation or embolization; and
and necrosis with bile leaks and parenchymal infarcts. splenorenal, portocaval or mesocaval shunts. Splanchnic
In addition, endothelial cell injury results in thrombosis vasoconstrictors such as octreotide or propranolol have
of small portal veins. also been used modify portal flows.
The clinical features of PHP syndrome are pro-
longed cholestasis, coagulopathy, and ascites within the
first week after transplantation in the absence of other
■ HEPATIC VENOUS OUTFLOW OBSTRUCTION
causes of ischemia. In severe cases, gastrointestinal (GI)
OR CONGESTIVE HEPATOPATHY
bleeding, acidosis, hypoglycemia, encephalopathy, renal
failure, and septic shock can occur. Doppler ultrasonog-
raphy, angiography, and direct pressure measurements Hepatic venous outflow obstruction (HVOO) is an
are used to document high portal flows and exclude uncommon yet serious posttransplant complication that
other vascular complications. results from impaired hepatic vein outflow from the
The histologic features of SFSS can be divided into transplanted liver caused by hepatic vein thrombosis
early and late phases of graft injury. Early histologic fea- or anatomical flattening or kinking of the hepatic vein
tures are somewhat nonspecific and include centrilobular due to graft positioning. Clinical signs of HVOO include
hepatocanalicular cholestasis, centrilobular steatosis, and ascites, pleural effusion, cholestasis, and liver enzyme
mild ductular reaction with neutrophils. There is often evi- abnormalities. Doppler ultrasonography shows absent or
dence of portal vein and sinusoidal injury, including focal abnormal hepatic vein flow, and computed tomography
endothelial cell denudation along with portal and peripor- shows nonopacified hepatic veins, luminal narrowing,
tal hemorrhage (Fig. 20.10). Endothelial cell hypertrophy or a geographic low attenuation area. Hepatic venogra-
with subendothelial edema are late features, and patients phy or manometry is used to confirm the diagnosis.
may develop thrombosis of small portal vein branches with As in native livers, the histologic features vary with
luminal obliteration or recanalization, nodular regener- the severity and rapidity of the insult. The lobular
ative hyperplasia and biliary strictures. The high portal parenchyma typically shows centrilobular sinusoidal
blood flow causes a reciprocal reduction in hepatic arterial dilation, hepatocyte atrophy, and sinusoidal congestion
flow, leading to ischemic cholangiopathy with bile leaks, as well as focal, predominantly perivenular hepatocyte
bile abscesses, and parenchymal infarcts. dropout (Fig. 20.11). Mild bile ductular reaction may

Denudation of the endothelial lining (arrows) in a portal vein in a case of Venous outflow impairment revealing centrizonal sinusoidal dilation and con-
small-fo-size disease. gestion with focal hepatocellular dropout.
also be present. HVOO leads to graft dysfunction, graft

loss, and increased patient mortality. Treatment strate-
gies include medical management with diuretics, place-
ment of vascular stents, surgical cavoplasty, and if these
strategies fail, retransplantation.
■ BILIARY COMPLICATIONS
Biliary complications occur in up to 30% of LT recipients

and can present within the first week or several weeks
to months after transplant. The most common types are
anastomotic strictures, biliary leaks (which may be tech-
A
nical or ischemic), and intrahepatic strictures. Patients
with biliary complications after LT may present with
jaundice, fever, or abdominal pain. Laboratory testing
reveals a cholestatic pattern of liver enzymes with bili-
rubin and ALP elevations.
Histologic features of biliary obstruction include
neutrophil-rich portal inflammatory cell infiltrates
with bile duct proliferation. Periductal edema is seen
in some cases. The bile ducts may show mild features
of injury, including biliary epithelial cells eosinophilia,
nuclear overlapping, and pleomorphism (Fig. 20.12A).
Hepatocellular or canalicular cholestasis may be evi-
dent, although this finding may be absent if the obstruc-
tion is incomplete. Although neutrophilic infiltration
of bile ducts may be seen in obstruction, intraluminal
collections of neutrophils are seen in acute ascending B
cholangitis (Fig. 20.12B). FIGURE 20.12
In acute ischemic bile duct injury, there may be portal Biliary complications. A, Bile duct obstruction is characterized by bile duct-
findings similar to those seen in obstruction, along with ular proliferation with accompanying neutrophils and stromal edema. B,
bile duct necrosis and marked biliary epithelial eosin- Ascending cholangitis may complicate a subset of cases and should be con-
sidered when neutrophils are noted within the lumen of the bile ducts.
ophilia with formation of intraluminal eosinophilic
bile duct casts. Large bile duct necrosis, bile leaks, and
abscess formation may be seen in resection or explant
specimens.
Biliary complications are a source of significant mor-
bidity and mortality and are particularly problematic
in living donor LT recipients. Anastomotic strictures TABLE 20.7
are often corrected by dilation and stent placement.
Post–Liver Transplantation Disease Recurrence
Intrahepatic strictures are difficult to treat and can lead Rates
to graft failure requiring retransplantation.
Peak Frequency (%)
Hepatitis C 4–6 wk >9 0a

Hepatitis B Rare <10
■ RECURRENT DISEASE Autoimmune hepatitis 4–6 wk 20–30
PBC >6 mo 20–50
Recurrence of the liver disease that led to primary organ PSC >6 mo 20–30
failure occurs at varying frequencies depending on the NAFLD >3 –4 wk 20–40
Alcohol >6 mo 10–30
etiology (Table 20.7 ). The following section covers
the most common forms of recurrent disease in liver a
Hepatitis C recurrence rates may be decreasing because of increased use of
antiviral regimens.
allografts and describes features that help in differenti- NAFLD, Nonalcoholic fatty liver disease; P BC, primary biliary cholangitis; P SC,
ating these findings from acute rejection or CR. primary sclerosing cholangitis.
TABLE 20.8
Histologic Features of Acute T Cell–Mediated Rejection Versus Recurrent Hepatitis C Infection in Liver
Allograft
Acute Cellular Rejection Recurrent Hepatitis C
Portal inflammation Mixed inflammation composed of large Chronic inflammatory infiltrate composed
“activated lymphocytes,” eosinophils, and of small mature lymphocytes and
scattered plasma cells sometimes lymphoid aggregates; the
infiltrate typical spares the bile duct and
veins
Bile duct injury Often present; more prominent in early ACR Uncommon; if present is focal and mild.
Endotheliitis Often present; more prominent in early ACR Uncommon
Lobular necroinflammatory activity Uncommon; may be seen in severe ACR, Common; often spotty distribution
mainly involving centrizonal perivenular
regions
Interface activity Uncommon; if seen may be focal and in late Common; typically focal
ACR
Central perivenulitis Often seen in moderate to severe ACR or Uncommon
isolated central perivenulitis or plasma cell–
rich rejection
ACR, Acute T cell–mediated rejection.
a predominant cholestatic profile of liver enzymes, with

Recurrent Hepatitis C marked elevation of bilirubin, ALP, and GGT. Hepatitis C
virus RNA by polymerase chain reaction (viral load) is
Recurrent viral hepatitis C is essentially universal among significantly elevated, ranging in the millions IU/mL.
hepatitis C–infected recipients, although recent avail- The biopsy findings include periportal sinusoidal
ability of highly effective direct-acting antiviral therapy fibrosis with diffuse hepatocyte swelling, lobular disar-
has drastically reduced the burden of recurrent hepatitis ray, bile ductular reaction, and cholestasis (Fig. 20.13).
C. Although hepatitis C tends to show more prominent Moreira et al. (2013) published a cohort of patients with
hepatocyte injury versus the bile duct injury and endo- hepatitis C recurrence and stratified patients’ prognosis
theliitis of ACR, bile duct injury and endotheliitis can based on assessing the presence of ductular reaction,
be seen in hepatitis C. Additional histologic findings are hepatocyte swelling, cholestasis, and fibrosis (Table 20.9).
described in T able 20.8. Demetris et al. (2004) reported The main differential diagnosis is biliary obstruction.
that errors were most often caused by overdiagnosis of Features such as portal edema, bile duct dilation, bile
rejection and suggested that at least 50% of bile ducts or infarcts, acute cholangitis, periductal fibrosis, and peri-
central veins should be involved to establish a diagnosis portal copper deposition favor biliary obstruction over
of ACR in patients with hepatitis C. In general, the rec- FCH.
ommendation is to be conservative in these cases, and The prognosis for patients with FCH C was poor
many patients fall in the category of “indeterminate for before direct-acting antiviral therapy became available.
acute cellular rejection” when they demonstrate border- Preliminary studies that have used newer direct antivi-
line ACR features. ral agents suggest that most patients seem to respond
favorably with full recovery and sustained virologic
response.
Fibrosing Cholestatic Hepatitis

Recurrent Primary Sclerosing Cholangitis
Fibrosing cholestatic hepatitis (FCH) is a virulent form
of chronic viral hepatitis B or hepatitis C that occurs
in immunocompromised hosts, including after liver or Primary sclerosing cholangitis recurs in 20% to 30% of
other organ transplantation. FCH is not necessarily con- cases with the classic features of bile duct injury, peri-
sidered a separate entity but a severe form of hepatitis C ductal fibrosis, and eventual bile duct loss and scarring.
recurrence. Patients may present with jaundice, abdom- Recurrent PSC can cause diagnostic confusion with CR
inal pain, and progression to acute hepatic failure over a and other biliary complications. When present, oblitera-
period of weeks. Laboratory abnormalities demonstrate tive arteriopathy is diagnostic of CR, and CR often lacks
TABLE 20.9
Hepatitis Aggressiveness Score and Histologic
Features Associated With Fibrosing Cholestatic
Hepatitis
Histologic Findings
1.P rominent ductular reaction, at least focally expanding

portal tracts, mimicking biliary obstruction
2.Prominent hepatocellular ballooning or swelling (enlarged
hepatocytes with cytoplasmic rarefaction) and lobular
disarray
3.Cholestasis (including at leas focal canalicular cholestasis)
4.Periportal sinusoidal fibrosis
A FINAL SCORING INTERPRETATION
HAS 1: 0 of 4 features: nonaggressive hepatitis CHAS 2:
1–2 of 4 features: aggressive hepatitis CHAS 3: 3–4 of 4
features: fibrosing cholestatic hepatitis C
Adapted from Moreira RK, Salomao M, Verna EC, et al. The Hepatitis
Aggressiveness Score (HAS): a novel classification system for post-liver
transplantation recurrent hepatitis C. A
m J Surg Pathol. 2013; 37(1):104–113.
HAS, Hepatitis Aggressiveness Score.
more mixed portal inflammatory cell infiltrates in ACR,

biopsies from patients with recurrent PBC show patchy
mononuclear inflammatory cell infiltrates. Collections
of portal histiocytes or poorly formed granulomas may
be found in association with injured ducts. Over time,
patients may develop progressive fibrosis and features of
B
chronic cholestasis. Although some histologic evidence
FIGURE 20.13 of recurrent PBC is common, it is often an incidental
Fibrosing cholestatic hepatitis C. A, Histologic findings that suggest this diag- finding, and recurrent PBC rarely results in cirrhosis or
nosis include bile ductular proliferation, canalicular cholestasis, and diffuse
swelling of hepatocytes. B , The trichrome stain highlights periportal pericellu-
graft failure.
lar perisinusoidal fibrosis.
Recurrent Autoimmune Hepatitis

a ductular response. Arterial changes (“pruning”) on
imaging favor CR over PSC, and perivenular fibrosis is a Autoimmune hepatitis recurs in 20% to 30% of patients
feature of CR not seen in PSC. Unlike PSC, CR usually and presents with clinical and histologic features iden-
occurs in patients who have had severe, refractory, or tical to those seen in the native liver. The microscopic
multiple episodes of ACR; this clinical history can serve features include plasma cell–rich portal inflammatory
to be helpful in distinguishing the two scenarios. cell infiltrates with well-established interface activity,
lobular inflammation, hepatocyte “rosetting,” and in
a subset of cases, centrilobular perivenular necroin-
flammatory activity. The portal infiltrates are usually
Recurrent Primary Biliary Cholangitis
more mononuclear and often contain more plasma
cells than those seen in ACR, although plasma cells are
Recurrent PBC is seen in 20% to 50% of LT patients not a required feature. Interface hepatitis is often a
at 5 years after transplantation and exhibits the same prominent feature of recurrent AIH. Recurrent AIH
histologic features of PBC as seen in the native liver. is distinguished from the plasma cell hepatitis pattern
Most patients have positive antimitochondrial anti- of late ACR based on the history of AIH in the
bodies. In contrast to ACR, in which there is a rapid native liver. Patients with recurrent AIH, early
and persistent elevation of serum ALP, PBC is usually ACR, and late ACR are all treated with heightened
associated with a slow rise in ALP. In contract to the immunosuppression.
Recurrent Fatty Liver Disease

TABLE 20.10
World Health Organization Categories of
The reported recurrence rate of nonalcoholic fatty Posttransplant Lymphoproliferative Disorder
liver disease in allografts ranges between 10% and
40%. Recurrence may be related to the persistence of NONDESTRUCTIVE PTLD
original risk factors for fatty liver disease (e.g., hyper- • Plasmacytic hyperplasia
• I nfectious mononucleosis
insulinemia, hyperlipidemia, obesity) and influence of
• Florid follicular hyperplasia
immunosuppressive drugs, among others. Advanced
POLYMORPHIC PTLD
fibrosis (bridging or cirrhosis) have been variably Monomorphic PTLD (B- and T- or NK cell types)
reported; the largest series (227 patients) reported a 5%
• Monomorphic B-cell PTLD
risk of advanced fibrosis in 5 years. Most patients fol- • D LBCL
low an indolent course without major complications or • Burkitt lymphoma
graft loss. Recurrent alcoholic liver disease is reported • Plasma cell myeloma
to occur in 10% to 30% of patients, and approximately • Plasmacytoma
• O thers
5% of patients die of recurrent alcohol-induced cirrho-
• Monomorphic T- or NK cell PTLD
sis. Patients who relapse are at an increased risk of com- • Peripheral T-cell lymphoma, not otherwise specified
plications including ACR. • H epatosplenic T-cell lymphoma
• O ther
Classic Hodgkin lymphoma PTLD
DLBCL, Diffuse large B-cell lymphoma; PTLD, posttransplant lymphoproliferative
Posttransplant Lymphoproliferative Disorder disorder.
Posttransplant lymphoproliferative disorder (PTLD)

represents a heterogeneous group of lymphoproliferative It is important to distinguish these lymphoid infiltrates
disorders associated with immunosuppression related to from “rejection-type” infiltrates of ACR. In PTLD, the
solid organ or hematopoietic cell transplant and often lymphoid infiltrates are of B-cell origin (95% are B-cell
affecting extranodal organs such as the GI tract, lung, lesions), but the lymphoid cells in ACR are T cells. This
and liver. PTLD occurring after liver transplantation distinction is critical because treatment for PTLD con-
may present within the first month or decades after sists of decreasing the immunosuppression and possibly
transplantation and affects 2% to 4% of adults and up to adding an anti–B cell agent for more aggressive lesions,
20% of pediatric recipients. The vast majority are B-cell while treatment for ACR is increasing patient’s immu-
disorders, and most (80%) are EBV-driven processes. nosuppression level. Chromogenic in situ hybridization
The pathogenesis of EBV-driven PTLD is attributed to for EBV-encoded RNA is the preferred test in most labo-
the loss of T cell–mediated cytotoxicity against EBV- ratories for identifying EBV-infected cells. However, it is
infected B cells because of immunosuppression. They important to remember that identification of occasional
comprise a spectrum ranging from EBV-driven poly- EBV-positive cells in a liver allograft biopsy in the absence
clonal proliferations to EBV-positive or EBV-negative of a characteristic lymphoid or plasmacytic infiltrate
polymorphic and a monomorphic population of B or T should not be considered as diagnostic of PTLD.
or natural killer (NK) cells. Although less common over- Posttransplant lymphoproliferative disorder treatment
all, EBV-negative PTLD tends to occur in the later after includes reduction of immunosuppression, monoclo-
transplant. The pathogenesis of EBV-negative PTLD is nal anti-CD20 antibody (rituximab), and chemother-
not well understood. apy. Surgical resection is performed in some cases. The
The clinical presentation is variable from asymp- prognosis is highly variable and multifactorial, but some
tomatic patients to those that present with lymph node authors have reported that more than half of patients
enlargement, fever, malaise, and hepatosplenomegaly. It experience a complete response after treatment and a
typically occurs in the first year after transplantation. median overall survival period ranging from 37 to 50
The histologic spectrum ( Table 20.10) of lymphoid months. Older studies reported mortality rates in the
proliferation in PTLD ranges from nondestructive and range of 25% to 60%, which has improved over the
polymorphic EBV-driven processes comparable to B-cell years with newer therapeutics options.
or (less commonly) T-cell lymphomas occurring out-
side of the setting of immunosuppression (see details in
Chapter 19). Monomorphic PTLDs are categorized as
Opportunistic Infections
B- and T- or NK cell PTLD and are classified according
to the lymphoma they resemble. Classic Hodgkin lym-
phoma PTLD corresponds to a separate category within The more common infections affecting the LT recipient
this spectrum. include wound infections, fungal infections, and viral
infections. Fungal infections, usually from C andida spp.

(Fig. 20.14), occur in up to 20% of LT recipients, most
often affecting the mouth, esophagus, and urine.
Cytomegalovirus infection is the most common
viral infection in this setting. It is most frequently
seen in recipients who are CMV negative but receive
an organ from a CMV-positive donor. CMV infection
may affect the transplanted organ or in other sites.
Typical viral inclusions can be seen in enlarged nuclei
and cytoplasm of hepatocytes, biliary epithelial cells,
endothelial cells, or stromal cells. The nuclear inclu-
sions consist of an intranuclear mass separated from
the nuclear membrane by a clear halo, creating an
“owl’s eye” effect. Cytoplasmic inclusions are granu-
lar and basophilic. Immunohistochemical staining can A
be helpful to identify or confirm the presence of viral
inclusions.
Adenovirus and herpes simplex virus (HSV) infec-
tions are rare and tend to occur in LT recipients who
are severely immunocompromised. Adenovirus hepa-
titis manifests as random foci of hepatocyte necrosis.
Infected hepatocytes and biliary epithelial cells show
characteristic basophilic, smudged intranuclear inclu-
sions. HSV infection results in large areas of geographic
necrosis that are randomly distributed throughout the
parenchyma. The hepatocytes adjacent to these foci of
necrosis show viral cytopathic effect characterized by
chromatin margination, nuclear multinucleation, and
molding. Immunohistochemical stains are available
to assist identification of CMV, HSV, or adenovirus
inclusions.
Epstein-Barr virus hepatitis is associated with portal
B
and lobular inflammation with a characteristic sinusoi-
dal “beading” pattern of the lymphocytic infiltrate. This FIGURE 20.14
feature can mimic the lobular hepatitis seen in some Opportunistic infections. A, Well-demarcated intrahepatic abscess with dirty
central necrosis and organizing inflammation at the periphery. B , Gomori
cases of late ACR. Chromogenic in situ hybridization for methenamine silver stain supports the diagnosis of C andida spp. as the
EBV-encoded RNA is used to diagnose EBV hepatitis. underlying pathogen in this case.
number is much lower compared with other solid organ

transplants and has been steadily stabilizing over the
■ SMALL BOWEL TRANSPLANTATION
recent years.
In children, intestinal transplant is commonly per-
Intestinal transplantation has evolved as one of the lead- formed for conditions that result in short bowel syn-
ing therapeutic options for patients with intestinal fail- drome (SBS), including necrotizing enterocolitis,
ure (IF) who are unresponsive to parenteral nutrition intestinal atresia, volvulus, and motility disorders. In
therapy. The main indications for intestinal transplan- adults, the causes of SBS include Crohn’s disease, mes-
tation that are approved by the Centers for Medicare & enteric thrombosis, trauma, and desmoid tumors.
Medicaid Services include depletion of central venous Most patients undergo isolated small bowel trans-
access sites, multiple episodes of catheter-related sepsis, plants in which the entire donor jejunum and ileum
electrolyte disturbance, dehydration, and progressive are anastomosed to the recipient proximal jejunum.
cholestatic liver failure. Additional indications for An ileostomy is then created from the distal ileum of
intestinal and multivisceral transplant include diffuse the allograft, with or without anastomosis of the distal
portomesenteric thrombosis, malignancies limited to small bowel with native colon. Combined liver–intes-
the abdominal compartment, and congenital motility tine graft is considered in patients with IF and concomi-
disorders of the intestine. Per the Organ Procurement tant IF-associated liver disease. Intestinal grafts can also
Transplant Network, a total of 22,914 intestinal trans- be a component of multivisceral transplants that include
plants were performed between 1990 and 2017. This stomach or colon in the liver–intestine allograft.
Allograft Dysfunction bacterial infections, although a subset of patients may

also develop viral enteritis. Clinically, infectious enteri-
tis often presents with increased stoma output and unex-
The mechanisms of small bowel allograft dysfunction plained fever, thus mimicking allograft rejection. The
are related to multiple causes, including infection, rejec- common viruses that can affect small bowel allografts
tion, chronic kidney disease, and PTLD. Histologic eval- include EBV, CMV, rotavirus, adenovirus, and calicivi-
uation plays an essential role in evaluating the allograft rus. Histologic changes range from mucosal congestion,
status, especially with regard to infection, allograft lamina propria edema, and focal neutrophilic epithelial
rejection, and PTLD. In addition to clinical history and injury to mucosal erosions and crypt abscesses. Crypt
symptoms, the following information is critical while apoptotic activity is generally minimal and restricted to
evaluating small bowel transplant biopsies: (1) location fragments with features of regenerating epithelium. As
of the biopsy and its relation to stoma site, (2) native with other allografts, CMV and adenoviral infections
organ versus graft, and (3) endoscopic appearance of the are accompanied by viral cytopathic changes. The pres-
mucosa and specific location of biopsies with respect to ence of scattered intranuclear glassy eosinophilic inclu-
endoscopic findings (i.e., close to ulcer or relatively nor- sions points to the diagnosis of adenoviral enteropathy
mal-appearing bowel). (Fig. 20.15). IHC for CMV and adenovirus can be very
helpful in this setting.
Infection
Rejection
Postoperative infection remains the most common com-
plication and cause of allograft loss. These are mostly In addition to biopsies performed in symptomatic
patients, protocol biopsies are generally performed –two
or three times a week for the first month and one to two
times per week for the next 2 months. These intervals
may vary depending on the transplant program. Because
changes of rejection can be focal, a minimum of three
biopsy fragments with ample number of crypts (at least 10)
is considered as an adequate sample.
ACUTE CELLULAR REJECTION
Clinical Features
A
Acute cellular rejection is the leading cause of allograft
loss in the first 2 months. Because the ileum has the
highest concentration of lymphoid tissue in the gut,
changes of rejection are most commonly observed in
this region. Most patients present with fever, nausea,
vomiting, abdominal pain, diarrhea, and distension.
Pathologic Findings
Acute Cell-Mediated Rejection

Endoscopically, the mucosal changes range from edema
and hyperemia in the early phase of rejection to loss of vas-
cular pattern and foci of erosion and ulcers in severe cases
B
of rejection. The key parameter for diagnosing rejection
FIGURE 20.15
is number of apoptotic bodies per 10 consecutive crypt
Adenovirus enteritis. A, The biopsy shows small bowel mucosa with villous
cross-sections (apoptotic body count). Apoptotic bodies
architectural distortion and regenerative epithelial changes along with intra-
nuclear basophilic inclusions. B, Immunohistochemical stain for adenovirus are characterized as fragmented nuclear debris within a
highlights the viral inclusion. cytoplasmic vacuole (“classical” exploding crypt cells).
Intraepithelial clusters of basophilic material account for Mild Acute Cellular Rejection
the other form of crypt apoptosis. Although some inves-
tigators have studied the use of special stains such as The villous architecture is usually distorted in frag-
cleaved caspase-3, the results have not been satisfactory. ments that show increased lamina propria inflamma-
Therefore, routine hematoxylin and eosin–stained slides tion. Apoptotic count is 6 or more per 10 consecutive
continue to be the gold standard for assessing features crypts (Fig. 20.16). There may be accompanying reac-
of rejection. One practical way of generating apoptotic tive epithelial changes.
body count is to scan the slide at low magnification and
then select an area of highest concentration of apoptotic Moderate Acute Cellular Rejection
bodies. These foci usually tend to be in areas of epithe-
lial injury or increased lamina propria inflammation. A The villi are often congested and edematous and show
high-power evaluation is then performed to generate the moderate to marked architectural distortion. The lamina
final count per 10 consecutive crypts.
Grading Acute T Cell–Mediated Rejection

The severity of rejection is graded based on the extent of
mucosal injury, the amount of lamina propria inflamma-
tory infiltrate, and the apoptotic body count (Table 20.11).
Negative for Rejection
The normal villous architecture is retained, and there is

no increase in lamina propria inflammation. The apop- A
totic body count is less than 2 per 10 consecutive crypts.
Indeterminate for Rejection
The villous architecture may either be completely nor-

mal or there may be focal mild blunting of villi. The
lamina propria is slightly expanded by a mixed popula-
tion of cells composed of activated lymphocytes, small
lymphocytes, neutrophils, and eosinophils. There is
usually some accompanying epithelial injury with reac-
tive changes. The apoptotic count is less than 6 per 10
B
consecutive crypts. A diagnosis of indeterminate for
rejection is used when the features of rejection are quan- FIGURE 20.16
titatively insufficient for a diagnosis of mild rejection or Small bowel allograft: mild acute cellular rejection. A, Low-magnification
image shows slight villous distortion with expansion of the lamina propria by
if other factors such as infection or nonrejection causes inflammatory infiltrate. B , Higher magnification image shows increased crypt
of mucosal injury are present in the biopsy. apoptotic activity ( black circles) at a rate of 9 per 10 consecutive crypts.
TABLE 20.11
Histologic Grading of Acute Cellular Rejection in Small Bowel Allografts
Apoptotic Body Count (per 10 Degree of Lamina Propria Mixed

Grade of ACR consecutive crypts) Inflammation Surface Epithelium
No ACR <6 /10; often <

2 –3/10 Normal; no activated lymphocytes Intact
Indeterminate <6 /10; often 4 or 5/10 Focal increase Intact
Mild ≥6 /10 Mild to focal moderate increase Intact
Moderate Same as above with confluent Moderate to severe increase Erosions may be present
apoptosis with or without crypt
dropout
Severe Same as above with extensive crypt Moderate to severe Extensive erosions and/
dropout or ulcers
ACR, Acute T cell–mediated rejection.
B
FIGURE 20.17
Small bowel allograft: severe acute cellular rejection. A, Low-magnification
image shows ulcerated small bowel mucosa with granulation tissue and
exudate. B, Higher magnification shows foci of crypt dropout and confluent
apoptosis ( yellow arrows).
propria shows prominent mononuclear cell infiltrate

with activated lymphocytes. The crypts show frequent B
apoptotic bodies, occasional confluent apoptosis, and
FIGURE 20.18
focal dropout.
Small bowel allograft: antibody-mediated rejection. A, Small bowel mucosa
shows mild architectural distortion and lamina propria congestion along with
Severe Acute Cellular Rejection fibrin thrombus (upper right aspect of image). B, C4d immunohistochemi-
cal stain shows diffuse staining of capillaries within the lamina propria.
There are moderate to marked increase in lamina pro-
pria inflammation and marked architectural distortion
with crypt damage and erosion (Fig. 20.17). Extensive finding of diffuse C4d capillary staining (Fig. 20.18B)
sloughing of the mucosa is accompanied by granulation within lamina propria is abnormal and should raise con-
tissue, in which case, the residual crypts should be care- cern for AMR in the appropriate clinical setting.
fully examined for changes of rejection.
■ CHRONIC REJECTION
■ ANTIBODY-MEDIATED REJECTION
Chronic rejection results in late allograft dysfunction and
Compared with other solid organ transplants, there are loss. Clinically, patients may present with nonspecific
limited data on AMR in small bowel allografts, especially long-standing symptoms of diarrhea with nonhealing
with regards to incidence and clinical significance of ulcers. These patients are often nonresponsive to antire-
AMR. Preformed immunoglobulin (Ig) G antibodies in the jection medications. Almost always, there is history of
first 2 weeks of transplant along with persistent mucosal repeated episodes of acute rejection. Endoscopically, the
congestion and hemorrhage should prompt work-up for mucosal surface show flattened appearance, and focal
AMR. Patients often have a strong crossmatch for T- or ulcers may be present. Histologically, early changes are
B-cell lymphocytotoxic antibodies. Other histologic find- generally patchy in distribution and include mild fibrosis
ings include neutrophilic margination and fibrin thrombi of the lamina propria and focal loss of crypts (Fig. 20.19A).
(Fig. 20.18A) without neutrophilic or necrotizing arte- Late changes of CR are characterized by lamina propria
ritis. C4d immunohistochemical stain has not been vali- fibrosis, submucosal fibrosis, pyloric gland metaplasia,
dated for use in small bowel allografts. Nonetheless, the architectural distortion, and minimal apoptosis. The
from stomal ulcers can show mucosal erosions, ulcers,

and granulation tissue, which are features that mimic
severe rejection. However, the residual crypts in these
biopsies typically do not harbor significant apoptotic
activity. CR can mimic ischemic enteritis with features
of lamina propria fibrosis and atrophic crypts. Clinical
history of repeated episodes of rejection as well as mild
increase in apoptotic activity favor CR over ischemia.
Ultimately, clinical context is helpful in distinguishing
these entities.
A
Immunosuppressive therapy is the mainstay therapy
for rejection and consists of tacrolimus and steroids
with or without additional induction therapy with
either cyclophosphamide or thymoglobulin. In some
instances, azathioprine, mycophenolate mofetil, or
sirolimus is added to the regimen. Patients with acute
rejection episodes are treated with steroids and/or ant-
ilymphocyte antibodies (OKT3 or thymoglobulin). Per
Organ Procurement and Transplantation Network/
Scientific Registry of Transplant Recipients annual
data report 2017, 1- and 5-year survival rates for adult
intestine–liver recipients were noted to be 66.7% and
42.6%, respectively. It was highest for pediatric intes-
tine recipients (1- and 5-year survival rates, 86.2% and
75.4%, respectively).
B
FIGURE 20.19
Small bowel allograft: Chronic rejection. A
, Small bowel resection specimen Small Bowel Allograft Rejection—Fact Sheet
with mucosal erosion, reactive epithelial changes, and lamina propria fibrosis.
B, The sampled mesenteric vessels show obliterative arteriopathy character- Definition
ized by myointimal hyperplasia of the arterial wall.
■ Immunologic injury resulting in progressive graft dysfunction
Incidence
hallmark lesion of CR is allograft vasculopathy charac- ■ Unknown
terized by prominent intimal hyperplasia (Fig. 20.19B)
of the mesenteric or submucosal arteries resulting in Morbidity and Mortality
obliterative arteriopathy and hypoperfusion of the graft. ■ High morbidity in patients with sepsis
Often, the biopsy samples may be noncontributory

because the submucosal arteries are seldom sampled in Gender, Race, and Age Distribution
■ Occurs in all age groups
these specimens.
■ No race predilection
Clinical Features
Differential Diagnosis ■ Acute rejection
■ Nausea, vomiting, abdominal pain, distension, diarrhea
■ Increased stoma output
In the early posttransplant period, it is important ■ Chronic rejection
■ Long-standing diarrhea and nonhealing ulcers

to distinguish infectious enteritis from acute cellu-
lar rejection because the management is different for
both conditions. Both bacterial and viral enteritis can
■ Prognosis depends on recognizing features of allograft rejection
show increased crypt apoptotic activity. However, clin- and prompt treatment
ical findings such as involvement of intravenous lines, ■ 1- and 5-year survival rates for adult intestine–liver recipients are
abdominal cavity, wounds, urinary tract, and respira- 66.7% and 42.6%, respectively
tory tract suggest bacterial infection. Biopsies obtained
diabetic nephropathy or uremic type 1 diabetes often

Small Bowel Allograft Rejection—Pathologic Features necessitate replacing both the kidney and pancreas to
achieve better glycemic control and prevent further
Gross Findings complications of diabetes such as neuropathy, dia-
■ Acute rejection betic gastroparesis, and retinopathy. In this type of
■ Edema, hemorrhage in early or mild rejection; erosions and transplant, both organs usually originate from cadav-
ulcers in severe rejection
ers. PAK transplants are performed in patients who
■ Can be patchy and focal
■ Chronic rejection
have previously undergone a successful kidney trans-
■ Flattened mucosa with or without ulcers plant, and PTA transplants are indicated in patients
with “brittle diabetes.” In whole-organ transplant,
Microscopic Findings exocrine secretions are managed either by intestinal
■ See T
able 20.11 or urinary bladder drainage. This is achieved by pan-
creaticoduodenal transplantation with anastomosis of
donor duodenum to recipient small intestine or blad-
■ Infectious enteritis
der. Although the pancreas graft survival rates of SPK
■ Ischemic enteritis
■ Peristomal biopsy changes

transplants at 1 year are very similar for both meth-
ods of duct drainage (bladder drainage, 83%; enteric
drainage, 82%), because of the unique metabolic and
urologic complications in cases of bladder drainage, the
latter are currently preferred.
■ PANCREAS TRANSPLANTATION
Islet Cell Transplantation
From its inception in 1966 to 2014, more than 48,000
pancreas transplants were reported to the International Islet transplantation is a novel way of achieving optimal
Pancreas and Islet Transplant Registry. Of these, more glycemic control without the inherent risks associated
than 29,000 were performed in the United States. with whole-pancreas transplantation such as surgical
Pancreas transplant is indicated primarily in patients risks and long-term immunosuppression. The proce-
with type 1 diabetes. Other indications include diabetes dure involves enzymatic separation of islets from exo-
resulting from pancreatectomy performed for acute or crine pancreatic tissue using enzymes and implantation
chronic pancreatitis, pancreatic neoplasms, trauma, var- of isolated islets into the recipient liver via portal vein
ious pediatric genetic abnormalities, and patients with infusions. Other potential infusion sites include the sub-
cystic fibrosis. Despite significant advances in surgical cutis, spleen, omentum, and renal capsule.
techniques, posttransplant immunosuppression, diag-
nosis of rejection on surveillance biopsies, better infec-
tion control regimens, and greatly improved long-term
results, the rate of transplants performed in the United ■ EVALUATING POSTTRANSPLANT NEEDLE
States has steadily decreased (≤20%) compared with CORE BIOPSIES
non-US countries. This is likely related to improved
medical management of diabetes, a decline in organ Allograft biopsies are obtained to evaluate status of the
donor quality (more obese and older donors), and lack graft, especially in patients who show signs of acinar or
of consistent referral of transplant candidates for pan- islet cell injury, such as decreased urinary insulin and
creas transplants from endocrinologists. C-peptide levels, increased serum amylase, and lipase
rejection. Irreversible rejection is still one of the leading
causes of allograft loss. However, because of the poor
Types of Pancreas Transplants and Indications specificity and sensitivity of these serologic markers,
needle core biopsies have become the “gold standard”
Pancreas transplants can be broadly categorized as: (1) for evaluating pancreas grafts.
whole-organ transplants and (2) islet transplants. Whole- A biopsy should have at least three lobular areas
organ transplants are more commonly performed and are and associated interlobular septa. The presence or
further classified as simultaneous pancreas and kidney absence of arterial branches should be documented
transplant (SPK; 70%), pancreas after kidney transplant because evaluation for arteritis is a crucial step of
(PAK; 20%), and pancreas transplant alone (PTA; 10%). diagnosing rejection. In contrast, the presence of
islets may be less critical in determining rejection
Whole-Organ Transplants because inflammation primarily affects exocrine pan-
creas before endocrine pancreas. The recommended
The choice of type of pancreatic transplant often steps for processing pancreas allograft biopsies are
depends on the patient’s renal function. Significant presented in T able 20.12.
Allograft Dysfunction
TABLE 20.12
The mechanisms of allograft dysfunction have been
Recommended Steps for Processing Pancreas
Allograft Biopsies broadly categorized as those related to technical failure
and immunologic factors.
• Three slides for hematoxylin and eosin staining
• O ne slide for trichrome staining
• O ne slide for C4d immunohistochemical staining Technical Failure
• Five or more intervening unstained sections for additional
stains as needed (i.e., hormone or viral markers)
Possible technical graft failures that can lead to removal
of the graft include bleeding, thrombosis, infections,
pancreatitis, and anastomotic leak. The rate of failure
because of technical reasons is highest during the first
year posttransplantation. In the early posttransplant
Pancreas Allograft Rejection—Fact Sheet period (usually within 1 month), one of the main causes
of technical failure is massive vascular thrombosis. This
Definition irreversible event is often encountered by pathologists
■ Immunologic injury resulting in progressive graft dysfunction
on whole explanted pancreas specimens with attached
donor duodenal cuff. The thrombosis can be “idio-
Incidence
pathic,” characterized by recent thrombotic occlusion
■ 15% to 21% at 1 year and 27% to 30% at 5 years
of large arteries, veins, or both. Histologic examination
Morbidity and Mortality of the allograft shows ischemic necrosis without any
■ 4% at 1 year and 9% at 5 years
parenchymal or vascular abnormality. In the setting
of vascular thrombosis, it is prudent to exclude AMR,
Gender, Race, and Age Distribution especially during the first month after transplantation.
■ Occurs in all age groups
■ No race predilection
Immunologic Factors
Clinical Features
■ Acute rejection Immunologic injury, specifically acute rejection as a
■ Abdominal pain, fever cause of graft loss is most frequent at 7 to 12 months
after transplant and decreases after the first year. In con-
■ Abdominal pain
trast, CR as a cause of failure accounts for 20% to 30%
of all graft failures after 1 year. Similar to other organs,
■ Prognosis depends on recognizing features of allograft rejection
histologic criteria for assessing allograft rejections were
and prompt treatment established at the 9th Banff conference on Allograft
■ Graft survival: 86% at 1 year and 54% at 10 years for Pathology in 2007 and revised in 2015. These specific
simultaneous pancreas and kidney transplant recipients criteria are presented in T able 20.13.
Normal Allograft Biopsy
Pancreas Allograft Rejection—Pathologic Features Normal allograft pancreas biopsies are usually encoun-
tered in the setting of protocol biopsies of well-function-
Gross Findings ing grafts. Normal allografts lack inflammatory infiltrates
■ Acute rejection or exhibit very sparse inflammation composed of small,
■ Edema, hemorrhage in early or acute rejection with or without mature-appearing lymphocytes and rare plasma cells. This
necrosis
sparse inflammation is confined to the septae and typi-
■ Can be patchy and focal
cally spares the vessels, nerves, ducts, and acini. There are
■ Parenchymal fibrosis other clinical circumstances in which a biopsy may appear
“normal.” These include the late phase of recurrent auto-
Microscopic Findings immune disease (i.e., after resolution of isletitis and dis-
■ See T
able 20.13 appearance of beta cells), drug toxicity, and acute AMR.
As in other solid organ transplants, two main mech-
anisms of graft rejection are recognized: cell-mediated
■ Infections
rejection and AMR. It is crucial to differentiate the two
■ Hemorrhagic necrosis caused by technical failure
forms of rejection because of significant therapeutic
implications. Cell-mediated rejection therapy includes
TABLE 20.13
Diagnostic Categories of Pancreas Allograft Rejection: Banff Working Grading Schema
Diagnostic Category Histologic Criteria
1. Normal • N o inflammation or Inactive septal, mononuclear inflammation not involving ducts, arteries,
veins, or acini
• Minimal fibrosis proportional to the size of enclosed structures (ducts and vessels)
• N o parenchymal atrophy or injury
• N o graft sclerosis
2. Indeterminate • A ctive septal inflammation but overall features do not fulfill the criteria for mild acute rejection
3. Cell-mediated rejection
ACUTE CELL-MEDIATED REJECTION
Grade I: mild acute cell- • A ctive septal inflammation composed of activated blastic lymphocytes and/or eosinophils
mediated rejection • Venulitis
a nd/or
• D uctitis
• Focal acinar inflammation (no more than two inflammatory foci per lobule with absent or
minimal acinar cell injury)
Grade II: moderate acute cell- • Multifocal (but not confluent or diffuse) acinar inflammation (≥ 3 foci per lobule) with spotty
mediated rejection (individual) acinar cell injury and dropout
and/or
• Minimal intimal arteritis (with minimal [< 2 5%] luminal compromise)
Grade III: severe acute cell- • D iffuse, widespread acinar inflammation with focal or diffuse multicellular or confluent acinar
mediated rejection cell necrosis
and/or
• Moderate or severe intimal arteritis (> 2 5% luminal compromise)
and/or
• Transmural inflammation or necrotizing arteritis
4. AMR Three diagnostic components:
• C4d positivity in interacinar capillaries (≥ 1% of acinar lobular surface)
• Serologic evidence of donor-specific antibodies (HLA or other antigens)
• H istologic evidence of acute tissue injury One of three diagnostic components present:
requires exclusion of AMR Two of three diagnostic components present: consider acute AMR
Three of three diagnostic components present: definite acute AMR Histologic evidence of
acute tissue injury:
• Grade I (mild acute AMR): well-preserved architecture, mild interacinar monocytic–
macrophagic or mixed (monocytic–macrophagic/neutrophilic) infiltrates with rare acinar cell
damage (swelling, necrosis)
• Grade II (moderate acute AMR): overall preservation of the architecture with interacinar
monocytic–macrophagic or mixed (monocytic–macrophagic/neutrophilic) infiltrates, capillary
dilation, interacinar capillaritis, intimal arteritis, congestion, multicellular acinar cell dropout,
and extravasation of RBCs
• Grade III (severe acute AMR): architectural disarray, scattered inflammatory infiltrates in a
background of interstitial hemorrhage, multifocal and confluent parenchymal necrosis, arterial
and venous wall necrosis, transmural or necrotizing arteritis, and thrombosis (in the absence
of any other apparent cause)
5. Chronic active AMR Features of category 3 and/or 4 with active chronic arteriopathy and/or category 6
6. Chronic arteriopathy Fibrointimal arterial thickening with narrowing of the lumen
• I nactive: fibrointimal arterial thickening with narrowing of the lumen
• A ctive: infiltration of the subintimal fibrous proliferation by mononuclear cells (T cells and
macrophages)Distinguish on the most affected artery:
• Grade 0: negative; no narrowing of the luminal area
• Grade 1: mild; ≤ 2 5% narrowing of luminal area
• Grade 2: moderate; 26%–50% narrowing of luminal area
• • Grade 3: severe; ≥ 5 0% narrowing of luminal area
7. Chronic graft fibrosis • Grade I (mild graft fibrosis): expansion of fibrous septa; fibrosis occupies < 3 0% of the
core surface, but acinar lobules have eroded, irregular contours; the central lobular areas are
normal
• Grade II (moderate graft fibrosis): fibrosis occupies 30%–60% of the core surface. The
exocrine atrophy affects the majority of the lobules in their periphery (irregular contours) and
in their central areas (thin fibrous strands criss-cross between individual acini)
• Grade III (severe graft fibrosis): the fibrotic areas predominate and occupy > 6 0% of the
core surface with only isolated areas of residual acinar tissue and/or islets present
Continued
TABLE 20.13
Diagnostic Categories of Pancreas Allograft Rejection: Banff Working Grading Schema
Diagnostic Category Histologic Criteria
8. Islet pathology • R ecurrence of autoimmune diabetes mellitus (insulitis and/or selective β - cell loss)
• I slet amyloid (amylin) deposition
• I slet cell calcineurin inhibitor toxicity
9. Other histologic diagnosis Pathologic changes not considered to be due to acute and/or chronic rejection (e.g., CMV
pancreatitis, PTLD, bacterial or fungal infection, ischemic pancreatitis, recurrent autoimmune
disease)
ACR, Acute T cell–mediated rejection; AMR, antibody-mediated rejection; CMV, cytomegalovirus; HLA, human leukocyte antigen; PTLD, posttransplant lymphoproliferative
disorder; RBC, red blood cell.
corticosteroids and anti–T cell antibodies such as anti-

thymocyte globulin and anti-CD3 monoclonal antibody.
In contrast, treatment for patients with AMR targets
circulating donor-specific antibodies with IVIg and
plasmapheresis.
■ CELL-MEDIATED REJECTION
Acute Rejection
Rejection in pancreas allograft can be difficult to diag-

nose clinically. Patients present with clinical findings of
fever and abdominal tenderness. Multiple serum mark-
ers are used to monitor graft function, including glucose,
FIGURE 20.20
amylase, lipase, and C-peptide levels. Of these, lipase is
Hematoxylin and eosin–stained section of pancreas allograft biopsy (5
the most specific. A pancreatic biopsy is performed in months posttransplant) with mild cellular rejection showing a polymorphous
patients with elevated lipase levels and those who do not periductal inflammatory infiltrate composed of activated lymphocytes, small
show evidence of vascular compromise or peripancre- mature-appearing lymphocytes, and rare eosinophils. Lymphocyte-mediated
duct epithelial damage (ductitis) is also noted.
atic fluid collection on imaging.
Three grades of ACR (mild, moderate, and severe) are
defined based on specific histologic lesions that predict
progressively worse outcome.
Mild Acute T Cell–Mediated Rejection (Grade I)
This grade of rejection is defined by predominantly

mononuclear septal inflammation composed of “acti-
vated blastic” lymphocytes admixed with variable num-
bers of eosinophils. These inflammatory cells extend
into the ducts (ductitis) (Fig. 20.20) and subendothelial
spaces of venules (venulitis) (Fig. 20.21). This is accom-
panied by mild (focal) acinar cell injury. The response to
treatment approaches nearly 90%.
Moderate Acute T Cell–Mediated Rejection (Grade II)

FIGURE 20.21
This grade is characterized by multiple foci (three Hematoxylin and eosin–stained section of pancreas allograft biopsy (31
or more foci per lobule) of acinar inflammation months posttransplant) with moderate acute cellular rejection characterized
by a venous endothelial injury by activated lymphocytes.
with associated single-cell necrosis or dropout
(Figs. 20.22and
20.23). Occasionally, along with
1. Severe acinar inflammation and damage character-

ized by confluent, diffuse or extensive acinar inflam-
mation associated with confluent necrosis. The
inflammatory cells include activated lymphocytes
and variable numbers of eosinophils and neutrophils.
Interstitial edema and hemorrhage are indicators of
severe tissue damage.
2. Moderate to severe intimal arteritis characterized
by subintimal mononuclear cells as well as evidence
of endothelial injury in the form of endothelial cell
hypertrophy, fibrin leakage, neutrophil margination,
macrophage activation, and activation of myointimal
fibroblasts. These changes should involve more than
25% of the vascular lumen.
3. Arteritis (vasculitis) characterized by complete or
partial circumferential necrosis often secondary to
FIGURE 20.22
transmural arterial inflammatory infiltrates.
months posttransplant) with moderate cellular rejection showing marked This form of rejection injury often manifests as
interstitial fibrosis and lymphocyte-mediated acinar injury ( inset). hyperglycemia with poor response to antirejection
regimens.
Antibody-Mediated Rejection
Primary humoral or AMR occurs in a recipient with

preformed antidonor antibodies. The main risk factor
is an ABO-incompatible graft. A diagnosis of AMR is
based on three components: (1) histologic evidence of
tissue injury, (2) complement deposition (C4d) posi-
tivity in interacinar capillaries (≥1% of acinar lobular
surface), and (3) donor-specific antibodies in the serum.
C4d staining in more than 5% of interacinar capillaries
is typically present in cases of acute AMR. C4d stain-
ing is characterized as focal ( > 5%–50%) or diffuse
(>50%), according to the extent of interacinar capillary
FIGURE 20.23 staining in the lobular surface areas.
months posttransplant) with moderate cellular rejection showing diffuse lym-
phocyte-mediated acinar injury and destruction with focal dropout necrosis. Grading Antibody-Mediated Rejection
Acute AMR typically occurs in the first few weeks after

activated lymphocytes, eosinophils can be the pre- transplantation. The histologic criteria were recently
dominant component of the inflammatory infil- outlined as follows.
trate. Alternatively, this pattern of injury may be
diagnosed when minimal intimal arteritis ( <25% Grade 1 (Mild Acute Antibody-Mediated Rejection)
luminal involvement) is identified (lymphocytes
beneath the intima of a muscular artery but no endo- Histologically, the pancreatic architecture is usually
thelial activation or injury). In patients with grade II well-preserved. The inflammatory infiltrate is usually
ACR, the response to antirejection therapy ranges mild and composed of monocytic–macrophagic or mixed
from 71% to 85%. monocytic–macrophagic/neutrophilic infiltrates located
between the acini. The acinar tissue shows rare foci of
Severe Acute T Cell–Mediated Rejection (Grade III) injury in the form of swelling or necrosis.
This form of acute rejection is recognized histologically Grade 2 (Moderate Acute Antibody-Mediated Rejection)
by three distinct lesions identified either in isolation
or concurrently. Each of these lesions portends a poor The parenchymal architecture is intact. However, in
prognosis. They include addition to the interacinar inflammatory cell infiltrate,
there are capillary dilation, interacinar capillaritis, inti-

mal arteritis, congestion, multicellular acinar cell drop-
out, and extravasation of red blood cells.
Grade 3 (Severe Acute Antibody-Mediated Rejection)
The parenchymal architecture is distorted. In addition

to scattered inflammatory infiltrates, there are intersti-
tial hemorrhage, multifocal and confluent parenchymal
necrosis, arterial and venous wall necrosis, transmural
or necrotizing arteritis, and thrombosis.
■ CHRONIC REJECTION AND GRAFT FIBROSIS
Chronic Antibody-Mediated Rejection FIGURE 20.25

Hematoxylin and eosin–stained section pancreas allograft biopsy (13
months posttransplant) with extensive fibrosis and scattered parenchymal
This form of rejection is also referred to as chronic active elements admixed with chronic inflammatory cells; changes are consistent
AMR. Histologically, it has combined features of acute with end-stage chronic rejection.
cell mediated or AMR along with chronic arteriopathy

(see next section).
lumen (inactive). When the subintimal fibrous prolifera-
tion is infiltrated by mononuclear cells (T cells and macro-
phages), the lesion is defined as active chronic arteriopathy.
Chronic Arteriopathy
The pathology report should specify how many medium
and large arteries were sampled. Depending on the most
Arterial findings of rejection are seldom seen in needle affected artery, the arteriopathy is graded as grade 0, neg-
biopsy samples. Sections from pancreatectomies performed ative (no narrowing of the luminal area); grade 1, mild (
for failed grafts with CR show extensive interstitial fibro- ≤25% narrowing of the luminal area); grade 2, moderate
sis or acinar atrophy along with the aforementioned oblit- (26%–50% narrowing of the luminal area); and grade 3,
erative arteriopathy (Figs. 20.24 and 20.25). This finding severe (≥50% narrowing of the luminal area).
is more common after the second year posttransplanta-
tion. Chronic arteriopathy is characterized by the presence
of fibrointimal arterial thickening with narrowing of the
■ CHRONIC GRAFT FIBROSIS
Chronic allograft rejection or graft sclerosis is semiquan-
titatively evaluated using a three-tier grading scheme as
the extent of parenchymal loss and fibrosis corresponds
with graft survival. The three stages of fibrosis correlate
to less than 30%, 30% to 60%, and greater than 60%
fibrosis in biopsy core samples. This is assessed in con-
junction with the degree of lobular parenchymal atro-
phy ranging from preservation of acinar lobules with
focal, irregular contours to stage II with atrophy affect-
ing the center and periphery of lobules, eventually lead-
ing to stage III with marked reduction in the functional
exocrine tissue (see Fig. 20.25). This grading scheme
has significant prognostic value and should be applied to
needle core biopsies (see T
able 20.13).
FIGURE 20.24
Islet Pathology
Hematoxylin and eosin–stained section of failed pancreatic transplant exci-
sion in a patient with simultaneous pancreas and kidney transplant showing
chronic rejection with obliterative arteriopathy characterized by subintimal
proliferation of fibroblasts, myofibroblasts, and smooth muscle cells with infil- As discussed earlier, biopsies with minimal inflam-
tration by mononuclear cells, including foamy histiocytes ( arrow). mation should be distinguished from recurrence of
autoimmune diabetes mellitus by performing stains for ■ OTHER COMPLICATIONS

insulin and glucagon to assess β-cell loss. In addition,
the islets are also prone to amyloid deposition and calci-
neurin inhibitor toxicity. Pancreatitis and Peripancreatic Abscess
Formation
Necrotizing infections as a result of bacterial or fungal

Differential Diagnosis of Acute Rejection infections can lead to parenchymal abscess formation,
which may affect graft anastomoses. Biopsies from these
Acute T Cell–Mediated Rejection allografts should be distinguished from rejection. In
contrast to acute rejection, which shows preservation of
The differential diagnosis for ACR includes peripan- overall parenchymal architecture, biopsies from patients
creatitis or superimposed infections such as CMV. with peripancreatic abscess show haphazard fibrotic
However, these entities are seldom associated with bands usually obliterating septal structures.
venulitis, ductitis, or arterial inflammation. Extensive
expansile inflammatory infiltrate requires differentia-
tion from PTLD; the work-up of which described a pre-
vious section. Viral Infezzctions
The histologic findings of early AMR can be quite
subtle, with only mild inflammation in the biopsy sam- Cytomegalovirus Pancreatitis
ples. Biopsies with minimal or absent inflammation,
especially in patients with hyperglycemia, should also Cytomegalovirus pancreatitis manifests as multifo-
be distinguished from other conditions such as recur- cal, predominantly acinar inflammation composed
rence of autoimmune diabetes. This distinction requires of mononuclear cells associated with viral cytopathic
immunohistochemical assessment of the islets for the changes within endothelial, stromal, or epithelial cells
number and ratio of insulin-positive β cells and gluca- (Fig. 20.25). These changes can be easily confused with
gon-positive αcells. Loss of βcells indicates recurrence acute rejection, especially if not accompanied by diag-
of type 1 diabetes mellitus. Extensive hemorrhagic nostic viral inclusions. Ancillary studies such as IHC,
necrosis in severe AMR needs to be distinguished from serology, and viral assays should be performed if there
thrombosis related to technical failure. Thrombosis is strong clinical suspicion because early detection and
related to technical failure typically occurs in the early diagnosis allow maintenance of good allograft function.
transplant period as opposed to acute AMR, which
occurs at a later time point. Furthermore, acute AMR Epstein Barr Virus–Related Posttransplantation
is associated with arterial and venous endotheliitis of Lymphoproliferative Disorder
the small and large vessels. Thrombosis secondary to
technical failure affects large arteries or veins (or both) This disorder should be considered in the differential diag-
without endothelial inflammation. nosis of acute allograft rejection. The distinction is particu-
larly important because the treatments for these conditions
are exactly opposite (see Liver Transplantation section).

■ RECURRENCE OF PRIMARY DISEASE
In most cases, pulse steroid therapy and antilymphocyte
therapy result in excellent treatment response in patients
who are diagnosed with acute rejection. Multiple epi- Recurrence of type 1 diabetes mellitus is diagnosed when
sodes of rejection may result in parenchymal fibrosis as there is sudden or progressive loss of glycemic control
well as disarray of the exocrine tissue. In early phases, associated with selective loss of beta cells in the graft and
islets are usually unaffected. However, eventually, ACR persistence of other types of islet cells, especially alpha
leads to diffuse graft fibrosis. Treatment of patients with cells. The destruction of beta cells is often associated with
AMR includes IVIg and plasmapheresis with or without appearance of islet cell autoantibodies in serum (glutamic
rituximab. In patients who do not respond to this initial acid decarboxylase 65-kilodalton isoform [GAD-65] and
line of therapy, graft failure may occur in a short period of islet antigen 2 [IA-2]). The reported overall incidences of
time (weeks or months) because of vascular thrombosis posttransplant diabetes mellitus are nearly 17% for type 1
and necrosis. Pancreas transplant is associated with all- and 45% for type 2 diabetes. This is attributed to a com-
cause mortality rates of 4% at 1 year and 9% at 5 years. bination of factors, which include increased pretrans-
The graft survival rates are 86% at 1 year and 54% at plant body mass index, higher pretransplant daily insulin
10 years for SPK recipients. dose, and the occurrence of acute rejection.
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morphologic changes such as cytoplasmic swelling and 792–799.
20. DemetrisAJ, AdeyiO, BellamyCO, et al. Liver biopsy interpre-
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in liver allografts: prospective assessment of diagnostic accuracy,
identification of pitfalls, and observations about pathogenesis.
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Index
Page numbers followed by “f ” indicate figures, “t” indicate tables, and “b” indicate boxes.
A Acute hepatitis pattern of injury, in liver Adenomatous polyps (Continued)

Abdominal pain (Continued) flat, 364
in actinomycosis, 272 fatty liver disease/steatohepatitis pattern intramucosal adenocarcinoma, 366
in celiac disease, 121 of injury, 505 molecular features of, 366–367
in graft-versus-host disease, 140–141 nonalcoholic fatty liver disease, 505–509 neuroendocrine proliferation in, 365–366
in intestinal lymphangiectasia, 147 nonhepatotropic viral infections, 493 tubular, 364
in mantle cell lymphoma, 626 Acute intermittent porphyria (AIP), 553 villous, 364
in mycophenolate mofetil colitis, 330 Acute pancreatitis, 458–459, 458f Adenomyoma
in strongyloidiasis, 294 Acute versus chronic cholestasis, 512 of gallbladder, differential diagnosis of,
in yersiniosis, 260 Acute viral (hepatotropic) hepatitis, in liver, 491 438f
Abetalipoproteinemia, 137 “Adenocarcinoid” tumors, 237, 240 gastric, differential diagnosis of, 98–99
Abscess, anal, 407–408 Adenocarcinoma, 155f Adenosquamous carcinoma, 471–472, 472f
Acanthosis, glycogenic, differential diagnosis of ampulla of Vater, 157–160, 157f Adenovirus enteritis, 677f
of, 16 subtyping of, 159t Adenovirus infection
Acetaminophen toxicity, 530–531, 532f–533f of anus, differential diagnosis, 419–420 appendicitis in, 220–221, 221f
Achalasia, esophageal, 22–24, 23f, 25f colonic, 384f, 385f of gastrointestinal tract, 247
Acid lipase deficiency, 549t, 550t colorectal, 379–380, 384f. See also inclusions in, 220–221, 221f, 247
Acinar cell carcinomas (ACCs), 471, 478f Colorectal cancer Advanced gallbladder carcinoma, 444–446
Acinar differentiation, tumors with (in in Crohn’s disease, 313–314 Aeromonas infection, 253t, 262, 263f
pancreas), 476–484 differential diagnosis, 156 AIDS. See HIV infection
acinar cell carcinoma, 476–479 of esophagus, 39–42 Alcoholic liver disease, 509–513
acinar cell cystadenocarcinoma, 479 intramucosal, 38–39, 38f Alcoholic steatohepatitis (ASH), 505, 515f
acinar cell cystadenoma, 476 ex goblet cell carcinoid, 237, 239f “Almost normal” biopsy/nonspecific
mixed acinar–ductal and ductal– differential diagnosis of, 237 findings, in liver, 535–537, 535t, 536f
neuroendocrine carcinoma, 484 of extrahepatic bile ducts, 444f, 445f, 451f hepatic granulomas, 537
mixed acinar–neuroendocrine carcinoma, gastric, 107–114 necrosis, 537–538
484 differential diagnosis of, 98–99 Alternative lengthening of telomeres (ALT)
mixed ductal–neuroendocrine carcinoma, diffuse type of, 108 phenotype, 474
484 infiltrating, 471f Amebiasis, 284f
pancreatoblastoma, 479–480 intestinal type of, 108, 108f Ampulla of Vater, adenocarcinomas of,
serous cystadenocarcinoma, 482 invasive, of gallbladder, 441 157–160, 157f
serous cystadenoma (SCA), 480–482 mucinous, 384f subtyping of, 159t
solid-pseudopapillary neoplasm (SPN), with Paget’s disease of anus, 431 Ampullary adenocarcinoma, 159f
482–483 signet ring cell, 385f intestinal type, 159f, 159t
Acinar–ductal and ductal–neuroendocrine small bowel, ampulla of Vater, 157–160, pancreaticobiliary type, 159f, 159t
carcinoma, of pancreas, 484 157f, 159t Ampullary adenoma, 157f, 160
Acinar–neuroendocrine carcinoma, of of small intestine, 154–157 Amyloidosis, 537
pancreas, 484 tubular, 468f esophageal achalasia in, 22
Actin, smooth muscle Adenoid cystic carcinoma in esophagus, 47f gastric, 64–67, 82, 83f, 84f
in gastrointestinal stromal tumors, 177 Adenoma, 225–226 differential diagnosis of, 75
in inflammatory myofibroblastic tumor, 203 of appendix, 225f Anal canal
Actinomyces infection, 219 colorectal. See Adenomatous polyps adenocarcinoma, 419
Actinomycosis differential diagnosis of, 226 anal tags in, 411–412
appendicitis in, 272 gastric, 101–104 anatomy and histologic landmarks of, 407
colonic, 253t, 272–273 differential diagnosis of, 101–104 Bowenoid papulosis, 427–428
differential diagnosis of, 272–273 foveolar-type, 102 Bowen’s disease, 426, 428f
Acute antibody-mediated rejection, diagnosis intestinal-type, 102 condyloma acuminatum of, 410–411, 424,
of, 662t hepatic, 560–564, 561f, 562f, 562t 425f
Acute appendicitis, 213–215, 214f pyloric gland, 104–106 perianal high-grade squamous
infectious causes of, 219–221 sessile serrated, 374–377 intraepithelial lesion, 426
Acute cellular rejection (ACR), 663–668, 664f, differential diagnosis of, 374–377 squamous cell carcinoma of, 415–416
666f Adenomatosis, 564 tumors and precursor lesions of, 412
Acute hepatitis pattern of injury, in liver, Adenomatous polyps, 363–365, 364f, 365f, 384f Anal canal squamous intraepithelial lesion
489–490, 490f carcinoma in situ, 366 (ASIL), 412–413
acute viral (hepatotropic) hepatitis, 491 and colorectal cancer risk, 363–364 Anal Crohn’s disease, 409f
alcoholic liver disease, 509–513 differential diagnosis of, 367 Anal fibroepithelial polyp. See Anal tag
autoimmune hepatitis, 502–505 diffuse, 192 Anal fistula tract, 408f
chronic hepatitis pattern of injury, 496–498 familial, 192, 198, 337, 340f, 341f Anal gland adenocarcinoma, 419f
chronic viral hepatitis, 498–502 differential diagnosis of, 341–343 Anal squamous neoplasia, 412
691
692 INDEX
Anal tag, 411–412 ATP7B gene, 542 Bile ducts, extrahepatic

Ancylostoma duodenale, 292 Atresia, esophageal, 17–19, 17f botryoid embryonal rhabdomyosarcoma
Anemia, in gastric antral vascular ectasia, tracheoesophageal fistula with, 17–19, 18f of, 453
84–85 Atypical lipomatous tumor, of esophagus, carcinoid tumors of, 452
Angina, intestinal, 145 30–31 cystadenomas of, 452–453
Angiomyolipoma, of liver neoplasms, Atypical lymphocytes, 496 Bile ducts in mesenchymal hamartoma,
598–600, 599f Autoimmune disorders 598f
Angiosarcomas, 602f gastritis, 64, 64t, 67t Biliary cholangitis, primary, 516–519
, malignant, 600–602 differential diagnosis of, 62, 67t Biliary cirrhosis, 516f, 517f
Anisakiasis, 295 Autoimmune enteropathy, 133–135, 134f Biliary cyst, 582f
differential diagnosis of, 73 differential diagnosis of, 135 Biliary cystadenomas. See Mucinous cystic
gastritis in, 73, 295 microvillus inclusion disease (MVID), neoplasms (MCNs)
Annular pancreas, 455 135 Biliary intraepithelial neoplasia (BilIN) of
Anomalies of appendiceal anatomy, 211 Autoimmune hepatitis, in liver, 502–505, gallbladder, 438–440
Anorectum, syphilis of, 269 502t Biliary intraepithelial neoplasia–type
Antibody-mediated rejection (AMR), 661f Autoimmune pancreatitis (AIP), 460–463, changes, 444f
Antinuclear antibodies (ANAs), 502 461b, 461f, 462b Biliary obstruction, 505
Anti–smooth muscle antibodies (ASMAs), Biliary tumors bile duct hamartoma,
502 B 578–579
α1-antitrypsin deficiency, 544 Bacterial enterocolitis, 252 Bland cholestasis, 512–513, 513f
Antral vascular ectasia gastric, differential Bacterial infections, of colon, 253t Bleeding
diagnosis of, 86t, 88 Bacterial overgrowth syndrome, differential in Dieulafoy’s lesion, 88
Anus diagnosis of, 124 gastrointestinal
Crohn’s disease of, 408–409, 409f Balantidium coli organisms, 284 in acute erosive/hemorrhagic gastritis,
giant condyloma of Buschke-Lowenstein, Bannayan-Riley-Ruvalcaba syndrome, 352 53
429–430 Barrett’s esophagus, 32–34, 33f in chemical gastropathy, 56
hemorrhoids of, 410, 411f CK7/20 staining pattern in, 40 in gastric antral vascular ectasia, 84
hidradenoma papilliferum of, 423, 424f differential diagnosis of, 1 in schistosomiasis, 295
melanoma of, 421, 422f follow-up guidelines in, 38–39, 39t in strongyloidiasis, 294
non-neoplastic lesions in, 407–408 goblet cells in, 32, 33f in hemorrhoids, 410
Paget’s disease of, 431, 432f high-grade dysplasia in, 35 in mycophenolate mofetil colitis, 330
squamous cell carcinoma of, 417f, 430f indefinite for dysplasia, 36, 36f Boerhaave’s syndrome, 26
tags in, 410 intestinal metaplasia in, 37f Botryoid embryonal rhabdomyosarcoma, of
verrucous carcinoma of, 429–430 low-grade dysplasia in, 37f extrahepatic bile ducts, 453
differential diagnosis of, 426 negative for dysplasia, 35–36, 36f Bowenoid papulosis, 427–428
APC gene/mutations, 198 and reflux esophagitis, 1 Bowen’s disease, 432
Apoptotic cells, enterocytes in AIDS Basidiobolus ranarum infection, 277 Bronchogenic carcinoma, esophageal varices
enterocolopathy, 249f differential diagnosis of, 278 in, 25–26
Appendiceal adenocarcinoma, 232 Batts and Ludwig classification system, 497f, Brunner’s gland hyperplasia, 151–152, 152f,
Appendiceal Crohn’s disease, 217f 498f 463
Appendiceal mucinous neoplasm, 224f B-cell lymphoma(s) differential diagnosis of, 151–152
high-grade, 228 Burkitt lymphoma, 624f, 638–641 Budd-Chiari syndrome, 523, 523f
low-grade, 228 diffuse large, 630–632, 631b, 631b–632b, Burkitt lymphoma, 624f, 638–641, 641b
Appendicitis, 214f 634f–635f Buschke-Lowenstein giant condyloma,
granulomatous, 218 differential diagnosis of, 640, 645 429–430
idiopathic granulomatous, 217t extranodal marginal zone. See MALT
periappendicitis, 215–216, 215f lymphomas
ulcerative, 216 Beckwith-Wiedemann syndrome, 575 C
Appendix, 211 Behçet’s disease, differential diagnosis of, 131 C4d staining, 660–661, 661t, 679
chronic inflammatory disorders of, 217t Benign cystic lesions in pancreas, 456–458 Calcifying fibrous tumor, 186, 186f
in Crohn’s disease, 214–218, 217f, 217t congenital cysts, 457 differential diagnosis of, 188
in cystic fibrosis, 211, 212f, 218–219, duodenal diverticulum, 458 Calcinosis, gastric mucosal, 76
219f simple mucinous cysts, 456–457 Caliber persistent artery, 88
deciduosis in, 221–223, 222f Benign lobular atrophy, 485f Calymmatobacterium granulomatis infection,
diverticula of, 211, 212f Bevacizumab, 531 anal, 270–271
endometriosis of, 221–223, 222f Bile duct adenomas (BDAdas), 579, 581f Campylobacter infections, 253t, 259, 259f
epithelial neoplasms of, 223 Bile duct hamartomas (BDHs), 578, 579f and immunoproliferative small intestinal
fibrous obliteration of lumen in, 211–213, Bile duct injury, 532f–533f disease, 620–621
212f Bile duct loss, 536–537 Campylobacter jejuni infection, 259f
in gliomatosis peritonei, 221–222 Bile duct margin, 486–487 Canalicular cholestasis, 513, 532f–533f
interval, 214–215, 214f Bile ducts, disorders of, 513 and hepatocyte injury, 501f
invasive adenocarcinoma of, 232f Budd-Chiari syndrome, 523, 523f Cancer development in Peutz-Jeghers
mucinous neoplasms of, 229f, 234f, 240f congestive (cardiac) hepatopathy, 524 syndrome, 346–347
neuroendocrine tumors of, 235 drug-induced liver injury, 530–531 Candida infection
retention cyst of, 230f hepatoportal sclerosis, 528 colonic, 273–275
serrated polyps of, 226, 227f large duct obstruction, 513–516 differential diagnosis of, 274t
in ulcerative colitis, 216 nodular regenerative hyperplasia, 527 esophagitis in, 3, 14
Arginase-1 immunohistochemistry, 590 overlap syndromes, 522 Candida spp., 675–676
Arteriosclerosis, differential diagnosis of, 84 peliosis hepatis, 530, 530f Capsulatum, histoplasma, 537f
Arthropathy, reactive, in Campylobacter portal vein thrombosis or obstruction, Carbon tetrachloride, 532f–533f
infection, 259 526–527 Carcinoembryonic antigen (CEA), 569
Ascaris lumbricoides infection, 292, 293f primary biliary cholangitis, 516–519 Carcinoid tumors
Aspergillosis, bowel infarction, 275f primary sclerosing cholangitis (PSC), 519 colorectal, 391–393, 392f
Aspergillus infection, colonic, 275–276, sinusoidal obstruction syndrome (SOS), differential diagnosis of, 195
276f 525 of extrahepatic bile ducts, 452
differential diagnosis of, 274t vascular pattern of injury, 522–523 gastric, 114–117
INDEX 693
Carcinoma. See also Adenocarcinoma Cholecystitis, 435, 436b Collagenous sprue, 125, 126f
adenosquamous, 472f acute, 435–436, 438f Colloid carcinoma, 471–472
of anal canal, squamous cell, 415–416 chronic, 435–437, 438f, 439, 444 Colon
of anus differential diagnosis of, 441–443 AIDS enterocolopathy of, 249f
differential diagnosis of, 431 eosinophilic, 435 bacterial infections of, 253t
squamous cell, 417f, 430f epithelial changes in, 436, 438f epithelial lymphocytosis of, 317
verrucous, 426, 431 hyalinizing (of gallbladder), 436–437 fibroblastic polyps of, benign, 189–191,
colorectal. See Colorectal cancer xanthogranulomatous, 435–436, 437f, 439f 189f, 190f
of esophagus Choledochal cysts, 452 fungus infections of, 273
intramucosal, 38–39, 38f Choledocholithiasis, of gallbladder, 446 herpesvirus infection of, 246f
squamous cell, 42–45, 43f Choledocholiths, of gallbladder, 435–436 smooth muscle tumors of, 176
of extrahepatic bile ducts Choleliths, of gallbladder, 435–436 submucosal leiomyoma, 177f
differential diagnosis of, 443f Cholestasis, 524 Colon cancer, metastatic, 609f
fibrolamellar, 572–575 acute versus chronic, 512 Colonic amebiasis, 284f
of gallbladder, 438–444 bland, 513f Colonic endometriosis, 390f
invasive, 446 patterns and manifestations of, 512–513 Colorectal cancer, 379–380, 384f
gastric Cholestatic pattern of injury, 512 differential diagnosis of, 390
intramucosal, 101 Cholestatic steatohepatitis, 505 fungating, 381
signet ring cell, differential diagnosis of, Cholesterolosis, of gallbladder, 435–436 hereditary nonpolyposis, 363
99–100 Chronic antibody-mediated rejection, 686 infiltrating adenomatous polyps, 379
in situ, 101 Chronic arteriopathy, 686 medullary carcinoma, 385–386, 386f
hepatocellular, 567–572, 568f. See also Chronic ductopenic rejection, 668–669 mucinous, 383, 384f
Hepatocellular carcinoma (HCC) Chronic graft fibrosis, 686–687 necrotic material in, 384f
medullary, 472f differential diagnosis of acute rejection, 687 polypoid, 381
metastatic, 609f acute T cell-mediated rejection, 687 risk factors in, 363–364, 379
undifferentiated, 472f islet pathology, 686–687 and serrated adenomas, 374–377
Cardiac-related venous congestion. See Chronic hepatitis pattern of injury, in liver, and serrated polyposis syndrome, 346
Congestive hepatopathy 496–498 signet ring, 383, 385f
Cast, esophageal mucosal, in caustic injury, Chronic inflammatory disorders, of undifferentiated, 385–386
14–15, 15f appendix, 217t Colorectal carcinomas
β-catenin, nuclear, in fibromatosis, 199, Chronic pancreatitis, 459–460, 459f, 460b HER2 immunohistochemistry in, 400, 401f
199f Chronic passive venous congestion. See micropapillary carcinoma, 385, 385f
Caustic injuries of esophagus, 14–15, 15f Congestive hepatopathy microsatellite instability testing of,
differential diagnosis of, 14–15 Chronic rejection (CR), 670f 395–396
Cavernous hemangiomas (CHs), 557, 593f Chronic viral hepatitis, in liver, 498–502 molecular oncology testing in, 400
CD10, 590 Cinar cell cystadenoma, 477f molecular testing of, 395
CD56, 589 Cirrhosis, 553 morphologic features associated with
CD system. See Immunohistochemistry Cloacogenic polyps of anus, inflammatory microsatellite instability, 385–391
Celiac disease, 121–122 differential diagnosis of, 372–373 mucinous adenocarcinoma, 384f
differential diagnosis of, 124, 645 Clonorchis sinensis, 448 signet ring cell adenocarcinoma, 385f
extraintestinal disorders with, 121t Clostridial infection, of gut, 264 uncommon variants of, 383–385
intestinal villi in, 121 Clostridium difficile infection, 253t Colorectal epithelial neoplasms, 363
lymphocytic gastritis in, 69 differential diagnosis of, 255, 320–321 adenocarcinoma, 379–380, 384f
nonresponsive, 124–125 Coccidial infection, 287–288 adenomatous polyps, 363–365, 384f
pathogenesis of, 122–124 Colitis colorectal carcinomas, 383–385
refractory, 124–125 chemotherapy effect/mucositis, 334–335, hyperplastic polyp (HP), 371–374, 371f,
Cell-mediated rejection, 684–686 334f 372f
acute rejection, 684–685 collagenous, 315, 316f intramucosal adenocarcinoma and
mild acute T cell-mediated rejection, 684 collagenous gastritis with, 74 carcinoma in situ, 366
moderate acute T cell-mediated differential diagnosis of, 320–321 invasive adenocarcinoma versus misplaced
rejection, 684–685 diversion, 323–324, 323f epithelium, 369–370
severe acute T cell-mediated rejection, diverticular disease-associated, 324–325, Lynch syndrome, 380–383
685 324f, 325f malignant polyps, 367–369
antibody-mediated rejection, 685–686 drug-induced, differential diagnosis of, microsatellite instability, morphologic
mild acute antibody-mediated rejection, 307–308 features associated with, 385–391
685 eosinophilic, 327–328, 327f molecular alterations, 378–379
moderate acute antibody-mediated in Hirschsprung’s disease, differential neuroendocrine, 391–393, 392f
rejection, 685–686 diagnosis of, 328 neuroendocrine neoplasms, 391–393
severe acute antibody-mediated infections, differential diagnosis of, neuroendocrine proliferation in
rejection, 686 307–308, 317 adenomatous polyps, 365–366
Central perivenulitis, 664, 665f ischemic, 319–321, 320f in polyposis syndromes, 337
Chagas disease, 25f differential diagnosis of, 281, 307–308 serrated colorectal polyps, 371
esophageal achalasia in, 22, 25f lymphocytic, 318–319, 318f serrated polyposis syndrome (SPS), 379
Chancres, syphilitic, 269–270 differential diagnosis of, 317 sessile serrated adenomas, 374–377
Chemotherapy mycophenolate mofetil, 330–331, 330f differential diagnosis of, 374–377
esophagitis from, 9–11 nonsteroidal anti-inflammatory drug, traditional serrated adenomas, 377–378,
mucositis from, 334–335, 334f 333–334 378f
Chlamydia trachomatis infection, 270–271 pseudomembranous, differential diagnosis Colorectal polyps, 363
Chloride levels in sweat in cystic fibrosis, of, 266, 294 Combined hepatocellular–
218 radiation, 320–323, 322f cholangiocarcinoma (HCC–CCs),
Cholangiocarcinoma (CC), 446–450, 451f, differential diagnosis of, 317 590–592, 591f
583–584, 589f ulcerative, 301. See also Ulcerative colitis Common bile duct (CBD), 446
of liver neoplasms, 586 Collagen in fibromatosis, 198 Common variable immunodeficiency, 132, 132f
peripheral/intrahepatic, 587f Collagenous disorders differential diagnosis of, 132–133, 134f, 135
Cholangitis lenta, 513 colitis, 315, 316f Condyloma, acuminata, differential diagnosis
Cholate stasis, 512 gastritis, 74, 75f of, 270
694 INDEX
Condyloma acuminatum, 410–411, 424, 425f Cystic fibrosis, appendix in, 211, 212f, Diverticula
Congenital cysts, of pancreas, 457 218–219, 219f appendiceal, 211, 212f
Congenital tufting enteropathy, 136f Cystic mucinous duct lesion, 456–457 in cystic fibrosis, 211, 218
Congestive hepatopathy, 525f, 671–672 Cystic neoplasm, mucinous, 584 esophageal, 19–20, 21f
Congestive (cardiac) hepatopathy, in liver, 524 Cyst(s) differential diagnosis of, 18
Constitutional MMR deficiency, 398 congenital, of pancreas, 457 Zenker’s, 20, 21f
Conventional adenoma epidermoid, of pancreas, 456 Diverticular disease-associated colitis,
differential diagnosis, 156 esophageal, congenital, 18f 324–325, 324f, 325f
of small intestine, 154–157 lymphoepithelial (of pancreas), 456 Donovan bodies in granuloma inguinale,
Copper accumulation disorder, in liver, 542 Cytokeratins, 518. See also 270–271
glycogen storage diseases, 546 Immunohistochemistry Doppler ultrasound study, 525
glycogenic hepatopathy, 552–553 in Barrett’s esophagus, 40 Downhill esophageal varices, 25–26
porphyrias, 553–555 in gallbladder carcinoma, 446 Down’s syndrome, and celiac disease, 121
Wilson’s disease, 542, 543f in gastric adenocarcinomas, 110–111 Doxycycline gastritis, 78
Cord colitis syndrome, 332–333, 332f Cytomegalovirus, of gallbladder, 435 differential diagnosis of, 78–79
Core antigen (HBcAg) Cytomegalovirus hepatitis, 494 Drug-induced disorders
immunohistochemistry, 501f Cytomegalovirus infection, 676 acute erosive/hemorrhagic gastritis in, 53, 54f
Cowden’s syndrome, 352–357, 357f colon in, 244f, 245f chemical gastropathy in, 56
differential diagnosis of, 355 Crohn’s disease with, 243, 245f colitis in, differential diagnosis of,
Cowdry’s inclusions, in adenovirus infection, differential diagnosis of, 245 307–308, 312, 320–321
220–221, 221f in adenovirus infection, 248 iron pill gastritis in, 77
C-reactive protein (CRP), 560 in chemotherapy effect/mucositis, 334 NSAID injury in, 130–131
Crohn’s disease, 9f, 137–138, 138f, 309 in herpesvirus infection, 247 differential diagnosis of, 131
anal, 408, 409f esophagitis in, 3, 14 and peptic ulcer disease, 126, 129
differential diagnosis of, 409–410 gastritis in, 71f parietal cell hyperplasia from proton pump
appendix in, 214–218, 217f, 217t differential diagnosis of, 80 inhibitors, 92f
biopsy findings in, 310–311 in gastrointestinal tract, 243, 244f, 245f pill esophagitis in, 11–12, 12f
cytomegalovirus infection with, 243, 245f Cytomegalovirus pancreatitis, 687 Drug-induced liver injury (DILI), 489–490,
differential diagnosis of, 8–9, 139–140, Cytoplasmic inclusions. See Inclusions, 530–531, 532f–533f, 534t
312–313 cellular Ductal adenocarcinoma, pancreatic,
in Aeromonas infection, 261 471–474, 471f
in amebiasis, 284–285 D Ductal cholestasis, 513
in cryptococcal infection, 281–283 Davidson’s disease, 135 Ductal neoplasms, of pancreas, 464–466
in cytomegalovirus infection, 245 De novo autoimmune hepatitis, 664 intraductal papillary mucinous neoplasm
in diversion colitis, 322 Deciduosis, appendiceal, 221–223 (IPMN), 466–469
in ischemic colitis, 320–321 Deep sequencing. See Next-generation intraductal tubulopapillary neoplasm,
in lymphogranuloma venereum, 270–271 sequencing (NGS) 470–471
in NSAID colitis, 333 Desmin in gastrointestinal stromal tumors, mucinous cystic neoplasm, 469–470
in NSAID injury, 131 177 pancreatic ductal adenocarcinoma, 471–474
in peptic duodenal disease, 128 Desmoid fibromatosis, 198f, 199f pancreatic intraepithelial neoplasia, 464–466
in shigellosis, 258 Desmoid tumors in familial adenomatous precursor lesions, 464
in strongyloidiasis, 294 polyposis, 338 Ductal–neuroendocrine carcinoma, of
in tuberculosis, 269 Developmental anomalies, of pancreas, 455 pancreas, 484
in typhoid fever, 256–257 annular pancreas, 455 Ductopenia, 536–537
in ulcerative colitis, 307–308 ectopic pancreas, 455 Ductular cholestasis, 513
in yersiniosis, 261, 261f pancreatic divisum, 455 Ductular reaction or proliferation, 513
endoscopy in, 309, 310f Devon family syndrome, 360 Duodenal adenoma, 154f
of esophagitis, 8–9 Diabetes mellitus, hepatic glycogen. See also Duodenal diverticula, 458f
gastric, 67–68, 68f Glycogenic hepatopathy (GH) Duodenal diverticulum, of pancreas, 458
gross appearance of, 310, 310f Diarrhea Duodenum
resection findings in, 311, 311f, 312f in adenovirus infection, 247 gangliocytic paraganglioma in, 194, 195f
Crohn’s enterocolitis, 310f in Aeromonas infection, 263 “lipid hang-up” biopsy of, 128–129, 128f
resection, 312f in AIDS enterocolopathy, 248 normal biopsy findings in, 127f
Crohn’s-like lymphoid response, 386f in autoimmune enteropathy, 133 peptic disease of, 126–129, 127f, 128f
Cronkhite-Canada syndrome (CCS), in celiac disease, 121 differential diagnosis of, 128
357–360, 359f in Clostridium difficile infection, 263 well-differentiated neuroendocrine tumor
differential diagnosis of, 358 in Escherichia coli infection, 252 of, 160f, 161f
in gastric hyperplastic polyps, 80, 95–96 in intestinal lymphangiectasia, 147 Dysphagia, 440b
in Ménétrier’s disease, 80 in mantle cell lymphoma, 626 in adenomatous polyps, 364–365
Cryptococcosis, colonic, 279f, 280–283 in mycophenolate mofetil colitis, 330 in Barrett’s esophagus, 35–38, 36f, 37f
differential diagnosis of, 274t in necrotizing enterocolitis, 263 in caustic esophageal injury, 14–15
Cryptogenic cirrhosis, 505 in schistosomiasis, 296 colorectal epithelial, in sessile serrated
Cryptosporidiosis, colonic, 288f in shigellosis, 257 adenomas, 374–377
Cryptosporidium parvum, 435 in strongyloidiasis, 294 in Crohn’s disease, 313–314
Crypts, colonic traveler’s, 252 differential diagnosis, 441–443
in ischemic colitis, 320, 320f in typhoid fever, 255 in eosinophilic esophagitis, 4
in mycophenolate mofetil colitis, 330 in ulcerative colitis, 301 in esophageal diverticula, 19–20
in sessile serrated adenomas, 374–377 in yersiniosis, 260 in esophageal motility disorders, 22–24
CTNNB1 gene, 480, 482 Diastase resistance in granular cell tumors of of gallbladder, 437, 446–447
Cyclospora infection, 288–290 anus, 431 gastric epithelial, 101–104
differential diagnosis of, 290 Dietary factors in colorectal cancer, 363 differential diagnosis of, 103
Cystadenocarcinoma, 584 Dieulafoy’s lesion, gastric, 88 high-grade, 441f
of pancreas, 482 Diffuse large B-cell lymphoma, 630–632, intestinal epithelial, 136
Cystadenoma 631b, 631b–632b, 634f–635f low-grade, 440f
hepatobiliary, 452–453 differential diagnosis of, 640, 645 in radiation esophagitis, 14
of pancreas, 480–482 Diversion colitis, 323–324, 323f in ulcerative colitis, 305–309, 306f
INDEX 695
Dysplasia and early gallbladder carcinoma, Epidermoid cyst in an intrapancreatic Esophagus (Continued)
438–444, 442b accessory spleen (ECIPAS), 456 heterotopic sebaceous glands in, 15
Dysplastic nodules (DNs), 564–567, 566f Epidermoid metaplasia, 16 lichenoid esophagitis, 8
Epithelial membrane antigen, luminal lymphocytic esophagitis, 6–8
E expression of, 589 motility disorders of, 22–24, 23f, 25f
Ectasia Epithelial neoplasms of colorectum, 363 mucosal cast in caustic injury, 14–15, 15f
gastric antral vascular, 84, 85f, 86t Epithelial tumors hepatocellular tumors focal neuroendocrine neoplasms of, 48
differential diagnosis of, 84, 86t, 88 nodular hyperplasia, 557 non-neoplastic disorders of, 1
Ectopia, esophageal epithelial, 15f Epithelioid cells in gangliocytic papillomas of, squamous, 30–31, 30f
Ectopic pancreas, 455 paraganglioma, 195f perforations and tears in, 25–27
Ectopic pancreatic tissue in Meckel’s Epithelioid hemangioendothelioma (EHE), polyps of, fibrovascular, 30–31
diverticulum, 456f of liver neoplasms, 590, 602–604 polyps of, giant fibrovascular, 31f
Embryonal rhabdomyosarcoma, botryoid, of Epithelioid inflammatory myofibroblastic reflux esophagitis, 1, 2f, 3f
extrahepatic bile ducts, 453 sarcoma, 203f salivary gland type tumors, 46
Embryonal sarcoma of liver, 604–606, 606f Epithelium secondary tumors of, 49–50
Encephalitozoon intestinalis infection, in cholecystitis, 436, 438f squamous cell carcinoma of, 42–45, 43f
288–289 gastric, dysplasia of, 101–104 squamous papillomas of, 29–30, 30f
Endocrine neoplasms. See Neuroendocrine Epstein-Barr virus (EBV), of gallbladder, stenosis of, congenital, 19f
tumors 444–445 stromal tumors in, 169
Endometrioma of colon, 390 Epstein-Barr virus hepatitis, 493, 495f, 496f, structural abnormalities of, 17–19
Endometriosis, 156 676 acquired, 19–22
appendiceal, 221–223, 222f Epstein-Barr virus infection and Burkitt congenital, 17–19
colonic, 390f lymphoma, 638b tumors of, 29
Endoscopic retrograde Epstein-Barr virus–related undifferentiated carcinoma, 45
cholangiopancreatography (ERCP), posttransplantation varices in, 25–27, 26f
446–447, 455 lymphoproliferative disorder, 687 webs and rings of, 19–22, 20f
Endoscopy Erosive gastritis, acute, 53 Essile serrated polyp/adenoma (SSP/A),
in Crohn’s disease, 310, 310f Erythropoietic protoporphyria (EPP), 375f, 376f
in ulcerative colitis, 301, 302f 553 Ex goblet cell carcinoid, 237, 239f
Endothelial lining, denudation of, 671f Escherichia coli infection, 252 Extended criteria, 657
Enema effect, differential diagnosis of, differential diagnosis of, 272–273 Extrahepatic bile ducts, 446–448
317 enteroadherent, 252, 253t, 254f carcinoma of, 448–452, 449b, 450b
Entamoeba histolytica infection, 283, 284f enterohemorrhagic, 252, 253t, 254f invasive carcinoma, 450–451
Enteric (typhoid) fever, 255, 257f differential diagnosis of, 320–321 precursor neoplasia, 449–450
Enteric ischemic disease, 142f, 145–147 enteroinvasive, 252 inflammatory disorders of, 446–447, 447b,
Enteritis enteropathogenic, 252, 253t 448b
infectious, 147 enterotoxigenic, 252 intraductal papillary neoplasms of, 450f
regional. See Crohn’s disease Esophageal carcinoma, risk factors for, mesenchymal tumors of, 453
Enterobiasis, 290f, 291 34–35 mucinous cystic neoplasm of, 453f
Enterobius, appendicitis in, 220, 220f Esophageal hyperkeratosis, 16 Extrahepatic CC, 451–452
Enterobius vermicularis, 220, 220f Esophageal neuroendocrine carcinoma,
Enterochromaffin-like cells, hyperplasia of differential diagnosis of, 48
in autoimmune gastritis, 62 Esophageal papillomatosis, 30f F
Enterocolitis Esophagitis, 1–4, 2f False-positive staining, 402
granulomatous. See Crohn’s disease differential diagnosis of, 3 Familial adenomatous polyposis, 337, 340f,
necrotizing, 264 eosinophilic, 4, 5f, 6f 341f
differential diagnosis of, 266, 328 differential diagnosis of, 3, 6 differential diagnosis of, 341–343
Enterocolopathy in AIDS, 248, 249f graft-versus-host disease, 9 Fatty liver disease, 505
Enterocytes, apoptotic, in AIDS infectious, 15f nonalcoholic, 505–509
enterocolopathy, 249f differential diagnosis of, 3, 6, 14–15 Ferroportin disease (type B), 539t
Enterocytozoon bieneusi infection, 288–289 inflammatory disorders, 1–2 Fibroblastic polyps of colon, benign,
Enteroendocrine cell dysgenesis, 136–137 reflux esophagitis, 1 189–191, 189f, 190f
Enteropathy pill, 11–12, 12f Fibrolamellar carcinoma, of liver neoplasms,
autoimmune, 133–135, 134f differential diagnosis of, 3, 11–12 572–575
gluten-induced. See Gluten-sensitive from radiation/chemotherapy, 9 Fibrolamellar hepatocellular carcinoma,
enteropathy reflux, 1, 2f, 3f 573f, 574f
in T-cell lymphoma, 125, 125f, 643–647, differential diagnosis of, 3, 6, 11–12, Fibromatosis
644f–645f, 646b 14–15 intraabdominal, 198–200, 198f
tufting, 136 Esophagitis dissecans superficialis, 12–14 mesenteric, 198f
Eosinophilic disorders Esophagus differential diagnosis of, 199
cholecystitis, 435–436 adenocarcinoma of, 39–42 Fibrosarcoma, inflammatory, 202–205
esophagitis, 4, 5f atresia of, 17–19, 17f Fibrosing cholestatic hepatitis (FCH),
differential diagnosis of, 3, 6 tracheoesophageal fistula with, 17–19, 18f 498–501, 672–673
gastritis, 72, 74f atypical lipomatous tumor, 30–31 Fibrosing cholestatic hepatitis C, 502, 674f
Eosinophilic esophagitis Barrett’s, 32–34 Fibrosis, 533
differential diagnosis of, 6 carcinoma of, intramucosal, 38–39, 38f portal based, 501f
endoscopy of, 5f caustic injuries of, 14–15, 15f Fibrous obliteration, of appendix, 212f
of esophagus, 4–6 differential diagnosis of, 14–15 Fissures, anal, 407–408
intraepithelial eosinophils, 6f cysts of, congenital, 18f Fistulas
Eosinophilic gastroenteritis (EGE), diverticula of, 19–22, 21f anal, 407
143–144 duplications of, 18f tracheoesophageal, esophageal atresia
differential diagnosis of, 144 ectopias of, 15f with, 17–19, 18f
Eosinophilic inflammation, intact villi with, eosinophilic esophagitis, 4–6 Florid duct lesions, 515–517
119–120 gastroesophageal reflux disease (GERD), 1 Focal nodular hyperplasia (FNH), 557, 558f
Eosinophilic proctocolitis, 327–328, 327f granular cell tumors of Follicular lymphoma, 623–626, 624f
Epidermoid cyst, of pancreas, 456 differential diagnosis of, 40–41 Food poisoning in Salmonella infection, 255
696 INDEX
Foveola, gastric Gastric-type intraductal papillary mucinous Gastrointestinal tract

in adenomas, 102 neoplasm, 467f adenovirus infection of, 247
hyperplasia of, 95–96 Gastrin levels in Zollinger-Ellison syndrome, AIDS enterocolopathy of, 248
differential diagnosis of, 95–96 80 bacterial enterocolitis in, 252
metaplasia in peptic duodenitis, 127, 127f, Gastrinoma bacterial infections
128f in multiple endocrine neoplasia type I, 81 Sarcina ventriculi, 249–250, 250f
Frozen section, 484–487, 486f, 487f in Zollinger-Ellison syndrome, 81 Tropheryma whipplei, 250–251
diagnosis of pancreatic ductal Gastritis bacterial infections in, 249
adenocarcinoma on, 485 acute erosive/hemorrhagic, 53, 54f clear cell sarcoma-like tumor of, 180–182
of donor liver biopsy with steatosis, 658f autoimmune, 64, 64t, 67t cytomegalovirus infection in, 243
resection margins, evaluation of, 485–487 chronic atrophic, and gastric carcinoids, herpesvirus infection of, 246–247
bile duct margin, 486–487 115 infectious disease of, 243
parenchymal margin, 485–486 differential diagnosis of, 59, 62, 67t parasitic infections of, 283
tissue adjacent to superior mesenteric collagenous, 74, 75f viral infections of, 243
artery/hepatic artery, 487 colitis with, 74 Gaucher disease, 549t, 550t
Fundic gland polyps, 91–94, 92f differential diagnosis of, 75 Genetic factors
differential diagnosis of, 93, 95–96 cystica glandularis, differential diagnosis in celiac disease, 122–123
Fungus infections of, 95–96 in gastric adenomas, 101–104
colonic, 273 cystica polyposa, 96–97 in gastric cancers, 107–108
differential diagnosis of, 274t differential diagnosis of, 96–97 in multiple endocrine neoplasia type 2, 360
eosinophilic, 72, 74f in neurofibromatosis type 1, 360
granulomatous, 67–68, 67t in squamous cell carcinoma of anus,
G differential diagnosis of, 67t 416–417
Gallbladder, 435–438 in gastric Crohn’s disease, 67–68 Giant fibrovascular polyp, 30–31, 31f
adenomyoma of, 438f in sarcoidosis, 68 Gliomatosis peritonei, appendix in, 221–222
advanced gallbladder carcinoma, 444–446 Helicobacter heilmannii in, 61, 62f Glomus tumors, 196–198, 197f
carcinoma of, 435, 438–444 Helicobacter pylori in, 57, 58t, 59f, 60f, gastric, differential diagnosis of, 116
invasive, 449–450 61f, 61t Glutamine synthetase (GS) immunostain,
cholecystitis of, 435 infectious, 71 560
dysplasia and early gallbladder carcinoma, parasitic, 71, 79f Gluten-sensitive enteropathy, 121
438–444 viral, 71f differential diagnosis of, 621–622
early invasive lesions in, 442–443 ischemic, differential diagnosis of, 84 Glycogenated nuclei, 508
gallbladder dysplasia and carcinoma, 437 lymphocytic, 69, 70f Glycogen storage diseases, in liver, 546, 547t
invasive adenocarcinoma of, 445f radiation, differential diagnosis of, 75 Glycogenic hepatopathy (GH), 552–553,
mesenchymal tumors of, 453 Gastroesophageal junction 552f
metaplasia of, 436 inflammation of, 17 GNAS mutations, 470
pyloric gland adenoma of, 442f intestinal metaplasia of, 17 Goblet cell adenocarcinoma (GCA), 237,
reactive changes in, 443f Gastrointestinal neoplasms 238f, 239f
undifferentiated gallbladder carcinoma, 445f colorectal carcinoma, molecular testing Goblet cell carcinoid (GCC), 237, 238f, 239f,
xanthogranulomatous cholecystitis of, of, 395 240f
435–436, 437f, 439f HER2 in colorectal carcinoma, 400 differential diagnosis of, 237
Gallbladder carcinoma, 446b HER2 testing in upper gastrointestinal Goblet cell–rich hyperplastic polyp, 373f
Gamma-glutamyl transferase (GGT), 511 tract adenocarcinoma, 400–404 Goblet cells
Gangliocytic paraganglioma, 163, 163f, background and rationale, 400–401 in adenomatous polyps, 365
194–196 immunohistochemistry, 402 in autoimmune enteropathy, 134–135
Ganglioneuroma, 193f in situ hybridization, 403 in Barrett’s esophagus, 32, 33f
differential diagnosis of PD-1/PDL-1 in esophageal and gastric carcinoid, 238f, 239f, 240f
in neurofibroma, 192–194 carcinomas, 403–404 differential diagnosis of, 237
in perineurioma, 192–194 specimen type, 402 in cystic fibrosis, 219, 219f
Ganglioneuromatosis, diffuse, 192, 193f mismatch repair function, assessment of, in Peutz-Jeghers syndrome, 347–348
Ganglionitis in esophageal achalasia, 23f 395–400 Gonorrhea, 271
Ganglion-like cells in gangliocytic future directions of molecular testing in Graft-versus-host disease, 140–141, 142f
paraganglioma, 194, 194f, 195f colorectal carcinoma, 400 and adenovirus infection, 247
Gangrenous appendicitis, 214 microsatellite instability-high carcinoma: differential diagnosis of, 9, 245, 330, 334
Gardner’s syndrome, 198, 338 sporadic versus lynch syndrome, Granular cell tumor, 179–180, 179f
Gastric adenocarcinoma 396–397 anal, differential diagnosis of, 418
differential diagnosis of, 111 mismatch repair immunohistochemistry differential diagnosis of, 179–180
risk factors of, 107–108 in, 397–399 gastric, differential diagnosis of, 99–100
Gastric amyloidosis, 82 polymerase chain reaction–based Granulocytic epithelial lesions, 460–461
differential diagnosis of, 84 microsatellite instability testing, in type 2 autoimmune pancreatitis, 462f
Gastric amyloids, 64–67, 83f, 84f 395–396 Granuloma, 532f–533f
differential diagnosis of, 75 RAS, extended RAS, and BRAF testing, in colonic tuberculosis, 269
Gastric antral vascular ectasia (GAVE), 57 399–400 in Crohn’s disease of anus, 409–410, 409f
Gastric carcinoma, gross appearance of, 108f molecular testing of, 395 inguinale, differential diagnosis of,
Gastric Crohn’s disease, 68, 68f Gastrointestinal stromal tumors (GISTs), 270–271
Gastric foveolar-type metaplasia, 152f 156, 169–176, 171f in liver and common associations, 538t
Gastric heterotopia, 152–153, 152f dedifferentiated, 173f Granulomatous appendicitis, 218
differential diagnosis of, 152 differential diagnosis of, 175 Granulomatous disorders
of small intestine, 152 in glomus tumors, 195 appendicitis, idiopathic, 217t
Gastric heterotopia inlet patch, 15, 15f in neurofibromas, 191–192 enterocolitis. See Crohn’s disease
Gastric peptic ulcer disease, 63 epithelioid, 173f gastritis, 67–68, 67t, 68f, 69f, 70f
differential diagnosis of, 63 platelet-derived growth factor receptor-a Groove pancreatitis, 153f
Gastric polyps, in stomach, 91 (PDGFRA) in, 172f “Groove” pancreatitis, 462–463, 463b
Gastric schwannoma, 187f, 188f risk defined in, 172–173 Guillain-Barré syndrome in Campylobacter
Gastric secondary tumors, 113 small intestinal, 172f infection, 259
Gastric-type epithelium, 584 succinate dehydrogenase (SDH) in, 172f GVHD. See Graft-versus-host disease
INDEX 697
H Hepatocellular–cholangiocarcinoma (HCC– coccidial infection in, 287–288

Halo effect around yeast forms, 279f, 280 CCs), of liver neoplasms, 590–592, 591f cryptosporidiosis in, 288f
Halothane, 532f–533f Hepatocellular cholestasis, 513 salmonellosis in, 255
Hamartoma, 151–152 Hepatocyte regeneration, 504f and squamous cell carcinoma of anus,
differential diagnosis of, 151–152 Hepatoid carcinoma, 471–472 417–418
mesenchymal, 595, 597f Hepatopathy, congestive, 524, 525f HMB-45 stain in melanoma of anus, 421–422
pancreatic, 455–456, 457f Hepatoportal sclerosis (HPS), 527–528, 529f HNF1α gene, 562–564
“Schwann cell,” 192 Hepatosplenic T-cell lymphoma, 649–651, HNF1A-mutated adenomas (HAs), 563f
Hamartoma polyposis syndromes, 346–350 650f, 651b Homosexual men
Helicobacter heilmannii gastritis, 61, 62f Herbal and dietary supplement (HDS), 531 amebiasis in, 283
Helicobacter pylori infection Hereditary hemochromatosis (HH), in liver, 539 anorectal syphilis in, 269
and diffuse large B-cell lymphoma, 630– Hereditary mixed polyposis syndrome, 360, 360f gonorrhea in, 271
632, 631b, 631b–632b Hereditary non polyposis CRC syndrome. See herpetic proctitis in, 246
and gastric cancer risk, 107 Lynch syndrome infectious proctocolitis in, 270
gastritis in, 57, 58t, 59f, 60f, 61f, 61t HER2 fluorescence in situ hybridization, 402f intestinal spirochetosis in, 271
differential diagnosis of, 54–55, 57, 59, HER2 in colorectal carcinoma, 400 Hookworms, 292
61–62, 71, 80 Herpes simplex hepatitis, 495f Human epidermal growth factor receptor 2
and gastric xanthomas, 99–100 Herpes simplex virus (HSV) infection, 495, 676 (HER2), 400
lymphocytic, 69 Herpesvirus infection “Humoral” rejection. See Antibody-mediated
and gastroesophageal reflux disease, 15 of colon, 246f rejection (AMR)
and immunoproliferative small intestinal differential diagnosis of Hyalinizing cholecystitis (HC), of
disease, 620–621 in chemotherapy effect/mucositis, 334 gallbladder, 435–437
and MALT lymphomas, 614 in esophagitis, 10 Hyalinizing chronic cholecystitis, 439f
immunoproliferative small intestinal esophagitis in, 3, 14 Hyperacute rejection, 660
disease, 614 differential diagnosis of, 10 Hyperbilirubinemia, 502
and peptic duodenitis, 126, 128 in gastrointestinal tract, 246–247 Hypereosinophilic syndrome, 73
Helminth infection, colonic, 290 HER2 testing algorithm, 403f Hyperplastic polyposis syndrome, 343
Helminthic infections, 290 HER2 testing in upper gastrointestinal tract Hyperplastic polyp(s) (HP), 371–374
Hemangioendothelioma, epithelioid, adenocarcinoma, 400–404 colorectal, 371–374, 371f, 372f
602–604 background and rationale, 400–401 differential diagnosis of, 372–373
Hemangioma, infantile, 593–595, 596f immunohistochemistry, 402 gastric, 94–96, 95f
Hematopoietic stem cell transplantation in situ hybridization, 403 goblet cell–rich, 373f
(HSCT), 525 PD-1/PDL-1 in esophageal and gastric Hypersensitivity reactions, 531
Hematoxylin carcinomas, 403–404 Hypertension, portal
and eosin–stained section of failed specimen type, 402 duodenopathy in, 128
pancreatic transplant excision, 686f Heterotopia esophageal varices in, 25–26
and eosin–stained section of pancreas, 684f gastric gastropathy in, 86t, 87, 88f
and eosin–stained section of pancreas differential diagnosis of, 128 Hypertrophied anal papilla. See Anal tag
allograft biopsy, 686f in esophagus, 15f
Hemochromatosis, 539t pancreatic, 97–99, 98f
Hemorrhagic gastritis, acute, 53 differential diagnosis of, 98–99 I
Hemorrhoids, 410, 411f sebaceous gland, in esophagus, 15f Idiopathic duct-centric chronic pancreatitis,
Hepatic adenoma (HA), of liver neoplasms, Heterotopic sebaceous glands, in esophagus, 460
557, 560–564, 561f, 562f 15, 15f Idiopathic inflammatory bowel disease,
classification of, 562t HFE mutation, 539 299–300
Hepatic adenomatosis, 560–561 Hidradenoma papilliferum, 423, 424f Idiopathic posttransplant chronic hepatitis.
Hepatic angiomyolipomas, 598, 599f differential diagnosis of, 423 See Posttransplant chronic hepatitis
Hepatic angiosarcoma (HAS), 600–601 High-grade appendiceal mucinous IgG4 cholangitis, 520
Hepatic artery, tissue adjacent to, 487 neoplasms, 228 IgG4-related esophageal disease, 9
Hepatic artery stenosis (HAS), 669–670 differential diagnosis of, 229–231 IgG4 sclerosing cholangitis, 447
Hepatic artery thrombosis (HAT), 669–670, Hirschsprung’s disease, colitis in, differential Ileal pouch enteritis, 314–315
671f diagnosis of, 328 differential diagnosis of, 314–315
Hepatic granulomas, in liver, 537 Histiocytic infiltrates in histoplasmosis, 279, Ileitis
Hepatic iron index (HII), 541 279f backwash, 301–302
Hepatic lymphoma, primary, 606–607, 607f Histiocytosis, Langerhans’ cell, differential terminal. See Crohn’s disease
Hepatic manifestations, glycogen storage diagnosis of, 73 Ileocecal tuberculosis, 267
diseases with, 547t Histologic patterns of liver injury Ileum, 161
Hepatic mass lesions, 558t acute, 489–490 Immune checkpoint receptor inhibitor–
Hepatic venous outflow obstruction acute viral (hepatotropic) hepatitis, 491 associated colitis, 331–332
(HVOO), 523, 671–672 alcoholic liver disease, 509–513 Immunohistochemistry
Hepatis, peliosis, 530 autoimmune hepatitis, 502–505 in celiac disease, 121
Hepatitis chronic hepatitis pattern of injury, 496–498 in deciduosis of gastrointestinal tract,
acute viral (hepatotropic), 491 chronic viral hepatitis, 498–502 222–223
autoimmune, 502–505 fatty liver disease/steatohepatitis pattern in endometriosis of gastrointestinal tract,
viral, 491t of injury, 505 222–223
Hepatitis B core antigen (HBcAg), 501 nonalcoholic fatty liver disease, 505–509 in fibroblastic polyps of colon, benign, 190
Hepatitis B virus (HBV), 499 nonhepatotropic viral infections, 493 in fibromatosis, 199, 199f
Hepatitis C virus (HCV) genotype 3 major, 489 in gastrointestinal stromal tumors,
infection, 499 Histoplasma capsulatum, 537f 171–172
Hepatobiliary cystadenomas, 452–453, 584 Histoplasmosis, colonic, 278–280, 279f in lymphangioma, 205–206
Hepatoblastoma, of liver neoplasms, differential diagnosis of, 274t, 287 in MALT lymphomas, 616
575–578, 576f, 577f HIV infection in neurofibroma, 191
Hepatocanalicular cholestasis, 513 adenovirus infection in, 247 in PEComa, 207
Hepatocellular carcinoma (HCC), 557, 568f, and AIDS enterocolopathy, 248, 249f in perineurioma, 190
570f, 573f anal condylomata in, 424 in schwannomas, 178
of liver neoplasms, 567–572 in Burkitt lymphoma, 638 in smooth muscle tumors, 177
698 INDEX
Immunoproliferative small intestinal disease, Interface hepatitis, 499 L

614–616, 620–623, 622b and lobular activity, 504f Lamina propria mucosae
Incidental pigmentation, 148–149 Interlobular bile ducts in PSC, 521f amyloid deposits in, 83f
pseudomelanosis duodeni, 149f Interval appendix, 214–215, 214f in autoimmune enteropathy, 134, 134f
Inclusions, cellular Intestinal disorders fibrosis in gastritis, 75
in adenovirus infection, 220–221, 221f, angina, 145 Langerhans’ cell histiocytosis, differential
247 metaplasia diagnosis of, 73
differential diagnosis of, 245 in Barrett’s esophagus, 33f Large duct obstruction, 513–516
Cowdry’s, in adenovirus infection, 220– Intestinal failure (IF), 676 Left-sided disease in ulcerative colitis, 301
221, 221f Intestinal metaplasia, of gallbladder, 436 Leiomyoblastomas, 172f
in cytomegalovirus infection, 244, 244f Intestinal-type neuroendocrine cells, 439f Leiomyoma, 176
herpetic, 246, 246f Intestines Leiomyosarcoma, 176, 178f
hyaline. See Mallory hyaline large. See Colitis; Colon; Colorectal cancer Leishmaniasis, visceral, 286
in microvillus inclusion disease, 135–136, small. See Small bowel disorders differential diagnosis of, 287
135f, 136f Intracholecystic papillary neoplasm (ICPN) Leukemia
owl’s eye, in cytomegalovirus infection, of gallbladder, 438–441 chronic lymphocytic, anorectal herpetic
244, 244f Intracholecystic papillary tubular neoplasm inclusions in, 246f
Indeterminate for rejection, 665–666 of gallbladder, 441f NK leukemia, differential diagnosis of,
Infantile hemangioendothelioma. See Intraductal papillary mucinous neoplasm 649–650
infantile hemangioma (IH) (IPMN), of pancreas, 466–469, 466f, Lichen planus, of esophagus, 8
Infantile hemangioma (IH), 593–595, 596f 467f Lichenoid esophagitis
Infectious disorders Intraductal papillary neoplasm of the bile Crohn’s disease, 8
colitis in, differential diagnosis of duct (IPNB), 449–450, 449f differential diagnosis of, 8
in Crohn’s disease, 312–313 Intraductal papillary neoplasms (IPNs), 584 graft-versus-host disease, 8
in diversion colitis, 322 Intraductal tubulopapillary neoplasm, of “Lipid hang-up” duodenal biopsy, 128–129,
in eosinophilic proctocolitis, 328 pancreas, 470–471, 470f 128f
in lymphocytic colitis, 317 Intraepithelial neoplasia, pancreatic, Lipogranulomas, 508
in ulcerative colitis, 307–308 464–466 Liver
enteritis in, 147 Intraluminal neutrophils, 514 acute hepatitis pattern of injury, 489–490,
esophagitis in, 14, 15f Intrapancreatic spleen, of pancreas, 456 490f
differential diagnosis of, 3, 6, 10–12 Invasive adenocarcinoma acute viral (hepatotropic) hepatitis, 491
in gastrointestinal tract, 243 of gallbladder, 441 alcoholic liver disease, 509–513
gastritis in, 71, 71f, 73f, 74f versus misplaced epithelium, 369–370 autoimmune hepatitis, 502–505
Infectious enteritis, 147 Invasive carcinoma, of extrahepatic bile chronic hepatitis pattern of injury,
Infiltrating adenocarcinoma, 471f ducts, 450–451 496–498
Inflammatory bowel disease, idiopathic, Invasive mucinous adenocarcinoma, in chronic viral hepatitis, 498–502
299–300 polyp, 370f fatty liver disease/steatohepatitis pattern
Inflammatory disorders Ipilimumab colitis, 331f of injury, 505
anal processes, 407–408 Iron-deficiency anemia in gastric antral nonalcoholic fatty liver disease, 505–509
bowel disease vascular ectasia, 84–85 nonhepatotropic viral infections, 493
chronic, differential diagnosis of, 317 Iron overload, in liver, 540–541 “almost normal” biopsy or nonspecific
Crohn’s disease, 309 Iron-related genes, common mutations in, findings, 535–537, 535t, 536f
pseudopolyps in, 351–352 539t hepatic granulomas, 537
ulcerative colitis, 301 Ischemia-reperfusion injury (IRI), 658 necrosis, 537–538
cloacogenic polyps Ischemic colitis, 319–321, 320f bile ducts, disorders of, 513
differential diagnosis of, 372–373 differential diagnosis of, 320–321 Budd-Chiari syndrome, 523, 523f
colitides in radiation colitis, 320–321 congestive (cardiac) hepatopathy, 524
collagenous colitis, 315, 316f in ulcerative colitis, 307–308 drug-induced liver injury, 530–531
diversion colitis, 323–324, 323f Ischemic disease, enteric, 142f, 145–147 hepatoportal sclerosis, 528
diverticular disease-associated colitis, Islet cell transplantation, 681 large duct obstruction, 513–516
324–325, 324f, 325f Islets of Langerhans, 455–456 nodular regenerative hyperplasia, 527
eosinophilic proctocolitis, 327f, 328 Isospora belli infection, 289 overlap syndromes, 522
ischemic colitis, 319–321, 320f Ito cell hyperplasia, 537 peliosis hepatis, 530, 530f
lymphocytic colitis, 318–319, 318f portal vein thrombosis or obstruction,
mucosal prolapse/solitary rectal ulcer 526–527
J
syndrome, 325–327, 326f primary biliary cholangitis, 516–519
Juvenile polyposis syndrome, 350–352,
radiation colitis, 320–321, 322f primary sclerosing cholangitis (PSC), 519
353f–354f
collagenous colitis, 316f sinusoidal obstruction syndrome (SOS),
differential diagnosis of, 351–352
pseudopolyps, differential diagnosis of, 525
351–352 vascular pattern of injury, 522–523
Inflammatory fibroid polyp, 183f K carcinoma of
differential diagnosis of, 183–184 Kala-azar, 286 hepatocellular. See Hepatocellular
Inflammatory myofibroblastic tumor, 202–205 Kayser-Fleischer rings, 542 carcinoma (HCC)
Injury, liver Keratinization, anal copper accumulation disorder, 542
acute hepatitis pattern of, 489–490 in condylomata, 424 glycogenic hepatopathy, 552–553
acute viral (hepatotropic) hepatitis, 491 in squamous cell carcinoma, 415–416, 417f glycogen storage diseases, 546
alcoholic liver disease, 509–513 in verrucous carcinoma, 429–430 porphyrias, 553–555
autoimmune hepatitis, 502–505 Keratoderma, nonepidermolytic Wilson’s disease, 542, 543f
chronic hepatitis pattern of injury, palmoplantar, 35 embryonal sarcoma of, 606f
496–498 Killian’s triangle, 20 major histologic patterns of injury, 489
chronic viral hepatitis, 498–502 Klatskin tumor, 448 metabolic diseases, 538
fatty liver disease/steatohepatitis pattern Klebsiella oxytoca infection, 267 hereditary hemochromatosis (HH), 539
of injury, 505 Koilocytes in anal condylomata, 424 iron overload, 540–541
nonalcoholic fatty liver disease, 505–509 KRAS mutations, 400, 441, 450–451, 465, secondary iron overload, 541–542, 542f
nonhepatotropic viral infections, 493 476, 585 T-cell lymphoma, hepatosplenic, 649–651,
major histologic patterns of, 489 Kupffer cells, 492, 561 650f, 651b
INDEX 699
Liver biopsy, 657 Low-grade mucinous carcinoma, 233 Malignant polyps, 367–369
Liver disease, alcoholic, 509–513 Lye strictures of esophagus. See Esophagus, Mallory bodies. See Mallory-Denk bodies
Liver injury patterns, drug-induced, 534t caustic injuries of Mallory-Denk bodies, 506–508, 515f
Liver necrosis, common entities associated Lymphangiectasia, intestinal, 147, 148f Mallory hyaline. See Mallory-Denk bodies
with, 538t Lymphangioma, 205–206, 205f Mallory-Weiss syndrome, 26
Liver neoplasms differential diagnosis of, 206 MALT lymphomas, 613–620, 620b
angiomyolipoma, 598–600 of duodenum, 205f differential diagnosis of, 57–58
bile duct adenoma, 579 Lymphocytic disorders immunoproliferative small intestinal
biliary tumors bile duct hamartoma, colitis, 318–319, 318f disease, 613–623
578–579 differential diagnosis of, 318–319 Mantle cell lymphoma, 624f, 626–629,
cholangiocarcinoma (CC), 586 gastritis, 69, 70f 627f–628f, 629b
combined hepatocellular– Lymphocytic esophagitis, 7f Massive hepatic necrosis, 532f–533f
cholangiocarcinoma (HCC–CCs), differential diagnosis of, 7 Massive parallel sequencing. See Next-
590–592, 591f Lymphocytosis, colonic epithelial, 317 generation sequencing (NGS)
dysplastic nodules (DNs), 564–567 Lymphoepithelial cyst, of pancreas, 456 Mast cell disease, differential diagnosis of, 73
embryonal sarcoma of the liver, 604–606 Lymphogranuloma venereum, colonic, 253t, Meckel’s diverticulum, ectopic pancreatic
epithelial tumors hepatocellular tumors 270–271 tissue in, 456f
focal nodular hyperplasia, 557 Lymphoma kinase, anaplastic, in inflammatory Medullary carcinoma, colorectal, 385–386,
epithelioid hemangioendothelioma, myofibroblastic tumor, 203, 203f 386f, 471–472, 472f
602–604 Lymphoma(s) Megamitochondria, 508
fibrolamellar carcinoma, 572–575 of anus, differential diagnosis of, 419–420 Melan-A stain in melanoma of anus, 421–422
hepatic adenoma (HA), 560–564 B-cell Melanoma, of anus, 421, 422f
hepatoblastoma, 575–578 Burkitt lymphoma, 624f, 638–641 differential diagnosis of, 418, 422
hepatocellular carcinoma, 567–572 diffuse large, 613, 630–632, 631b, Melena in glomus tumors, 196
infantile hemangioma (IH), 593–595 631b–632b, 634f–635f, 640 Ménétrier’s disease, 79, 79f, 80f
macroregenerative nodules (MRNs), extranodal marginal zone. See MALT differential diagnosis of, 59, 80, 95–96, 358
564–567 lymphomas Mesenchymal hamartoma, of liver
malignant angiosarcoma, 600–602 follicular, 623–626, 624f neoplasms, 595, 597f, 598f
mesenchymal hamartoma, 595 gastrointestinal, 613 Mesenchymal sarcoma. See Embryonal
mesenchymal tumors benign hemangioma, hepatic, 607f sarcoma of liver
592–593 immunoproliferative small intestinal Mesenchymal tumors, 169
metastases, 607–611 disease, 613, 620–623 fibroblastic polyps of colon, benign,
mucinous cystic neoplasm, 584 MALT lymphomas. See MALT lymphomas 189–191, 189f, 190f
polycystic liver disease, 583–584 mantle cell, 624f, 626–629, 627f–628f fibromatosis, intra-abdominal, 198–200, 198f
primary hepatic lymphoma, 606–607 NK lymphoma, differential diagnosis of, gangliocytic paraganglioma, 194–196,
solitary biliary cyst, 580–583 649–650 194f, 195f
Liver transplantation, 657 T-cell, 643–647, 646b ganglioneuroma, 192–194, 193f
acute cellular rejection, 663–668 enteropathy-associated, 125, 643–647, differential diagnosis of, 190–192
differential diagnosis of, 666–667 644f–645f, 646b glomus, 196–198, 197f
antibody-mediated rejection, 660 hepatosplenic, 649–651, 650f, 651b gastric, differential diagnosis of, 116
differential diagnosis of, 661–663 Lymphomatosis polyposis, 360 inflammatory fibrosarcoma/inflammatory
biliary complications of, 672 Lymphoplasmacytic inflammation, intact myofibroblastic tumor, 202–205, 203f
chronic ductopenic rejection, 668–669 villi with, 120 neurofibroma
differential diagnosis of, 668–669 Lynch syndrome, 380–383, 395–397 differential diagnosis of, 193
complications of, 669–670 Lysosomal storage diseases, 549t, 550t, 551f perineurioma, 189–191, 189f, 190f
hepatic artery stenosis (HAS), 669–670 schwannomas, 186–189, 187f, 188f
hepatic artery thrombosis (HAT), differential diagnosis of, 191–192
669–670, 671f M sclerosing mesenteritis, 200–202, 201f
congestive hepatopathy, 671–672 Macrocephaly, multiple lipomas, and smooth muscle, 176–179, 177f
differential diagnosis of, 659 hemangiomata syndrome, 352 stromal, 169–176. See also Gastrointestinal
hepatic venous outflow obstruction Macrophages stromal tumors (GISTs)
(HVOO), 671–672 tangible body, in Burkitt lymphoma, 623, Mesenchymal tumors benign hemangioma,
laboratory findings of, 658–660 624f of liver neoplasms, 592–593
portal hyperperfusion (PHP), 670–671 Macroregenerative nodules (MRNs), Mesenchymal tumors of gallbladder and
preservation/ischemia-reperfusion injury, 523–524, 564–567 extrahepatic bile ducts, 453
658 Macrovesicular steatosis, 506f–507f, 532f–533f Mesenteric artery/hepatic artery, tissue
pretransplant donor evaluation, 657–658 Magnetic resonance adjacent to, 487
recurrent disease, 672–676 cholangiopancreatography (MRCP), Mesenteric disorders
fibrosing cholestatic hepatitis (FCH), 446–447 acute ischemia, 142f
673 Major histologic patterns of injury, in liver, epithelioid tumors, 170, 172f
opportunistic infections, 675–676, 676f 489 fibromatosis, 198f
posttransplant lymphoproliferative Malabsorptive disorders, 120 Mesenteritis, sclerosing, 200–202, 201f
disorder (PTLD), 675 celiac disease, 121–122 Metabolic diseases, in liver, 538
recurrent autoimmune hepatitis, 674 Malacoplakia, 220f hereditary hemochromatosis (HH), 539
recurrent fatty liver disease, 675 in appendicitis, 219–220 iron overload, 540–541
recurrent primary biliary cholangitis, appendicitis in, 220f secondary iron overload, 541–542, 542f
674 Malignancies. See Neoplasms Metachromatic leukodystrophy, 549t, 550t
recurrent viral hepatitis C, 673 Malignant angiosarcoma, of liver neoplasms, Metaplasia
small-for-size graft syndrome (SFSS), 600–602 of gallbladder, 436
670–671 Malignant colon polyp, lymphovascular intestinal, 436
Lobular disarray, 504f invasion in, 369f gastric foveolar, in peptic duodenitis, 127,
Lobular neutrophils, 508 Malignant gastrointestinal neuroectodermal 127f, 128f
Low-grade appendiceal mucinous neoplasms, tumor, 180–182, 181f intestinal
228, 228f, 229f differential diagnosis of, 181–182 in Barrett’s esophagus, 33f
differential diagnosis of, 229–231 Malignant mesenchymoma. See Embryonal pancreatic acinar, in gastric biopsies, 65
Low-grade B-cell lymphomas, 608f sarcoma of liver Paneth cell, differential diagnosis of, 65
700 INDEX
Metastases to colorectum, 390 Mucinous cystadenoma, 225 Neoplasms (Continued)

Metastatic carcinoma, 609f Mucinous cystic neoplasms (MCNs), mucinous. See Mucinous neoplasms
Metastatic colon cancer, 609f 452–453, 585f, 586f in Peutz-Jeghers syndrome, 346–347
Metastatic melanoma, 164f of liver, 469f, 584 small intestinal, 151
Metastatic tumors, of liver neoplasms, of pancreas, 469–470 of stomach, 91
607–611 Mucinous cysts, simple Neoplastic cells, 603f, 604f
Metastatic well-differentiated of pancreas, 456–457 Neoplastic pancreatic ductal lesions, 464–474
neuroendocrine tumors, 610f Mucinous neoplasms ductal neoplasms, 464–466
Methotrexate, Roenigk scoring system for, appendiceal, 229f, 234f, 240f intraductal papillary mucinous
534t carcinoma neoplasm (IPMN), 466–469
Michaelis-Gutmann bodies in malacoplakia, colorectal, 383, 384f intraductal tubulopapillary neoplasm,
99–100, 220f Mucinous non-neoplastic cyst, 456–457 470–471
Micropapillary carcinoma, 385, 385f Mucolipidoses, 549t, 550t mucinous cystic neoplasm, 469–470
Microsatellite instability-high carcinoma Mucopolysaccharidoses (MPS), 549t, 550t pancreatic ductal adenocarcinoma,
(MSI-H), 380, 396–397 Mucormycosis, colonic, 276, 277f 471–474
Microsatellite instability testing, of colorectal differential diagnosis of, 274t pancreatic intraepithelial neoplasia,
carcinoma, 395–396 Mucosa-associated lymphoid tissue. See 464–466
Microsporidia infection, 288–289, 289f MALT lymphomas precursor lesions, 464
Microvesicular steatosis, 506f–507f, Mucosal calcinosis, gastric, 76 Neuroendocrine carcinoma (NECs), 475–476
532f–533f Mucosal neuroma, differential diagnosis of, of ampulla, 163–164
Microvillus inclusion disease (MVID), 191–192 of small intestine, 163–164
135–136, 135f, 136f Mucosal prolapse, 370f, 373f of pancreas, 476
Miscellaneous patterns of injury, in liver, 535 with solitary rectal ulcer, 325–327, 326f Neuroendocrine cells, 584
“almost normal” biopsy/nonspecific Mucosal Schwann cell hamartoma, 191–192, Neuroendocrine neoplasms, of esophagus, 48
findings, 535–537, 535t, 536f 191f Neuroendocrine tumor (NET), 161–162, 452f,
hepatic granulomas, 537 differential diagnosis of, 191–192 455–456. See also Carcinoid tumors
necrosis, 537–538 Muir-Torre, syndrome, 381 appendiceal, 235
Mismatch repair function, assessment of, Multilocular lymphoepithelial cyst, 458f colorectal, 391–393, 392f
395–400, 396t Multiple endocrine neoplasia differential diagnosis of, 393
immunohistochemistry interpretation, type I differential diagnosis, 163
396t colorectal, 391 gangliocytic paraganglioma, 163f
microsatellite instability-high carcinoma, gastrinomas, 81 gastric, 114–117
396–397 type II, 360 differential diagnosis of, 98–99
mismatch repair immunohistochemistry multiple neuroma syndrome in, 360 of pancreas, 474–476
in, 397–399 type IIB, diffuse ganglioneuromatosis in, neuroendocrine carcinomas, 476
molecular testing in colorectal carcinoma, 192, 193f well-differentiated, 474–476
future directions of, 400 Multiple hamartoma syndrome. See Cowden’s of small bowel, 162f
polymerase chain reaction–based syndrome of small intestine, 160–163
microsatellite instability testing, Multiple neuroma syndrome, 360 tubular pattern of, 236f
395–396 Murphy sign, 435 well-differentiated, 236f
RAS, extended RAS, and BRAF testing, Mycobacterial infection, of gut, 267–269 Neurofibroma, 190
399–400 Mycobacterium avium-intracellulare complex differential diagnosis of, 190, 193
Mismatch repair immunohistochemistry, infection, 268f Neurofibromatosis type 1, 360. See also von
397–399 Mycobacterium avium-intracellulare infection Recklinghausen’s disease
Mixed neuroendocrine–non-neuroendocrine of colon, 253t Neuroma, multiple, 360
neoplasm (MiNEN), 163–164 differential diagnosis of, 269 Neutrophilic inflammation, intact villi with,
Mixed tumors, of pancreas, 483–484 differential diagnosis of, 99–100, 147 119
mixed acinar–ductal and ductal– Mycobacterium tuberculosis infection. See Neutrophils, 489
neuroendocrine carcinoma, 484 Tuberculosis Next-generation sequencing (NGS), 400
mixed acinar–neuroendocrine carcinoma, Mycophenolate mofetil (MMF) colitis, Niemann-Pick disease, 549t, 550t
484 330–331, 330f NK leukemia/lymphoma, differential
mixed ductal–neuroendocrine carcinoma, Myeloablative high-dose chemoradiation diagnosis of, 649–650
484 treatment, 525 Nocardia infection, differential diagnosis of,
MLH1 immunostain, 399f Myofibroblastic tumor, inflammatory, 272–273
MMR gene, 398 202–205, 203f Nodular regenerative hyperplasia (NRH), in
Model for End-Stage Liver Disease (MELD) Myxoid stroma in IH, 595 liver, 523–524, 527, 528f
score, 660 Nonalcoholic fatty liver disease (NAFLD),
Molecular alterations, 378–379 N 499, 505–509, 506f
Molecular oncology testing, in colorectal Necrosis pediatric, 508
carcinoma, 400 of colorectal cancer, 384f Nonalcoholic steatohepatitis (NASH), 505
Molecular pathways, for colorectal in liver, 537–538 Noncirrhotic portal hypertension, 528
carcinogenesis, 380 Necrotizing disorders Nonhepatotropic viral infections, in liver, 493
Molecular testing in colorectal carcinoma, enterocolitis, 264 Non-neoplastic diseases of pancreas,
future directions of, 400 differential diagnosis of, 266, 328 455–458
Motility disorders, esophageal, 22–24, 23f, 25f Necrotizing enterocolitis, 265f, 266f benign cystic lesions in pancreas, 456–458
MSH6 immunostain, 399f Neisseria gonorrhoeae, 253t, 271 congenital cysts, 457
MTOR (mammalian target of rapamycin) Nematode infections, 291 duodenal diverticulum, 458
pathway, 474 Neoplasia, of gallbladder, 437 simple mucinous cysts, 456–457
Mucin Neoplasms developmental anomalies, 455
extracellular “adenocarcinoid” tumors, 237, 240 annular pancreas, 455
in adenocarcinoma of anus, 419 bronchogenic carcinoma, esophageal ectopic pancreas, 455
inspissated eosinophilic, in cystic fibrosis, varices in, 25–26 pancreatic divisum, 455
219, 219f colorectal epithelial, 363. See also intrapancreatic spleen and epidermoid
stains in Paget’s disease of anus, 432 Colorectal epithelial neoplasms cyst, 456
Mucin-depleted hyperplastic polyp, 373f of esophagus, 29 lymphoepithelial cyst, 456
Mucinous (colloid) adenocarcinomas, 383 differential diagnosis of, 10 pancreatic hamartoma, 455–456
INDEX 701
Non-neoplastic disorders, of colon, 299–335 Pancreas (Continued) Pancreatoblastoma, of pancreas, 479–480,

Nonresponsive celiac disease, 124–125 acute pancreatitis, 458–459 479f
Nonsteroidal anti-inflammatory drug- autoimmune pancreatitis (AIP), Paneth cells, 439f
associated injury. See NSAID injury 460–463, 462b in adenomatous polyps, 365
NSAID injury, 130–131, 130f chronic pancreatitis, 459–460 in autoimmune enteropathy, 134–135
colitis, 333–334 pseudocysts, 463–464 in gastric adenomas, 102
differential diagnosis of, 131 tumors with acinar differentiation, metaplasia of, differential diagnosis of, 65
and peptic duodenal disease, 126, 129 476–484 in Peutz-Jeghers syndrome, 346–347
Nuclear β-catenin in fibromatosis, 199, 199f acinar cell carcinoma, 476–479 Papilloma, esophageal, squamous, 30–31, 30f
Nutcracker esophagus, 22 acinar cell cystadenocarcinoma, 479 Papillomavirus infection and esophageal
acinar cell cystadenoma, 476 papillomatosis, 30f
O mixed acinar–ductal and ductal– Paraduodenal/“groove” pancreatitis,
Obliterative phlebitis, 460–461 neuroendocrine carcinoma, 484 462–463, 463b
Odynophagia, in caustic esophageal injury, mixed acinar–neuroendocrine Paraduodenal pancreatitis, 463, 463f
14 carcinoma, 484 Paraganglioma, gangliocytic, 194–196
in eosinophilic esophagitis, 4 mixed ductal–neuroendocrine differential diagnosis of, 193, 195
in esophageal webs, 14 carcinoma, 484 Parasitic infection, 283
in radiation esophagitis, 14 pancreatoblastoma, 479–480 appendicitis in, 220
Olmesartan-associated sprue-like serous cystadenocarcinoma, 482 Enterobius vermicularis, 220, 220f
enteropathy, 131–132, 132f serous cystadenoma (SCA), 480–482 Parasitic infestations, eosinophilia in, 72, 74f
Omental stromal tumors, 169 solid-pseudopapillary neoplasm (SPN), Parenchymal margin, 485–486
Opisthorchis viverrini, 448 482–483 Parietal cell hyperplasia from proton pump
Opportunistic infections, 675–676, 676f Pancreas transplantation, 681 inhibitors, 92f
Overlap syndromes, in liver, 522 cell-mediated rejection, 684–686 Patchy glycogenosis, 508
“Owl’s eye” inclusions in cytomegalovirus mild acute antibody-mediated rejection, Paucicellular inflammation, intact villi with,
infection, 244 685 120
Oxyntic gland adenoma, stomach mild acute T cell-mediated rejection, 684 PEComa, 206–209, 207f
differential diagnosis of, 106 moderate acute antibody-mediated differential diagnosis of, 208
rejection, 685–686 Pediatric nonalcoholic fatty liver disease, 508
moderate acute T cell-mediated Pediatric steatohepatitis, 508f
P rejection, 684–685 Pedunculated ampullary adenoma, 160
Paget cell, 431, 432f severe acute antibody-mediated Peliosis hepatis, in liver, 530, 530f
signet ring type of, 431, 432f rejection, 686 Penicillium marneffei infection, 280
Paget’s disease of anus, 431, 432f severe acute T cell-mediated rejection, Peptic duodenal diseases, 126–129, 127f,
adenocarcinoma with, 431 685 128f
differential diagnosis of, 432 chronic graft fibrosis, 686–687 Peptic duodenitis, 152f
Pain, abdominal. See Abdominal pain differential diagnosis of acute rejection, Peptic ulcer disease in Zollinger-Ellison
Pancolitis, 301 687 syndrome, 80
Pancreas islet pathology, 686–687 Perforations, esophageal, 25–27
acinar metaplasia in gastric biopsies, 65 chronic rejection and graft fibrosis, 686 Perianal skin
frozen section, 484–487, 486f, 487f chronic antibody-mediated rejection, squamous cell carcinoma of, 428–429, 429f
bile duct margin, 486–487 686 tumors and precursor lesions of, 423
pancreatic ductal adenocarcinoma chronic arteriopathy, 686 Perianal squamous neoplasia, 412
diagnosis on, 485 posttransplant needle core biopsy, Peribiliary glands, 487
parenchymal margin, 485–486 evaluation of, 681–684 Pericellular fibrosis, 515f
resection margins, evaluation of, allograft dysfunction, 682–684 Perineurioma, 189–191, 189f, 190f
485–487 immunologic factors, 682 Periodic acid-Schiff reaction, in granular cell
superior mesenteric artery/hepatic normal allograft biopsy, 682–684 tumors of anus, 431
artery, tissue adjacent to, 487 technical failure, 682 Periodic acid–Schiff (PAS) stain, 471
heterotopia of, 97–99, 98f types of, 678 Periodic acid–Schiff with diastase (PAS-D)
differential diagnosis of, 65 islet cell transplantation, 681 stain, 489
neoplastic diseases, 464–474 whole-organ transplants, 681 Peripancreatic abscess formation, 687
intraductal papillary mucinous Pancreatic divisum, 455 Peripheral/intrahepatic cholangiocarcinoma,
neoplasm (IPMN), 466–469 Pancreatic ductal adenocarcinoma (PDAC), 587f
intraductal tubulopapillary neoplasm, 455–456, 471f, 473f Periportal hepatocytes, eosinophilic
470–471 Pancreatic hamartoma, 457f cytoplasmic inclusions in, 545f
mucinous cystic neoplasm, 469–470 Pancreatic heterotopia, 152f, 153 Peutz-Jeghers syndrome, 346–348, 347f,
pancreatic ductal adenocarcinoma, differential diagnosis, 153 348f, 349f–350f
471–474 groove pancreatitis, 153 differential diagnosis of, 348–350
pancreatic intraepithelial neoplasia, of small intestine, 153 in Cronkhite-Canada syndrome, 358
464–466 Pancreatic intraepithelial neoplasia (PanIiN) in gastric hyperplastic polyps, 95–96
precursor lesions, 464 lesion, 465f in juvenile polyposis syndrome, 351–352
neuroendocrine tumors, 474–476 Pancreatic neuroendocrine carcinomas Peyer’s patches
neuroendocrine carcinomas, 476 (PanNECs), 475–476 in histoplasmosis, 279
well-differentiated neuroendocrine Pancreatic neuroendocrine tumors in typhoid fever, 256
tumors, 474–476 (PanNETs), 474, 475f in Yersinia infection, 260
non-neoplastic diseases of, 455–458 Pancreaticobiliary neoplasm, 160 Phycomycosis, colonic, 276
congenital cysts, 457 Pancreatitis, 458–464, 687 Piecemeal necrosis, 499
developmental anomalies, 455 acute, 458–459, 458f Pigmented tumors in melanoma of anus, 421
duodenal diverticulum, 458 autoimmune, 461b, 461f, 462b PIK3CA mutations, 470
intrapancreatic spleen and epidermoid autoimmune pancreatitis (AIP), 460–463, Pill esophagitis, 11–12, 12f
cyst, 456 462b differential diagnosis of, 3, 11–12
lymphoepithelial cyst, 456 chronic, 459–460, 459f, 460b Pinworms, 290f, 291
pancreatic hamartoma, 455–456 paraduodenal/“groove,” 462–463, 463b, Plasma cell hepatitis, 664
simple mucinous cysts, 456–457 463f Plasma cell–rich rejection, 664
pancreatitis, 458–464 pseudocysts, 463–464 diagnostic criteria for, 665t
702 INDEX
Plexiform fibromyxoma, 185f Primary intestinal lymphangiectasia, 148f Roenigk grade, 533
differential diagnosis of, 185 Primary sclerosing cholangitis (PSC), 519f Roenigk scoring system for methotrexate,
Plummer-Vinson syndrome, 20 of gallbladder, 446–447, 448f 534t
and squamous cell carcinoma of in liver, 515–516, 519 Rokitansky-Aschoff sinuses, 436
esophagus, 34–35 Proctitis in cholecystitis, 436, 438f, 442–443, 446
Polycystic liver disease, 583–584, 583f herpetic, 246 of gallbladder, 442–443, 446
Polymerase chain reaction–based syphilitic, 269 Roundworms, 292, 293f
microsatellite instability testing, Proctocolitis, eosinophilic, 327–328, 327f Rrokitansky-Aaschoff sinuses, 438f
395–396 Prolapse, mucosal
Polypoid mucosal prolapse, 373f with solitary rectal ulcer, 325–327, 326f S
Polyposis syndromes, 337 Proton pump inhibitors, parietal cell Saccharomyces cerevisiae antibody, test for,
adenomatous, 337–343 hyperplasia from, 92f 311–312
classification of, 338t Protozoal infections, 283 Salmonella infection, 253t, 255
Cowden’s syndrome, 352–357, 357f Pruritus, anal, in enterobiasis, 291 differential diagnosis of, 256–257, 261
Cronkhite-Canada, 357–360 Pseudocysts, 463–464, 464f Sarcina infection, 249–250, 250f
familial adenomatous, 340f, 341f Pseudodiverticula, esophageal, differential differential diagnosis of, 250
hereditary mixed, 360 diagnosis of, 21 Sarcoidosis
hyperplastic, 343 Pseudodiverticulosis, diffuse esophageal differential diagnosis of, 281–283
juvenile, 350–352, 353f–354f intramural, differential diagnosis granulomatous gastritis in, 68, 69f
differential diagnosis of, 95–96 of, 21 Sarcoma, embryonal, 604–606
Peutz-Jeghers. See Peutz-Jeghers syndrome Pseudomembranous colitis, 265 Sausage-shaped pancreas, 460
serrated, 343–346 differential diagnosis of, 266, 294 Scattered mononuclear infiltrates within
Polyp(s) Pseudomonas infection, differential diagnosis portal tracts, 535–536
adenomatous, 363–365, 384f. See also of, 272–273 Schatzki’s ring, 20
Adenomatous polyps Pseudomyxoma peritonei, 233–235, 234f Schistosomiasis, 295
of colon, benign fibroblastic, 189–191, Pseudopolyps, inflammatory, differential granulomatous gastritis in, 67t, 69f
189f, 190f diagnosis of, 351–352 Schwann cell hamartoma, 192
esophageal, fibrovascular, 30–31 Pseudotumor, 460–461 Schwannomas, 186–189, 187f, 188f
esophageal, giant fibrovascular, 31f Pyloric antrum, vascular ectasia of, 84, 85f, differential diagnosis of, 191–192
fundic gland, 91–94, 92f 86t esophageal achalasia in, 22, 24–25
differential diagnosis of, 91–94 differential diagnosis of, 86t lamina propria fibrosis in, 75
gastric amyloidosis, differential diagnosis Pyloric gland, of gallbladder, 436 Sclerosing cholangitis, primary, 519
of, 57 Pyloric gland adenoma, 104–106, 153–154, Sclerosing hyaline necrosis, 511
gastric hyperplastic, 94–96, 95f 154f Sclerosing mesenteritis, 200–202, 201f
differential diagnosis of, 80, 94–96 of small intestine, 153 Sclerosis, hepatoportal, 528, 529f
hyperplastic, 371–374, 371f, 372f Pyloric gland metaplasia, 439f Secondary iron overload, in liver,
differential diagnosis of, 372–373 541–542
inflammatory cloacogenic, differential R Secondary tumors
diagnosis of, 372–373 Radiation colitis, 321–323, 322f differential diagnosis of, 50
neurofibroma, 190 differential diagnosis of, 322 of esophagus, 49–50
Porcelain gallbladder, 435–437, 439f Radiation-induced disorders of small intestine, 164–167
Porphyria cutanea tarda (PCT), 553, 554f colitis, 320–321, 322f Sentinel tag, anal, 407–408
Porphyrias, in liver, 553–555 differential diagnosis of, 317, 320–321 Serous cystadenocarcinoma, of pancreas,
Portal-based fibrosis, 501f esophagitis, 9 482
Portal hyperperfusion (PHP) injury, 670–671 gastritis, differential diagnosis of, 75 Serous cystadenoma (SCA), of pancreas,
Portal hypertension Rectum, solitary ulcer with mucosal 480–482, 481f
duodenopathy in, 128 prolapse, 325–327, 326f Serrated adenocarcinomas, 383
esophageal varices in, 25–26 differential diagnosis of, 326–327 Serrated adenomas
gastropathy in, 86t, 87, 88f Recurrent autoimmune hepatitis, 674 sessile, 374–377
Portal tracts, 527f Recurrent fatty liver disease, 675 differential diagnosis of, 372–373
scattered mononuclear infiltrates within, Recurrent hepatitis C, 669–670 traditional (colorectal), 377–378, 378f
535–536 Recurrent primary biliary cholangitis, 674 Serrated colorectal polyps, 371
Portal vein thrombosis/obstruction, in liver, Recurrent primary sclerosing cholangitis, of appendix, 226, 227f
526–527 673–674 Serrated polyposis syndrome (SPS),
Positive staining, 402 Recurrent viral hepatitis C, 673 343–346, 344f, 379
Posttransplant chronic hepatitis, 664 Reflux disease, gastrointestinal (GERD), 1, differential diagnosis of, 346
Posttransplant lymphoproliferative disorder 2f, 3f dysplasia in, 345f
(PTLD), 675 Reflux esophagitis, 1, 2f, 3f serrated polyps in, 345f
Posttransplant needle core biopsy, evaluation Refractory celiac disease, 124–125 Serrated polyps
of, 681–684 Rejection Activity Index, 665–666, 666t differential diagnosis, 156
allograft dysfunction, 682–684 Rendu-Osler-Weber disease, 593 of small intestine, 154–157
immunologic factors, 682 Resection margins, evaluation of, 485–487 Sessile serrated adenomas, 374–377
normal allograft biopsy, 682–684 bile duct margin, 486–487 differential diagnosis of, 372–373
technical failure, 682 parenchymal margin, 485–486 Shigellosis, 253t, 257
Precursor lesions, of pancreas, 464 superior mesenteric artery/hepatic artery, differential diagnosis of, 258
Precursor neoplasia, of extrahepatic bile tissue adjacent to, 487 Signet ring cell carcinoma, 471–472
ducts, 449–450 Reticulin stain, 528f colorectal, 383, 385f
Preservation/ischemia-reperfusion injury, Rhabdomyosarcoma gastric, differential diagnosis of,
658 botryoid embryonal, of extrahepatic bile 99–100
Primary biliary cholangitis (PBC), 516–519, ducts, 453 Signet-ring type of Paget cell, 431, 432f
667 Rhodacoccus equi infection, 253t Simple mucinous cysts, of pancreas,
Primary biliary cirrhosis, 517f Rhodanine/orcein stains, 518 456–457, 458f
Primary disease, recurrence of, 679 Rhodococcus equi infection, 269 Sinusoidal lymphocytosis, 494
Primary hepatic lymphoma, of liver Rituximab, 531 Sinusoidal obstruction syndrome (SOS), in
neoplasms, 606–607 RNF43 gene, 467 liver, 525, 526f, 532f–533f
INDEX 703
Sloughing esophagitis, 12–14, 13f Small intestine (Continued) Stomach (Continued)

differential diagnosis of, 13 neuroendocrine tumors of small intestine, amyloidosis, 64–67, 83f, 84f
Small bowel allografts 160–163 differential diagnosis of, 75
acute cellular rejection in, 678t pancreatic heterotopia, 152f, 153 antral vascular ectasia of, 84, 85f, 86f, 86t
antibody-mediated rejection, 679f pyloric gland adenoma, 153–154, 154f differential diagnosis of, 88
chronic rejection, 680f secondary tumors of small intestine, autoimmune gastritis, 64, 64t, 67t
mild acute cellular rejection, 678f 164–167 chemical gastropathy, 56
severe acute cellular rejection, 679f serrated polyps, 154–157 collagenous gastritis, 74, 75f
Small bowel disorders, 119 Smoking Dieulafoy’s lesion of, 88
adenocarcinomas, of ampulla of Vater, and gastric adenocarcinoma, 107 doxycycline gastritis, 78
157–160, 157f, 159t and peptic duodenal diseases, 129 dysplasia of, epithelial, 101–104
autoimmune enteropathy, 134f Smooth muscle cells in glomus tumors, eosinophilic gastritis, 72, 74f
bacterial overgrowth, 129–130, 129f 196 gastric amyloidosis, 82
celiac disease, 121–122 Smooth muscle tumors, 176–179, 177f gastric carcinomas of, 100–101
clear cell sarcoma-like tumor, 180–182 Smudgy nuclear inclusions, 71f gastric Crohn’s disease, 68
collagenous sprue, 125 Solid-pseudopapillary neoplasm (SPN), of gastric peptic ulcer disease, 63
common variable immunodeficiency, 132 pancreas, 482–483, 483f gastric polyps in, 91
Crohn’s disease, 137–138 Solitary biliary cyst, of liver neoplasms, gastric secondary tumors of, 113
enteric ischemic disease, 142f 580–583 gastritis cystica polyposa, 96–97
flattened villi pattern of, 119 Solitary rectal ulcer syndrome, mucosal glomus tumors of, 196–198, 197f
granular cell tumor, 179–180 prolapse in, 325–327, 326f differential diagnosis of, 116
GVHD. See Graft-versus-host disease differential diagnosis of, 326–327 granulomatous gastritis, 67–68, 67t, 68f,
immunoproliferative small intestinal Somatostatin-producing NETs, 161 69f, 70f
disease, 613, 620–623 Spastic disorders, esophageal, 22–23 Helicobacter pylori gastritis, 57, 58t, 59f,
infectious enteritis, 147 Sphincterotomy of the minor papilla, 455 60f, 61f, 61t
inflammatory fibroid polyp, 182–184 Spindle cells heterotopia
intact villi pattern of, 119–120 in gangliocytic paraganglioma, 195, 195f differential diagnosis of, 128
lymphangiectasia, 147–148, 148f in ganglioneuroma, 192, 193f pancreatic, 97–99, 98f
malabsorptive disorders in inflammatory myofibroblastic tumor, infectious gastritis, 71, 71f, 73f, 74f
celiac disease, 120 203 linitis plastica, 108, 108f
microvillus inclusion disease, 135–136, in obliteration of appendiceal lumen, lobular metastatic carcinoma of, 113f
135f, 136f 211–213 lymphocytic gastritis, 69, 70f
neoplasms, 151 in perineurioma, 189–190, 189f Ménétrier’s disease of, 79, 79f
nonresponsive celiac disease, 124–125 in smooth muscle tumors, 176–179, 177f mucosal calcinosis of, 76
nonsteroidal anti-inflammatory drug- Spirochetosis, intestinal, 253t, 271, 272f neoplasms of, 91
associated injury, 130–131 Spleen, hepatosplenic T-cell lymphoma, 649, neuroendocrine tumors of, 100–101, 114–117
olmesartan-associated sprue-like 650f differential diagnosis of, 116
enteropathy, 131–132 Spleen, intrapancreatic (of pancreas), 456 non-neoplastic disorders of, 53
pattern-based approach of, 120 Splendore-Hoeppli material in actinomycosis, oxyntic gland adenoma of, 106–107
patterns of, 119–120, 120t 272 polyps in
flattened villi pattern, 119 Sporadic versus lynch syndrome, 396–397 fundic gland, 91–94, 92f
intact villi pattern, 119–120 Sporadic versus Lynch syndrome, 396–397 hyperplastic, 94–96, 95f
peptic duodenal diseases, 126–129, 127f, S-100 protein portal hypertensive gastropathy, 86t, 87,
128f in granular cell tumor of anus, 418 88f
plexiform fibromyxoma of, 184–186 in melanoma of anus, 421–422 pyloric gland adenoma, 104–106
refractory celiac disease, 124–125 Sprue schwannomas in, 186–189, 187f, 188f
sclerosing mesenteritis, 200–202, 201f celiac, 124 stromal tumors in, 169, 170f, 171f, 172f
smooth muscle tumors, 176–179 collagenous, 125 syndromic gastric cancer of, 112
stromal tumors, 169, 170f, 171f, 172f differential diagnosis of, 124 xanthomas in, 99–100, 99f, 100f
tropical sprue, 126 nontropical, 124 in Zollinger-Ellison syndrome, 80, 81f
Whipple disease, 147 tropical, 126 Stress gastritis, acute, 53
Small bowel transplantation, 676–677 Squamous cell carcinoma (SCC), 429f Strictures
acute cellular rejection, 677–679 of anal canal, 415–416, 417f in colonic tuberculosis, 267
allograft dysfunction, 677 differential diagnosis of, 418–420, 430f esophageal
antibody-mediated rejection, 679 colorectal, 383 in caustic injuries, 14–15, 15f
chronic rejection, 679–681 of esophagus, 42–45, 43f in eosinophilic esophagitis, 4
differential diagnosis of, 680 of perianal skin, 428–429, 429f in radiation injury, 9–10
Small-for-size graft syndrome (SFSS), 670–671 Squamous metaplasia, 584 Stromal tumors, gastrointestinal. See
Small intestinal adenocarcinoma, 155–156 Squamous papillomas, of esophagus, 29–30 Gastrointestinal stromal tumors
Small intestinal bacterial overgrowth, differential diagnosis of, 29–30 (GISTs)
129–130 Steatohepatitis, 506f–507f Strongyloides stercoralis infection, 293–294
Small intestinal inflammatory bowel disease, pediatric, 508f Strongyloidiasis, 294f
137 pattern of injury, in liver, 505 Submassive hepatic necrosis, 538f
Small intestine Steatosis, 505–506 Submassive/massive hepatic necrosis,
adenocarcinoma, 154–157 congenital esophageal, 19f 537–538
adenoma and adenocarcinoma of ampulla liver with, 510f Sulfur granules in actinomycosis, 272
of Vater, 157–160 macrovesicular, 506f–507f Surgical hepatitis, 489–490
Brunner’s gland hyperplasia, 151–152, microvesicular, 506f–507f Sweat chloride test for cystic fibrosis, 218
152f Sterile acalculous cholecystitis, of gallbladder, Synaptophysin
conventional adenoma, 154–157 435 in colorectal carcinoid tumors, 393
gangliocytic paraganglioma, 163, 163f Stomach. See also Gastritis in glomus tumors, 195
gastric heterotopia, 152–153, 152f acute erosive/hemorrhagic gastritis, 53, Syphilis, 269
hamartoma, 151–152 54f Systemic mastocytosis, 328–330, 329f
neuroendocrine carcinoma of small adenocarcinoma of, 107–114, 108f differential diagnosis of, 329
intestine, 163–164 adenomas of, 101–104 Systemic sclerosis, 24–25
704 INDEX
T Ulcerative colitis (Continued) Vibrio cholerae infection, 262

Tags, anal, 410 biopsy findings in, 302–304, 303f differential diagnosis of, 262
Target lesion in aspergillosis, 275, 276f chronic, 301f Viral hepatitis, 491t
T-cell lymphoma, 643–647, 646b cytomegalovirus (CMV) infection in, chronic, 498–502
enteropathy-associated, 125, 643–647, 304f Viral infections
644f–645f, 646b differential diagnosis of, 307–308 appendicitis in, 220–221, 221f
hepatosplenic, 649–651, 650f in Aeromonas infection, 263 nonhepatotropic, 493
Tears, esophageal, 25–27 in amebiasis, 284–285 gastritis in, 71f
Technetium-99 sulfur colloid scan, 558 in Crohn’s disease, 312–313 of gastrointestinal tract, 243
Telangiectatic FNHs, 558–560, 562–564 in cryptococcosis, 281–283 Volcano lesions in Clostridium difficile
Thyroid transcription factor 1 (TTF-1), in diversion colitis, 322 infection, 265
589–590 in diverticular disease, 325 Von Hippel-Lindau (VHL) syndrome, 460
Torsion, appendiceal, 211 in radiation colitis, 320–321 Von Meyenburg complexes. See Bile duct
Toxic injuries, 532f–533f in shigellosis, 258 hamartomas (BDHs)
Toxoplasma gondii infection, 288 in strongyloidiasis, 294 Von Recklinghausen’s disease, 360
Tracheoesophageal fistula, esophageal atresia dysplasia in, 305–309, 306f
with, 17–19, 18f endoscopy in, 301, 302f, 303f
Traditional serrated adenomas (colorectal), gross findings in, 301–302, 302f W
154f, 377–378, 378f invisible low-grade dysplasia in, 306f Waldmann’s disease, 148b
Trematodes, 295–296 resection findings in, 303f, 304–305 Warthin-Starry stain in spirochetosis, 271,
Treponema pallidum infection, 269 visible dysplasia in, 307f 272f
Triangle of Killian, 20 Ulcer(s) Watermelon stomach, 84, 85f, 86f, 86t
Trichuris trichiura infection, 292 in amebiasis, 283 differential diagnosis of, 88
Trisomy 18, 575 anal, 407 Webs, esophageal, 20f
Tropheryma whipplei, 250–251 of colon Weibel-Palade bodies, 602
Tuberculosis in candidiasis, 273 Well-differentiated neuroendocrine tumors
of appendix, 218 in cytomegalovirus infection, 244f, 245f of duodenum, 160f, 161f
of colon, 253t, 267 in mucormycosis, 276 of pancreas, 474–476
differential diagnosis of, 269 in tuberculosis, 267 Whipple disease, 147, 250–251
Tubular adenocarcinoma, 468f of gastrointestinal tract differential diagnosis of, 147, 252
Tubulopapillary neoplasm, intraductal of in cytomegalovirus infection, 243 in gastric xanthomas, 99–100
pancreas, 470–471 in herpetic colitis, 246 Whipworm, 292
Tubulovillous adenoma, 365f in peptic duodenal disease, 126–129, 128f Whole-organ transplants, 681
Tufting enteropathy, 136 rectal, solitary, mucosal prolapse with, Wilson’s disease, in liver, 502, 542, 543f
Tumor budding, 389f 325–327, 326f Worm infection, 291
Tumors. See Neoplasms Undifferentiated (anaplastic) carcinoma,
Tumors, metastatic, 607–611 471–472
Tumors with acinar differentiation, in Undifferentiated carcinoma, 472f X
pancreas, 476–484 colorectal, 385–386, 386f Xanthogranulomatous cholecystitis
acinar cell carcinoma, 476–479 Undifferentiated carcinoma with osteoclast- of gallbladder, 435–436, 437f, 439f
acinar cell cystadenocarcinoma, 479 like giant cells (UCOGC), 471–472 Xanthogranulomatous disorders
acinar cell cystadenoma, 476 Undifferentiated gallbladder carcinoma, appendicitis, 214
mixed acinar–ductal and ductal– 445f cholecystitis, 435–436, 437f, 439f
neuroendocrine carcinoma, 484 Undifferentiated sarcoma. See Embryonal differential diagnosis of, 441–443
mixed acinar–neuroendocrine carcinoma, sarcoma of liver Xanthomas, gastric, 99–100, 99f, 100f
484 Unilocular cystic dilations of the bile duct, differential diagnosis of, 99–100
mixed ductal–neuroendocrine carcinoma, 452 X-linked inheritance (IPEX) syndrome,
484 Uphill esophageal varices, 25–26 133–134
pancreatoblastoma, 479–480 Upper gastrointestinal tract adenocarcinoma,
serous cystadenocarcinoma, 482 HER2 testing in, 400–404
serous cystadenoma (SCA), 480–482
Y
background and rationale, 400–401
Yeast forms, halo effect around, 279f, 280
solid-pseudopapillary neoplasm (SPN), immunohistochemistry, 402
Yersiniosis, 253t, 260, 261f, 263f
482–483 in situ hybridization, 403
differential diagnosis of, 261
Turcot’s syndrome, 338, 381 PD-1/PDL-1 in esophageal and gastric
in Crohn’s disease, 312–313
Tylosis, and squamous cell carcinoma of carcinomas, 403–404
in tuberculosis, 269
esophagus, 35 specimen type, 402
in typhoid fever, 256–257
Type 2 autoimmune pancreatitis, Ursodeoxycholic acid, 519
granulocytic epithelial lesion in, 462f
Type 2 pediatric NAFLD, 508 V Z
Typhlitis. See Enterocolitis, necrotizing Varices, esophageal, 25–27, 26f Zenker’s diverticulum, 19–20, 21f
Typhoid fever, 255, 257f Vascular ectasia, gastric antral, 84, 85f, 86f, Zollinger-Ellison syndrome, 80, 81f, 82f
differential diagnosis of, 256–257 86t differential diagnosis of, 80–82
Tyrosine kinase inhibitors, 531 differential diagnosis of, 86t, 88 gastric carcinoid tumors in, 114
Vascular pattern of injury, in liver, 522–523 peptic ulcers in, 126
U common causes of, 522t Zone 3 pericellular and perisinusoidal
Ulcerative colitis, 301 Veno-occlusive disease, 525, 532f–533f fibrosis, 511
appendix in, 216 Verrucous carcinoma of anus, 429, 430f Zygomycete infections, colonic, 277f
backwash ileitis in, 304f differential diagnosis of, 426, 430f, 431 differential diagnosis of, 274t

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GASTROINTESTINAL AND LIVER PATHOLOGY, ISBN: 978-0-323-52794-1

Copyright © 2024 by Elsevier Inc. All rights reserved.​

Previous editions copyrighted 2012 and 2005.​

Executive Content Strategist: Michael Houston​

Last digit is the print number: 9 8 7 6 5 4 3 2 1​

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Mari​ Mino-Kenudson​, MD​ Safia Nawazish​Salaria​, MD, MMHC​

The editors acknowledge the tireless support and patience

Amitabh Srivastava, MBBS

1​ Non-Neoplastic Disorders of the 12​ Epithelial Neoplasms of the

2​ Tumors of the Esophagus 29 13​ Molecular Testing of Gastrointestinal

6​ Neoplasms of the Small Intestine 151 17​ Non-Neoplastic Disorders of the

9​ Infectious Diseases of the 20​ Pathology of Liver, Small Bowel, and

10​ Non-Neoplastic Disorders of the Index 691

11​ Gastrointestinal Polyposis

The esophagus is designed to simply serve as a conduit ■ ESOPHAGITIS

proximal segment of esophagus. The typical histo-

FIGURE 1.1 FIGURE 1.4

Definition Clinical Features

caused by acid reflux from the stomach

and surgical procedures (Nissen fundoplication) in severe cases

n Deep ulcers are followed by strictures in severe disease

papillae, and spongiosis

and/or neutrophils EOSINOPHILIC ESOPHAGITIS—FACT SHEET

n Balloon cell change, hyperkeratosis, and increased total epithelial Definition

n Can present alone or as part of eosinophilic gastroenteritis

dyspepsia, and solid food impaction

and abdominal pain

Prognosis and Therapy

n May lead to severe esophageal strictures if untreated

n Elimination of food allergens and topical corticosteroids are the

Classic endoscopic findings include mucosal rings, fur-

Biopsies show increased intraepithelial eosinophils

be generated by examining the fragments at low magni-

be seen in patients with reflux esophagitis. Distal esopha­

the papillae, spongiosis, and fibrosis of the lamina propria and

Lymphocytic esophagitis is a poorly defined clinico-

FIGURE 1.9 Symptoms include dysphagia, chest pain, heartburn,

Pathologic Features neutrophils and eosinophils. Esophageal Crohn’s disease

The esophageal biopsy shows increased intraepithelial

n Can be seen anywhere along the esophagus

Gender and Age Distribution

to sixth decade of life

disease, inflammatory bowel disease, or allergy

Prognosis and Therapy

n Gastrointestinal symptoms and histologic findings persist in some

FIGURE 1.10 patients

cell types are not prominent. Direct immunofluores-

features of motility disorder, erythema, nodularity, plaques,

spongiosis and rare to no neutrophils or eosinophils on

Differential Diagnosis Graft-versus-host disease, achalasia and other motility

hyperkeratosis, and dyskeratotic keratinocytes

Daniela S. Allende, MD, MBA

Copyright © 2024 by Elsevier Inc. All rights reserved.

Previous editions copyrighted 2012 and 2005.

Executive Content Strategist: Michael Houston

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Daniela S.Allende, MD, MBA Ilyssa O.Gordon, MD, PhD

Mari Mino-Kenudson, MD Safia NawazishSalaria, MD, MMHC

1 Non-Neoplastic Disorders of the 12 Epithelial Neoplasms of the

2 Tumors of the Esophagus 29 13 Molecular Testing of Gastrointestinal

6 Neoplasms of the Small Intestine 151 17 Non-Neoplastic Disorders of the

9 Infectious Diseases of the 20 Pathology of Liver, Small Bowel, and

10 Non-Neoplastic Disorders of the Index 691

11 Gastrointestinal Polyposis

be seen in patients with reflux esophagitis. Distal esopha