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Differential Diagnoses in Surgical
Pathology:
Gastrointestinal System

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Differential Diagnoses in Surgical
Pathology:
Gastrointestinal System
Elizabeth A. Montgomery, MD
Professor of Pathology, Oncology, and Orthopedic Surgery
Department of Pathology
Division of Gastrointestinal and Liver Pathology
Johns Hopkins Medical Institutions
Baltimore, Maryland

Whitney M. Green, MD
Resident
Department of Pathology
Johns Hopkins Medical Institutions
Baltimore, Maryland

SERIES EDITOR

Jonathan I. Epstein, MD
Professor of Pathology, Urology and Oncology
The Reinhard Professor of Urological Pathology
Director of Surgical Pathology
Johns Hopkins Medical Institutions
Baltimore, Maryland

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mebooksfree.com
Acquisitions Editor : Ryan Shaw
Product Manager : Kate Marshall
Production Product Manager : David Orzechowski
Senior Manufacturing Coordinator : Beth Welsh
Designer : Doug Smock
Production Service : SPi Global

Copyright © 2015 by WOLTERS KLUWER

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Philadelphia, PA 19103 USA
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All rights reserved. This book is protected by copyright. No part of this book
may be reproduced in any form by any means, including photocopying, or
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permission from the copyright owner, except for brief quotations embodied in
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covered by the above-mentioned copyright.

Printed in China

Library of Congress Cataloging-in-Publication Data

Montgomery, Elizabeth (Elizabeth A.), 1958- , author.
Differential diagnoses in surgical pathology. Gastrointestinal system /
Elizabeth A. Montgomery, Whitney M. Green.
p. ; cm.
Gastrointestinal system
Includes bibliographical references and index.
ISBN 978-1-4511-9189-9 (alk. paper)
I. Green, Whitney M., author.II. Title.III. Title: Gastrointestinal system.
[DNLM:1. Gastrointestinal Diseases—diagnosis—Handbooks.2. Diagnosis,
Differential—Handbooks. 3. Gastrointestinal Diseases—surgery—Handbooks.4.
Gastrointestinal Tract—surgery—Handbooks.5. Pathology, Surgical—methods
—Handbooks. WI 39]
RD540

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 617.4'3059—dc23
2014036983

Care has been taken to confirm the accuracy of the information presented and to
describe generally accepted practices. However, the authors, editors, and
publisher are not responsible for errors or omissions or for any consequences
from application of the information in this book and make no warranty,
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ongoing research, changes in government regulations, and the constant flow of
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check the package insert for each drug for any change in indications and dosage
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 Dedication

To my mentors and colleagues for all they have taught and shared
with me, to my mother and father for their unconditional love,
support, and constant encouragement, and to Shiitake for always
lending a helpful paw.
Whitney M. Green
To all the residents and fellows from and with whom I have learned
and will continue to learn as time passes and to my perfect children,
Sasha, Peter, and Sean.
Elizabeth A. Montgomery

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 Preface

Interpreting the findings in gastrointestinal biopsies and resections is

often easy—except when it is not. The difficulty is often that
specimens from the gastrointestinal tract generally consist of tiny
biopsies that may or may not show the affected layer of the
gastrointestinal tract; a sample of the gastric mucosa will not show
most gastrointestinal stromal tumors, since they arise in the
muscularis propria.
Moreover, nonneoplastic forms of injury to the gastrointestinal
tract display overlapping features, and it can be difficult to separate
them without knowledge of the clinical findings. For example, both
mycophenolate-associated damage and graft versus host disease
feature prominent crypt apoptosis in colonic samples but, in general,
the injury associated with mycophenolate is eosinophil rich, whereas
eosinophils are scarce in graft versus host disease. Various
medications can results in mitotic arrest (typically colchicine and
taxanes), and the pathologists must accept that only the mitotic arrest
can be identified and one must reconcile with the medication list. Both
amyloidosis and radiation can result in thick basement membranes,
but the quality of the material that thickens differs between the two.
Nowadays, many patients are treated endoscopically rather than
surgically for several entities, and these resections result in samples
with their own difficulties. For example, the esophageal muscularis
mucosae becomes both thickened and duplicated in patients with
Barrett metaplasia, and it is important to know which layer is which in
determining prognosis in endoscopic mucosal resections.
In developing the differential diagnoses to show for this manual,
we used both the perspective of residents learning the basics (e.g.,

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complete vs. incomplete intestinal metaplasia in the upper tract) and
colleagues with more advanced skills (e.g., tufting enteropathy vs.
other causes of intractable diarrhea in infants) derived from our rich
consultation material to show many entities side by side. Whipple
disease is rare and exciting to diagnose, but it can be confused with
mundane crushed Brunner glands in biopsies. Signet cell carcinoma
cannot be missed in any site, but it is not terribly difficult to recognize
the congener—signet cell change—if one is knowledgeable about it.
Of course, it is important to check small bowel biopsies for what is
absent—a lack of Paneth and/or goblet cells is a clue to autoimmune
enteropathy, and absent plasma cells tell us that the patient has
common variable immunodeficiency. Even gastrointestinal
mesenchymal tumors are not terribly difficult once one pays attention
to the layers of the gastrointestinal tract in which they tend to arise—
such as gastrointestinal stromal tumors in the muscularis propria
versus inflammatory fibroid polyp in the submucosa.
Unfortunately, some conditions cannot be diagnosed in the
absence of clinical history, but we have attempted to point out some of
these issues as well.
We hope this small array of differential diagnoses in
gastrointestinal pathology will offer fresh information to trainees and
help solidify fine points for more experienced pathologists. Mainly we
hope that it will be enjoyable to review the findings of similar entities
presented side by side.
Whitney M. Green
Elizabeth A. Montgomery

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 Acknowledgments

We acknowledge all the colleagues who allow us to review interesting

(and mundane) cases each and every day that add to our
understanding of gastrointestinal pathology, which perpetually
changes and amazes. We also thank Kate Marshall for her role as
product manager, David Orzechowski for overseeing production,
Ryan Shaw, Acquisition Editor, for keeping us on task for this project,
and Vedhapriya Rameshbabu and her team at SPi-Global for
transforming the manuscript to final printer files. Lastly, seeing to all
the images and text of such a project is time consuming and we thank
our families for their encouragement.

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 Contents

Preface
Acknowledgments

Chapter 1 ESOPHAGUS

Chapter 2 STOMACH

Chapter 3 SMALL INTESTINE

Chapter 4 COLON

Chapter 5 APPENDIX

Chapter 6 ANAL CANAL

Index

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 1
Esophagus

1.1 Iron pill esophagitis vs. Squamous dysplasia

1.2 Reactive multinucleated squamous cells vs. Herpes virus
cytopathic effect
1.3 Reactive stromal changes vs. Cytomegalovirus esophagitis
1.4 Goblet cells in Barrett esophagus vs. Multilayered epithelium
1.5 Goblet cells of Barrett mucosa vs. Esophageal submucosal
glands
1.6 Goblet cells of Barrett mucosa vs. Alcianophilic foveolar cells
1.7 Carryover of small bowel mucosa into esophageal sample vs.
Barrett mucosa
1.8 Complete intestinal metaplasia vs. Incomplete intestinal
metaplasia
1.9 Oncocytic change of submucosal glands vs. Pyloric gland
adenoma
1.10 Eosinophilic esophagitis vs. Reflux esophagitis
1.11 Taxane effect vs. Squamous and columnar epithelial dysplasia
1.12 Esophagitis dissecans (sloughing esophagitis) vs. Esophageal
pemphigus vulgaris
1.13 Lichenoid esophagitis vs. Reflux change
1.14 Atypical stromal cells in ulcers vs. Sarcomatoid squamous cell
carcinoma
1.15 Multilayered epithelium vs. Squamous dysplasia
1.16 Columnar epithelial dysplasia vs. Reactive epithelial changes
1.17 Low-grade columnar epithelial dysplasia vs. High-grade
columnar epithelial dysplasia

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1.18 High-grade columnar epithelial dysplasia vs. Intramucosal
adenocarcinoma
1.19 Lamina propria in columnar-lined esophagus vs. Submucosa
in columnar-lined esophagus
1.20 Pseudoepitheliomatous hyperplasia vs. Squamous cell
carcinoma
1.21 Esophageal smooth muscle tumors vs. Esophageal
gastrointestinal stromal tumors
1.22 Melanoma vs. Esophageal gastrointestinal stromal tumor
1.23 Melanoma vs. Melanosis (melanocytosis)

1.1 Iron pill esophagitis vs. Squamous

dysplasia
Iron Pill Esophagitis Squamous Dysplasia
Typically adults; male
Age/Gender No specific age; female predominance
predominance
Often in middle third
Any part of esophagus; more likely in
Location of the esophagus but
area of preexisting stricture
can be anywhere
No specific symptoms
unless accompanied
Symptoms Dysphagia
by invasive carcinoma
(dysphagia)
None—patient may have iron deficiency
Signs No specific signs
anemia and thus taking iron supplements
Like squamous cell
carcinoma, associated
Damage due to mechanical effects of pill
with alcohol,
Etiology in preexisting ulcer/erosion as well as to
smoking, male gender,
toxicity of the medication itself
ALDH1
polymorphisms
1. Ulcer or erosion with golden brown

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 pigment embedded within the lesion 1. Usually without
(early injury accompanied by ulcers; cells show
regenerative squamous epithelium with nuclear
reparative changes including enlarged hyperchromasia, lack
Histology nuclei and prominent nucleoli) (Fig. nucleoli (Fig. 1.1.4)
1.1.1) 2. Sometimes
2. Pigment becomes more green-blue- accompanied by
black over time (Fig. 1.1.2) invasive carcinoma
3. Iron staining shows deeper pigment (Fig. 1.1.5)
than apparent on H&E-stained slides 3. Not pigmented
(Fig. 1.1.3) (Fig. 1.1.6)

Iron stain can be helpful in Generally

Special some cases to confirm the not
studies presence of iron performed

Iron pills can be administered with Ablation therapy such

Treatment abundant fluids or with soft foods as radiofrequency
(applesauce, yogurt) ablation
Low-grade dysplasia
unlikely to progress to
invasive carcinoma,
Prognosis Most symptoms resolve quickly
whereas high-grade
dysplasia has a high
risk of progression

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Figure 1.1.1 Iron pill esophagitis. Note the brown appearance of the iron
embedded in eroded squamous epithelium. At the bottom of the field, the tissue
has a more purplish appearance attributable to oxidization.

Figure 1.1.2 Iron pill esophagitis. In this image, the iron deposition is more
subtle but has resulted in a purplish appearance of the damaged tissue in the
left side of the field. Note the striking reactive squamous epithelial changes.

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Figure 1.1.3 Iron pill esophagitis. This is an iron stain from the case depicted
in Figure 1.1.2.

Figure 1.1.4 Squamous dysplasia. There is no erosion and no foreign debris.

The nuclei, even at this magnification, are more hyperchromatic than those in
the reparative squamous epithelium in Figure 1.1.2.

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Figure 1.1.5 Squamous dysplasia. There is low-grade dysplasia on the right
and an early carcinoma on the left in a background lacking inflammation.

Figure 1.1.6 Squamous dysplasia. This is high-grade squamous dysplasia. It is

difficult to see cell borders, and the nuclei are hyperchromatic. Note that cell
borders are readily identifiable in the reparative squamous epithelium in
Figure 1.1.2.

1.2 Reactive multinucleated

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squamous cells vs. Herpes virus
cytopathic effect
Reactive Multinucleated
Herpes Simplex Esophagitis
Squamous Cells
Typically adults (mean Immunosuppressed persons of all
Age/Gender age about 60); male ages, typically adults; no gender
predominance predilection
Location Usually distal esophagus Throughout esophagus
Since associated with
esophageal mucosal
injury, related to
strictures,
Symptoms gastroesophageal reflux Odynophagia, dysphagia
disease, dysphagia,
odynophagia, heartburn,
abdominal pain,
gastrointestinal bleeding
Endoscopically, ulcers, Vesicles (early) or ulcers (late). The
erosions, strictures, and endoscopist must biopsy squamous
Signs
mucosal plaques can all epithelium (rather than ulcer bed) to
be seen detect organisms
Etiology Presumed to be reparative Infection with herpes simplex virus
1. Often seen at
squamocolumnar junction 1. Ulcers and erosions are seen. The
with or without infected cells are seen at the
accompanying Barrett epithelialized edges of the ulcers (Fig.
esophagus (with goblet 1.2.4)
cells) (Fig. 1.2.1) 2. Infected cells are either
2. May be accompanied multinucleated or have a single
Histology by pseudoepitheliomatous
nucleus (Fig. 1.2.5)
hyperplasia (Fig. 1.2.2) 3. Both Cowdry A (with a clearing
3. The nuclei in the around the inclusion) and Cowdry B
multinucleated cells (smudged) inclusions can be seen
typically have prominent

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 nucleoli but not true within nuclei (Fig. 1.2.6)
inclusions (Fig. 1.2.3)
Generally not
Immunolabeling for herpes
needed. Herpes
Special simplex virus can be
simplex virus
studies confirmatory if diagnosis is
immunolabeling
uncertain
is negative

Oral antivirals such as acyclovir,

famciclovir, and valacyclovir may be
Treatment is of the used. Intravenous acyclovir is used
underlying condition that for individuals who cannot swallow
Treatment
resulted in the reactive due to odynophagia, persons with
changes other systemic manifestations of
herpes, or severely
immunocompromised individuals
The prognosis is related
to the underlying Good for the herpes itself—the root
Prognosis condition, typically reflux cause of the immunosuppression must
disease, but unrelated to be addressed to prevent reinfection
the multinucleated cells

Figure 1.2.1 Reactive multinucleated squamous cells. The multinucleated cell

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in the center of the field has the same reparative changes as those in the cells
with only one nucleus. It is at the basal layer.

Figure 1.2.2 Reactive multinucleated squamous cells. At low magnification,

note the lamina propria granulation tissue. A fragment of gastrocardiac
mucosa is present. These samples were from the gastroesophageal junction of a
patient with erosive reflux disease.

Figure 1.2.3 Reactive multinucleated squamous cells. Note the nucleoli in the
reactive cells. Note also how prominent the intercellular bridges appear in this

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reactive squamous epithelium, a finding attributable to edema.

Figure 1.2.4 Herpes esophagitis. The infected cells are sloughed at the surface.

Figure 1.2.5 Herpes esophagitis. A multinucleated cell with smudged nuclei is

in the center of the field. Similar binucleate cells are nearby. Note the sloughed
debris at the lower left.

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Figure 1.2.6 Herpes esophagitis. Both eosinophilic and basophilic smudged
Cowdry B inclusions are present.

1.3 Reactive stromal changes vs.

Cytomegalovirus esophagitis
Reactive Stromal Changes in
Cytomegalovirus Esophagitis
Ulcers and Polyps
Older individuals, often with
comorbidities that might result Typically adults; no gender
Age/Gender
in ischemia; no gender predilection
predilection
Anywhere in esophagus as No specific location in
Location
associated with ulcers esophagus
Related to the ulcers—
Symptoms Odynophagia, dysphagia
dysphagia, odynophagia
Endoscopists often see ulcers
and must biopsy some of the
Signs Ulcer visible endoscopically ulcerated portion in order to
maximize the likelihood of
detection

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 Cytomegalovirus, often found in
Whatever the etiology of the
immunocompromised persons
ulcer; reflux associated,
regardless of the etiology of the
Etiology medication associated,
immunocompromise. The patient
chemoradiation associated;
may have evidence of systemic
often in debilitated persons
cytomegalovirus infection
1. Erosions, granulation tissue
1. Markedly atypical
typical (Fig. 1.3.4)
fibroblasts that are found at the
2. Often a background of
interface of necrotic ulcer
monohistiocytic cells that can
exudate and viable granulation
result in consideration of
tissue (Fig. 1.3.1)
lymphoma (Fig. 1.3.5)
2. The fibroblasts have
Histology 3. Both nuclear and cytoplasmic
enlarged smudged nuclei but a
inclusions can be encountered.
low nuclear-to-cytoplasmic
The infected cells are typically
ratio; a pseudosarcomatous
endothelial rather than epithelial
appearance (Fig. 1.3.2)
cells (Fig. 1.3.6)
3. The fibroblasts intercalate
4. Immunolabeling can be used
among capillaries (Fig. 1.3.3)
if there is uncertainty (Fig. 1.3.7)
If immunolabeling is
performed, the
fibroblasts are
“vimentin-only” cells Immunolabeling can
Special (although vimentin confirm the presence
studies staining is not of virus
needed). Importantly,
keratins and S100
protein are negative

None for the fibroblasts

themselves. Any treatment is
directed at the underlying Foscarnet and ganciclovir appear
Treatment etiology of the ulcer (generally to be similarly effective and safe
gastroesophageal reflux
disease)
Cytomegalovirus esophagitis
Excellent for the atypical
responds to antiviral treatment,
stromal cells. The underlying

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Prognosis condition responsible for the but the underlying cause of
ulcers must be addressed immunosuppression needs to be
addressed if feasible

Figure 1.3.1 Pseudosarcomatous stromal cells in ulcers. Note that the atypical
cells form a rind at the junction between the necroinflammatory cap at the right
side of the fiend and the underlying healthy tissue.

Figure 1.3.2 Pseudosarcomatous stromal cells in ulcers. The large cell in the
center is a pseudosarcomatous fibroblastic cell. It has abundant amphophilic

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cytoplasm and nucleoli.

Figure 1.3.3 Pseudosarcomatous stromal cells in ulcers. At the interface

between the necrotic surface and the viable underlying tissue, the atypical
fibroblasts proliferate between capillaries.

Figure 1.3.4 Cytomegalovirus esophagitis. This process has reactive

fibroblasts but also shows viral cytopathic effect. At low magnification, a
virocyte can be seen at the lower left.

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Figure 1.3.5 Cytomegalovirus esophagitis. This example shows a prominent
lymphomonocytic infiltrate that raises the possibility of lymphoma. In such
cases, it can be difficult to detect viral cytopathic effect.

Figure 1.3.6 Cytomegalovirus esophagitis. Classic viral cytopathic effect. Both

nuclear and cytoplasmic inclusions are present.

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Figure 1.3.7 Cytomegalovirus esophagitis. This is an immunostain for
cytomegalovirus on the area shown in Figure 1.3.5.

1.4 Goblet cells in Barrett esophagus

vs. Multilayered epithelium
Goblet Cells of Barrett Esophagus
Typically adults; strong male
Age/Gender
predominance
Location Distal esophagus
None attributable to the goblet cells finding does correlate with
per se. The patient may have
Symptoms
symptoms of gastroesophageal
reflux such as heartburn or cough
Multilayered Epithelium
in the Esophagus
Adults. Median age in the
initial immunolabeling
series reporting this
finding: 57 years. Male
predominance
Distal esophagus
No symptoms attributable
to the multilayered
epithelium per se. This
gastroesophageal reflux,
and it may be a precursor to
conventional Barrett

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Endoscopic “tongues” or “islands”
of salmon-colored mucosa
Signs (columnar appearance) proximal to
the gastric folds are seen in Barrett
mucosa
Long-standing gastroesophageal
Etiology
reflux
1. Typically incomplete intestinal
metaplasia showing interspersed
goblet cells and gastric foveolar-
type cells. Goblet cells are
characterized by an acid mucin
vacuole that indents the nucleus in a
cup shape. Nuclei are in more or
less a monolayer and only
minimally stratified (Figs. 1.4.1 and
1.4.2). Occasional examples show
complete intestinal metaplasia with
Histology
goblet cells interspersed between
absorptive cells with a brush border
(Figs. 1.4.3 and 1.4.4)
2. PAS/AB staining shows a dark
blue to purple appearance of goblet
cells with neutral mucin in gastric
foveolar-type cells between the
goblet cells in incomplete intestinal
metaplasia (Fig. 1.4.5) or no mucin
in absorptive cells of complete
intestinal metaplasia (Fig. 1.4.6)
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mucosa. Patients can
manifest symptoms of
gastroesophageal reflux
None. Usually found on
biopsies from the
gastroesophageal junction
Associated with reflux
1. This epithelium consists
of four to eight layers of
cells that appear to be
squamous in the basal
aspect and columnar in the
superficial portion with an
appearance reminiscent of
that of immature squamous
metaplasia of the uterine
cervix (Figs. 1.4.7–1.4.10)
2. PAS/AB shows a purple
in cells that appear similar
to conventional goblet cells
in fully columnar
epithelium (Figs. 1.4.11
and 1.4.12)
In multilayered
epithelium, there
is expression of
p63 and SOX2
(squamous
 PAS/AB highlights the differentiation
acid mucin in goblet cells. markers) in all
Goblet cells express cases and a subset
CDX2 and MUC2 on displays CDX2,
immunolabeling and do villin, or MUC2
Special (intestinal
not express p63 or SOX2
studies differentiation
(the latter are found in
squamous epithelium, but markers), but not
these stains are not needed all examples
for diagnosis) display the latter
intestinal
markers. PAS/AB
shows a purple
color akin to that
of classic goblet
cells in columnar
mucosa

None currently generally suggested.

Some observers have suggested
radiofrequency ablation for
Treatment
nondysplastic Barrett esophagus, but
this is not recommended for most
patients
Most examples do not progress to
adenocarcinoma, but Barrett
Prognosis
esophagus is a precursor to
esophageal adenocarcinoma
None
Multilayered epithelium is
correlated with
gastroesophageal reflux
disease and may progress to
conventional Barrett
mucosa. It does not itself
appear to be associated
with dysplasia or
adenocarcinoma in the
absence of progression to
conventional Barrett
mucosa

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Figure 1.4.1 Barrett esophagus. This example shows a mixture of complete and
incomplete intestinal metaplasia.

Figure 1.4.2 Barrett esophagus. This example shows incomplete intestinal

metaplasia. There are cells producing neutral mucin between goblet cells.

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Figure 1.4.3 Barrett esophagus. This case shows complete intestinal
metaplasia. There are cells that have a brush border between the goblet cells.

Figure 1.4.4 Barrett esophagus. This field shows complete intestinal

metaplasia. Paneth cells are present.

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Figure 1.4.5 Barrett esophagus. This is a periodic acid Schiff–Alcian blue
(PAS/AB) stain of incomplete intestinal metaplasia. The foveolar cells contain
magenta neutral mucin, and the goblet cells are alcianophilic.

Figure 1.4.6 Barrett esophagus. This is a periodic acid Schiff–Alcian blue

(PAS/AB) stain of complete intestinal metaplasia. There are no foveolar cells
admixed with the goblet cells (although some are present on the surface of the
mucosa), and the goblet cells are alcianophilic. There is a magenta strip on the
surface of the cells between the goblet cells—the brush border.

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Figure 1.4.7 Multilayered epithelium. There is a stratified area of multilayered
epithelium in a “U”-shaped configuration at the surface.

Figure 1.4.8 Multilayered epithelium. The deep portion resembles immature

squamous metaplasia of the uterine cervix. The more superficial cells contain
bubbly mucin reminiscent of the acid mucin seen in goblet cells of intestinal
epithelium.

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Figure 1.4.9 Multilayered epithelium. This example has more layers of
stratification than that seen in Figure 1.4.7.

Figure 1.4.10 Multilayered epithelium.

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Figure 1.4.11 Multilayered epithelium. PAS/AB staining shows staining that is
tinctorially similar to that in goblet cells at the surface of the multilayered
area.

Figure 1.4.12 Multilayered epithelium. The globules of acid mucin (the mucin
that is purplish on the PAS/AB stain) are not as crisply demarcated as are those
in the goblet cells in Figures 1.4.5 and 1.4.6.

1.5 Goblet cells of Barrett mucosa vs.

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Esophageal submucosal glands
Goblet Cells of Barrett
Esophageal Submucosal Glands
Esophagus
Typically adults; strong Normal anatomic structure found in
Age/Gender
male predominance all persons regardless of age/gender
Throughout esophagus. These glands
provide lubrication for the passage of
Location Distal esophagus
swallowed food from the esophagus
to the stomach
None attributable to the
goblet cells per se. The
patient may have
Symptoms symptoms of None
gastroesophageal reflux
such as heartburn or
cough
Endoscopic “tongues” or
“islands” of salmon-
colored mucosa
Signs (columnar appearance) None—these are normal structures
proximal to the gastric
folds are seen in Barrett
mucosa
Long-standing
Etiology Unknown
gastroesophageal reflux
1. Goblet cells in Barrett 1. As per their designation as
esophagus are found in “submucosal glands,” esophageal
the surface epithelium and submucosal glands are found in the
not in the submucosa. submucosa rather than the mucosa,
They are usually and they are therefore not seen on
interspersed with gastric most esophageal mucosal biopsies.
foveolar-type cells that They are commonly found on
contain sharply delineated endoscopic mucosal resection
mucin at the apex of the samples or submucosal dissection
Histology cell that does not indent samples. They consist of glands

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 the nucleus (Figs. arranged in lobules with plump cells
1.5.1–1.5.3) containing abundant microvesicular
2. PAS/AB staining shows mucin that appears pale on H&E
a dark blue to purple staining (Figs. 1.5.7–1.5.9)
appearance of goblet cells 2. PAS/AB staining shows dark
with neutral mucin in purple to blue glands with a
gastric foveolar-type cells monotonous color situated in the
between the goblet cells submucosa (Figs. 1.5.10–1.5.12)
(Figs. 1.5.4–1.5.6)
PAS/AB
highlights the
acid mucin in
PAS/AB appears as shown.
Special goblet cells.
Negative CDX2 and MUC2
studies Goblet cells
on immunolabeling
express CDX2
and MUC2 on
immunolabeling

None currently generally

suggested. Some
observers have suggested
radiofrequency ablation
Treatment Not applicable—normal structures
for nondysplastic Barrett
esophagus, but this is not
recommended for most
patients
Most examples do not
progress to
adenocarcinoma, but
Prognosis Not applicable—normal structures
Barrett esophagus is a
precursor to esophageal
adenocarcinoma

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Figure 1.5.1 Barrett mucosa showing incomplete intestinal metaplasia. Goblet
cells are interspersed with cells containing apical mucin.

Figure 1.5.2 Barrett mucosa showing complete intestinal metaplasia. Goblet

cells are interspersed with cells with a brush border.

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Figure 1.5.3 Barrett mucosa showing incomplete intestinal metaplasia.

Figure 1.5.4 Barrett mucosa with both complete and incomplete intestinal
metaplasia. Some areas show a brush border between goblet cells, whereas
others show cells containing neutral mucin (PAS/AB).

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Figure 1.5.5 Barrett mucosa showing complete intestinal metaplasia. Note the
brush border.

Figure 1.5.6 Barrett mucosa showing incomplete intestinal metaplasia.

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Figure 1.5.7 Esophageal submucosal glands, endoscopic mucosal resection
specimen. This shows large submucosal glands in the deep portion of the
biopsy. The upper left of the field shows an area of high-grade columnar
epithelial dysplasia.

Figure 1.5.8 Esophageal submucosal glands. These glands are usually not
encountered on biopsies of squamous mucosa, but occasionally they are
present. They contain abundant bubbly mucin.

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Figure 1.5.9 Esophageal submucosal glands.

Figure 1.5.10 Esophageal submucosal glands, endoscopic mucosal resection

specimen. Note the dark purple appearance of esophageal submucosal glands
on PAS/AB.

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Figure 1.5.11 Esophageal submucosal gland, biopsy, PAS/AB.

Figure 1.5.12 Esophageal submucosal gland, biopsy, PAS/AB.

1.6 Goblet cells of Barrett mucosa vs.

Alcianophilic foveolar cells
Goblet Cells of Barrett Alcianophilic Columnar Cells in the

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 Esophagus
Typically adults; strong
Age/Gender
male predominance
Location Distal esophagus
None attributable to the
goblet cells per se. The
patient may have
Symptoms
symptoms of
gastroesophageal reflux
such as heartburn or cough
Endoscopic “tongues” or
“islands” of salmon-
colored mucosa (columnar
Signs
appearance) proximal to
the gastric folds are seen
in Barrett mucosa
Long-standing
Etiology
gastroesophageal reflux
1. Goblet cells in Barrett
esophagus are usually
interspersed with gastric
foveolar-type cells that
contain sharply delineated
mucin at the apex of the
cell that does not indent
the nucleus. Usually,
goblet cells in Barrett
esophagus are separated
from one another by one
to three cells that have the
appearances of gastric
foveolar in incomplete
metaplasia or by one to
Histology three cells that have
absorptive qualities in
complete intestinal
metaplasia (Figs. 1.6.1
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Esophagus
Typically adults; strong male
predominance
Distal esophagus
None attributable to the columnar
cells per se. The patient may have
symptoms of gastroesophageal reflux
such as heartburn or cough
Endoscopic salmon-colored mucosa
(columnar appearance) proximal to
the gastric folds can be seen as a
corollary to any type of columnar
mucosa
Long-standing gastroesophageal
reflux
1. In the United States and much of
Europe, the presence of goblet cells
is required to diagnose Barrett
mucosa so Alcian blue (AB) staining
is often performed with or without
PAS. In contrast, only columnar
epithelium is required for a diagnosis
of Barrett esophagus in the United
Kingdom and Japan. As such, in the
United States, some examples of
columnar epithelium lacking goblet
cells display a bluish appearance on
Alcian blue that appears similar to
Barrett goblet cells. These
alcianophilic cells often appear as
 and 1.6.2)
2. PAS/AB staining shows
a dark blue to purple
appearance of goblet cells
with neutral mucin in
gastric foveolar-type cells
between the goblet cells or
a brush border between the
goblet cells in complete
intestinal metaplasia (Figs.
1.6.3 and 1.6.4)
several mucin-containing cells
adjoining one another rather than
separated by obvious foveolar or
absorptive cells (Figs. 1.6.5 and
1.6.6)
2. PAS/AB staining shows tall blue
cells that are usually adjacent to
similar cells (Figs. 1.6.7 and 1.6.8)

PAS/AB
highlights the
acid mucin in
goblet cells.
PAS/AB shows a blue
Goblet cells
color. These cells lack
Special express CDX2
CDX2 and MUC2
studies and MUC2 on
immunolabeling and
immunolabeling,
express MUC5AC
whereas gastric
foveolar-type
cells express
MUC5AC

None currently generally

suggested. Some observers
have suggested
radiofrequency ablation
Treatment None currently generally suggested
for nondysplastic Barrett
esophagus, but this is not
recommended for most
patients
Most examples do not
progress to Probably less likely to progress to
adenocarcinoma, but adenocarcinoma than Barrett mucosa
Prognosis
Barrett esophagus is a with classic goblet cells, at least in
precursor to esophageal data from the United States

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 adenocarcinoma

Figure 1.6.1 Barrett esophagus with incomplete intestinal metaplasia. Between

the goblet cells, each of which has a crisply delineated mucin droplet that
appears slightly bluish on H&E, there are foveolar cells containing apical
mucin.

Figure 1.6.2 Barrett esophagus with complete intestinal metaplasia. Note the
brush border of the absorptive-type cells between goblet cells.

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Figure 1.6.3 Barrett esophagus with incomplete intestinal metaplasia, PAS/AB
stain. There are magenta-colored foveolar-type cells between the purple goblet
cells.

Figure 1.6.4 Barrett esophagus with complete intestinal metaplasia, PAS/AB

stain. There is a sharp thin brush border that is dark blue between the goblet
cells.

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Figure 1.6.5 “Alcianophilic” foveolar cells in esophageal biopsies. The cells
are reminiscent of goblet cells, but their mucin is the same color as that of
foveolar cells.

Figure 1.6.6 “Alcianophilic” foveolar cells in esophageal biopsies . This biopsy

shows cardio-oxyntic mucosa lacking goblet cells.

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Figure 1.6.7 “Alcianophilic” foveolar cells in esophageal biopsies, PAS/AB
stain. This is the same field as that shown in Figure 1.6.5. The purple cells do
not correspond to goblet cells.

Figure 1.6.8 “Alcianophilic” foveolar cells in esophageal biopsies, PAS/AB

stain. This cardio-oxyntic mucosa contains purple cells. These are not goblet
cells and should not be reported as such.

1.7 Carryover of small bowel mucosa

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into esophageal sample vs. Barrett
mucosa
Carryover of Small Intestinal
Mucosa into Esophageal Barrett Mucosa
Samples
Typically adults; strong male
Age Any age
predominance
Frequently, when upper
gastrointestinal tract endoscopy
is performed, endoscopists
introduce the endoscope into the
small bowel and retract the
endoscope and take biopsy
samples as they remove the
endoscope. Thus, often the
duodenum is biopsied first,
followed my other biopsies in
the upper gastrointestinal tract.
When a biopsy is taken, the
forceps are rinsed into a
container containing formalin,
Location then washed with saline, and Distal esophagus
then reinserted to take
additional sample/s. Sometimes,
if the esophagus is biopsied
after the duodenum, a portion of
duodenal tissue can remain
adherent to the forceps and
finally dislodge into the
specimen jar intended for a
subsequent esophagus sample.
Also, occasionally, based on
operator error, a sample from
the duodenum can be submitted
in a specimen container labeled

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 “esophagus”
Symptoms Unrelated to the sample
A clue is that the pathologist
may find goblet cells in the
Signs esophagus in the absence of a
clinical impression of Barrett
esophagus
Operator error in labeling
specimen site or adherence of a
duodenal sample to forceps and
Etiology
deposit of this sample into a
specimen container labeled
“esophagus”
1. Among a sample showing
histomorphology of
gastroesophageal junction
(gastrocardiac and squamous
fragments), a separate fragment goblet cells in Barrett esophagus
shows goblet cells, a perfect
brush border, numerous lamina one to three cells that have the
propria plasma cells, and
Histology numerous Paneth cells at the
bases of the crypts. In some
examples, the sample is
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None attributable to the Barrett
mucosa per se. The patient may
have symptoms of
gastroesophageal reflux such as
heartburn or cough
Endoscopic “tongues” or
“islands” of salmon-colored
mucosa (columnar appearance)
proximal to the gastric folds are
seen in Barrett mucosa
Long-standing gastroesophageal
reflux
1. Barrett esophagus contains
goblet cells interspersed with
gastric foveolar-type cells that
contain sharply delineated mucin
at the apex of the cell that does
not indent the nucleus. This
pattern has been termed
“specialized columnar
epithelium” or “Barrett
esophagus” of the distinctive type
since in years past in the United
States, all columnar mucosa of
the esophagus was included in
Barrett esophagus. Usually,
are separated from one another by
appearances of gastric foveolar in
incomplete metaplasia or by one
to three cells that have absorptive
 superficial and may not qualities in complete intestinal
demonstrate the Paneth cells metaplasia (Figs. 1.7.5 and
(Figs. 1.7.1–1.7.3) 1.7.6). However, even in
2. PAS/AB staining shows a complete intestinal metaplasia,
perfect brush border (Fig. 1.7.4) the glands are less orderly than
those of true small bowel and
there are fewer Paneth cells in
complete intestinal metaplasia
2. PAS/AB staining shows a dark
blue to purple appearance of
goblet cells with neutral mucin in
gastric foveolar-type cells
between the goblet cells or a
brush border between the goblet
cells in complete intestinal
metaplasia (Figs. 1.7.7 and 1.7.8)
PAS/AB highlights the
acid mucin in goblet
cells. Goblet cells
None necessary. express CDX2 and
Special Common sense is MUC2 on
studies critical! immunolabeling,
whereas gastric
foveolar-type cells
express MUC5AC

None currently generally

suggested. Some observers have
suggested radiofrequency
Treatment None
ablation for nondysplastic Barrett
esophagus, but this is not
recommended for most patients
Most examples do not progress to
Reflective of any actual adenocarcinoma, but Barrett
Prognosis
pathology in the sample esophagus is a precursor to
esophageal adenocarcinoma

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Figure 1.7.1 “Carryover” of a fragment of duodenal mucosa into a sample
labeled “esophagus.” Note the tiny fragment in the center of the field. This
patient had a duodenal biopsy followed by an esophagus biopsy that shows
squamous and cardiac-type mucosa. A small fleck of duodenal mucosa became
adherent to the forceps and finally dislodged into the esophagus sample cup.
This is not Barrett mucosa.

Figure 1.7.2 “Carryover” of a fragment of duodenal mucosa into a sample

labeled “esophagus.” Higher magnification. Note the perfect brush border
between the goblet cells.

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Figure 1.7.3 “Carryover” of a fragment of duodenal mucosa into a sample
labeled “esophagus.” There are Paneth cells in addition to goblet cells in this
fragment. It is unusual to have such perfect complete intestinal metaplasia in
the esophagus. This sample was from a child with no endoscopic evidence of
Barrett esophagus.

Figure 1.7.4 “Carryover” of a fragment of duodenal mucosa into a sample

labeled “esophagus,” PAS/AB.

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Figure 1.7.5 Barrett mucosa. There is incomplete intestinal metaplasia, and the
fragment is sizable.

Figure 1.7.6 Barrett mucosa. Although there are villiform structures in this
fragment that shows complete intestinal metaplasia (unusual for Barrett
esophagus), there are no Paneth cells. The esophagus showed a tongue of
columnar mucosa endoscopically.

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Figure 1.7.7 Barrett mucosa. This is a PAS/AB from the mucosa seen in Figure
1.7.5.

Figure 1.7.8 Barrett mucosa. This is a PAS/AB from the mucosa seen in Figure
1.7.6.

1.8 Complete intestinal metaplasia vs.

Incomplete intestinal metaplasia

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 Complete Intestinal
Metaplasia
Age/Gender Adults; male predominance
Usually found in the stomach
and less frequently found in the
esophagus or other organs in the
Location
body that are not the focus of
this book (bladder,
pancreatobiliary system)
Typically asymptomatic—any
symptoms relate to the
underlying source of injury that
caused the intestinal metaplasia
Symptoms
(usually Helicobacter pylori
gastritis in the stomach and
gastroesophageal reflux in the
esophagus)
Signs None
Many cycles of damage and
Etiology repair of (usually) gastric
mucosa
1. Goblet cells interspersed with
absorptive columnar cells with a
brush border in glands with
minimal architectural distortion
(Figs. 1.8.1 and 1.8.2). Paneth
Histology cells may be present
2. PAS/AB stain shows goblet
cells separated by absorptive-
type cells with an accentuated
brush border (Figs. 1.8.3 and
1.8.4)
Goblet cells stain with
MUC2 and CDX2,
Special brush border with
studies CD10, negative
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Incomplete Intestinal
Metaplasia
Adults; male predominance
Usually found in the esophagus
and less frequently found in the
stomach or other organs in the
body that are not the focus of
this book (pancreatobiliary
system)
Typically asymptomatic—any
symptoms relate to the
underlying source of injury that
caused the intestinal metaplasia
(usually Helicobacter pylori
gastritis in the stomach and
gastroesophageal reflux in the
esophagus)
None
Many cycles of damage and
repair of (usually) esophageal
mucosa
1. Goblet cells interspersed with
gastric foveolar-type cells in
glands with moderate
architectural distortion (Figs.
1.8.5 and 1.8.6)
2. PAS/AB stain shows goblet
cells separated by neutral
mucin-producing cells (Figs.
1.8.7 and 1.8.8)
Goblet cells stain with
MUC2 and CDX2, no
brush border with
CD10, positive
 MUC5AC MUC5AC in gastric
foveolar-type cells

Treatment None None

Lower but finite risk of entering
the dysplasia–carcinoma
sequence on epidemiologic
Prognosis grounds than incomplete
intestinal metaplasia but not a
prognostic marker in any
individual case
Higher but finite risk of
entering the dysplasia–
carcinoma sequence on
epidemiologic grounds than
complete intestinal metaplasia
but not a prognostic marker in
any individual case

Figure 1.8.1 Complete intestinal metaplasia. This biopsy is actually from the
gastric antrum rather than the esophagus since the antrum is a more likely
location for complete intestinal metaplasia. There are goblet cells separated by
absorptive cells, each with a brush border.

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Figure 1.8.2 Complete intestinal metaplasia. This example shows goblet cells,
a brush border, and even Paneth cells.

Figure 1.8.3 Complete intestinal metaplasia, PAS/AB stain. The gastric antral
glands in the deep part of the biopsy contain pink neutral mucin as do the
surface gastric foveolar cells. The complete intestinal metaplasia shows goblet
cells between absorptive cells lacking cytoplasmic mucin.

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Figure 1.8.4 Complete intestinal metaplasia, PAS/AB stain. Note the difference
between the Paneth cells and the goblet cells.

Figure 1.8.5 Incomplete intestinal metaplasia. There are mostly gastric

foveolar cells and scattered bluish goblet cells.

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Figure 1.8.6 Incomplete intestinal metaplasia. Note the bubbly bluish
appearance of the goblet cells.

Figure 1.8.7 Incomplete intestinal metaplasia, PAS/AB. The goblet cells are
easy to spot!

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Figure 1.8.8 Incomplete intestinal metaplasia, PAS/AB. The goblet cells show
bubbly cytoplasm on PAS/AB.

1.9 Oncocytic change of submucosal

glands vs. Pyloric gland adenoma
Oncocytic Change of
Esophageal Submucosal Pyloric Gland Adenoma
Glands
Unknown—presumably
Age/Gender middle-aged persons; male Adults; female predominance
predominance
Location Esophagus Body of stomach
None attributable to the pyloric
None attributable to the gland adenoma, although these
oncocytic change, which is an tumors can become eroded and
Symptoms incidental finding, usually on produce gastric bleeding and the
endoscopic mucosal resection patients with these tumors are
specimens likely to have autoimmune
gastritis
None attributable to the

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Signs esophageal submucosal gland The patient may have pernicious
changes anemia
In some cases, gastric pyloric
gland adenomas are attributable
Presumably esophageal
to pyloric metaplasia from many
Etiology epithelial damage and
cycles of damage and repair of
obstruction of the ducts
gastric oxyntic mucosa by
autoimmune damage
Plump eosinophilic cells are Neoplastic polyps composed of
seen in esophageal submucosal closely packed tubules formed by
glands. Nuclei are usually cells that contain round nuclei
Histology
small and the nuclear-to- and relatively abundant ground-
cytoplasmic ratio is low (Figs. glass cytoplasm (Figs.
1.9.1–1.9.4) 1.9.5–1.9.8)
The tubules express
MUC6, and there is
often MUC5
expression of cells at
Special None the surface of the
studies polyps. The
background stomach
mucosa often shows
autoimmune gastritis

Complete polypectomy is
Treatment None. Incidental finding indicated since a subset
progresses to adenocarcinoma
Excellent. However, these are
sometimes encountered in
Overall good following
endoscopic mucosal resection.
polypectomy, but the affected
Prognosis Samples to the prognosis are
patients tend to be at risk for a
that of the lesion for which the
host of gastric neoplasms
mucosal resection was
performed

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Figure 1.9.1 Oncocytic change in esophageal submucosal glands. This
esophageal biopsy contains a duct (center) and submucosal glands at the lower
part of the field that show pink oncocytic cytoplasm. There seems to be
inflammation, and presumably, the change is secondary to the inflammation.

Figure 1.9.2 Oncocytic change in esophageal submucosal glands. This example

is striking, but note the low nuclear-to-cytoplasmic ratio.

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Figure 1.9.3 Oncocytic change in esophageal submucosal glands.

Figure 1.9.4 Oncocytic change in esophageal submucosal glands.

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Figure 1.9.5 Pyloric gland adenoma. These lesions are more likely to be
encountered in the gastric body than the esophagus and consist of tightly
packed tubules.

Figure 1.9.6 Pyloric gland adenoma. The cytoplasm is not bright pink, nor does
it contain classic gastric foveolar mucin. Instead, it has a ground-glass
appearance.

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Figure 1.9.7 Pyloric gland adenoma. This example has zones of surface
nuclear stratification.

Figure 1.9.8 Pyloric gland adenoma. Note the ground-glass appearance of the
cytoplasm.

1.10 Eosinophilic esophagitis vs.

Reflux esophagitis

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 Eosinophilic Esophagitis Reflux Esophagitis
Usually adults;
Age/Gender Children, young adults; male predominance
male predominance
Location Esophagus (distal and mid/proximal) Esophagus (distal)
Dysphagia, failure to thrive in young
Heartburn,
children, food impaction (classically
Symptoms hoarseness if reflux
encountered in adolescent/young adult
reaches larynx
males). Strictures may be found
“Trachealization of esophagus” with rings
and furrows reminiscent of a cat's esophagus
Esophagitis, distal
Signs (“Feline esophagus”) (Figs. 1.10.1 and
predominant
1.10.2), variable peripheral blood
eosinophilia, eczema, asthma
Esophageal
damage resulting
from reflux of
gastric contents
into the esophagus.
Esophageal damage probably resulting from
Etiology These contents
an allergic response
contain
gastroduodenal
secretions. Patients
tend to be adult,
male, and obese
Mild basal cell
Sheets of eosinophils, often toward the hyperplasia,
surface of the epithelium, lamina propria elongation of
scarring, prominent basal cell hyperplasia vascular papillae,
(Figs. 1.10.3–1.10.6). Suggesting the spongiosis of basal
possibility requires >15 eosinophils/hpf. If cells, occasional
there are large numbers (typically >100 lymphocytosis,
Histology eosinophils/hpf), then the biopsy is mild acute
diagnostic of eosinophilic esophagitis. In inflammation,
cases with only 15–20 eosinophils/hpf, scattered
better to report as “esophagitis with up to X eosinophils (Figs.
eosinophils/hpf.” Additionally, findings can 1.10.4–1.10.12),
be very focal/patchy usually <15

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 eosinophils/hpf
Special None None
studies
Patients are treated
with proton pump
inhibitors. Some
Correlation with skin testing and elimination
require
Treatment of dietary antigens. Topical steroids are also
fundoplication
used (budesonide, oral)
operations to
reduce their reflux
of gastric contents
Patients with
gastroesophageal
reflux disease are
at risk for Barrett
Responsive to dietary and/or steroid
Prognosis esophagus and
treatment
esophageal
adenocarcinoma,
but this risk is low
overall

Figure 1.10.1 Feline esophagus. This image is from an autopsy of a domestic

cat. The mucosa of the feline esophagus is reminiscent of that of trachea.

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Figure 1.10.2 Feline esophagus. This is an endoscopic image of the esophagus
of a child with eosinophilic esophagitis. The appearance is similar to that of
the cat's esophagus seen in Figure 1.10.1.

Figure 1.10.3 Eosinophilic esophagitis. This example is interesting because

there are only a few eosinophils in the epithelium but many in the lamina
propria, which is scarred.

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Figure 1.10.4 Eosinophilic esophagitis. This is the lamina propria from the
lesion shown in Figure 1.10.3.

Figure 1.10.5 Eosinophilic esophagitis. There is prominent basal cell

hyperplasia, and there are a number of intraepithelial eosinophils.

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Figure 1.10.6 Eosinophilic esophagitis. Note the surface eosinophilic
abscesses.

Figure 1.10.7 Reflux esophagitis. This field shows mild basal cell hyperplasia
and elongation of vascular papillae.

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Figure 1.10.8 Reflux esophagitis. There are two eosinophils in this field.

Figure 1.10.9 Reflux esophagitis. There are a few eosinophils. The basal layer
shows a peculiar vacuolated change. The intercellular bridges are striking, a
result of intercellular edema in the basal layer.

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Figure 1.10.10 Reflux esophagitis. This is high power of the basal cell layer
showing intercellular edema as manifested by prominent intercellular bridges.

Figure 1.10.11 Reflux esophagitis. This example shows “incipient” vascular

lakes around damaged vascular papillae.

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Figure 1.10.12 Reflux esophagitis. Edema in the area of a vascular papilla.

1.11 Taxane effect vs. Squamous and

columnar epithelial dysplasia
Squamous and
Taxane Effect
Columnar Dysplasia
Usually adults since taxanes (paclitaxel,
docetaxel, and cabazitaxel) are
administered to treat cancers and have
been used for breast, lung, and prostate
carcinomas, among other malignant
neoplasms. There is no gender
predominance for the epithelial changes
Adults; usually male
Age/Gender associated with taxane use. Although
for both conditions
some patients show such epithelial
changes because they have taxane
toxicity, usually the epithelial changes
simply reflect administration of the
medications within 2–4 days from when
the biopsy of the esophagus (or other
gastrointestinal tract sites) is taken

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 Distal esophagus
(columnar lesions)
Location Throughout gastrointestinal tract
and all of esophagus
(squamous lesions)
Asymptomatic unless toxic. Patients
typically simply happen to have
gastrointestinal tract biopsies for another
Symptoms reason a few days after administration of None
their taxane drug for a malignant
neoplasm unrelated to the gastrointestinal
tract
Columnar epithelium
seen in the esophagus
(columnar dysplasia);
Signs Usually none
lack of retention of
Lugol iodine
(squamous dysplasia)
Columnar dysplasia is
associated with
accumulation of
genetic alterations in
Taxanes interfere with microtubule Barrett mucosa in
function so their effects are seen in patients with
proliferating cells—the basal cells in gastroesophageal
squamous epithelium and the proliferative reflux disease,
Etiology
compartment in columnar epithelium (the whereas squamous
neck of the glands in the dysplasia is associated
stomach/esophagus, the bases of the with accumulation of
crypts in intestinal epithelium) genetic alterations in
squamous mucosa in
patients with risk
factors of smoking
and alcohol use
1. In squamous
dysplasia, epithelium
of varying thickness
depending on the

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 grade of dysplasia
appears markedly
atypical since the cells
1. In squamous epithelium, the basal layer are markedly enlarged
appears markedly atypical since the cells and basophilic (Figs.
are markedly enlarged and basophilic 1.11.6–1.11.8)
(Fig. 1.11.1) 2. If the mucosa is
2. At higher magnification, there is columnar, epithelial
striking mitotic arrest restricted to the changes generally
basal layer manifested as ring mitoses and extend onto the
Histology surface (Figs. 1.11.9
prominent apoptosis (Figs. 1.11.2 and
1.11.3) and 1.11.10)
3. If the mucosa is columnar, the mitotic 3. The epithelial
arrest is restricted to the proliferative changes feature ring
compartment, above the cardiac glands mitoses occasionally,
and below the surface mucosa (Figs. but this is not a
1.11.4 and 1.11.5) prominent feature.
Apoptosis may be
encountered. In all
forms of esophageal
dysplasia, whether
squamous or
columnar, nucleoli are
not a prominent
feature of most cases
p53 often
labels nuclei
None. If Ki-67 labeling is in dysplasia,
Special performed, the surface cells and Ki-67
studies lack nuclear labeling shows
increased
proliferation

Mucosal ablation,
often with
radiofrequency
ablation and
Treatment None endoscopic mucosal

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 resection, is used for
both squamous and
columnar lesions of
the esophagus
Overall favorable for
in situ lesions but
The prognosis is related to the underlying
Prognosis some patients
indication for taxane chemotherapy
progress to
carcinomas

Figure 1.11.1 Taxane-associated changes, squamous mucosa. Note the ring

mitosis and apoptosis in the proliferative compartment (the basal layer).

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Figure 1.11.2 Taxane-associated changes, squamous mucosa. High
magnification of the findings shown in Figure 1.11.1.

Figure 1.11.3 Taxane-associated changes, squamous mucosa.

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Figure 1.11.4 Taxane-associated changes, columnar mucosa. This is cardiac
mucosa. Note that the proliferative compartment is between the surface and the
deep glands, so only this is affected. Ring mitosis and apoptotic bodies are
abundant, but the surface is normal.

Figure 1.11.5 Taxane-associated changes, columnar mucosa.

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Figure 1.11.6 Squamous dysplasia. The left portion of the tissue is affected,
and there is full-thickness damage. The right portion is normal. This contrasts
with the diffuse effect of taxane-associated changes.

Figure 1.11.7 Squamous dysplasia. The process affects the full thickness of the
tissue, and ring mitoses are not a feature.

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Figure 1.11.8 Squamous dysplasia. This process affects only part of the
thickness of the epithelium and may be so-called lateral spread of squamous
cells carcinoma in the mucosa, but it features markedly atypical cells and no
ring forms and minimal apoptosis.

Figure 1.11.9 High-grade columnar epithelial dysplasia. This process affects

the full thickness of the mucosa.

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Figure 1.11.10 High-grade columnar epithelial dysplasia. Note the surface
alteration.

1.12 Esophagitis dissecans (sloughing

esophagitis) vs. Esophageal
pemphigus vulgaris
Esophagitis Dissecans Pemphigus Vulgaris
Typically 50 to elderly;
Adults (30s and 40s); no gender
Age/Gender probably no gender
predilection
predilection
Usually in distal or mid Usually affects skin and oral cavity.
esophagus but some Most patients with oral involvement
Location
patients have damage to (the classic site) also have
the entire esophagus esophageal involvement
Some patients have
Symptoms Odynophagia, dysphagia
dysphagia
Normal mucosa initially with the
appearance of erosions and sheets of
At endoscopy, sheets of sloughed epithelium upon

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 desquamated squamous withdrawal of the endoscope. May be
Signs
esophagus are found and Nikolsky sign (a skin finding in
there are white plaques which the top layers of the skin slip
away from the lower layers when
slightly rubbed)
Not clear. Patients are
often taking multiple
Not clear—the process is
medications or are
autoimmune, resulting in painful
bedridden. Some are
Etiology blistering of the skin and mucus
alcoholics, and some take
membranes. Immunofluorescence
medications that result in
shows deposition of IgG and C3
central nervous system
depression
1. Superficial epithelium is
eosinophilic and displays
coagulative necrosis (Figs.
1.12.1 and 1.12.2)
2. There may be a blistered
appearance between the 1. Zone of separation of squamous
viable and nonviable epithelium at the basal layer (Fig.
portion and viable portions 1.12.6)
of squamous epithelium 2. Viable squamous epithelium above
with scattered the basal layer (Fig. 1.12.7)
Histology
inflammatory cells (Figs. 3. Acantholysis of the basal cell layer
1.12.3 and 1.12.4) with a cobblestone appearance of
3. Strips of detached upper basal squamous cells (Fig. 1.12.8)
portion of squamous 4. Basal cells with “bullet-shaped”
epithelium may be nucleoli (Figs. 1.12.9 and 1.12.10)
encountered. The line of
breakage is midway in the
squamous epithelium
rather than at the basal
layer (Fig. 1.12.5)
Negative fungal Direct
stains and immunofluorescence
Special negative stains studies for anti-IgG
studies for viral antibodies may be helpful
organisms in doubtful cases to

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 confirm the diagnosis

Corticosteroid treatment has been the

mainstay of therapy, but numerous
Treatment None
immune modulators have been used,
most recently rituximab (anti-CD20)
About half of patients can achieve
Most patients have sustained remission of lesions with
Prognosis
resolution of the condition treatment, but this is a chronic
disease

Figure 1.12.1 Esophagitis dissecans/sloughing esophagitis. The epithelium has

a “two-toned” appearance with a division of viable and “mummified”
epithelium that will soon slough.

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Figure 1.12.2 Esophagitis dissecans/sloughing esophagitis.

Figure 1.12.3 Esophagitis dissecans/sloughing esophagitis. This example has a

tissue cleft that is about to separate. This appearance can result in a concern
for a bullous disease.

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Figure 1.12.4 Esophagitis dissecans/sloughing esophagitis.

Figure 1.12.5 Esophagitis dissecans/sloughing esophagitis. This portion has

sloughed off. The nuclei show coagulative necrosis, and bacterial forms are
abundant.

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Figure 1.12.6 Pemphigus vulgaris. The tissue fragment at the left shows a
residual basal layer (rather than a break in the middle of the epithelium). The
portion at the right has sloughed off but is viable.

Figure 1.12.7 Pemphigus vulgaris. This epithelium has chipped off the basal
layer. There is acantholysis in the deep portion.

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Figure 1.12.8 Pemphigus vulgaris. There is prominent inflammation.

Figure 1.12.9 Pemphigus vulgaris. Note the striking acantholysis of the basal
zone.

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Figure 1.12.10 Pemphigus vulgaris. Some observers liken the appearance of
these nucleoli to bullets.

1.13 Lichenoid esophagitis vs. Reflux

change
Lichenoid Esophagitis Reflux Esophagitis
Late 50s or early 60s. Female
predominance for lichenoid
esophagitis that is not lichen planus Usually adults; male
Age/Gender
esophagitis and striking female predominance
predominance for proven lichen
planus esophagitis
Location Distal and mid esophagus Esophagus (distal)
Dysphagia from strictures (especially
in patients proven to have lichen
planus esophagitis but also found in Heartburn, hoarseness if
Symptoms patients with histologically identical
reflux reaches larynx
changes in which lichen planus

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 cannot be confirmed)
Strictures, endoscopic appearance of
esophagitis. Some cases are
associated with skin or oral lichen
planus, and other patients have
identical histologic findings but Esophagitis, distal
Signs
cannot be confirmed to have lichen predominant
planus. Such patients can sometimes
be shown to have viral hepatitis C or
human immunodeficiency virus, or
they are taking multiple medications
Esophageal damage
resulting from reflux of
gastric contents into the
Etiology esophagus. These contents
contain gastroduodenal
secretions. Patients tend to
be adult, male, and obese
1. There is striking esophageal
lymphocytosis and prominent
inflammation at the interface between
the basal layer and the lamina propria
Mild basal cell
(Figs. 1.13.1 and 1.13.2). In contrast
hyperplasia, elongation of
to the skin, there is no granular layer
vascular papillae,
so no hypergranulosis or
spongiosis of basal cells,
parakeratosis is seen.
occasional lymphocytosis,
2. Many apoptotic squamous
Histology mild acute inflammation,
epithelial cells are seen (“Civatte
scattered eosinophils
bodies” if lichen planus can be
(Figs. 1.13.5–1.13.8),
confirmed by immunofluorescence
usually <15
studies) (Fig. 1.13.3). Some patients
eosinophils/hpf. Apoptotic
have only lymphocytosis
cells are not a feature
(lymphocytic esophagitis); in
children, this finding correlates with
Crohn disease but not in adults (Fig.
1.13.4)
Direct immunofluorescence

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 may confirm lichen planus.
Special None
A subset of patients has
studies
complicating candidiasis so
biopsies should be assessed
for this

Patients are treated with

proton pump inhibitors.
Treatment is supportive. Strictures
Some require
Treatment can be dilated, and some patients
fundoplication operations
have some response to steroids
to reduce their reflux of
gastric contents
Patients with
gastroesophageal reflux
There is a small but finite (about 5%) disease are at risk for
Prognosis chance of development of squamous Barrett esophagus and
cell neoplasia esophageal
adenocarcinoma, but this
risk is low overall

Figure 1.13.1 Lichenoid esophagitis. This appearance can be seen in

esophageal lichen planus or in association with a host of conditions (hence the
descriptive terminology). There is striking intraepithelial lymphocytosis and a

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few brightly eosinophilic apoptotic squamous cells (termed Civatte bodies in
the setting of lichen planus).

Figure 1.13.2 Lichenoid esophagitis. This biopsy was from a patient who did
not have lichen planus but had recently begun taking a monoclonal antibody
(adalimumab) for her rheumatoid arthritis.

Figure 1.13.3 Lichen planus esophagitis. A Civatte body is present.

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Figure 1.13.4 Esophageal lymphocytosis/“lymphocytic esophagitis.” There are
fewer lymphocytes than in Figures 1.13.1 and 1.13.2. This pattern is
nonspecific although in children, it is associated with Crohn disease.

Figure 1.13.5 Reflux esophagitis. The salient features are basal cell
hyperplasia and elongation of vascular papillae.

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Figure 1.13.6 Reflux esophagitis. This example shows only a few
intraepithelial lymphocytes around vascular papillae.

Figure 1.13.7 Reflux esophagitis. This example has striking elongation of

vascular papillae.

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Figure 1.13.8 Reflux esophagitis. Minimal lymphocytosis is typical.

1.14 Atypical stromal cells in ulcers

vs. Sarcomatoid squamous cell
carcinoma
Reactive Stromal Changes in Sarcomatoid Squamous Cell
Ulcers and Polyps Carcinoma
Older individuals, often with
Age/Gender comorbidities that might result in Older males
ischemia; no gender predilection
Anywhere in esophagus as
Location Mid esophagus
associated with ulcers
Related to the ulcers—dysphagia, Progressive dysphagia from
Symptoms
odynophagia polypoid mass
Ulcer visible endoscopically. In Large typically polypoid mass
Signs esophageal examples, there is that obstructs the esophageal
generally no polyp or mass lumen (Fig. 1.14.4)
Whatever the etiology of the All the risk factors for typical

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 ulcer; reflux associated, squamous cell carcinoma
Etiology medication associated, apply—male gender, alcohol,
chemoradiation associated; often tobacco, black race, lower
in debilitated persons socioeconomic grouping
1. Markedly atypical fibroblasts
1. Eosinophilic cytologically
that are found at the interface of
malignant spindle cells
necrotic ulcer exudate and viable
forming an exophytic mass
granulation tissue (Fig. 1.14.1)
(Fig. 1.14.5). The cells have a
2. The fibroblasts have enlarged
high nuclear-to-cytoplasmic
Histology smudged nuclei but a low nuclear-
ratio (Fig. 1.14.6)
to-cytoplasmic ratio; a
2. An in situ or conventional
pseudosarcomatous appearance
squamous cell carcinoma may
(Fig. 1.14.2)
accompany the lesion (Figs.
3. The fibroblasts intercalate
1.14.7 and 1.14.8)
among capillaries (Fig. 1.14.3)
If immunolabeling is
performed, the
Sometimes but not
fibroblasts are
always positive for
“vimentin-only” cells
Special keratins, such as
(although vimentin
studies CAM5.2 or
staining is not needed).
AE1/Ae3. P63 may
Importantly, keratins
be reactive
and S100 protein are
negative

None for the fibroblasts

themselves. Any treatment is
Generally chemoradiation and
Treatment directed at the underlying etiology
esophagectomy
of the ulcer (generally
gastroesophageal reflux disease)
Excellent for the atypical stromal
cells. The underlying condition Poor despite an initially
Prognosis
responsible for the ulcers must be favorable outcome
addressed

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Figure 1.14.1 Pseudosarcomatous stromal cells in ulcers. Note the
margination. The atypical cells are accentuated just under the ulcer and in a
somewhat organized arrangement.

Figure 1.14.2 Pseudosarcomatous stromal cells in ulcers. The atypical cells

form a rund at the base of the ulcer.

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Figure 1.14.3 Pseudosarcomatous stromal cells in ulcers. They often have a
low nuclear-to-cytoplasmic ratio.

Figure 1.14.4 Sarcomatoid squamous cell carcinoma, gross specimen. These

tumors tend to be exophytic masses.

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Figure 1.14.5 Sarcomatoid squamous cell carcinoma. There is no margination
of the atypical cells, which are spread haphazardly throughout the sample.

Figure 1.14.6 Sarcomatoid squamous cell carcinoma.

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Figure 1.14.7 Sarcomatoid squamous cell carcinoma. This example also
features a conventional squamous cell carcinoma component as the flat
component whereas the exophytic component is sarcomatoid.

Figure 1.14.8 Sarcomatoid squamous cell carcinoma. Higher magnification of

the lesion seen in Figure 1.14.7.

1.15 Multilayered epithelium vs.

Squamous dysplasia

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 Multilayered Epithelium in the Squamous Dysplasia
Esophagus
Adults. Median age in the initial
Age/Gender immunolabeling series reporting this Adult males
finding: 57 years. Male predominance
Throughout esophagus,
Location Distal esophagus probably more likely in
mid esophagus
No symptoms attributable to the
multilayered epithelium per se. This
finding does correlate with
Symptoms gastroesophageal reflux, and it may be Typically asymptomatic
a precursor to conventional Barrett
mucosa. Patients can manifest
symptoms of gastroesophageal reflux
There may be lack of
retention of Lugol
iodine on endoscopic
None. Usually found on biopsies from
Signs examination. Some
the gastroesophageal junction
examples show a
whitish plaquelike
appearance
Associated with
Etiology Associated with reflux smoking and alcohol
intake
1. There is atypical
squamous epithelium of
varying thickness with
variable degrees of
maturation depending on
grade of squamous
dysplasia (Figs. 1.15.4
and 1.15.5)
1. This epithelium consists of four to
2. There is no
eight layers of cells that appear to be
suggestion of columnar
squamous in the basal aspect and
differentiation at the
Histology columnar in the superficial portion with
surface
an appearance reminiscent of that of
3. An associated finding

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 an appearance reminiscent of that of
immature squamous metaplasia of the
uterine cervix (Figs. 1.15.1–1.15.3)
3. An associated finding
is so-called epidermoid
metaplasia, also called
“orthokeratotic
dysplasia,” which is
essentially like skin,
displaying a granular
layer and hyperkeratosis
but minimal cytologic
atypia (Fig. 1.15.6)

In multilayered epithelium,
Shows p63
there is expression of p63 and
and increased
SOX2 (squamous
Ki-67 and p53
differentiation markers) in all
but no markers
cases and a subset displays
of columnar
CDX2, villin, or MUC2
Special cell
(intestinal differentiation
studies differentiation
markers), but not all
(MUC5AC,
examples display the latter
MUC2,
intestinal markers. PAS/AB
CDX2)
shows a purple color akin to
No mucin on
that of classic goblet cells in
PAS/AB stain
columnar mucosa

Mucosal ablation with

radiofrequency or with
Treatment None
localized endoscopic
mucosal resection
Multilayered epithelium is correlated
with gastroesophageal reflux disease
and may progress to conventional
May progress to
Barrett mucosa. It does not itself appear
Prognosis squamous cell
to be associated with dysplasia or
carcinoma
adenocarcinoma in the absence of
progression to conventional Barrett
mucosa

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Figure 1.15.1 Multilayered epithelium. This area appears similar to immature
squamous metaplasia of the uterine cervix. It is usually seen in association with
gastrocardiac-type mucosa rather than in purely squamous mucosa.

Figure 1.15.2 Multilayered epithelium. Note the bubbly appearance of the cells
towards the surface.

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Figure 1.15.3 Multilayered epithelium, PAS/AB stain. The bubbly surface cells
gave an alcianophilic appearance similar to that of goblet cells, but classic
goblet cell morphology is absent. There is a small amount of adjoining cardiac-
type epithelium.

Figure 1.15.4 Squamous dysplasia. The nuclei are enlarged, and there is no
bubbly appearance towards the surface. This is a purely squamous lesion.

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Figure 1.15.5 Squamous dysplasia. Note the overt cytologic alterations.

Figure 1.15.6 Epidermoid metaplasia. This lesion was in the esophagus but has
a granular layer just like skin, which is usually absent in the esophagus. This
zone was nearby a squamous cell carcinoma. However, it is not clear whether
this finding is a precursor lesion or simply a marker for risk for squamous cell
carcinoma.

1.16 Columnar epithelial dysplasia vs.

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Reactive epithelial changes
Reactive Changes in Barrett
Columnar Epithelial Dysplasia
Esophagus
Usually 60 years or older; male Typically 50 to elderly; male
Age/Gender
predominance predominance
Location Distal esophagus Distal esophagus
May be dysphagia, heartburn
Asymptomatic or symptoms
Symptoms attributable to reflux or to
attributable to reflux
erosions from reflux
At endoscopy, columnar
epithelium is present but without
advanced endoscopic techniques, Erosions/ulcers may be
Signs
dysplastic columnar epithelium present at endoscopy
appears similar to nondysplastic
columnar epithelium
Typically uncontrolled reflux
of gastric contents into the
esophagus. These contents
Columnar epithelial dysplasia is
may be alkaline if there is a
Etiology epidemiologically attributable to
significant component of
gastroesophageal reflux disease
duodenal contents into the
stomach and then, in turn,
into the esophagus
1. Low-grade dysplasia displays
cytologic alterations that
predominate in the bases of the
1. Barrett mucosa, often with
pits with some extension onto the
inflammation (Figs.
surface (Figs. 1.16.1 and 1.16.2)
1.16.6–1.16.8)
2. High-grade dysplasia shows
2. There is generally gradual
alterations that involve the full
maturation of the cells toward
thickness of the epithelium (Figs.
the mucosal surface. Nucleoli
Histology 1.16.3 and 1.16.4)
may be present (Fig. 1.16.9)
3. Usually not inflammatory but if
3. In cases in which there is
high-grade dysplasia has
diagnostic uncertainty, the
inflammation, the nuclear

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 alterations are in excess of those term “indefinite for
that can be attributed to a dysplasia” can be applied
reparative process, with striking (Fig. 1.16.10)
nuclear hyperchromasia. Nucleoli
are not prominent (Fig. 1.16.5)

Numerous
Dysplasia often displays published studies
prominent p53 reactivity focus on
with focal surface proliferation
involvement in low- markers, p53, and
grade dysplasia and AMACR, but
Special prominent surface histology is critical
studies involvement in high- Additional
grade dysplasia. A sampling after
similar pattern is measures to reduce
observed with Ki-67 inflammation is
immunolabeling often the practical
solution

Radiofrequency ablation or
endoscopic mucosal resection is
the treatment of choice for high- Measures to reduce the effect
grade dysplasia. Treatment of low- of reflux disease (proton
Treatment
grade dysplasia remains pump inhibitor treatment,
controversial since observer fundoplication operations)
variability in interpretation is not
good
About 6% of patients with high-
grade dysplasia per year progress Most examples do not
Prognosis to adenocarcinoma if untreated. progress to
The data are less clear for low- dysplasia/neoplasia
grade dysplasia

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Figure 1.16.1 Low-grade dysplasia in Barrett esophagus. Hyperchromatic
stratified enlarged nuclei extend onto the surface. Nuclear polarity is
maintained.

Figure 1.16.2 Low-grade dysplasia in Barrett esophagus. Higher magnification

of the lesion seen in Figure 1.16.1. Tangential embedding gives an impression
of loss of nuclear polarity, but the well-oriented zones lack it.

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Figure 1.16.3 High-grade dysplasia in Barrett esophagus. Even at this
magnification, loss of nuclear polarity is apparent at the surface. The glands
are lined by hyperchromatic nuclei.

Figure 1.16.4 High-grade dysplasia in Barrett esophagus. Hyperchromatic

nuclei have lost their relationship to the basement membrane (loss of polarity).

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Figure 1.16.5 High-grade dysplasia in Barrett esophagus. This example shows
a surface erosion. This may be a result of technique when seen in endoscopic
mucosal resection (EMR) specimens because the mucosa is pressed against a
plastic cap during the procedure.

Figure 1.16.6 Barrett esophagus with reactive changes. It is normal to see some
degree of nuclear enlargement at the bases of the glands, and this gradually
matures. Tangential embedding can cause the basal glands to appear more
prominent, as in this case.

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Figure 1.16.7 Barrett esophagus with reactive changes. Higher magnification
of the field shown in Figure 1.16.6.

Figure 1.16.8 Barrett esophagus with reactive changes. At very high

magnification, reparative basal glands can appear alarming.

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Figure 1.16.9 Barrett esophagus with reactive changes. A mature surface is
generally reassuring.

Figure 1.16.10 Barrett esophagus with epithelial changes indefinite for

dysplasia. Prominent surface stratification is accompanied by neutrophils in
this example.

1.17 Low-grade columnar epithelial

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dysplasia vs. High-grade columnar
epithelial dysplasia
Low-Grade Columnar Epithelial High-Grade Columnar
Dysplasia Epithelial Dysplasia
Adults, male predominance. Adults, male predominance.
Age/Gender
Usually patients are in 60s Usually patients are in 60s
Location Distal esophagus Distal esophagus
Symptoms Asymptomatic Asymptomatic
Endoscopist sees columnar
Endoscopist sees columnar mucosa, but generally biopsy
mucosa, but generally biopsy is is required to confirm high-
Signs required to confirm low-grade grade dysplasia. Some
dysplasia. Some examples produce examples are polypoid,
a polypoid lesion however, and produce a mass
or polyp
Associated with chronic Associated with chronic
Etiology
gastroesophageal reflux gastroesophageal reflux
1. Crowded glands (Fig.
1. Slightly crowded glands (Fig. 1.17.8)
1.17.1) 2. Nuclear hyperchromasia
2. Nuclear hyperchromasia and and prominent nuclear
some nuclear membrane membrane irregularities (Fig.
irregularities, especially in bases of 1.17.9)
pits (Fig. 1.17.2) 3. Loss of nuclear polarity
3. Minimal loss of nuclear polarity (Fig. 1.17.10)
(Fig. 1.17.3) 4. Variable luminal necrosis
4. No luminal necrosis in glands in glands (Fig. 1.17.11)
Histology (Fig. 1.17.4) 5. Surface involvement.
5. Surface involvement in most Sometimes, inflammation is
cases without inflammation (Fig. present (Fig. 1.17.12)
1.17.5) 6. Some cases show small
6. Occasional cases lacking surface hyperchromatic nuclei
involvement (basal dysplasia) (Fig. arranged in a monolayer
rather than stratified

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 1.17.6) (“nonadenomatous”
7. Nucleoli not a feature in most dysplasia) (Fig. 1.17.13)
cases 7. Nucleoli not a feature in
most cases
Numerous
Numerous published published studies
Special studies using Ki-67, p53 using Ki-67, p53
studies (Fig. 1.17.7), AMACR (Fig. 1.17.14),
to confirm dysplasia AMACR to
confirm dysplasia

Most patients followed. Since there

is not good interobserver
Ablation therapy and
reproducibility, second opinions
mucosal resections. Some
Treatment are sought. Individuals with
patients opt for
extensive low-grade dysplasia are
esophagectomy
offered ablation therapy and
mucosal resections
Good response to ablation
but lifelong follow-up is
Good response to ablation but required. Morbidity
Prognosis
lifelong follow-up is required associated with
esophagectomy but the
procedure is curative

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Figure 1.17.1 Low-grade dysplasia in Barrett esophagus. Stratified
hyperchromatic cells extend to the surface, unaccompanied by inflammation.

Figure 1.17.2 Low-grade dysplasia in Barrett esophagus. Surface changes

consist of nuclear stratification and hyperchromasia.

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Figure 1.17.3 Low-grade dysplasia in Barrett esophagus. High magnification
of Figure 1.16.2. This lesion borders on high-grade dysplasia.

Figure 1.17.4 Low-grade dysplasia in Barrett esophagus.

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Figure 1.17.5 Low-grade dysplasia in Barrett esophagus. Another example
showing surface stratification and nuclear hyperchromasia and enlargement.

Figure 1.17.6 So-called basal crypt dysplasia. This pattern is unusual. In this
example, there is focal surface nuclear stratification at the right side of the
image but the surface overlying the overtly dysplastic glands on the left is
normal. Such lesions have been “lumped” with low-grade dysplasia but, since
the suggested follow-up for low-grade dysplasia is rebiopsy, this would not
seem to result in harm.

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Figure 1.17.7 So-called basal crypt dysplasia, p53 stain. This is a different
lesion from the one shown in Figure 1.17.6.

Figure 1.17.8 High-grade dysplasia. There is luminal necrosis unaccompanied

by neutrophils, but only in a single gland. The surface shows prominent loss of
nuclear polarity, and there are hyperchromatic tubules.

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Figure 1.17.9 High-grade dysplasia. There are tubules composed of cells with
round nuclei that have lost their relationship to the basement membrane (loss
of nuclear polarity).

Figure 1.17.10 High-grade dysplasia. Note the loss of nuclear polarity.

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Figure 1.17.11 High-grade dysplasia. This example shows tubules with luminal
necrosis and is thus borderline for intramucosal carcinoma and would be
regarded as such by some observers. This is of little consequence since
intramucosal carcinomas invading only the superficial lamina propria and
high-grade dysplasia are managed identically.

Figure 1.17.12 High-grade dysplasia. Compare the surface here to that of the
surface of low-grade dysplasia depicted in Figures 1.17.2 and 1.17.5. Figure
1.17.2 is at the same magnification—the nuclei are twice as wide in this image.

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Figure 1.17.13 High-grade dysplasia. This pattern of small hyperchromatic
tubules has been described using the terms “nonadenomatous dysplasia” and
“gastric-type dysplasia” in the literature. Terminology is less important than
recognizing it as a pattern of high-grade dysplasia.

Figure 1.17.14 High-grade dysplasia. Most examples show strong diffuse

nuclear p53 labeling, but 10% to 15% of examples lack such labeling.

1.18 High-grade columnar epithelial

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dysplasia vs. Intramucosal
adenocarcinoma
High-Grade Columnar Intramucosal Adenocarcinoma
Epithelial Dysplasia (T1a)
Adults, usually patients are in Adults, usually patients are in the
Age/Gender
the 60s; male predominance. 60s; male predominance.
Location Distal esophagus Distal esophagus
Symptoms Asymptomatic Asymptomatic
Endoscopist sees columnar
Endoscopist sees columnar
mucosa, but generally biopsy
mucosa, but generally biopsy is
is required to confirm high-
required to confirm high-grade
Signs grade dysplasia. Some
dysplasia. Some examples are
examples are polypoid,
polypoid, however, and produce a
however, and produce a mass
mass or polyp
or polyp
Associated with chronic Associated with chronic
Etiology
gastroesophageal reflux gastroesophageal reflux
1. Glands overrun the “lamina
1. Clearly distinct glands propria” (Fig. 1.18.6)
rather than “overgrowth of 2. Luminal necrosis (Fig. 1.18.7)
lamina propria” (Fig. 1.18.1) 3. No neutrophils in glands (Fig.
2. Minimal luminal necrosis 1.18.8)
(Fig. 1.18.2) 4. Nucleoli (Fig. 1.18.9)
Histology
3. Usually, no neutrophils in 5. Usually, only minimal
glands (Fig. 1.18.3) desmoplasia (Fig. 1.18.10).
4. No nucleoli (Fig. 1.18.4) Desmoplasia becomes developed
5. No desmoplasia (Fig. with submucosal invasion (T1b)
1.18.5) 6. Several schemes for assessing
depth of invasion (Fig. 1.18.11)
Numerous
published studies Numerous published
Special using Ki-67, p53, studies using Ki-67,
studies and AMACR to p53, and AMACR

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 confirm dysplasia

Ablation therapy and mucosal Ablation therapy and mucosal

Treatment resections. Some patients opt resections. Some patients opt for
for esophagectomy esophagectomy
Good response to ablation but
Good response to ablation but
lifelong follow-up is required.
lifelong follow-up is required.
Small but finite risk of metastases
No risk of metastases from
from intramucosal
Prognosis high-grade dysplasia (Tis).
adenocarcinomas. Morbidity
Morbidity associated with
associated with esophagectomy
esophagectomy but the
but the procedure is usually
procedure is curative
curative

Figure 1.18.1 High-grade dysplasia. Closely packet tubules composed of cells

with hyperchromatic nuclei showing loss of nuclear polarity. It is easy to draw
a line around each tubule as a discreet gland despite scant lamina propria
separating the tubules.

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Figure 1.18.2 High-grade dysplasia. Even under oil immersion microscopy,
nucleoli are not conspicuous.

Figure 1.18.3 High-grade dysplasia.

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Figure 1.18.4 High-grade dysplasia.

Figure 1.18.5 High-grade dysplasia. Note the surface loss of nuclear polarity.

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Figure 1.18.6 Intramucosal carcinoma. Note the syncytial arrangement of the
glands in the lower right portion of the biopsy.

Figure 1.18.7 Intramucosal carcinoma. Back-to-back glands have effaced the

lamina propria, and there is prominent luminal necrosis in them. It is difficult
to trace the contours of several of the glands in this field.

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Figure 1.18.8 Intramucosal carcinoma. The glands have overrun the lamina
propria and effaced it.

Figure 1.18.9 Intramucosal carcinoma. At this point, despite the lack of

desmoplasia, nucleoli are often prominent.

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Figure 1.18.10 Intramucosal carcinoma. This example shows early
desmoplasia.

Figure 1.18.11 Schemes for measuring the depth of invasion of intramucosal

carcinoma.

1.19 Lamina propria in columnar-

lined esophagus vs. Submucosa in

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columnar-lined esophagus
Lamina Propria in Endoscopic Submucosa in Endoscopic
Mucosal Resection Samples Mucosal Resection Samples
Age/Gender Adults (50+); mostly males Adults (50+); mostly males
Location Distal esophagus Distal esophagus
Symptoms Asymptomatic Asymptomatic
Columnar epithelium in the Columnar epithelium in the
Signs tubular esophagus seen at tubular esophagus seen at
endoscopy endoscopy
Multiple cycles of damage and Multiple cycles of damage and
repair to the esophagus that repair to the esophagus that
result in Barrett mucosa also result in Barrett mucosa also
result in duplication or result in duplication or
thickening of the muscularis thickening of the muscularis
Etiology mucosae. In biopsies and mucosae. In biopsies and
endoscopic resections, it is endoscopic resections, it is
important to understand the important to understand the
layers of the esophagus in order layers of the esophagus in order
to avoid misinterpretation of to avoid misinterpretation of
depth of invasion and thus stage depth of invasion and thus stage
1. Submucosa contains large
1. Mucosa consists of vessels, variably adipose tissue
epithelium, lamina propria, and and variably submucosal glands
muscularis mucosae, as (Figs. 1.19.6 and 1.19.7)
indicated for squamous and 2. In columnar mucosa, the
columnar mucosa (Figs. 1.19.1 muscularis mucosae becomes
and 1.19.2) duplicated but the layer in
2. In columnar mucosae, the between the two layers of
muscularis mucosae becomes muscularis mucosae is
duplicated but the layer in nonetheless still lamina propria
Histology between the two layers of whereas the tissue below the
muscularis mucosae is deeper thicker original
nonetheless still lamina propria muscularis mucosae is the
(Figs. 1.19.3 and 1.19.4) submucosa (Figs. 1.19.8 and
3. Since endoscopic mucosal 1.19.9)

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 resection samples are altered by
diathermy, it is important to
identify later mucosal margins
vs. deep submucosal margins,
as indicated (Fig. 1.19.5)
Special None
studies
None available to change
Treatment
duplicated muscularis mucosae
Depends on the presence of
Prognosis
neoplasia in the esophagus
3. Since endoscopic mucosal
resection samples are altered by
diathermy, it is important to
identify lateral mucosal margins
vs. deep submucosal margins,
as indicated (Fig. 1.19.10)
None
None available to change
duplicated muscularis mucosae
Depends on the presence of
neoplasia in the esophagus

Figure 1.19.1 Diagram showing the layers of the esophagus. In the absence of
mucosal damage and Barrett esophagus, the layers are easy to identify and the
muscularis mucosae (MM) is slender and forms a single layer.

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Figure 1.19.2 Endoscopic mucosal resection (EMR). At the time of the
procedure, the edges of the specimen curl inward. As such, lateral mucosal
margins can give the false impression of being deep submucosal margins. In
this EMR specimen, the submucosal layer is obvious because it contains
submucosal glands. Note also that there is duplicated muscularis mucosae
(indicated). There is also a focus of dysplasia at the upper right.

Figure 1.19.3 Endoscopic mucosal resection (EMR). In this example, there is

intramucosal carcinoma at the lateral mucosal (not deep submucosal) margin.

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Figure 1.19.4 Endoscopic mucosal resection (EMR). Just above the bottom of
the figure is a large submucosal vessel that has been bisected in the image. A
thick muscularis mucosae is above it. The delicate strands of smooth muscle
towards the surface are duplicated muscularis mucosae.

Figure 1.19.5 Endoscopic mucosal resection (EMR). This example shows thick
muscularis mucosae at the bottom of the sample and thin duplicated muscularis
mucosae toward the top.

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Figure 1.19.6 Endoscopic mucosal resection (EMR). In this sample lacking
Barrett mucosa, the layers are readily seen. The submucosal glands allow
identification of the submucosa, and the portion above the muscularis mucosae
is lamina propria (NOT submucosa). Note the prominent vascular channels in
the lamina propria.

Figure 1.19.7 Resection sample. There is muscularis propria at the bottom of

the image. The submucosa contains adipose tissue, and there is muscularis
mucosa above it. Note the disorganized muscularis mucosae at the right side of
the field.

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Figure 1.19.8 Resection sample. This field is from the submucosa. Note the
large vessels.

Figure 1.19.9 Endoscopic mucosal resection (EMR). The vessels in the true
submucosa are much larger than those in the space between the original and
duplicated muscularis mucosae.

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Figure 1.19.10 Endoscopic mucosal resection (EMR). The submucosa has
been outlined.

1.20 Pseudoepitheliomatous
hyperplasia vs. Squamous cell
carcinoma
Pseudoepitheliomatous
Squamous Cell Carcinoma
Hyperplasia
No age or gender
preferentially affected.
This results from any
Age/Gender Adults, usually 50+; male predilection
form of injury and can
be seen atop granular
cell tumors
Mid esophagus most common but may
Location Anywhere in esophagus
be in distal or proximal esophagus
There may be
dysphagia or
Symptoms odynophagia from the Dysphagia, odynophagia

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 underlying source of
the healing ulcer
An ulcer may be
Signs apparent at endoscopy. Mass lesion at endoscopy
No mass lesion is seen
Found in areas of
Associated with alcohol use and
Etiology healing ulcers from any
smoking
etiology
1. Often a zone of
ulceration adjoining the
1. If an ulcer is present, infiltrating
pseudoepitheliomatous
carcinoma extends from the base (Figs.
hyperplasia (Figs.
1.20.6 and 1.20.7)
1.20.1 and 1.20.2)
2. The lesion destroys the basement
2. A basal layer is
membrane and is accompanied by a
Histology usually apparent and
desmoplastic response (Figs. 1.20.8 and
intracellular edema is
1.20.9)
common (Figs. 1.20.3
3. An aberrant pattern of brightly
and 1.20.4)
eosinophilic keratinization is present
3. Keratinization is
(Fig. 1.20.10)
usually inconspicuous
(Fig. 1.20.5)
Lesions
express CK,
p63, and
CK5/CK6, Lesions express CK, p63, and
but this does CK5/CK6, but this does not
Special not allow allow distinction from
studies distinction pseudoepitheliomatous
from hyperplasia
squamous
cell
carcinoma

For early (T1a) lesions, endoscopic

ablation and endoscopic mucosal
resections or submucosal dissections are
Treatment None
reasonable therapy but esophagectomy

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 and chemoradiation are indicated for
higher-stage lesions
Variably aggressive depending on stage.
Benign with minimal
Early lesions can be cured, but the
Prognosis risk of subsequent
prognosis is poor for most lesions as
carcinoma
they present at advanced stage

Figure 1.20.1 Pseudoepitheliomatous hyperplasia in an area of ulcer/erosion.

The nests are pale and have rounded contours.

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Figure 1.20.2 Pseudoepitheliomatous hyperplasia in an area of ulcer/erosion.
Overall, the cells have a low nuclear-to-cytoplasmic ratio, and there is no
abnormal keratinization.

Figure 1.20.3 Pseudoepitheliomatous hyperplasia in an area of ulcer/erosion.

At high magnification, the cells have smooth nuclear membranes.

Figure 1.20.4 Pseudoepitheliomatous hyperplasia in an area of ulcer/erosion.

In this example, there is multinucleation as the cells attempt to fill in the
erosion to the left. The cells contain nucleoli rather than viral inclusions.

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Figure 1.20.5 Pseudoepitheliomatous hyperplasia in an area of ulcer/erosion.
Note the intercellular bridges and overall low nuclear-to-cytoplasmic ratio.

Figure 1.20.6 Squamous cell carcinoma. The process is disorganized, and there
is abnormal keratinization on the right.

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Figure 1.20.7 Squamous cell carcinoma. Bizarre abnormally keratinized cells
are present in sloughed tissue fragments.

Figure 1.20.8 Squamous cell carcinoma. There is striking desmoplasia.

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Figure 1.20.9 Squamous cell carcinoma. The nests of tumor penetrate the
desmoplastic tissue at acute angles.

Figure 1.20.10 Squamous cell carcinoma. Abnormal keratinization is present.

The basal layer on nonneoplastic epithelium is present at the upper right of the
field.

1.21 Esophageal smooth muscle

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tumors vs. Esophageal
gastrointestinal stromal tumors
Esophageal
Esophageal Smooth Muscle
Gastrointestinal Stromal
Tumors
Tumors (GISTs)
Esophageal leiomyomas have a
male predominance and are found Median age 60–96 years;
in young patients (median age 35 male predominance—rare—
years). Esophageal far less common than
Age/Gender
leiomyosarcomas are truly rare and esophageal leiomyomas but
probably have a male more common than
predominance and arise in older esophageal leiomyosarcomas
adults (60s)
Location Distal esophagus Distal esophagus
Most patients with leiomyomas are
asymptomatic, and the lesions are
incidental findings. About a quarter
present with dysphagia, and some
Symptoms present with chest pain. Esophageal Dysphagia
leiomyosarcomas are rare but
reported patients have presented
with dysphagia secondary to large
bulky tumors
Esophageal-based masses usually
Mass lesion in distal
Signs centered in muscularis propria but
esophagus
result in a mucosal bulging mass
Etiology Unknown No known risk factors
Cellular spindle cell lesion
Brightly eosinophilic of muscularis propria that is
perpendicularly oriented fascicles less eosinophilic than a
Histology of cytologically bland cells smooth muscle tumor and
(leiomyomas) (Figs. 1.21.1 and more cellular than a
1.21.2) leiomyoma (Figs. 1.21.4 and
1.21.5)

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 The rare reported
tumors have been
CD117+ (Fig.
Leiomyomas express 1.21.6) and
desmin, actin, calponin, CD34+ with
and caldesmon but can variable actin
easily be diagnosed on expression as per
Special H&E. A pitfall is that GISTs in other
studies Cajal cells can be anatomic
entrapped and these locations. Tested
express CD117/c kit tumors have
(Fig. 1.21.3) displayed exon 11
KIT mutations in
about half of tested
cases

Surgical excision and

Excision or follow-up only (for
targeted therapy with
Treatment leiomyomas). Radical surgery (for
imatinib or newer tyrosine
leiomyosarcoma)
kinase inhibitors
The rare esophageal
gastrointestinal stromal
Leiomyomas are benign. Reported tumors that have been
Prognosis leiomyosarcomas have behaved reported have been
aggressively aggressive (9/17 patients
died of disease in the pre-
imatinib era)

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Figure 1.21.1 Leiomyoma. This lesion has developed in the muscularis propria
at the gastroesophageal junction.

Figure 1.21.2 Leiomyoma. Note the bland cytology of this brightly eosinophilic
lesion.

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Figure 1.21.3 Leiomyoma. CD117 in entrapped Cajal cells can be ignored. It
is not necessary to stain these lesions in the first place.

Figure 1.21.4 Gastrointestinal stromal tumor (GIST). These are rare in the
esophagus, but most in this location are aggressive lesions. This example is
epithelioid and far more cellular than is a leiomyoma.

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Figure 1.21.5 Gastrointestinal stromal tumor (GIST). High magnification.

Figure 1.21.6 Gastrointestinal stromal tumor (GIST), CD117 stain.

1.22 Melanoma vs. Esophageal

gastrointestinal stromal tumor
Esophageal

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 Esophageal Melanoma Gastrointestinal
Stromal Tumors
(GISTs)
Median age 60–96
years; male
predominance—rare
—far less common
Adults, mean age about 60 years; male
Age/Gender than esophageal
predominance
leiomyomas but
more common than
esophageal
leiomyosarcomas
Location Distal esophagus Distal esophagus
Symptoms Dysphagia, odynophagia Dysphagia
Polypoid masses; can be pigmented at
Mass lesion in distal
Signs endoscopy; bulky polypoid masses on
esophagus
imaging
No known risk
Etiology Unknown
factors
1. Cellular spindle
cell lesion of
muscularis propria
1. May be an in situ component (Fig.
rather than the more
1.22.1)
superficial layers
2. May have nested typical appearance
that is usually
Histology (Fig. 1.22.2) or a spindle cell appearance
composed of more
(Fig. 1.22.3) and cells are often
monotonous cells
pleomorphic
than a melanoma
3. Pigment may be found (Fig. 1.22.4)
and lacks pigment
(Figs.
1.22.6–1.22.9)
The rare
reported
tumors
have been
CD117+
(Fig.

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 S100 is nearly always reactive; 1.22.10)
CD34 is almost always negative. and
“Melanoma markers” such as CD34+
HMB45, MART1, tyrosinase, and with
SOX10 are reactive in many variable
examples, but HMB45, MART1, actin
and tyrosinase are often negative expression
in spindle cell examples. as per
Special CD117/kit expression is common GISTs in
studies in melanomas (Fig. 1.22.5). A other
subset of cases displays KIT such anatomic
that patients may be candidates locations.
for targeted tyrosine kinase Tested
treatment and many examples tumors
display BRAF mutations with have
response to vemurafenib displayed
exon 11
KIT
mutations
in about
half of
tested
cases

Surgical excision
and targeted therapy
Treatment Chemotherapy and surgery with imatinib or
newer tyrosine
kinase inhibitors
The rare esophageal
gastrointestinal
stromal tumors that
have been reported
Prognosis Poor have been
aggressive (9/17
patients died of
disease in the pre-
imatinib era)

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Figure 1.22.1 Melanoma. This lesion is mostly spindled but note the nested in
situ component on the right, a clue to the diagnosis.

Figure 1.22.2 Melanoma. With its pigment and epithelioid nests, it is easy to
recognize this lesion as melanoma.

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Figure 1.22.3 Melanoma. Spindled examples such as this are easily confused
with GIST.

Figure 1.22.4 Melanoma. Prominent pigment is present here.

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Figure 1.22.5 Melanoma, CD117 stain. A sizable minority of melanomas
express CD117.

Figure 1.22.6 GIST. This example is spindled and appears similar to, but less
atypical than, the melanomas depicted. Of course, GIST is centered in the
muscularis propria whereas melanomas originate in the mucosa.

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Figure 1.22.7 GIST. This example has a palisaded appearance.

Figure 1.22.8 GIST. Note the prominent vacuoles in this epithelioid example.

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Figure 1.22.9 GIST. This epithelioid example is composed of cells with brightly
eosinophilic cytoplasm.

Figure 1.22.10 GIST. Strong expression of CD117 does not distinguish GIST
from melanoma.

1.23 Melanoma vs. Melanosis

(melanocytosis)

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 Esophageal
Esophageal Melanoma
Melanosis/Melanocytosis
Adults, mean age about 60 years; Middle-aged adults; male
Age/Gender
male predominance predominance
Lower or middle third of
Location Distal esophagus
esophagus
Symptoms Dysphagia, odynophagia None
Polypoid masses; can be pigmented at
Blue to black macules on
Signs endoscopy; bulky polypoid masses on
endoscopy. No mass
imaging
Unknown—probably
more common in persons
Etiology Unknown
with pigmented rather
than pale skin
1. Increased basal
melanocytes in
esophageal squamous
epithelium (Figs.
1. May be an in situ component (Fig. 1.23.5–1.23.8). Consisting
1.23.1) of pigmented dendritic
2. May have nested typical cells. The cells lack
appearance (Fig. 1.23.2) or a spindle tonofilaments and
Histology
cell appearance (Fig. 1.22.3) and cells desmosomes. Nuclei are
are often pleomorphic small and hyperchromatic
3. Pigment may be found (Fig. without nucleoli. The
1.23.4) processes extend through
several layers of cells.
Pigmented macrophages
may be present in lamina
propria
S100 is nearly always
reactive; CD34 is almost
always negative.
“Melanoma markers” such
as HMB45, MART1,
tyrosinase, and SOX10 are

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 reactive in many examples,
but HMB45, MART1, and
The cells
tyrosinase are often
express S100
Special negative in spindle cell
studies examples. CD117/kit protein, Melan
expression is common in A, and HMB45
melanomas. A subset of
cases displays KIT such that
patients may be candidates
for targeted tyrosine kinase
treatment and many
examples display BRAF
mutations with response to
vemurafenib

Treatment Chemotherapy and surgery None. Incidental

Incidental finding. Rare
reports of association with
Prognosis Poor melanoma but no reports
of progression in a given
lesion

Figure 1.23.1 Melanoma. Note the in situ component on the right.

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Figure 1.23.2 Melanoma. This is an overtly malignant spindle cell lesion.

Figure 1.23.3 Melanoma. This spindle cell melanoma contains pigment.

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Figure 1.23.4 Melanoma, CD117 stain.

Figure 1.23.5 Esophageal melanosis (melanocytosis). The pigmented cells are

slender and intermingle with the basal layer.

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Figure 1.23.6 Esophageal melanosis (melanocytosis).

Figure 1.23.7 Esophageal melanosis (melanocytosis). The delicate processes of

the melanocytes extend for some distance from their nuclei.

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 Figure 1.23.8 Esophageal melanosis (melanocytosis). The process lacks
cytologic atypia.

SUGGESTED READINGS
Abraham SC, Yardley JH, Wu TT. Erosive injury to the upper gastrointestinal
tract in patients receiving iron medication: an underrecognized entity. Am J
Surg Pathol. 1999;23(10):1241–1247. PubMed PMID: 10524525.
Carmack SW, Vemulapalli R, Spechler SJ, et al. Esophagitis dissecans
superficialis (“sloughing esophagitis”): a clinicopathologic study of 12 cases.
Am J Surg Pathol. 2009;33(12):1789–1794. doi:
10.1097/PAS.0b013e3181b7ce21. PubMed PMID: 19809273.
Chang F, Deere H. Esophageal melanocytosis morphologic features and review
of the literature. Arch Pathol Lab Med. 2006;130(4):552–557. Review.
PubMed PMID: 16594751.
Chen ZM, Scudiere JR, Abraham SC, et al. Pyloric gland adenoma: an entity
distinct from gastric foveolar type adenoma. Am J Surg Pathol.
2009;33(2):186–193. doi: 10.1097/PAS.0b013e31817d7ff4. PubMed PMID:
18830123.
Daniels JA, Gibson MK, Xu L, et al. Gastrointestinal tract epithelial changes
associated with taxanes: marker of drug toxicity versus effect. Am J Surg
Pathol. 2008;32(3):473–477. doi: 10.1097/PAS.0b013e3181582331.
PubMed PMID: 18300801.

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Dellon ES. Diagnostics of eosinophilic esophagitis: clinical, endoscopic, and
histologic pitfalls. Dig Dis. 2014;32(1–2):48–53. doi: 10.1159/000357009.
Epub February 28, 2014. PubMed PMID: 24603380.
Glickman JN, Chen YY, Wang HH, et al. Phenotypic characteristics of a
distinctive multilayered epithelium suggests that it is a precursor in the
development of Barrett's esophagus. Am J Surg Pathol. 2001;25(5):569–578.
PubMed PMID: 11342767.
Glickman JN, Spechler SJ, Souza RF, et al. Multilayered epithelium in mucosal
biopsy specimens from the gastroesophageal junction region is a histologic
marker of gastroesophageal reflux disease. Am J Surg Pathol.
2009;33(6):818–825. doi: 10.1097/PAS.0b013e3181984697. PubMed PMID:
19295405.
Hruban RH, Yardley JH, Donehower RC, et al. Taxol toxicity. Epithelial necrosis
in the gastrointestinal tract associated with polymerized microtubule
accumulation and mitotic arrest. Cancer. 1989;63(10):1944–1950. PubMed
PMID: 2564803.
Jessurun J, Paplanus SH, Nagle RB, et al. Pseudosarcomatous changes in
inflammatory pseudopolyps of the colon. Arch Pathol Lab Med.
1986;110(9):833–836. PubMed PMID: 3755892.
Kaneshiro DK, Post JC, Rybicki L, et al. Clinical significance of the duplicated
muscularis mucosae in Barrett esophagus-related superficial
adenocarcinoma. Am J Surg Pathol. 2011;35(5): 697–700. doi:
10.1097/PAS.0b013e3182159c4b. PubMed PMID: 21490446.
Miettinen M, Sarlomo-Rikala M, Sobin LH, et al. Esophageal stromal tumors: a
clinicopathologic, immunohistochemical, and molecular genetic study of 17
cases and comparison with esophageal leiomyomas and leiomyosarcomas.
Am J Surg Pathol. 2000;24(2):211–222. PubMed PMID: 10680889.
Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the
diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol.
2001;32(4):368–378. PubMed PMID: 11331953.
Purdy JK, Appelman HD, McKenna BJ. Sloughing esophagitis is associated
with chronic debilitation and medications that injure the esophageal mucosa.
Mod Pathol. 2012;25(5):767–775. doi: 10.1038/modpathol.2011.204. Epub
January 27, 2012. PubMed PMID: 22282305.
Salaria SN, Abu Alfa AK, Cruise MW, et al. Lichenoid esophagitis:
clinicopathologic overlap with established esophageal lichen planus. Am J
Surg Pathol. 2013;37(12):1889–1894. doi: 10.1097/PAS.0b013e31829dff19.

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 PubMed PMID: 24061525.
Shekitka KM, Helwig EB. Deceptive bizarre stromal cells in polyps and ulcers
of the gastrointestinal tract. Cancer. 1991;67(8): 2111–2117. PubMed PMID:
2004330.
Vieth M, Stolte M. Pathology of early upper GI cancers. Best Pract Res Clin
Gastroenterol. 2005;19(6):857–869. Review. PubMed PMID: 16338646.
Vieth M, Kushima R, Borchard F, et al. Pyloric gland adenoma: a clinico-
pathological analysis of 90 cases. Virchows Arch. 2003;442(4):317–321.
Epub March 26, 2003. PubMed PMID: 12715167.
Westerterp M, Koppert LB, Buskens CJ, et al. Outcome of surgical treatment for
early adenocarcinoma of the esophagus or gastro-esophageal junction.
Virchows Arch. 2005;446(5):497–504. Epub April 19, 2005. PubMed PMID:
15838647.
Yerian L, Fiocca R, Mastracci L, et al. Refinement and reproducibility of
histologic criteria for the assessment of microscopic lesions in patients with
gastroesophageal reflux disease: the Esohisto Project. Dig Dis Sci.
2011;56(9):2656–2665. doi: 10.1007/s10620-011-1624-z. Epub March 2,
2011. PubMed PMID: 21365241.

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 2
Stomach

2.1 Crush artifact vs. Signet-ring cell carcinoma

2.2 Signet-ring cell change vs. Signet-ring cell carcinoma
2.3 Xanthoma vs. Signet-ring cell carcinoma
2.4 Iron pill gastritis vs. Dysplasia
2.5 Reactive changes of stress gastritis vs. In situ signet-ring cell
carcinoma in patients with CDH1 germline mutations
2.6 Russell body gastritis vs. Signet-ring cell carcinoma
2.7 Antrum vs. Body
2.8 Antrum vs. Cardia
2.9 Watermelon stomach (gastric antral vascular ectasia) vs.
Chemical gastropathy
2.10 Mucosal calcinosis vs. Parasitic gastritis
2.11 Proton pump inhibitor effect vs. Fundic gland polyp and
oxyntic gland polyp
2.12 Iron pill gastritis vs. Gastric siderosis
2.13 Colchicine and taxol–associated gastropathy vs. Dysplasia
2.14 Autoimmune gastritis vs. Environmental gastritis
2.15 Sarcina gastropathy vs. Micrococcus
2.16 Ménétrier disease vs. Zollinger-Ellison syndrome
2.17 Ménétrier disease vs. Hyperplastic polyp
2.18 Hyperplastic polyp vs. Syndromic polyps (Juvenile polyposis
and Peutz-Jeghers polyposis)
2.19 Pyloric gland adenoma vs. Intestinal-type adenoma
2.20 Pyloric gland adenoma vs. Gastric foveolar-type gastric
adenoma

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2.21 Oxyntic gland polyp/adenoma vs. Fundic gland polyp
2.22 Lymphoepithelial-like carcinoma vs. Lymphoma
2.23 Metastatic lobular breast carcinoma vs. Signet-ring cell gastric
carcinoma
2.24 Well-differentiated neuroendocrine (carcinoid) tumor vs.
Adenocarcinoma
2.25 Type 1 endocrine tumor vs. Type 2 endocrine tumor
2.26 Type 1 endocrine tumor vs. Type 3 endocrine tumor
2.27 Mucosa associated lymphoid tissue (MALT) lymphoma vs.
Chronic gastritis
2.28 Diffuse large B-cell lymphoma vs. Carcinoma
2.29 Gastrointestinal stromal tumor (GIST) vs. Inflammatory
fibroid polyp
2.30 Epithelioid gastrointestinal tumor vs. Carcinoma
2.31 Gastrointestinal stromal tumor (GIST) vs. Schwannoma
2.32 Gastrointestinal stromal tumor (GIST) vs. Glomus tumor
2.33 Gastrointestinal stromal tumor (GIST), pediatric type vs.
Plexiform fibromyxoma
2.34 Kaposi sarcoma vs. Lamina propria

2.1 Crush artifact vs. Signet-ring cell

carcinoma
Crush Artifact Signet-Ring Cell Carcinoma
Any age; male =
Age/Gender Mean age mid-50; males > females
female
Predominantly antrum (60%); less
Usually at the edges
Location commonly body (20%), cardia/fundus
of the specimen
(10%), diffuse/entire stomach (1%)
Related to extent of tumor growth; most
Symptoms None commonly present with early-onset satiety,
decreased appetite, reflux

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 Palpable stomach with occasional
succussion splash, enlarged supraclavicular
Signs None
and/or axillary lymph nodes, anemia,
obstruction
Environmental risk factors include dietary
factors (e.g., nitrites) and smoking.
Related to the
Increased risk in association with
biopsy procedure
Etiology autoimmune metaplastic atrophic gastritis.
and specimen
A subset of cases are familial and show
processing
inactivating germline mutations of the
CDH1 gene
1. Crushed oxyntic 1. Cells with large, atypical,
glands with hyperchromatic, and eccentrically placed
predominance of nuclei and intracytoplasmic mucin vacuoles
mucous neck cells that displace the nucleus (Fig. 2.1.3)
(Fig. 2.1.1) 2. Individual or poorly formed groups of
2. Mucous cells cells
Histology located within the 3. Mucous cells generally located outside
lumina of the glands the lumina of the glands, within the lamina
(Fig. 2.1.2) propria; however, in familial forms can be
3. Focal mucosal located within the glands, underneath the
hemorrhage foveolar cells, and within the basement
4. No background membrane (Fig. 2.1.4)
dysplasia 4. Increased mitotic rate (Fig. 2.1.5)
Immunostains for keratin (e.g.,
CAM 5.2) highlight the malignant
cells. The cells also show
immunolabeling with EMA and
CEA with variable labeling for
Not
CK7 and CK20 (most are CK7
Special generally
studies positive and CK20 negative); PAS
performed
and mucin stains are also positive.
Inherited familial tumors show
loss of immunolabeling for E-
cadherin but so do many sporadic
ones

Surgical resection for early-stage disease;

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Treatment None adjuvant chemoradiation for late-stage
disease
Related to any other Related to stage and location of disease, but
Prognosis pathology present in overall poor prognosis; worst prognosis for
the specimen proximal late-stage disease

Figure 2.1.1 Crushed oxyntic glands. Distorted and crushed glands.

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Figure 2.1.2 Crushed oxyntic glands. Distorted glands with displaced mucous
cells located within the gland lumen.

Figure 2.1.3 Signet-ring cell carcinoma. Signet ring cells with prominent
intracytoplasmic mucin vacuoles infiltrating as clusters of cells in the lamina
propria.

Figure 2.1.4 Signet-ring cell carcinoma. Signet-ring cell carcinoma infiltrating

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through the lamina propria.

Figure 2.1.5 Signet-ring cell carcinoma. Signet ring cells with hyperchromatic,
pleomorphic nuclei and prominent mitoses.

2.2 Signet-ring cell change vs. Signet-

ring cell carcinoma
Signet-Ring Cell Change
Age/Gender Any age; males = females
Location Any location
Related to any underlying
Symptoms condition; can present with
diarrhea and abdominal pain
Related to any underlying
Signs condition; can present with
Signet-Ring Cell Carcinoma
Mean age mid-50; males >
females
Predominantly antrum (60%);
less commonly body (20%),
cardia/fundus (10%),
diffuse/entire stomach (1%)
Related to extent of tumor
growth; patients commonly
present with early satiety,
decreased appetite, reflux
Palpable stomach with
occasional succession splash,
enlarged supraclavicular and/or

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 abdominal tenderness or fever axillary lymph nodes, anemia,
obstruction
Environmental risk factors
Displacement and distortion of include dietary factors (e.g.,
cells secondary to sloughing in nitrites) and smoking. Increased
the setting of mucosal damage risk in association with
Etiology
often seen in association with autoimmune metaplastic
pseudomembranous colitis or atrophic gastritis. Inherited—
gastric ulcers 48% with inactivating germline
mutations of the CDH1 gene
1. Background often shows a
fibroinflammatory infiltrate
1. Cells with large, atypical,
composed of neutrophils,
hyperchromatic, and
mucus, and fibrin extending
eccentrically placed nuclei and
upwards from the surface
intracytoplasmic mucin
epithelium and focal epithelial
vacuoles that displace the
necrosis
nucleus (Figs. 2.2.4 and 2.2.5)
2. Sloughed epithelial cells
2. Individual or poorly formed
congregate in the lumen and
groups of cells (Fig. 2.2.6)
become distorted such that the
3. Malignant cells infiltrate
intracytoplasmic mucin vacuole
through the basement
Histology displaces the nucleus imparting
membrane into the lamina
a signet-ring cell appearance
propria and often into the
(Fig. 2.2.1)
submucosa and deeper tissue; in
3. Signet ring cells contained
familial forms can be located
within the basement membrane
within the glands, underneath
of the glands; no extension into
the foveolar cells, and within
the lamina propria (Fig. 2.2.2)
the basement membrane (Fig.
4. Minimal nuclear atypia
2.2.7)
4. Prominent nuclear atypia
5. Frequent mitoses (Figs. 2.2.5
(Fig. 2.2.8)
and 2.2.8)
5. Few to no mitoses or
apoptotic bodies
An E-cadherin stain
An E-cadherin stain shows loss of
shows intact membranous labeling.
membranous labeling Most show
(Fig. 2.2.3). Cells are immunolabeling for

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 negative for p53 and
Special Ki-67.
studies Immunohistochemical
stains for collagen IV
and laminin highlight
the intact basement
membrane.
Specific to any underlying
Treatment
etiology
Varies; related to any
Prognosis
underlying etiology.
Figure 2.2.1 Signet-ring cell change. Focal ulceration and acute inflammation
associated with signet-ring cell change.
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p53, and the Ki-67
index is high ranging
from 42% to 60%.
Immunohistochemical
stains for collagen IV
and laminin show
disruption of the
basement membrane.
Surgical resection for early-
stage disease; adjuvant
chemoradiation for late-stage
disease
Related to stage and location of
disease, but overall poor
prognosis; worst prognosis for
proximal late-stage disease
Figure 2.2.2 Signet-ring cell change. Signet ring cells within the lumen of
glands confined within the basement membrane.

Figure 2.2.3 Signet-ring cell change. Signet-ring cell change showing positive
immunolabeling for E-cadherin.

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Figure 2.2.4 Signet-ring cell carcinoma. Markedly atypical signet ring cells.

Figure 2.2.5 Signet-ring cell carcinoma. Infiltrating signet ring cells with
prominent mitoses.

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Figure 2.2.6 Signet-ring cell carcinoma. Infiltrating signet ring cells located
outside of the basement membrane.

Figure 2.2.7 Signet-ring cell carcinoma. Signet ring cells infiltrating within the
lamina propria.

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Figure 2.2.8 Signet-ring cell carcinoma. Signet-ring cell carcinoma with
marked nuclear atypia and mitotic figures.

2.3 Xanthoma vs. Signet-ring cell

carcinoma
Xanthoma Signet-Ring Cell Carcinoma
Typically adults (mean age
Age/Gender 60 years old); male Mean age mid-50; males > females
predominance
Predominantly antrum (60%); less
commonly body (20%),
Location Lesser curvature; pylorus
cardia/fundus (10%), diffuse/entire
stomach (1%)
Incidental lesions;
nonspecific symptoms
include dyspepsia,
abdominal pain, and Related to extent of tumor growth;
Symptoms vomiting related to most commonly present with early
association with other satiety, decreased appetite, reflux
gastric conditions

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 including ulcers, bile
reflux, and chronic gastritis
Palpable stomach with occasional
succession splash, enlarged
Signs None; incidental lesion
supraclavicular and/or axillary
lymph nodes, anemia, obstruction
Environmental risk factors include
dietary factors (e.g., nitrites) and
Presumably due to prior or smoking
current gastric irritation; Increased risk in association with
Etiology not associated with autoimmune metaplastic atrophic
hyperlipidemia or skin gastritis
xanthomas Inherited—48% with inactivating
germline mutations of the CDH1
gene
1. Cells with large, atypical,
1. Lipid-laden
hyperchromatic, and eccentrically
macrophages in the lamina
placed nuclei and intracytoplasmic
propria, with bland
mucin vacuoles that displace the
centrally placed nuclei
nucleus (Fig. 2.3.3)
Histology (Figs. 2.3.1 and 2.3.2)
2. Diffuse infiltration by individual
2. Lesions usually less than
or poorly formed groups of cells,
3 mm
often with dense desmoplastic
3. No increase in mitoses
stroma (Figs. 2.3.4 and 2.3.5)
(Fig. 2.3.2)
3. Increased mitotic rate
Immunostains for keratin
Generally not
(e.g., CAM 5.2) highlight
needed;
the malignant cells. The
immunolabeling
cells also show
for CD68 is
immunolabeling with EMA
Special confirmatory; the
and CEA with variable
cells do not
studies labeling for CK7 and
express
CK20 (most are CK7
cytokeratin.
positive and CK20
Stains for mucin
negative); mucin stains are
are negative.
also positive

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 Inherited familial tumors
show loss of
immunolabeling for E-
cadherin (as do many
sporadic examples)

None; specific treatment Surgical resection for early-stage

Treatment for any associated disease; adjuvant chemoradiation for
underlying conditions late-stage disease
Benign; of little Related to stage and location of
significance; reported disease, but overall poor prognosis;
Prognosis
association with worst prognosis for proximal late-
Helicobacter gastritis stage disease

Figure 2.3.1 Xanthoma. Lipid-laden macrophages diffusely infiltrating the

lamina propria.

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Figure 2.3.2 Xanthoma. Lipid-laden macrophages with foamy cytoplasm and
minimal atypia.

Figure 2.3.3 Signet-ring cell carcinoma. Signet ring cells with large, atypical
nuclei and prominent intractyoplasmic mucin vacuoles.

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Figure 2.3.4 Signet-ring cell carcinoma. Diffuse infiltration of the mucosa
extending into the submucosa.

Figure 2.3.5 Signet-ring cell carcinoma. Signet ring cells with prominent
mitoses.

2.4 Iron pill gastritis vs. Dysplasia

Iron Pill Gastritis Dysplasia

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Age/Gender Any age; predominantly female
Location Any part of the stomach
Abdominal pain, vomiting, and
Symptoms
some present with GI bleeding
None; patient may have a history
Signs
of iron deficiency anemia
Unknown, likely related to
concentration-dependent
chemical toxicity of iron and its
Etiology metabolites; up to 50% of
patients have comorbid
conditions that predispose them
to gastric injury
1. Mucosal erosion with
associated acute and chronic
inflammation, granulation tissue (Figs. 2.4.4 and 2.4.5)
and/or necrosis (Fig. 2.4.1)
2. Reactive epithelial changes
consisting of enlarged nuclei
with prominent nucleoli (Fig.
2.4.2)
Histology
3. Retained architectural
structure
4. Yellow-brown-gray
discoloration of the epithelium 4. Most lesions associated with
(H&E) due to iron deposition
(Fig. 2.4.2)
5. Mitoses limited to the base of 5. Not pigmented
crypts
Prussian blue stain
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Typically adults;
predominantly males 50s–70s
Predominantly in the antrum
No specific symptoms, unless
associated with invasive
disease (abdominal pain, early
satiety, gastric reflux)
No specific signs
Precancerous lesion associated
with history of chronic
Helicobacter infection and
autoimmune atrophic gastritis
and familial adenomatous
polyposis.
1. Low-grade dysplasia
characterized by
hyperchromatic, elongated,
and pseudostratified cells
2. Not associated with erosion
or ulceration
3. High-grade dysplasia shows
architectural distortion
including glandular crowding
and nuclear
pseudostratification (Fig.
2.4.6)
background intestinal
metaplasia (Fig. 2.4.5)
6. Mitoses present at both the
base and tips of crypts (Fig.
2.4.6)
 highlights iron Generally not
Special deposition within the performed
studies epithelium and lamina
propria (Fig. 2.4.3)

If polypoid, removal of polyp;

for polypoid adenomatous and
Symptomatic treatment; flat dysplasia, repeat biopsy
Treatment
supplement with liquid iron with representative sampling
of the entire stomach to
evaluate for invasive disease
Variable; low-grade dysplasia
sometimes regresses
Good; symptoms usually resolve spontaneously, while high-
Prognosis
quickly grade dysplasia usually persists
and can progress to invasive
carcinoma

Figure 2.4.1 Iron pill gastritis. Mucosal ulceration with mixed acute and
chronic inflammation, necrosis, and iron deposition.

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Figure 2.4.2 Iron pill gastritis. Reactive changes in iron pill gastritis.

Figure 2.4.3 Iron pill gastritis. Iron stain in iron pill gastritis.

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Figure 2.4.4 Dysplasia. Low-grade dysplasia showing nuclear crowding,
elongation, and pseudostratification.

Figure 2.4.5 Dysplasia. Low-grade dysplasia and intestinal metaplasia.

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Figure 2.4.6 Dysplasia. High-grade dysplasia showing pleomorphism, mucin
loss, and loss of nuclear polarity.

2.5 Reactive changes of stress gastritis

vs. In situ signet-ring cell carcinoma
in patients with CDH1 germline
mutations
In Situ Signet-Ring Cell
Reactive Changes of Stress
Carcinoma in Patients with
Gastritis
CDH1 Germline Mutations
Typically older adults Typically middle-aged adults
Age/Gender though can occur at any age; (mean age 38); no gender
no gender predominance predominance
Often in the proximal third of the
Location Any location
stomach
Few, if any due to increased
Abrupt abdominal pain, surveillance and prophylactic
Symptoms vomiting, and bleeding surgery. Advanced lesions present
with abdominal pain, early satiety,

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Depends on the extent of GI
bleeding; in mild cases
patients present with light-
headedness, dizziness, and
fatigue; in more severe cases Nonspecific. Surveillance
Signs patients present with
unstable vital signs.
Endoscopy shows shallow
erosions and edematous
mucosa with petechial
hemorrhages
Acute stress injury due to
various etiologies, most
Etiology
commonly alcohol,
NSAIDs, and ischemia
1. Dark, hyperchromatic,
enlarged, often pleomorphic, and 2.5.6)
nuclei with prominent
nucleoli (Figs. 2.5.1 and
2.5.2)
2. Changes generally limited
to the deep mucosa with
Histology
normal surface maturation
(Fig. 2.5.3)
3. Background usually
shows erosion or ulceration
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vomiting, and weight loss
endoscopy occasionally detects
early lesions
The CDH1 gene encodes for E-
cadherin, an intercellular adhesion
molecule Inactivating mutations are
inherited in an autosomal dominant
pattern with 70% penetrance. The
average lifetime risk of gastric
cancer by age 80 is 67% for men
and 83% for women. Women are
also at an increased risk of lobular
breast carcinoma
1. Early lesions are essentially in
situ signet-ring cell carcinoma
characterized by signet ring cells
scattered within glands, beneath
foveolar cell nuclei, and within the
basement membrane (Figs. 2.5.5
2. Late lesions histologically
similar to sporadic diffuse gastric
carcinoma
a. Cells with large,
atypical,
hyperchromatic, and
eccentrically placed
nuclei; inconspicuous
nucleoli; and
 and acute and or chronic intracytoplasmic mucin
inflammation (Fig. 2.5.4) vacuoles that displace
the nucleus (Fig. 2.5.7)
b. Individual or poorly
formed groups of cells
(Fig. 2.5.7)
c. Increased mitotic rate
d. Desmoplastic response
Immunostains for keratin
(e.g., CAM 5.2) highlight
the malignant cells. The
cells also show
immunolabeling with
Not usually
EMA and CEA with
performed. An E-
Special variable labeling for CK7
cadherin
studies and CK20 (most are CK7
immunostain is
positive and CK20
positive.
negative); PAS and
mucin stains are also
positive. Immunostaining
for E-cadherin is
negative

Identified carriers are often treated

Mainstay of therapy is
with prophylactic gastrectomy. In
supportive care including
advanced disease, resection with or
intravenous fluids and blood
without neoadjuvant chemotherapy
transfusion as well as
Treatment and/or radiation is the primary
pharmaceutical therapy with
treatment. Genetic screening is
PPIs and H2 blockers and
important to identify at-risk
discontinuation of any
families followed by routine
inciting drugs
surveillance for carriers
Variable; prognosis is generally
Very good; most patients
very good for early detected
Prognosis recover within a few days to
lesions, but advanced disease
weeks
portends a very poor prognosis

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Figure 2.5.1 Reactive epithelial changes with enlarged, hyperchromatic nuclei
and conspicuous mitoses.

Figure 2.5.2 Reactive epithelial changes with enlarged, hyperchromatic nuclei

with prominent nucleoli.

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Figure 2.5.3 Reactive changes predominant in the crypts with normal surface
maturation.

Figure 2.5.4 Reactive changes in association with granulation tissue.

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Figure 2.5.5 In situ signet-ring cell carcinoma.

Figure 2.5.6 In situ signet-ring cell carcinoma with pagetoid spread.

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Figure 2.5.7 Infiltration of the lamina propria by malignant signet ring cells.

2.6 Russell body gastritis vs. Signet-

ring cell carcinoma
Russell Body Gastritis
Typically adults; no gender
Age/Gender
predominance
Lamina propria of the antrum and
Location
body
Nonspecific; usually presents in
association with chronic gastritis;
Symptoms patients present with the common
symptoms of vague abdominal pain,
dyspepsia, nausea
Signet-Ring Cell
Carcinoma
Mean age mid-50; males >
females
Predominantly antrum
(60%); less commonly
body (20%), cardia/fundus
(10%), diffuse/entire
stomach (1%)
Related to extent of tumor
growth; most commonly
present with early satiety,
decreased appetite, reflux
Palpable stomach with
occasional succussion

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Signs Few, if any splash, enlarged
supraclavicular and/or
axillary lymph nodes,
anemia, obstruction
Environmental risk factors
include dietary factors (e.g.,
Unknown; some cases are thought to
nitrites) and smoking.
be associated with Helicobacter
Increased risk in
pylori infection to suggest a causal
association with
Etiology relationship, but no conclusive
autoimmune metaplastic
evidence exists; other associations
atrophic gastritis. Inherited
include monoclonal gammopathy
—48% with inactivating
and EBV-related gastric carcinoma
germline mutations of the
CDH1 gene
1. Cells with large, atypical,
hyperchromatic, and
1. Focal collections of plasma cells eccentrically placed nuclei
with cytoplasmic eosinophilic and intracytoplasmic clear,
globules composed of round mucin vacuoles that
immunoglobulins (Russell bodies) displace the nucleus (Fig.
that displace the nucleus (Fig. 2.6.1) 2.6.5)
2. Expansion of the lamina propria 2. Diffuse infiltration of the
Histology
with distortion of the adjacent submucosa by individual or
gastric glands (Fig. 2.6.2) poorly formed groups of
3. Background mucosa with diffuse cells, often with dense
acute and mononuclear chronic desmoplastic stroma (Fig.
inflammatory infiltrate (Fig. 2.6.2) 2.6.6)
4. No nuclear atypia 3. Nonfocal nuclear atypia
(Fig. 2.6.7)
4. High mitotic rate
Stain for mucin
PAS/AB stain highlights confirms the
the accumulated presence of
intracellular intracytoplasmic
immunoglobulin. mucin. The cells
Immunolabeling for express
CD138, CD79a confirms cytokeratin and
the presence of plasma other epithelial

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Special cells, while markers,
studies immunolabeling for kappa including EMA
and lambda light chains and CEA,
confirms the presence of CD79a, kappa, or
immunoglobulin and may lambda light
show the presence of light chains. CD138
chain restriction (Figs. may show “false
2.6.3 and 2.6.4). positivity” in
epithelial cells.

Given the association with Surgical resection for early-

Helicobacter pylori infection, most
Treatment
patients are treated with standard
triple-antibiotic therapy
Prognosis Excellent; benign
stage disease; adjuvant
chemoradiation for late-
stage disease
Related to stage and
location of disease, but
overall poor prognosis;
worst prognosis for
proximal late-stage disease

Figure 2.6.1 Russell body gastritis. Neutrophilic and plasmacytic infiltrate

within the glands and lamina propria.

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Figure 2.6.2 Russell body gastritis. Diffuse infiltration of the lamina propria,
distortion of glands, and marked acute and chronic inflammation.

Figure 2.6.3 Russell body gastritis. CD138 stain highlighting numerous plasma
cells.

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Figure 2.6.4 Russell body gastritis. Kappa- (brown) and lambda-light (red)
chain dual stain showing a predominance of lambda-expressing plasma cells.

Figure 2.6.5 Signet-ring cell carcinoma with pleomorphic nuclei infiltrating as

single cells.

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Figure 2.6.6 Signet-ring cell carcinoma infiltrating the lamina propria.

Figure 2.6.7 Signet-ring cell carcinoma. Markedly atypical signet ring cells.

2.7 Antrum vs. Body

Antrum Body
Age/Gender Any age; male = female Any age; male = female

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 Distal third of the Center part of Stomach (body and
Location stomach, extending from fundus)
the incisura to the pylorus
Symptoms Not applicable Not applicable
Signs Not applicable Not applicable
Etiology Not applicable Not applicable
1. Mucinous surface epithelium with
underlying tightly packed glands
composed of two cell types—chief
cells with basophilic cytoplasm and
1. Loosely packed glands parietal cells with eosinophilic
composed of mucinous granular cytoplasm (Figs. 2.7.4 and
cells (Figs. 2.7.1 and 2.7.5)
2.7.2) 2. Long pits and tubular glands that
2. Mucinous surface span approximately 70% of the
Histology 3. Short pits and branched epithelial thickness; 1:4 ratio of
glands span pit:gland (Fig. 2.7.6)
approximately half of the 3. Scattered endocrine cells at the
epithelial thickness; 1:1 base of crypts that secrete histamine
ratio of pit:gland (Fig. (enterochromaffin-like)
2.7.3) 4. Scattered endocrine cells present
below the surface epithelium
including cells that secrete gastrin,
somatostatin, and serotonin
(enterochromaffin-like) (Fig. 2.7.2)
Immunolabeling
for gastrin is a Immunolabeling for gastrin
Special
studies hallmark of the is negative
antrum

Treatment Not applicable Not applicable

Prognosis Not applicable Not applicable

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Figure 2.7.1 Antrum. Superficial mucosa of the antrum composed of short
mucous pits.

Figure 2.7.2 Antrum. Deep mucosa of the antrum composed of branching

mucous glands and scattered endocrine cells.

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Figure 2.7.3 Antrum. Antrum architecture composed of short pits and glands
in a 1:1 ratio.

Figure 2.7.4 Body. Superficial mucosa of the body composed of short pits of
mucous cells.

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Figure 2.7.5 Body. Deep mucosa of the body composed of intermixed parietal
and chief cells.

Figure 2.7.6 Body architecture composed of short pits and long glands in a 1:4
ratio.

2.8 Antrum vs. Cardia

Antrum Cardia

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Age/Gender Any age; male = female
Distal third of the stomach,
Location extending from the incisura to the
pylorus
Symptoms Not applicable
Signs Not applicable
Etiology Not applicable
1. Loosely packed glands
composed of mucinous cells (Fig.
2.8.1)
2. Short pits and branched glands
that span approximately half of
the epithelial thickness; 1:1 ratio
of pit:gland (Fig. 2.8.1)
Histology
3. Scattered endocrine cells
present below the surface
epithelium including cells that
secrete gastrin, somatostatin, and
serotonin (enterochromaffin-like)
4. Adjacent to the duodenal
mucosa
Immunolabeling for
Special
gastrin is a hallmark of
studies
the antrum
Any age; male = female
Extends from the lower
esophageal sphincter to the
fundus
Not applicable
Not applicable
Not applicable
1. More loosely packed glands
composed of mucinous cells
(Fig. 2.8.2)
2. Short pits and short glands
span approximately half of the
epithelial thickness; 1:1 ratio
of pit:gland (Fig. 2.8.2)
3. Scattered endocrine cells
present below the surface
epithelium including cells that
secrete somatostatin and
serotonin (enterochromaffin)
4. Adjacent to the esophageal
mucosa
Immunolabeling for
gastrin is negative

Treatment Not applicable Not applicable

Prognosis Not applicable Not applicable

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Figure 2.8.1 Antrum architecture composed of short pits and glands in a 1:1
ratio.

Figure 2.8.2 Cardia architecture composed of short pits and glands in a 1:1
ratio.

2.9 Watermelon stomach (gastric

antral vascular ectasia) vs. Chemical

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gastropathy
Watermelon Stomach
(Gastric Antral Vascular Chemical Gastropathy
Ectasia)
Typically elderly (mean age
Typically adults; no gender
Age/Gender 70); predominantly females
predominance
(75%)
Location Predominantly antrum Predominantly antrum
Both acute and chronic GI
Nonspecific epigastric pain, nausea,
bleeding presents as light-
vomiting; severe disease can
Symptoms headedness, dizziness,
present with GI bleeding and acute
fatigue, hematemesis,
achy pain related to ulcers
hematochezia
Due to chronic blood loss,
iron deficiency anemia,
heme-positive stool,
melena; endoscopy shows
Signs classic appearance of red Few, if any
linear stripes at the peak of
mucosal folds radiating to
the pylorus like “stripes of
watermelon”
Chemical-induced injury due most
Associated with commonly to NSAID use, as well as
autoimmune and connective bile reflux in patients with a history
Etiology tissue diseases; some cases of antrectomy or functional gastric
have been associated with disorders. Other risk factors include
antral prolapse anticonvulsant and
chemotherapeutic drugs
1. Foveolar hyperplasia
with dilated mucosal 1. Reactive mucosal changes
capillaries and including marked hyperplasia of the
fibromuscular hypertrophy foveolar epithelium resulting in
of the lamina propria (Figs. increased pit length
2.9.1, 2.9.2, and 2.9.5) (“corkscrewing”), focal loss of

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 2. Intraluminal fibrin mucin, lamina propria edema,
Histology thrombi (corresponding to smooth muscle proliferation in the
the characteristic linear lamina propria, and vascular
vascular stripes at the tips congestion (Figs. 2.9.6 and 2.9.7)
of the mucosal folds 2. No fibrin thrombi (Fig. 2.9.8)
radiating from the pylorus 3. Minimal inflammation; rare acute
seen endoscopically) (Figs. inflammation can be present in
2.9.2–2.9.4) association with erosions or ulcers
3. Minimal to no (Figs. 2.9.9 and 2.9.10)
inflammation
While not
required,
immunolabeling
Special for CD61 will Not generally performed
studies confirm the
presence of fibrin
thrombi

Varies depending on the

severity of disease; mild
cases are managed with iron
supplementation and blood Antacid therapy with proton pump
Treatment transfusion as needed, while inhibitors and discontinuation of
more severe cases require any relevant medications
endoscopic vascular
ablation or surgical
antrectomy
Endoscopic ablation is very
effective; surgical therapy is
Prognosis Excellent; benign
definitive but has a much
higher risk of mortality

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Figure 2.9.1 Watermelon stomach. Foveolar hyperplasia.

Figure 2.9.2 Watermelon stomach. Foveolar hyperplasia, proliferation of

lamina propria smooth muscle, and fibrin thrombi (center).

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Figure 2.9.3 Watermelon stomach. Intravascular fibrin thrombi.

Figure 2.9.4 Watermelon stomach. Intravascular fibrin thrombi (upper right).

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Figure 2.9.5 Watermelon stomach. Fibromuscular hypertrophy of the lamina
propria.

Figure 2.9.6 Chemical gastropathy. Foveolar hyperplasia of glands with a

“corkscrew” appearance.

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Figure 2.9.7 Chemical gastropathy. Marked reactive epithelial changes.

Figure 2.9.8 Chemical gastropathy. Foveolar hyperplasia with no vascular or

muscular changes.

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Figure 2.9.9 Chemical gastropathy. Mucosal ulceration with mixed acute and
chronic inflammation.

Figure 2.9.10 Chemical gastropathy. Mixed acute and chronic inflammation.

2.10 Mucosal calcinosis vs. Parasitic

gastritis
Mucosal Calcinosis Parasitic Gastritis

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Age/Gender Typically adults; female predominance Any age; male =
female
Antrum and body; superficial mucosa
Location Any location
beneath the surface foveolar epithelium
Nonspecific
epigastric pain,
Nonspecific; symptoms related to
Symptoms nausea, vomiting,
predisposing underlying disease
diarrhea, weight
loss, fatigue
Few; some present
with nutritional
Signs None deficiencies and
serum IgE is often
elevated
Most commonly due to the deposition of
calcium related to tertiary
hyperparathyroidism of renal failure.
Patients with renal failure most commonly
have hypocalcemia due to disordered
calcium metabolism. They also develop Infectious gastritis
hyperphosphatemia as well as low vitamin most often seen in
D levels, all of which result in increased immunosuppressed
PTH secretion by the parathyroid glands patients; common
Etiology (tertiary hyperparathyroidism). This infections include
marked increase in PTH increases both Strongyloidiasis and
calcium and phosphate absorption schistosomiasis,
subsequently resulting in hypercalcemia which are rarely
with deposition of calcium in various seen in the stomach
organs. Mucosal calcinosis has also been
associated with atrophic gastritis,
hypervitaminosis A, organ transplantation,
gastric neoplasia, uremia, citrate-containing
blood products, isotretinoin, and sucralfate
1. Strongyloides: All
stages (e.g., larva,
egg, adult) of worm
embedded in gastric

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 pits with background
crypt hyperplasia
and marked mixed
inflammatory
infiltrate in the
lamina propria
composed of
lymphocytes, plasma
cells, and
1. Irregular, amorphous basophilic deposits eosinophils (Fig.
present in the superficial mucosa beneath 2.10.3)
the foveolar tips, which are slightly 2. Schistosomiasis:
refractile and do not polarize (Fig. 2.10.1) Ulcerate and
Histology edematous mucosa
2. Deposits lack internal structure (Fig.
2.10.2) with Schistosoma
3. No eosinophils or Charcot-Leyden ova within the
crystals lamina propria
associated with
prominent
eosinophils and
occasionally giant
cells. Eggs are
deeply basophilic
and oval shaped
with a lateral spine
(Fig. 2.10.4)
3. Prominent
eosinophils and
Charcot-Leyden
crystals are common
(Fig. 2.10.5)
Not generally performed; von Not
Kossa and alizarin red stains are generally
Special positive. X-ray analysis shows performed.
the presence of calcium, Clinical
studies
aluminum, phosphorus, and history is
chlorine important.

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Treatment Nonspecific; patients are treated for any Antiparasitic therapy
underlying disease
Generally good;
most cases resolve
with treatment.
Variable, nonspecific—mucosal calcinosis There is a rare risk
is considered an incidental finding; of complications
prognosis is determined by the extent of including
Prognosis
systemic calcinosis and the severity of perforation, and
renal failure and/or other underlying some develop
disease dysplasia and/or
carcinoma
presumably due to
chronic irritation.

Figure 2.10.1 Mucosal calcinosis.

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Figure 2.10.2 Mucosal calcinosis.

Figure 2.10.3 Strongyloides organisms at various life stages in colonic crypts.

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Figure 2.10.4 Schistosomiasis. The ova are uniform structures.

Figure 2.10.5 Parasitic infestation. There are numerous eosinophils in the field.

2.11 Proton pump inhibitor effect vs.

Fundic gland polyp and oxyntic gland
polyp

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Proton Pump Inhibitor Effect
Typically adults; no gender
Age/Gender
predominance
Location Fundus
Nonspecific, unrelated to the finding;
symptoms may reflect underlying
Symptoms
disease that necessitated proton pump
inhibitor therapy
Few, if any. Endoscopy usually
Signs
negative for polyps
Proton pump inhibitors inhibit the
H/K ATPase ion channel that
maintains the acidic pH of the gastric
lumen, which consequently activates
feedback mechanisms (i.e., increased
secretion of gastrin) in an attempt to
increase acid secretion and normalize
Etiology
the pH. Gastrin stimulates parietal cell
growth resulting in the cytologic
changes of the proton pump inhibitor
effect. Use of proton pump inhibitors
is not necessary to see this effect; it is
present in patients with no known
history of PPI use
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Fundic Gland Polyp and
Oxyntic Gland Polyp
Typically adults
(sporadic, mean age 50s;
familial, mean age 20s);
female predominance
(familial forms show no
gender predominance)
Fundic gland polyp: body
and fundus; oxyntic gland
polyp: body and cardia
Generally asymptomatic;
nonspecific abdominal
pain is most common
Few, if any. Endoscopy
usually shows multiple
small, sessile,
hemispherical polyps
occurring in clusters
sometimes
Fundic gland polyp: Most
common type of gastric
polyp, which is either
familial or sporadic;
familial lesions are
associated with familial
adenomatous polyposis
syndrome
Oxyntic gland polyp:
Rare polyp of unknown
etiology
Fundic gland polyp:
1. Random, disordered
 proliferation of oxyntic
mucosa with dilated
fundic glands and/or
microcysts lined by
flattened oxyntic
epithelium (Figs.
2.11.4–2.11.6)
2. Background gastric
1. Hyperplastic parietal cells with mucosa is normal
apocrine-like changes including Oxyntic gland polyp:
Histology cytoplasmic swelling, vacuolated 1. Irregularly branched
cytoplasm, and apical blebbing (Figs. tubules arranged in
2.11.1–2.11.3) anastomosing cords (Fig.
2.11.7)
2. Tubules composed of
monomorphous epithelial
cells with small, central,
round nuclei and ample
amphophilic cytoplasm
(Fig. 2.11.8)
3. Scattered intermixed
parietal cells
4.Normal background
mucosa
Not generally
performed;
however,
immunolabeling
for beta-catenin
is seen is most
sporadic fundic
gland polyps
while some
Special Not generally performed
familial lesions
studies
are positive for
APC gene
mutation
Oxyntic gland

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 polyp: MUC6
positive to
“special
studies”

Fundic gland polyp: Most

Nonspecific; related to any other
Treatment
pathology present in the specimen
Variable, nonspecific, incidental
Prognosis finding; prognosis related to any other
pathology present in the specimen
lesions regress.
Polypectomy for larger
lesions Oxyntic gland
adenoma: Complete
polypectomy
Excellent; generally
considered benign lesions.

Figure 2.11.1 Proton pulp inhibitor effect. Hyperplastic glands of proton pump
inhibitor effect.

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Figure 2.11.2 Proton pulp inhibitor effect. Apical blebbing of proton pump
inhibitor effect.

Figure 2.11.3 Proton pulp inhibitor effect. Cytoplasmic vacuolization of proton

pump inhibitor effect.

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Figure 2.11.4 Fundic gland polyp.

Figure 2.11.5 Fundic gland polyp. Focal cystically dilated glands.

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Figure 2.11.6 Fundic gland polyp. Cystically dilated glands lined by flattened
oxyntic epithelium.

Figure 2.11.7 Oxyntic gland adenoma. Irregular branching tubules arranged

in cords.

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Figure 2.11.8 Oxyntic gland adenoma. Monomorphous cells with prominent
apical eosinophilic cytoplasm.

2.12 Iron pill gastritis vs. Gastric

siderosis
Iron Pill Gastritis Gastric Siderosis
Any age; predominantly Typically adults; no gender
Age/Gender
female predominance
Location Any part of the stomach Predominantly antrum and fundus
Related to underlying disorder,
patients with hemochromatosis may
present with symptoms of diffuse
Abdominal pain, vomiting,
iron overload including cirrhosis,
Symptoms and some present with GI
diabetes, and joint pain while those
bleeding
with secondary iron overload
generally present with symptoms of
anemia
None; patient may have a Related to underlying disorder;
Signs history of iron deficiency clinical lab tests will show increased
anemia ferritin

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 Unknown, likely related to
concentration-dependent Iron deposition due to either primary
chemical toxicity of iron iron overload related to
and its metabolites; up to hemochromatosis or secondary iron
Etiology
50% of patients have overload associated with chronic
comorbid conditions that blood transfusion, cirrhosis, and
predispose them to gastric supplemental iron
injury
1. Mucosal erosion with
associated acute and
chronic inflammation,
granulation tissue, and/or
necrosis (Fig. 2.12.1)
2. Reactive epithelial 1. Few mucosal changes
changes consisting of 2. Iron deposition in deep glands of
Histology
enlarged nuclei with the antrum and fundus (Figs. 2.12.4
prominent nucleoli (Fig. and 2.12.5)
2.12.2)
3. Iron deposition within
the lamina propria and
surface epithelium (Fig.
2.12.1)
Prussian blue
stain highlights
iron deposition Prussian blue stain
Special within the highlights iron in the deep
studies epithelium and gastric glands (Fig. 2.12.6)
lamina propria
(Fig. 2.12.3)

Symptomatic treatment;
Variable, depending on underlying
Treatment supplement with liquid
disorder
iron
Variable; it suggests a diagnosis of
Good; symptoms usually hemochromatosis that can be
Prognosis
resolve quickly associated with morbidity related to
iron deposition in other organs

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Figure 2.12.1 Iron pill gastritis. Mucosal erosion and iron deposition.

Figure 2.12.2 Iron pill gastritis. Reactive changes of iron pill gastritis.

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Figure 2.12.3 Iron pill gastritis. Iron stain highlighting iron within the
superficial mucosa.

Figure 2.12.4 Gastric siderosis. Iron deposition in the lower half of the
epithelium.

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Figure 2.12.5 Gastric siderosis. Iron deposition in the deep glands.

Figure 2.12.6 Gastric siderosis. Iron stain highlighting iron deposition limited
to the deep mucosa.

2.13 Colchicine and taxol–associated

gastropathy vs. Dysplasia

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 Colchicine and Taxol–Associated
Dysplasia
Gastropathy
Typically adults;
Typically adults; no gender
Age/Gender predominantly males
predominance
50s–70s
Colchicine: Antrum and duodenum;
Location sparing of the gastric body Any location
Taxol: Any location
No specific symptoms,
Nonspecific abdominal pain, nausea, unless associated with
Symptom vomiting, otherwise related to invasive disease
underlying disease (abdominal pain, early
satiety, gastric reflux)
Signs Related to underlying disease No specific signs
Colchicine: Injury related to colchicine Precancerous lesion
toxicity, an antimitotic drug used associated with history
primarily in the treatment of gout. of chronic Helicobacter
Etiology Colchicine at therapeutic levels causes infection and
no injury, but patients with renal failure autoimmune atrophic
can develop colchicine toxicity due to gastritis and familial
impaired drug clearance adenomatous polyposis
Taxol: Nontoxic pattern of injury due
to Taxol, an antimitotic drug used in
the treatment of various malignancies.
Taxol effect is seen at both therapeutic
and toxic drug levels

Colchicine: 1. Low-grade dysplasia

1. Epithelial changes including nuclear characterized by
pseudostratification with subsequent hyperchromatic,
loss of nuclear polarity (Fig. 2.13.1) elongated,
2. Metaphase ring mitoses (Fig. 2.13.2) pseudostratified nuclei
3. Apoptotic bodies in the proliferative and nuclear crowding
compartment (between the pits and (Figs. 2.13.7 and 2.13.8)
surface). (Fig. 2.13.3) 2. High-grade dysplasia
Taxol: shows loss of nuclear
1. Marked epithelial changes including polarity, glandular

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Histology loss of nuclear polarity, diffuse loss of crowding, and
mucin, and hyperchromasia (Fig. cribriform glands (Fig.
2.13.4) 2.13.9)
2. Epithelial changes prominent at the 3. Epithelial changes and
base of the crypts, do not extend to the mitoses involve the base
surface—limited to the proliferative of crypts, extending to
compartment (Fig. 2.13.5) the surface mucosa (Fig.
3. Mitotic arrest associated with ring 2.13.9)
mitoses, and marked apoptosis (Figs. 4. Most lesions
2.13.6 and 2.13.7) associated with
4. Background mucosa with cell background intestinal
necrosis and multifocal ulceration metaplasia
Generally not
Not generally performed, but
performed but
a Ki-67 stain does not show
strong p53
Special increased proliferation and
nuclear
studies can help reassure that no
labeling can
dysplasia is present. Clinical
be
history is important
confirmatory

If polypoid, removal of
polyp; for polypoid and
Colchicine: Immediate discontinuation flat dysplasia, repeat
of the offending drug biopsy with
Treatment
Taxol: Generally none, continue representative sampling
therapy of the entire stomach to
evaluate for invasive
disease
Colchicine: Potentially fatal due to Variable; low-grade
similar effects in other organs resulting dysplasia can regress
in multiorgan failure; early diagnosis is spontaneously, while
Prognosis critical high-grade dysplasia
Taxol: Related to the underlying usually persists and can
disorder for which the drug is being progress to invasive
administered carcinoma

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Figure 2.13.1 Colchicine toxicity. Nuclear pseudostratification and loss of
polarity.

Figure 2.13.2 Colchicine toxicity. Prominent ring mitoses.

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Figure 2.13.3 Colchicine toxicity. Apoptotic bodies in the proliferative
compartment.

Figure 2.13.4 Taxane effect. Reactive epithelial changes including focal loss of
mucin and nuclear pseudostratification. The surface is uninvolved.

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Figure 2.13.5 Taxane effect. Epithelial changes predominant in the
proliferative compartment.

Figure 2.13.6 Taxane effect. Ring mitoses and apoptotic bodies.

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Figure 2.13.7 Low-grade dysplasia.

Figure 2.13.8 Low-grade dysplasia showing nuclear elongation, crowding, and

pseudostratification at the surface.

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Figure 2.13.9 High-grade dysplasia showing nuclear crowding, nuclear
pleomorphism, loss of nuclear polarity, and prominent mitoses.

2.14 Autoimmune gastritis vs.

Environmental gastritis
Environmental
Autoimmune Gastritis
Gastritis
Typically older adults (50s–60s); Typically adults; no
Age/Gender
predominantly female gender predominance
Predominantly antrum
at the incisura
Location Body and fundus
angularis, extending
into the body
Many patients develop iron deficiency
anemia and present with fatigue,
weakness, and vague abdominal pain
related to iron deficiency anemia; others,
typically older patients, present with
pernicious anemia because parietal cells Nonspecific epigastric
Symptoms are responsible for secretion of intrinsic and abdominal pain,

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 factor, which is critical for absorption of nausea, vomiting, GI
vitamin B12; common symptoms include bleeding
numbness and paresthesias of the distal
extremities related to demyelinating
effects of subacute combined
degeneration of the spinal cord

Few; chronic GI
bleeding can present
with iron deficiency
anemia; serology
Abnormal iron studies including low
studies are positive for
ferritin and high transferrin, vitamin B12
H. pylori and negative
Signs deficiency, abnormal blood smear with for anti–parietal cell
megaloblastosis and hypersegmented and anti–intrinsic
neutrophils, Schilling test positive factor antibodies;
normal serum vitamin
B12 level, normal
serum gastrin level
Various causes, most
commonly due to H.
pylori infection, but
also seen in
Unknown, immune-mediated disease in
association with other
which antibodies specific for parietal
Etiology dietary risk factors
cells cause mucosal atrophy; associated
including nitrites, high
with HLA-B8 and DR3 haplotypes
sodium, smoked
foods, nitrosamines,
and low fruit and
vegetable intake
1. Body and fundus:
1. Prominent
a. Prominent chronic
inflammation of the
inflammation of the lamina
superficial mucosa
propria (Fig. 2.14.1)
consisting of
b. Loss of oxyntic glands (Fig.
lymphocytes, plasma
2.14.2)
cells, and variable
c. Metaplastic changes including
numbers of
intestinal, pseudopyloric

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 (antralized), and pancreatic
acinar cell (Figs.
2.14.3–2.14.5)
d. Nodular and linear hyperplasia
Histology of enterochromaffin-like cells
(Fig. 2.14.6)
2. Antrum
a. Few to no metaplastic or
inflammatory changes in the
antrum (Figs. 2.14.7 and
2.14.8)
G cell hyperplasia
3. Background mucosa may show
hyperplastic polyps, multifocal carcinoid
tumors, dysplastic changes, and
sometimes invasive carcinoma
neutrophils (Figs.
2.14.11 and 2.14.12)
2. H. pylori organisms
present—curved,
flagellated gram-
negative rods usually
clustered at the surface
of the mucosa and
within gastric pits
(Figs. 2.14.13 and
2.14.14)
3. Multifocal intestinal
metaplasia, atrophy,
and reactive changes
(Figs. 2.14.15 and
2.14.16)
4. Antrum universally
affected

Gastrin stain can confirm the

location of the biopsy—lack of
staining for gastrin confirms
that the biopsy is from the body
(Fig. 2.14.9), and conversely Diff-Quik
positive immunolabeling for stain or
gastrin is consistent with a immunostain
biopsy from the antrum (Fig. for H. pylori
2.14.10). Chromogranin stain confirms the
Special
studies highlights endocrine cell presence of
hyperplasia in the body (Fig. organisms
2.14.6). Additional clinical (Figs.
evaluation shows elevated 2.14.13 and
serum gastrin level, anti– 2.14.14)
parietal cell and anti–intrinsic
factor antibodies detected in
the serum. Serology for H.
pylori is most often negative

Standard triple drug

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 Most patients are treated with vitamin therapy consisting of
Treatment B12 supplementation; surgical resection two antibiotics and
for hyperplastic, dysplastic, or invasive either bismuth or a
lesions proton pump inhibitor

Very good; drug

Fair; chronic progressive disease. There
therapy is very
is not only an increased risk of gastric
effective though
adenocarcinoma but also a measurable
Prognosis measurable risk of
risk of neuroendocrine tumors due to the
lymphoma or
uninhibited gastrin secretion that causes
carcinoma without
chronic endocrine cell hyperplasia
treatment

Figure 2.14.1 Autoimmune metaplastic atrophic gastritis (AMAG). Marked

chronic inflammation with germinal center formation in AMAG (body).

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Figure 2.14.2 Autoimmune metaplastic atrophic gastritis (AMAG). Body with
loss of oxyntic glands in AMAG.

Figure 2.14.3 Autoimmune metaplastic atrophic gastritis (AMAG). Intestinal

metaplasia in AMAG (body).

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Figure 2.14.4 Autoimmune metaplastic atrophic gastritis (AMAG). Antralized
mucosa in AMAG (body).

Figure 2.14.5 Autoimmune metaplastic atrophic gastritis (AMAG). Pancreatic

acinar cell metaplasia in AMAG (body).

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Figure 2.14.6 Autoimmune metaplastic atrophic gastritis (AMAG).
Chromogranin stain in AMAG showing hyperplasia of enterochromaffin-like
cells (body).

Figure 2.14.7 Autoimmune metaplastic atrophic gastritis (AMAG).

Histologically unremarkable antrum in AMAG.

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Figure 2.14.8 Autoimmune metaplastic atrophic gastritis (AMAG). Few
changes in the antrum in AMAG.

Figure 2.14.9 Autoimmune metaplastic atrophic gastritis (AMAG). Negative

gastrin stain in the body.

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Figure 2.14.10 Autoimmune metaplastic atrophic gastritis (AMAG). Gastrin
stain highlighting G cells in the antrum.

Figure 2.14.11 H. pylori–associated gastritis. Mixed acute and chronic

inflammation within the lamina propria with intraepithelial neutrophils.

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Figure 2.14.12 H. pylori–associated gastritis. Prominent intraepithelial
neutrophils and background chronic inflammation.

Figure 2.14.13 H. pylori–associated gastritis. Diff-Quik stain highlighting H.

pylori organisms.

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Figure 2.14.14 H. pylori–associated gastritis. Immunohistochemical stain for
H. pylori.

Figure 2.14.15 H. pylori–associated gastritis. Reactive epithelial changes.

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Figure 2.14.16 H. pylori–associated gastritis. Marked acute inflammation and
intestinal metaplasia.

2.15 Sarcina gastropathy vs.

Micrococcus
Sarcina Gastropathy
Any age, but typically adults; no
Age/Gender
gender predominance
Location Fundus and body
Characteristic “frothy vomit,”
Symptoms upper abdominal pain, nausea,
hematemesis
Nonspecific; signs of diseases
Signs associated with gastric outlet
obstruction may be present
Micrococcus
Any age, typically adults; no
gender predominance
Fundus and body
Nonspecific, though since
sometimes seen in
association with proton
pump inhibitor therapy,
symptoms may include those
of chronic gastritis or a
history of hyperchlorhydria
Nonspecific

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 Infection with Sarcina ventriculi, a
gram-positive strict anaerobic
coccus. It is an environmental
organism found in soil that is
tolerant of the acidic environment
of the stomach and grows readily
via the fermentation of
Etiology carbohydrates. Its metabolism
results in the production of ethyl
alcohol and carbon dioxide to
cause emphysematous gastritis.
Risk factors for infection include
gastroparesis and delayed gastric
emptying; however, the extent of
causal relationship has not been
clarified
1. Organism present on the surface
of the mucosa, cocci approximately
the size of yeast occurring in
characteristic tetrads of 4 or 8 cells,
abutting each other at flattened
interfaces—similar to a ball of
cotton (Fig. 2.15.1)
2. Some cases show
Histology
emphysematous gastritis with acute
suppurative inflammation of the
mucosa and submucosa, ulceration,
necrosis, and gastric pneumatosis
consisting of air dissecting within
the gastric mucosa occasionally
with surrounding giant cells (Figs.
2.15.2 and 2.15.3)
Generally not performed;
the organism has a
characteristic
morphology that can be
Special
studies detected on H&E.
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Unknown; small gram-
positive aerobic coccus that
is occasionally found in the
oro- and nasopharynx as a
commensal organism but
also isolated from abscesses.
It is considered a saprophytic
organism with minimal
virulence. There are reported
associations of the presence
of the organism in patients
treated with chronic proton
pump inhibitor therapy, but
no definitive evidence of a
casual relationship
1. Organism present on the
surface of the mucosa, often
in tetrads surrounded by a
capsule, which may not
always be readily identified
on H&E; it also appears in
larger clusters of cells. The
organism is similar in size to
Staphylococcus, smaller than
Sarcina spp. (Figs. 2.15.4
and 2.15.5)
2. Rarely associated with any
specific pathology, may be
present as a saprophytic
organism associated with
infection due to more
virulent bacteria
Not generally
performed; culture
and 16s rRNA
sequencing
 Molecular studies can be provide definitive
performed to confirm the diagnosis
species, if necessary

Generally none; patients are

Treatment of mild, limited disease
treated for any other
Treatment involves antibiotics; for severe
underlying pathology present
disease, gastrectomy is required
in the specimen
Excellent, for noninvasive disease;
Excellent; considered a
mortality is high in cases of severe
Prognosis commensal, nonpathogenic
disease that progress to
organism
emphysematous gastritis

Figure 2.15.1 Sarcina ventriculi organisms arranged in tetrads.

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Figure 2.15.2 Sarcina ventriculi. Emphysematous gastritis.

Figure 2.15.3 Sarcina ventriculi. Gastric pneumatosis.

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Figure 2.15.4 Micrococcus associated with an ulcer bed.

Figure 2.15.5 Micrococcus organisms arranged in clusters.

2.16 Ménétrier disease vs. Zollinger-

Ellison syndrome
Zollinger-Ellison

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 Ménétrier Disease
Adults and children (mean age 40s);
Age/Gender
male predominance
Location Body
Severe, unrelenting stomach pain;
Symptoms edema; nausea; vomiting; weight
loss, diarrhea
Related to chronic protein loss,
malnutrition, low blood protein,
Signs hypogammaglobulinemia, anemia;
endoscopy shows prominently
thickened gastric folds
Unknown; a role of TGF-alpha has Gastrin acts in the gastric
Etiology
been suggested
1. Mucosal thickening with marked
foveolar hyperplasia resulting in
tortuosity and elongation of the
epithelium and cystic dilation of
deeper mucous glands (Fig. 2.16.1)
2. Replacement of oxyntic cells by
Histology
mucous glands (Fig. 2.16.2)
3. Usually minimal to no
inflammation; some cases show
prominent chronic inflammation
4. No ulcers, intestinal metaplasia, or
reactive, reactive epithelial changes
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Syndrome
Adults and children (mean
age 50); no gender
predominance
Body
Severe abdominal pain,
diarrhea, weight loss,
Elevated fasting serum
gastrin greater than 1,000
pg/mL; radiology shows
prominent thickened
gastric folds; hormone
scintigraphy reveals an
extragastric tumor
Result of increased plasma
gastrin due to gastrin-
secreting tumors of the
duodenum and pancreas.
fundus to cause
hyperplasia of chief and
parietal cells, and
consequently increased
acid production
1. No foveolar hyperplasia
2. Hyperplasia of parietal
and chief cells that extend
near the surface, as well as
enterochromaffin-like cells
in the gastric body that
extend near the surface
(Figs. 2.16.3 and 2.16.4)
3. Multiple ulcers
 Not generally
performed; the
gastrinoma
producing the
syndrome can be
immunolabeled
with gastrin
Special Not generally performed (Fig. 2.16.5),
studies and sometimes
gastric well-
differentiated
neuroendocrine
(carcinoid)
tumor can form
in the stomach
(Fig. 2.16.6)

For mild disease, symptomatic Surgical resection, if

therapy with H2 histamine blockers,
anticholinergic drugs, steroids, and present with distant or
somatostatin analogues. For severe
disease, gastrectomy. Most patients
Treatment
are also supplemented on high-
protein diets. Antibody inhibitor
therapy targeted against epidermal
growth factor receptor has been
effective in some cases
Poor; most adults have chronic,
progressive disease; prognosis is
Prognosis
better in children who usually have a
self-limited transient course
possible. Up to 30%
lymph node metastases
and are managed with
chemotherapy.
Symptomatic treatment
includes antacid therapies
including proton pump
inhibitors
Variable; prognosis is
excellent for surgically
resectable disease and
relatively poor for
unresectable disease.

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Figure 2.16.1 Ménétrier disease. Marked foveolar hyperplasia.

Figure 2.16.2 Ménétrier disease. Marked foveolar hyperplasia with

replacement of the oxyntic glands.

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Figure 2.16.3 Zollinger-Ellison syndrome. Hyperplasia of chief cells, parietal
cells, and neuroendocrine cells extending to the surface epithelium.

Figure 2.16.4 Zollinger-Ellison syndrome. This is a duodenal gastrinoma that

produced the syndrome.

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Figure 2.16.5 Zollinger-Ellison syndrome. Gastrin stain in Zollinger-Ellison
syndrome; this is a duodenal gastrinoma that produced Zollinger-Ellison
syndrome.

Figure 2.16.6 Zollinger-Ellison syndrome. Gastrin stain in Zollinger-Ellison

syndrome; this is a small gastric well-differentiated neuroendocrine (carcinoid)
tumor that is gastrin negative because it is composed of ECL cells.

2.17 Ménétrier disease vs.

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Hyperplastic polyp
Ménétrier Disease
Adults and children (mean age 40s);
Age/Gender
male predominance
Location Body
Severe, relenting stomach pain; edema;
Symptoms
nausea; vomiting; weight loss; diarrhea
Related to chronic protein loss,
malnutrition, low blood protein,
Signs hypogammaglobulinemia, anemia;
endoscopy shows prominently
thickened gastric folds
Unknown; a role of TGF-alpha has
Etiology:
been suggested
1. Mucosal thickening with marked
foveolar hyperplasia resulting in
tortuosity and elongation of the
epithelium and cystic dilation of deeper outpouchings and no
mucous glands (Fig. 2.17.1)
2. Mucous hyperplasia with
replacement of oxyntic cells by mucous 2. Inflammation and
Histology glands (Fig. 2.17.2)
3. Edema of the lamina propria, with
usually minimal to no inflammation;
some cases show prominent chronic
inflammation
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Hyperplastic Polyp
Typically adults (mean
age 60s); slight female
predominance
Any location, but
predominantly antrum
Many are asymptomatic;
common symptoms
include abdominal pain,
nausea, vomiting,
weight loss
Generally none;
endoscopy detects most
lesions
Unknown; thought to be
a manifestation of
chronic injury and repair
1. Diffuse hyperplasia of
foveolar epithelium with
elongation and dilation
of the foveolae with an
elaborated architecture
of papillae and
loss of oxyntic glands
(Figs. 2.17.3 and 2.17.4)
edema of the lamina
propria (Fig. 2.17.5)
3. Reactive epithelial
cells are common,
typically in association
 4. No ulcers, intestinal metaplasia, or with erosions (Fig.
reactive, reactive epithelial changes 2.17.6)
4. Background mucosa
often shows intestinal
metaplasia
Not generally
Special Not generally performed
performed
studies
For mild disease, symptomatic therapy
with H2 histamine blockers,
anticholinergic drugs, steroids and Endoscopic or surgical
somatostatin analogues. For severe resection for larger
disease, gastrectomy. Most patients are polyps; relevant
Treatment
also supplemented on high-protein treatment for any other
diets. Antibody inhibitor therapy pathology present in the
targeted against epidermal growth specimen
factor receptor has been effective in
some cases
Excellent; most are
Poor; most adults have chronic,
benign. Minimal, but
progressive disease; prognosis is better
Prognosis measurable risk (4%) of
in children who usually have a self-
dysplasia and/or
limited transient course
invasive carcinoma

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Figure 2.17.1 Ménétrier disease. Elongated and tortuous glands.

Figure 2.17.2 Ménétrier disease. Tortuous glands with replacement of oxyntic

glands with mucous glands.

Figure 2.17.3 Hyperplastic polyp. Hyperplastic polyp with elongation of the

papillae and retained oxyntic glands.

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Figure 2.17.4 Hyperplastic polyp. Elongated hyperplastic glands.

Figure 2.17.5 Hyperplastic polyp. Foveolar hyperplasia and increased chronic

inflammation within the lamina propria.

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Figure 2.17.6 Hyperplastic polyp. Granulation tissue and marked reactive
changes.

2.18 Hyperplastic polyp vs.

Syndromic polyps (Juvenile polyposis
and Peutz-Jeghers polyposis)
Syndromic Polyps (Juvenile Polyposis
Hyperplastic Polyp
and Peutz-Jeghers Polyposis)
Juvenile polyposis: Typically children
Typically adults (mean (less than 10); male predominance
Age/Gender age 60s); slight female Peutz-Jeghers polyposis: Typically
predominance young adults (mean age 20s); no
gender predominance
Juvenile polyposis: Body, more
Any location, but common in the rectum
Location
predominantly antrum Peutz-Jeghers polyposis: Body, more
common in the small intestine
Juvenile polyposis: Most patients
present with painless rectal bleeding;

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 other symptoms include abdominal
Many are asymptomatic; pain, constipation, diarrhea
common symptoms Peutz-Jeghers polyposis: Variable;
Symptoms include abdominal pain, related to extent and severity of
nausea, vomiting, weight disease; many patients present with
loss obstruction due to large polyps of the
small bowel, or symptoms of related
malignancies including those of the
breast, lung, pancreas, ovary, testis, and
GI tract
Juvenile polyposis: Sporadic forms of
disease are associated with congenital
anomalies including congenital heart
disease, hydrocephalus, digital
Generally none;
clubbing and intestinal malrotation;
Signs endoscopy detects most
failure to thrive due to severe protein-
lesions
losing enteropathy
Peutz-Jeghers polyposis: Pigmented
macules on mucous membranes and
skin
Juvenile polyposis: Both an autosomal
dominant inherited and sporadic
disorder that results in multiple
hamartomatous polyps throughout the
GI tract associated with mutations in
the SMAD4 or BMPR1A genes
Unknown; thought to be
Peutz-Jeghers polyposis: Autosomal
Etiology a manifestation of
dominant inherited disorder with
chronic injury and repair
variable penetrance due to mutations of
the STK11/LKB1 gene on chromosome
19p that results in hamartomatous
polyps throughout the GI tract and
pigmented macules of the skin and
mucous membranes
Juvenile polyposis
1. Smooth rounded, lobulated polyp
surface frequently associated with
1. Diffuse hyperplasia of erosion and granulation tissue (Figs.

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 foveolar epithelium with 2.18.5–2.18.7)
elongation and dilation 2. Hyperplastic foveolar epithelium
of the foveolae with an (Fig. 2.18.8)
elaborated architecture 3. Reactive epithelial changes are
of papillae and common, which can be associated with
outpouchings (Figs. dysplasia (Figs. 2.18.9 and 2.18.10)
2.18.1 and 2.18.2) 4. Marked mixed inflammation of the
2. Inflammation and lamina propria, often with cystically
Histology edema of the lamina dilated glands filled with neutrophils
propria (Fig. 2.18.3) (Fig. 2.18.11)
3. Reactive epithelial 5. Smooth muscle is not prominent
cells are common, Peutz-Jeghers polyps
typically in association 1. Hyperplasia of the epithelium,
with erosions (Fig. containing all of the usual cellular
2.18.3) components, with splitting by
4. Background mucosa arborizing bundles of smooth muscle
often shows intestinal (Figs. 2.18.12–2.18.15)
metaplasia (Fig. 2.18.4) 2. Occasional reactive epithelium
associated with erosion
3. Lamina propria generally
unremarkable
Generally not performed;
Special Generally not most patients with familial
studies performed forms of disease harbor
genetic mutations

Endoscopic or surgical
resection for larger Surgical or endoscopic resection of
polyps; relevant polyps; routine surveillance is required
Treatment
treatment for any other to screen and evaluate any lesions for
pathology present in the dysplasia or invasive disease
specimen
Juvenile polyposis: Relatively poor;
high risk of invasive carcinoma of the
Excellent; most are colon, as well as throughout the GI
benign. Minimal, but tract
Prognosis measurable risk (4%) of Peutz-Jeghers polyposis: Relatively
dysplasia and/or poor; high risk of malignancy at

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 invasive carcinoma multiple sites and most patients (90%)
develop cancer in their lifetime.

Figure 2.18.1 Hyperplastic polyp.

Figure 2.18.2 Hyperplastic polyp. Hyperplastic foveolar epithelium.

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Figure 2.18.3 Hyperplastic polyp. Reactive epithelial changes and background
inflammation.

Figure 2.18.4 Hyperplastic polyp. Intestinal metaplasia (PAS/AB stain).

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Figure 2.18.5 Juvenile polyp.

Figure 2.18.6 Juvenile polyp with cystically dilated glands.

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Figure 2.18.7 Juvenile polyp. Surface epithelium with granulation tissue.

Figure 2.18.8 Juvenile polyp. Hyperplastic foveolar epithelium.

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Figure 2.18.9 Low-grade dysplasia in a juvenile polyp.

Figure 2.18.10 High-grade dysplasia in a juvenile polyp.

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Figure 2.18.11 Juvenile polyp. Mixed inflammation within the stroma of a
juvenile polyp.

Figure 2.18.12 Peutz-Jeghers polyp.

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Figure 2.18.13 Peutz-Jeghers polyp with hyperplastic glands.

Figure 2.18.14 Peutz-Jeghers polyp. Hyperplastic smooth muscle

interdigitating among glands.

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Figure 2.18.15 Peutz-Jeghers polyp. Hyperplastic smooth muscle radiating
between the glands.

2.19 Pyloric gland adenoma vs.

Intestinal-type adenoma
Pyloric Gland
Intestinal Type Adenoma
Adenoma
Typically older adults
Typically older adults (mean age 70); male
Age/Gender (mean age 70s);
predominance
female predominance
Body; also occur in
the gallbladder,
Location Predominantly antrum
duodenum, and main
pancreatic duct
Nonspecific
abdominal pain,
nausea, vomiting, Nonspecific; may have vague abdominal
Symptoms other symptoms
pain, nausea, vomiting
related to underlying
disorder

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 Few to none; most
Nonspecific; most lesions detected via
Signs lesions identified via
endoscopy
endoscopy
Unknown, but up to
one-third occur in
patients with
autoimmune
Etiology metaplastic atrophic Unknown
gastritis; some cases
have been associated
with H. pylori and
chemical gastritis
1. Densely packed
pyloric gland cells
with round nuclei
without nucleoli,
cuboidal to flattened
epithelium, and
eosinophilic “ground-
glass” cytoplasm
1. Enlarged hyperchromatic nuclei with
(Figs. 2.19.1 and
interspersed goblet cells and/or Paneth
2.19.2)
cells (Figs. 2.19.5 and 2.19.6)
2. High-grade
2. High-grade dysplasia and/or invasive
dysplasia and/or
carcinoma is common, characterized by
Histology invasive carcinoma is
glandular crowding, cribriform glands,
common,
nuclear pseudostratification (Figs. 2.19.7
characterized by
and 2.19.8)
glandular crowding,
3. Background mucosa often shows
cribriform glands,
atrophic intestinal metaplasia (Fig. 2.19.9)
nuclear
pseudostratification
(Figs. 2.19.3 and
2.19.4)
3. Background
mucosa often has
features of
autoimmune gastritis

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 Mucin PAS/AB stain highlights
stains can intestinal-type goblet cells with
be used to acid mucin (blue). Mucin stains
confirm the can be used to confirm the
diagnosis; diagnosis; intestinal-type
Special pyloric adenomas express MUC2 and
studies gland CDX2 but do not express MUC6
adenomas or MUC5AC. Molecular
express analysis shows variable
MUC6 and mutations in APC, Kras, and
MUC5AC p53 genes and microsatellite
instability

Resection with
surveillance biopsy
Complete endoscopic or surgical resection
of the background
Treatment with representative sampling of the entire
mucosa; treatment of
stomach
any other pathology
in the specimen
Fair; considered a precursor lesion of
Fair; relatively high
carcinoma as well as a marker of general
risk of dysplasia
risk of invasive disease; more likely to be
Prognosis and/or invasive
dysplastic than gastric foveolar-type
carcinoma (10%–
gastric adenomas; size greater than 2 cm is
15%)
an important prognostic indicator

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Figure 2.19.1 Pyloric gland adenoma. Densely packed and cystically dilated
pyloric glands.

Figure 2.19.2 Pyloric gland adenoma. Densely packed pyloric glands with
small round nuclei and ample eosinophilic cytoplasm.

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Figure 2.19.3 Pyloric gland adenoma. High-grade dysplasia in a pyloric gland
adenoma showing complex architecture of glands.

Figure 2.19.4 Pyloric gland adenoma. High-grade dysplasia in a pyloric gland

adenoma showing marked pleomorphism and loss of nuclear polarity.

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Figure 2.19.5 Intestinal-type adenoma.

Figure 2.19.6 Intestinal-type adenoma. Nuclear pseudostratification in an

intestinal-type adenoma.

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Figure 2.19.7 Intestinal-type adenoma. High-grade dysplasia in an intestinal-
type adenoma.

Figure 2.19.8 Intestinal-type adenoma. High-grade dysplasia with marked

pleomorphism and prominent mitoses.

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Figure 2.19.9 Intestinal-type adenoma. Background intestinal metaplasia.

2.20 Pyloric gland adenoma vs.

Gastric foveolar-type gastric
adenoma
Gastric Foveolar-Type Gastric
Pyloric Gland Adenoma
Adenoma
Typically older adults
Typically older adults (mean age 70);
Age/Gender (mean age 70s); female
male predominance
predominance
Body; also occur in the
Location gallbladder, duodenum and Body
main pancreatic duct
Nonspecific abdominal Many are asymptomatic; nonspecific
pain, nausea, vomiting, symptoms include abdominal pain,
Symptoms
other symptoms related to

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 underlying disorder nausea, vomiting
Few to none; most lesions
Signs Few; most lesions are sessile/flat
identified via endoscopy
Unknown, but up to one-
third occur in patients with
autoimmune metaplastic
Most are associated with familial
Etiology atrophic gastritis; some
adenomatous polyposis
cases have been associated
with H. pylori and
chemical gastritis
1. Densely packed pyloric
gland cells with round
nuclei without nucleoli,
cuboidal to flattened
epithelium, and
eosinophilic “ground-
1. Enlarged hyperchromatic nuclei
glass” cytoplasm (Figs.
(Figs. 2.20.6–2.20.8) Gastric
2.20.1–2.20.3)
foveolar type cytoplasm.
2. High-grade dysplasia
Histology 2. Dysplasia, especially invasive
and/or invasive carcinoma
carcinoma, is rare (Fig. 2.20.9)
is common, characterized
3. Background mucosa usually
by glandular crowding,
unremarkable
cribriform glands, nuclear
pseudostratification (Figs.
2.20.4 and 2.20.5)
3. Background mucosa
often has features of
autoimmune gastritis
PAS/AB stain highlights
Mucin stains can the foveolar-type cells with
be used to neutral mucin (pink).
confirm the Mucin stains can be used
Special diagnosis; to confirm the diagnosis;
pyloric gland gastric foveolar type
studies
adenomas gastric adenomas express
express MUC6 MUC5AC but do not
and MUC5AC. express MUC6 or MUC 2

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 Resection with surveillance
biopsy of the background Complete endoscopic or surgical
Treatment mucosa; treatment of any resection with representative
other pathology in the sampling of the entire stomach
specimen
Fair; relatively high risk of
Very good; low risk of dysplasia or
Prognosis dysplasia and/or invasive
invasive carcinoma.
carcinoma (10%–15%)

Figure 2.20.1 Pyloric gland adenoma. Densely packed pyloric glands.

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Figure 2.20.2 Pyloric gland adenoma. Densely packed pyloric glands with
small round nuclei and ample eosinophilic cytoplasm.

Figure 2.20.3 Pyloric gland adenoma. Densely packed pyloric glands with
bland nuclei and ample apical ground-glass cytoplasm.

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Figure 2.20.4 Pyloric gland adenoma. High-grade dysplasia in a pyloric gland
adenoma.

Figure 2.20.5 Pyloric gland adenoma. High-grade dysplasia showing marked

pleomorphism, prominent mitoses, and loss of nuclear polarity.

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Figure 2.20.6 Foveolar-type gastric adenoma.

Figure 2.20.7 Foveolar-type gastric adenoma with prominent apical mucin and
polarized nuclei.

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Figure 2.20.8 Foveolar-type gastric adenoma with prominent apical mucin
vacuoles.

Figure 2.20.9 Focal low-grade dysplasia in a foveolar-type gastric adenoma.

2.21 Oxyntic gland polyp/adenoma vs.

Fundic gland polyp
Oxyntic Gland
Fundic Gland Polyp
Polyp/Adenoma

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 Typically adults (sporadic, mean age
Typically adults; male = 50s; familial, mean age 20s); female
Age/Gender
female predominance (familial forms show
no gender predominance)
Location Cardia and body Body and fundus
Generally asymptomatic;
Generally asymptomatic; nonspecific
Symptoms nonspecific abdominal
abdominal pain is most common
pain is most common
Few, if any. Endoscopy Few, if any. Endoscopy shows
Signs usually shows a single multiple small, sessile, hemispherical
polyp polyps occurring in clusters
Most common type of gastric polyp,
which is either sporadic or familial.
Unknown; thought to arise Most sporadic lesions have mutations
Etiology
from chief cells in beta-catenin. Familial lesions are
associated with familial adenomatous
polyposis syndrome
1. Irregularly branched
tubules arranged in
anastomosing cords (Figs.
2.21.1 and 2.21.2).
2. Tubules composed of 1. Random, disordered proliferation
monomorphous epithelial of oxyntic mucosa with dilated
cells with small, central, fundic glands and/or microcysts lined
round nuclei and ample by flattened oxyntic epithelium (Figs.
Histology amphophilic cytoplasm 2.21.6 and 2.21.7)
(Figs. 2.21.3 and 2.21.4) 2. Background gastric mucosa is
3. Scattered intermixed normal
parietal cells (Fig. 2.21.5) 3. Dysplasia can be seen (Figs.
4. Focal nuclear atypia 2.21.8 and 2.21.9)
with nuclear stratification
can be present
5. Often seen adjacent to a
fundic gland polyp
Not generally performed;
Generally not however, immunolabeling
performed. The for beta-catenin is seen is

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Special cells are positive most sporadic lesions,
studies for pepsinogen-I while some familial lesions
and MUC6 are positive for APC gene
mutation

Most lesions regress spontaneously;

Treatment Polypectomy
polypectomy for larger lesions.
Excellent; minimal risk of Excellent; generally considered
Prognosis recurrence though data are benign lesions. Familial polyps have
limited. a measurable risk of dysplasia.

Figure 2.21.1 Oxyntic gland adenoma.

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Figure 2.21.2 Oxyntic gland adenoma. Irregularly branched anastomosing
cords of cells.

Figure 2.21.3 Oxyntic gland adenoma. Tubules of monomorphic cells with

intermixed parietal cells.

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Figure 2.21.4 Oxyntic gland adenoma. Small, round monomorphic cells with
nucleoli and ample eosinophilic cytoplasm.

Figure 2.21.5 Oxyntic gland adenoma. Intermixed parietal cells.

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Figure 2.21.6 Fundic gland polyp.

Figure 2.21.7 Fundic gland polyp. Dilated gland lined by flattened oxyntic
epithelium.

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Figure 2.21.8 Fundic gland polyp. Low-grade dysplasia in a fundic gland
polyp.

Figure 2.21.9 Fundic gland polyp. High-grade dysplasia in a fundic gland

polyp.

2.22 Lymphoepithelial-like carcinoma

vs. Lymphoma

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 Lymphoepithelial-Like
Lymphoma
Carcinoma
Typically older adults (mean age
Typically younger age; more
Age/Gender 50s–60s); slight female
common in males than females
predominance
Often in the cardia/body, but Most arise in the gastric body
Location
can occur in any location and prepyloric area
Related to extent of tumor
Nonspecific; some present with
growth; most commonly
Symptoms weakness, or B symptoms
present with early onset satiety,
including fever and night sweats
decreased appetite, reflux
Palpable stomach with
occasional succussion splash,
Few, if any; usually diagnosed
Signs enlarged supraclavicular and/or
via biopsy
axillary lymph nodes, anemia,
obstruction
Most gastric lymphomas are
Subset of gastric carcinomas
extranodal marginal zone B-cell
associated with EBV infection,
Etiology lymphomas that develop in
as well as Caucasian and
association with H. pylori
Hispanic ethnicity, male gender
gastritis and autoimmune disease
1. Prominent reactive follicles
surrounded by a proliferation of
1. Poorly differentiated
neoplastic marginal B cells that
carcinoma characterized by
are small and round with a
markedly atypical cells with
monocytoid appearance
polygonal-shaped nuclei with
characterized by a clear “halo”
prominent mitoses (Figs. 2.22.1
surrounding the nucleus (Fig.
and 2.22.2)
2.22.8)
2. Lacelike pattern of neoplastic
Histology 2. Neoplastic B cells diffusely
cells that invade with a pushing
infiltrate the lamina propria,
border (Fig. 2.22.3)
involving the muscularis
3. Prominent lymphocytic
mucosae (Fig. 2.22.9)
response composed of both B
3. Lymphoepithelial lesions
and T cells and variable
present, in most but not all cases,
numbers of acute inflammatory
characterized by infiltration of
cells (Figs. 2.22.4 and 2.22.5)
benign glands by neoplastic

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 lymphocytes (Fig. 2.22.10)
Immunohistochemistry
is critical to diagnosis.
The neoplastic B cells
show immunolabeling
for CD20 (Figs.
An
2.22.11 and 2.22.12)
immunohistochemical
as well as aberrant
panel for lymphocytic
expression of CD43. A
markers highlights
CD3 stain (Fig.
the mixed nature of
2.22.13) highlights
the infiltrate
background T cells,
composed of
which also normally
phenotypically
express CD43.
normal CD20+ B
Special Cytokeratin stains are
cells without
studies negative (Fig.
expression of CD43
2.22.14). Cytogenetic
and CD3+ T cells.
analysis often shows
The cells are positive
translocations
for cytokeratin
involving t(11;18),
markers (Fig. 2.22.6).
t(14;18), t(3;14), and
In situ hybridization
t(1;14) as well as
for EBV is positive in
trisomies of
75%–80% of cases
chromosomes 3, 12
(Fig. 2.22.7).
and 18. Additional
stains or H. pylori
must be performed to
evaluate for the
presence of organisms

Similar to other variants of

poorly differentiated gastric
carcinoma, including surgical
Treatment resection with or without
neoadjuvant chemotherapy
and/or radiation depending on
stage of disease
As most cases are associated
with H. pylori infection, the
mainstay of therapy is triple
antibiotic therapy for eradication
of infection
Generally good; most lesions are

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 Generally poor, but overall,
LEL carcinoma has a better
Prognosis prognosis than conventional
gastric carcinoma for matched
stage disease
low grade and indolent with a 5-
year survival rate of up to 90%.
A subset of lesions (8%)
transform to diffuse large B-cell
lymphoma portending a worse
prognosis

Figure 2.22.1 Lymphoepithelioma-like carcinoma. Infiltrating poorly

differentiated malignant cells arranged in a lymphocytic background.

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Figure 2.22.2 Lymphoepithelioma-like carcinoma. Prominent
lymphoplasmacytic background with conspicuous mitoses.

Figure 2.22.3 Lymphoepithelioma-like carcinoma. Diffuse infiltration of

malignant cells in a lacelike pattern.

Figure 2.22.4 Lymphoepithelioma-like carcinoma. Malignant cells in a mixed

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acute and chronic inflammatory background.

Figure 2.22.5 Lymphoepithelioma-like carcinoma. Malignant cells in a mixed

acute and chronic inflammatory background.

Figure 2.22.6 Lymphoepithelioma-like carcinoma. A Cam5.2 stain highlighting

the malignant cells.

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Figure 2.22.7 Lymphoepithelioma-like carcinoma. In situ hybridization for
EBV.

Figure 2.22.8 Mucosa-associated lymphoid tissue (MALT) lymphoma.

Monocytoid lymphocyte infiltrating the lamina propria.

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Figure 2.22.9 Mucosa-associated lymphoid tissue (MALT) lymphoma. MALT
lymphoma infiltrating the lamina propria.

Figure 2.22.10 Mucosa-associated lymphoid tissue (MALT) lymphoma.

Lymphoepithelial lesion.

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Figure 2.22.11 Mucosa-associated lymphoid tissue (MALT) lymphoma. CD20
stain highlighting malignant B cells.

Figure 2.22.12 Mucosa-associated lymphoid tissue (MALT) lymphoma.

Malignant B cells showing aberrant expression of CD43.

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Figure 2.22.13 Mucosa-associated lymphoid tissue (MALT) lymphoma. CD3
stain highlighting background T cells.

Figure 2.22.14 Mucosa-associated lymphoid tissue (MALT) lymphoma. An

AE1/AE3 stain highlighting background benign mucosa.

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2.23 Metastatic lobular breast
carcinoma vs. Signet-ring cell gastric
carcinoma
Metastatic Lobular Breast
Carcinoma
Age/Gender Typically adults; females
Location Any location
Related to extent of tumor
growth; most commonly
Symptoms
present with early onset satiety, with early onset satiety,
decreased appetite, reflux
Anemia, obstruction, possible
Signs
palpable mass
Metastatic spread from a
primary lobular breast
Etiology carcinoma that often occurs up with autoimmune metaplastic
to 10–20 years after the primary atrophic gastritis
diagnosis
1. Diffuse infiltrate of poorly
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Signet-Ring Cell Gastric
Carcinoma
Mean age mid-50; males >
females
Predominantly antrum (60%);
less commonly body (20%),
cardia/fundus (10%),
diffuse/entire stomach (1%)
Related to extent of tumor
growth; most commonly present
decreased appetite, reflux
Palpable stomach with
occasional succussion splash,
enlarged supraclavicular and/or
axillary lymph nodes, anemia,
obstruction
Environmental risk factors
include dietary factors (e.g.,
nitrites) and smoking
Increased risk in association
Inherited—48% with
inactivating germline mutations
of the CDH1 gene
1. Cells with large, atypical,
hyperchromatic, and
eccentrically placed nuclei and
intracytoplasmic mucin
 cohesive cells with small, round vacuoles that displace the
nuclei and small intracellular nucleus
mucin vacuoles (Fig. 2.23.1) 2. Individual or poorly formed
2. Infiltrate singly in linear groups of cells
Histology
arrangements (Indian file) or in 3. Mucous cells located outside
small cell clusters (Figs. 2.23.2 the lumina of the glands, within
and 2.23.3) the lamina propria; however, in
3. Background mucosa is familial forms can be located
histologically unremarkable within the glands, underneath
(Fig. 2.23.4) the foveolar cells, and within
the basement membrane
4. Increased mitotic rate
Clinical history is
Immunostains for
important for
keratin (e.g., CAM
diagnosis.
5.2) highlight the
Immunostains for
malignant cells. The
keratin highlight the
cells also show
malignant cells (Fig.
variable labeling for
2.23.5); most express
CK7 and CK20 (most
CK7 but not CK20.
are CK7 positive and
Mucin stains are also
CK20 negative); PAS
positive. Most lobular
and mucin stains are
Special breast carcinomas
also positive. The
studies express estrogen (Fig.
cells are generally
2.23.6) and
negative for ER, PR,
progesterone
and mammaglobin
receptors, and they
with variable E-
are also positive for
cadherin though
gross cystic disease
tumors associated
(Fig. 2.23.7) fluid
with inherited forms
protein and
of disease show loss
mammaglobin. All
of immunolabeling for
show loss of staining
E-cadherin
for E-cadherin

Surgical resection for early-

Chemotherapy is standard for stage disease; adjuvant
Treatment metastatic disease chemoradiation for late-stage

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Variable; depends on the extent
of metastatic spread as well as
Prognosis
the hormonal profile of the
tumor cells.
disease
Related to stage and location of
disease, but overall poor
prognosis; worst prognosis for
proximal late-stage disease

Figure 2.23.1 Metastatic lobular carcinoma. Signet ring cells with

intracytoplasmic mucin vacuoles.

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Figure 2.23.2 Metastatic lobular carcinoma. Diffuse infiltration of the lamina
propria.

Figure 2.23.3 Metastatic lobular carcinoma. Malignant cells infiltrating as

clusters and linear arrangements of single cells.

Figure 2.23.4 Metastatic lobular carcinoma. Background unremarkable

mucosa.

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Figure 2.23.5 Metastatic lobular carcinoma. AE1/AE3 stain highlighting
infiltrating malignant cells.

Figure 2.23.6 Metastatic lobular carcinoma. Malignant cells show nuclear

staining for ER.

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Figure 2.23.7 Metastatic lobular carcinoma. Malignant cells show focal
cytoplasmic staining for GCDFP-15.

2.24 Well-differentiated
neuroendocrine (carcinoid) tumor vs.
Adenocarcinoma
Well-Differentiated
Neuroendocrine Adenocarcinoma
(Carcinoid) Tumor
Adults (50s–60s), Type I:
female > male (2.5:1)
Typically older adults (mean age 70s),
Age/Gender Type II: female = male,
males > females
Type III: male > female
(2.8:1)
Majority in the body and
fundus (Types I and II); a
Location Majority in the pylorus and antrum
subset in the prepyloric
region (Type III)
Vague, nonspecific

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 epigastric pain, nausea,
vomiting, hematemesis,
Symptoms weight loss, melena; 10% Epigastric pain, vomiting, nausea,
present with carcinoid weight loss, early satiety
syndrome of flushing,
wheezing, and diarrhea
(mostly Type III tumors)
Abdominal tenderness, palpable
Few, if any, most detected
Signs epigastric mass; endoscopy shows a
via endoscopy
mass or resistance to insufflation
Disease occurs in both sporadic and
inherited forms. Sporadic forms of
disease have been associated with
various environmental risk factors
including diets high in nitrites, low
socioeconomic status, and tobacco
Variable; there are three
use. Moreover, there is a striking
subtypes with different
geographical distribution of disease
etiologies. Type I tumors
with the incidence of disease being
are associated with
much higher in Asia and Eastern
chronic atrophic
Europe and lower in Western Europe
autoimmune gastritis,
and North America. Patients with
Etiology Type II tumors are
chronic gastritis and H. pylori gastritis
associated with Zollinger-
and those with a history of partial
Ellison syndrome and
gastrectomy are also at high risk.
multiple endocrine
These sporadic tumors are associated
neoplasia syndromes, and
with mutations in APC, Kras, and p53
Type III tumors are
genes. Familial inherited forms of
sporadic lesions
disease occur in patients with
germline CDH1 mutations, as well as
patients with Li-Fraumeni syndrome,
familial adenomatous polyposis,
hereditary nonpolyposis colon cancer,
and BRCA 2 mutations
1. Uniform cells with
small, uniform, round
nuclei, central prominent
nucleoli and speckled Two histologic types:

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 chromatin (“salt and 1. Intestinal type: Well-formed glands
pepper”), and eosinophilic lined by columnar to cuboidal
cytoplasm (Fig. 2.24.1) epithelial cells with elongated,
2. Cells arranged in hyperchromatic nuclei; prominent
variable architectural nucleoli; and variable loss of nuclear
patterns including polarity; arranged in angulated
trabecular, solid, acinar, tubules or complex cribriform and
and nested (Fig. 2.24.2) back-to-back glands; often arises in a
Histology 3. Delicate intervening background adenoma (Figs.
capillary network (Fig. 2.24.7–2.24.9)
2.24.3) 2. Diffuse type: Proliferation of
4. Usually located in the dyscohesive single cells with a signet-
mucosa and submucosa, ring cell morphology (Figs. 2.24.10
though some invade the and 2.24.11)
gastric wall and elicit a 3. Marked desmoplastic response
desmoplastic reaction often with transmural wall thickening
(Fig. 2.24.4) (Fig. 2.24.12)
5. Mitotic rate varies;
necrosis is rare but can be
seen
The cells show
immunolabeling
for
neuroendocrine
markers
including
synaptophysin
(Fig. 2.24.5),
chromogranin A
(Fig. 2.24.6),
and NSE. They
are also positive The lesional cells express
for cytokeratin cytokeratins (Fig. 2.24.13),
markers. The generally show
Ki-67 immunolabeling for CK7,
Special proliferative and are negative for CK20.
studies index is used to They also express CEA and
classify well- EMA. Neuroendocrine

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 differentiated markers are generally
tumor—grade 1 negative
tumors have an
index of less
than or equal to
2%, grade 2
tumors have an
index of 2–
20%, and grade
3 tumors have
an index of
greater than
20%

Early-stage disease is treated with

surgical resection. Treatment of late-
Surgical excision and/or
Treatment stage disease involves neoadjuvant
somatostatin analogues
therapy with surgical resection if
possible
Generally good;
prognosis is related to the
subtype of gastric
carcinoid. Type I tumors
Poor; prognosis is highly related to
are generally considered
grade and stage of disease and most
benign with a 5-year
patients present at a late stage. Other
survival rate of 90%.
Prognosis poor prognostic factors include age,
Type III tumors are the
proximal tumor location, and
most aggressive with a 5-
lymphovascular invasion. The 5-year
year survival rate of 50%
survival rate is 10%–15%
and many patients present
with distant metastases,
and Type II tumors have
an intermediate prognosis.

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Figure 2.24.1 Well-differentiated neuroendocrine (carcinoid) tumor. Small,
round nuclei with prominent nucleoli and “salt and pepper” chromatin.

Figure 2.24.2 Well-differentiated neuroendocrine (carcinoid) tumor. Cells

arranged in a nested architecture.

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Figure 2.24.3 Well-differentiated neuroendocrine (carcinoid) tumor. Cells
arranged in a nested architecture with a prominent intervening capillary
network.

Figure 2.24.4 Well-differentiated neuroendocrine (carcinoid) tumor. Carcinoid

tumor centered in the submucosa.

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Figure 2.24.5 Well-differentiated neuroendocrine (carcinoid) tumor.
Synaptophysin stain in carcinoid tumor.

Figure 2.24.6 Well-differentiated neuroendocrine (carcinoid) tumor.

Chromogranin stain in carcinoid tumor.

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Figure 2.24.7 Moderately differentiated adenocarcinoma.

Figure 2.24.8 Adenocarcinoma. Infiltrating glands with markedly atypical,

hyperchromatic, and pleomorphic nuclei and prominent mitoses.

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Figure 2.24.9 Adenocarcinoma. Background intestinal type adenoma.

Figure 2.24.10 Adenocarcinoma. Signet-ring cell carcinoma.

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Figure 2.24.11 Adenocarcinoma. Infiltrating signet-ring cell carcinoma.

Figure 2.24.12 Infiltrating glands set in a desmoplastic stroma.

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Figure 2.24.13 Adenocarcinoma. An AE1/AE3 stain in infiltrating
adenocarcinoma.

2.25 Type 1 endocrine tumor vs. Type

2 endocrine tumor
Type 2 Neuroendocrine
Type 1 Neuroendocrine Tumor
Tumor
Typically adults (mean age
Typically adults (mean age 60s);
Age/Gender 50); no gender
predominantly women
predominance
Location Fundus and body Fundus and body
Vague and nonspecific; 30% of
patients are asymptomatic;
symptoms related to underlying
Chest and abdominal pain,
Symptoms disease include upper abdominal
diarrhea, weight loss
pain, weight loss, lower extremity
weakness, vomiting, hematemesis,
diarrhea, weight loss, melena.
Severe esophagitis and
Megaloblastic anemia, serum
duodenitis, fasting serum

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 analysis is positive for anti–parietal
Signs cell and anti–intrinsic factor
antibodies, elevated serum gastrin,
positive Schilling test corrected by
administration of intrinsic factor
Develops in association with
autoimmune metaplastic atrophic
gastritis; in this condition, patients
develop antibodies against parietal
cells resulting in parietal cell loss,
mucosal atrophy, and intestinal
metaplasia. Hypochlorhydria
Etiology secondary to parietal cell loss
activates feedback mechanisms that
increase the secretion of gastrin by
G cells in the antrum which
manifests in the body as
proliferation of neuroendocrine cells
(ECL cells). Patients have G cell
hyperplasia and hypergastrinemia.
1. Small round blue cells with “salt
and pepper” chromatin arranged in
nests and cords (Figs. 2.25.1 and
2.25.2)
2. Background antralized, atrophic
Histology mucosa with intestinal metaplasia
composed predominantly of
mucinous cells with few parietal
cells (Fig. 2.25.3)
3. Distortion and loss of pit/gland
architecture
Cells express
synaptophysin (Fig.
Special 2.25.4), chromogranin
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gastrin greater than 1,000
pg/mL, hypercalcemia,
kidney stones, recurrent and
multiple duodenal and
jejunal ulcers
Proliferation of
neuroendocrine cells as a
result of hypergastrinemia
from an extragastric (e.g.,
pancreas, duodenum)
gastrin-secreting tumor in
patients with Zollinger-
Ellison syndrome as a
manifestation of multiple
endocrine neoplasia I
1. Small round blue cells
with “salt and pepper”
chromatin arranged in nests
and cords (Fig. 2.25.6)
2. Background mucosa with
parietal cell hyperplasia
(Fig. 2.25.7)
3. Lesions are small and
often multifocal
Since the lesional
cells are
enterochromaffin-
like cells,
immunolabeling
for gastrin is
studies (Fig. 2.25.5), and neuron-
specific enolase
Endoscopic or surgical resection,
with regular follow-up, endoscopic
Treatment surveillance, somatostatin analogues
to inhibit gastrin secretion, and
antrectomy to eliminate G cells
Very good; lesions are considered
benign; prognosis highly related to progression to dysplasia
Prognosis
the size of tumor; tumors greater
than 2 cm are more aggressive
Figure 2.25.1 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.
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negative; the cells
express
synaptophysin,
chromogranin,
and neuron-
specific enolase
Surgical resection of
gastrin-secreting tumor
Good; lesions are
considered benign though
are associated with mildly
increased risk of
and invasive carcinoma;
prognosis highly related to
the size of tumor; tumors
greater than 2 cm are more
aggressive
Small, round cells arranged in a nested architecture.

Figure 2.25.2 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.

Small, round cells with prominent nucleoli and “salt and pepper” chromatin
set in a delicate vascular network.

Figure 2.25.3 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.

Background antralized mucosa characteristic of AMAG (body).

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Figure 2.25.4 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.
Synaptophysin stain in type I neuroendocrine tumor.

Figure 2.25.5 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.

Chromogranin stain in type I neuroendocrine tumor.

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Figure 2.25.6 Type 2 well-differentiated neuroendocrine (carcinoid) tumor.
Small, round cells with prominent nucleoli and salt and pepper chromatin
arranged in cords.

Figure 2.25.7 Type 2 well-differentiated neuroendocrine (carcinoid) tumor.

Background hyperplasia of chief and parietal cells.

2.26 Type 1 endocrine tumor vs. Type

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3 endocrine tumor
Type 3 Neuroendocrine
Type 1 Neuroendocrine Tumor
Tumor
Typically adults (mean
Typically adults (mean age 60s);
Age/Gender age mid-50s); male
predominantly women
predominance
Location Fundus and body Prepyloric region
Most likely of the
endocrine tumor types to
present with classical
Vague and nonspecific; 30% of patients
symptoms of carcinoid
are asymptomatic; symptoms related to
syndrome—flushing,
underlying disease include upper
diarrhea, wheezing,
Symptoms abdominal pain, weight loss, lower
arrhythmias; also present
extremity weakness, vomiting,
with nonspecific
hematemesis, diarrhea, weight loss,
symptoms including
melena
abdominal pain,
vomiting, diarrhea,
weight loss
Megaloblastic anemia; serum analysis
is positive for anti–parietal cell and
anti–intrinsic factor antibodies,
Signs Vague, nonspecific
elevated serum gastrin, positive
Schilling test corrected by
administration of intrinsic factor
Develops in association with
autoimmune metaplastic atrophic
gastritis; in this condition, patients
develop antibodies against parietal cells
resulting in parietal cell loss, mucosal
atrophy, and intestinal metaplasia.
Hypochlorhydria secondary to parietal Unknown; sporadic
Etiology cell loss activates feedback lesions
mechanisms that increase the secretion
of gastrin by G cells in the antrum

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 which manifests in the body as
proliferation of neuroendocrine cells
(ECL cells). G cell hyperplasia results
in hypergastrinemia.
1. Small round blue cells with “salt and
1. Small round blue cells
pepper” chromatin arranged in nests with “salt and pepper”
and cords (Figs. 2.26.1 and 2.26.2) chromatin arranged in
2. Background mucosa—antralized, nests and cords (Figs.
atrophic with intestinal metaplasia 2.26.5–2.26.7)
Histology
composed predominantly of mucinous 2. Background mucosa
cells with few parietal cells (Figs. generally unremarkable
2.26.3 and 2.26.4) (Fig. 2.26.7)
3. Distortion and loss of pit/gland 3. Lesions usually large
architecture and solitary
Cells express
synaptophysin,
Cells express synaptophysin,
Special chromogranin,
chromogranin, and neuron-
studies and neuron-
specific enolase
specific
enolase

Endoscopic or surgical resection, with

regular follow-up, endoscopic Extensive radical
Treatment surveillance, somatostatin analogues to surgery with local
inhibit gastrin secretion, and lymphadenectomy
antrectomy to eliminate G cells
Fair; worst prognosis of
all the endocrine tumor
Very good; lesions are considered types, with tumor size
benign; prognosis highly related to the greater than 2 cm; most
Prognosis
size of tumor; tumors greater than 2 cm lesions are large and
are more aggressive have a higher risk of
invasion and metastatic
spread

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Figure 2.26.1 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.
Small, round cells with prominent nucleoli and “salt and pepper” chromatin.

Figure 2.26.2 Type 1 well-differentiated neuroendocrine (carcinoid) tumor

Carcinoid tumor composed of nests of small, round cells with extensive
involvement of the muscularis propria and lymphovascular spaces.

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Figure 2.26.3 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.
Background antralized mucosa of AMAG.

Figure 2.26.4 Type 1 well-differentiated neuroendocrine (carcinoid) tumor.

Intestinal metaplasia associated with AMAG.

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Figure 2.26.5 Type 3 well-differentiated neuroendocrine (carcinoid) tumor.
Proliferation of small round cells with prominent nucleoli and salt and pepper
chromatin.

Figure 2.26.6 Type 3 well-differentiated neuroendocrine (carcinoid) tumor.

Carcinoid tumor arranged in trabeculae infiltrating through the muscularis
propria.

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Figure 2.26.7 Type 3 well-differentiated neuroendocrine (carcinoid) tumor.
Background mucosa with carcinoid tumor centered in the submucosa.

2.27 Mucosa associated lymphoid

tissue (MALT) lymphoma vs. Chronic
gastritis
MALT Lymphoma Chronic Gastritis
Typically adults (mean age 50s–60s), Typically adults, no
Age/Gender
slight female predominance gender predominance
Location Body and pylorus Body
Most asymptomatic,
Nonspecific—abdominal pain, nausea, nonspecific
Symptoms
weakness, fever, chills abdominal pain,
nausea
Signs Few, if any Few, if any
Low-grade B-cell neoplasms associated
with the chronic inflammatory response Most cases reflect
most commonly to H. pylori infection, but the residual

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Etiology also that of autoimmune disease, inflammatory
associated with various translocations response to prior H.
t(11;18)(q21;q21), t(1;14)(p22;q32), pylori infection
t(14,18);(q32,q21), and t(3;14)(p14.1;p32)
1. At low power, the
lamina propria has
increased “dot
density,” which
1. Nodular architecture of expanded reflects the presence
reactive follicles infiltrated and surrounded of increased numbers
by monotonous neoplastic marginal zone B of plasma cells and
cells with a “monocytoid/fried egg” lymphocytes (Figs.
appearance of small, round nuclei with 2.27.7 and 2.27.8)
occasional perinuclear halos and abundant 2. Prominent plasma
cytoplasm (Fig. 2.27.1) cells with
2. Expansion of the lamina propria, with inflammation
Histology extension into the muscularis propria (Fig. confined to the
2.27.2) lamina propria with
3. Occasional lymphoepithelial lesions more than 5 plasma
composed of centrocyte-like lymphocytes cells per high power
infiltrating among cells of mucosal glands field or more than 3
(Fig. 2.27.3). present between
4. Few plasma cells foveolae (Fig.
5. H. pylori organisms usually present in 2.27.9)
the background mucosa 3. H. pylori
organisms usually
present in the
background mucosa
(Fig. 2.27.10)
Most lesions are confirmed using
a panel of immunostains
Generally
including CD3 (Fig. 2.27.4),
not
CD20 (Fig. 2.27.5), and CD43
performed,
(Fig. 2.27.6). The lesional cells
unless the
are B cells that immunolabel for
infiltrate is
CD20, with aberrant expression
particularly
of CD43 as well. Not all cases
florid. It is
express CD43, but the presence

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Special of a CD20+ infiltrate with composed
studies classic morphologic features is of T cells,
consistent with the diagnosis. that
CD3 stain highlights scattered express
associated T cells. In addition, CD3 and
they express CD20, CD79a, and CD5, but
BCL2, but do not express CD5, not CD20,
CD10, or CD23. FISH analysis CD21, or
can be used to detect various CD34.
translocations

Standard triple
therapy for H pylori
infection if
Standard triple therapy for H. pylori
Treatment organisms are
infection, with complete eradication
present; otherwise
treatment is
symptomatic.
Very good; most lesions regress with
treatment of H. pylori infection. Certain
translocations, particularly t(11;18)
(q21;q21) translocation, have not been
Prognosis Very good
associated with H. pylori and are least
likely to respond to antibiotic therapy. Few
lesions recur or progress to diffuse large B-
cell lymphoma

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Figure 2.27.1 Mucosa-associated lymphoid tissue (MALT) lymphoma.
Proliferation of monocytoid lymphocytes with a thin rim of clear cytoplasm.

Figure 2.27.2 Mucosa-associated lymphoid tissue (MALT) lymphoma.

Expansion of the lamina propria by a lymphocytic infiltrate.

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Figure 2.27.3 Mucosa-associated lymphoid tissue (MALT) lymphoma.
Lymphoepithelial lesion.

Figure 2.27.4 Mucosa-associated lymphoid tissue (MALT) lymphoma. CD3

stain highlighting background T cells.

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Figure 2.27.5 Mucosa-associated lymphoid tissue (MALT) lymphoma. CD20
stain highlighting malignant B cells.

Figure 2.27.6 Mucosa-associated lymphoid tissue (MALT) lymphoma. CD43

stain showing aberrant expression of malignant B cells.

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Figure 2.27.7 Chronic gastritis. Increased “dot density” within the lamina
propria.

Figure 2.27.8 Chronic gastritis. Infiltration of lymphocytes and plasma cells

within the lamina propria.

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Figure 2.27.9 Chronic gastritis. Prominent plasma cells within the lamina
propria.

Figure 2.27.10 Chronic gastritis. Diff-Quik stain showing H. pylori organisms.

2.28 Diffuse large B-cell lymphoma

vs. Carcinoma

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 Diffuse Large B-Cell
Carcinoma
Lymphoma
Typically adults (mean
Typically older adults (mean age 70s);
Age/Gender age 50s); slight male
males > females
predominance
Location Predominantly body Majority in the pylorus and antrum
Nonspecific epigastric
Epigastric pain, vomiting, nausea,
Symptoms abdominal pain,
weight loss, early satiety
dyspepsia, weight loss
Few; most cases Abdominal tenderness, palpable
Signs diagnosed via epigastric mass; endoscopy shows a
endoscopy mass or resistance to insufflation
Disease occurs in both sporadic and
inherited forms. Sporadic forms of
disease have been associated with
various environmental risk factors
including diets high in nitrites, low
socioeconomic status, and tobacco use.
Moreover, there is a striking
geographical distribution of disease
Unknown; most are with the incidence of disease being
thought to arise from much higher in Asia and Eastern
transformation of low- Europe and lower in Western Europe
grade MALT B-cell and North America. Patients with
Etiology
lymphomas. Others have chronic gastritis, those with H. pylori
been shown to be gastritis, and those with a history of
associated with EBV partial gastrectomy are also at high
infection risk. These sporadic tumors are
associated with mutations in APC, Kras
and p53 genes. Familial inherited forms
of disease occur in patients with
germline CDH1 mutations, as well as
patients with Li-Fraumeni syndrome,
familial adenomatous polyposis,
hereditary nonpolyposis colon cancer,
and BRCA 2 mutations
1. Diffuse infiltration of

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 the lamina propria by Two histologic types:
sheets of large cells 1. Intestinal type: Well-formed glands
(nuclei two times larger lined by columnar to cuboidal epithelial
than the size of a small cells with elongated, hyperchromatic
lymphocyte) with nuclei, prominent nucleoli and variable
vesicular chromatin, loss of nuclear polarity; arranged in
prominent nucleoli and angulated tubules or complex
prominent basophilic cribriform and back-to-back glands
cytoplasm (Figs. 2.28.1 (Figs. 2.28.9 and 2.28.10)
Histology and 2.28.2) 2. Diffuse type: Proliferation of
2. Background mucosa dyscohesive single cells with a signet-
may show features of ring cell morphology (Fig. 2.28.11)
low-grade MALT 3. Poorly differentiated tumors consist
lymphoma (Fig. 2.28.3) predominantly of single cells with
3. Increased mitotic rate markedly pleomorphic, hyperchromatic
with prominent nuclei with mucin loss and prominent
apoptotic bodies (Figs. mitoses
2.28.4 and 2.28.5) 4. Desmoplastic stroma is common
4. No in situ mucosal (Fig. 2.28.12)
component
5. No gland formation
The
differential
diagnosis is
broad and an
immunostain
panel
including
S100,
cytokeratins,
CD20/CD3
(Fig. 2.28.6),
CD117/C-kit,
and CD30 is
often used.
The neoplastic
cells are B
cells and as

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 such express
CD19, CD20 Lesion cells express
(Fig. 2.28.7), cytokeratin markers, and are
CD22, and negative for most
Special CD79a with immunologic markers
studies variable including CD20, CD3, CD19,
expression for CD20, and CD30. Mucin
CD10, BCL6, stains are positive
and MUM1.
Note, some
cases can
show no
staining and
are best
diagnosed via
flow
cytometric
analysis. In
EBV-related
cases, in situ
hybridization
is useful for
diagnosis.
Stains for
mucin and
cytokeratins
are negative
(Fig. 2.28.8)

Chemotherapy is the
mainstay of treatment;
surgery reserved for Early-stage disease is treated with
patients with acute surgical resection. Treatment of late-
Treatment complications such as stage disease involves neoadjuvant
perforation or severe therapy with surgical resection if
bleeding. Lesions do not possible
respond to H. pylori
eradication therapy

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 Good; prognosis is most
related to the stage of Poor; prognosis is highly related to
disease. However, cases grade and stage of disease, and most
that are related to patients present at a late stage. Other
Prognosis progression from a poor prognostic factors include age,
MALT lymphoma have proximal tumor location, and
a better prognosis. EBV- lymphovascular invasion. The 5-year
related tumors have a survival rate is 10%–15%
worse prognosis, but
constitute only 5%–10%
of cases

Figure 2.28.1 Diffuse large B-cell lymphoma. Markedly atypical, pleomorphic

cells with prominent nucleoli.

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Figure 2.28.2 Diffuse large B-cell lymphoma. Background ulceration with
infiltration and destruction of glands.

Figure 2.28.3 Diffuse large B-cell lymphoma. Background MALT lymphoma.

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Figure 2.28.4 Diffuse large B-cell lymphoma. Markedly atypical cells with
prominent mitoses and apoptotic bodies.

Figure 2.28.5 Diffuse large B-cell lymphoma. Markedly elevated Ki-67

proliferation rate.

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Figure 2.28.7 Diffuse large B-cell lymphoma. CD20 stain highlighting
malignant cells.

Figure 2.28.6 Diffuse large B-cell lymphoma. CD3 stain showing rare
scattered T cells.

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Figure 2.28.8 Diffuse large B-cell lymphoma. An AE1/AE3 stain highlights
background glands; malignant cells are negative.

Figure 2.28.9 Adenocarcinoma. Moderately to poorly differentiated

adenocarcinoma.

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Figure 2.28.10 Adenocarcinoma. Infiltrating moderately to poorly
differentiated glands of adenocarcinoma.

Figure 2.28.11 Adenocarcinoma. Infiltrating signet-ring cell carcinoma.

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Figure 2.28.12 Adenocarcinoma. Infiltrating glands of adenocarcinoma set in
a desmoplastic stroma.

2.29 Gastrointestinal stromal tumor

(GIST) vs. Inflammatory fibroid
polyp
Gastrointestinal Stromal Tumor Inflammatory Fibroid
(GIST) Polyp
Typically older adults
Typically adults (mean age 60s); slight (mean age 60s) but
Age/Gender
male predominance occurs in children; slight
male predominance
Mural tumors, located within the Predominantly antrum in
Location submucosa and muscularis propria the prepyloric region,
(Fig. 2.29.1) mucosa, and submucosa
Predominantly GI bleeding, but also
abdominal pain, palpable abdominal Most asymptomatic;
Symptoms mass, and/or specific symptoms nonspecific abdominal
related to organ dysfunction at sites of pain, nausea, vomiting
distant metastases
Few; physical exam may show
Signs abdominal tenderness, palpable None

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 abdominal mass
Unknown; cells are derived from the
interstitial cells of Cajal. GIST is
Unknown; related to
associated with neurofibromatosis type
mutations in the platelet-
1 as well as seen in association with
derived growth factor
Etiology familial mutations in C-kit. Most
receptor alpha gene
lesions are related to mutations in the
(PDGFRA), thought to be
C-kit gene, but a subset have
a reparative process
mutations in platelet-derived growth
factor receptor alpha gene (PDGFRA)
1. Well-circumscribed,
unencapsulated lesion
composed of spindle
cells with pale nuclei and
prominent cytoplasm that
infiltrate both the mucosa
and submucosa (Fig.
1. Spindle (Fig. 2.29.2) to epithelioid 2.29.7)
(Fig. 2.29.3) cells with slightly tapered 2. Loose myxoid stroma
ovoid nuclei, often with paranuclear with prominent
vacuoles, and ample amphophilic intratumoral
cytoplasm arranged in sheets and inflammatory cells
tightly to loosely arranged fascicles including eosinophils,
Histology (Fig. 2.29.4) with focal to prominent lymphocytes, and plasma
cellular palisading infiltrating centered cells (Fig. 2.29.8)
in the muscularis propria 3. Prominent capillary
2. Rare, if any intratumoral network with concentric
inflammatory cells perivascular proliferation
3. Mitoses present, can be prominent of stromal cells—“onion
and atypical skinning” (Fig. 2.29.9)
4. Occasional reactive
epithelial changes of the
superficial mucosa (Fig.
2.29.10)
5. Rare mitotic figures,
but no atypical mitoses
and no necrosis
Nearly all GISTs express C- The lesional

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 kit (CD117) (Fig. 2.29.5) cells are of
with associated mutations. myofibroblastic
However, approximately 5% differentiation
of tumors do not express C- and express
kit or harbor mutations; vimentin,
Special instead they have mutations CD34, smooth
studies in the platelet-derived muscle actin,
growth factor-A gene. Most muscle-specific
GISTs also show positive actin, KP-1,
immunolabeling for CD34 and CD34.
(70%) and DOG1. Variable They are
immunolabeling for actin negative for C-
and S100 (Fig. 2.29.6) kit (CD117)

Conservative surgical resection;

extensive radical resection is not
recommended. Tumors with KIT
mutations are treated with targeted Endoscopic or surgical
Treatment
tyrosine-kinase inhibitors; of note, resection is curative
tumors with mutations in exon 9 do
not respond as well to inhibitor
therapy
Good; while up to 20% of tumors are
malignant, long-term survival is high.
Tumor characteristics that portend a
worse prognosis include size greater
than 5 cm and more than 5 mitoses per
50 high power fields. These two
Prognosis factors are used for risk stratification Excellent; always benign.
of individual tumors according to the
AFIP criteria. Additional poor
prognostic factors include tumor at the
gastroesophageal junction or fundus,
necrosis, ulceration, and mucosal
invasion

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Figure 2.29.1 Gastrointestinal stromal tumor (GIST). GIST involving the
muscularis propria.

Figure 2.29.2 Gastrointestinal stromal tumor (GIST). Spindle cell component

of GIST.

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Figure 2.29.3 Gastrointestinal stromal tumor (GIST). Epithelioid cell
component of GIST.

Figure 2.29.4 Gastrointestinal stromal tumor (GIST). Spindle cells in loosely

arranged fascicles.

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Figure 2.29.5 Gastrointestinal stromal tumor (GIST). CKIT stain in GIST.

Figure 2.29.6 Gastrointestinal stromal tumor (GIST). S100 stain in GIST. This
example shows many dendritic cells, but the tumor cells are only focally
reactive.

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Figure 2.29.7 Inflammatory fibroid polyp. Spindle cells with pale nuclei and
ample cytoplasm set in a myxofibrous background.

Figure 2.29.8 Inflammatory fibroid polyp. Mixed inflammatory infiltrate with

prominent eosinophils.

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Figure 2.29.9 Perivascular onion-skinning and background inflammation.

Figure 2.29.10 Inflammatory fibroid polyp. Reactive epithelial changes.

2.30 Epithelioid gastrointestinal

tumor vs. Carcinoma
Epithelioid

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 Gastrointestinal Tumor
Typically adults (mean
Age/Gender age 60s); slight male
predominance
Mural tumors, located
within the submucosa and
Location
muscularis propria (Fig.
2.30.1)
Predominantly GI
bleeding, but also
abdominal pain, palpable
Symptoms abdominal mass, and/or
specific symptoms related
to organ dysfunction at
sites of distant metastases
Few; physical exam may
show abdominal
Signs
tenderness, palpable
abdominal mass
Unknown; cells are
derived from the
interstitial cells of Cajal.
GIST is associated with
Etiology
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Carcinoma
Typically older adults
(mean age 70s); males >
females
Majority in the pylorus and
antrum
Epigastric pain, vomiting,
nausea, weight loss, early
satiety
Abdominal tenderness,
palpable epigastric mass;
endoscopy shows a mass
or resistance to insufflation
Disease occurs in both
sporadic and inherited
forms. Sporadic forms of
disease have been
associated with various
environmental risk factors
including diets high in
nitrites, low
socioeconomic status, and
tobacco use. Moreover,
there is a striking
geographical distribution
of disease with the
incidence of disease being
much higher in Asia and
Eastern Europe and lower
in Western Europe and
North America. Patients
Etiology
neurofibromatosis type 1 with chronic gastritis and
as well as seen in H. pylori gastritis and
association with familial those with a history of
mutations in C-kit partial gastrectomy are
also at high risk. These
sporadic tumors are
associated with mutations
in APC, Kras, and p53
genes. Familial inherited
forms of disease occur in
patients with germline
CDH1 mutations, as well
as patients with Li-
Fraumeni syndrome,
familial adenomatous
polyposis, hereditary
nonpolyposis colon cancer,
and BRCA 2 mutations
Two histologic
types:
1. Intestinal
type: Well-
formed glands
lined by
columnar to
cuboidal
epithelial cells
with elongated,
hyperchromatic
nuclei,
prominent
nucleoli, and
variable loss of
nuclear
polarity;
1. Epithelioid cells with arranged in
ovoid nuclei and ample angulated
amphophilic cytoplasm, tubules or

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 perinuclear halos and complex
distinct cell membranes cribriform and
arranged in sheets, and back-to-back
randomly oriented tight glands
Histology fascicles with focal to 2. Diffuse type:
prominent palisading Proliferation of
(Figs. 2.30.2 and 2.30.3) dyscohesive
2. Minimal to no single cells
pleomorphism with a signet-
3. No mucosal component ring cell
4. No gland formation morphology
5. Only rare mitotic figures 3. Poorly
(Fig. 2.30.2) differentiated
tumors consist
predominantly
of single cells
with markedly
pleomorphic,
hyperchromatic
nuclei with
mucin loss
4. Background
often shows an
in situ mucosal
component
5. Often focal
gland
formation
6. Mitoses
prominent
Lesion cells
Lesion cells
express
will show
cytokeratin
immunolabeling
markers, but do
for CD117/c-kit
not express
(Fig. 2.30.4),
CD34. Mucin
CD34 (Fig.
stains are
Special 2.30.5), and
studies positive, and
DOG1, but are

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studies DOG1, but are
negative for
cytokeratin
markers. Mucin
stains are
negative
Conservative surgical
resection; extensive
radical resection is not
recommended. Tumors
with KIT mutations are
Treatment treated with targeted
tyrosine-kinase inhibitors;
of note, tumors with
mutations in exon 9 do
not respond as well to
inhibitor therapy
Very good; most (75%)
are benign. The most
important prognostic
indicators are tumor
location with tumors in
Prognosis the posterior wall, as well
as those in the cardia and
fundus being generally
more aggressive, as well
as size, necrosis,
increased mitotic rate
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CD117 stain can
be positive.
DOG1 may be
reactive in
adenocarcinomas
(pitfall)
Early-stage disease is
treated with surgical
resection. Treatment of
late-stage disease involves
neoadjuvant therapy with
surgical resection if
possible.
Poor; prognosis is highly
related to grade and stage
of disease, and most
patients present at a late
stage. Other poor
prognostic factors include
age, proximal tumor
location, and
lymphovascular invasion.
The 5-year survival rate is
10%–15%.
Figure 2.30.1 Gastrointestinal stromal tumor (GIST). Epithelioid GIST
centered in the muscularis propria.

Figure 2.30.2 Gastrointestinal stromal tumor (GIST). Proliferation of

epithelioid cells with small, round nuclei and moderate eosinophilic cytoplasm.

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Figure 2.30.3 Gastrointestinal stromal tumor (GIST). Epithelioid cells with
variable clear to eosinophilic cytoplasm.

Figure 2.30.4 Gastrointestinal stromal tumor (GIST). C-KIT stain in epithelioid

GIST.

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Figure 2.30.5 Gastrointestinal stromal tumor (GIST). CD34 stain in epithelioid
GIST.

2.31 Gastrointestinal stromal tumor

(GIST) vs. Schwannoma
Gastrointestinal Stromal Tumor
Schwannoma
(GIST)
Typically adults (mean age 60s); Typically adults; female
Age/Gender
slight male predominance predominance
Mural tumors, located
Mural tumors, located within the
Location within the submucosa and
submucosa and muscularis propria
muscularis propria
Many are asymptomatic,
incidental lesions; some
Predominantly GI bleeding, but also
present with nonspecific
abdominal pain, palpable abdominal
symptoms are related to the
Symptoms mass, and/or specific symptoms
size and site of tumor,
related to organ dysfunction at sites
nonspecific symptoms
of distant metastases
including abdominal pain,
dyspepsia, early satiety

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 Few; physical exam may show Generally none; may have
Signs abdominal tenderness, palpable abdominal tenderness or
abdominal mass palpable abdominal mass
Unknown; cells are derived from the
interstitial cells of Cajal. GIST is Unknown; sporadic lesions
Etiology associated with neurofibromatosis unassociated with any
type 1 as well as seen in association known syndromes
with familial mutations in C-kit
1. Well-circumscribed
tumor, unencapsulated
1. Spindle (Fig. 2.31.1) to
tumor composed of spindle
epithelioid cells with slightly tapered
cells arranged in loose
ovoid nuclei, often with paranuclear
fascicles (Figs. 2.31.5 and
vacuoles, and ample amphophilic
2.31.6)
cytoplasm arranged in sheets and
2. No cellular palisading
tightly to loosely arranged fascicles
Histology 3. Prominent peripheral
(Fig. 2.31.2)
lymphoid cuff with
2. Focal to prominent cellular
scattered germinal centers
palisading (Fig. 2.31.2)
in the majority of tumors
3. No lymphoid cuff
(90%, Fig. 2.31.7 )
4. Rare, if any, intratumoral
4. Diffuse intratumoral
inflammatory cells
lymphocytes and plasma
cells (Fig. 2.31.8)
Lesions are
strongly positive
for S100 (Fig.
Nearly all GISTs express
2.31.9), a
C-kit (CD117) (Fig.
fraction are
2.31.3) with associated
positive for
mutations in the kit gene.
GFAP, and some
However, approximately
show focal
5% of tumors do not
immunolabeling
express C-kit or harbor
for CD34 (Fig.
mutations in the C-kit
2.31.10); they do
gene; instead they have
Special not express
mutations in the platelet-
studies markers of
derived growth factor-A
muscle
gene. Most GISTs also
differentiation

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 show positive (Fig. 2.31.11) or
immunolabeling for CD34 C-kit (CD117)
(70%) and DOG1. (Fig. 2.31.12).
Variable immunolabeling Molecular
for actin and S100 (Fig. analysis for
2.31.4) mutations in KIT
and PDGFRA
genes is negative

Conservative surgical resection;

extensive radical resection is not
recommended. Tumors with KIT
mutations are treated with targeted
Treatment Surgical excision
tyrosine-kinase inhibitors; of note,
tumors with mutations in exon 9 do
not respond as well to inhibitor
therapy
Good; while up to 20% of tumors
are malignant, long-term survival is
high. Tumor characteristics that
portend a worse prognosis include
size greater than 5 cm and more than
5 mitoses per 50 high power fields.
These two factors are used for risk Excellent; universally
Prognosis
stratification of individual tumors benign.
according to the AFIP criteria.
Additional poor prognostic factors
include tumor at the
gastroesophageal junction or fundus,
necrosis, ulceration, and mucosal
invasion

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Figure 2.31.1 Gastrointestinal stromal tumor (GIST). Spindle cells component
of GIST with focal epithelioid features.

Figure 2.31.2 Gastrointestinal stromal tumor (GIST). Spindle cells in tightly

arranged fascicles and focal nuclear palisading.

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Figure 2.31.3 Gastrointestinal stromal tumor (GIST). CKIT stain in GIST.

Figure 2.31.4 Gastrointestinal stromal tumor (GIST). S100 stain in GIST.

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Figure 2.31.5 Gastric schwannoma. Spindle cells arranged in loose fascicles.

Figure 2.31.6 Gastric schwannoma. Bland spindle cells with tapered nuclei.

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Figure 2.31.7 Gastric schwannoma. Peripheral lymphoid cuff.

Figure 2.31.8 Gastric schwannoma. Intratumoral germinal center.

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Figure 2.31.9 Gastric schwannoma. S100 stain in schwannoma. There is strong
nuclear and cytoplasmic staining.

Figure 2.31.10 Gastric schwannoma. CD34 stain in schwannoma.

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Figure 2.31.11 Gastric schwannoma. SMA stain in schwannoma.

Figure 2.31.12 Gastric schwannoma. CKIT stain in schwannoma.

2.32 Gastrointestinal stromal tumor

(GIST) vs. Glomus tumor
Gastrointestinal Stromal Tumor

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 (GIST)
Typically adults (mean age 60s);
Age/Gender
slight male predominance
Mural tumors, located within the
Location submucosa and muscularis propria
(Fig. 2.32.1)
Predominantly GI bleeding, but
also abdominal pain, palpable
abdominal mass, and/or specific
Symptoms
symptoms related to organ
dysfunction at sites of distant
metastases
Few; physical exam may show
Signs abdominal tenderness, palpable
abdominal mass
Unknown; cells are derived from
the interstitial cells of Cajal. GIST
is associated with
Etiology
neurofibromatosis type 1 as well
as seen in association with familial
mutations in C-kit
1. Spindle (Fig. 2.32.2) to
epithelioid cells with slightly
tapered ovoid nuclei, often with
paranuclear vacuoles, and ample
Histology amphophilic cytoplasm arranged
in sheets and tightly arranged
fascicles (Fig. 2.32.3)
2. No vascular clustering or
prominent vessels
Nearly all GISTs express
C-kit (CD117) (Fig.
2.32.4) with associated
mutations in the kit
gene. However,
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Glomus Tumor
Typically adults (mean age
50); female predominance
Outer muscularis propria
Most commonly present with
severe gastrointestinal
bleeding, also aching,
incessant abdominal pain
GI bleeding manifests as
melena, sometimes as
hematemesis
No known risk factors
1. Circumscribed lesions
composed of multiple
nodules of small cells with
round nuclei and distinct cell
membranes clustered around
vessels (Figs. 2.32.5–2.32.7)
2. Hemangiopericytoma-like
enlarged, angulated vessels
(Fig. 2.32.8)
Tumor cells are
modified smooth
muscle cells that
express certain
muscle-specific
markers including
smooth muscle
 gene. However, smooth muscle
approximately 5% of actin, calponin, and
tumors do not express C- h-caldesmon, but
kit or harbor mutations; notably, they do
Special instead they have not express
studies mutations in the platelet- desmin.
derived growth factor-A Immunolabeling
gene. Most GISTs also for C-kit (CD117)
show positive is negative, and
immunolabeling for they do not harbor
CD34 (70%) and DOG1. mutations in the
Variable KIT gene. Stains
immunolabeling for for laminin and
actin and S100 collagen type IV
show a pericellular
staining pattern

Conservative surgical resection;

extensive radical resection is not
recommended. Tumors with KIT
mutations are treated with targeted
Treatment Surgical resection
tyrosine-kinase inhibitors; of note,
tumors with mutations in exon 9
do not respond as well to inhibitor
therapy
Good; while up to 20% of tumors
are malignant, long-term survival
is high. Tumor characteristics that
portend a worse prognosis include
size greater than 5 cm and more Very good; most tumors are
than 5 mitoses per 50 high power benign, but have an uncertain
fields. These two factors are used risk of malignant potential as
Prognosis for risk stratification of individual there are no known
tumors according to the AFIP prognostic factors associated
criteria. Additional poor with the rare metastatic
prognostic factors include tumor at tumors
the gastroesophageal junction or
fundus, necrosis, ulceration, and
mucosal invasion

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Figure 2.32.1 Gastrointestinal stromal tumor (GIST). GIST centered in the
submucosa.

Figure 2.32.2 Gastrointestinal stromal tumor (GIST). Spindle to epithelioid

cells of GIST.

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Figure 2.32.3 Gastrointestinal stromal tumor (GIST). Spindle cells arranged in
tightly arranged fascicles.

Figure 2.32.4 Gastrointestinal stromal tumor (GIST). CKIT stain in GIST.

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Figure 2.32.5 Glomus tumor surrounded by thick fibrous capsule.

Figure 2.32.6 Glomus tumor. Perivascular proliferation of tumor cells.

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Figure 2.32.7 Glomus tumor. Small, round cells with nuclear halo and
prominent cellular borders.

Figure 2.32.8 Glomus tumor. Hemangiopericytoma-like vessels.

2.33 Gastrointestinal stromal tumor

(GIST), pediatric type vs. Plexiform

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fibromyxoma
Gastrointestinal Stromal Tumor
Plexiform Fibromyxoma
(GIST), Pediatric Type
Typically younger age (pediatric and
Any age (mean age 40s);
Age/Gender young adults); marked female
no gender predominance
predominance (9:1)
Muscularis propria of the
antrum, rarely extending
Location Predominantly antrum and body
to the duodenum and
perigastric soft tissues
Predominantly GI bleeding, but also
abdominal pain, palpable abdominal
Symptoms mass, and/or specific symptoms GI bleeding most common
related to organ dysfunction at sites
of distant metastases
Few; GI bleeding may
Few; physical exam may show
manifest as anemia,
Signs abdominal tenderness, palpable
abdominal tenderness,
abdominal mass
palpable abdominal mass
Both sporadic and syndromic forms
of disease are related to succinate
dehydrogenase subunit B (SDHB)
Etiology No known risk factors
deficiency. Syndromic forms occur in
Carney triad and Carney-Stratakis
Syndrome
1. Plexiform, (“weblike”)
multinodular architecture
consisting of paucicellular
nodules with scattered
1. Multifocality is common oval spindle cells in a
2. Variable architecture including a variably myxoid and
multinodular pattern composed of fibromyxoid stroma (Figs.
well-circumscribed nodules and a 2.33.5 and 2.33.6)
plexiform pattern composed of bands 2. Prominent
of tumor that infiltrate through the anastomosing capillary

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 muscularis propria between bundles network (Fig. 2.33.7)
of smooth muscle (Fig. 2.33.1) 3. Lesion centered in the
Histology 3. Epithelioid and mixed muscular propria, and
epithelioid/spindle cell morphologies extends superficially to
are the most common cytologic the mucosa and
patterns, pure spindle cell submucosa and deep to
morphology is rare; epithelioid cells the perigastric soft tissues
have round to oval nuclei and (Fig. 2.33.5)
variable amounts of clear to 4. Variable presence of
eosinophilic cytoplasm (Figs. mucosal ulceration and
2.33.2–2.33.4) lymphovascular invasion
5. Absent features—
necrosis, nuclear
palisading, and skenoid
fibers
Most tumors (90%) show
immunolabeling for CKIT The cells
and DOG1; however, express smooth
molecular analysis is muscle actin
negative for mutations in and CD10.
Special CKIT and PDGFRA. The Immunolabeling
studies cells are rarely positive for for C-kit
CD10 and smooth muscle (CD117), CD34,
actin. Succinate and DOG1 is
dehydrogenase negative
immunolabeling shows loss

Most cases do not respond to standard

molecular inhibitor therapy used in
the treatment of conventional GISTs.
Treatment Surgical resection
Thus, primary therapy is surgical
resection with close clinical follow-
up
Generally good; while lymph node
metastasis is common, the disease is
usually indolent. Of note, current risk Excellent; benign—no
Prognosis assessment criteria used in the known risk of recurrence
evaluation of conventional GIST are or metastasis

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 unreliable for pediatric-type GIST

Figure 2.33.1 Pediatric-type gastrointestinal stromal tumor/GIST (succinate

dehydrogenase deficient). Multinodular architecture.

Figure 2.33.2 Pediatric-type gastrointestinal stromal tumor/GIST (succinate

dehydrogenase deficient). Predominant epithelioid morphology.

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Figure 2.33.3 Pediatric-type gastrointestinal stromal tumor/GIST (succinate
dehydrogenase deficient). Predominant epithelioid morphology with prominent
capillaries.

Figure 2.33.4 Pediatric-type gastrointestinal stromal tumor/GIST (succinate

dehydrogenase deficient). Focal spindle cell morphology.

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Figure 2.33.5 Plexiform fibromyxoma centered in the muscularis propria.

Figure 2.33.6 Plexiform fibromyxoma. Bland spindle cells set in a fibromyxoid

stroma.

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Figure 2.33.7 Plexiform fibromyxoma. Anastomosing vascular network.

2.34 Kaposi sarcoma vs. Lamina

propria
Kaposi Sarcoma Lamina Propria
Any age but typically adults; male Any age; male =
Age/Gender
predominance female
Location Any location Any location
Most asymptomatic; presenting
symptoms include GI bleeding,
Symptoms Not applicable
abdominal pain, perforation, nausea,
vomiting, and intussusception
Chronic bleeding may be associated with
iron deficiency anemia, hematemesis, or
melena; given the association with
Signs Not applicable
HIV/AIDS, most patients have
leukopenia, HIV antibodies are positive,
and HIV viral load is high
Virus-induced tumor caused by human

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 herpesvirus 8, which primarily affects
Etiology patients with HIV/AIDS, as well as those Not applicable
who are otherwise immunosuppressed;
endemic forms occur in Africa and the
Mediterranean
1. Loose connective
tissue located between
the epithelium and the
muscularis mucosae,
which contains
fibroblasts, smooth
muscle, vessels,
1. Spindle cells with intracytoplasmic
lymphatics, and
hyaline globules that form slitlike spaces
inflammatory cells
filled with extravasated red blood cells
(Figs. 2.34.9 and
(Figs. 2.34.1–2.34.5)
2.34.10)
Histology 2. Lamina propria with
2. Lamina propria
lymphoplasmacytic infiltrate and
with scattered
hemosiderin (Fig. 2.34.6)
lymphocytes and
3. Distortion of normal architecture via
plasma cells, no more
destruction of glands
than five per HPF or
two to three plasma
cells between foveolae
(Figs. 2.34.10 and
2.34.11)
3. Intact mucosal
architecture
Immunolabeling with HHV8
stain is confirmatory (Fig.
2.34.7). The cells express Generally
Special vascular markers including not
studies CD31 (Fig. 2.34.8), CD34, and performed
factor VIII. PAS stain
highlights hyaline globules

For symptomatic patients, injection, heat

coagulation, sclerotherapy, and antacid
drugs are standard. For disease related to

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 HIV/AIDS, continuation of highly active
Treatment antiretroviral therapy is most effective Not applicable
with regression of many lesions. For
patients with disease secondary to other
causes of immunosuppression, cessation
of immunosuppressive drugs is
recommended
Generally good; related to the severity of
Prognosis the underlying immunosuppression rather Not applicable
than the lesion itself in most patients

Figure 2.34.1 Kaposi sarcoma. Marked expansion of the lamina propria by an

inflammatory infiltrate.

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Figure 2.34.2 Kaposi sarcoma. Proliferation of spindle cells forming slitlike
spaces.

Figure 2.34.3 Kaposi sarcoma. Proliferation of spindle cells with extravasated

red blood cells.

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Figure 2.34.4 Kaposi sarcoma. Hyaline globules.

Figure 2.34.5 Kaposi sarcoma. Conspicuous mitosis.

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Figure 2.34.6 Hemosiderin deposition and prominent infiltrating plasma cells.

Figure 2.34.7 Kaposi sarcoma. HHV8 stain highlighting malignant cells within
the lamina propria.

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Figure 2.34.8 Kaposi sarcoma. CD31 stain highlighting malignant cells within
the lamina propria.

Figure 2.34.9 Normal lamina propria composed of loose connective tissue and
scattered inflammatory cells.

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Figure 2.34.10 Normal lamina propria composed of loose connective tissue.

Figure 2.34.11 Normal lamina propria with scattered lymphocytes and plasma
cells.

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cell gastric lymphoma. Lancet. 1991;338:1175–1176.
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Gastroenterol. 2014;27(1):27–33.

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 3
Small Intestine

3.1 Crushed Brunner glands vs. Whipple disease

3.2 Crushed Brunner glands vs. Mesenchymal lesions in small
bowel mucosa
3.3 Chronic duodenitis vs. Intracytoplasmic lipid
3.4 Chronic duodenitis vs. Abetalipoproteinemia
3.5 Atypical stromal cells in ulcers vs. Small bowel sarcomas
3.6 Whipple disease vs. Mycobacterium avium complex
3.7 Common variable immunodeficiency vs. Normal small
intestine
3.8 Autoimmune enteropathy vs. Normal small bowel
3.9 Autoimmune enteropathy vs. Common variable
immunodeficiency
3.10 Celiac disease vs. Small bowel bacterial overgrowth of enteric
contents
3.11 Celiac disease vs. Common variable immunodeficiency
3.12 Collagenous sprue/enteritis vs. Radiation change
3.13 Behcet syndrome affecting small bowel vs. Crohn disease
3.14 Microvillus inclusion disease vs. Intracytoplasmic lipid
3.15 Microvillus inclusion disease vs. Tufting enteropathy
3.16 Nonsteroidal anti-inflammatory drug (NSAID)–associated
injury requiring surgery vs. Crohn disease requiring surgery
3.17 Infectious enteritis vs. Crohn disease
3.18 Pyloric gland adenoma vs. Tubular adenoma
3.19 Nodular duodenitis vs. Tubular/tubulovillous adenoma
3.20 Peutz-Jeghers polyp vs. Juvenile polyp

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3.21 Cronkhite-Canada Polyps vs. Juvenile polyps
3.22 Primary small bowel cancer vs. Metastases to small bowel
3.23 Small bowel follicular lymphoma vs. Reactive lymphoid
hyperplasia
3.24 Small bowel follicular lymphoma vs. Mucosa-associated
lymphoid tissue (MALT) lymphoma
3.25 Small bowel follicular lymphoma vs. Mantle cell lymphoma
3.26 Burkitt lymphoma vs. Diffuse large B-cell lymphoma
3.27 Enteropathy-associated T-cell lymphoma vs.
Enteropathy/celiac disease
3.28 Systemic mastocytosis vs. Langerhans cell histiocytosis
3.29 Small bowel gastrointestinal stromal tumor vs. Inflammatory
fibroid polyp
3.30 Epithelioid small bowel gastrointestinal stromal tumor vs.
Carcinoma
3.31 Small bowel gastrointestinal stromal tumor vs.
Leiomyosarcoma
3.32 Small bowel gastrointestinal stromal tumor vs. Clear cell
sarcoma–like tumor (malignant gastrointestinal
neuroectodermal tumor)
3.33 Small bowel gastrointestinal stromal tumor vs. Melanoma
3.34 Clear cell sarcoma–like tumor (malignant gastrointestinal
neuroectodermal tumor) vs. Melanoma
3.35 Small bowel gastrointestinal stromal tumor vs. Mesenteric
fibromatosis
3.36 Mesenteric Fibromatosis vs. Sclerosing mesenteritis
3.37 Mesenteric Fibromatosis vs. Calcifying fibrous tumors
3.38 Duodenal well-differentiated neuroendocrine carcinoid tumor
vs. Duodenitis

3.1 Crushed Brunner glands vs.

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Whipple disease
Crushed Brunner
Whipple Disease
Glands
Can be
encountered in
any duodenal
Age/Gender biopsy (Brunner Adults; male predominance
glands are
specific to the
duodenum)
Any part of Anywhere in the small bowel or anywhere in
Location
duodenum the body, for that matter
Depends on presentation—classically
malabsorption-associated symptoms but
None. This is an
Symptoms patients can present with central nervous
artifact of biopsy
system manifestations, adenopathy, or
rheumatologic symptoms
Site dependent, classically with diarrhea and
wasting but patients with central nervous
Signs None
system disease can present with seizures or
other central nervous system signs
Damage to the
duodenal mucosa
as a result of the
Etiology act of performing Infection with Tropheryma whipplei
the biopsy and
very commonly
encountered
1. Nodules of
crushed Brunner
glands, often in
continuity with
well-preserved
Brunner glands
(Fig. 3.1.1).

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 Lacteals are not 1. Small bowel samples show expansion of
dilated the lamina propria with foamy macrophages
Histology 2. PAS/AB and multiple dilated spaces (Fig. 3.1.4)
strongly positive 2. PAS/AB staining shows granular cytoplasm
in “foamy” in the distended macrophages (Fig. 3.1.5)
pattern (Fig. 3. Whipple bacillus immunolabeling is
3.1.2) reactive (Fig. 3.1.6)
3. Negative
Whipple bacillus
immunostain but
not necessary to
perform this stain
(Fig. 3.1.3)

Immunolabeling and PCR can

confirm the presence of the
organisms. Following treatment, the
findings can be subtle, and also,
nonviable organisms can remain
Special None
immunoreactive within
studies
macrophages. Treatment required
prolonged antibiotic administration,
and monitoring with PCR studies
has been suggested

Antibiotics: Doxycycline and

hydroxychloroquine for 12 months followed
by lifelong treatment with doxycycline, as
potentially fatal relapses can occur. T.
Treatment None
whipplei seems to be an opportunistic
bacterium that causes chronic infections in
susceptible patients with as yet unknown
predisposing factors
Not applicable.
The infection is difficult to eradicate, and, as
Prognosis This is an
above, lifelong antibiotic treatment is needed
incidental finding

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Figure 3.1.1 Duodenum, crushed Brunner glands. Note the area in the center of
the field. There is a crushed Brunner gland in the lumen in close association
with surface mucosa. Material from Bruner glands is also in the lumina of
some of the crypts at the lower right. Note also the cellularity of duodenal
lamina propria.

Figure 3.1.2 Duodenum, crushed Brunner glands, PAS/AB stain. This is a

PAS/AB of the same are seen in Figure 3.1.1. Brunner glands stain magenta.
There are small compact nuclei and abundant neutral mucin with a slightly
fibrillary appearance.

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Figure 3.1.3 Duodenum, crushed Brunner glands. At very high magnification,
the slightly fibrillary crushed cytoplasm appears vacuolated as well.

Figure 3.1.4 Whipple disease. The lamina propria is expanded with foamy
macrophages, but the lumina of the crypts are empty. Note the dilated spaces, a
characteristic feature of Whipple disease.

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Figure 3.1.5 Whipple disease, PAS/AB stain. The macrophages contain coarse
granular deposits in contrast to the delicate fibrillary material in crushed
Brunner glands.

Figure 3.1.6 Whipple disease, immunolabeling. There is strong coarsely

granular staining in untreated cases, which becomes less prominent after
treatment.

3.2 Crushed Brunner glands vs.

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Mesenchymal lesions in small bowel
mucosa
Crushed Mesenchymal Lesions in Small Bowel
Brunner Glands Mucosa
Can be
encountered in
any duodenal
Male predominance; usually middle-aged
Age/Gender biopsy (Brunner
males
glands are
specific to the
duodenum)
Any part of
Location Throughout the small bowel
duodenum
Related to the size and location. For example,
inflammatory fibroid polyp presents with
intussusception and therefore with symptoms
of obstruction. Leiomyomas are associated
with the muscularis mucosae in the small
None. This is an bowel. Clear cell sarcoma–like tumors arise in
Symptoms
artifact of biopsy the ileum in young patients. Nerve sheath
tumors are the most likely to appear myxoid
and resemble Brunner glands. Gastrointestinal
stromal tumors (GISTs) are usually not seen on
mucosal biopsies, but when they are seen, they
are more cellular than crushed Brunner glands
Those of obstruction in patients whose tumors
Signs None
grow large or cause intussusception
Damage to the
duodenal
mucosa as a
result of the act
Etiology of performing Various tumor types
the biopsy and
very commonly

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 encountered
1. Nodules of
crushed Brunner
glands, often in
continuity with
well-preserved
Brunner glands
(Fig. 3.2.1).
They involve
either the lamina
propria or the
1. This is a leiomyoma arising in association
submucosa.
with muscularis mucosae (Fig. 3.2.4)
These are very
2. This nerve sheath tumor lacks the bubbly
common in
Histology cytoplasm present in crushed Brunner glands
biopsies
(Fig. 3.2.5)
2. PAS/AB
3. This nerve sheath tumor expresses S100
strongly positive
protein (Fig. 3.2.6)
in “foamy”
pattern (Fig.
3.2.2)
3. Negative
S100 protein
immunostain but
not necessary to
perform this
stain (Fig.
3.2.3)
Immunolabeling and histochemical
stains can be helpful. Brunner glands
Special are PAS positive as well as keratin
None
positive. Mesenchymal lesions tend
studies
to lack keratins and are classified
separately from epithelial lesions

Depends on tumor type. Most mesenchymal

lesions seen on mucosal biopsies of the small
Treatment None bowel (and thus in the differential diagnosis of
Brunner glands) are clearly different from

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 Brunner glands
Not applicable. Depends on tumor type. Inflammatory fibroid
This is an polyp and most nerve sheath tumors and
Prognosis
incidental leiomyoma are all benign, whereas some GISTs
finding are malignant

Figure 3.2.1 Duodenum, crushed Brunner glands. The material from the
crushed Brunner glands is in the lumina of the crypts extending as sloughed
material onto the surface but also in contiguity with more well-formed Brunner
glands at the lower left.

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Figure 3.2.2 Duodenum, crushed Brunner glands, PAS/AB. There are well-
preserved Brunner glands in the deeper part of the sample, and they have
extruded themselves into the lumen.

Figure 3.2.3 Duodenum, crushed Brunner glands. These glands are less
crushed than are those in other images. The Brunner glands become more
prominent after cycles of damage and repair to the duodenal mucosa.

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Figure 3.2.4 Leiomyoma. This brightly eosinophilic lesion has arisen in
association with the muscularis mucosae.

Figure 3.2.5 Nerve sheath tumor. Note that the nuclei differ dramatically from
those in the crushed Brunner glands and the fibrillary cytoplasm appears less
vacuolated.

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Figure 3.2.6 Nerve sheath tumor. The strong S100 protein staining is
characteristic.

3.3 Chronic duodenitis vs.

Intracytoplasmic lipid
Intracytoplasmic
Chronic Duodenitis Lipid in Duodenal
Biopsies
Classically encountered in associated with
H. pylori gastritis but can be encountered
Typically adults; no
Age/Gender for any of a variety of reasons. As such
gender predilection
there is a wide age range and no real
gender predilection
Anywhere in duodenum but typically in the
No specific location
Location bulb (the first part receiving the gastric
in duodenum
contents)
None from the chronic duodenitis itself but
from the cause of the duodenitis. For
example, persons with H. pylori gastritis
may have pain from gastric ulcers and have
Usually none except

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 duodenitis on biopsies. If there is chronic when associated
Symptoms duodenitis from Crohn disease, the patient with
may have diarrhea, abdominal pain, and abetalipoproteinemia
small bowel obstruction. If the patient has
chronic duodenitis from taking nonsteroidal
anti-inflammatory drugs, the patient may
have vague abdominal pain
Usually none unless
No specific signs. The duodenum may
Signs in case of
appear nodular at endoscopy
abetalipoproteinemia
In most cases,
dietary indiscretion.
Patients are advised
to refrain from
Cycles of damage and repair to the
eating prior to upper
Etiology duodenal mucosa, which results in gastric
endoscopy, but some
mucin cell metaplasia
are noncompliant so
absorbed lipid may
be seen on
endoscopic samples
1. The brush border
is intact, but bubbly
material can be seen
in enterocytes. It is
1. The key finding is gastric mucin cell not well demarcated
metaplasia of the surface epithelium (Fig. like mucin droplets
3.3.1). Often, there are reparative epithelial in mucin cell
changes as well metaplasia (Fig.
2. At higher magnification, there is a 3.3.4)
surface cap of neutral mucin in the 2. At higher
Histology
epithelium. This contrasts to the normal magnification, the
brush border seen in the duodenum (Fig. adjoining cells lack
3.3.2) cytoplasmic lipid in
3. PAS/AB staining highlights neutral most patients and
mucin in the metaplastic surface epithelium the finding is focal
(Fig. 3.3.3) (Fig. 3.3.5)
3. PAS/AB staining
is negative (Fig.

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 3.3.6)

None; PAS/AB can be helpful if

Special one is not familiar with this None
studies finding

None for the metaplasia itself. Any

treatment is directed at the underlying
Treatment None
etiology of the metaplasia—for example,
treatment of H. pylori gastritis
Excellent for the metaplasia. The
Incidental finding in
Prognosis underlying condition responsible for the
most cases
metaplasia can be addressed if it is known

Figure 3.3.1 Chronic duodenitis. Regardless of the type of injury, when the
duodenal mucosa is injured, it responds with gastric-type metaplasia. This can
be recognized by noticing the gastric-type surface mucin in the area just to the
right of center.

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Figure 3.3.2 Chronic duodenitis, gastric mucin cell metaplasia. Compare the
smaller caps of apical gastric-type metaplastic mucin at the right to the
appearance of the mucin in the goblet cells to the left.

Figure 3.3.3 Chronic duodenitis, gastric mucin cell metaplasia, PAS/AB. The
apical caps of neutral mucin are magenta and on the right, and the quantity of
mucin is less than that in the blue/purple goblet cells toward the left side of the
field.

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Figure 3.3.4 Intracytoplasmic lipid in duodenal biopsies (“lipid hang-up”).
Usually this is a reflection of “cheating” on the NPO requirement prior to
upper endoscopy. The surface absorptive cells are stuffed with lipid (not
neutral mucin) that has been absorbed, but the brush border is intact.

Figure 3.3.5 Intracytoplasmic lipid in duodenal biopsies (“lipid hang-up”).

Higher magnification of the area shown in Figure 3.3.4.

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Figure 3.3.6 Intracytoplasmic lipid in duodenal biopsies (“lipid hang-up”),
PAS/AB stain. There is no mucin in the cytoplasm, only nonstaining lipids, but
the brush border is intact.

3.4 Chronic duodenitis vs.

Abetalipoproteinemia
Chronic Duodenitis Abetalipoproteinemia
Classically encountered in
Abetalipoproteinemia (ABL)
associated with H. pylori
and homozygous
gastritis but can be encountered
hypobetalipoproteinemia
Age/Gender for any of a variety of reasons.
(HHBL) present in infancy with
As such, there is a wide age
chronic diarrhea and failure to
range and no real gender
thrive
predilection
Anywhere in the duodenum but No specific location in
typically in the bulb (the first duodenum but most pronounced
Location
part receiving the gastric there since it is the site of
contents) absorption
None from the chronic
duodenitis itself but from the

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 cause of the duodenitis. For
example, persons with H.
pylori gastritis may have pain
from gastric ulcers and have
duodenitis on biopsies. If there
Symptoms is chronic duodenitis from
Crohn disease, the patient may
have diarrhea, abdominal pain,
and small bowel obstruction. If
the patient has chronic
duodenitis from taking
nonsteroidal anti-inflammatory
drugs, the patient may have
vague abdominal pain
No specific signs. The
Signs duodenum may appear nodular
at endoscopy
Cycles of damage and repair to gene encoding microsomal
the duodenal mucosa, which
Etiology
results in gastric mucin cell (MTP) or both alleles of the
metaplasia
1. The key finding is gastric
mucin cell metaplasia of the
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Diarrhea initially. The disease
leads to hypocholesterolemia
and malabsorption of fat-soluble
vitamins and thus to retinal
degeneration, neuropathy,
coagulopathy, and hepatic
steatosis
Retinal degeneration,
neuropathy, and coagulopathy.
Acanthocytes are seen in
peripheral blood, and the
patients have nearly absent
LDL-C, TG, and apo B
Patients have improper
packaging and secretion of
apolipoprotein (apo) B–
containing lipoprotein particles
due to mutations either in both
alleles of the MTP (alias MTTP)
triglyceride transfer protein
APOB gene itself in the case of
ABL and HHBL. Definitive
diagnosis involves sequencing
the MTP and APOB genes, for
which >30 and >60 mutations
have been described for ABL
and HHBL, respectively
 surface epithelium (Fig.
3.4.1). Often, there are
reparative epithelial changes as
well
2. At higher magnification,
there is a surface cap of neutral
Histology mucin in the epithelium. This
contrasts to the normal brush
border seen in the duodenum
(Fig. 3.4.2)
3. PAS/AB staining highlights
neutral mucin in the
metaplastic surface epithelium
(Fig. 3.4.3)
None; PAS/AB can
Special be helpful if one is
studies not familiar with this
finding
None for the metaplasia itself.
Any treatment is directed at the
underlying etiology of the
Treatment
metaplasia—for example,
treatment of H. pylori
gastritis
Excellent for the metaplasia.
The underlying condition
Prognosis
responsible for the metaplasia
can be addressed if it is known
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1. The brush border is intact, but
bubbly material can be seen in
enterocytes in a diffuse pattern
with no area spared. There can
be villous blunting, and all
enterocytes are stuffed with lipid
(Fig. 3.4.4)
2. At higher magnification, the
adjoining all the cells contain the
lipid (Fig. 3.4.5)
3. PAS/AB staining is negative
(Fig. 3.4.6)
Examination of the
blood smear (Figs.
3.4.7 and 3.4.8) and
performance of lipid
profile testing as well
as sequencing the
involved genes
Low-fat diet and
supplementation with essential
fatty acids and oral fat-soluble
vitamins
Strict adherence to diet can
reduce neurologic damage and
halt progression, but overall life
expectancy is reduced. Some
patients have successful
pregnancies. Many patients live
until the sixth decade
Figure 3.4.1 Chronic duodenitis. This lesion appeared nodular. The eye-
catching feature is that there is extensive gastric mucin cell metaplasia on the
surface.

Figure 3.4.2 Chronic duodenitis. The surface mucin is very different from
intracytoplasmic lipid.

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Figure 3.4.3 Chronic duodenitis, PAS/AB. This stain shows a striking contrast
between the absorptive epithelium with a crisply delineated brush border on
the left and the metaplastic gastric-type surface showing crisply demarcated
apical mucin caps on the right.

Figure 3.4.4 Abetalipoproteinemia. This is essentially completely dramatic

“lipid hang-up” in which essentially the entire sample shows the
intracytoplasmic lipid in the surface absorptive. It appears similar to the
findings in Figures 3.3.4–3.3.6 but is diffusely present in the sample.

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Figure 3.4.5 Abetalipoproteinemia. Higher magnification of the case seen in
Figure 3.4.4. Note that the surface brush border is intact, but the absorptive
cells are stuffed with lipid.

Figure 3.4.6 Abetalipoproteinemia, PAS/AB stain. The brush border and

goblet cells are highlighted, but the material in the absorptive cells is not
mucin but lipid, so it shows no staining.

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Figure 3.4.7 Abetalipoproteinemia. This peripheral blood smear shows striking
acanthocytosis.

Figure 3.4.8 Abetalipoproteinemia. Ultrastructure of an acanthocyte (right)

compared to a normal erythrocyte (left).

3.5 Atypical stromal cells in ulcers vs.

Small bowel sarcomas
Atypical Stromal

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 Cells in Ulcers Small Bowel Sarcomas

Predominance in older adults; male

predominance overall for most lesions
(leiomyosarcoma and malignant
Age/Gender Typically adult
gastrointestinal stromal tumor/GIST). Clear
cell sarcoma–like tumor predominates in
young adults
GISTS and leiomyosarcomas seem to be
more common in the jejunum and ileum
than duodenum, presumably since the
jejunum and ileum are longer. GISTs are far
more common than leiomyosarcomas
Anywhere in the
Location overall. Clear cell sarcoma–like tumors
small bowel
predominate in the ileum and are extremely
rare. Occasionally, other sarcomas (such as
dedifferentiated liposarcomas) can extend
into the small intestines and erode into the
mucosa
None attributable to
the atypical stromal
cells per se.
Whatever has
resulted in the ulcer
Typically, patients present with abdominal
Symptoms (including
pain or symptoms of obstruction
inflammatory bowel
disease or ulcers
associated with
nonsteroidal anti-
inflammatory drugs)
Endoscopic ulcers
Signs may be seen and A mass is identified
biopsied
Small intestinal GISTs are related to KIT
mutations and found sporadically but also
without KIT mutations in patients with
neurofibromatosis, type 1 (the GISTS
Atypical stromal found in children and patients with Carney
Etiology cells in ulcers are

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 found in children and patients with Carney
Etiology cells in ulcers are syndrome or Carney-Stratakis syndrome
attributed to hypoxia are in the stomach). Leiomyomas arise
sporadically, as do clear cell sarcoma–like
tumors; the latter are associated with EWS
gene fusions

1. At low
magnification,
atypical stromal
cells are seen at the
interface of the
nonviable exudate
1. In general, in contrast to atypical stromal
and underlying
cells, the lesional cells in sarcomas do not
Histology granulation tissue
show zonation and form a bulky mass
(Fig. 3.5.1)
(Figs. 3.5.5–3.5.8)
2. Atypical stromal
cells have smudged
nuclei and a low
nuclear-to-
cytoplasmic ratio
(Figs. 3.5.2–3.5.4)
Atypical
stromal
cells are
typically Immunolabeling with KIT,
“vimentin- DOG1, S100 protein, actin, and
only” cells desmin can clarify several
and lack sarcoma types. Rarely, types
Special
expression other than those noted above are
studies
of encountered, including Ewing
keratins, sarcoma and low-grade
S100 fibromyxoid sarcoma
protein,
KIT, and
desmin

Resection and targeted therapy or

Treatment None
chemotherapy, depending on sarcoma type

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 chemotherapy, depending on sarcoma type
These reactive cells
are related to the
etiology of the ulcer The overall prognosis depends on tumor
Prognosis and measures to size, type, and grade as well as the
address the ulcer availability of targeted therapy
result in their
disappearance

Figure 3.5.1 Atypical stromal cells in ulcers. This is a resection from a patient
with Crohn disease. There is an ulcer at the top of the image. Even at this low
magnification, enlarged nucleus can be seen in the bed of the ulcer at the
interface between the hypoxic ulcer and the viable granulation tissue below.
This architectural pattern would be unusual for a sarcoma.

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Figure 3.5.2 Atypical stromal cells in ulcers. The atypical cells proliferate at
the interface of viable and nonviable tissue.

Figure 3.5.3 Atypical stromal cells in ulcers. At high magnification, the cells
are large and atypical with “smudged” nuclei and a relatively low nuclear-to-
cytoplasmic ratio. Note the necroinflammatory debris of the ulcer around the
atypical cell.

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Figure 3.5.4 Atypical stromal cells in ulcers. These cells manifest
macronucleoli but otherwise degenerative chromatin.

Figure 3.5.5 Dedifferentiated liposarcoma involving small bowel. This lesion

has extended from the retroperitoneum into the muscularis propria but not into
the mucosa (sarcomas typically do not involve the small bowel mucosa). Note
that it is a large confluent mass rather than an atypical rind of enlarged spindle
cells.

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Figure 3.5.6 Dedifferentiated liposarcoma involving small bowel. The
malignant cells feature nuclear heterochromatin.

Figure 3.5.7 Angiosarcoma involving small bowel. This lesion proliferates in a

confluent fashion, extending from the submucosa into the lamina propria on
this mucosal biopsy.

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Figure 3.5.8 Low-grade fibromyxoid sarcoma involving small bowel. This
tumor has extended into the muscularis. It is difficult to diagnose specifically
on this low-power view, but the principle is that sarcomas for confluent masses
rather than an atypical layer as in the pseudosarcomatous cells seen in Figures
3.5.1–3.5.4.

3.6 Whipple disease vs.

Mycobacterium avium complex
Whipple Disease Mycobacterium Avium Infection
Typically adults; strong male
predominance since most common in
patients infected with human
immunodeficiency virus (HIV). May
be encountered in any
immunosuppressed person, including
patients with inflammatory bowel
disease taking immune modulation
Adults; male treatments. Patients commonly
Age/Gender
predominance manifest mycobacterium infection in
the duodenum. Prophylaxis against
this infection is suggested in persons
with HIV infection with CD4 counts

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 of <50 cells/μL. The incidence of
such immunosuppression has
declined with the advent of
combination antiretroviral therapy
Anywhere in the small
Location bowel or anywhere in the Duodenum
body, for that matter
Depends on presentation
—classically
malabsorption-associated
symptoms but patients can
Symptoms present with central Diarrhea and wasting
nervous system
manifestations,
adenopathy, or
rheumatologic symptoms
Site dependent, classically
with diarrhea and wasting
but patients with central
EGD discloses white nodules and
Signs nervous system disease
plaques in the duodenum
can present with seizures
or other central nervous
system signs
Infection with
Etiology Mycobacterium avium spp.
Tropheryma whipplei
1. Small bowel samples
show expansion of the
lamina propria with 1. Villi are distended with foamy
foamy macrophages and macrophages, but there are no cystic
multiple dilated spaces spaces/dilated lacteals (Fig. 3.6.4)
(Fig. 3.6.1) 2. PAS/AB staining shows a delicate
2. PAS/AB staining shows material within the macrophages and
Histology
granular cytoplasm in the “negative” outlines of the slender
distended macrophages bacterial forms (Fig. 3.6.5)
(Fig. 3.6.2) 3. Whipple stain is negative, but acid-
3. Whipple bacillus fast staining highlights organisms
immunolabeling is (Fig. 3.6.6)

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 reactive (Fig. 3.6.3)
Immunolabeling
and PCR can
confirm the
presence of the
organisms.
Following
treatment, the
findings can be
subtle and also,
nonviable
Not necessary to stain in
organisms can
order to diagnose in the
Special remain
correct clinical setting.
studies immunoreactive
Acid-fast stain is sufficient
within
in doubtful cases
macrophages.
Treatment
required
prolonged
antibiotic
administration,
and monitoring
with PCR
studies has been
suggested

Antibiotics: Doxycycline
and hydroxychloroquine
for 12 months followed
by lifelong treatment with
doxycycline, as Azithromycin or clarithromycin as
potentially fatal relapses prophylaxis, which can be
can occur. T. whipplei discontinued once CD4 counts are
Treatment seems to be an >100 cells/μL for greater than or
opportunistic bacterium equal to 3 months. For treatment,
that causes chronic clarithromycin is recommended as
infections in susceptible primary therapy
patients with as yet

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 unknown predisposing
factors
The infection is difficult
to eradicate, and, as Excellent if combined with a goal or
Prognosis
above, lifelong antibiotic immune restoration
treatment is needed

Figure 3.6.1 Whipple disease. The lamina propria is stuffed with macrophages,
and there are numerous dilated spaces as well.

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Figure 3.6.2 Whipple disease, PAS/AB. Note the “chunky,” coarse granular
appearance of the contents of the macrophages.

Figure 3.6.3 Whipple disease, Whipple bacillus immunolabeling. The

immunostain also shows a coarse granular appearance.

Figure 3.6.4 Mycobacterium avium complex enteritis. The appearance

overlaps that of Whipple disease, but the quality of the macrophages in the
lamina propria is different, even on the H&E stain. In addition, there are no
cystic spaces.

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Figure 3.6.5 Mycobacterium avium complex enteritis, PAS/AB. Note the
delicate appearance of the PAS reactive mycobacteria in the macrophages
compared to that of Whipple disease. In this case, a negative image imparted
by the waxy coats of the organisms can be appreciated.

Figure 3.6.6 Mycobacterium avium complex enteritis, acid-fast stain. Lamina

propria macrophages are bursting with acid-fast organisms.

3.7 Common variable

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immunodeficiency vs. Normal small
intestine
Common Variable
Normal Small Intestine
Immunodeficiency
Bimodal distribution in
children and then in
middle-aged adults for first
Age/Gender Not applicable
presentation. Probably,
more than one disorder is
represented
Systemic manifestations but
Images here are of duodenum since
Location findings attributable to the
it is most commonly biopsied
small bowel are common
Diarrhea, abdominal pain.
Sometimes, the diarrhea is
Symptoms Not applicable
attributable to infections,
classically giardiasis
Nothing specific. Patients
have manifestations of
hypogammaglobulinemia or
agammaglobulinemia
Signs Not applicable
including multiple
infections. At endoscopy,
prominent small lymphoid
nodules are common
Probably, many
mechanisms, but patients
have reduced
immunoglobulin.
Etiology Frequently, the Not applicable
immunoglobulins are
autoantibodies, and patients
may have multiple immune
alterations

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 1. The key finding is loss of
lamina propria plasma cells,
1. Normal duodenum shows a brush
which is seen in about 70%
border, slender long villi, and short
of patients. In the other
crypts. The lamina propria contains
30% of patients, the
lymphocytes, plasma cells,
Histology diagnosis is impossible on
eosinophils, and mast cells. There
histologic grounds in
are intraepithelial lymphocytes in
isolation (Figs. 3.7.1–3.7.3)
the crypts but fewer at the tips of the
2. Some examples show
villi (Figs. 3.7.5–3.7.8)
celiac disease–like findings
(Fig. 3.7.4)
Findings must be
correlated with PAS/AB highlights the
Special serum brush border, as does
studies immunoglobulin CD10
studies!

Management of the ensuing

Treatment infections. Administration Not applicable
of immunoglobulin
Patients are at risk of
infections and neoplasms.
Prognosis Not applicable
Lifelong management is
required

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Figure 3.7.1 Common variable immunodeficiency. Diagnosis of this condition
usually requires clinical correlation, but the majority of cases have a key
finding—namely, the lack of plasma cells in the lamina propria, which will be
overlooked if not specifically assessed. At low magnification, this case appears
wholly nonspecific (although there is a crushed Brunner gland to enjoy).

Figure 3.7.2 Common variable immunodeficiency. Slightly higher power than

that seen in Figure 3.7.1 offers a hint—the lamina propria seems to have
rescued numbers of cells. Normally, it is chock-full of plasma cells.

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Figure 3.7.3 Common variable immunodeficiency. At high magnification,
plasma cells are absent from the lamina propria, a finding that supports the
diagnosis of common variable immunodeficiency, but one that is present in
about two-thirds of cases rather than in all cases.

Figure 3.7.4 Common variable immunodeficiency. There is prominent surface

lymphocytosis in this example, a feature that can lead to an incorrect
interpretation of celiac disease. Unfortunately, small bowel biopsies from a
host of conditions display overlapping features such that correlation with
clinical and laboratory features is always key to diagnosis.

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Figure 3.7.5 Normal small intestinal mucosa. Tall slender villi are present.
Even at this low magnification, plasma cells are apparent, populating the
lamina propria along with lymphocytes, eosinophils, and mast cells.
Neutrophils should be absent.

Figure 3.7.6 Normal small intestinal mucosa, PAS/AB stain. This image offers
a good view of the anticipated density of lymphoplasmacytic cells in the small
bowel lamina propria. Note the lymphoid aggregate.

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Figure 3.7.7 Normal small intestinal mucosa, PAS/AB stain. Note the slender
brush border, goblet cells, and density of lamina propria contents.

Figure 3.7.8 Normal small intestinal mucosa, PAS/AB stain. Minimal lamina
propria is present, but it shows plasma cells.

3.8 Autoimmune enteropathy vs.

Normal small bowel

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 Autoimmune Enteropathy Normal Small Intestine
The term “autoimmune
enteropathy” can be used to
encompass several
conditions. So-called immune
dysregulation,
polyendocrinopathy,
enteropathy, X-linked (IPEX)
syndrome is included and
Age/gender Not applicable
manifests in boys, whereas
common variable
immunodeficiency can be
also associated with
autoantibodies against
enterocytes. All forms are
associated with immune
dysregulation
Affects the small bowel and Images here are of the duodenum
Location colon, primarily the small since it is most commonly
bowel biopsied
Symptoms Diarrhea, wasting Not applicable
Signs Hypoalbuminemia Not applicable
Variable but some examples
in individuals with FOXP3
Etiology mutations (this molecule Not applicable
governs regulatory T cells
(Tregs))
1. Small bowel samples may
appear celiac disease–like
1. Normal duodenum shows a
with prominent intraepithelial
brush border, slender long villi,
lymphocytosis and can be
and short crypts. The lamina
indistinguishable. The key in
propria contains lymphocytes,
some cases is to recognize the
plasma cells, eosinophils, and mast
absence of goblet cells and/or
cells. There are intraepithelial
Paneth cells and prominent
lymphocytes in the crypts but
Histology crypt apoptosis (Figs. fewer at the tips of the villi. Lastly,
3.8.1–3.8.3)

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 2. Some patients taking
olmesartan (Benicar) or
similar angiotensin II receptor
blockers show celiac-like
findings as well, with
prominent apoptosis (Fig.
3.8.4)
nearly every crypt has several
Paneth cells (Figs. 3.8.5–3.8.8).
In fact, these biopsies were taken
from the same patient as that seen
in Figures 3.8.1–3.8.3 after
intensive treatment

Confirmation with
testing for
PAS/AB highlights the
Special antienterocyte or
brush border, as does
anti–goblet cell
studies CD10
antibodies is of
interest

Treatment Steroids Not applicable

Reflective of the etiology for
the autoimmunity. Patients
can be managed but are often
Prognosis Not applicable
at risk for life-threatening
infections based on associated
conditions

Figure 3.8.1 Autoimmune enteropathy. This biopsy shows a packed lamina

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propria, but what is missing? There is not a single goblet cell or Paneth cell, a
clue to autoimmune enteropathy. Sometimes, severe mucosal injury results in
foci lacking these constituents as well, so a clinicopathologic dialogue is
always indicated when evaluating such patients, who are typically quite ill.

Figure 3.8.2 Autoimmune enteropathy. Lots of endocrine cells are present

(their delicate cytoplasmic granules are oriented away from the lumen to reach
the capillaries) but no Paneth cells, which have coarser granules than
endocrine cells. Normally, the majority of small bowel crypts show Paneth cells
at their bases.

Figure 3.8.3 Autoimmune enteropathy. This example shows striking crypt

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apoptosis as well as absence of goblet cells and Paneth cells.

Figure 3.8.4 Enteropathy associated with olmesartan (Benicar, a blood pressure

medication) can display features difficult to separate from celiac disease,
collagenous sprue, and autoimmune diseases. This example shows prominent
surface lymphocytosis akin to celiac disease and also featured prominent crypt
apoptosis.

Figure 3.8.5 Normal small bowel. The brush border, long villi, lamina propria
plasma cells, goblet cells, and Paneth cells are all present and normal.

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Figure 3.8.6 Normal small bowel. The crypt at the right crypt shows a few
Paneth cells in the lower part with large luminally facing granules and
endocrine cells in the upper part f the crypt with smaller, redder granules that
point towards the lamina propria.

Figure 3.8.7 Normal small bowel. This field is from the base of a villus and
shows a few intraepithelial lymphocytes, a normal finding. There should be
fewer lymphocytes in the tips of the villi.

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Figure 3.8.8 Normal small bowel. This villous tip only shows a few
intraepithelial lymphocytes and certainly fewer than the base. In fact, all these
images are from the same patient as that seen in Figures 3.8.1–3.8.3 after an
intensive course of immunomodulatory therapy. A success!

3.9 Autoimmune enteropathy vs.

Common variable immunodeficiency
Common Variable
Autoimmune Enteropathy
Immunodeficiency
The term “autoimmune enteropathy”
can be used to encompass several
conditions. So-called immune
dysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX) Bimodal distribution in
syndrome is included and manifests in children and then in
boys. All forms are associated with middle-aged adults for
Age/gender
immune dysregulation. Patients with first presentation.
common variable immunodeficiency Probably, more than one
can have autoimmune enteropathy as disorder is represented
a component so the two overlap, but
the key feature of autoimmune

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 enteropathy is immune damage to
enterocytes and Paneth cells
Systemic manifestations
Affects the small bowel and colon, but findings attributable to
Location
primarily the small bowel the small bowel are
common
Diarrhea, abdominal pain.
Sometimes the diarrhea is
Symptoms Diarrhea, wasting
attributable to infections,
classically giardiasis
Nothing specific. Patients
have manifestations of
hypogammaglobulinemia
or agammaglobulinemia
Signs Hypoalbuminemia
including multiple
infections. At endoscopy,
prominent small lymphoid
nodules are common
Probably, many
mechanisms, but patients
have reduced
Variable but some examples in immunoglobulin.
individuals with FOXP3 mutations Frequently, the
Etiology
(this molecule governs regulatory T immunoglobulins are
cells) autoantibodies, and
patients may have
multiple immune
alterations
1. The key finding is loss
1. Small bowel samples may appear of lamina propria plasma
celiac disease–like with prominent cells, which is seen in
intraepithelial lymphocytosis and can about 70% of patients. In
be indistinguishable. The key in some the other 30% of patients,
Histology
cases is to recognize the absence of the diagnosis is
goblet cells and/or Paneth cells and impossible on histologic
prominent crypt apoptosis (Figs. grounds in isolation (Figs.
3.9.1–3.9.3) 3.9.4–3.9.6)

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 Findings must
Confirmation with testing
be correlated
for antienterocyte or anti–
Special with serum
studies goblet cell antibodies is of
immunoglobulin
interest
studies!

Management of the
ensuing infections.
Treatment Steroids
Administration of
immunoglobulin
Patients are at risk of
infections and neoplasms.
Reflective of the etiology for the
Some patients acquire an
autoimmunity. Patients can be
autoimmune enteropathy
Prognosis managed but are often at risk for life-
component so the
threatening infections based on
conditions are
associated conditions
overlapping. Lifelong
management is required

Figure 3.9.1 Autoimmune enteropathy. This process appears very similar to

celiac disease, but if one pays attention to checking each compartment in a
small bowel biopsy, it becomes apparent that this biopsy lacks goblet cells and
Paneth cells.

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Figure 3.9.2 Autoimmune enteropathy. Higher magnification of the case seen
in Figure 3.9.1. There is intraepithelial lymphocytosis in addition to loss of
goblet cells and Paneth cells.

Figure 3.9.3 Autoimmune enteropathy. This case also shows some acute
inflammation, so correlation with studies for organisms is also important.

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Figure 3.9.4 Common variable immunodeficiency. This biopsy appears
unremarkable other than a bit of intraepithelial lymphocytosis in the tips of the
villi, which should raise the possibility of “latent” celiac disease. However, the
lamina propria appears slightly empty.

Figure 3.9.5 Common variable immunodeficiency. This intraepithelial

lymphocytosis should prompt a concern for celiac disease but look in the
lamina propria. Plasma cells are absent.

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Figure 3.9.6 Common variable immunodeficiency. Plasma cells are absent.
Unfortunately, some cases have plasma cells. In such cases, antibody testing
for celiac disease is typically negative, and the patients are prone to many
infections, clues that might prompt testing.

3.10 Celiac disease vs. Small bowel

bacterial overgrowth of enteric
contents
Small Bowel Bacterial
Celiac Disease Overgrowth from Stasis of
Enteric Contents
Presents at any age and race but
classically in white children with
female predilection (1.5–2X) and
associated with certain HLA types
(HLA-DQ2 and HLA-DQ8). More
Age/Gender common in developing countries Adults
than in the past with introduction of
wheat into the diet. Once

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 vanishingly rare in Southeast Asia,
now emerging there
Affects entire body, typically
Location
assessed on duodenal biopsies
Chronic diarrhea, weight loss,
Symptoms
abdominal distension
Abdominal distension, aphthous
stomatitis, short stature, iron
Signs
deficiency, dermatitis herpetiformis,
reduced bone density
Systemic immune-mediated
response to dietary gluten in
genetically susceptible hosts.
Diagnosis is confirmed by serologic
Etiology
testing. IgA anti–tissue
transglutaminase detection is the
preferred initial screen. Cannot be
used in persons with IgA deficiency
1. In classic case, villous blunting, lymphocytosis, and crypt
crypt hyperplasia, prominent
intraepithelial lymphocytosis, and can be a component, but
expansion of lamina propria,
usually not prominent acute
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Anywhere in the small
bowel
Abdominal pain, flatulence,
bloating, loose stools
Defined as the presence of
bacteria in excess of 105
colony forming units per
millimeter on culture of
upper intestinal (duodenal)
aspirates. Alternate
noninvasive test include
lactulose and glucose
hydrogen breath tests
Classically attributed to
changes in small bowel
flora dues to stasis, usually
in patients with obstruction
from strictures and
adhesions but more recently
found in patients lacking
anatomic abnormalities.
There is controversial
overlap with irritable bowel
syndrome, especially since
office breath testing can be
lucrative
1. Can be essentially
identical to celiac disease
with villous blunting,
intraepithelial
hyperplasia. Neutrophils
there are no histologic
features that allow perfect
Histology inflammation (Figs. 3.10.1–3.10.3) distinction (Figs.
2. Some examples show preserved 3.10.5–3.10.7)
villous architecture but 2. Intraepithelial
intraepithelial lymphocytosis lymphocytosis without
concentrated in the tips of the villi villous blunting can be
(Fig. 3.10.4) present, as per celiac
disease (Fig. 3.10.8)
3. Essentially the histologic
features in such cases must
be correlated with
laboratory findings
None. Some laboratories
use CD3 to highlight the
T cells in the epithelium.
This is not needed. Some
observers also suggest
assessment for loss of
CD8 in cases of refractory
celiac disease (loss of Bacterial cultures
Special CD8 correlates with cases from duodenal
studies more likely to progress to aspirates
enteropathy-associated
lymphoma). The
diagnosis cannot be made
in isolation but must
always be in the context
of pertinent laboratory
testing

Antibiotics, ideally based on

Treatment Lifelong gluten-free diet
culture sensitivities
Overall excellent with adherence to
diet. Patients at slightly increased
risk for lymphomas and small Depends on the etiology of
Prognosis
bowel adenocarcinoma but these the enteric stasis
risks are still small. Life expectancy
normal to slightly shortened

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Figure 3.10.1 Celiac disease. This classic lesion shows complete villous
atrophy and striking surface lymphocytosis. The lamina propria is expanded
with plasma cell–rich contents.

Figure 3.10.2 Celiac disease. Note the lamina plasmacytosis and surface
lymphocytosis.

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Figure 3.10.3 Celiac disease. The crypts also display lymphocytosis.

Figure 3.10.4 Celiac disease. This proven example shows incomplete villous
atrophy but prominent intraepithelial lymphocytosis, which would be regarded
as “Marsh 2 pattern” in one of the classification schemes. However, with this
pattern of injury, a diagnosis of celiac disease can be confirmed only about
20% of the time. As such, “Marsh grading” is meaningless unless the
pathologist already knows that the patient has celiac disease.

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Figure 3.10.5 Small bowel bacterial overgrowth (often attributed to stasis of
enteric contents). Unfortunately, the findings are nonspecific, but this example
appears very “busy” at lower power. Goblet cells are reduced, presumably as a
result of rapid mucosal regeneration, but Paneth cells are present.

Figure 3.10.6 Small-bowel bacterial overgrowth (often attributed to stasis of

enteric contents). Note the neutrophils in the epithelium.

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Figure 3.10.7 Small bowel bacterial overgrowth (often attributed to stasis of
enteric contents). This field shows prominent lamina propria neutrophils.
Plasma cells and damaged goblet cells are also seen.

Figure 3.10.8 Small bowel bacterial overgrowth (often attributed to stasis of

enteric contents). This example is difficult to separate from latent celiac disease
in the absence of correlation with laboratory testing and clinical history.

3.11 Celiac disease vs. Common

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variable immunodeficiency
Common Variable
Celiac Disease
Immunodeficiency
Presents at any age and race but
classically in white children with
female predilection (1.5–2X) and
Bimodal distribution in
associated with certain HLA types
children and then in
(HLA-DQ2 and HLA-DQ8). More
middle-aged adults for
Age/Gender common in developing countries than
first presentation.
in the past with introduction of wheat
Probably, more than one
into the diet. Once vanishingly rare in
disorder is represented
Southeast Asia, now emerging there,
presumably as a result of dietary
changes from rice to wheat
Systemic manifestations
Affects the entire body, typically but findings attributable to
Location
assessed on duodenal biopsies the small bowel are
common
Diarrhea, abdominal pain.
Protean but classic cases with
Sometimes the diarrhea is
Symptoms chronic diarrhea, weight loss, and
attributable to infections,
abdominal distension
classically giardiasis
Nothing specific. Patients
have manifestations of
Abdominal distension, aphthous hypogammaglobulinemia
stomatitis, short stature, iron or agammaglobulinemia
Signs
deficiency, dermatitis herpetiformis, including multiple
reduced bone density infections. At endoscopy,
prominent small lymphoid
nodules are common
Probably, many
Systemic immune-mediated response mechanisms, but patients
to dietary gluten in genetically have reduced
susceptible hosts. Diagnosis is immunoglobulin.
confirmed by serologic testing. IgA Frequently, the

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Etiology anti–tissue transglutaminase detection immunoglobulins are
is the preferred initial screen. Cannot autoantibodies, and
be used in persons with IgA patients may have
deficiency multiple immune
alterations

1. The key finding is loss

of lamina propria plasma
1. In classic case, villous blunting, cells, which is seen in
crypt hyperplasia, prominent about 70% of patients. In
intraepithelial lymphocytosis, and the other 30% of patients,
expansion of lamina propria, usually the diagnosis is
Histology
not prominent acute inflammation impossible on histologic
(Figs. 3.11.1–3.11.3) grounds in isolation but
2. There are ample plasma cells in the the presence of infectious
lamina propria (Fig. 3.11.3) agents such as Giardia or
cytomegalovirus (Figs.
3.11.4–3.11.6)
None. Some laboratories
use CD3 to highlight the T
cells in the epithelium. This
is not needed. Some
observers also suggest
assessment for loss of CD8
Findings must
in cases of refractory celiac
be correlated
Special disease (loss of CD8
with serum
studies correlates with cases more
immunoglobulin
likely to progress to
studies!
enteropathy-associated
lymphoma). The diagnosis
cannot be made in isolation
but must always be in the
context of pertinent
laboratory testing

Management of the
ensuing infections.
Treatment Lifelong gluten-free diet Administration of

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 immunoglobulin
Patients are at risk of
Overall excellent with adherence to infections and neoplasms.
diet. Patients at slightly increased risk Some patients acquire an
for lymphomas and small bowel autoimmune enteropathy
Prognosis
adenocarcinoma but these risks are component so the
still small. Life expectancy normal to conditions are
slightly shortened overlapping. Lifelong
management is required

Figure 3.11.1 Celiac disease. This classic example shows striking

intraepithelial lymphocytosis and a “stuffed” lamina propria with numerous
plasma cells. Goblet and Paneth cells are plentiful.

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Figure 3.11.2 Celiac disease. Numerous lymphocytes are present in the surface
epithelium, and there are many lamina propria plasma cells.

Figure 3.11.3 Celiac disease. Intraepithelial lymphocytes are present in the

crypts. Plasma cells are the primary lamina propria constituent.

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Figure 3.11.4 Common variable immunodeficiency. The lamina propria is
expanded but, in this case, not by plasma cells. Patients with common variable
immunodeficiency are prone to infections, and this appearance may reflect this.

Figure 3.11.5 Common variable immunodeficiency. At high magnification in

this case, plasma cells are absent from the lamina propria but neutrophils are
present, probably a reflection of infection.

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Figure 3.11.6 Common variable immunodeficiency. This example shows
prominent crypt apoptosis. Note the lack of lamina propria plasma cells.

3.12 Collagenous sprue/enteritis vs.

Radiation change
Collagenous Sprue
Late 50s to older with female
Age/Gender
predominance
Typically in duodenum but
similar collagen deposition can
be found in the stomach
(collagenous gastritis) and colon
Location
(collagenous colitis) in the same
patients. Similar findings can
also complicate the use of
olmesartan for hypertension
Radiation Injury to Small
Bowel
Usually adults; male
predominance secondary to
overall male predominance in
cancer
Anywhere in the small bowel
near radiation sites but
typically detected in duodenal
samples in patients with
pancreatobiliary or gastric
cancers
Typically those of obstruction

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Symptoms Prominent chronic diarrhea and —abdominal pain, vomiting,
weight loss and constipation

At endoscopy, similar
appearances to those of celiac
disease with evidence of atrophy.
Patients may have laboratory
profiles that include
hypoalbuminemia. Celiac Abdominal tenderness on
Signs disease serology is negative or is palpation. Atrophic appearance
initially positive, and then, the or ulcers on endoscopy
patient stops responding to
gluten withdrawal, and celiac
serology is negative. HLA-
DQ2/HLA-DQ8 panels negative
in many cases as well
Some cases are associated with
celiac disease that becomes
refractory to gluten, and some
Tissue damage from
Etiology are idiopathic. Medications can
therapeutic radiation
trigger this pattern of injury (e.g.,
olmesartan, a blood pressure
medication)
1. Sclerosis of lamina propria
(can be transmural but on
mucosal biopsies the lamina
propria is the damaged
component that is seen)
generally without
accompanying lymphocytosis.
Vascular ectasia and vascular
1. The key finding is increased wall sclerosis can be present.
subepithelial collagen that However, the stasis from
encircles capillaries and extends transmural fibrosis can result
into the lamina propria. The in some lymphocytosis (Figs.
quality rather than the quantity is 3.12.5 and 3.12.6)
Histology key, so measuring the collagen is 2. Differs from amyloidosis by
not necessary. Intraepithelial appearing more eosinophilic

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 lymphocytosis should be present, collagen. An example of
and some examples feature amyloidosis is shown, which
prominent crypt apoptosis (Figs. also tends to affect the vessels
3.12.1–3.12.4) but with a different appearance
on H&E (Fig. 3.12.7)
3. Occasionally, the pathologist
is fortunate enough to
encounter selective internal
radiation microspheres (SIRS)
used to administer yttrium
therapy, usually to liver
metastases (Fig. 3.12.8)
A trichrome stain can
highlight the collagen.
Some observers
Special suggest that evaluation
None
studies of T-cell subsets is
important, but it is not
necessary in routine
diagnosis

Steroids are the first line of

therapy, and some patients have
complete recovery, whereas Generally none but some
Treatment others require additional patients may require resections
immunosuppression. A small to relieve obstruction
subset progresses to T-cell
lymphomas
Overall favorable following
immune modulation but some
That of the cancer that was
Prognosis patients have persistent
treated by radiation
nutritional impairment or
progression to lymphoma

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Figure 3.12.1 Collagenous sprue/collagenous enteritis. The subepithelial
collagen is thickened and encircles fibroblasts, inflammatory cells, and
capillaries. There is mild intraepithelial lymphocytosis. The deep lamina
propria is expanded.

Figure 3.12.2 Collagenous sprue/collagenous enteritis. In this example, the

friable surface epithelium has “chipped off,” but intraepithelial lymphocytosis
is apparent. Note the lamina propria plasma cells, lymphocytes, and
eosinophils.

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Figure 3.12.3 Collagenous sprue/collagenous enteritis. Several apoptotic
bodies are seen in the crypts in this case.

Figure 3.12.4 Collagenous sprue/collagenous enteritis. Note the appearance of

the thick collagen beneath the surface epithelium. It has encircled capillaries.

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Figure 3.12.5 Radiation enteritis. The sample is not particularly inflamed, and
the lamina propria vessels are prominent and thick, and much of the lamina
propria is hyalinized rather than expanded by inflammatory cells.

Figure 3.12.6 Radiation enteritis. There is hyalinization from the surface to the
muscularis mucosae, and tiny capillaries in the lamina propria appear thick
walled.

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Figure 3.12.7 Amyloidosis. The deposited amyloid assumes a “waxy” slightly
bluish appearance. Of course, Congo red staining can be applied in doubtful
cases.

Figure 3.12.8 Radiation enteritis. This case shows severe radiation-associated

injury with ulceration and striking epithelial changes. In this case, we are lucky
enough to see the culprit. The black blob is a yttrium sphere for radiation
treatment. These are injected into tumor (typically hepatobiliary cancers) but
sometimes spread through the bloodstream to the stomach or duodenum and
result in ulcers with radiation injury.

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3.13 Behcet syndrome affecting small
bowel vs. Crohn disease
Behcet Syndrome Crohn Disease
Onset of presentation is
usually in fourth decade (30s)
with gender equity in some Presents in patients in their teens
populations and some with and 20s with a second peak in the
female predominance. In 50s and 60s. Most patients are
cases associated with HLA- diagnosed before they are 40, and
Age/Gender
B51, there is a male there is an overall female
predominance. Most cases predominance. Those who present
are found in individuals from as children have more severe
Middle East, Mediterranean disease
area, and Asia, but there is a
worldwide distribution
Can arise anywhere in the body
The disease is essentially a
but the most common location is
Location systemic vasculitis, so it can
the distal small bowel (ileum) and
present anywhere in the body
proximal colon
Variable depending on where
the vasculitis manifests. In
the gastrointestinal tract, deep Diarrhea or constipation,
Symptoms
ulcers are found, often in the abdominal pain
intestines, especially the right
colon or small bowel
Patients have oral and genital
ulcers, ocular inflammation
At ileocolonoscopy, patients show
(uveitis), skin lesions, joint
ileal ulceration, cobblestone-like
Signs disease, vascular, neurologic,
appearance, and zones of
pulmonary, gastrointestinal,
narrowing
renal, vascular, and
genitourinary manifestations
Immune disease in which patients
It is a poorly understood have an altered response to

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 vasculitis, but the trigger to intestinal flora. Vasculitis is
Etiology the immune alteration is not
clear. The condition is rare, classically in arteries. Extensive
so studies of large numbers
of patients are difficult
1. Variable transmural
inflammation, ulcers, and
reparative epithelial with
deep ulcers and sometimes
Histology fissures (Figs. 3.13.1–3.13.3) of mucosa secondary to multiple
2. The key finding is
vasculitis, which
preferentially affects veins
(Figs. 3.13.4 and 3.13.5)
None for histologic
diagnosis per se.
The patient can
undergo HLA
testing and a
“pathergy test,”
Special
which involves
studies
injuring the skin
and assessing a
reparative response
attributable to the
vasculitis
usually absent but when present,
research on various involved
genes—NOD2 described early and
many others since
1. Transmural inflammation with
granulomas, neural hyperplasia,
and prominent lymphoplasmacytic
inflammation with numerous
lymphoid aggregates. Metaplasia
cycles of mucosal damage (Figs.
3.13.6–3.13.8)
2. If vasculitis is present (rare), it
is classically arteritis (Figs. 3.13.9
and 3.13.10)
Not necessary for
histologic diagnosis but
special stains for acid-
fast organisms and fungi
important as pertinent
negatives in patients
with prominent
granulomas. Clinically
serology for p-ANCA
and bacterial antibodies
(ASCA IgA, ASCA
IgG/Saccharomyces
cerevisiae, anti-ompC/E.
coli, and anti-CBir1) can
be important in patients
with nonspecific
findings

None for the fibroblasts

As per other immune disease.
themselves. Any treatment is
Pharmacologic agents can include
directed at the underlying

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Treatment etiology of the ulcer corticosteroids, azathioprine, and
(generally gastroesophageal tumor necrosis factor (TNF)–α
reflux disease) inhibitors, among others

There is no cure, but some patients

Excellent for the atypical
stromal cells. The underlying
Prognosis
condition responsible for the
ulcers must be addressed
respond well to immune
modulation, whereas others have a
relentless course complicated by
multiple operations to relieve
obstruction and by neoplasia
arising in areas subjected to many
cycles of inflammatory damage
and repair

Figure 3.13.1 Behcet syndrome. There are deep penetrating ulcers with fissure
formation. Note the submucosal vessels at the lower left. The crypt architecture
is normal. This disease process cannot be diagnosed on histologic findings in
isolation and is essentially a vasculitis. Since vessels are often not well
represented on mucosal biopsies, it is virtually impossible to specifically
diagnose on mucosal biopsies, but a clinical impression of enteritis can be
confirmed.

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Figure 3.13.2 Behcet syndrome. Note the deep penetrating fissure. This
process is similar to Crohn disease but lacks striking lymphoid aggregates.

Figure 3.13.3 Behcet syndrome. The enteritis appears rather nonspecific.

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Figure 3.13.4 Behcet syndrome. The lower part of the field shows a normal
submucosal artery, but the vein in the upper half of the field is severely
inflamed.

Figure 3.13.5 Behcet syndrome. The artery at the left is unremarkable, but the
vein at the right has striking phlebitis.

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Figure 3.13.6 Crohn disease. There is dense transmural chronic inflammation
forming many lymphoid aggregates and a wide ulcer at the right.

Figure 3.13.7 Crohn disease. Prominent ileitis is present. Note the pyloric
metaplasia (the lowest gland at the right side of the field and the lobulated
gland in the center of the field). This is a feature of chronic injury and
characteristic but not diagnostic of Crohn enteritis.

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Figure 3.13.8 Crohn disease. This field shows abundant pyloric metaplasia. All
of the glands in the bottom half of the field have the appearances of antral
glands.

Figure 3.13.9 Crohn disease. Vasculitis is unusual in Crohn disease, but when
it is present, it is often a giant cell arteritis. Note the giant cells congregating in
the zone of the elastic lamina of this medium-sized serosal artery.

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Figure 3.13.10 Crohn disease. Higher magnification of the vascular injury seen
in Figure 3.13.9.

3.14 Microvillus inclusion disease vs.

Intracytoplasmic lipid
Intracytoplasmic
Microvillus Inclusion Disease
Lipid
Found in infants with intractable diarrhea
of infancy. Most infants present in first
week of life with life-threatening secretory
diarrhea. No apparent gender predilection None—“incidental”
Age/Gender
but found in a population with common finding
consanguinity—most cases found in
Arabs. In the United States, the disease is
found in Navajos
Usually seen on
Location Seen best in duodenal biopsies mucosal biopsies of
the duodenum
Those of the
condition that

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Symptoms Severe diarrhea in infancy prompted upper
endoscopy

None (other than if

Those attributable to severe secretory the patient has
Signs diarrhea—electrolyte disorders and abetalipoproteinemia;
cachexia please see Chapter
3.4)
Appears to have an autosomal recessive
Usually ingestion of
mode of inheritance and associated with
Etiology lipids prior to the
mutations in the gene encoding for myosin
procedure
vb and in MYO5B in Navajos
1. Intact brush border
1. There is minimal inflammation and villi
and intracytoplasmic
are somewhat blunted. Plasma cells, goblet
lipid (Figs.
cells, and Paneth cells are all present. The
3.14.7–3.14.9)
brush border is altered, showing a smudgy
2. PAS/AB shows
appearance (Figs. 3.14.1–3.14.3)
normal brush border
Histology 2. PAS/AB staining shows a “blush” of
(Figs. 3.14.10 and
positivity. It is not crisply demarcated like
3.14.11)
gastric mucin cell metaplasia (Figs. 3.14.4
3. Normal
and 3.14.5)
ultrastructural
3. There is a characteristic ultrastructural
appearance (Fig.
appearance (Fig. 3.14.6)
3.14.12)
Stains for CD10, Rab11, and
Myo5b all can be used to
enhance detection of the brush
border alterations. Ultrastructure
is very useful as well. In general,
Special None
in institutions that do not see
studies
many such cases, it is probably
prudent to collect material for
ultrastructure at the time of
endoscopy

Supportive measures (parenteral nutrition),

Treatment None
small bowel and liver transplantation

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 According to the
Guarded since patients must receive indication for the
transplantation in infancy. However, some procedure. No
Prognosis prognostication for
patients' disease regresses for unclear
reasons lipid findings in
enterocytes in
otherwise healthy
persons

Figure 3.14.1 Microvillus inclusion disease. The key finding is a brush border
abnormality. In this case, the villi are attenuated but there is no increase in
inflammation. Even at this magnification, the surface epithelium has a bubbly
appearance.

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Figure 3.14.2 Microvillous inclusion disease. Note the bubbly vacuolated
appearance of the surface and the smudged brush border.

Figure 3.14.3 Microvillous inclusion disease. The surface epithelium shows

both vacuoles and probable lipid that has been incompletely absorbed.

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Figure 3.14.4 Microvillous inclusion disease. This is a PAS stain. The brush
border shows a blurry smudged appearance that some refer to as a “blush”
pattern.

Figure 3.14.5 Microvillus inclusion disease, PAS. At higher magnification, the

reactivity is not crisply demarcated like the mucin in gastric mucin cell
metaplasia.

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Figure 3.14.6 Microvillous inclusion disease, CD10 stain. In the crypts, the
brush border is a crisp normal line, whereas the surface shows internalized
immunolabeling within the cytoplasm of the surface enterocytes.

Figure 3.14.7 Intracytoplasmic lipid in enterocytes. The brush border is intact,

and the cytoplasm is bubbly, but the bubbles are unstained rather than pinkish
on H&E stain.

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Figure 3.14.8 Intracytoplasmic lipid in enterocytes. At high magnification,
lipid stuffs the surface enterocytes. This is usually a focal finding.

Figure 3.14.9 Intracytoplasmic lipid in enterocytes. The brush border is

apparent at the surface, and the cytoplasm has been washed out during tissue
processing.

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Figure 3.14.10 Intracytoplasmic lipid in enterocytes, PAS/AB stain. There is no
staining of the lipid, but the attenuated brush border is apparent.

Figure 3.14.11 Intracytoplasmic lipid in enterocytes, PAS/AB stain. Note the

normal absorptive at the lower left portion of the image.

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Figure 3.14.12 Intracytoplasmic lipid in enterocytes, PA/AB stain.
3.15 Microvillus inclusion disease vs.
Tufting enteropathy
Microvillus Inclusion Disease
Found in infants with intractable
diarrhea of infancy. Most infants
present in first week of life with
life-threatening secretory diarrhea.
No apparent gender predilection
Age/Gender
but found in a population with
common consanguinity—most
cases found in Arabs. In the United
States, the disease is found in
Navajos
Location Seen best in duodenal biopsies
Symptoms Severe diarrhea in infancy
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Tufting Enteropathy
(Intestinal Epithelial
Dysplasia)
Infants with refractory
diarrhea similar to those
with microvillus inclusion
disease. Shows autosomal
recessive features and, like
microvillus inclusion
disease, is overrepresented
in Middle Eastern persons
Typically, the small bowel is
biopsied
Severe diarrhea in a neonate
 Those attributable to severe Failure to thrive and
Signs secretory diarrhea—electrolyte laboratory anomalies of
disorders and cachexia malabsorption
Appears to have an autosomal
recessive mode of inheritance and Mutations in the gene
Etiology associated with mutations in the encoding the adhesion
gene encoding for myosin vb and molecule EpCAM
in MYO5B in Navajos
1. Some villous atrophy,
1. There is minimal inflammation, minimal inflammation,
and villi are somewhat blunted. plasma cells, Paneth cells,
Plasma cells, goblet cells, and and goblet cells present. The
Paneth cells are all present. The brush border appears
brush border is altered, showing a unremarkable, but the
smudgy appearance (Figs. 3.15.1 hallmark is the presence of
and 3.15.2) abnormal surface
Histology
2. PAS/AB staining shows a enterocytes forming so-
“blush” of positivity. It is not called tufts (Figs.
crisply demarcated like gastric 3.15.6–3.15.10)
mucin cell metaplasia (Figs. 3.15.3 2. PAS shows an
and 3.15.4) unremarkable brush border
3. There is a characteristic 3. Ultrastructure shows some
ultrastructural appearance abnormalities but is often
not diagnostic
Stains for CD10 (Fig.
3.15.5), Rab11, and
Myo5b all can be used to
enhance detection of the
brush border alterations.
Loss of EpCAM
Ultrastructure is very
Special expression using
useful as well. In general,
MOC31 is
studies in institutions that do not
confirmatory
see many such cases, it is
probably prudent to
collect material for
ultrastructure at the time
of endoscopy

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 Supportive measures (parenteral
Treatment nutrition), small bowel and liver Small bowel transplant
transplantation
As per microvillus inclusion
disease—overall guarded
Guarded since patients must
since transplantation often
receive transplantation in infancy.
Prognosis required but some patients
However, some patients' disease
do well and perhaps have
regresses for unclear reasons
attenuated forms of the
disease

Figure 3.15.1 Microvillous inclusion disease. This example is more subtle than
the one shown in Chapter 3.14. However, note the overall lack of lymphocytosis
and excess inflammation, and note the frothy appearance of the surface
enterocytes.

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Figure 3.15.2 Microvillus inclusion disease. The surface enterocytes have a
bubble appearance.

Figure 3.15.3 Microvillus inclusion disease, PAS stain. There is smudged

intracytoplasmic material.

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Figure 3.15.4 Microvillus inclusion disease, PAS/AB stain shows an
incomplete brush border and smudged cytoplasm. There is an internal normal
control in the deep portion of the sample with an intact brush border.

Figure 3.15.5 Microvillous inclusion disease, CD10 stain mirrors the

appearance of the PAS/AB stain.

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Figure 3.15.6 Tufting enteropathy. The sample appears unremarkable at first
glance but was from an infant with intractable diarrhea. However, note the
fringelike appearance of the sloughing surface enterocytes.

Figure 3.15.7 Tufting enteropathy. At low magnification, like microvillous

inclusion disease, tufting enteropathy does not feature increased inflammation.

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Figure 3.15.8 Tufting enteropathy. Note the sloughing epithelial tufts.

Figure 3.15.9 Tufting enteropathy. The tufts of epithelial cells round up and
slough into the lumen.

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Figure 3.15.10 Tufting enteropathy. Note the rounded appearance of the nuclei
of the sloughing epithelial cells.

3.16 Nonsteroidal anti-inflammatory

drug (NSAID)–associated injury
requiring surgery vs. Crohn disease
requiring surgery
NSAID-Associated Injury
Crohn Disease Requiring Surgery
Requiring Surgery
Presents in patients in their teens and
20s with a second peak in the 50s and
60s. Most patients are diagnosed
Adults; male
before they are 40, and there is an
predominance. Usually
overall female predominance. Those
Age/Gender patients are in 60s and
who present as children have more
have long-term use of
severe disease and are the patients
NSAIDs
likely to require surgery at some

point

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 Can arise anywhere in the body but
the most common location is the
Location Distal ileum
distal small bowel (ileum) and
proximal colon
Obstruction (bloating,
vomiting, and abdominal Diarrhea or constipation, abdominal
Symptoms
pain), perforation (severe pain
pain abdominal pain)
Endoscopist sees erosions, At ileocolonoscopy, patients show
Signs inflammation, and ileal ulceration, cobblestone-like
occasionally “diaphragms” appearance, and zones of narrowing
Immune disease in which patients
have an altered response to intestinal
Mucosal barrier damage
flora. Vasculitis is usually absent but
results in many cycles of
Etiology when present, classically in arteries.
damage and repair to
Extensive research on various
mucosa
involved genes—NOD2 described
early and many others since
1. Can be
indistinguishable from
Crohn disease on biopsy
1. Transmural inflammation with
but features signs of
granulomas, neural hyperplasia, and
chronic injury (including
prominent lymphoplasmacytic
pyloric metaplasia),
inflammation with numerous
Histology thickened muscularis
lymphoid aggregates. Metaplasia of
mucosae, erosions, and
mucosa secondary to multiple cycles
ulcers. These are usually
of mucosal damage (Figs.
unaccompanied by
3.16.5–3.16.8)
abundant chronic
inflammation (Figs.
3.16.1–3.16.4)
Not necessary for
histologic diagnosis but
special stains for acid-fast
organisms and fungi
important as pertinent
negatives in patients with

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 prominent granulomas.
Special None Clinically serology for p-
studies ANCA and bacterial
antibodies (ASCA IgA,
ASCA IgG/Saccharomyces
cerevisiae, anti-ompC/E.
coli and anti-CBir1) can be
important in patients with
nonspecific findings

As per other immune disease.

Modification of NSAID Pharmacologic agents can include
Treatment use (a different agent or corticosteroids, azathioprine, and
alternate medication) tumor necrosis factor (TNF)–α
inhibitors, among others
There is no cure, but some patients
respond well to immune modulation,
whereas others have a relentless
Favorable following
course complicated by multiple
Prognosis resection of the injured
operations to relieve obstruction and
area
by neoplasia arising in areas
subjected to many cycles of
inflammatory damage and repair

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Figure 3.16.1 Nonsteroidal anti-inflammatory disease–associated injury
resulting in resection. In this case, a thick submucosal ledge with a
circumferential distribution (a diaphragm) was present. Note that the process is
essentially devoid of inflammation. In the event of a perforation, of course,
inflammation would be present. Lesions of this type form following multiple
cycles of mucosal ulceration and repair with proliferation of submucosal
smooth muscle, nerves, and fat but with minimal inflammation.

Figure 3.16.2 Nonsteroidal anti-inflammatory disease–associated injury

resulting in resection. In this case, there is an ulcer and proliferation of
submucosal fibrous tissue and smooth muscle but minimal inflammation.

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Figure 3.16.3 Nonsteroidal anti-inflammatory disease–associated injury
resulting in resection. The areas away from the damaged one appear
completely normal.

Figure 3.16.4 Nonsteroidal anti-inflammatory disease–associated injury

resulting in resection. This area near the diaphragm shown in Figure 3.16.1
shows pyloric metaplasia, but there are no lymphoid aggregates as would be
expected in Crohn disease and no vasculitis as in Behcet syndrome.

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Figure 3.16.5 Crohn disease. Note the abundance of lymphoid aggregates near
the ulcer.

Figure 3.16.6 Crohn disease. There is ample transmural inflammation.

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Figure 3.16.7 Crohn disease. This is the muscularis mucosa. It is thickened and
shows prominent chronic inflammation.

Figure 3.16.8 Crohn disease. The pyloric metaplasia here is accompanied by

ample chronic inflammation.

3.17 Infectious enteritis vs. Crohn

disease

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 Infectious Enteritis
Variable depending on the
Age/Gender
infection
Anywhere in the small
Location bowel depending on the
organism
Symptoms Fever and chills, diarrhea
Endoscopist may see ulcers,
Signs but generally flat mucosa is
inflamed
Etiology Various organisms
1. In general, less evidence
of chronic injury and
chronic inflammation than
in Crohn disease, with many
exceptions (Figs.
3.17.1–3.17.3)
Histology 2. Numerous eosinophils
can suggest strongyloidiasis
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Crohn Disease
Presents in patients in their teens
and 20s with a second peak in the
50s and 60s. Most patients are
diagnosed before they are 40, and
there is an overall female
predominance. Those who present
as children have more severe
disease and are the patients likely to
require surgery at some point
Can arise anywhere in the body but
the most common location is the
distal small bowel (ileum) and
proximal colon
Diarrhea or constipation, abdominal
pain
At ileocolonoscopy, patients show
ileal ulceration, cobblestone-like
appearance, and zones of narrowing
Immune disease in which patients
have an altered response to
intestinal flora. Vasculitis is usually
absent but when present, classically
in arteries. Extensive research on
various involved genes—NOD2
described early and many others
since
1. Transmural inflammation with
granulomas, neural hyperplasia, and
prominent lymphoplasmacytic
inflammation with numerous
lymphoid aggregates. Metaplasia of
mucosa secondary to multiple
cycles of mucosal damage (Figs.
3.17.8–3.17.10)
2. Eosinophils can be prominent but
usually relatively evenly dispersed
 (Figs. 3.17.4 and 3.17.5)
3. Granulomas that are
necrotizing suggest
infection (Figs. 3.17.6 and
3.17.7)
Cultures and
Special studies for stool
studies ova and parasites
Antibiotics/antifungal
Treatment
preparations
Depending on immune
status. Of course, some
patients with inflammatory
bowel disease taking
immunomodulatory therapy
develop infection
Prognosis superimposed on their
Crohn disease, and
prominent necrosis in
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rather than clustered (around area of
parasite) (Figs. 3.17.11 and
3.17.12)
3. Granulomas generally lack
central necrosis (Figs. 3.17.13 and
3.17.14)
Not necessary for
histologic diagnosis but
special stains for acid-fast
organisms and fungi
important as pertinent
negatives in patients with
prominent granulomas.
Clinically serology for p-
ANCA and bacterial
antibodies (ASCA IgA,
ASCA
IgG/Saccharomyces
cerevisiae, anti-ompC/E.
coli, and anti-CBir1) can
be important in patients
with nonspecific findings
As per other immune disease.
Pharmacologic agents can include
corticosteroids, azathioprine, and
tumor necrosis factor (TNF)–α
inhibitors, among others
There is no cure, but some patients
respond well to immune
modulation, whereas others have a
relentless course complicated by
multiple operations to relieve
obstruction and by neoplasia arising
in areas subjected to many cycles of
 granulomas of a patient with inflammatory damage and repair
known Crohn disease
should prompt a search for
organisms

Figure 3.17.1 Infectious enteritis. This is an example of anisakiasis (from

eating sushi). There is minimal crypt distortion, but sheets of eosinophils are
apparent even at this magnification, and the eosinophils are out of proportion
to the degree of chronic inflammation.

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Figure 3.17.2 Infectious enteritis. An offending organism from the case shown
in Figure 3.17.1 is seen here.

Figure 3.17.3 Infectious enteritis. This example of strongyloidiasis is difficult,

but the poorly formed granuloma at the upper right differs from those seen in
Crohn disease, and the lamina propria shows more fibrosis than chronic
inflammation.

Figure 3.17.4 Infectious enteritis. This case of strongyloidiasis is not subtle,

but note that there is minimal crypt distortion.

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Figure 3.17.5 Infectious enteritis. This is a select focus from the same case as
that shown in Figure 3.17.3. The Strongyloides organism in the center is poorly
preserved and surrounded by histiocytes and eosinophils.

Figure 3.17.6 Infectious enteritis. Necrotizing granulomas are a clue that an

infection is present. This patient has histoplasmosis. Unfortunately,
histoplasmosis can be a perfect mimic of Crohn disease but usually features
necrotizing granulomas.

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Figure 3.17.7 Infectious enteritis. This is a Gomori methenamine stain from the
case seen in Figure 3.17.6 and shows Histoplasma organisms.

Figure 3.17.8 Crohn disease. The chronic inflammation is dense and

transmural.

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Figure 3.17.9 Crohn disease. Neural hyperplasia is characteristic of Crohn
disease. This is a large proliferated submucosal nerve.

Figure 3.17.10 Crohn disease. Pyloric metaplasia reflects multiple cycles of

mucosal damage and repair.

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Figure 3.17.11 Crohn disease. This poorly formed granuloma is flanked by
eosinophils but is not necrotizing.

Figure 3.17.12 Crohn disease. Typically, the inflammation in Crohn disease

consists primarily of lymphoplasmacytic cells with scattered eosinophils.

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Figure 3.17.13 Crohn disease. A nonnecrotizing sharply demarcated
granuloma is seen here.

Figure 3.17.14 Crohn disease. This granuloma is poorly formed but not
necrotizing and flanked mostly by lymphocytes and plasma cells.

3.18 Pyloric gland adenoma vs.

Tubular adenoma

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 Tubular or Tubulovillous
Pyloric Gland Adenoma
Adenoma of Small Bowel
Adults (50+). Most cases
Adults (50+). Uncommon in
arise in the stomach with a
sporadic setting but very common
Age/Gender female predominance but no
in patients with familial
real gender predominance in
adenomatous polyposis
small bowel cases. Rare
Most in duodenum but some Most in duodenum but some in
Location
in ileum ileum
Vomiting, abdominal pain Vomiting, abdominal pain
Symptoms (obstruction), or incidental (obstruction), or incidental finding
finding at endoscopy at endoscopy
Mass lesion on upper
endoscopy (most commonly
in gastric body of females) Mass lesion/polyp on upper
Signs
but if lesion involves small endoscopy
bowel usually in the
duodenum
Biallelic inactivation of the APC
Etiology Unclear
gene is the initiating event
1. Polyp composed of
1. Polyp composed of tubules and
closely packed tubules
sometimes with a villiform surface
(Figs. 3.18.1 and 3.18.2)
(Figs. 3.18.5 and 3.18.6)
2. At high magnification,
2. At high magnification, glands
glands consist of cells with a
consist of cells with a stratified
Histology monolayer of perfectly
elongated nuclei and cytoplasm.
round nuclei and ground-
Goblet cells or Paneth cells can be
glass cytoplasm that lacks
present. Sometimes, Paneth cells
apical mucin and also lacks
are prominent in small bowel
goblet cells (Fig. 3.18.3)
adenomas (Fig. 3.18.7)11. 12
3. 10
These lesions
label with MUC6
with variable These lesions do not label
expression of with MUC6 or MUC5AC
MUC5AC. Some but show strong CDX2

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Special examples shown and MUC2 labeling.
studies to have GNAS Some examples shown to
mutations. have beta catenin
Minimal to no mutations/APC mutations
CDX2 and MUC2
expression

Complete removal of the Complete removal of the lesion

Treatment lesion since a subset
progresses to carcinoma
Excellent following removal
Prognosis
of the lesion
since a subset progresses to
carcinoma
Excellent following removal of the
lesion

Figure 3.18.1 Pyloric gland adenoma. The lesion is composed of closely

packed tubules.

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Figure 3.18.2 Pyloric gland adenoma. The cytoplasm has a ground-glass
appearance, and the nuclei are round, forming a nonstratified monolayer along
the basement membrane of each tubular gland.

Figure 3.18.3 Pyloric gland adenoma. This example shows surface high-grade
dysplasia. These lesions are graded with a low threshold for diagnosing high-
grade dysplasia and some progress to carcinoma.

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Figure 3.18.4 Pyloric gland adenoma, PAS/AB stain. This lesion arose at the
junction of the gastric antrum (left with neutral magenta-colored mucin in
foveolar epithelium) and duodenum. Note that the pyloric gland adenoma does
not take up the PAS/AB stain much.

Figure 3.18.5 Tubular adenoma. The lesion has more hyperchromatic nuclei
than does the pyloric gland adenoma.

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Figure 3.18.6 Tubular adenoma. The nuclei are elongated, stratified, and
hyperchromatic.

Figure 3.18.7 Tubular adenoma. This example features a hearty complement of

Paneth cells.

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Figure 3.18.8 Tubular adenoma, PAS/AB stain. Note the goblet cells and
stratified elongated nuclei.

3.19 Nodular duodenitis vs.

Tubular/tubulovillous adenoma
Tubular or Tubulovillous
Nodular Duodenitis
Adenoma of Small Bowel
No age or gender preferentially
Adults (50+). Uncommon in
affected but seen in adults since it
sporadic setting but very
is a result of cycles of damage
Age/Gender common in patients with
and repair with metaplasia. This
familial adenomatous
results from any form of injury to
polyposis
the duodenum (usually the bulb)
Mostly in the duodenum but
Location Usually the duodenal bulb
some in ileum
None attributable to the nodular
duodenitis per se but there may Vomiting, abdominal pain
Symptoms be pain associated with the cause (obstruction), or incidental
of the injury such as abdominal finding at endoscopy
pain from H. pylori gastritis

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 Nodularity may be apparent at
Signs endoscopy. A mass lesion can
even be present
Initiated by mucosal damage of
Etiology any type, including that
associated with use of NSAIDs
1. Hyperplasia of Brunner glands
and gastric mucin cell metaplasia
(Figs. 3.19.1 and 3.19.2)
Histology 2. PAS/AB staining highlights
gastric mucin cell metaplasia
(Figs. 3.19.3 and 3.19.4)
3. 10
None needed. The
Brunner glands are
MUC6 positive, but
Special this is a feature of
studies benign Brunner glands.
MUC5AC is expressed
in the metaplastic
gastric foveolar cells
Treatment None
Benign. However, the
endoscopist should be
encouraged to resample if the
findings are clinically suspicious Excellent following removal
Prognosis
as a biopsy may miss a nearby
malignancy that has resulted in
the reactive changes
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Mass lesion/polyp on upper
endoscopy
Biallelic inactivation of the
APC gene is the initiating
event
1. Polyp composed of tubules
and sometimes with a
villiform surface (Figs. 3.19.6
and 3.19.7)
2. PAS/AB shows a surface
with an intact brush border
and lipid within the surface
cells (Figs. 3.19.8 and
3.19.9)11. 12
These lesions do not
label with MUC6 or
MUC5AC but show
strong CDX2 and
MUC2 labeling.
Some examples
shown to have beta
catenin
mutations/APC
mutations
Complete removal of the
lesion since a subset
progresses to carcinoma
of the lesion
Figure 3.19.1 Nodular duodenitis. The characteristic finding is prominent
surface gastric mucin cell metaplasia. Note the prominent Brunner glands as
well.

Figure 3.19.2 Nodular duodenitis. The gastric foveolar cells display reactive
nuclear stratification, but the nuclei are smaller than those of tubular
adenomas.

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Figure 3.19.3 Nodular duodenitis, PAS/AB stain. At the right, adjoining
normal duodenal mucosa is seen. The metaplastic component shows crisply
demarcated globules of mucin in the foveolar-type cells.

Figure 3.19.4 Nodular duodenitis, PAS/AB stain. This is a high-magnification

image of the interface between metaplastic gastric foveolar-type cells and the
absorptive cells, which show a thin brush border on the left.

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Figure 3.19.5 Nodular duodenitis, Diff-Quik stain. Some examples harbor H.
pylori organisms in the metaplastic gastric foveolar mucosa.

Figure 3.19.6 Tubular adenoma. The lesion is hyperchromatic and composed of

tightly packed tubules.

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Figure 3.19.7 Tubulovillous adenoma. This lesion was found in a patient with
familial adenomatous polyposis and was one of many.

Figure 3.19.8 Tubular adenoma. On PAS/AB staining, the adenoma itself lacks
gastric differentiation although note that there is some gastric mucin cell
metaplasia in epithelium adjoining the lesion. The surface has an intact brush
border, and the adenoma has even absorbed a bit of lipid!

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Figure 3.19.9 Tubular adenoma. Note the absorbed lipid just beneath the
surface as well as the shape of the nuclei.

Figure 3.19.10 This is not a tubular adenoma. This is an example of colorectal

carcinoma that has metastasized to the small bowel. The carcinoma is seen in
the lower part of the field and has spread onto the surface in a fashion that
perfectly mimics an in situ component. This pitfall must always be borne in
mind when interpreting small bowel biopsies.

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3.20 Peutz-Jeghers polyp vs. Juvenile
polyp
Peutz-Jeghers Polyp
Young adults without gender
predominance. About half of
patients have symptoms by age 20
Age/Gender
and often by age 10. Polyps are
found in about 1/150,000 to
1/200,000 persons
Most common in small bowel but
Location can be detected throughout the
stomach and colorectum
Abdominal pain, rectal pain,
Symptoms passage of polyp in stool,
symptoms of obstruction
In patients with obstruction,
intussusception is common. Those
with the syndrome have (A) three
or more histologically confirmed
Peutz-Jeghers polyps, (B) any
number of Peutz-Jeghers polyps
Signs with a family history of PJS, (C)
characteristic, prominent,
mucocutaneous pigmentation with
a family history of PJS, or (D) any
number of Peutz-Jeghers polyps
and characteristic, prominent,
mucocutaneous pigmentation
Mutations in STK11/LKB1 in
50%–70% of cases in patients with
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Juvenile Polyp
Presents in childhood with
no gender predominance.
Solitary juvenile polyps are
found in about 2% of
children as incidental
lesions. Syndromic ones are
more rare (about 1/100,000
live births)
Most common in the colon
but can be detected
throughout the stomach and
small bowel
Abdominal pain, rectal pain,
passage of polyp in stool,
symptoms of obstruction
Usually heme-positive stool.
The syndrome consists of
(A) more than 3–5 juvenile
polyps in the colorectum, (B)
juvenile polyps throughout
the gastrointestinal tract,
and/or (C) any number of
juvenile polyps in a patient
with a family history of the
syndrome. Related
syndromes include
Bannayan-Ruvalcaba-Riley,
Cowden, and Gorlin
syndrome
Mutations in SMAD4 and
BMPR1A. Both encode
Etiology the syndrome proteins involved in TGF-
b/BMP signaling

1. Small bowel cases easy to 1. Disorganized-appearing

recognize. Disorganized lobules ofpolyps characterized by
site-specific mucosa (small bowel expanded lamina propria,
Histology type in small bowel) are separatededema, and cystically dilated
by cords of smooth muscle (Figs. crypts (Figs. 3.20.4–3.20.6).
3.20.1–3.20.3). The adjoining flatThe adjoining flat mucosa is
mucosa is normal (Fig. 3.20.1) normal (Fig. 3.20.4)
The syndrome is
transmitted as an
autosomal
None on the polyps dominant
themselves but genetic condition so worth
testing of affected considering genetic
Special patients is worth testing to identify
studies considering since the family members at
syndrome is transmitted risk. However,
as an autosomal only about half of
dominant condition patients are shown
to have a mutation
in a characteristic
gene

Treatment Polypectomy is adequate Polypectomy is adequate

The risk of malignant
transformation in Peutz-Jeghers
polyps is minimal. However,
patients with Peutz-Jeghers
syndrome are at extremely high
lifetime risk for cancer of various
Prognosis
organs and must be
screened/followed closely. Some
data suggest that finding even a
single such polyp is indicative of
the syndrome
Patients with the syndrome
have a high risk (probably
about 50%) of colorectal
cancer. The polyps can
undergo a
dysplasia/carcinoma
sequence. Children who
present with one or two
incidental colorectal polyps
are not at increased risk

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Figure 3.20.1 Peutz-Jeghers polyp. There is normal mucosa at the left. The
polyp consists of disorganized structurally normal mucosa. The mucosa is
small intestinal type and not neoplastic appearing. The characteristic finding is
the arborizing cords of smooth muscle. They are obvious in this large
polypectomy, but a tiny superficial biopsy would not be diagnostic.

Figure 3.20.2 Peutz-Jeghers polyp. The thick smooth muscle bundles are
reminiscent of tree branches with the mucosa forming leaves.

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Figure 3.20.3 Peutz-Jeghers polyp. This image shows the cords of smooth
muscle that partition lobules of small bowel mucosa into sectors.

Figure 3.20.4 Juvenile polyp. There is normal mucosa on the left. The polyp is
disorganized, without smooth muscle cords but has dilated glands.

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Figure 3.20.5 Juvenile polyp. These lesions are unusual in the small bowel.
This example has a lot of gastric metaplasia but arose in a child with the
syndrome and many classic colonic juvenile polyps. It is unlikely that this polyp
is simply nodular duodenitis in a young child.

Figure 3.20.6 Juvenile polyp. Note the cystically dilated gland.

3.21 Cronkhite-Canada Polyps vs.

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Juvenile polyps
Cronkhite-Canada
Juvenile Polyp
Syndrome
Presents in childhood with no gender
Adults, mean age about 60
predominance. Solitary juvenile
years; male
polyps are found in about 2% of
Age/Gender predominance. Acquired
children as incidental lesions.
severe wasting syndrome
Syndromic polyps are rarer (about
of unknown etiology
1/100,000 live births)
Throughout
Most common in colon but can be
gastrointestinal tract,
Location detected throughout the stomach and
sparing only the
small bowel
esophagus
Diarrhea, wasting,
dysgeusia (things do not Abdominal pain, rectal pain, passage
Symptoms taste right), skin and of polyp in stool, symptoms of
fingernail changes, obstruction
alopecia
Usually heme-positive stool. The
syndrome consists of (A) more than
3–5 juvenile polyps in the
colorectum, (B) juvenile polyps
throughout the gastrointestinal tract,
Electrolyte abnormalities,
Signs and/or (C) any number of juvenile
protein loss
polyps in a patient with a family
history of the syndrome. Related
syndromes include Bannayan-
Ruvalcaba-Riley, Cowden, and Gorlin
syndrome
Mutations in SMAD4 and BMPR1A.
Etiology Unknown genetic defect Both encode proteins involved in
TGF-b/BMP signaling
1. Marked lamina propria
edema with minimal
inflammation very similar 1. These polyps have site-specific

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 to that of juvenile polyps mucosa and prominent inflammation
Histology but less inflamed (Fig. with expanded lamina propria and
3.21.1). disordered glands with cystic dilation
2. The flat mucosa is (Figs. 3.21.4–3.21.6). The adjoining
abnormal. Mucosa is site flat mucosa is normal (Fig. 3.21.4)
specific (Figs. 3.21.2 and
3.21.3)
None BUT in The syndrome is
such cases, it is transmitted as an autosomal
worthwhile to dominant condition so
perform worth considering genetic
Special cytomegalovirus testing to identify family
studies immunolabeling members at risk. However,
to detect a only about half of patients
potentially are shown to have a
treatable mutation in a characteristic
condition gene

Nutritional support,
Treatment steroids, immune Polypectomy is adequate
modulation
Patients with the syndrome have a
Some patients die from high risk (probably about 50%) of
severe malabsorption. colorectal cancer. The polyps can
Prognosis There may be an undergo a dysplasia/carcinoma
increased risk of sequence. Children who present with
neoplasms one or two incidental colorectal
polyps are not at increased risk

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Figure 3.21.1 Cronkhite-Canada polyposis. These polyps are found in ill adults
with extensive polyposis and abnormal flat mucosa, but the polyps themselves
have a very nonspecific appearance. Lamina propria edema is a key finding
and is cystically a dilated gland.

Figure 3.21.2 Cronkhite-Canada polyposis. The endoscopic appearance is

quite dramatic.

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Figure 3.21.3 Cronkhite-Canada polyposis. Note the cystically dilated glands
and edematous lamina propria.

Figure 3.21.4 Juvenile polyp. An important feature is the adjoining normal

mucosa (on the left).

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Figure 3.21.5 Juvenile polyp. This example shows pyloric metaplasia and a
cystically dilated gland.

Figure 3.21.6 Juvenile polyp. A cystically dilated gland is seen here.

3.22 Primary small bowel cancer vs.

Metastases to small bowel

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 Primary Small Bowel Carcinoma of Other Organs Involving
Adenocarcinoma Small Bowel
Adults, mean age about
60 years; male
predominance; most
common in patients
with familial
Age/Gender Middle-aged adults; male predominance
adenomatous polyposis
(FAP) but also increased
in persons with Crohn
disease (ileal) and celiac
disease
Duodenum most
commonly except in
Location Usually duodenum
patients with Crohn
disease (ileum)
Obstructive symptoms
Obstructive symptoms (abdominal pain,
Symptoms (abdominal pain,
nausea, and vomiting)
nausea, and vomiting)
Signs Polypoid masses Mass in duodenum
Spread of various cancers to small
Etiology Mutations in APC
bowel
1. May be an in situ
component (Fig. 3.22.1) 1. “Bottom-up” appearance at low
and the bulk of the power. Since tumors are often from the
lesion is in the lumen pancreatobiliary tree (direct extension
2. Has appearance or metastatic spread), they are often
Histology
similar to that of very sclerotic (Fig. 3.22.3)
colorectal carcinoma 2. Prominent mucin suggests spread
with luminal necrosis from a pancreatobiliary lesion (Fig.
and stratified nuclei 3.22.4)
(Fig. 3.22.2)
Immunolabeling often not
useful since so much overlap
CDX2 is among various
reactive, but gastrointestinal tract organs.
some cases Loss of SMAD4/DPC4 can

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Special show CK7+, suggest pancreatobiliary
studies CK20−, or origin, but it is important to
CK7/CK20 inform colleagues that
“double correlation with imaging is
positive” often necessary and not to
attempt to offer more
information than is possible

Chemotherapy and
Treatment Per primary tumor site
surgery
Usually poor as such tumors have
Prognosis Depends on tumor stage
spread from the pancreas or biliary tree

Figure 3.22.1 Primary small bowel adenocarcinoma. This example is

straightforward since it has arisen in a patient with familial adenomatous
polyposis and adjoins an adenoma, but it is typically difficult to be certain that
small bowel carcinomas are indeed primary.

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Figure 3.22.2 Primary small bowel adenocarcinoma. The appearance is similar
to that of colorectal carcinoma. In cases in which the differential diagnosis is
between metastatic colorectal carcinoma to them small bowel and primary
small intestinal carcinoma (other than the ampulla), CK7/CK20 is helpful since
small bowel primary adenocarcinomas are CK7+/CK20+ or CK7+/CK20−,
whereas metastases from the colon are CK20+/CK7− in general.

Figure 3.22.3 Spread of carcinoma to the small bowel. This is a

pancreatobiliary cancer extending into the small bowel. The small bowel
surface shows ischemic change, and the malignant cells are “bottom heavy.”

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Figure 3.22.4 Spread of carcinoma to the small bowel. Note the lack of an in
situ component in this case.

3.23 Small bowel follicular lymphoma

vs. Reactive lymphoid hyperplasia
Reactive Lymphoid
Primary Small Bowel Follicular
Hyperplasia in
Lymphoma
Duodenum
Age/Gender Young or middle-aged women Any age
Duodenum (overall
Location Duodenum lymphoid hyperplasia is a
feature of ileum)
Variable depending on the
Symptoms None reason for lymphoid
hyperplasia
Nodular appearance at
Signs None
endoscopy
Associated with BCL2 gene Variable. Infection,
Etiology
rearrangements unknown

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 1. Appearance is that of exaggerated 1. Even at low
lymphoid follicles (Fig. 3.23.1) magnification, tingible
Histology 2. Cytology of lymphoid cells within body macrophages
the follicles is monotonous (Fig. apparent in follicles (Figs.
3.23.2) 3.23.5 and 3.23.6)
Immunolabeling
The lesional cells are B
can be very
cells and express CD20,
helpful. BCL2
and the cells inside the
is negative in
follicles express BCL2
the reactive
(abnormal) (Fig. 3.23.3).
lymphoid
Special BLC6 (Fig. 3.23.4) and
follicles (Fig.
studies CD10 and CD23 can be
3.23.7), which
used to show where the
also are marked
follicles are (CD23 shows a
by BCL6 (Fig.
meshwork of dendritic
3.23.8). Cyclin
cells). Cyclin D1 (BCL1) is
D1 (BCL1) is
negative
negative

None in the absence of disease

Treatment None
outside the duodenum
Not applicable. Lymphoid
Prognosis Favorable with only rare progression hyperplasia is usually an
incidental finding

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Figure 3.23.1 Follicular lymphoma. Note the appearance of exaggerated
lymphoid follicles in the ileum.

Figure 3.23.2 Follicular lymphoma. The center of the follicle has a

monotonous appearance; no tingible body macrophages are apparent.

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Figure 3.23.3 Follicular lymphoma. This is a BCL2 stain, and it should be
negative in the center of normal follicles.

Figure 3.23.4 Follicular lymphoma. This is a BCL6 stain, and it proves that the
aberrantly BCL2-labeled cells shown in Figure 3.23.3 are indeed follicular-
type cells.

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Figure 3.23.5 Reactive lymphoid hyperplasia. Even at low magnification,
tingible body macrophages are apparent in the germinal centers.

Figure 3.23.6 Reactive lymphoid hyperplasia. Note the tingible body

macrophages in the germinal centers.

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Figure 3.23.7 Reactive lymphoid hyperplasia. This is a BCL2 stain, and it is
negative inside the follicles.

Figure 3.23.8 Reactive lymphoid hyperplasia. This is a BCL6 stain, and it

highlights the follicular cells.

3.24 Small bowel follicular lymphoma

vs. Mucosa-associated lymphoid

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tissue (MALT) lymphoma
Primary Small Bowel
Follicular Lymphoma
Young or middle-aged
Age/Gender
women
Location Duodenum
Symptoms None
Can be detected incidentally
on biopsies performed
during upper endoscopy for
Signs other reasons or can present
as small bowel polyps,
usually in the second part of
the duodenum
Unknown overall although
Etiology lesions have BCL2 gene
rearrangements
1. Appearance is that of
exaggerated lymphoid
follicles (Fig. 3.24.1)
Histology 2. Cytology of lymphoid
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Mucosa-Associated Lymphoid
Tissue (MALT)
Lymphoma/Extranodal Marginal
Zone Lymphoma
Adults, typically about 60 years,
with a slight female predominance
Most examples arise in the stomach
associated with H. pylori, but
lesions may also arise in the small
bowel, where they have overlap
with immunoproliferative small
intestinal disease (IPSID), which is
reported mostly in the Middle East
and other tropical or subtropical
sites worldwide
Most patients present with early-
stage disease. Some with small
intestinal disease have diarrhea
No specific ones. However, some
MALT lymphomas have
plasmacytic differentiation and can
result in production of a serum
paraprotein. Patients with IPSID
can have peripheral blood alpha
heavy chain.
Small bowel examples likely to
have t(11:18). IPSID may be
triggered by Campylobacter in
susceptible hosts
1. A diffuse population of small
lymphocytes “overruns” the normal
lymphoid aggregates/germinal
centers (Fig. 3.24.4). There is often
a cleared space around each cell (a
 cells within the follicles is “halo”) as per follicular lymphoma,
monotonous (Fig. 3.24.2) but there are also lymphoepithelial
lesions (Fig. 3.24.5)
The lesional cells
are B cells and The lymphoma cells are
express CD20, B cells, and they often
and the cells express IgM (in IPSID
inside the follicles both plasma cells and the
express BCL2 marginal zone cells
(abnormal) (Fig. express alpha heavy chain
3.24.3). BLC6 and but not alpha light chain).
Special CD10 and CD23 Since they are B cells,
studies can be used to they express CD20 (Fig.
show where the 3.24.6) and CD79a but
follicles are not CD5, CD10, and
(CD23 shows a CD23. Some cases show
meshwork of aberrant expression of
dendritic cells). CD43 in B cells (Fig.
Cyclin D1 (BCL1) 3.24.6)
is negative

None in the absence of

disease outside the
duodenum but patients must
Treatment Tumors are radiosensitive
be evaluated to assure that
the disease is indeed
restricted to the duodenum
Favorable with only rare Indolent behavior with little
Prognosis
progression diminution in life expectancy

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Figure 3.24.1 Follicular lymphoma. This duodenal biopsy shows an incidental
lesion with the appearance of follicular lymphoma.

Figure 3.24.2 Follicular lymphoma. The cells in the follicle are monotonous,
lacking associated tingible body macrophages.

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Figure 3.24.3 Follicular lymphoma. A BCL2 stain aberrantly labels the cells
within the follicles.

Figure 3.24.4 Mucosa-associated lymphoid tissue (MALT) lymphoma

involving the small bowel. This was from a resection specimen from years ago
—resections are currently unusual for such tumors. Small lymphocytic cells
have overrun the tissue, destroying the muscularis mucosae.

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Figure 3.24.5 Mucosa-associated lymphoid tissue (MALT) lymphoma
involving the small bowel. The cells are each surrounded by a clear space (a
halo), and there are lymphoepithelial lesions in this case (lesional cells within
the epithelium).

Figure 3.24.6 Mucosa-associated lymphoid tissue (MALT) lymphoma

involving the small bowel. This is a CD20 stain—note that many of the cells
are in the epithelium—usually the lymphoid cells found in epithelium are T
lymphocytes.

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3.25 Small bowel follicular lymphoma
vs. Mantle cell lymphoma
Primary Small Bowel Follicular
Lymphoma
Age/Gender Young or middle-aged women
Location Duodenum
Symptoms None
Can be detected incidentally on
biopsies performed during upper
endoscopy for other reasons or can
Signs
present as small bowel polyps,
usually in the second part of the
duodenum
Unknown overall although lesions CCND1 gene that encodes
Etiology
have BCL2 gene rearrangements
1. Appearance is that of
exaggerated lymphoid follicles
Histology (Fig. 3.25.1)2.Cytology of
lymphoid cells within the follicles cleared space around each
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Mantle Cell Lymphoma
Adults, typically about 60
years, with a male
predominance
Small bowel and colon. A
characteristic presentation is
that of lymphomatous
polyposis. GI tract polyposis
is encountered in the
majority of patients with
systemic mantle cell
lymphoma
Variable depending on
presentation. Most patients
present with high stage
disease
Polyposis at endoscopy.
Otherwise,
lymphadenopathy,
hepatomegaly
A t(11;14) involving the
for cyclin D1 is considered
the key genetic event
1. A diffuse population of
small lymphocytes
“overruns” the polypoid
zones. There is often a
 is monotonous (Fig. 3.25.2) cell (a “halo”) (Figs. 3.25.4
and 3.25.5)
The lymphoma
The lesional cells are B cells are B cells
cells and express CD20, and thus positive
and the cells inside the for CD20, PAX5,
follicles express BCL2 CD22, and CD19
(abnormal) (Fig. 3.25.3). and display
BLC6 and CD10 and aberrant
Special
CD23 can be used to expression of
studies
show where the follicles CD5. The key
are (CD23 shows a stain is cyclin D1
meshwork of dendritic (BCL1) (Fig.
cells). Cyclin D1 (BCL1) 3.25.6). There is
is negative no need to perform
genetic studies

CHOP regimen
(cyclophosphamide,
None in the absence of disease
vincristine, doxorubicin, and
outside the duodenum but patients
prednisone) or a
Treatment must be evaluated to assure that the
nonanthracycline
disease is indeed restricted to the
combination (COP or MCP),
duodenum
rituximab, and stem cell
transplant
Virtually impossible to cure
Favorable with only rare
Prognosis —median survival is 3–5
progression
years

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Figure 3.25.1 Follicular lymphoma. This resection was not necessary to treat
the lymphoma. This follicular lymphoma was an incidental finding in a
resection performed for a gastrointestinal stromal tumor. Note the exaggerated
lymphoid follicles.

Figure 3.25.2 Follicular lymphoma. The lymphocytic cells are monotonous and
tend to have a cleared area around them, as do those in both mucosa-
associated lymphoid tissue (MALT) lymphoma and mantle cell lymphoma. As
such, attention to architecture and immunolabeling can be important.

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Figure 3.25.3 Follicular lymphoma. This BCL2 stain labels the abnormal
follicular cells.

Figure 3.25.4 Mantle cell lymphoma. The lamina propria is overrun with small
round lymphoid cells.

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Figure 3.25.5 Mantle cell lymphoma. The cells have a clear space (halo)
around them.

Figure 3.25.6 Mantle cell lymphoma. Nuclear labeling with cyclin D1 (BCL1)
is characteristic. Proliferating epithelial cell nuclei also react with this
antibody.

3.26 Burkitt lymphoma vs. Diffuse

large B-cell lymphoma

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 Burkitt Lymphoma Diffuse Large B-Cell Lymphoma
Children with no gender
predilection or persons who
are immunodeficient at any
age. There are three overall
Adults, typically about 60 years,
Age/Gender forms—endemic (equatorial
with a male predominance
Africa, children), sporadic
(children), and
immunodeficiency
associated (HIV/AIDS)
Patients may present with nodal or
Distal ileum is the classic
extranodal disease, but the
gastrointestinal site—in
gastrointestinal tract is the main
general, most cases are
Location extranodal location, particularly the
extranodal. The classic
stomach and ileocecal region.
location for endemic
Lesions usually form large masses
disease is the jaw
or ulcers
Variable depending on presentation.
Bulky disease results in
Symptoms Ileal examples present with
symptoms of obstruction
obstructive symptoms
Mass at endoscopy. Otherwise,
High tumor burden results
Signs lymphadenopathy and
in B symptoms
hepatomegaly
Epstein-Barr virus is
strongly associated and
seen in >90% of endemic
cases, 30%–80% of
Etiology immunodeficiency- Rearrangements of IGH are detected
associated cases, and 10%–
85% of sporadic cases. A
Myc/IGH translocation is
present in most cases

1. Highly mitotic lesions

composed of uniform cells
medium-sized cells (Fig.
3.26.1). Numerous
apoptotic bodies and 1. Large atypical lymphoid cells are

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 apoptotic bodies and
Histology tingible body macrophages present that are more variable in
often impart a “starry-sky” size and shape than those in Burkitt
pattern in which the
macrophages are the stars
and the dense lymphocytic
cells are the sky (Fig.
3.26.2)
The lesional cells
are B cells and
express CD20.
They lack TdT.
They express
BCL6 and CD10
Special and have a
studies proliferation
index of nearly
100% (Fig.
3.26.3).
Importantly,
BCL2 is typically
negative
These tumors are highly
aggressive but can be cured.
EPOCH (etoposide,
Treatment prednisone, vincristine,
cyclophosphamide,
doxorubicin) plus rituximab
is the current protocol
There is a 50%–70% 5-year
Prognosis
survival with chemotherapy
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lymphoma (Figs. 3.26.4 and 3.26.5)
The lymphoma cells are B
cells and thus positive for
CD20, CD19, CD22, and
CD79a. Some examples
express CD10, BCL6, and
MUM1. The proliferation
index is generally 40%–
70% (Fig. 3.26.6). A
subset overlaps with
Burkitt lymphoma and
shows a concurrent IGH–
BCL2 rearrangement and
MYC breakpoint and a
high proliferation index
CHOP regimen (cyclophosphamide,
vincristine, doxorubicin, and
prednisone) with rituximab. Some
cases require treatment more like
that for Burkitt lymphoma
Virtually impossible to cure—
median survival is 3–5 years
Figure 3.26.1 Burkitt lymphoma. This is a highly proliferative lymphoma and
resulted in a resection due to small bowel obstruction. Even at this
magnification, the “starry-sky pattern” is apparent in which the rapidly
dividing lymphoid cells are the sky and many tingible body macrophages are
the stars.

Figure 3.26.2 Burkitt lymphoma. There are sheets of highly monotonous-

appearing lymphoma cells punctuated by tingible body macrophages.

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Figure 3.26.3 Burkitt lymphoma. A Ki-67 stain highlights nearly every nucleus
except for those of the macrophages.

Figure 3.26.4 Diffuse large B-cell lymphoma. The lymphoma is seen at the
base of the biopsy and is less monotonous than the Burkitt lymphoma.

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Figure 3.26.5 Diffuse large B-cell lymphoma. This example is mildly
pleomorphic.

Figure 3.26.6 Diffuse large B-cell lymphoma. A Ki-67 labels about 90% of
nuclei in this example, which is a bit high. Typically, it is closer to 70% to 80%.

3.27 Enteropathy-associated T-cell

lymphoma vs. Enteropathy/celiac

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disease
Enteropathy-Associated T-
Enteropathy/Celiac Disease
Cell Lymphoma
Presents at any age and race but
classically in white children with
female predilection (1.5–2X) and
associated with certain HLA
Adults, often with a history of types (HLA-DQ2 and HLA-
Age/Gender enteropathy, no gender DQ8). More common in
predilection developing countries than in the
past with introduction of wheat
into the diet. Once vanishingly
rare in Southeast Asia, now
emerging there
Affects entire body, typically
Location Jejunum and ileum
assessed on duodenal biopsies
Abdominal pain. Symptoms Chronic diarrhea, weight loss,
Symptoms
of obstruction abdominal distension
Abdominal distension, aphthous
stomatitis, short stature, iron
Mass, sometimes with
Signs deficiency, dermatitis
perforation
herpetiformis, reduced bone
density
Patients often have a
Systemic immune-mediated
prodromal phase of so-called
response to dietary gluten in
refractory celiac
genetically susceptible hosts.
disease/refractory sprue or so-
Diagnosis is confirmed by
called ulcerative jejunitis.
Etiology serologic testing. IgA anti–tissue
Some lack classic celiac
transglutaminase detection is the
disease/enteropathy. Those
preferred initial screen. Cannot be
associated with celiac disease
used in persons with IgA
likely associated with HLA-
deficiency
DQ2/HLA-DQ8
1. The malignant cells form an
ulcerated mucosal mass that 1. In classic case, villous

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 invades the muscularis propria blunting, crypt hyperplasia,
of the intestine prominent intraepithelial
Histology 2. The tumor cells are lymphocytosis, and expansion of
monotonous and often are lamina propria, usually not
seen within the epithelium prominent acute inflammation
(Fig. 3.27.1) and have atypical (Figs. 3.27.4–3.27.6)
cytologic features (Figs.
3.27.2 and 3.27.3)
The lesional cells
are T cells and
None. Some
express CD3. In
laboratories use CD3 to
EATL, the cells are
highlight the T cells in
usually CD7+, CD8
the epithelium. This is
variable, CD4−, and
not needed. Some
TCBR+.
observers also suggest
Sometimes, they
assessment for loss of
express CD30.
CD8 in cases of
Cases associated
refractory celiac disease
Special with refractory
(loss of CD8 correlates
studies sprue may show
with cases more likely
loss of CD8 in the T
to progress to
cells in the
enteropathy-associated
adjoining
lymphoma). The
epithelium. The so-
diagnosis cannot be
called
made in isolation but
“monomorphic” of
must always be in the
T-cell lymphoma is
context of pertinent
CD3+, CD4−,
laboratory testing
CD8+, CD56+, and
TCRB+

These tumors are highly

aggressive but can be cured.
EPOCH (etoposide,
Treatment prednisone, vincristine, Lifelong gluten-free diet
cyclophosphamide,
doxorubicin) plus rituximab is
the current protocol

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 Overall excellent with adherence
to diet. Patients at slightly
increased risk for lymphomas and
Prognosis The prognosis is poor small bowel adenocarcinoma but
these risks are still small. Life
expectancy normal to slightly
shortened

Figure 3.27.1 Enteropathy-associated T-cell lymphoma. Note that this T-cell

lymphoma shows epitheliotropism. It expands the lamina propria, and plasma
cells are inconspicuous.

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Figure 3.27.2 Enteropathy-associated T-cell lymphoma. Enlarged cells expand
the lamina propria.

Figure 3.27.3 Enteropathy-associated T-cell lymphoma. High magnification

shows enlarged hyperchromatic cells. The lymphomas depicted in these images
all arose in a background of enteropathy.

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Figure 3.27.4 Celiac disease. The small lymphocytic cells are in the epithelium,
whereas the lamina propria shows a predominance of plasma cells. This
mucosa is from the background of one of the T-cell lymphomas depicted.

Figure 3.27.5 Celiac disease. Note the intraepithelial lymphocytosis. This was
the background mucosa in a patient with a T-cell lymphoma.

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Figure 3.27.6 Celiac disease. Note the prominent T cells in the tips of the villi.
3.28 Systemic mastocytosis
Langerhans cell histiocytosis
Systemic Mastocytosis in
Gastrointestinal Tract
Adults, female predominance; median
Age/Gender
age about 60 with a wide range
Most common in the colon, followed disease, throughout the GI
Location
by ileum, duodenum, and stomach
Diarrhea, abdominal pain, nausea,
Symptoms
vomiting, weight loss, bloating
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vs.
Langerhans Cell
Histiocytosis of GI Tract
Bimodal distribution in
young children with
severe systemic disease
and in adults presenting
as an incidental findings
at time of colonoscopic
screening
In children with systemic
tract. In adults, usually
presents as colon polyp
In infants/children with
systemic disease, severe
diarrhea, and wasting.
Typically, adults are
 asymptomatic
Extensive mucosal
disease in systemic form
Nodular or erythematous mucosa at
and mucosal
Signs endoscopy. Some patients have skin
irregularities. In isolated
involvement
adults disease, typically
presents as a polyp
Unclear. The disorder involves a
clonal proliferation of mast cells and
most commonly affects the skin
(urticarial pigmentosa) but probably
the GI tract more commonly than
Unclear. BRAF mutations
realized. It is associated with KIT
Etiology in some cases (about a
mutations that differ from the ones in
third)
GIST. It differs from so-called
mastocytic enterocolitis,” which is
probably nonspecific and essentially
equivalent to diarrhea-predominant
irritable bowel syndrome
1. The abnormal mast cells are found 1. Expansion of lamina
in sheets (Fig. 3.28.1) in the lamina propria with atypical cells
propria or in a rind beneath the with nuclear grooves and
Histology
surface (Fig. 3.28.2) a background of
2. The cells are often accompanied by eosinophils (Figs.
numerous eosinophils (Fig. 3.28.3) 3.28.6–3.28.8)
The cells react
with both S100
protein (Fig.
The abnormal mast cells 3.28.9) and
express CD117 (Fig. CD1a (Fig.
3.28.4) and CD25 (Fig. 3.28.10) or
3.28.5) and the latter an Langerin. Some
Special
studies abnormal antigen for mast cases express
cells and therefore BRAF by
characteristic of the immunolabeling
disorder in line with
mutational

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 status

Mast cell stabilizers (cromolyn,

proton pump inhibitors,
Vinblastine, prednisone,
antihistamines). In advanced cases,
and 6-mercaptopurine for
steroids, and midostaurin (multikinase
Treatment systemic disease.
inhibitor). Agents directed against
Observation for isolated
GIST usually not effective since the
disease
KIT mutation is on a different part of
the molecule
Most patients remain alive and
treatment controls symptoms Excellent for isolated
attributable to the mast cell load. disease. Poor for systemic
Prognosis
Occasional patients with aggressive disease involving the GI
multisystem disease die of the tract
disorder

Figure 3.28.1 Systemic mastocytosis. This is usually found in the colon and not
the small bowel, and this example was from the colon. There are sheets of mast
cells and a backdrop of eosinophils.

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Figure 3.28.2 Systemic mastocytosis. In this case (colonic), the cells are in a
ring around the glands, but the eye-catching feature is the abundance of
eosinophils.

Figure 3.28.3 Systemic mastocytosis. This is a high magnification of the area

seen in Figure 3.28.2.

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Figure 3.28.4 Systemic mastocytosis. This is a CD117 stain on the case shown
in Figures 3.28.2 and 3.28.3.

Figure 3.28.5 Systemic mastocytosis. This is a CD25 stain.

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Figure 3.28.6 Langerhans cell histiocytosis. This case is from a child with
severe systemic disease and involved most of the GI tract. In adults,
Langerhans cell histiocytosis presents in a localized fashion, usually as a colon
polyp, and behaves indolently. There is a backdrop of eosinophils.

Figure 3.28.7 Langerhans cell histiocytosis. Higher magnification of the lesion

depicted in Figure 3.28.7.

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Figure 3.28.8 Langerhans cell histiocytosis. Note the eosinophils.

Figure 3.28.9 Langerhans cell histiocytosis. S100 protein stain. Both nuclei
and cytoplasm should be reactive.

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Figure 3.28.10 Langerhans cell histiocytosis, CD1a stain.

3.29 Small bowel gastrointestinal

stromal tumor vs. Inflammatory
fibroid polyp
Small Bowel Gastrointestinal Inflammatory Fibroid
Stromal Tumor Polyp
Lesion of adults (median age
Almost exclusively adults about 60 years). Most
(pediatric GISTs are usually common in the gastric
Age/Gender
gastric), median age about 60 with antrum, but small bowel
a male predominance examples well known.
Female predominance
About 30% of all GISTS arise in
the small bowel and 5% in the
Location Throughout the small bowel
duodenum, where 35%–40% are
malignant
Symptoms of obstruction
Symptoms Usually obstructive symptoms since the lesions frequently

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Mass on imaging, intussusception
Signs
at operation
Some associated with
neurofibromatosis type 1 (NF1).
Only gastric examples are
Etiology
associated with Carney triad and
Carney-Stratakis syndrome (SHD-
deficient GISTs)
1. Spindle cell lesions of
muscularis propria (Fig. 3.29.1), serosa or luminally into the
composed of uniform cells (Fig.
3.29.2)
Histology
2. Sometimes there are collagen
fibrils (“skeinoid fibers”) (Fig.
3.29.3) but usually minimal
inflammation
Most cases express
CD117 (Fig. 3.29.4) and
DOG1, and about half
express CD34 and
smooth muscle actin. A
minority can display
S100 protein expression.
Special
studies KIT-activating mutations
are typical. PDGFRA
mutations have been
described in duodenal
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undergo intussusception
Mass, often with
intussusception
Unclear. PDGFRA mutations
are present in 50%–60% of
cases
1. These tumors are
essentially always
submucosal based although
some extend through the
muscularis propria into
mucosa (Fig. 3.29.5). They
can be markedly edematous,
particularly when the lesion
has intussuscepted
2. The tumors are composed
of plump spindle cells in a
richly vascularized
background with prominent
eosinophils (Fig. 3.29.6)
3. 10
The cells CD34
(Fig. 3.29.8) in
most cases but not
with CD117 or
DOG1 antibodies.
Some examples
express PDGFRA.
Some cases
express BRAF by
immunolabeling in
line with
mutational status.
 GISTs but not those from PDGFRA
other small bowel sites mutations are
shared with some
GISTs

Surgery and tyrosine kinase

Treatment inhibitors, of which imatinib is the Excision
prototype
Depends on size and mitotic
activity. Overall about 40% of These tumors are benign,
small bowel GISTs were lethal in even those that extend
Prognosis
the pre-imatinib era, but many through the muscularis
patients currently enjoy response propria
to newer treatments

Figure 3.29.1 Gastrointestinal stromal tumor. At low power, the lesion is

centered in the muscularis propria.

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Figure 3.29.2 Gastrointestinal stromal tumor. The tumor consists of fascicles of
monotonous-appearing spindle cells.

Figure 3.29.3 Gastrointestinal stromal tumor. Small intestinal examples often

display so-called skeinoid fibers. Note again the monotonous cytologic features
of the spindle cells.

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Figure 3.29.4 Gastrointestinal stromal tumor. CD117 stain.

Figure 3.29.5 Inflammatory fibroid polyp. The muscularis mucosae is thick in

this example, but the lesion is centered in the submucosa. Small bowel
examples are often very edematous because they tend to undergo
intussusception.

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Figure 3.29.6 Inflammatory fibroid polyp. The tumor cells are very bland
appearing. There is nearly always a background of eosinophils.

Figure 3.29.7 Inflammatory fibroid polyp. These tumors are richly

vascularized. Gastric examples often show an onionskin appearance around
vessels, but this feature is not prominent in small bowel examples.

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Figure 3.29.8 Inflammatory fibroid polyp. CD34 is usually reactive.

3.30 Epithelioid small bowel

gastrointestinal stromal tumor vs.
Carcinoma
Epithelioid Small Bowel
Carcinoma
Gastrointestinal Stromal Tumor
Overall adults. Carcinomas
Almost exclusively adults
found in the small bowel can
(pediatric GISTs are usually
Age/Gender be metastases of primary
gastric), median age about 60 with
lesions. Probably an overall
a male predominance
male predominance
About 30% of all GISTS arise in
the small bowel and 5% in the
Location Throughout the small bowel
duodenum, where 35%–40% are
malignant. Any can be epithelioid
Symptoms Usually obstructive symptoms Symptoms of obstruction
Mass on imaging, intussusception
Signs Mass
at operation
Various carcinomas have

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 Associated with KIT and PDGFRA variable associations.
Etiology Metastases of gastric, breast
mutations
carcinoma common; some
lesions are primary
1. In some cases, there is an
in situ component (Fig.
3.30.4) associated with the
1. Epithelioid lesions of
lesion
muscularis propria (Fig. 3.30.1),
2. Tumor cells may have a
Histology composed of uniform cells, some
mucinous appearance, which
of which can have a vacuolated
differs from the more
appearance (Fig. 3.30.2)
vacuolated appearance of
epithelioid GIST (Fig.
3.30.5)
The cells are
Most cases express usually negative
CD117 (Fig. 3.30.3) and for CD34. Some
DOG1, and about half carcinomas express
express CD34 and CD117, and about
smooth muscle actin. A a third of gastric
minority can display carcinomas react
S100 protein expression. with DOG1
Special Keratin expression is antibodies.
studies distinctly unusual. KIT- However, keratin
activating mutations are expression is
typical. PDGFRA helpful in
mutations have been identifying
described in duodenal carcinomas (Fig.
GISTs but not those 3.30.6). Of course,
from other small bowel other markers can
sites confirm various
sites of origin

Surgery and tyrosine kinase Resection and

Treatment inhibitors, of which imatinib is the chemoradiation therapy,
prototype depending on tumor type
Depends on size and mitotic
activity. Overall about 40% of

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 small bowel GISTs were lethal in Variable, depending on the
Prognosis the pre-imatinib era, but many type of carcinoma, but
patients currently enjoy response generally poor
to newer treatments

Figure 3.30.1 Epithelioid gastrointestinal stromal tumor. The tumor is centered

in the muscularis propria.

Figure 3.30.2 Epithelioid gastrointestinal stromal tumor. Note the monotonous

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appearance of the nuclei, which appear plasmacytoid in this example. The
cytoplasm is vacuolated but not distended by mucin.

Figure 3.30.3 Epithelioid gastrointestinal stromal tumor. This is a CD117 stain.

Figure 3.30.4 Carcinoma. This is a primary ileal carcinoma in a patient with

Crohn disease. It arose in associated with high-grade ileitis-associated
dysplasia and is composed of glands.

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Figure 3.30.5 Carcinoma. The appearance of the mucin differs from that of the
vacuoles in epithelioid gastrointestinal stromal tumor.

Figure 3.30.6 Carcinoma. A pitfall is that gastric carcinomas (which often

spread to the small bowel) can express DOG1, as in this case.

3.31 Small bowel gastrointestinal

stromal tumor vs. Leiomyosarcoma

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 Small Bowel Gastrointestinal
Leiomyosarcoma
Stromal Tumor
Lesion of adults (median
Almost exclusively adults (pediatric
age about 60 years).
Age/Gender GISTs are usually gastric), median age
Much more rare that
about 60 with a male predominance
GISTs
About 30% of all GISTS arise in the
Throughout the small
Location small bowel and 5% in the duodenum,
bowel
where 35%–40% are malignant
Symptoms of obstruction
since the lesions
Symptoms Usually obstructive symptoms
frequently undergo
intussusception
Mass on imaging, intussusception at
Signs Mass
operation
Some associated with
neurofibromatosis type 1 (NF1). Only
Etiology gastric examples are associated with Unclear
Carney triad and Carney-Stratakis
syndrome (SHD-deficient GISTs)
1. These tumors usually
arise in the muscularis
propria and are more
brightly eosinophilic than
1. Spindle cell lesions of muscularis GISTs (Fig. 3.31.4) and
Histology propria (Fig. 3.31.1), composed of arranged in
uniform cells (Figs. 3.31.2 and 3.31.3) perpendicularly oriented
fascicles (Fig. 3.31.5)
2. They display far more
nuclear pleomorphism
than GISTs (Fig. 3.31.6)
The cells
express desmin
Most cases express CD117 and caldesmon
and DOG1, and about half as well as
express CD34 and smooth actins but

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 muscle actin. A minority can generally lack
display S100 protein CD117 and
Special
expression. KIT-activating DOG1. There
studies
mutations are typical. are no KIT
PDGFRA mutations have mutations or
been described in duodenal PDGFRA
GISTs but not those from mutations.
other small bowel sites Some cases
show weak
keratin labeling

Surgery and tyrosine kinase inhibitors, Resection and some

Treatment
of which imatinib is the prototype chemotherapy regimens
Depends on size and mitotic activity.
Overall, about 40% of small bowel
Better when grade and
Prognosis GISTs were lethal in the pre-imatinib
mitotic activity are low
era, but many patients currently enjoy
response to newer treatments

Figure 3.31.1 Gastrointestinal stromal tumor. This lesion arose in the

muscularis propria but has extended into the submucosa.

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Figure 3.31.2 Gastrointestinal stromal tumor. Note the monotonous cytologic
features and the pale pink cytoplasm.

Figure 3.31.3 Gastrointestinal stromal tumor. At high magnification, the

cytoplasm is delicately fibrillary.

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Figure 3.31.4 Leiomyosarcoma. Even at low magnification, the lesion shows
pleomorphic nuclei. The fascicles are also perpendicularly oriented, and the
overall appearance is “pinker” than that of the gastrointestinal stromal tumor.

Figure 3.31.5 Leiomyosarcoma. Note the perpendicular orientation of the

fascicles one to another.

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Figure 3.31.6 Leiomyosarcoma. There is dense nuclear heterochromatin in
cells with brightly eosinophilic cytoplasm. The nuclei are blunt ended.

3.32 Small bowel gastrointestinal

stromal tumor vs. Clear cell sarcoma–
like tumor (malignant gastrointestinal
neuroectodermal tumor)
Clear Cell Sarcoma-Like
Small Bowel Gastrointestinal
Tumor/Gastrointestinal
Stromal Tumor
Neuroectodermal Tumor
Almost exclusively adults Lesion of younger adults than
(pediatric GISTs are usually GIST (median age <40 years) but
Age/Gender
gastric), median age about 60 wide age range. No gender
with a male predominance predominance
About 30% of all GISTS arise
in the small bowel and 5% in
Location Most common in the ileum
the duodenum, where 35%–
40% are malignant

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Symptoms Usually obstructive symptoms Symptoms of obstruction
Mass on imaging,
Signs
intussusception at operation
Some associated with
neurofibromatosis type 1
(NF1). Only gastric examples
Etiology are associated with Carney
triad and Carney-Stratakis
syndrome (SHD-deficient
GISTs)
1. Spindle cell lesions of
muscularis propria (Fig.
3.32.1), composed of uniform
Histology cells (Fig. 3.32.2)
2. Tumor is seen as zones of
spindle cells rather than in
“nests” (Fig. 3.32.3)
Most cases express
CD117 (Fig. 3.32.4)
and DOG1, and
about half express
CD34 and smooth
muscle actin. A
minority can display
S100 protein
Special expression. KIT-
studies activating mutations
are typical.
PDGFRA mutations
have been described
in duodenal GISTs
but not those from
other small bowel
sites
Surgery and tyrosine kinase
Treatment inhibitors, of which imatinib is Excision and chemotherapy
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Mass
Unclear. EWS rearrangements
present
1. These tumors involve the
muscularis propria (Fig. 3.32.5)
2. The tumors are composed of
nests of uniform cells (Fig.
3.32.6), often with prominent
nucleoli
3. 10
The tumor cells
positive for S100
protein (Fig. 3.32.8)
and SOX10. Over half
of cases express CD56
and synaptophysin, and
some express NSE and
NFP. They lack
specific melanocytic,
gastrointestinal stromal
tumors, epithelial, and
myoid markers. Most
cases have EWS
rearrangements with
either ATF1 or CREB1
 the prototype
Depends on size and mitotic
activity. Overall about 40% of
small bowel GISTs were lethal Aggressive lesions with little
Prognosis
in the pre-imatinib era, but response to chemotherapy
many patients currently enjoy
response to newer treatments

Figure 3.32.1 Gastrointestinal stromal tumor. Note that the tumor is paler than
the adjoining muscularis propria.

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Figure 3.32.2 Gastrointestinal stromal tumor. The tumor consists of
monotonous spindle cells.

Figure 3.32.3 Gastrointestinal stromal tumor. There is a background of delicate

fibrillary collagen.

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Figure 3.32.4 Gastrointestinal stromal tumor, CD117 stain.

Figure 3.32.5 Clear cell sarcoma–like tumor of gastrointestinal tract. This

lesion involves the muscularis propria of the ileum and appears overtly
malignant at low magnification.

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Figure 3.32.6 Clear cell sarcoma–like tumor of gastrointestinal tract. The
malignant cells are monotonous, and many have prominent nucleoli. The
cytoplasm is pale.

Figure 3.32.7 Clear cell sarcoma–like tumor of gastrointestinal tract. Some

examples have a pseudopapillary pattern.

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Figure 3.32.8 Clear cell sarcoma–like tumor of gastrointestinal tract. Note the
strong S100 protein stain, which marks both cytoplasm and nuclei.

3.33 Small bowel gastrointestinal

stromal tumor vs. Melanoma
Small Bowel Gastrointestinal Metastatic Melanoma
Stromal Tumor Involving Small Bowel
Almost exclusively adults (pediatric
GISTs are usually gastric), median
Age/Gender Lesion of adults in general
age about 60 with a male
predominance
About 30% of all GISTS arise in the
small bowel and 5% in the Throughout the small
Location
duodenum, where 35%–40% are bowel
malignant
Symptoms Usually obstructive symptoms Symptoms of obstruction
Mass on imaging, intussusception at
Signs Mass
operation
Some associated with

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 neurofibromatosis type 1 (NF1). Only Spread of melanoma from
Etiology
gastric examples are associated with skin is the typical scenario
Carney triad and Carney-Stratakis
syndrome (SHD-deficient GISTs)
1. Tumors found in any
layer. In some cases,
pigment can be a clue
(Fig. 3.33.5)
1. Spindle cell lesions of muscularis
2. They usually display far
propria (Fig. 3.33.1), composed of
Histology more nuclear
uniform cells (Figs. 3.33.2 and
pleomorphism than GISTs
3.33.3)
(Fig. 3.33.6)
3. Often deposits of tumor
are seen in lacteals (Fig.
3.33.7)
The pitfall is
that the
Most cases express CD117 melanoma cells
and DOG1, and about half can express
express CD34 (Fig. 3.33.4) CD117 but
and smooth muscle actin. A typically also
minority can display S100 strong diffuse
Special protein expression. KIT- S100 protein
studies activating mutations are (Fig. 3.33.8).
typical. PDGFRA mutations Melanomas
have been described in usually lack
duodenal GISTs but not CD34. Both
those from other small melanoma and
bowel sites GIST can
display BRAF
mutations

Resection and
Surgery and tyrosine kinase
chemotherapy regimens
Treatment inhibitors, of which imatinib is the
depending on mutational
prototype
status
Depends on size and mitotic activity.
Overall about 40% of small bowel

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Prognosis GISTs were lethal in the pre-imatinib Poor
era, but many patients currently enjoy
response to newer treatments

Figure 3.33.1 Gastrointestinal stromal tumor. The tumor is seen with adjoining
smooth muscle of the muscularis propria, the pink zone at the upper left.

Figure 3.33.2 Gastrointestinal stromal tumor. Monotonous cytologic features

are characteristic.

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Figure 3.33.3 Gastrointestinal stromal tumor. Note the lack of nucleoli.

Figure 3.33.4 Gastrointestinal stromal tumor, CD117 stain.

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Figure 3.33.5 Melanoma. This example is pigmented (lower right) and even is
seen in lacteals.

Figure 3.33.6 Melanoma. The cells show irregular nuclei with prominent
nucleoli.

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Figure 3.33.7 Melanoma. These cells have “rounded up” inside this duodenal
lacteal.

Figure 3.33.8 Melanoma. Note the strong diffuse S100 protein reactivity.

3.34 Clear cell sarcoma–like tumor

(malignant gastrointestinal
neuroectodermal tumor) vs.

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Melanoma
Clear Cell Sarcoma-Like
Tumor/Gastrointestinal
Neuroectodermal Tumor
Lesion of younger adults than
GIST (median age <40 years)
Age/Gender
but wide age range. No gender
predominance
Location Most common in the ileum
Symptoms Symptoms of obstruction
Signs Mass
Unclear. EWS rearrangements
Etiology
present
1. These tumors involve the
muscularis propria (Fig.
3.34.1)
2. The tumors are composed
Histology of nests of uniform cells (Fig.
3.34.2), often with prominent
nucleoli. No melanin
deposition is seen
3. 10
The tumor cells
positive for S100
protein and SOX10.
Over half of cases
express CD56 and
synaptophysin, and
some express NSE
and NFP. They lack
specific
Special melanocytic,
studies gastrointestinal
stromal tumors,
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Metastatic Melanoma involving
Small Bowel
Lesion of adults in general
Throughout the small bowel
Symptoms of obstruction
Mass
Spread of melanoma from skin is
the typical scenario
1. Tumors found in any layer. In
some cases, pigment can be a
clue (Fig. 3.34.4)
2. They usually display far more
nuclear pleomorphism than clear
cell sarcoma–like tumors (Fig.
3.34.5)11. 12
Melanomas express
S100 protein but also
frequently show
labeling with HMB45,
Melan-A, and
tyrosinase. Of course a
metastasis from a soft
tissue clear cell
sarcoma might also
have “melanoma
markers.” In some
 epithelial, and cases, assessment for
myoid markers. EWS rearrangements
Most cases have (positive in clear cell
EWS sarcoma–like tumor) is
rearrangements with required to clarify the
either ATF1 or diagnosis
CREB1

Resection and chemotherapy

Treatment Excision and chemotherapy
Aggressive lesions with little
Prognosis
response to chemotherapy
regimens depending on
mutational status
Poor

Figure 3.34.1 Clear cell sarcoma–like tumor of gastrointestinal tract. The

tumor extends through all the layers of the ileum but is centered in the
muscularis propria. There is a nested pattern at the lower right.

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Figure 3.34.2 Clear cell sarcoma–like tumor of gastrointestinal tract.
Monotonous small malignant cells comprising the lesion often have prominent
nucleoli.

Figure 3.34.3 Clear cell sarcoma–like tumor of gastrointestinal tract. This

example has a pseudopapillary appearance.

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Figure 3.34.4 Melanoma. This example is deeply pigmented.

Figure 3.34.5 Melanoma. The cells are large and pleomorphic and have large
nucleoli.

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Figure 3.34.6 Melanoma. Higher magnification of the case seen in Figure
3.34.5.

3.35 Small bowel gastrointestinal

stromal tumor vs. Mesenteric
fibromatosis
Small Bowel Gastrointestinal
Mesenteric Fibromatosis
Stromal Tumor
Young adults (median age
about 40 with wide age
Almost exclusively adults (pediatric
range) with male
GISTs are usually gastric), median
Age/Gender predominance overall
age about 60 with a male
(whereas abdominal wall
predominance
desmoids have a female
predominance)
About 30% of all GISTS arise in the
Location small bowel and 5% in the duodenum, Small bowel mesentery
where 35%–40% are malignant
Symptoms Usually obstructive symptoms Symptoms of obstruction

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 Mass on imaging, intussusception at
Signs Mass
operation
Unknown. Associated
with familial
Some associated with
adenomatous
neurofibromatosis type 1 (NF1). Only
polyposis/Gardner
Etiology gastric examples are associated with
syndrome and APC and
Carney triad and Carney-Stratakis
CTNNB1 (the gene that
syndrome (SHD-deficient GISTs)
encodes for β-catenin)
mutations
1. Tumors found in the
mesentery, sometimes
with extension into the
muscularis propria. They
1. Spindle cell lesions of muscularis are less cellular than
propria (Fig. 3.35.1), composed of GISTs (Fig. 3.35.5)
Histology
uniform cells (Figs. 3.35.2 and 2. They usually display
3.35.3) prominent vessels and
bland nuclei (Fig.
3.35.6)3. A myxoid
pattern can be seen (Fig.
3.35.7)
The pitfall is
that some
Most cases express CD117
fibromatoses
and DOG1, and about half
express CD117
express CD34 (Fig. 3.35.4)
(Fig. 3.35.8).
and smooth muscle actin. A
They usually
minority can display S100
lack CD34.
protein expression. KIT-
Special They are
studies activating mutations are
myofibroblastic
typical. PDGFRA mutations
so they can
have been described in
show actin
duodenal GISTs but not
expression.
those from other small
Many examples
bowel sites
show nuclear β-
catenin labeling

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 Surgery and tyrosine kinase
Resection. Sometimes
Treatment inhibitors, of which imatinib is the
low-dose chemotherapy
prototype
Depends on size and mitotic activity.
Overall about 40% of small bowel
Recurrences are common,
Prognosis GISTs were lethal in the pre-imatinib
but most patients survive
era, but many patients currently enjoy
response to newer treatments

Figure 3.35.1 Gastrointestinal stromal tumor. This example is seen in the

muscularis propria. The serosa, with India ink, is below.

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Figure 3.35.2 Gastrointestinal stromal tumor. There are long fascicles of
spindle cells with minimal collagen deposition.

Figure 3.35.3 Gastrointestinal stromal tumor. The nuclei are elongated with
tapered ends, and nucleoli are inconspicuous.

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Figure 3.35.4 Gastrointestinal stromal tumor, CD117.

Figure 3.35.5 Mesenteric fibromatosis. Note the collagen deposition pattern

and note that the vessels appear prominent even though they are small because
the surrounding lesion is so pale. Leiomyosarcomas are bright pink,
gastrointestinal stromal tumors are paler pink, and mesenteric fibromatoses are
still paler.

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Figure 3.35.6 Mesenteric fibromatosis. The myofibroblastic cytoplasm is
somewhat stellate and amphophilic. Nearly every nucleus has a small distinct
nucleolus.

Figure 3.35.7 Mesenteric fibromatosis. The amphophilic cytoplasm can be

seen at low magnification.

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Figure 3.35.8 Mesenteric fibromatosis. This is a CD117 stain; some
fibromatoses display CD117 labeling, a potential pitfall.

3.36 Mesenteric Fibromatosis vs.

Sclerosing mesenteritis
Mesenteric Fibromatosis Sclerosing Mesenteritis
Young adults (median age about
40 with wide age range) with
Adults (median age about 60
male predominance overall
Age/Gender with wide age range) without
(whereas abdominal wall
gender predominance
desmoids have a female
predominance)
Location Small bowel mesentery Small bowel mesentery
Symptoms Symptoms of obstruction Symptoms of obstruction
Signs Mass Mass
Unknown. Associated with
familial adenomatous Unknown. There is overlap
polyposis/Gardner syndrome and
Etiology with IgG4-related
APC and CTNNB1 (the gene that fibrosclerosing disease

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 encodes for β-catenin) mutations
1. Tumors found in the
mesentery, sometimes with
extension into the muscularis
propria. They are less cellular
Histology then GISTs (Fig. 3.36.1)
2. They usually display
prominent vessels and bland
nuclei (Fig. 3.36.2)
3. 10
The pitfall is that some
fibromatoses express
CD117 (but not
DOG1). They usually
lack CD34. They are
Special myofibroblastic so
studies they can show actin
expression. Most
examples show nuclear
β-catenin labeling
(Fig. 3.36.4)
1. Tumors found in the root of
the mesentery, usually without
extension into the muscularis
propria. They are less cellular
then fibromatosis (Fig. 3.36.4)
2. There is often prominent fat
necrosis (Fig. 3.36.5)11. 12
Some cases show
aberrant CD117
expression. They are
myofibroblastic so
they can show actin
expression. There is
no nuclear β-catenin
labeling. Some cases
have IgG4-labeled
plasma cells (Fig.
3.36.8)

Resection. Sometimes low-dose
Treatment
chemotherapy
Recurrences are common, but
Prognosis
most patients survive
Resection. In contrast to
classic IgG4-related
fibrosclerosing disease, these
tumors do not respond well to
steroids
Recurrences are uncommon,
and most patients do well
following surgery

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Figure 3.36.1 Mesenteric fibromatosis. This mesenteric lesion has extended
into the muscularis propria.

Figure 3.36.2 Mesenteric fibromatosis. Look how the small vessels appear
dramatic and ectatic.

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Figure 3.36.3 Mesenteric fibromatosis. The cells have amphophilic stellate
cytoplasm and are separated by collagen.

Figure 3.36.4 Mesenteric fibromatosis. Beta catenin immunostaining labels

many nuclei. Note that the endothelial cell nuclei in the vessel in the center of
the field are negative.

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Figure 3.36.5 Sclerosing mesenteritis. This field shows fat necrosis and lots of
inflammation.

Figure 3.36.6 Sclerosing mesenteritis. Note the fat necrosis and calcification.

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Figure 3.36.7 Sclerosing mesenteritis. This area shows prominent
lymphoplasmacytic inflammation.

Figure 3.36.8 Sclerosing mesenteritis. Some examples show IgG4-labeled

plasma cells despite their nonidentity with IgG4-related fibrosclerosing
disease.

3.37 Mesenteric Fibromatosis vs.

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Calcifying fibrous tumors
Mesenteric Fibromatosis Calcifying Fibrous Tumor
Young adults (median age
about 40 with wide age
range) with male Adults (median age about 60 with
Age/Gender predominance overall wide age range) without gender
(whereas abdominal wall predominance
desmoids have a female
predominance)
Location Small bowel mesentery Small bowel mesentery
Symptoms Symptoms of obstruction Symptoms of obstruction
Signs Mass Mass or multiple small masses
Unknown. Associated with
familial adenomatous
polyposis/Gardner
Etiology syndrome and APC and Unknown
CTNNB1 (the gene that
encodes for β-catenin)
mutations
1. Tumors found in the
1. Tumors found in the root of the
mesentery, sometimes with
mesentery, usually without
extension into the
extension into the muscularis
muscularis propria (Fig.
propria. They are less cellular then
Histology 3.37.1)
fibromatosis (Fig. 3.37.4)
2. They usually display
2. Extremely hypocellular with a
prominent vessels and
backdrop of plasma cells (Fig.
bland nuclei (Fig. 3.37.2)
3.37.5)11. 12
3. 10
The pitfall is that
There is no nuclear β-
some
catenin labeling. Some
fibromatoses
cases have IgG4-labeled
express CD117
plasma cells, but there is
(but not DOG1).
no storiform fibrosis, and
They usually lack
the lesions are extremely

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Special CD34. They are hypocellular. They are
studies myofibroblastic always negative with
so they can show ALK, so they are not
actin expression. “burned out”
Many examples inflammatory
show nuclear β- myofibroblastic tumors
catenin labeling

Resection. Sometimes low-

Treatment Resection
dose chemotherapy
Recurrences are common, These are benign, even when
Prognosis
but most patients survive multiple

Figure 3.37.1 Mesenteric fibromatosis. This lesion has extended from the
mesentery to involve the muscularis propria, which is brightly eosinophilic and
at the upper left.

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Figure 3.37.2 Mesenteric fibromatosis. Note the stellate contours of the
cytoplasm of the lesional cells and the prominent vessels.

Figure 3.37.3 Mesenteric fibromatosis. Each nucleus has a delicate nucleolus

and a smooth nuclear membrane.

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Figure 3.37.4 Calcifying fibrous pseudotumor. The lesion is hypocellular,
sometimes densely collagenized, and has scattered plasma cells and
calcifications.

Figure 3.37.5 Calcifying fibrous pseudotumor. Note the bland lesional cells
and scattered plasma cells.

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Figure 3.37.6 Calcifying fibrous pseudotumor. These tumors can display either
dystrophic- or psammomatous-type calcifications.

3.38 Duodenal well-differentiated

neuroendocrine carcinoid tumor vs.
Duodenitis
Well-Differentiated Neuroendocrine
Chronic Duodenitis
Tumor of Duodenum
About 60 years with a male
predominance. Gastrinomas of the
duodenum in patients with Zollinger-
Age/Gender Ellison syndrome present at a mean Usually adults
age of about 40 years. Patients with
neurofibromatosis (NF1) are at risk for
ampullary neuroendocrine tumors
Location First and second portion of duodenum Duodenum
Many patients are asymptomatic.
Often none. Sometimes
Symptoms Those with Zollinger-Ellison have
abdominal pain
symptoms attributable to gastric ulcers
Mass or hypergastrinemia (in case of
Signs Nodular duodenum
Zollinger-Ellison)
Unknown overall. Familial examples

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 Unknown overall. Familial examples
associated with multiple endocrine
neoplasia (MEN) have alterations of
the MEN locus. Associated with Often associated with H.
Etiology
familial adenomatous pylori infection
polyposis/Gardner syndrome and APC
and CTNNB1 (the gene that encodes
for β-catenin) mutations
1. Prominent lymphoid
1. Tumors are usually found on
inflammation, often with
duodenal biopsies (Fig. 3.38.1)
germinal centers (Fig.
2. The cells appear nested at low
3.38.7)
Histology magnification but can be difficult to
2. Often associated
recognize as neoplastic when there is
gastric mucin cell
duodenal injury (Figs. 3.38.2 and
metaplasia (Fig. 3.38.8)
3.38.3)
3. 10
Usually no
need to stain
These tumors express with any stains.
synaptophysin and Occasionally, a
chromogranin (Fig. 3.38.4) negative
and sometime specific chromogranin
hormones (e.g., gastrin, or
somatostatin). At times, synaptophysin
Special consideration is given to can be
studies gangliocytic paraganglioma reassuring
but that has three since it can be
components (Schwann cells, easy to
ganglionic cells, and overlook some
epithelioid cells) (Figs. well-
3.38.5 and 3.38.6) differentiated
neuroendocrine
tumors

Excision. Sometimes various forms of None. Unless patient has

Treatment chemotherapy H. pylori, which can be
eradicated

Prognosis Overall favorable but according to Unrelated to duodenitis!

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 stage

Figure 3.38.1 Well-differentiated neuroendocrine tumor (sneaky carcinoid).

Can you spot the tumor? It is in the lower part of the center of the field!

Figure 3.38.2 Well-differentiated neuroendocrine tumor (sneaky carcinoid).

The lesion is more apparent now, but this case demonstrates the need to study
apparent duodenitis cases carefully.

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Figure 3.38.3 Well-differentiated neuroendocrine tumor (sneaky carcinoid).
Higher magnification of the lesion depicted in Figures 3.38.1 and 3.38.2.

Figure 3.38.4 Well-differentiated neuroendocrine tumor (sneaky carcinoid).

Often performing a chromogranin stain discloses far more tumor than
anticipated in such cases.

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Figure 3.38.5 Gangliocytic paraganglioma. These are centered in the
submucosa with extensions into the mucosa. The lesion consists of three
elements, namely, schwannian elements, ganglion-like cells, and epithelioid
cells.

Figure 3.38.6 Gangliocytic paraganglioma. This example shows schwannian

elements toward the top of the field (spindle cells), ganglion-like cells at the
middle right, and epithelioid cells on the lower right. These lesions are rarely
and virtually always encountered in the duodenum.

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Figure 3.38.7 Chronic duodenitis. There is no carcinoid tumor hiding here, but
it is worth checking. Note the surface gastric mucin cell metaplasia.

Figure 3.38.8 Chronic duodenitis. The lamina propria is expanded with plasma
cells, and there is gastric mucin cell metaplasia.

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Figure 3.38.9 Chronic duodenitis. This is a high-magnification image of the
case seen in Figures 3.38.7 and 3.38.8.

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SUGGESTED READINGS
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Arnold CA, Moreira RK, Lam-Himlin D, et al. Whipple disease a century after
the initial description: increased recognition of unusual presentations,
autoimmune comorbidities, and therapy effects. Am J Surg Pathol.
2012;36(7):1066–1073.
Bajpai J, Rekhi B, Iyer K, et al. Multifocal calcifying fibrous tumor of the
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implications. J Cancer Res Ther. 2011;7(4):500–502.
Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation,
polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of
immunodeficiency with autoimmunity. Front Immunol. 2012;3:211.
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cases with clinical follow-up. Am J Surg Pathol. 2014;38(2):215–223.
Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, et al. Nuclear beta-catenin
expression distinguishes deep fibromatosis from other benign and malignant
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Brosens LA, van Hattem WA, Jansen M, et al. Gastrointestinal polyposis
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Brosens LA, Langeveld D, van Hattem WA, et al. Juvenile polyposis syndrome.
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exist? Experience of a large teaching hospital. Am J Surg Pathol.
2007;31(8):1209–1214.
Burke AP, Sobin LH, Shekitka KM. Mesenteric fibromatosis. A follow-up study.
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Burke AP, Sobin LH, Shekitka KM, et al. Intra-abdominal fibromatosis. A
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 Pathol. 2003;119(6):811–815.
Chen TS, Montgomery EA. Are tumefactive lesions classified as sclerosing
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Chen ZM, Scudiere JR, Abraham SC, et al. Pyloric gland adenoma: an entity
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Cortina G, Wren S, Armstrong B, et al. Clinical and pathologic overlap in
nonsteroidal anti-inflammatory drug-related small bowel diaphragm disease
and the neuromuscular and vascular hamartoma of the small bowel. Am J
Surg Pathol. 1999;23(11):1414–1417.
Daniels JA, Lederman HM, Maitra A, et al. Gastrointestinal tract pathology in
patients with common variable immunodeficiency (CVID): a
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2007;31(12):1800–1812.
de Sanctis S, Qureshi T, Stebbing JF. Clinical and pathological overlap in
nonsteroidal anti-inflammatory drug-related small bowel diaphragm disease
and the neuromuscular and vascular hamartoma of the small bowel. Am J
Surg Pathol. 2001;25(4):539–541.
Doyle LA, Sepehr GJ, Hamilton MJ, et al. A clinicopathologic study of 24 cases
of systemic mastocytosis involving the gastrointestinal tract and assessment
of mucosal mast cell density in irritable bowel syndrome and asymptomatic
patients. Am J Surg Pathol. 2014;38(6):832–843.
Estrella JS, Wu TT, Rashid A, et al. Mucosal colonization by metastatic
carcinoma in the gastrointestinal tract: a potential mimic of primary
neoplasia. Am J Surg Pathol. 2011;35(4):563–572.
Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med.
2012;367(25):2419–2426.
Ghoshal UC, Srivastava D. Irritable bowel syndrome and small intestinal
bacterial overgrowth: meaningful association or unnecessary hype. World J
Gastroenterol. 2014;20(10):2482–2491. doi: 10.3748/wjg.v20.i10.2482.
Review.
Ghoshal UC, Srivastava D, Ghoshal U, et al. Breath tests in the diagnosis of
small intestinal bacterial overgrowth in patients with irritable bowel
syndrome in comparison with quantitative upper gut aspirate culture. Eur J
Gastroenterol Hepatol. 2014;26(7):753–760.
Gouda MR, Al-Amin A, Grabsch H, et al. A multidisciplinary approach to

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 management of autoimmune polyendocrinopathy candidiasis ectodermal
dystrophy (APECED). BMJ Case Rep. 2013;2013.
Groisman GM, Amar M, Livne E. CD10: a valuable tool for the light
microscopic diagnosis of microvillous inclusion disease (familial
microvillous atrophy). Am J Surg Pathol. 2002;26(7):902–907.
Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal
mast cells is specific for systemic mastocytosis. Am J Surg Pathol.
2007;31(11):1669–1676.
Hatemi G, Yazici Y, Yazici H. Behçet's syndrome. Rheum Dis Clin North Am.
2013;39(2):245–261.
Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers
in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209–3215.
Jain A, Sebastian K, Quigley B. Collagenous sprue, an enigma in the spectrum
of celiac disease. Clin Gastroenterol Hepatol. 2014;12(1):e2–e3; quiz e4–e6.
Kobayashi I, Kubota M, Yamada M, et al. Autoantibodies to villin occur
frequently in IPEX, a severe immune dysregulation, syndrome caused by
mutation of FOXP3. Clin Immunol. 2011;141(1):83–89.
Lasota J, Wang ZF, Sobin LH, et al. Gain-of-function PDGFRA mutations,
earlier reported in gastrointestinal stromal tumors, are common in small
intestinal inflammatory fibroid polyps. A study of 60 cases. Mod Pathol.
2009;22(8):1049–1056.
Laurini JA, Zhang L, Goldblum JR, et al. Low-grade fibromyxoid sarcoma of
the small intestine: report of 4 cases with molecular cytogenetic
confirmation. Am J Surg Pathol. 2011;35(7):1069–1073.
Lee J, Hegele RA. Abetalipoproteinemia and homozygous
hypobetalipoproteinemia: a framework for diagnosis and management. J
Inherit Metab Dis. 2014;37(3):333–339.
Liu TC, Lin MT, Montgomery EA, et al. Inflammatory fibroid polyps of the
gastrointestinal tract: spectrum of clinical, morphologic, and
immunohistochemistry features. Am J Surg Pathol. 2013;37(4):586–592.
Mat C, Yurdakul S, Sevim A, et al. Behçet's syndrome: facts and controversies.
Clin Dermatol. 2013;31(4):352–361.
Miettinen M, Makhlouf H, Sobin LH, et al. Gastrointestinal stromal tumors of
the jejunum and ileum: a clinicopathologic, immunohistochemical, and
molecular genetic study of 906 cases before imatinib with long-term follow-
up. Am J Surg Pathol. 2006;30(4):477–489.
Miettinen M, Sobin LH, Lasota J. True smooth muscle tumors of the small

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 intestine: a clinicopathologic, immunohistochemical, and molecular genetic
study of 25 cases. Am J Surg Pathol. 2009;33(3):430–436.
Montgomery E, Torbenson MS, Kaushal M, et al. Beta-catenin
immunohistochemistry separates mesenteric fibromatosis from
gastrointestinal stromal tumor and sclerosing mesenteritis. Am J Surg Pathol.
2002;26(10):1296–1301.
Nielsen JA, Steephen A, Lewin M. Angiotensin-II inhibitor (olmesartan)-
induced collagenous sprue with resolution following discontinuation of drug.
World J Gastroenterol. 2013;19(40):6928–6930.
Nielsen OH, Riis LB, Danese S, et al. Proximal collagenous gastroenteritides:
clinical management. A systematic review. Ann Med. 2014;46(5):311–317.
O'Malley DP, Goldstein NS, Banks PM. The recognition and classification of
lymphoproliferative disorders of the gut. Hum Pathol. 2014;45(5):899–916.
Otsubo K, Kanegane H, Kamachi Y, et al. Identification of FOXP3-negative
regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with
immune dysregulation, polyendocrinopathy, enteropathy, X-linked
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Ranganathan S, Schmitt LA, Sindhi R. Tufting enteropathy revisited: the utility
of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol.
2014;38(2):265–272.
Seminerio J, McGrath K, Arnold CA, et al. Medication-associated lesions of the
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Shekitka KM, Helwig EB. Deceptive bizarre stromal cells in polyps and ulcers
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 4
Colon

4.1 Signet-ring cell change vs. Signet-ring cell carcinoma

4.2 Atypical stromal cells in polyps and ulcers vs. Sarcoma
4.3 Crohn colitis vs. Diverticular-associated colitis
4.4 Squeeze artifact vs. Ischemic colitis
4.5 Normal macrophages and foreign body granulomas vs.
Granulomas typical of Crohn disease
4.6 Melanosis coli vs. Chronic granulomatous disease
4.7 Mastocytosis vs. Collagenous colitis
4.8 Ulcerative colitis vs. Self-limiting colitis
4.9 Ulcerative colitis vs. Crohn colitis
4.10 Sexually transmitted disease–associated proctocolitis vs.
Inflammatory bowel disease
4.11 Pouchitis vs. Diversion colitis
4.12 Diversion colitis vs. Ulcerative colitis
4.13 Collagenous colitis vs. Thick basement membrane
4.14 Collagenous colitis vs. Radiation colitis
4.15 Collagenous colitis vs. Crohn colitis
4.16 Collagenous colitis vs. Amyloidosis
4.17 Amyloidosis vs. Thick basement membrane
4.18 Amyloidosis vs. Radiation colitis
4.19 Eosinophilic colitis vs. Mastocytosis
4.20 Mastocytosis vs. Langerhans cell histiocytosis
4.21 Ischemic colitis vs. Pseudomembranous colitis
4.22 Ischemic colitis vs. Thick basement membrane
4.23 Autoimmune colopathy vs. Normal colon

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4.24 Common variable immunodeficiency vs. Normal colon
4.25 Kayexalate injury vs. Cholestyramine and related bile
sequestrants
4.26 Mucosal prolapse polyps vs. Peutz-Jeghers polyps
4.27 Mucosal prolapse polyps vs. Sessile serrated adenoma
4.28 Mucosal prolapse polyps vs. Juvenile polyps
4.29 Juvenile polyps vs. Peutz-Jeghers polyps
4.30 Juvenile polyps vs. Adenomas
4.31 Juvenile polyps vs. Cronkhite-Canada polyp
4.32 Endometriosis vs. Sarcoma
4.33 Adenoma vs. Reparative changes
4.34 Colitis-associated dysplasia vs. Reactive changes
4.35 Colitis-associated dysplasia vs. Adenoma
4.36 Adenoma with invasive carcinoma vs. Pseudoinvasion
4.37 Neuroendocrine tumors vs. Colorectal carcinoma
4.38 Sessile serrated adenoma vs. Hyperplastic polyp
4.39 Sessile serrated adenoma vs. Traditional serrated adenoma
4.40 Smooth muscle tumors vs. Gastrointestinal stromal tumor
4.41 Granular cell tumor vs. Gastrointestinal stromal tumor
4.42 Ganglioneuroma vs. Schwann cell hamartoma
4.43 Neuroma vs. Schwann cell hamartoma
4.44 Perineurioma/fibroblastic polyp vs. Schwann cell hamartoma
4.45 Benign epithelioid nerve sheath tumor vs. Melanoma
4.46 Kaposi sarcoma vs. Lamina propria
4.47 Mantle cell lymphoma vs. Reactive lymphoid hyperplasia
4.48 Metastatic carcinoma vs. Colorectal carcinoma

4.1 Signet-ring cell change vs. Signet-

ring cell carcinoma
Signet-Ring Cell Change Signet-Ring Cell Carcinoma

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Age/Gender Any age; males = females Older adults (mean age 70s);
male = female
Location Any location Any location
Related to any underling Abdominal pain, alternating
Symptoms condition; can present with constipation and diarrhea,
diarrhea and abdominal pain weight loss, GI bleeding
Related to any underlying
Abdominal tenderness, positive
Signs condition; can present with
fecal occult blood test
abdominal tenderness or fever
Variant of mucinous
adenocarcinoma often
Displacement and distortion of associated with mutations in the
cells secondary to sloughing in APC, KRAS, and p53 genes; risk
Etiology the setting of mucosal damage factors include diet, ethnicity,
often seen in association with and genetic factors including
pseudomembranous colitis several inherited syndromes
such as HNPCC and familial
adenomatous polyposis (FAP)
1. Background often shows
features of pseudomembranous
colitis characterized by a 1. Minimal to no background
fibroinflammatory infiltrate inflammation unless associated
composed of neutrophils, with ulceration (Fig. 4.1.5)
mucus, and fibrin extending 2. Proliferation of dyscohesive
upward from the surface signet ring cells with enlarged,
epithelium and focal epithelial hyperchromatic nuclei with
necrosis (Fig. 4.1.1) prominent nucleoli (Fig. 4.1.6)
2. Sloughed epithelial cells 3. Malignant cells infiltrate
congregate in the lumen and through the basement
become distorted such that the membrane into the lamina
Histology intracytoplasmic mucin vacuole propria and often into the
displaces the nucleus imparting submucosa and deeper tissues;
a signet-ring cell appearance extravasated mucin with
(Figs. 4.1.2 and 4.1.3) entrapped signet ring cells
3. Signet ring cells contained within the submucosa and
within the basement membrane muscularis propria are often
of the glands; no extension into present (Fig. 4.1.7)

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 the lamina propria (Fig. 4.1.4) 4. Prominent nuclear atypia
4. Minimal nuclear atypia (Fig. (Figs. 4.1.5 and 4.1.6)
4.1.3) 5. Frequent mitoses (Fig. 4.1.8)
5. Few to no mitoses or
apoptotic bodies (Fig. 4.1.3)
An E-cadherin stain
shows loss of
An E-cadherin stain
membranous labeling.
shows intact
Most show
membranous labeling.
immunolabeling for
Cells are negative for
p53, and the Ki-67
Special p53 and Ki-67.
index is high ranging
studies Immunohistochemical
from 42% to 60%.
stains for collagen IV
Immunohistochemical
and laminin highlight
stains for collagen IV
the intact basement
and laminin show
membrane
disruption of the
basement membrane

Surgical resection with adjuvant

Specific to any underlying
Treatment chemotherapy for advanced-
etiology
stage disease
Fair to poor; prognosis related
to stage and grade of the tumor.
Most patients with signet-ring
Varies; related to any
Prognosis cell carcinoma present at an
underlying etiology
advanced stage, and many
present with lymph node
metastases

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Figure 4.1.1 Signet ring cell change. Mucosal ulceration with acute and
chronic inflammation and distortion of the residual glands with extruded signet
ring cells.

Figure 4.1.2 Signet ring cell change. Sloughed epithelial cells congregating
within the gland lumen.

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Figure 4.1.3 Signet ring cell change. Extruded signet ring cells with minimal to
no nuclear atypia.

Figure 4.1.4 Signet ring cell change. Signet ring cells contained within the
basement membrane of the gland.

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Figure 4.1.5 Signet ring cell carcinoma. Markedly atypical signet ring cells
seen in association with acute inflammation secondary to ulceration.

Figure 4.1.6 Signet ring cell carcinoma. Dyscohesive signet ring cells with
pleomorphic, hyperchromatic nuclei and prominent nucleoli.

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Figure 4.1.7 Signet-ring cell carcinoma infiltrating the muscularis propria.

Figure 4.1.8 Signet-ring cell carcinoma with marked atypia and prominent
mitoses.

4.2 Atypical stromal cells in polyps

and ulcers vs. Sarcoma

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 Sarcoma (or other
Atypical Stromal Cells in Polyps
malignant spindle cell
and Ulcers
lesions)
Age/Gender Any age; males = females Any age; any location
Location Any location Any location
Abdominal pain,
Related to any underlying etiology,
Symptoms constipation, diarrhea, GI
but often asymptomatic
bleeding
Abdominal tenderness;
Signs Related to any underlying etiology radiologic studies may
show a mass
Reactive process in which reactive Malignant transformation
fibroblasts proliferate in response to of mesenchymal
Etiology
mucosal injury; often seen in components in the bowel
association with ulcers or polyps wall
1. Proliferation of spindle
1. Bizarre; markedly atypical cells
to epithelioid cells with
characterized by nuclear enlargement,
enlarged, pleomorphic
pleomorphism, and/or
nuclei, scant to moderate
multinucleation often with prominent
cytoplasm (high N/C
nucleoli, smudgy chromatin, and
ratio), and often prominent
ample eosinophilic cytoplasm (low
nucleoli (Fig. 4.2.4)
N/C ratio) (Figs. 4.2.1 and 4.2.2)
2. Malignant cells
Histology 2. Background ulceration and acute
arranged in clusters and
inflammatory exudate with atypical
sheets that form a mass,
cells arranged in a monolayer at the
not in a monolayer (Fig.
interface between granulation tissue
4.2.5)
and necroinflammatory debris; no
3. Mitoses usually
mass formation (Fig. 4.2.3)
prominent, atypical
3. Mitoses can be present, with rare
mitoses readily identified
atypical mitotic figures
(Fig. 4.2.6)
The cell of
origin can vary,
Not generally performed.
but sarcomas
The cells are negative for
show
most immunohistochemical
Special immunolabeling
markers including keratins,
for cell type–

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studies S100, desmin, and CD117 specific markers
and show immunolabeling (e.g.,
only for vimentin leiomyosarcoma
—desmin, actin)

Surgical excision followed

Treatment None by adjuvant therapy if
indicated
Excellent, benign finding with no Variable, related to the
Prognosis
clinical significance type and stage of sarcoma

Figure 4.2.1 Atypical stromal cells (reactive). Markedly atypical cells with
enlarged nuclei, prominent nucleoli, and ample eosinophilic cytoplasm.

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Figure 4.2.2 Atypical stromal cells. Markedly atypical stromal cells with
hyperchromatic enlarged nuclei and prominent cytoplasm.

Figure 4.2.3 Atypical stromal cells at the base of an ulcer bed.

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Figure 4.2.4 Infiltrating sarcomatoid lung carcinoma with markedly atypical,
hyperchromatic cells with scant cytoplasm.

Figure 4.2.5 Leiomyosarcoma arranged as sheets of cells.

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Figure 4.2.6 Markedly atypical cells of sarcomatoid lung carcinoma with a
prominent mitosis.

4.3 Crohn colitis vs. Diverticular-

associated colitis
Diverticular-Associated
Crohn Colitis
Colitis
Typically adults (20s–30s and 60s– Older adults (60s); male =
Age/Gender
70s); no gender predominance female
Usually prominent in the proximal Restricted to sigmoid
Location
colon; rectum is often spared colon
Cramping abdominal pain,
Symptoms nonbloody diarrhea, fever, fatigue, Hematochezia is common
weight loss
Hypoalbuminemia, iron deficiency
anemia, fistulas, and stenosis;
extraintestinal manifestations affect Positive fecal occult blood
Signs the liver, eyes, and joints; endoscopic test; colonoscopy shows
features include aphthous erosions, patchy hyperemia
longitudinal ulcers, cobblestoning,

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 strictures, and fistulas
Unknown; thought to be an
immunologic disorder but
Unknown; more prevalent in
the lesions could represent
Caucasians and Ashkenazi Jews;
Etiology spread of inflammation
10% of patients have an affected
from within diverticula to
family member
adjacent mucosa of
redundant folds
1. Expansion of the lamina
propria by an
1. Focal surface epithelial injury
inflammatory infiltrate
characterized by epithelial necrosis
consisting of plasma cells,
(Fig. 4.3.1) with a mixed chronic
lymphocytes, and
inflammatory infiltrate often
eosinophils (Fig. 4.3.7)
associated with a lymphoid aggregate
2. Neutrophilic cryptitis
(aphthous ulcers) and discrete foci of
(Fig. 4.3.8) and crypt
cryptitis (neutrophils within crypts)
abscesses (Fig. 4.3.9)
(Fig. 4.3.2)
3. Basal lymphoid
2. Transmural inflammation, often
aggregates (Fig. 4.3.10)
more pronounced in the submucosa
and basal plasmacytosis
(Fig. 4.3.3)
(Fig. 4.3.11)
3. Chronic changes include crypt
Histology 4. Crypt distortion (Fig.
distortion (Fig. 4.3.4), basal
4.3.12)
plasmacytosis (Fig. 4.3.5), and
5. Focal Paneth cell
fibrosis, which extends deep into the
metaplasia is often present
lamina propria
6. Some have
4. Discontinuous involvement—
granulomatous cryptitis
areas with inflammatory changes
7. Inflammatory changes
adjacent to unaffected areas; no
are only seen in
association of inflammation with
association with
distribution of diverticula
diverticula; biopsies from
5. Rare poorly formed granulomas
rectal mucosa are
with associated chronic inflammation
histologically
(Fig. 4.3.6)
unremarkable (Figs. 4.3.13
and 4.3.14)
Not generally
performed.
Clinical history

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 Diagnosis is primarily of diverticular
based on history and disease is the
Special pathology; 70% of patients key to diagnosis.
studies are positive for the - a clue is that
anti–Saccharomyces the process is
cerevisiae antibody restricted to the
(ASCA) sigmoid colon
(unusual for
Crohn disease)

Mainstay of therapy is symptomatic

and anti-inflammatory and Antibiotics and fiber diet,
immunosuppressive therapies; as well as anti-
Treatment surgical resection is generally inflammatory therapies
avoided unless necessary for and/or surgical resection
complications including fissures, for severe cases
fistulas, obstruction
Fair; chronic incurable disease;
prognosis related to extent and
severity of complications and
Good; most cases resolve
Prognosis therapy-related side effects.
with antibiotic therapy
Increased risk of dysplasia and
adenocarcinoma associated with an
80% mortality rate

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Figure 4.3.1 Focal surface epithelial injury with erosion and associated
neutrophils in Crohn colitis.

Figure 4.3.2 Cryptitis and crypt abscesses in Crohn colitis.

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Figure 4.3.3 Marked mucosal inflammation in Crohn colitis.

Figure 4.3.4 Prominent chronic inflammation within the lamina propria with a
lymphoid aggregate and crypt distortion in Crohn colitis.

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Figure 4.3.5 Basal plasmacytosis in Crohn colitis. These plasma cells are
found between the bases of the crypts and the muscularis mucosae.

Figure 4.3.6 Mucosal granuloma in Crohn colitis.

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Figure 4.3.7 Diverticular disease-associated colitis. Marked chronic
inflammation, predominantly plasma cells, in the lamina propria.

Figure 4.3.8 Cryptitis in diverticular-associated colitis.

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Figure 4.3.9 Crypt abscess in diverticular-associated colitis.

Figure 4.3.10 Submucosal lymphoid aggregate in diverticular-associated

colitis.

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Figure 4.3.11 Marked basal plasmacytosis in diverticular-associated colitis.

Figure 4.3.12 Crypt distortion and marked chronic inflammation in

diverticular-associated colitis.

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Figure 4.3.13 Background diverticulum in diverticular-associated colitis.

Figure 4.3.14 Marked chronic inflammation and prominent lymphoid

aggregates expanding the lamina propria in diverticular-associated colitis.

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4.4 Squeeze artifact vs. Ischemic
colitis
Squeeze Artifact Ischemic Colitis
Any age; male = Usually adults (50s or older), but can occur
Age/Gender
female in children; male = female
Most common in watershed regions (e.g.,
Any location;
splenic flexure), descending colon, and
Location usually at the edges
sigmoid colon, but can occur at any
of the specimen
location; rectum is least affected
Variable; some present with abdominal
Symptoms None
pain, vomiting, bloody diarrhea
Variable; some present with abdominal
tenderness, fever, positive fecal occult
blood test; many have a history of
cardiovascular disease with signs of
peripheral vascular disease or other vascular
Signs None
diseases; barium enema shows
characteristic “thumb printing”; CT scan
can show “target lesions,” and angiography
can be used to directly identify vascular
obstruction
Mucosal damage secondary to decreased
An artifact of the blood flow often due to obstruction (e.g.,
biopsy procedure atherosclerosis, vasospasm, thrombus),
and specimen hypovolemia, and hypoperfusion (i.e., low
processing due to cardiac output). It can also occur due to
physical trauma drugs and infection. Risk factors include
Etiology
caused by the hypertension, diabetes, COPD, coronary
biopsy forceps, artery disease, abdominal surgery, use of
which displace the opioids, antihypertensives, hormone
epithelium from the replacement therapy, performance-
crypts enhancing supplements, and
immunomodulators
1. Empty crypts

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 (Fig. 4.4.1) with
displaced glands
1. Superficial mucosal necrosis with loss of
usually detached
the surface epithelium but preservation of
and adjacent to the the deep crypts (Fig. 4.4.3)
specimen and 2. Hyalinization of the lamina propria, with
appear occasional hemorrhage
histologically 3. Residual crypts are atrophic and appear
unremarkable (Fig. closer together (lamina propria “collapse”)
Histology 4.4.2) (Fig. 4.4.4)
2. No changes in the 4. Often marked regenerative atypia
lamina propria
characterized by enlarged, hyperchromatic,
3. Residual crypts
pleomorphic nuclei, prominent nucleoli, and
unaffected
loss of mucin (Fig. 4.4.5)
4. Minimal to no
5. Mitoses often conspicuous; atypical
atypia
mitoses can be seen (Fig. 4.4.6)
5. No mitoses
6. May have pseudomembranes (Fig. 4.4.7)
6. No inflammation
or
pseudomembranes
Not
Special generally Not generally performed
studies performed

Supportive care; surgical resection for

Treatment None
severe or complicated disease
Good; most resolve with supportive care,
Related to any
though a subset require surgical resection
Prognosis underlying
due to complications, including perforation,
pathology
peritonitis, and strictures

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Figure 4.4.1 Empty crypt in squeeze artifact.

Figure 4.4.2 Squeeze artifact showing empty crypt with displaced epithelium
adjacent to the crypt.

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Figure 4.4.3 Focal superficial mucosal erosion and reactive epithelial changes
in ischemic colitis.

Figure 4.4.4 Hyalinization of the lamina propria with back-to-back crypts in

ischemic colitis.

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Figure 4.4.5 Marked reactive epithelial changes in ischemic colitis.

Figure 4.4.6 Prominent reactive epithelial changes and mitoses in ischemic

colitis.

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Figure 4.4.7 Hyalinization of the lamina propria in association with a
fibrinopurulent exudate in ischemic colitis.

4.5 Normal macrophages and foreign

body granulomas vs. Granulomas
typical of Crohn disease
Normal Macrophages and Granulomas Typical of Crohn
Foreign Body Granulomas Disease
Any age; no gender Typically adults (20s–30s and 60s–
Age/Gender
predominance 70s); no gender predominance
Usually prominent in the proximal
Location Any location
colon; rectum is often spared
Usually none; some patients Cramping abdominal pain,
Symptoms may present with abdominal nonbloody diarrhea, fever, fatigue,
pain weight loss
Hypoalbuminemia, iron deficiency

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Usually none; some patients
Signs present with abdominal
tenderness
Etiology Reaction to foreign material
1. Normal macrophages:
aggregate in the superficial
lamina propria beneath the
surface epithelium (Figs.
4.5.1 and 4.5.2)
2. Aggregates of epithelioid
histiocytes mixed with
foreign body–type
multinucleated giant cells
composed of up to 20 nuclei
haphazardly arranged and
Histology often overlapping (Figs.
4.5.3 and 4.5.4)
3. Giant cells usually seen in
reaction to a ruptured crypt
but foreign material can be
seen within the aggregate of
histiocytes either with light
microscopy or under
polarized light
4. Minimal to no background
inflammation and no features
of chronicity
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anemia, fistulas, and stenosis;
extraintestinal manifestations affect
the liver, eyes, and joints;
endoscopic features include
aphthous erosions, longitudinal
ulcers, cobblestoning, strictures,
and fistulas
Unknown; more prevalent in
Caucasian and Ashkenazi Jews;
10% of patients have an affected
family member
1. Poorly formed and associated
with chronic inflammation (Fig.
4.5.5)
2. Nonnecrotizing
3. No foreign material seen
a. Background features of
Crohn disease
b. Focal surface epithelial
injury characterized by
epithelial necrosis with
a mixed chronic
inflammatory infiltrate
often associated with a
lymphoid aggregate
(aphthous ulcers) and
discrete foci of cryptitis
c. Transmural
inflammation, often
more pronounced in the
submucosa
d. Chronic changes include
crypt distortion and
fibrosis, which extends
deep into the lamina
propria
e. Discontinuous
involvement—areas
 with inflammatory
changes adjacent to
unaffected areas
Diagnosis is primarily
Not generally
based on history and
performed.
pathology; 70% of
Special Clinical history
patients are positive for
studies especially history
the anti–Saccharomyces
of surgery can be
cerevisiae antibody
important
(ASCA)

Mainstay of therapy is
symptomatic and anti-
inflammatory and
None to surgical excision for
Treatment immunosuppressive therapies;
complications
surgical resection for
complications including fissures,
fistulas, obstruction
Good; most are incidental
Chronic incurable disease;
findings; however, some are
prognosis related to extent and
associated with
severity of complications and
complications such as
Prognosis therapy-related side effects.
persistent abdominal pain,
Increased risk of dysplasia and
obstruction, or perforation
adenocarcinoma associated with an
and require surgical
80% mortality rate.
intervention

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Figure 4.5.1 Normal macrophages primarily distributed beneath the
epithelium.

Figure 4.5.2 Macrophages intermixed with lymphocytes and plasma cells in

the lamina propria of the colon.

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Figure 4.5.3 Ruptured crypt with surrounding histiocytic reaction.

Figure 4.5.4 Ruptured crypt with prominent eosinophils and foreign body giant
cell reaction.

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Figure 4.5.5 Loosely formed granuloma in Crohn disease characterized a
collection of histiocytes with associated lymphocytes.

4.6 Melanosis coli vs. Chronic

granulomatous disease
Melanosis Coli
Age/Gender Adults; male = female
Most common in the cecum and
Location
rectum; can occur in any location
Symptoms None
Signs None
Deposition of lipofuscin in
macrophages, which is most often disorder caused by mutations
seen in association with laxative in any of the genes that
use, with a particularly strong
Chronic Granulomatous
Disease
Infants to young children;
male > female (10:1)
Anywhere in the colorectum.
Findings classically
described in the lung
Recurrent bacterial and
fungal infections
Fever
Inherited immune deficiency
encode for proteins of the

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Etiology association with anthraquinone
and other laxatives that induce
apoptosis; also seen in association
with NSAID use and inflammatory
bowel disease
1. Prominent pigment-laden
macrophages within the lamina
Histology propria (Figs. 4.6.1 and 4.6.2)
2. Eosinophils not prominent
3. No abscess formation
Not generally
Special performed. The pigment
studies stains with a PAS stain
Treatment None
Excellent; incidental benign
Prognosis
finding
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superoxide-generating
phagocyte NADPH oxidase
system involved in the
elimination of organisms
ingested by neutrophils
1. Lamina propria replaced
by poorly formed granulomas
(Fig. 4.6.3) or loose clusters
of macrophages
2. Prominent eosinophils
(Fig. 4.6.4)
3. Macrophages often
pigmented (Fig. 4.6.5)
4. Rare abscess formation
Not generally
performed; clinical
history is important
(multiple
infections)
Prophylactic and infection-
specific antibiotics,
interferon gamma, bone
marrow transplantation, and
gene therapy
Poor; patients have recurrent
infections, and complications
are associated with
significant morbidity and
mortality with an average life
expectancy of 25–30 years
Figure 4.6.1 Brown-pigmented macrophages infiltrating the lamina propria
with no changes in the background mucosa of melanosis coli.

Figure 4.6.2 Dark brown to black pigmented macrophages within the lamina
propria of melanosis coli.

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Figure 4.6.3 Poorly formed granuloma composed of pigmented histiocytes in
chronic granulomatous disease.

Figure 4.6.4 Prominent eosinophils in the lamina propria in chronic

granulomatous disease.

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Figure 4.6.5 Lightly pigmented histiocytes scattered within the lamina propria
in chronic granulomatous disease.

4.7 Mastocytosis vs. Collagenous

colitis
Mastocytosis Collagenous Colitis
Typically adults (mean age 55);
Age/Gender Any age; any gender
female predominant (6–8:1)
Most prominent in the proximal
Location Any location colon; less prominent in the
rectosigmoid
Nonspecific; in systemic
mastocytosis, patients can
present with symptoms related
to increased histamine Chronic watery diarrhea,
secretion, while in localized abdominal pain, fatigue, weight
Symptoms mastocytosis, patients often loss; some may have
have chronic diarrhea; patients constipation
may present with symptoms
related to increased histamine

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 secretion
Signs None
Unknown; some cases are
associated with inflammatory
disease including allergic
disease, parasitic infections, and
eosinophilic colitis, while other
cases are manifestations of
Etiology systemic mastocytosis. So-
called "mastocytic
enterocolitis" is probably not an
entity but was described in
patients with diarrhea
predominant irritable bowel
syndrome
1. Few to no surface epithelial
changes (Fig. 4.7.1)
2. Increased mast cells with
round, basophilic nuclei and
abundant cytoplasm in the
lamina propria (Fig. 4.7.2)
Histology 3. Increased eosinophils in the
lamina propria; no infiltration
of the surface or crypt
epithelium (Fig. 4.7.3)
4. No increase in subepithelial
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Few, if any; endoscopic
evaluation is usually normal;
rarely shows linear ulcers or
pseudomembranes
Unknown; thought to be related
to an immunologic response to a
luminal antigen; up to 40% of
patients have an associated
disease, most commonly
rheumatoid arthritis, thyroid
disorders, celiac disease; some
cases are related to medications
including lansoprazole, a proton
pump inhibitor, and NSAIDs;
rare cases are associated with
procedure-related perforation
1. Surface epithelial injury
characterized by intraepithelial
lymphocytes with associated
cellular degeneration including
cytoplasmic vacuoles, mucin
loss, irregular nuclear contours,
and pyknosis (Figs. 4.7.6 and
4.7.7)
2. No increase in mast cells
3. Expansion of the lamina
propria by an infiltrate of
plasma cells and lymphocytes
and often neutrophils (in
lymphocytic colitis); increased
eosinophils within the lamina
propria and within the surface
and crypt epithelium (Fig.
4.7.8)
4. Subepithelial deposition of
collagen beneath the surface
 collagen (Fig. 4.7.1) epithelium, usually 10–30 μm,
which has an irregular lower
border and extends into the
lamina propria in association
with dilated capillaries and
fibroblasts (Figs. 4.7.7 and
4.7.9); intermittent separation of
the surface epithelium from the
basement membrane
(collagenous colitis) (Fig. 4.7.9)
Immunohistochemical
stains for CD117
(Fig. 4.7.4) or mast
cell tryptase highlight
the increased mast
A stain for CD117
cells; in cases of
highlights scattered
systemic
mast cells. The mast
mastocytosis, the
cells are negative for
mast cells will show
Special CD25. Trichrome
immunolabeling with
studies stain highlights the
CD25 (Fig. 4.7.5),
abnormal deposition
and molecular
of collagen
analysis will be
(collagenous colitis)
positive for the
(Fig. 4.7.10)
D816V KIT mutation.
Trichrome stain
shows no thickening
of the basement
membrane

Varies, from none to

Mainstay of treatment is
symptomatic and/or anti-
histamine receptor antagonists
Treatment inflammatory therapy and
and cromolyn sodium, a mast
diverting ileostomy for
cell mediator–release inhibitor
refractory disease
Generally good; some cases
Generally good; systemic
resolve spontaneously; most
disease and the prognosis is

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Prognosis related to morbidity of other cases respond well to
involvement of other sites therapy; Paneth cell metaplasia
may portend a worse prognosis

Figure 4.7.1 Systemic mastocytosis involving the lamina propria with few
surface epithelial changes and no basement membrane thickening.

Figure 4.7.2 Systemic mastocytosis. Increased mast cells within the lamina
propria.

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Figure 4.7.3 Systemic mastocytosis. Increased eosinophils within the lamina
propria.

Figure 4.7.4 Systemic mastocytosis. CKIT stain highlighting increased mast

cells within the lamina propria.

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Figure 4.7.5 Systemic mastocytosis. CD25 stain highlighting aberrant
expression by abnormal mast cells.

Figure 4.7.6 Surface epithelial injury with intraepithelial lymphocytes seen in

adjacent to a thickened basement membrane in collagenous colitis.

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Figure 4.7.7 Surface epithelial injury with prominent intraepithelial
lymphocytes and cytoplasmic vacuoles associated with a thickened basement
membrane that entraps capillaries and inflammatory cells in collagenous colitis.

Figure 4.7.8 Collagenous colitis. Mixed inflammation in the lamina propria

composed of plasma cells and prominent eosinophils in collagenous colitis.

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Figure 4.7.9 Thickened basement membrane with focal epithelial detachment
in collagenous colitis.

Figure 4.7.10 Collagenous colitis. Trichrome stain highlighting thickened

basement membrane, which extends into the lamina propria and entraps
capillaries and lymphocytes.

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4.8 Ulcerative colitis vs. Self-limiting
colitis
Self-Limiting
Ulcerative Colitis
Colitis
Typically adults (15–25 and 60s–70s); no Any age; either
Age/Gender
gender predominance gender.
Involves the rectum and extends
Location Any location
proximally
Diarrhea,
Recurrent bloody diarrhea, abdominal pain,
Symptoms hemorrhagic with
fatigue, weight loss
certain organisms.
Varies from few to fever and tachycardia
associated with toxic megacolon;
endoscopic findings are variable: active
Signs phase—erythematous, friable, granular Positive stool culture
mucosa, quiescent phase—granular mucosa
with punctate erythema and loss of haustral
folds; polyps
Inflammation
secondary to
bacterial infection
Unknown; more prevalent in Caucasians most commonly due
Etiology and Ashkenazi Jews; 25% of patients have to Campylobacter
an affected relative sp. and Aeromonas
sp. (except
enterohemorrhagic
E. coli)
1. Prominent
neutrophilic
infiltrate most
prominent in the
1. Active disease characterized by cryptitis upper half of the
(Fig. 4.8.1) and crypt abscesses (Fig. 4.8.2) lamina propria and
often in association with pseudopolyps within crypts (Figs.

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 characterized by heaps of mucosa 4.8.8–4.8.10)
surrounded by extensive ulceration (Fig. 2. No marked
4.8.3); neutrophils predominantly within increase in chronic
crypts not in the lamina propria inflammation or
Histology 2. Increased mucosal chronic inflammation basal plasmacytosis
with lymphoid aggregates often prominent 3. Preserved
at the mucosal–submucosal interface (Fig. glandular
4.8.4) and basal plasmacytosis (Fig. 4.8.5) architecture; no
3. Chronic changes include crypt distortion crypt distortion (Fig.
(Fig. 4.8.6) and background reactive and 4.8.11)
regenerative epithelial changes (Fig. 4.8.7); 4. Reactive
minimal to no fibrosis in the submucosa epithelial changes
4. Dysplasia can be seen with enlarged nuclei,
prominent nucleoli,
and mucin loss, but
no dysplasia (Fig.
4.8.12)
Not
generally
performed.
Stool
culture is
Diagnosis is primarily based on
Special often
history and pathology. Patients
studies positive,
often have p-ANCA antibodies
but may be
negative in
the setting
of viral
infection

Mainstay of therapy is symptomatic and

anti-inflammatory drugs including 5-ASA
compounds and steroids. Routine
surveillance colonoscopy to screen for
Treatment dysplasia and/or adenocarcinoma is Antibiotics
recommended for patients with extensive
disease for longer than 8 years. Surgical
resection for high-grade dysplasia or

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 adenocarcinoma
Fair; chronic incurable disease; prognosis
related to the extent and severity of
complications and therapy-related side
effects. Patients are at increased risk of Excellent; the colitis
Prognosis
dysplasia and adenocarcinoma, and there is is self-limiting
a small but measurable risk of early
mortality due to toxic colitis as well as
other complications

Figure 4.8.1 Cryptitis in ulcerative colitis.

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Figure 4.8.2 Crypt abscess in ulcerative colitis.

Figure 4.8.3 Pseudopolyp in ulcerative colitis.

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Figure 4.8.4 Marked chronic inflammation within the lamina propria with a
lymphoid aggregate at the mucosal–submucosal interface in ulcerative colitis.

Figure 4.8.5 Basal plasmacytosis in ulcerative colitis. The plasma cells are
present between the bases of the crypts and the muscularis mucosae

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Figure 4.8.6 Crypt distortion in ulcerative colitis.

Figure 4.8.7 Ulcerative colitis. Marked reactive epithelial changes

characterized by enlarged, hyperchromatic nuclei with prominent nucleoli and
mucin loss.

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Figure 4.8.8 Intraepithelial neutrophils and prominent crypt apoptosis in self-
limiting colitis.

Figure 4.8.9 Prominent inflammatory infiltrate, predominantly neutrophils, in

the upper half of the lamina propria and within glands and crypts in self-
limiting colitis.

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Figure 4.8.10 Neutrophilic infiltrate most prominent in the superficial lamina
propria directly beneath the epithelium in self-limiting colitis. The surface is at
the right.

Figure 4.8.11 No crypt distortion in self-limiting colitis.

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Figure 4.8.12 Marked reactive changes in self-limiting colitis.

4.9 Ulcerative colitis vs. Crohn colitis

Ulcerative Colitis Crohn Colitis
Typically adults (20s–30s and
Typically adults (15–25 and 60s–
Age/Gender 60s–70s); no gender
70s); no gender predominance
predominance
Usually prominent in the
Always involves the rectum and
Location proximal colon; rectum is
extends proximally
often spared
Recurrent bloody diarrhea, Cramping abdominal pain,
Symptoms abdominal pain, fatigue, weight nonbloody diarrhea, fever,
loss fatigue, weight loss
Varies from few to fever and Hypoalbuminemia, iron
tachycardia associated with toxic deficiency anemia, fistulas,
megacolon; endoscopic findings and stenosis; extraintestinal
are variable: active phase— manifestations affect the liver,
Signs erythematous, friable, granular eyes, and joints; endoscopic
mucosa; quiescent phase— features include aphthous
granular mucosa with punctate erosions, longitudinal ulcers,
erythema and loss of haustral cobblestoning, strictures, and

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 folds; polyps
Unknown; more prevalent in
Caucasians and Ashkenazi Jews;
Etiology
25% of patients have an affected
relative
1. Active disease characterized
by cryptitis (Fig. 4.9.1) and crypt
abscesses (Fig. 4.9.2) often in
association with pseudopolyps
characterized by heaps of mucosa
surrounded by extensive
ulceration (Fig. 4.9.3)
2. Increased mucosal chronic
inflammation with lymphoid
aggregates often prominent at the
mucosal–submucosal interface
(Fig. 4.9.4); inflammation
confined to the mucosa with
limited involvement of the
submucosa
Histology 3. Chronic changes include crypt
distortion (Fig. 4.9.5) and
background regenerative
epithelial changes (Fig. 4.9.6);
minimal to no fibrosis in the
submucosa
4. Continuous involvement from
the rectum extending proximally
with more severe changes in
distant regions
5. Terminal ileum often
uninvolved
6. Loss of submucosal vascular
network
7. Rectum always involved
8. Granulomas are not seen
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fistulas
Unknown; more prevalent in
Caucasian and Ashkenazi
Jews; 10% of patients have an
affected family member
1. Focal surface epithelial
injury (Fig. 4.9.7)
characterized by epithelial
necrosis with a mixed chronic
inflammatory infiltrate often
associated with a lymphoid
aggregate (aphthous ulcers)
(Fig. 4.9.8) and discrete foci
of cryptitis (neutrophils within
crypts) (Fig. 4.9.9) and crypt
abscesses (Fig. 4.9.10)
2. Transmural inflammation,
often more pronounced in the
submucosa (Fig. 4.9.11)
3. Chronic changes include
crypt distortion (Fig. 4.9.12),
basal plasmacytosis (Fig.
4.9.13), and fibrosis, which
extends deep into the lamina
propria
4. Discontinuous involvement
—areas with inflammatory
changes adjacent to unaffected
areas
5. Terminal ileum often
involved
6. Loss of submucosal
vascular network
7. Rectal sparing is common
8. Rare poorly formed
granulomas with associated
chronic inflammation (Fig.
4.9.14)
 Diagnosis is
primarily based on
Diagnosis is primarily history and
based on history and pathology; 70% of
Special pathology. Patients patients are positive
studies often have p-ANCA for the
antibodies anti–Saccharomyces
cerevisiae antibody
(ASCA)

Mainstay of therapy is
symptomatic and anti-
Mainstay of therapy is
inflammatory drugs including 5-
symptomatic and anti-
ASA compounds and steroids.
inflammatory and
Routine surveillance colonoscopy
immunosuppressive therapies;
Treatment to screen for dysplasia and/or
surgical resection is generally
adenocarcinoma is recommended
avoided unless necessary for
for patients with extensive
complications including
disease for longer than 8 years.
fissures, fistulas, obstruction
Surgical resection for high-grade
dysplasia or adenocarcinoma
Fair; chronic incurable disease;
prognosis related to the extent Fair; chronic incurable
and severity of complications and disease; prognosis related to
therapy-related side effects. extent and severity of
Patients are at increased risk of complications and therapy-
Prognosis
dysplasia and adenocarcinoma, related side effects. Increased
and there is a small but risk of dysplasia and
measurable risk of early mortality adenocarcinoma associated
due to toxic colitis as well as with an 80% mortality rate
other complications

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Figure 4.9.1 Intraepithelial neutrophils (cryptitis) in ulcerative colitis.

Figure 4.9.2 Crypt abscess in ulcerative colitis.

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Figure 4.9.3 Pseudopolyp in ulcerative colitis.

Figure 4.9.4 Marked increase in chronic inflammation within the lamina

propria with a lymphoid aggregate at the mucosal–submucosal interface and
background crypt distortion in ulcerative colitis.

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Figure 4.9.5 Crypt distortion in ulcerative colitis.

Figure 4.9.6 Reactive epithelial changes characterized by enlarged,

hyperchromatic nuclei with conspicuous nucleoli in ulcerative colitis.

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Figure 4.9.7 Focal surface erosion in Crohn colitis.

Figure 4.9.8 Aphthous ulcer consisting of a mucosal lymphoid aggregate with

an overlying erosion.

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Figure 4.9.9 Cryptitis in Crohn disease with background reactive epithelial
changes.

Figure 4.9.10 Crypt abscess in Crohn disease.

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Figure 4.9.11 Prominent chronic inflammation within the lamina propria of
Crohn disease.

Figure 4.9.12 Crypt distortion in Crohn disease.

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Figure 4.9.13 Basal plasmacytosis in Crohn disease.

Figure 4.9.14 Poorly formed mucosal granuloma in Crohn disease.

4.10 Sexually transmitted disease–

associated proctocolitis vs.
Inflammatory bowel disease

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 Sexually Transmitted Disease–
Associated Proctocolitis
Typically adults; males >
Age/Gender
females
Location Usually rectum
Anorectal pain, mucoid and/or
Symptoms bloody discharge, tenesmus,
urgency
Few, if any. A mass may be
present at endoscopy, resulting fistulas.UC: varies from few to
Signs
in a clinical impression of
neoplasm.
Inflammatory disease
associated with various
sexually transmitted infections Unknown; more prevalent in
including Neisseria
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Inflammatory Bowel Disease
Typically adults (20s–30s and
60s–70s); no gender
predominance
Crohn: usually prominent in the
proximal colon; rectum is often
sparedUC: always involves the
rectum and extends proximally
Crohn: cramping abdominal
pain, nonbloody diarrhea, fever,
fatigue, weight lossUC:
recurrent bloody diarrhea,
abdominal pain, fatigue, weight
loss
Crohn: hypoalbuminemia, iron
deficiency anemia, fistulas, and
stenosis; extraintestinal
manifestations affect the liver,
eyes, and joints; endoscopic
features include aphthous
erosions, longitudinal ulcers,
cobblestoning, strictures, and
fever and tachycardia associated
with toxic megacolon;
endoscopic findings are
variable: active phase—
erythematous, friable, and
granular mucosa; quiescent
phase—granular mucosa with
punctate erythema and loss of
haustral folds; polyps
Caucasian and Ashkenazi Jews;
Etiology gonorrhoeae (30%), Chlamydia a subset of patients have an
trachomatis (19%), Herpes affected relative
simplex (2%), and Treponema
pallidum (2%)

1. Neisseria gonorrhoeae: most

are histologically normal; some
show mild increase in
neutrophils and lymphocytes
with focal cryptitis
2. Chlamydia trachomatis
—lymphogranuloma venereum:
prominent follicular
lymphohistiocytic infiltrate and 1. Active disease characterized
plasma cell infiltrate in the by cryptitis (Fig. 4.10.4) and
mucosa and submucosa; crypt abscesses (Fig. 4.10.5)
occasional granulomatous and ulceration
inflammation; minimal crypt 2. Increased chronic
distortion, only rare crypt inflammation with prominent
abscesses, ulceration, fissuring eosinophils and prominent
ulcers, fibrosis, few eosinophils lymphoid aggregates, which can
3. Treponema pallidum: be transmural (Crohn) or limited
Histology neutrophilic cryptitis (Fig. to the mucosa (UC) (Fig.
4.10.1) with associated 4.10.6)
ulceration, granulation tissue; 3. Chronic changes include
marked lymphoplasmacytic crypt distortion (Fig. 4.10.7)
inflammation with a and fibrosis
predominance of plasma cells 4. Rare poorly formed
within the mucosa and granulomas with associated
submucosa, which is often chronic inflammation (Fig.
angiocentric (Fig. 4.10.2); 4.10.8)
occasional granulomatous 5. Dysplasia can be seen
inflammation, but few
eosinophils
4. Glandular architecture intact,
no crypt distortion
5. Reactive and regenerative
atypia can be seen, but no
dysplasia

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 Organism-specific
immunofluorescent or
immunohistochemical
Special stains can be used
studies (Fig. 4.10.3). Culture
and serologic studies
are important to
diagnosis
Diagnosis is primarily
based on history and
pathology; 70% of
patients are positive
for the
anti–Saccharomyces
cerevisiae antibody
(ASCA)

Treatment Organism-specific antibiotics
Good; most infections resolve
Prognosis
with antibiotic therapy
Mainstay of therapy is
symptomatic and anti-
inflammatory and
immunosuppressive therapies;
surgical resection is generally
avoided unless necessary for
complications including
fissures, fistulas, obstruction
Fair; chronic incurable disease;
prognosis related to extent and
severity of complications and
therapy-related side effects.
Increased risk of dysplasia
and adenocarcinoma associated
with an 80% mortality rate

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Figure 4.10.1 Prominent lymphoplasmacytic and neutrophilic infiltrate within
the lamina propria with focal cryptitis in syphilis proctitis. Note that although
there is basal plasmacytosis, there is no crypt distortion.

Figure 4.10.2 Angiocentric lymphoplasmacytic infiltrate within the lamina

propria in syphilis proctitis.

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Figure 4.10.3 Syphilis proctitis. Positive immunohistochemistry for syphilis.
Immunolabeling suffers from poor sensitivity and a negative study does not
exclude syphilis proctitis.

Figure 4.10.4 Intraepithelial neutrophils in Crohn colitis.

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Figure 4.10.5 Crypt abscess and prominent crypt distortion in ulcerative colitis.

Figure 4.10.6 Marked chronic inflammation within the lamina propria with
reactive lymphoid aggregate in ulcerative colitis.

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Figure 4.10.7 Crypt distortion in ulcerative colitis.

Figure 4.10.8 Poorly formed granuloma in Crohn disease.

4.11 Pouchitis vs. Diversion colitis

Pouchitis Diversion Colitis

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Age/Gender Adults (mean age 40s); no gender Any age; no gender
predominance predominance
Location Distal ileal pouch
Diarrhea, nausea, vomiting,
malaise abdominal pain,
Symptoms
abdominal cramps, tenesmus,
rectal bleeding
Fever, abdominal tenderness;
Signs radiologic studies may show peri-
intestinal inflammation
Unknown, though some evidence
suggests that it is related to
impaired butyrate oxidation by the
intestinal mucosa; an
inflammatory lesion that develops
most commonly in patients with
ulcerative colitis who undergo an
ileal pouch–anal anastomosis
procedure involves creating a
continent pouch from the distal
ileum that can function as a
Etiology rectum and rarely in patients who
undergo the procedure as
treatment for a neoplasm. It
occurs in approximately 50% of
patients with a continent pouch.
Risk factors include the diffuse
chronic duodenitis, presence of
severe colitis that extends into the
cecum, early fissuring ulcers,
active inflammation of the
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Bypassed or excluded
segments of bowel, usually
rectosigmoid
Most are asymptomatic;
symptoms can include
abdominal pain and mucoid
or bloody discharge
Few, if any. Radiologic
studies, specifically a double-
contrast barium enema, can
show changes consistent with
lymphoid follicular
hyperplasia characteristic of
the lesion
Unknown; thought to be
related to the absence of
luminal, short-chain fatty
acids, which alters the
microbiome of the segment
with consequent
inflammatory changes. An
inflammatory lesion that
develops in patients who
undergo surgical resection,
which is completed with a
colostomy rather than
reanastomosis of the bowel
resulting in a blind segment
of bowel with no fecal
stream. This is commonly
performed in patients with
diverticulitis and results in a
blind pouch of colon
continuous with the anus
(Hartmann pouch). Occurs in
 appendix, and appendiceal 50%–100% of all patients
ulceration with a bypassed segment of
bowel
1. Acute pouchitis is characterized 1. Prominent lymphoid
by prominent infiltration by aggregates are characteristic
neutrophils, crypt abscesses (Fig. (Fig. 4.11.6)
4.11.1), and ulceration 2. The colitis is mild, but the
2. The changes are seen in changes can not only mimic
association with chronic changes ulcerative colitis including
Histology
in the background including crypt distortion and increased
variable villous atrophy (colonic chronic inflammation within
metaplasia) (Fig. 4.11.2), the lamina propria (Fig.
plasmacytosis (Fig. 4.11.3), 4.11.7) but also Crohn disease
reactive changes (Fig. 4.11.4), and including aphthous ulcers and
crypt distortion (Fig. 4.11.5) cryptitis (Fig. 4.11.8)
Not generally
performed. Specials
stains for organisms
Not generally
including PAS/AB and
performed. Clinical
Special GMS can be important
history is critical to
studies to rule out infection.
the diagnosis
Clinical history is
important to the
differential diagnosis

Surgical reanastomosis to
First-line therapy is metronidazole
Treatment reestablish the continuity of
and/or other antibiotics
the fecal stream
Fair; pouchitis recurs in most
patients and has a relapsing– Good; most cases resolve
remitting course. The prognosis is within 3 months of
Prognosis related to long-term complications reanastomosis of the bowel
of recurrent disease that include and restoration of the normal
abscesses, fistulae, stenosis, and fecal stream
adenocarcinoma

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Figure 4.11.1 Pouchitis. Prominent infiltration of neutrophils within the crypt
in pouchitis.

Figure 4.11.2 Villous atrophy with colonic metaplasia in pouchitis.

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Figure 4.11.3 Prominent plasma cell infiltrate within the lamina propria of
pouchitis.

Figure 4.11.4 Reactive epithelial changes with enlarged, hyperchromatic nuclei

with conspicuous nucleoli seen in a background of cryptitis in pouchitis.

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Figure 4.11.5 Crypt distortion in pouchitis.

Figure 4.11.6 Prominent mucosal lymphoid aggregate in diversion colitis.

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Figure 4.11.7 Crypt distortion and marked chronic inflammation within the
lamina propria in diversion colitis.

Figure 4.11.8 Focal cryptitis in diversion colitis.

4.12 Diversion colitis vs. Ulcerative

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colitis
Diversion Colitis Ulcerative Colitis
Typically adults (15–
Age/Gender Any age; no gender predominance 25 and 60s–70s); no
gender predominance
Involves the rectum
Bypassed or excluded segments of bowel,
Location and extends
usually rectosigmoid
proximally
Recurrent bloody
Most are asymptomatic; symptoms can
diarrhea, abdominal
Symptoms include abdominal pain and mucoid or
pain, fatigue, weight
bloody discharge
loss
Varies from few to
fever and tachycardia
associated with toxic
megacolon;
Few, if any. Radiologic studies, endoscopic findings
specifically a double-contrast barium are variable: active
Signs enema, can show changes consistent with phase—erythematous,
lymphoid follicular hyperplasia friable, granular
characteristic of the lesion mucosa; quiescent
phase—granular
mucosa with punctate
erythema and loss of
haustral folds; polyps
Unknown; thought to be related to the
absence of luminal, short-chain fatty
acids, which alters the microbiome of the
segment with consequent inflammatory
changes. An inflammatory lesion that
develops in patients who undergo surgical Unknown; more
resection, which is completed with a prevalent in
colostomy rather than reanastomosis of Caucasians and
Etiology the bowel resulting in a blind segment of Ashkenazi Jews; 25%
bowel with no fecal stream. This is of patients have an

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 commonly performed in patients with affected relative
diverticulitis and results in a blind pouch
of colon continuous with the anus
(Hartmann pouch). Occurs in 50%–100%
of all patients with a bypassed segment of
bowel
1. Active disease
characterized by
cryptitis (Fig. 4.12.5)
and crypt abscesses
(Fig. 4.12.6) often in
association with
pseudopolyps
characterized by heaps
of mucosa surrounded
1. Prominent lymphoid aggregates are
by extensive
characteristic usually in a background of
ulceration (Fig.
marked chronic inflammation
4.12.7)
2. The colitis is mild but includes chronic
2. Increased mucosal
changes such as crypt distortion and
chronic inflammation
Histology increased chronic inflammation within
with lymphoid
the lamina propria (Figs. 4.12.1 and
aggregates often
4.12.2)
prominent at the
3. Acute inflammation characterized by
mucosal–submucosal
crypt abscesses (Fig. 4.12.3) and cryptitis
interface (Fig. 4.12.8)
(Fig. 4.12.4) can be seen
3. Chronic changes
include crypt
distortion (Fig.
4.12.9), basal
plasmacytosis (Fig.
4.12.10), background
reactive and
regenerative epithelial
changes (Fig. 4.12.11)
Diagnosis is
primarily
based on
Not generally performed. history and

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Special Clinical history is critical to the pathology.
studies diagnosis Patients
often have
p-ANCA
antibodies

Mainstay of therapy is
symptomatic and anti-
inflammatory drugs
including 5-ASA
compounds and
steroids. Routine
surveillance
colonoscopy to screen
Surgical reanastomosis to reestablish the
Treatment for dysplasia and/or
continuity of the fecal stream
adenocarcinoma is
recommended for
patients with
extensive disease for
longer than 8 years.
Surgical resection for
high-grade dysplasia
or adenocarcinoma
Fair; chronic incurable
disease; prognosis
related to the extent
and severity of
complications and
therapy-related side
Good; most cases resolve within 3 effects. Patients are at
Prognosis months of reanastomosis of the bowel increased risk of
and restoration of the normal fecal stream dysplasia and
adenocarcinoma, and
there is a small but
measurable risk of
early mortality due to
toxic colitis as well as
other complications

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Figure 4.12.1 Marked chronic inflammation within the lamina propria in
diversion colitis.

Figure 4.12.2 Paneth cell metaplasia in diversion colitis.

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Figure 4.12.3 Crypt abscess in diversion colitis.

Figure 4.12.4 Cryptitis in diversion colitis.

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Figure 4.12.5 Cryptitis in ulcerative colitis.

Figure 4.12.6 Crypt abscess in ulcerative colitis.

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Figure 4.12.7 Pseudopolyp in ulcerative colitis.

Figure 4.12.8 Marked mucosal chronic inflammation and reactive lymphoid

aggregate at the mucosal–submucosal interface in ulcerative colitis.

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Figure 4.12.9 Crypt distortion, increased chronic inflammation within the
lamina propria, and basal plasmacytosis in ulcerative colitis.

Figure 4.12.10 Basal plasmacytosis in ulcerative colitis.

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Figure 4.12.11 Reactive epithelial changes seen in association with cryptitis in
ulcerative colitis.

4.13 Collagenous colitis vs. Thick

basement membrane
Thick Basement
Collagenous Colitis
Membrane
Typically adults (mean age 55); female Any age; any
Age/Gender
predominant (6–8:1) gender
Most prominent in the proximal colon; less
Location Any location
prominent in the rectosigmoid
Chronic watery diarrhea, abdominal pain,
Symptoms fatigue, weight loss, some may have Nonspecific
constipation
Few, if any; endoscopic evaluation is
Signs usually normal; rarely shows linear ulcers Nonspecific
or pseudomembranes
Unknown; thought to be related to an
immunologic response to a luminal antigen;

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 up to 40% of patients have an associated Repair due to prior
disease, most commonly rheumatoid injury including
Etiology arthritis, thyroid disorders, celiac disease; ischemia, radiation,
some cases are related to medications ulcerative colitis,
including lansoprazole, a proton pump and mucosal
inhibitor, and NSAIDs; rare cases are prolapse
associated with procedure-related
perforation
1. Surface epithelial injury characterized by
1. Surface epithelial
intraepithelial lymphocytes with associated
damage and
cellular degeneration including cytoplasmic
increased
vacuoles, mucin loss, irregular nuclear
intraepithelial
contours, and pyknosis (Fig. 4.13.1)
lymphocytes not
2. Expansion of the lamina propria by an
always present (Fig.
infiltrate of plasma cells, eosinophils,
4.13.7)
lymphocytes, and often neutrophils (Fig.
2. Thickened
4.13.2)
Histology basement
3. Subepithelial deposition of collagen
membrane, 10–30
beneath the surface epithelium, usually 10–
μm (normal 2–5
30 μm, which has an irregular lower border
μm) with a smooth
and extends into the lamina propria in
lower border that
association with dilated capillaries and
does not extend into
fibroblast (Figs. 4.13.3 and 4.13.4);
and surround cells
intermittent separation of the surface
in the lamina
epithelium from the basement membrane
propria
(Fig. 4.13.5)
Trichrome
stain
Trichrome stain highlights the highlights
Special abnormal deposition of collagen the
studies (Fig. 4.13.6) thickened
basement
membrane

Varies, from none to symptomatic and/or Varies; depends on

Treatment anti-inflammatory therapy and diverting the underlying
ileostomy for refractory disease condition
Generally good; some cases resolve

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 spontaneously; most other cases respond Related to the
Prognosis well to therapy; Paneth cell metaplasia may underlying
portend a worse prognosis pathology

Figure 4.13.1 Surface epithelial injury in collagenous colitis showing surface

erosion and prominent intraepithelial lymphocytes.

Figure 4.13.2 Expansion of the lamina propria by a chronic inflammatory

infiltrate with scattered neutrophils and eosinophils in collagenous colitis.

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Figure 4.13.3 Markedly thickened basement membrane with entrapped
capillaries in collagenous colitis.

Figure 4.13.4 Markedly thickened basement membrane with entrapped

lymphocytes and capillaries in collagenous colitis.

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Figure 4.13.5 Focal epithelial erosion in collagenous colitis.

Figure 4.13.6 Collagenous colitis. Trichrome stain highlighting a thickened

basement with a lacy appearance entrapping capillaries and inflammatory
cells.

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Figure 4.13.7 Thickened basement membrane in Hirschsprung disease with no
surface epithelial damage of intraepithelial inflammation.

4.14 Collagenous colitis vs. Radiation

colitis
Collagenous Colitis
Typically adults (mean age 55);
Age/Gender
female predominant (6–8:1)
Most prominent in the proximal
Location colon; less prominent in the
rectosigmoid
Chronic watery diarrhea,
Symptoms abdominal pain, fatigue, weight
loss; some may have constipation
Few, if any; endoscopic
evaluation is usually normal;
Radiation Colitis
Typically adults, older men
and middle-aged women
Most common in the rectum;
often most prominent in the
submucosa, but can affect all
layers of the bowel wall
Acute—nonspecific, few if
any; chronic, diarrhea,
abdominal pain, and rectal
bleeding
Acute—endoscopy shows
edema of the mucosa with loss
of the usual vascular pattern;

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Signs rarely shows linear ulcers or
pseudomembranes
Unknown; thought to be related
to an immunologic response to a
luminal antigen; up to 40% of
patients have an associated
disease, most commonly
rheumatoid arthritis, thyroid
Etiology
disorders, celiac disease; some
cases are related to medications
including lansoprazole, a proton
pump inhibitor, and NSAIDs;
rare cases are associated with
procedure-related perforation
1. Surface epithelial injury
characterized by intraepithelial
lymphocytes (Fig. 4.14.1) with
associated cellular degeneration
including cytoplasmic vacuoles,
mucin loss, irregular nuclear
contours, and pyknosis
2. Expansion of the lamina
propria by an infiltrate of plasma
cells, eosinophils, lymphocytes,
and often neutrophils (Fig.
4.14.2)
Histology 3. Minimal to no crypt distortion
4. Subepithelial deposition of
collagen beneath the surface
epithelium, usually 10–30 μm,
which has an irregular lower
border and extends into the
lamina propria in association
with dilated capillaries and
fibroblasts (Figs. 4.14.3–4.14.5);
intermittent separation of the
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chronic—endoscopy shows
erythema and can show ulcers,
strictures, fistulas, and
adhesions
Injury due to radiation, which
occurs immediately after or
years later, commonly related
to treatment for cervical and
prostate cancer
1. Acute—changes primarily
in epithelial cells; increased
apoptosis with nuclear
pyknosis (Fig. 4.14.7) and
karyorrhexis (Fig. 4.14.8),
enlarged nuclei, and loss of
mucin (Fig. 4.14.9)
2. Chronic—changes in
epithelial cells and
mesenchymal cells;
hyalinization of the lamina
propria with back-to-back
glands (Fig. 4.14.10) and
vessels, which are aligned
parallel to the basement
membrane. Atypical
fibroblasts, telangiectasias
(Fig. 4.14.11), and
phlebosclerosis. Atrophy of
the muscularis propria. Crypt
distortion
3. No expansion of the lamina
 surface epithelium from the propria by an inflammatory
basement membrane infiltrate
Clinical history is
important to
document radiation
Trichrome stain treatment. PAS stain
highlights the abnormal highlights the
Special
deposition of collagen collagen within the
studies
(Fig. 4.14.6) lamina propria, but
stains less intensely
than in collagenous
colitis

Acute colitis often resolves

Varies, from none to symptomatic
spontaneously; chronic colitis
and/or anti-inflammatory therapy,
Treatment is treated with steroids and
and diverting ileostomy for
laser therapy; severe cases
refractory disease
require surgery
Acute radiation colitis self-
Generally good; some cases
limiting and reversible over
resolve spontaneously; most
several months; chronic
Prognosis other cases respond well to
radiation colitis is irreversible
therapy; Paneth cell metaplasia
and persists without surgical
may portend a worse prognosis
intervention

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Figure 4.14.1 Marked intraepithelial lymphocytes in collagenous colitis.

Figure 4.14.2 Marked mixed acute and chronic inflammation in the lamina
propria of collagenous colitis.

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Figure 4.14.3 Thickened basement membrane and prominent chronic
inflammation within the lamina propria in collagenous colitis.

Figure 4.14.4 Thickened basement membrane encircling capillaries and

inflammatory cells in collagenous colitis.

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Figure 4.14.5 Detached superficial epithelium in collagenous colitis.

Figure 4.14.6 Collagenous colitis. Trichrome stain in collagenous colitis

highlighting the thickened basement membrane, which entraps capillaries and
inflammatory cells.

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Figure 4.14.7 Marked apoptosis and nuclear pyknosis in the crypts of radiation
colitis.

Figure 4.14.8 Karyorrhectic debris in the lumen of a gland in radiation colitis.

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Figure 4.14.9 Reactive changes of radiation colitis with enlarged,
hyperchromatic cells and loss of mucin.

Figure 4.14.10 Hyalinization of the lamina propria with back-to-back glands in

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radiation colitis.

Figure 4.14.11 Telangiectasias in the lamina propria of radiation colitis.

4.15 Collagenous colitis vs. Crohn

colitis
Collagenous Colitis
Typically adults (mean age 55);
Age/Gender
female predominant (6–8:1)
Most prominent in the proximal
Location colon; less prominent in the
rectosigmoid
Chronic watery diarrhea,
Symptoms abdominal pain, fatigue, weight nonbloody diarrhea, fever,
loss; some may have constipation fatigue, weight loss
Crohn Colitis
Typically adults (20s–30s and
60s–70s); no gender
predominance
Any part of the GI tract;
usually prominent in the
proximal colon; rectum is
often spared
Cramping abdominal pain,
Hypoalbuminemia, iron
deficiency anemia, fistulas,
and stenosis; extraintestinal

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 Few, if any; endoscopic
Signs evaluation is usually normal;
rarely shows linear ulcers or
pseudomembranes
Unknown; thought to be related to
an immunologic response to a
luminal antigen; up to 40% of
patients have an associated
disease, most commonly
rheumatoid arthritis, thyroid
Etiology
disorders, celiac disease; some
cases are related to medications
including lansoprazole, a proton
pump inhibitor, and NSAIDs; rare
cases are associated with
procedure-related perforation
1. Surface epithelial injury
characterized by intraepithelial
lymphocytes with associated
cellular degeneration including
cytoplasmic vacuoles, mucin loss,
irregular nuclear contours, and
pyknosis (Fig. 4.15.1)
2. Expansion of the lamina
propria by an infiltrate of plasma
cells, eosinophils, lymphocytes,
and often neutrophils (Fig.
4.15.2)
Histology 3. Minimal to no crypt distortion
4. Subepithelial deposition of
collagen beneath the surface
epithelium, usually 10–30 μm,
which has an irregular lower
border and extends into the upper
lamina propria in association with
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manifestations affect the liver,
eyes, and joints; endoscopic
features include aphthous
erosions, longitudinal ulcers,
cobblestoning, strictures, and
fistulas
Unknown; more prevalent in
Caucasian and Ashkenazi
Jews; 10% of patients have an
affected family member
1. Focal surface epithelial
injury characterized by
epithelial necrosis with a
mixed chronic inflammatory
infiltrate often associated with
a lymphoid aggregate
(aphthous ulcers) and discrete
foci of crypt abscesses (Fig.
4.15.5) and cryptitis (Fig.
4.15.6)
2. Transmural inflammation,
often more pronounced in the
submucosa (Fig. 4.15.7)
3. Chronic changes include
crypt distortion (Fig.
4.15.8), basal plasmacytosis
(Fig. 4.15.9), and fibrosis
which extends deep into the
lamina propria
 dilated capillaries and fibroblasts
(Fig. 4.15.3); intermittent
separation of the surface
epithelium from the basement
membrane
5. Terminal ileum uninvolved
Trichrome stain
Special highlights the abnormal
studies deposition of collagen
(Fig. 4.15.4)
Varies, from none to symptomatic
and/or anti-inflammatory
Treatment
therapy and diverting ileostomy
for refractory disease
Generally good; some cases
resolve spontaneously; most other
Prognosis cases respond well to therapy;
Paneth cell metaplasia may
portend a worse prognosis
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4. Discontinuous involvement
—areas with inflammatory
changes adjacent to
unaffected areas
5. Terminal ileum often
involved
Diagnosis is
primarily based on
history and
pathology; 70% of
patients are positive
for the
anti–Saccharomyces
cerevisiae antibody
(ASCA)
Mainstay of therapy is
symptomatic and anti-
inflammatory and
immunosuppressive therapies;
surgical resection for
complications including
fissures, fistulas, obstruction
Chronic incurable disease;
prognosis related to extent
and severity of complications
and therapy-related side
effects. Increased risk of
dysplasia and
adenocarcinoma associated
with an 80% mortality rate
Figure 4.15.1 Prominent intraepithelial lymphocytes and focal apoptosis in
collagenous colitis.

Figure 4.15.2 Mixed acute and chronic inflammation in the lamina propria of
collagenous colitis.

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Figure 4.15.3 Thickened subepithelial basement membrane with extension into
the lamina propria and prominent chronic inflammation of collagenous colitis.

Figure 4.15.4 Collagenous colitis. Trichrome stain showing thickened

basement membrane with extension into the lamina propria and entrapment of
capillaries and inflammatory cells in collagenous colitis.

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Figure 4.15.5 Crypt abscess in Crohn colitis.

Figure 4.15.6 Cryptitis in Crohn colitis.

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Figure 4.15.7 Marked chronic inflammation diffusely distributed within the
lamina propria of Crohn colitis.

Figure 4.15.8 Crypt distortion seen as branching crypts in Crohn colitis.

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Figure 4.15.9 Basal plasmacytosis in Crohn colitis.

4.16 Collagenous colitis vs.

Amyloidosis
Collagenous Colitis Amyloidosis
Typically adults (mean age 55); female
Age/Gender Any age
predominant (6–8:1)
Most prominent in the proximal colon;
Location Any location
less prominent in the rectosigmoid
Usually asymptomatic;
Chronic watery diarrhea, abdominal
some present with
Symptoms pain, fatigue, weight loss; some may
abdominal pain and
have constipation
rectal bleeding
Few, endoscopy any
Few, if any; endoscopic evaluation is
show erythema,
Signs usually normal; rarely shows linear
petechiae, nodularity,
ulcers or pseudomembranes
and/or ulceration
Unknown; thought to be related to an
immunologic response to a luminal Deposition of
abnormal amyloid

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 antigen; up to 40% of patients have an protein due to various
associated disease, most commonly causes including
Etiology rheumatoid arthritis, thyroid disorders, advance age,
celiac disease; some cases are related to malignancy, chronic
medications including lansoprazole, a inflammation, dialysis,
proton pump inhibitor, and NSAIDs; rare and plasma cell
cases are associated with procedure- neoplasm
related perforation
1. Few if any changes
1. Surface epithelial injury characterized in epithelial cells (Fig.
by intraepithelial lymphocytes with 4.16.6)
associated cellular degeneration 2. Minimal to no
including cytoplasmic vacuoles, mucin inflammation
loss, irregular nuclear contours, and 3. Deposits of
pyknosis (Fig. 4.16.1) acellular, eosinophilic
2. Expansion of the lamina propria by an material in all parts of
infiltrate of plasma cells, eosinophils, the bowel wall
lymphocytes, and often neutrophils (Fig. including the lamina
Histology 4.16.2) propria, muscularis
3. Subepithelial deposition of collagen mucosae, submucosa,
beneath the surface epithelium, usually and vessel walls (Figs.
10–30 μm, which has an irregular lower 4.16.7 and 4.16.8)
border and extends into the lamina 4. Not limited to
propria in association with dilated lamina propria; can be
capillaries and fibroblasts (Figs. 4.16.3 transmural
and 4.16.4); intermittent separation of 5. Occasionally
the surface epithelium from the basement thickened basement
membrane membrane; if present,
does not entrap nuclei
Congo red
stain
highlights
amyloid,
which shows
apple green
Trichrome stain highlights the birefringence
Special abnormal deposition of under
studies collagen (Fig. 4.16.5) polarized

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 light (Fig.
4.16.9).
Trichrome
stain is
negative

Systemic amyloidosis
Varies, from none to symptomatic and/or is treated with
Treatment anti-inflammatory therapy and diverting alkylating agents;
ileostomy for refractory disease localized amyloidosis
requires no treatment
Systemic amyloidosis
has a poor prognosis
due to complications
Generally good; some cases resolve
of amyloid deposition
spontaneously; most other cases respond
Prognosis in the heart, liver, and
well to therapy; Paneth cell metaplasia
lungs. Localized
may portend a worse prognosis
amyloidosis is
generally benign and
has a good prognosis

Figure 4.16.1 Intraepithelial lymphocytes in collagenous colitis.

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Figure 4.16.2 Mixed acute and chronic inflammation in the lamina propria in
collagenous colitis.

Figure 4.16.3 Thickened subepithelial basement membrane and prominent

chronic inflammation in the lamina propria of collagenous colitis.

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Figure 4.16.4 Thickened basement membrane with extension into the lamina
propria and entrapment of lymphocytes and capillaries in collagenous colitis.

Figure 4.16.5 Trichrome stain showing thickened basement membrane

extending into the lamina propria and entrapping capillaries and inflammatory
cells in collagenous colitis.

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Figure 4.16.6 Amyloidosis. Background mucosa with vascular congestion but
otherwise minimal to no epithelial changes.

Figure 4.16.7 Amyloid deposition within the lamina propria.

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Figure 4.16.8 Amyloid deposition within submucosal vessels.

Figure 4.16.9 Congo red stain highlights amyloid deposition within vessel
walls.

4.17 Amyloidosis vs. Thick basement

membrane

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 Thick Basement
Amyloidosis
Membrane
Age/Gender Any age Any age; any gender
Location Any location Any location
Usually asymptomatic; some present
Symptoms Nonspecific
with abdominal pain and rectal bleeding
Few; endoscopy may show erythema,
Signs Nonspecific
petechiae, nodularity, and/or ulceration
Repair due to prior
Deposition of abnormal amyloid protein
injury including
due to various causes including advance
Etiology ischemia, radiation,
age, malignancy, chronic inflammation,
ulcerative colitis, and
dialysis, and plasma cell neoplasm
mucosal prolapse
1. Deposits of acellular, eosinophilic
material in all parts of the bowel wall
including the lamina propria, muscularis
1. Thickened basement
mucosae, submucosa, and vessel walls
membrane, 10–30 μm
(Figs. 4.17.1 and 4.17.2)
Histology (normal 2–5 μm) with
2. Affects lamina propria, but can be
a smooth lower border
transmural
(Fig. 4.17.4)
3. Occasionally thickened basement
membrane; if present, does not entrap
nuclei
Trichrome
stain
highlights
Congo red stain highlights
the
amyloid, which shows apple
thickened
Special green birefringence under
basement
studies polarized light (Fig. 4.17.3).
membrane.
Trichrome stain is negative
Congo red
stain is
negative

Systemic amyloidosis is treated with

Varies; depends on the
Treatment alkylating agents; localized amyloidosis
underlying condition
requires no treatment

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 requires no treatment
Systemic amyloidosis has a poor
prognosis due to complications of
amyloid deposition in the heart, liver, Related to the
Prognosis
and lungs. Localized amyloidosis is underlying pathology
generally benign and has a good
prognosis

Figure 4.17.1 Thickened vessel within the lamina propria due to amyloid
deposition.

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Figure 4.17.2 Amyloid deposition within a vessel wall appearing as hard glass.

Figure 4.17.3 Congo red stain highlighting amyloid within the vessel wall.

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Figure 4.17.4 Thickened basement membrane in Hirschsprung disease with no
surface epithelial damage of intraepithelial inflammation.

4.18 Amyloidosis vs. Radiation colitis

Amyloidosis Radiation Colitis
Typically adults, older men and middle-
Age/Gender Any age
aged women
Most common in the rectum; often most
Location Any location prominent in the submucosa, but can
affect all layers of the bowel wall
Usually asymptomatic;
Acute—nonspecific, few if any; chronic
some present with
Symptoms —diarrhea, abdominal pain, and rectal
abdominal pain and
bleeding
rectal bleeding
Acute—endoscopy shows edema of the
Few; endoscopy may
mucosa with loss of the usual vascular
show erythema,
Signs pattern; chronic—endoscopy shows
petechiae, nodularity,
erythema and can show ulcers, strictures,
and/or ulceration
fistulas, and adhesions
Deposition of

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 abnormal amyloid
protein due to various Injury due to radiation, which occurs
causes including immediately after or years later;
Etiology
advance age, commonly related to treatment for
malignancy, chronic cervical and prostate cancer
inflammation, dialysis,
and plasma cell
neoplasm
1. Deposits of
Two forms—acute and chronic:
acellular, eosinophilic
1.Acute—changes primarily in epithelial
material (Fig. 4.18.1)
cells; increased apoptosis with nuclear
2. Affects lamina
pyknosis and karyorrhexis, enlarged
propria, as well all
nuclei, and loss of mucin (Fig. 4.18.4)
parts of the bowel wall
2. Chronic—changes in epithelial cells
including the lamina
and mesenchymal cells; hyalinization of
propria, muscularis
Histology the lamina propria with back-to-back
mucosae, submucosa,
glands (Fig. 4.18.4) and vessels, which
and vessel walls, and
are aligned parallel to the basement
can be transmural (Fig.
membrane. Atypical fibroblasts,
4.18.2)
telangiectasias (Fig. 4.18.5), and
3. Minimal to no crypt
phlebosclerosis. Atrophy of the
distortion
muscularis propria. Crypt distortion (Fig.
4. Telangiectasias are
4.18.6)
absent
Congo red
stain
highlights
amyloid,
which shows
apple green
birefringence Clinical history is important to
under document radiation treatment.
polarized PAS stain highlights the
Special light (Fig.
studies collagen within the lamina
4.18.3). propria. Congo red stain is
Trichrome negative
stain is
negative. No

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 history of
prior
radiation
therapy

Systemic amyloidosis
Acute colitis often resolves
is treated with
spontaneously; chronic colitis is treated
Treatment alkylating agents;
with steroids and laser therapy; severe
localized amyloidosis
cases require surgery
requires no treatment
Systemic amyloidosis
has a poor prognosis
due to complications
Acute radiation colitis self-limiting and
of amyloid deposition
reversible over several months; chronic
Prognosis in the heart, liver, and
radiation colitis is irreversible and
lungs. Localized
persists without surgical intervention
amyloidosis is
generally benign and
has a good prognosis

Figure 4.18.1 Amorphous acellular eosinophilic material consistent with

amyloid.

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Figure 4.18.2 Amyloid deposition in the deep mucosa and submucosa.

Figure 4.18.3 Congo red stain highlighting amyloid deposition in the

submucosa.

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Figure 4.18.4 Radiation colitis. Hyalinization of the lamina propria and
“collapse” with back-to-back glands.

Figure 4.18.5 Telangiectasias of the lamina propria and focal superficial

epithelial detachment in radiation colitis.

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Figure 4.18.6 Focal crypt distortion and hyalinization of the lamina propria in
radiation colitis.

4.19 Eosinophilic colitis vs.

Mastocytosis
Eosinophilic Colitis Mastocytosis
Age/Gender Any age Any age; any gender
Any location; gastrointestinal
Location Any location
involvement usually in colon
Nonspecific; in systemic
mastocytosis, patients can present
with symptoms related to increased
histamine secretion, while in localized
Symptoms None
mastocytosis, patients often have
chronic diarrhea. Patients may present
with symptoms related to increased
histamine secretion
Signs None None
Varies; some cases are

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 related to allergic disease,
but increased eosinophils
can also be seen in
Etiology
association with IBD,
medications, parasitic
infections, mastocytosis,
and Langerhans cell
histiocytosis
1. Increased
intraepithelial eosinophils
or eosinophils within the
lamina propria or
Histology
muscularis mucosae
(Figs. 4.19.1 and 4.19.2)
2. No increase in mast
cells (Fig. 4.19.3)
CD117 and
mast cell
tryptase stains
Special
show no
studies
increase in mast
cells
Unknown; some cases are associated
with inflammatory disease including
allergic disease, parasitic infections,
and eosinophilic colitis, while other
cases are manifestations of systemic
mastocytosis
1. Increased mast cells with round,
basophilic nuclei and abundant
cytoplasm in the lamina propria (Figs.
4.19.4 and 4.19.5)
2. Increased eosinophils in the lamina
propria
Immunohistochemical
stains for CD117 (Fig.
4.19.6) or mast cell tryptase
highlight the increased mast
cells; in cases of systemic
mastocytosis, the mast cells
show immunolabeling with
CD25 (Fig. 4.19.7), and
molecular analysis will be
positive for the D816V KIT
mutation

Mainstay of treatment is histamine

Related to any underlying receptor antagonists and cromolyn
Treatment
condition sodium; a mast cell mediator–release
inhibitor
Related to any underlying Related to any other pathology
Prognosis
condition present in the specimen

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Figure 4.19.1 Increased eosinophils within the lamina propria in eosinophilic
colitis.

Figure 4.19.2 Eosinophilic colitis. Markedly increased eosinophils within the

lamina propria and within glands.

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Figure 4.19.3 Eosinophilic colitis. Increased inflammation within the lamina
propria consists predominantly of eosinophils but also of lymphocytes and
plasma cells, but no increase in mast cells.

Figure 4.19.4 Systemic mastocytosis involving the lamina propria.

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Figure 4.19.5 Increased mast cells within the lamina propria.

Figure 4.19.6 CKIT staining highlighting an increase in mast cells within the
lamina propria.

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Figure 4.19.7 CD25 stain showing aberrant expression by neoplastic mast
cells.

4.20 Mastocytosis vs. Langerhans cell

histiocytosis
Langerhans Cell
Mastocytosis
Histiocytosis
Primarily children, but also
Age/gender Any age; any gender adults; no gender
predominance
Location Any location Any location
Nonspecific; in systemic
mastocytosis, patients can present
with symptoms related to increased
histamine secretion, while in
localized mastocytosis, patients
Nonspecific; abdominal
often have chronic diarrhea.
Symptoms pain, diarrhea, GI
Patients may present with
bleeding, weight loss
symptoms related to increased
histamine secretion. So called
"mastocytic enterocolitis" has been
debunked and describes nonspecific
findings.

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Signs None
Unknown; some cases are
associated with inflammatory
disease including allergic disease,
Etiology parasitic infections, and
eosinophilic colitis, while other
cases are manifestations of
systemic mastocytosis
1. Increased mast cells with oval,
basophilic nuclei and abundant
cytoplasm in the lamina propria
Histology
(Figs. 4.20.1 and 4.20.2)
2. Increased eosinophils in the
lamina propria (Fig. 4.20.3)
Immunohistochemical
stains for CD117 (Fig.
4.20.4) or mast cell
tryptase highlight the
increased mast cells; in
cases of systemic
mastocytosis, the mast
Special cells will show
studies immunolabeling with
CD25 (Fig. 4.20.5), and
molecular analysis will
be positive for the D816V
KIT mutation. Stains for
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Few; endoscopy may show
edema, erythema, or
ulceration in children. Most
adults present with polyps
discovered at colonoscopy.
Unknown; due to
unregulated proliferation or
improved survival of
macrophage-like cells
similar to antigen-presenting
cells. Up to 57% of cases
have a mutation in the BRAF
gene
1. Infiltrate of macrophages
with “boomerang”-shaped
nuclei in the lamina propria
and submucosa (Figs. 4.20.6
and 4.20.7)
2. Background inflammatory
infiltrate predominantly of
eosinophils, but also T
lymphocytes and giant cells
(Fig. 4.20.8)
The infiltrating
cells show
immunolabeling
for S100 (Fig.
4.20.9), CD1a
(Fig. 4.20.10), and
CD68 (Fig.
4.20.11). Electron
microscopy,
though generally
not performed,
shows
characteristic
intracytoplasmic
Birbeck granules.
 S100 and CD1a are Stains for CD117
negative and mast cell
tryptase are
negative

Varies, depending on the

Mainstay of treatment is histamine
receptor antagonists and cromolyn
Treatment
sodium, a mast cell mediator–
release inhibitor
Related to any other pathology
Prognosis
present in the specimen
extent and systemic
distribution of disease.
Standard therapy includes
steroids and other
immunosuppressive and
chemotherapeutic agents
including vinblastine and
mercaptopurine
Varies; in adults, LCH is
usually an isolated finding
with few clinical
manifestations; in children,
LCH is often systemic, and
the prognosis is determined
by the extent of involvement
of extraintestinal organs.
Most patients have a chronic
course though a subset
achieves remission

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Figure 4.20.1 Systemic mastocytosis involving the lamina propria.

Figure 4.20.2 Systemic mastocytosis. Increased mast cells within the lamina
propria.

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Figure 4.20.3 Systemic mastocytosis. Increased eosinophils within the lamina
propria.

Figure 4.20.4 Systemic mastocytosis. CKIT stain highlighting increased mast

cells within the lamina propria.

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Figure 4.20.5 Systemic mastocytosis. CD25 stain highlighting aberrant
expression by neoplastic mast cells.

Figure 4.20.6 Langerhans cell histiocytosis involving the submucosa.

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Figure 4.20.7 Langerhans cell histiocytosis. Proliferation of macrophages with
“boomerang”-shaped nuclei in a background of eosinophils.

Figure 4.20.8 Langerhans cell histiocytosis. Abundant background

inflammation composed primarily of eosinophils with scattered lymphocytes.

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Figure 4.20.9 Langerhans cell histiocytosis. S100 stain highlighting malignant
cells in LCH.

Figure 4.20.10 Langerhans cell histiocytosis. CD1a stain highlighting

malignant cells in LCH.

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Figure 4.20.11 Langerhans cell histiocytosis. CD68 stain highlighting
malignant cells in LCH.

4.21 Ischemic colitis vs.

Pseudomembranous colitis
Pseudomembranous
Ischemic Colitis
Colitis
Typically older
Typically older adults; also occurs in
Age/Gender adults; no gender
younger patients; no gender predominance
predominance
Localized and segmental; splenic flexure is
Any location; rectum
commonly affected as well as the ileocecal
Location less commonly
region (“watershed” regions); rectum is
affected
least affected
Profuse watery
Abdominal pain, hematochezia, vomiting, diarrhea, abdominal
Symptoms
fever pain, cramping,
fever
Nonspecific, fever,
leukocytosis; in

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 Most are radiologic—barium enema shows severe cases, CT
“thumb printing,” and CT scan shows scan shows toxic
Signs
“target lesions.” Angiography is key to megacolon.
diagnosis Endoscopy often
shows diffuse
pseudomembranes
Injury due to reduced blood flow, which is
most commonly due to vascular occlusion Most commonly due
secondary to atherosclerotic mesenteric to overgrowth of C.
vascular disease, but also occurs in the difficile usually
setting of reduced cardiac output and related to antibiotic
splanchnic constriction. Other cases are use, particularly
Etiology
related to infections including clindamycin. Other
enterohemorrhagic E. coli and C. difficile. cases are related to
Risk factors include hypertension, diabetes, other infective
COPD, atherosclerosis, abdominal surgery, organisms or
antihypertensives, hormone replacement ischemia
therapy, and other medications
1. Intercrypt necrosis
with ballooned
crypts containing
aggregates of
neutrophils and
1. Necrosis of the mucosa, often
mucin, which project
predominantly of the superficial mucosa
into the lumen as
with subsequent detachment from the
pseudomembranes
underlying mucosa and submucosa (Fig.
(Figs. 4.21.7 and
4.21.1)
4.21.8)
2. Focal pseudomembranes composed of
2. Diffuse
fibrin, mucin, and neutrophils (Fig. 4.21.2)
pseudomembranes
3. Hemorrhage with hemosiderin-laden
composed of fibrin,
macrophages in the lamina propria
mucin, and
4. Intravascular fibrin thrombi, highly
Histology neutrophils (Fig.
suggestive of enterohemorrhagic E. coli
4.21.9)
infection
3. Minimal crypt
5. Crypt atrophy (Fig. 4.21.3)
atrophy (Fig.
6. Hyalinization of the lamina propria
4.21.10)
resulting in the glands appearing closer
4. No hyalinization
together (Figs. 4.21.4 and 4.21.5)

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 7. Variable cellular atypia characterized by of the lamina propria
enlarged, hyperchromatic nuclei (Fig. (Fig. 4.21.11)
4.21.6) 5. Histologic
8. Histologic changes are segmental changes are diffuse
with
pseudomembranes
distributed along the
length of the colon
(Fig. 4.21.12)
Clinical
history is
usually
remarkable
for a
history of
antibiotic
use. Stool
toxin
studies are
Trichrome stain highlights
Special often
collagen deposition in the lamina
studies positive
propria
for C.
difficile.
Trichrome
stain is
negative
for
increased
collagen in
the lamina
propria

Oral antibiotic
therapy with
vancomycin or
metronidazole,
Supportive care and surgical resection for combined with
Treatment severe disease and complications cessation of any

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 other antibiotics
thought to have
precipitated the
infection, and
supportive care
Varies; depending on
the underlying
etiology. Most
patients with C.
Varies; depends on the underlying etiology.
difficile
Up to 30% of cases resolve with time;
pseudomembranous
Prognosis some patients develop complications
colitis respond to
including perforation, peritonitis, and
antibiotic therapy,
stricture formation
though some have
prolonged infection
requiring long-term
therapy

Figure 4.21.1 Focal mucosal necrosis with detachment of the superficial

epithelium in ischemic colitis.

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Figure 4.21.2 Focal pseudomembrane composed of fibrin and neutrophils at
the epithelial surface and prominent reactive epithelial changes in ischemic
colitis.

Figure 4.21.3 Crypt atrophy in ischemic colitis.

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Figure 4.21.4 Hyalinization of the lamina propria and focal reactive changes in
ischemic colitis.

Figure 4.21.5 Hyalinization of the lamina propria with “back-to-back”–

appearing glands in ischemic colitis.

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Figure 4.21.6 Marked reactive epithelial changes in a background of acute
inflammation in ischemic colitis.

Figure 4.21.7 Pseudomembrane in pseudomembranous colitis.

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Figure 4.21.8 Pseudomembranous colitis. Intercrypt necrosis with ballooned
crypt containing aggregates of neutrophils and fibrin.

Figure 4.21.9 Pseudomembrane exudate composed of neutrophils, fibrin, and

necrotic cells.

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Figure 4.21.10 Minimal to no crypt distortion in pseudomembranous colitis.

Figure 4.21.11 No hyalinization of the lamina propria in pseudomembranous

colitis.

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Figure 4.21.12 Pseudomembranes distributed along the length of the colon.

4.22 Ischemic colitis vs. Thick

basement membrane
Thick Basement
Ischemic Colitis
Membrane
Typically older adults; also occurs in Any age; any
Age/Gender
younger patients; no gender predominance gender
Localized and segmental; splenic flexure is
commonly affected as well as the ileocecal
Location Any location
region (“watershed” regions); rectum is
least affected
Abdominal pain, hematochezia, vomiting,
Symptoms Nonspecific
fever
Most are radiologic—barium enema shows
“thumb printing,” and CT scan shows
Signs Nonspecific
“target lesions.” Angiography is key to
diagnosis
Injury due to reduced blood flow, which is

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 most commonly due to vascular occlusion Repair due to prior
secondary to atherosclerotic mesenteric injury including
vascular disease, but also occurs in the ischemia, radiation,
setting of reduced cardiac output and ulcerative colitis,
Etiology splanchnic constriction. Other cases are and mucosal
related to infections including prolapse or simply
enterohemorrhagic E. coli and C. difficile. an artifact of
Risk factors include hypertension, diabetes, tangential
CIOD, atherosclerosis, abdominal surgery, embedding.
antihypertensives, hormone replacement
therapy, and other medications
1. Thickened
1. Necrosis of the mucosa, often
basement
predominantly of the superficial mucosa
membrane, 10–30
with subsequent detachment from the
μm (normal 2–5
underlying mucosa and submucosa (Fig.
μm) with a smooth
4.22.1)
lower border that
2. Focal pseudomembranes composed of
does not extend into
fibrin, mucin, and neutrophils
and surround cells
3. Hemorrhage with hemosiderin-laden
in the lamina
macrophages in the lamina propria
propria (Fig. 4.22.5)
4. Intravascular fibrin thrombi, highly
Histology 2. Few to no other
suggestive of enterohemorrhagic E. coli
changes in the
infection
lamina propria or
5. Crypt atrophy (Fig. 4.22.2)
the deep epithelium
6. Hyalinization of the lamina propria
3. Surface
resulting in the glands appearing closer
epithelium may
together (Fig. 4.22.3)
have focal injury
7. Variable cellular atypia characterized by
with associated
enlarged, hyperchromatic nuclei (Fig.
inflammatory
4.22.4)
reaction, but not
8. Histologic changes are segmental
common
Trichrome
stain
Trichrome stain highlights highlights
Special collagen deposition in the lamina the
studies propria thickened
basement

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 membrane

Varies; depends on
Supportive care and surgical resection for
Treatment the underlying
severe disease and complications
condition
Varies; depends on the underlying etiology.
Up to 30% of cases resolve with time; some Related to the
Prognosis patients develop complications including underlying
perforation, peritonitis, and stricture pathology
formation

Figure 4.22.1 Early lamina propria hyalinization in ischemic colitis.

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Figure 4.22.2 Focal crypt atrophy and hyalinization of the lamina propria in
ischemic colitis.

Figure 4.22.3 Ischemic colitis. Hyalinization of the lamina propria with “back-
to-back”–appearing glands.

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Figure 4.22.4 Ischemic colitis. Marked reactive changes and prominent
mitoses in the crypts.

Figure 4.22.5 Thickened basement membrane in Hirschsprung disease with no

surface epithelial damage of intraepithelial inflammation.

4.23 Autoimmune colopathy vs.

Normal colon

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 Autoimmune Colopathy Normal Colon
Infants and children as well as
adults; no gender predominance
Age/Gender Any age
(Except IPEX - male infants/children
since it is X-linked).
Location Any location Any location
Many patients present with chronic
Symptoms None
diarrhea, abdominal pain, fatigue
Colonoscopy may show focal
Signs None
mucosal erythema and friability
Unknown in most examples; most
cases demonstrate abnormal
expression of HLA II on the surface
of the epithelial cells suggesting that
Etiology the pathogenesis is related to loss of None
self-tolerance with subsequent T-cell
activation. Anti–goblet cell and
antienterocyte antibodies have been
detected in a large subset of patients
1. Mixed inflammatory
cells within the lamina
propria, predominantly
lymphocytes, plasma cells,
1. Mild changes include infiltration and scattered eosinophils
of the lamina propria by a population (Figs. 4.23.5 and 4.23.6)
of neutrophils, lymphocytes, more marked in the
histiocytes, and eosinophils (Fig. proximal colon than in the
Histology 4.23.1) distal colon (Figs. 4.23.7
2. More severe changes include crypt and 4.23.8)
distortion, loss of goblet and/or 2. Few to no neutrophils
Paneth cells (Figs. 4.23.2 and 3. Prominent goblet cells,
4.23.3), crypt apoptosis (Fig. 4.23.4) more marked in the distal
colon than the proximal
colon
4. No crypt distortion or
crypt abscesses

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 Not generally performed. Not generally
Special Special stains for PAS/AB performed
studies can be used to show the
loss of goblet cells

Most patients are treated with

Treatment immunosuppression as well as None
nutritional supplementation
Variable; some patients may have
concurrent autoimmune enteropathy
of the small bowel, and many
Prognosis None
patients have other autoimmune
diseases. The prognosis is related to
the severity of these other conditions

Figure 4.23.1 Autoimmune colopathy. Mixed acute and chronic inflammation

within the lamina propria.

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Figure 4.23.2 Autoimmune colopathy. Diffuse loss of goblet cells and focal
crypt distortion.

Figure 4.23.3 Autoimmune colopathy. Crypt apoptosis and loss of goblet cells.

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Figure 4.23.4 Autoimmune colopathy. Prominent crypt apoptosis.

Figure 4.23.5 Normal colon. Right colon with prominent lymphocytic

inflammation within the lamina propria.

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Figure 4.23.6 Normal colon. Lamina propria of the right colon with
lymphocytic inflammation and scattered three eosinophils.

Figure 4.23.7 Normal colon. Left colon with scattered lymphocytes within the
lamina propria and prominent goblet cells.

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Figure 4.23.8 Normal colon. Lamina propria of the left colon with scattered
lymphocytes and plasma cells, few eosinophils.

4.24 Common variable

immunodeficiency vs. Normal colon
Common Variable
Normal Colon
Immunodeficiency
Any age (mean age 20s–30s); no
Age/Gender Any age
gender predominance
Location Any location Any location
Most patients present with
recurrent and chronic sinonasal
Symptoms None
infections; some present with
abdominal pain and diarrhea
Serum studies show
hypogammaglobulinemia
(decreased below at least 2
Signs None
standard deviations in at least
two of the three
immunoglobulin classes)

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 Sporadic and inherited primary
immunodeficiency disorder
characterized by dysfunctional
B-cell maturation resulting in
Etiology None
hypogammaglobulinemia. Some
cases have been associated with
single gene mutations including
TACI and TNFRSF13B
1. Few to no plasma cells within
the lamina propria in two thirds 1. Mixed inflammatory cells
of cases. (Figs. 4.24.1 and within the lamina propria,
4.24.2) predominantly lymphocytes,
2. Lymphoid aggregates usually plasma cells, and scattered
prominent with increased eosinophils (Figs. 4.24.6 and
intraepithelial lymphocytes 4.24.7) more marked in the
(Figs. 4.24.3 and 4.24.4) proximal colon than in the
Histology 3. Variable crypt distortion distal colon (Figs. 4.24.8 and
4. Increased apoptosis 4.24.9)
5. Sometimes seen in association 2. Only scattered lymphoid
with collagenous colitis or aggregates
lymphocytic colitis 3. No crypt distortion
6. Occasional intraepithelial 4. Minimal to no apoptosis
neutrophils usually in 5. No features of collagenous
association with infection (Fig. or lymphocytic colitis
4.24.5)
Not generally
performed.
Immunostains for
CD138, kappa, and
Special Not generally
lambda can be used to
performed
studies show absence of
plasma cells. Clinical
history is important to
the diagnosis

Standard therapy is
Treatment immunoglobulin replacement None
via pooled human IVIG

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 Variable; CVID is a chronic
disease, and patients are at high
risk for recurrent infections as
Prognosis well as small intestinal None
lymphoma and gastric
carcinoma. The mortality rate
averages 25%

Figure 4.24.1 Common variable immunodeficiency. Scattered inflammatory

cells in the lamina propria with few to no plasma cells.

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Figure 4.24.2 Common variable immunodeficiency. Increased inflammation
within the lamina propria primarily composed of lymphocytes with few to no
plasma cells.

Figure 4.24.3 Common variable immunodeficiency. Submucosal lymphoid

aggregate.

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Figure 4.24.4 Common variable immunodeficiency. Increased intraepithelial
lymphocytes.

Figure 4.24.5 Common variable immunodeficiency. Increased intraepithelial

neutrophils.

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Figure 4.24.6 Normal colon. Right colon with prominent lymphocytic
inflammation within the lamina propria.

Figure 4.24.7 Normal colon. Lamina propria of the right colon with
lymphocytic inflammation and scattered 73 eosinophils.

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Figure 4.24.8 Normal colon. Left colon with scattered lymphocytes within the
lamina propria and prominent goblet cells.

Figure 4.24.9 Normal colon. Lamina propria of the left colon with scattered
lymphocytes and plasma cells, few eosinophils.

4.25 Kayexalate injury vs.

Cholestyramine and related bile
sequestrants

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 Cholestyramine and
Kayexalate Injury Related Bile
Sequestratants
Typically older adults;
Typically older adults; no gender
Age/Gender no gender
predominance
predominance
Location Any location Any location
Few, if any. Used in
Abdominal pain, abdominal distension, patients with a history
Symptoms
nausea, vomiting, diarrhea, GI bleeding of diarrhea and itching
related to liver failure
Few, if any. Serum
Melena, hematochezia, abdominal
studies may show
tenderness; some patient present with
Signs evidence of liver
unstable vital signs due to bleeding and
failure or
most patients have chronic kidney disease
hypercholesterolemia
Cholestyramine is an
Kayexalate is a cation exchange resin, ion exchange resin
which facilitates lowering of serum used in the treatment
potassium through the exchange of of
hydrogen ions for potassium ions. Injury hypercholesterolemia,
is due to the administration of Kayexalate which exchanges
Etiology as a suspension in hypertonic sorbitol and chloride ions with bile
thought to result from the hyperosmotic acid ions facilitating
action of the formulation and vasospasm excretion of bile acids
of the intestinal vessels. The incidence of and stimulating
injury is higher among patients with increased conversion
uremia and in posttransplant patients of cholesterol to bile
acids
1. Kayexalate crystals, which appear as
polygonal, lightly basophilic crystals with
a cracked appearance resembling fish
scales, which are retractile but not
polarizable (Fig. 4.25.1); crystals can
appear green-brown when bile stained but 1. Cholestyramine
retain cracks (Fig. 4.25.2) crystals are red and
2. Ischemic pattern of mucosal damage

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Histology characterized by damage to the epithelial lack cracks (Fig.
surface, loss of goblet cells, small 4.25.5)
microcrypts, and hyalinization of the 2. No background
lamina propria with glands arranged in mucosal injury
closer proximity (Fig. 4.25.3)
3. Some cases show mucosal necrosis
(Fig. 4.25.3)
4. Scattered hyperchromatic, enlarged
reactive nuclei (Fig. 4.25.4)
Not
Not generally performed.
generally
However, the crystals appear
Special performed.
red on PAS/AB and AFB stains
studies The crystals
and blue on Diff-Quik stains.
are pink on
Clinical history is important
AFB stain

Discontinuation of Kayexalate, with

Treatment administration of a different drug to lower None
potassium if necessary
Generally good; the injury is usually self-
resolving with supportive care. The Excellent;
Prognosis
prognosis relates to the severity of nonpathologic finding
underlying renal disease

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Figure 4.25.1 Kayexalate crystal.

Figure 4.25.2 Bile-stained crystal. This particular crystal lacks cracking and is
probably a bile sequestrant crystal.

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Figure 4.25.3 Kayexalate-associated injury. Mucosal ischemic injury with focal
necrosis.

Figure 4.25.4 Kayexalate-associated injury. There is granulation tissue in

association with acute inflammation.

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Figure 4.25.5 Cholestyramine crystal.

4.26 Mucosal prolapse polyps vs.

Peutz-Jeghers polyps
Mucosal Prolapse Polyps
Typically adults (mean age
Age/Gender 50s); slight female
predominance
Predominantly in the distal
Location
colon
Nonspecific, abdominal
pain, constipation,
Symptoms diarrhea, GI bleeding;
there is usually history of
straining to defecate
Few, if any, nonspecific.
Endoscopy commonly
shows ulcers usually on
Signs the anterior and
anterolateral wall of the
Peutz-Jeghers Polyps
Children to young adults (mean age
at diagnosis 20s); no gender
predominance
Any location in colon - usually in
small bowel.
Nonspecific; abdominal pain,
dyspepsia, vomiting
Few, if any; some cases present with
intussusception, obstruction, or GI
bleeding. Patients often present with
pigmented macules of the skin and

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 rectum
Unknown; thought to be
related to abnormal
function of the pelvic floor
during defecation causing
Etiology
mucosal prolapse, which
results in ischemic damage
secondary to vascular
obstruction
1. Erosion of the epithelial
surface with reactive
changes (Figs. 4.26.1 and
4.26.2)
2. Lamina propria shows
congestion, vascular
ectasia (Fig. 4.26.3), and
fibrosis (Fig. 4.26.4) with
interdigitating thin strands
of smooth muscle
Histology extending up from (Fig.
4.26.5) the thickened
muscularis mucosae (Fig.
4.26.6)
3. Crypt distortion
characterized by
elongation and hyperplasia
(“diamond shaped”)
(Fig. 4.26.7) ; crypts are
surrounded by thin strands
of smooth muscle
Not generally
Special
studies performed
Surgical excision. Medical
therapy includes diet
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mucous membranes
An autosomal dominant inherited
disorder with complete penetrance,
which causes hamartomatous polyps
throughout the GI tract and
pigmented macules of the skin and
mucous membranes. Up to 80%–
90% of families have mutations in
the STK11/LKB1 gene
1. Hyperplastic mature epithelium
predominantly composed of goblet
cells (Fig. 4.26.8) arranged in
elongated and branching villi, which
are separated by intervening
radiating thick cords of mature
smooth muscle (Figs. 4.26.9 and
4.26.10); some cases may lack the
arborizing bundles of smooth muscle
2. Large polyps often show erosion
of the surface epithelium with
associated reactive changes and
increased mitoses
3. Normal lamina propria (Fig.
4.26.11)
4. Rare cases show epithelial
dysplasia
Not generally performed.
Clinical and family history
is important to the
diagnosis
Treatment modification (e.g., fiber), Complete excision and surveillance.
psychological counseling, These patients are at extremely high
and biofeedback therapy risk for cancers of a host of organs.

Fair; the polyps are benign, but

Good; recurrence is
patients have up to 90% lifetime risk
Prognosis common, but medical
of malignancies of the reproductive
therapy is often effective
tract, breast, and GI tract

Figure 4.26.1 Surface erosion with associated granulation tissue in mucosal

prolapse polyp.

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Figure 4.26.2 Mild reactive epithelial changes in mucosal prolapse polyp with
slightly enlarged hyperchromatic nuclei with conspicuous mitoses and scattered
mitoses.

Figure 4.26.3 Vascular ectasia in the lamina propria of mucosal prolapse polyp.

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Figure 4.26.4 Fibrosis and increased inflammation within the lamina propria of
mucosal prolapse polyp.

Figure 4.26.5 Smooth muscle interdigitating among glands in mucosal

prolapse polyp.

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Figure 4.26.6 Thickened muscularis mucosae with radiating smooth muscle
bundles in mucosal prolapse polyp.

Figure 4.26.7 Crypt elongation and hyperplasia with “diamond-shaped” crypts

at the base in mucosal prolapse polyp.

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Figure 4.26.8 Glands in Peutz-Jeghers polyp lined by mature colonic
epithelium.

Figure 4.26.9 Peutz-Jeghers polyp with a round superficial surface and

elongated crypts separated by thick bands of radiating smooth muscle.

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Figure 4.26.10 Arborizing bundles of smooth muscle in Peutz-Jeghers polyp.

Figure 4.26.11 Lamina propria in Peutz-Jeghers polyp with a mixed

lymphoplasmacytic infiltrate but no other changes.

4.27 Mucosal prolapse polyps vs.

Sessile serrated adenoma

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 Mucosal Prolapse Polyps
Typically adults (mean age
Age/Gender 50s); slight female
predominance
Predominantly in the distal
Location
colon
Nonspecific, abdominal pain,
constipation, diarrhea, GI
Symptoms
bleeding; there is usually
history of straining to defecate
Few, if any, nonspecific.
Endoscopy commonly shows
Signs ulcers usually on the anterior
and anterolateral wall of the
rectum
Unknown; thought to be related
to abnormal function of the
pelvic floor during defecation
Etiology causing mucosal prolapse,
which results in ischemic
damage secondary to vascular
obstruction
1. Usually sessile and ulcerated
2. Crypt distortion
characterized by elongation and
hyperplasia (“diamond
shaped”) (Figs. 4.27.1 and
4.27.2); crypts are surrounded
by thin strands of smooth
muscle (Fig. 4.27.3)
3. Lamina propria shows
Histology congestion, vascular ectasia,
and fibrosis with interdigitating
thin strands of smooth muscle
extending up from the
thickened muscularis mucosae
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Sessile Serrated Adenoma
Typically older adults (mean age
70s); female > male
Predominantly proximal colon,
but can occur throughout the
colon
Few; usually asymptomatic
Few; colonoscopy shows a
sessile polyp
Unknown; though has been
shown to be related to sporadic
microsatellite instability, they
also commonly show mutations
in BRAF
1. Sessile
2. Elongated crypts with
micropapillary growth of the
epithelium imparting a serrated
appearance (Figs. 4.27.6 and
4.27.7)
3. Widened crypt bases that
resemble “duck feet” (Figs.
4.27.8 and 4.27.9)
4. No smooth muscle
proliferation (Fig. 4.27.10)
5. Nuclear atypia characterized
by enlarged nuclei with
prominent nucleoli and
 (Fig. 4.27.4) asymmetric proliferation, which
4. Erosion of the epithelial extends from the base to the
surface with reactive changes mid- and upper crypt (Figs.
(Fig. 4.27.5) 4.27.11 and 4.27.12)
Not generally
performed; loss of
Special Not generally immunolabeling for
studies performed MLH1 in those
complicated by
dysplasia/carcinoma

Surgical excision. Medical

therapy includes diet
Treatment modification (e.g., fiber),
psychological counseling, and
biofeedback therapy
Good; recurrence is common,
Prognosis but medical therapy is often
effective
Surgical excision, followed by
routine colonoscopy
surveillance
Generally good, though patients
are at increased risk for
colorectal carcinoma as the
lesions are the precursors to
tumor that are microsatellite
unstable

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Figure 4.27.1 Elongated and hyperplastic crypts in mucosal prolapse polyp.

Figure 4.27.2 Markedly hyperplastic crypts in mucosal prolapse polyp.

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Figure 4.27.3 Mucosal prolapse polyp. Radiating smooth muscle surrounding
crypts and extending to the epithelial surface.

Figure 4.27.4 Lamina propria with fibrosis, telangiectasias, and wispy strands
of smooth muscle in mucosal prolapse polyp.

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Figure 4.27.5 Focal surface erosion in mucosal prolapse polyp.

Figure 4.27.6 Sessile serrated adenoma with prominent serrations extending to

the surface.

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Figure 4.27.7 Serrated epithelium of sessile serrated adenoma with apoptotic
bodies and prominent apical mucin.

Figure 4.27.8 Widened crypts at the base of a sessile serrated adenoma.

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Figure 4.27.9 Widened, horizontally oriented crypts at the base of a sessile
serrated adenoma resembling “duck feet.”

Figure 4.27.10 Sessile serrated adenoma with prominent mitoses and minimal
to no changes in the lamina propria.

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Figure 4.27.11 High-grade dysplasia in a sessile serrated adenoma
characterized by hyperchromatic, pleomorphic, enlarged cells with loss of
nuclear polarity and mucin loss.

Figure 4.27.12 Invasive carcinoma arising in a sessile serrated adenoma.

4.28 Mucosal prolapse polyps vs.

Juvenile polyps

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 Mucosal Prolapse Polyps Juvenile Polyps
Typically adults (mean age
Children (mean age 10); males >
Age/Gender 50s); slight female
females
predominance
Predominantly in the distal Predominantly left colon, sigmoid,
Location
colon and rectum
Nonspecific, abdominal
Painless rectal bleeding is
pain, constipation, diarrhea,
common; other symptoms include
Symptoms GI bleeding; there is usually
abdominal pain, rectal prolapse,
history of straining to
constipation, diarrhea
defecate
Rare cases present with
intussusception and malabsorption;
Few, if any, nonspecific.
patients with nonfamilial form of
Endoscopy commonly shows
disease often present with
Signs ulcers usually on the anterior
congenital anomalies including
and anterolateral wall of the
congenital heart disease, digital
rectum
clubbing, intestinal malrotation,
and hydrocephalus
Unknown; thought to be Both sporadic and inherited forms.
related to abnormal function Up to 50% of cases are of the
of the pelvic floor during inherited form, which is an
Etiology defecation causing mucosal autosomal dominant disorder
prolapse, which results in associated with mutations in
ischemic damage secondary SMAD4 and BMPR1A genes in a
to vascular obstruction subset of families
1. Commonly sessile and
appear ulcerated (Fig.
1. Most are pedunculated (Fig.
4.28.1)
4.28.7)
2. Erosion of the epithelial
2. Surface epithelium erosion with
surface with reactive
associated acute inflammation,
changes
granulation tissue, and reactive
3. Crypt distortion
changes
characterized by elongation
3. Rounded surface with cystically
and hyperplasia (“diamond
dilated glands containing acellular
shaped”) (Figs. 4.28.2 and
debris arranged beneath (Fig.
4.28.3); crypts are

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 surrounded by thin strands of
Histology smooth muscle (Fig. 4.28.4)
4. Lamina propria shows
congestion, vascular ectasia,
and fibrosis with
interdigitating thin strands of
smooth muscle extending up
from the thickened
muscularis mucosae (Figs.
4.28.5 and 4.28.6)
5. Minimal inflammation
within the lamina propria
6. Rare cytologic atypia
other than regenerative
changes
Special Not generally
studies performed
Polypectomy. Medical
therapy includes diet
Treatment modification (e.g., fiber),
psychological counseling,
and biofeedback therapy
Good; recurrence is
Prognosis common, but medical
therapy is often effective
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4.28.8)
4. Lamina propria expanded by a
dense mixed inflammatory
infiltrate composed of acute and
chronic inflammatory cells (Fig.
4.28.9), ectatic vessels (Fig.
4.28.10), and granulation tissue
(Fig. 4.28.11)
5. No smooth muscle hyperplasia
or prominent fibrosis within the
lamina propria (Fig. 4.28.12)
6. Mild to severe cytologic atypia
can occur, more commonly in
syndromic cases (Fig. 4.28.13)
Not generally performed.
Family history is
important, and mutations
are only confirmatory in
50% of inherited cases
Polypectomy with routine
surveillance. Colectomy is
recommended for extensive
involvement
Good to fair; the polyps are benign,
but patients have a high risk of
gastrointestinal malignancies
Figure 4.28.1 Extensive ulceration with fibrinopurulent exudate in mucosal
prolapse polyp.

Figure 4.28.2 Crypt elongation and hyperplasia in mucosal prolapse polyp.

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Figure 4.28.3 Diamond-shaped distorted glands in the deep mucosa in mucosal
prolapse polyp.

Figure 4.28.4 Radiating smooth muscle bundles extending from the muscularis
mucosae interdigitating among the glands.

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Figure 4.28.5 Wispy bundles of smooth muscle interdigitating among glands in
mucosal prolapse polyp.

Figure 4.28.6 Marked vascular ectasia in the lamina propria of mucosal

prolapse polyp seen in association with fibrinopurulent exudate.

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Figure 4.28.7 Pedunculated juvenile polyp with a rounded surface. This
particular example has extensive low-grade dysplasia.

Figure 4.28.8 Cystically dilated glands containing acellular debris in a juvenile

polyp.

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Figure 4.28.9 Mixed acute and chronic inflammation within the lamina propria
of a juvenile polyp.

Figure 4.28.10 Ectatic vessels within the lamina propria of a juvenile polyp.

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Figure 4.28.11 Granulation tissue seen in association with ulceration in a
juvenile polyp.

Figure 4.28.12 Lamina propria of a juvenile polyp with mixed inflammation

but no fibrosis or smooth muscle hyperplasia.

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Figure 4.28.13 Focal reactive atypia in a juvenile polyp.

4.29 Juvenile polyps vs. Peutz-Jeghers

polyps
Juvenile Polyps Peutz-Jeghers Polyps
Children to young adults (mean age
Children (mean age 10);
Age/Gender at diagnosis 20s); no gender
males > females
predominance
Predominantly left colon,
Location Any location
sigmoid, and rectum
Painless rectal bleeding is
common; other symptoms
Nonspecific; abdominal pain,
Symptoms include abdominal pain,
dyspepsia, vomiting
rectal prolapse,
constipation, diarrhea
Rare cases present with
intussusception and
malabsorption; patients Few, if any; some cases present with
with nonfamilial form of intussusception, obstruction, or GI
disease often present with

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Signs congenital anomalies bleeding. Patients often present with
including congenital heart pigmented macules of the skin and
disease, digital clubbing, mucous membranes
intestinal malrotation, and
hydrocephalus
Both sporadic and inherited An autosomal dominant inherited
forms. Up to 50% of cases disorder with complete penetrance,
are of the inherited form, which causes hamartomatous polyps
which is an autosomal throughout the GI tract and
Etiology
dominant disorder pigmented macules of the skin and
associated with mutations mucous membranes. Up to 80%–
in SMAD4 and BMPR1A 90% of families have mutations in
genes in a subset of families the STK11/LKB1 gene
1. Surface epithelium
erosion with associated
acute inflammation,
1. Hyperplastic mature epithelium
granulation tissue, and
predominantly composed of goblet
reactive changes (Fig.
cells (Fig. 4.29.7) arranged in
4.29.1)
elongated and branching villi, which
2. Rounded surface with
are separated by intervening
cystically dilated glands
radiating thick cords of mature
containing cellular debris
smooth muscle (Figs. 4.29.8 and
arranged beneath (Figs.
4.29.9); some cases may lack the
4.29.2–4.29.4)
arborizing bundles of smooth
Histology 3. Lamina propria expanded
muscle
by a dense mixed
2. Large polyps often show erosion
inflammatory infiltrate
of the surface epithelium with
composed of acute and
associated reactive changes
chronic inflammatory cells
3. Granulation tissue can be present
(Fig. 4.29.5), ectatic vessels
but is limited to the surface of the
(Fig. 4.29.6), and
polyp; no inflammation or
granulation tissue (Fig.
granulation tissue within the lamina
4.29.1)
propria
4. No broad bands of
smooth muscle within the
lamina propria
Not generally

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 performed. Not generally performed.
Family history is Clinical history and
Special important, and family history are
studies mutations are important to the diagnosis
only documented
in 50% of
inherited cases

Surgical resection with

routine surveillance. Complete excision and routine
Treatment
Colectomy is recommended surveillance
for extensive involvement
Fair; the polyps are benign, but
Good to fair; the polyps are
patients have up to 90% lifetime
benign, but patients have a
Prognosis risk of malignancies of the
high risk of gastrointestinal
reproductive tract, breast, and GI
malignancies
tract

Figure 4.29.1 Granulation tissue associated with ulceration in a juvenile polyp.

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Figure 4.29.2 Rounded surface of juvenile polyp with prominent cystically
dilated glands.

Figure 4.29.3 Juvenile polyp. Cystically dilated glands with intraluminal

acellular debris.

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Figure 4.29.4 Mature colonic epithelium lining surface of juvenile polyp.

Figure 4.29.5 Mixed chronic inflammation in the lamina propria of juvenile

polyp.

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Figure 4.29.6 Ectatic vessels in the lamina propria of juvenile polyp.

Figure 4.29.7 Mature colonic epithelium lining Peutz-Jeghers polyp.

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Figure 4.29.8 Peutz-Jeghers polyp with hyperplastic epithelium separated by
arborizing bundles of smooth muscle.

Figure 4.29.9 Arborizing smooth muscle in Peutz-Jeghers polyp.

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4.30 Juvenile polyps vs. Adenomas
Juvenile Polyps Adenomas
Children (mean age Typically older adults (60s); males >
Age/Gender
10); males > females females
Predominantly left
Any location; larger adenomas are more
Location colon, sigmoid, and
commonly in the left colon
rectum
Painless rectal
bleeding is common;
other symptoms Few, if any; abdominal pain, fatigue,
Symptoms
include abdominal melena
pain, rectal prolapse,
constipation, diarrhea
Rare cases present
with intussusception
and malabsorption;
patients with
nonfamilial form of
Few, if any; some patients present with
disease often present
iron deficiency anemia related to chronic
Signs with congenital
bleeding. Colonoscopy is critical to
anomalies including
diagnosis
congenital heart
disease, digital
clubbing, intestinal
malrotation, and
hydrocephalus
Both sporadic and inherited forms. Several
Both sporadic and risk factors are associated with sporadic
inherited forms. Up cases including diet (e.g., high fat, low
to 50% of cases are fiber, alcohol use). Many of these tumors
of the inherited form, have mutations in APC, KRAS, and p53.
which is an There are several inherited syndromes,
Etiology autosomal dominant which are associated with an increased risk
disorder associated of adenomas including familial
with mutations in adenomatous polyposis in which patients

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 SMAD4 and harbor inactivating mutations in APC and
BMPR1A genes in a hereditary nonpolyposis colorectal cancer
subset of families in which patients have inactivating
mutations in hMLH1 and hMSH2
1. Surface epithelium
erosion with
associated acute
inflammation,
granulation tissue,
and reactive changes
(Fig. 4.30.1)
2. Rounded surface
with cystically
dilated glands
containing cellular
debris arranged
beneath (Figs. 4.30.2
and 4.30.3) 1. Most show low-grade epithelial
3. Mature colonic dysplasia characterized by elongated,
epithelium (Fig. hyperchromatic, pseudostratified, nuclei
4.30.4) with focal oriented perpendicular to the basement
mild to severe membrane; prominent nucleoli; and mucin
cytologic atypia loss (Fig. 4.30.8)
characterized by 2. Cells are arranged in tubules and/or villi
Histology hyperchromatic, (Fig. 4.30.9)
elongated, 3. High-grade dysplasia is characterized by
pseudostratified cribriform architecture of glands,
nuclei can occur crowding, and loss of nuclear polarity
(more commonly in 4. Lamina propria is histologically
syndromic cases)— unremarkable (Fig. 4.30.10)
dysplasia is 5. Apoptotic bodies are prominent at the
histologically base of crypts
identical to
adenomatous
dysplasia
4. Lamina propria
expanded by a dense
mixed inflammatory

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 infiltrate composed
of acute and chronic
inflammatory cells
(Fig. 4.30.5), ectatic
vessels (Fig. 4.30.6)
and granulation
tissue (Fig. 4.30.7)
Not
generally
performed.
Family
history is
Special important,
Not generally performed
studies and
mutations
can be seen
in 50% of
inherited
cases

Surgical resection
with routine
surveillance.
Complete surgical excision followed by
Treatment Colectomy is
routine colonoscopy surveillance
recommended for
extensive
involvement
Good to fair; the
polyps are benign, Generally good; up to 10% progress to
but patients have a invasive carcinoma. Poor prognostic
Prognosis
high risk of factors include tumor size, villous
gastrointestinal morphology, and location in the left colon
malignancies

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Figure 4.30.1 Juvenile polyp. Surface ulceration with marked acute
inflammation.

Figure 4.30.2 Rounded surface of juvenile polyp with prominent cystically

dilated glands.

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Figure 4.30.3 Juvenile polyp. Cystically dilated gland with intraluminal
acellular debris.

Figure 4.30.4 Juvenile polyp. Mature colonic epithelium lining dilated gland in
juvenile polyp.

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Figure 4.30.5 Mixed acute and chronic inflammation within the lamina propria
of juvenile polyp.

Figure 4.30.6 Ectatic vessels within the lamina propria of juvenile polyp.

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Figure 4.30.7 Surface granulation tissue in juvenile polyp.

Figure 4.30.8 Low-grade dysplasia in an adenoma with elongated,

hyperchromatic, pseudostratified nuclei and prominent mitoses and apoptotic
bodies.

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Figure 4.30.9 Villous adenoma with prominent finger-like projections.

Figure 4.30.10 Histologically unremarkable lamina propria in adenoma

composed of mixed inflammatory cells.

4.31 Juvenile polyps vs. Cronkhite-

Canada polyp

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 Juvenile Polyps Cronkhite-Canada Polyp
Children (mean age 10); Older adults (mean age at diagnosis
Age/Gender
males > females 59); male > female (3:2)
Predominantly left
Location colon, sigmoid, and Any location
rectum
Painless rectal bleeding
is common; other Most are symptomatic and present with
symptoms include diarrhea, nausea, vomiting, and weight
Symptoms
abdominal pain, rectal loss; severe cases can present with
prolapse, constipation, seizures, arrhythmias, and paresthesias
diarrhea
Rare cases present with Most patients have multiple ectodermal
intussusception and abnormalities including alopecia,
malabsorption; patients onychodystrophy, and/or skin
with nonfamilial form hyperpigmentation of the extremities,
of disease often present face, palms/soles, and neck; Lab studies
Signs with congenital show hypoalbuminemia, hypocalcemia,
anomalies including hypomagnesemia, anemia, and
congenital heart disease, sodium/potassium abnormalities;
digital clubbing, Endoscopy shows diffuse polyposis
intestinal malrotation, throughout the GI tract with sparing of
and hydrocephalus the esophagus
Both sporadic and
inherited forms. Up to
50% of cases are of the
inherited form, which is
Unknown; thought to be an
Etiology an autosomal dominant
autoimmune-related disorder
disorder associated with
mutations in the SMAD4
and BMPR1A genes in a
subset of families
1. Most are
pedunculated (Fig.
4.31.1)
2. Rounded surface with
cystically dilated glands

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 lined by mature 1. Most are sessile and broad based
epithelium (Figs. (Fig. 4.31.7)
4.31.1–4.31.3) 2. Rounded surface (Fig. 4.31.7) with
3. Lamina propria cystically dilated glands lined by
expanded by a dense mature epithelium (Figs. 4.31.8 and
mixed inflammatory 4.31.9)
Histology infiltrate composed of 3. Lamina propria expanded by edema
acute and chronic and a mixed inflammatory infiltrate
inflammatory cells (Fig. composed of acute and chronic
4.31.4), ectatic vessels inflammatory cells (Fig. 4.31.10)
(Fig. 4.31.5), and 4. Intervening mucosa shows similar
granulation tissue (Fig. changes as the polyp (Figs. 4.31.11 and
4.31.6) 4.31.12)
4. Intervening mucosa 5. No dysplasia (Fig. 4.31.9)
histologically
unremarkable
5. Mild to moderate
dysplasia can be present

Not generally
performed.
Family history Not generally performed.
is important, Clinical history is important
Special and mutations as most patients have skin
studies can be seen in lesions, which can be used to
50% of confirm the diagnosis
inherited
cases

Surgical resection with Primarily supportive therapy with

routine surveillance. nutritional support, electrolyte
Treatment Colectomy is repletion, vitamin supplementation in
recommended for combination with antibiotics and
extensive involvement steroids
Generally poor; complications are
Good to fair; the polyps common and include malnutrition due
are benign, but patients to severe protein and electrolyte losses,
Prognosis have a high risk of GI bleeding, and infection. The 5-year

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 gastrointestinal mortality rate is approximately 60%.
malignancies However, some patients up to 5%–10%
have spontaneous regression

Figure 4.31.1 Pedunculated juvenile polyp with a rounded surface and

prominent cystically dilated glands.

Figure 4.31.2 Mature colonic epithelium lining a juvenile polyp.

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Figure 4.31.3 Cystically dilated gland with intraluminal acellular debris in
juvenile polyp.

Figure 4.31.4 Mixed inflammation in the lamina propria of juvenile polyp.

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Figure 4.31.5 Ectatic vessels in the lamina propria of juvenile polyp.

Figure 4.31.6 Granulation tissue in juvenile polyp.

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Figure 4.31.7 Broad-based sessile Cronkhite-Canada polyp.

Figure 4.31.8 Cystically dilated glands throughout the flat mucosa as well as
the polyps in Cronkhite-Canada polyp.

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Figure 4.31.9 Glands in Cronkhite-Canada polyp lined by mature colonic
epithelium with no dysplasia.

Figure 4.31.10 Mixed acute and chronic inflammatory infiltrate within the
lamina propria of Cronkhite-Canada polyp.

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Figure 4.31.11 Flat mucosa adjacent to Cronkhite-Canada polyp with similar
changes including cystic dilation of glands and increased lamina propria
inflammation.

Figure 4.31.12 Mixed acute and chronic inflammatory infiltrate within the
background mucosa adjacent to a Cronkhite-Canada polyp.

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4.32 Endometriosis vs. Sarcoma
Endometriosis Sarcoma
Typically young to middle-aged
Age/Gender Any age; any location
adults; women > men
Location Most common in the sigmoid colon Any location
Few, if any. Some patients present Abdominal pain,
Symptoms with cyclical abdominal pain, constipation, diarrhea, GI
diarrhea, nausea, vomiting bleeding
Few, if any. Some patients present Abdominal tenderness;
Signs with abdominal tenderness, intestinal radiologic studies may
obstruction show a mass
Unknown; retrograde menstruation
resulting in displacement of
endometrial cells into the peritoneal
cavity is thought to be a key initiating
factor, though stem cells have been
Malignant transformation
proposed to contribute as well. Other
of mesenchymal
Etiology factors thought to be involved in the
components in the bowel
complex pathogenesis include
wall
metaplasia of peritoneal tissues,
hormone interactions, oxidative stress
and inflammation, immune
dysregulation, inhibited apoptosis,
and genetic factors
1. Deposits of endometrial-type
glands composed of bland 1. Proliferation of spindle
longitudinal nuclei with apical cilia, to epithelioid cells with
arranged in a horizontal orientation enlarged, pleomorphic
parallel to the epithelial surface, and nuclei; scant to moderate
surrounded by endometrial-type cytoplasm (high N/C
stroma composed of bland spindle ratio); and often
cells and thin-walled capillaries (Fig. prominent nucleoli (Fig.
4.32.1) 4.32.4)
Histology 2. Usually centered in the serosa 2. Malignant cells
and/or muscularis propria, but can arranged in clusters and

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 involve the submucosa (Fig. 4.32.2) sheets that form a mass,
3. Background mucosa unaffected not in a monolayer (Fig.
4. Associated hemorrhage, 4.32.5)
hemosiderin deposition, and an 3. Mitoses usually
extensive fibroblastic response prominent; atypical
characterized by prominent fibrosis mitoses readily identified
and adhesions; no hyaline bodies (Fig. 4.32.6)
(Fig. 4.32.3)
The cell of
origin can vary,
but sarcomas
The epithelial cells are show
positive for ER and PR, and immunolabeling
Special the stroma shows for cell type–
studies immunolabeling for CD10. specific markers
A PAS stain is negative (e.g.,
leiomyosarcoma
—desmin,
actin)

Primarily symptomatic including

analgesics as well as hormone Surgical excision
Treatment therapy. Severe cases with extensive followed by adjuvant
adhesions, obstruction, or intractable therapy if indicated
pain require surgical excision
Good; the lesions are considered
benign, but patients can develop intra- Variable; related to the
Prognosis
abdominal adhesions, which can be a type and stage of sarcoma
cause of morbidity

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Figure 4.32.1 Endometrial-type glands with surrounding endometrial stroma
within the muscularis propria.

Figure 4.32.2 Endometriosis centered in the deep muscularis propria and

serosa.

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Figure 4.32.3 Hemorrhage and hemosiderin-laden macrophages in association
with endometriosis.

Figure 4.32.4 Infiltrating leiomyosarcoma with markedly atypical,

hyperchromatic cells with scant cytoplasm.

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Figure 4.32.5 Leiomyosarcoma arranged as sheets of cells.

Figure 4.32.6 Markedly atypical cells of leiomyosarcoma with a prominent

atypical mitosis.

4.33 Adenoma vs. Reparative changes

Reparative
Adenoma
Changes

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 Any age; no gender
Age/Gender Older adults (60s); males > females
predominance
Commonly in the left colon, but can occur
Location Any location
in any location
Few, if any; usual incidental findings at Varies; related to
Symptoms colonoscopy; some patients may present the underlying
with diarrhea, constipation, or GI bleeding etiology
Varies; related to
Signs Few, if any; most detected via colonoscopy the underlying
etiology
Dysplasia of the intestinal epithelium
secondary to complex genetic alterations
involving KRAS, APC, and p53 genes. Risk
factors include environmental factors as
adenomas are more common in Reparative response
Etiology industrialized nations, obesity, tobacco use, to acute and/or
dietary factors including high-fat and low- chronic injury
fiber diets, and inherited syndromes such as
familial adenomatosis polyposis coli due to
mutations in the APC gene and hereditary
nonpolyposis colorectal cancer
1. Cells with
enlarged nuclei,
1. Low-grade dysplasia is characterized by a
vesicular chromatin,
proliferation of pseudostratified cells with
prominent nucleoli,
enlarged, elongated, and cigar-shaped
reduced mucin, and
nuclei; prominent nucleoli; loss of apical
an increased
mucin; prominent apoptosis bodies; and
nuclear/cytoplasmic
scattered mitoses (Figs. 4.33.1 and 4.33.2)
ratio (Figs. 4.33.5
2. The dysplasia develops in a “top-down”
and 4.33.6)
fashion such that in early lesions it is more
2. Mitoses are often
prominent at the surface of the mucosa (Fig.
prominent, but
4.33.3)
Histology apoptotic bodies are
3. High-grade lesions demonstrate greater
rare (Figs. 4.33.5
nuclear pleomorphism and show
and 4.33.6)
architectural changes including glandular
3. The changes are
crowding, cribriform glands, and loss of
“bottom-up” and
nuclear polarity

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 4. Variable architecture from tubular most prominent at
consisting of complex networks of the base of crypts
branching dysplastic glands to villous (Figs. 4.33.7 and
consisting of elongated, finger-like 4.33.8)
projections (Fig. 4.33.4) 4. Normal glandular
architecture (Fig.
4.33.7)
Not
Special Not generally performed. generally
studies performed

Endoscopic polypectomy followed by Varies depending on

Treatment advanced follow-up screening colonoscopy the underlying
for high-risk patients etiology
Good to fair; the lesions are precancerous,
but only a subset of patients are at high risk Variable; depending
for recurrence or invasive carcinoma. Risk on the underlying
Prognosis
factors include greater than three or more etiology but most
adenomas, high-grade dysplasia, villous lesions resolve
features, or an adenoma >1 cm in size

Figure 4.33.1 Low-grade dysplasia in adenoma showing elongated,

hyperchromatic, pseudostratified nuclei with prominent mitoses and apoptotic

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bodies.

Figure 4.33.2 Low-grade dysplasia in adenoma involving the deep crypts.

Figure 4.33.3 Dysplasia extending from the surface to the base of crypts in
adenoma with low-grade dysplasia.

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Figure 4.33.4 Variable architecture composed of tubular and villous structures.

Figure 4.33.5 Reparative changes consisting of enlarged, hyperchromatic

nuclei with variably prominent nucleoli and conspicuous mitoses.

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Figure 4.33.6 Reparative changes consistent of enlarged, hyperchromatic
nuclei with vesicular chromatin, increased N/C ratio, and conspicuous mitoses.

Figure 4.33.7 Reparative changes confined to the crypts with normal surface
maturation and normal glandular architecture.

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Figure 4.33.8 Reparative changes most prominent in the crypts with minimal
to no changes in the surface epithelium imparting a “bottom-up” appearance.

4.34 Colitis-associated dysplasia vs.

Reactive changes
Colitis-Associated Dysplasia Reactive Changes
Typically adults (20s–30s and 60s–70s); no Any age; male =
Age/Gender
gender predominance female
Crohn: usually prominent in the proximal
Location colon; rectum is often sparedUC: always Any location
involves the rectum and extends proximally
Crohn: cramping abdominal pain,
Variable; depends
nonbloody diarrhea, fever, fatigue, weight
Symptoms on the underlying
lossUC: recurrent bloody diarrhea,
etiology
abdominal pain, fatigue, weight loss
Crohn: hypoalbuminemia, iron deficiency
anemia, fistulas, and stenosis;

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 extraintestinal manifestations affect the
liver, eyes, and joints; endoscopic features
include aphthous erosions, longitudinal
ulcers, cobblestoning, strictures, and Variable; depends
Signs fistulas.UC: varies from few to fever and on underlying
tachycardia associated with toxic etiology
megacolon; endoscopic findings are
variable: active phase, erythematous,
friable, granular mucosa, quiescent phase,
granular mucosa with punctate erythema
and loss of haustral folds; polyps
Unknown; more prevalent in Caucasian and Nonspecific
Etiology Ashkenazi Jews; a subset of patients have response to acute or
an affected relative chronic injury
1. Low-grade dysplasia: proliferation of 1. Proliferation of
stratified cells with enlarged, elongated cells with enlarged
cigar-shaped nuclei; prominent nucleoli; nuclei, vesicular
loss of apical mucin; prominent mitoses; open chromatin, and
and scattered mitoses; nuclei stratified at prominent nucleoli
various different levels (Figs. 4.34.1 and (Fig. 4.34.10)
4.34.2) 2. Nuclear polarity
2. High-grade dysplasia: moderate to maintained (Fig.
marked nuclear pleomorphism and 4.34.11)
architectural changes including glandular 3. Atypia most
crowding, cribriform glands, and loss of prominent at the
nuclear polarity (Fig. 4.34.3) base of crypts with
Histology 3. Dysplasia at any location within the full maturation or
crypt; surface has a mixture of only slight atypia at
nonneoplastic and neoplastic glands (Fig. the surface (Fig.
4.34.4) 4.34.12)
4. Irregular distribution of mucin with 4. Focal loss of
frequent dystrophic goblet cells (mucin mucin but no
vacuole in a basal location) dystrophic goblet
5. Background mucosa usually shows active cells (Fig. 4.34.11)
inflammatory bowel disease with cryptitis 5. Usually seen in
(Fig. 4.34.5) and crypt abscesses (Fig. association with
4.34.6) and chronic changes including background acute
marked architectural distortion (Fig. 4.34.7) inflammation (Fig.

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 and basal plasmacytosis (Fig. 4.34.8) 4.34.13)
Not generally performed. A p53 Not
Special stain highlights the dysplastic generally
studies nuclei (Fig. 4.34.9). performed

Surgical resection. Patients with ulcerative

Treatment colitis undergo regular surveillance None
screening colonoscopy
Fair; chronic incurable disease; prognosis
related to extent and severity of
Variable; depends
complications and therapy-related side
Prognosis on underlying
effects. Increased risk of dysplasia and
etiology
adenocarcinoma associated with an 80%
mortality rate

Figure 4.34.1 Low-grade dysplasia with elongated, pseudostratified,

hyperchromatic nuclei.

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Figure 4.34.2 Low-grade dysplasia with a prominent superficial mitotic figure.

Figure 4.34.3 Focal high-grade dysplasia in a background of acute colitis.

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Figure 4.34.4 Dysplasia. Background acute colitis with intermixed dysplastic
and normal glands.

Figure 4.34.5 Low-grade dysplasia in association with intraepithelial

neutrophils of background acute colitis.

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Figure 4.34.6 Low-grade dysplasia in association with cryptitis of background
acute colitis.

Figure 4.34.7 Crypt distortion.

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Figure 4.34.8 Basal plasmacytosis.

Figure 4.34.9 p53 stain highlighting dysplastic epithelium adjacent to

unaffected epithelium.

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Figure 4.34.10 Reactive epithelial changes in ischemic colitis characterized by
enlarged, hyperchromatic, oval nuclei with prominent nucleoli and open
chromatin.

Figure 4.34.11 Reactive epithelial changes with enlarged, hyperchromatic

nuclei, which retain nuclear polarity and focal mucin loss.

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Figure 4.34.12 Marked reactive epithelial changes seen in association with
granulation tissue, which are most prominent in the crypts with normal surface
maturation.

Figure 4.34.13 Marked reactive epithelial changes seen in association with

acute inflammation and granulation tissue.

4.35 Colitis-associated dysplasia vs.

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Adenoma
Colitis-Associated Dysplasia Adenoma
Typically adults (20s–30s and
Adults (>50 years); males >
Age/Gender 60s–70s); no gender
females
predominance
Crohn: usually prominent in the
proximal colon; rectum is often Commonly in the left colon,
Location
sparedUC: always involves the but can occur in any location
rectum and extends proximally
Crohn: cramping abdominal pain, Few, if any; usually,
nonbloody diarrhea, fever, incidental findings at
Symptoms fatigue, weight lossUC: recurrent colonoscopy; some patients
bloody diarrhea, abdominal pain, may present with diarrhea,
fatigue, weight loss constipation, or GI bleeding
Crohn: hypoalbuminemia, iron
deficiency anemia, fistulas, and
stenosis; extraintestinal
manifestations affect the liver,
eyes, and joints; endoscopic
features include aphthous
erosions, longitudinal ulcers,
Few, if any; most detected via
cobblestoning, strictures, and
colonoscopy, which usually
Signs fistulas.UC: varies from few to
shows a well-marginated
fever and tachycardia associated
pedunculated lesion
with toxic megacolon; endoscopic
findings are variable: active phase
—erythematous, friable, granular
mucosa; quiescent phase—
granular mucosa with punctate
erythema and loss of haustral
folds; polyps
Dysplasia of the intestinal
epithelium secondary to
complex genetic alterations
involving KRAS, APC, and

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 p53 genes. Risk factors
include environmental factors
Unknown; more prevalent in as adenomas are more
Caucasian and Ashkenazi Jews; a common in industrialized
Etiology
subset of patients have an affected nations, obesity, tobacco use,
relative dietary factors including high-
fat and low-fiber diets, and
inherited syndromes such as
familial adenomatosis
polyposis coli due to
mutations in the APC gene
and hereditary nonpolyposis
colorectal cancer
1. Low-grade dysplasia:
1. Low-grade dysplasia:
proliferation of stratified cells
proliferation of stratified cells
with enlarged, elongated cigar-
with enlarged, elongated
shaped nuclei; prominent
cigar-shaped nuclei;
nucleoli; loss of apical mucin;
prominent nucleoli; loss of
prominent mitoses; and scattered
apical mucin; prominent
mitoses; nuclei stratified at
mitoses; and scattered
various different levels (Fig.
mitoses; nuclei stratified at
4.35.1)
the same level (Fig. 4.35.8)
2. High-grade dysplasia: moderate
2. High-grade dysplasia:
to marked nuclear pleomorphism
moderate to marked nuclear
and architectural changes
pleomorphism and
including glandular crowding,
architectural changes
cribriform glands, and loss of
including glandular crowding,
nuclear polarity (Fig. 4.35.2)
cribriform glands, and loss of
3. Dysplasia at any location
nuclear polarity
within the crypt; surface has a
3. Dysplasia has a “top-down”
mixture of nonneoplastic and
distribution—most prominent
neoplastic glands (Fig. 4.35.3)
at the surface and extending
4. Gradual transition of dysplasia
Histology down the crypts; surface with
from surrounding mucosa
neoplastic glands only (Fig.
5. Irregular configuration of
4.35.9)
glands (Fig. 4.35.4)
4. Sharp demarcation of
6. Irregular distribution of mucin
dysplasia from surrounding
with frequent dystrophic goblet
mucosa

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 cells (mucin vacuole in a basal
location)
7. Variable stroma with marked
increase of mononuclear cells and
neutrophils within the lamina
propria (Fig. 4.35.5)
8. Background mucosa usually
shows active inflammatory bowel
disease with cryptitis (Fig. 4.35.6)
and crypt abscesses and chronic
changes including marked
architectural distortion (Fig.
4.35.4), basal plasmacytosis (Fig.
4.35.5), and Paneth cell
metaplasia (Fig. 4.35.7)
Not generally
performed. The cells are
Special diffusely positive for
studies p53 (Fig. 4.35.8) and
negative for beta-
catenin
Surgical resection. Patients with
ulcerative colitis undergo regular
Treatment
surveillance screening
colonoscopy
Fair; chronic incurable disease;
prognosis related to extent and
severity of complications and
Prognosis therapy-related side effects.
Increased risk of dysplasia and
adenocarcinoma associated with
an 80% mortality rate
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5. Regular configuration of
glands (Fig. 4.35.10)
6. Mucin predominantly near
the surface with rare
dystrophic goblet cells
7. Sparse stroma with no
increase in mononuclear cells
within the lamina propria and
variable neutrophils (Fig.
4.35.11)
8. Background mucosa can
show either inactive or active
disease with minimal
architectural distortion
Not generally
performed. The
cells are generally
negative for p53
and show nuclear
immunolabeling for
beta-catenin
Endoscopic polypectomy
followed by advanced follow-
up screening colonoscopy for
high-risk patients
Good to fair; the lesions are
precancerous, but only a
subset of patients are at high
risk for recurrence or invasive
carcinoma. Risk factors
include greater than three or
more adenomas, high-grade
dysplasia, villous features, or
an adenoma >1 cm in size
Figure 4.35.1 Low-grade dysplasia with elongated, hyperchromatic,
pseudostratified nuclei.

Figure 4.35.2 High-grade dysplasia showing marked pleomorphism,

hyperchromasia, loss of nuclear polarity, and mucin loss.

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Figure 4.35.3 Colitis-associated dysplasia. A p53 stain highlights epithelial
dysplasia.

Figure 4.35.4 Crypt distortion.

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Figure 4.35.5 Basal plasmacytosis.

Figure 4.35.6 Low-grade dysplasia in association with intraepithelial

neutrophils of acute colitis.

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Figure 4.35.7 Paneth cell metaplasia of chronic colitis.

Figure 4.35.8 Low-grade dysplasia in an adenoma characterized by elongated,

hyperchromatic, pseudostratified nuclei and prominent apoptotic debris.

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Figure 4.35.9 Low-grade dysplasia in an adenoma extending from the surface
epithelium to the base in a “top-down” fashion.

Figure 4.35.10 Normal distribution of glands with low-grade dysplasia in

adenoma.

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Figure 4.35.11 Minimal to no changes in the lamina propria in adenoma.

4.36 Adenoma with invasive

carcinoma vs. Pseudoinvasion
Adenoma with Invasive Carcinoma Pseudoinvasion
Older adults (60s)
Age/Gender Older adults (60s); males > females
males > females
Most common in
Commonly in the left colon, but can occur the rectosigmoid,
Location
in any location but can occur at any
location
Few, if any; usual incidental findings at Few, if any; most
Symptoms colonoscopy; some patients may present lesions are
with diarrhea, constipation, or GI bleeding incidental findings
Few, if any; most
lesions are detected
Signs Few, if any; most detected via colonoscopy
incidentally via
colonoscopy
Dysplasia of the intestinal epithelium
secondary to complex genetic alterations
involving KRAS, APC, and p53 genes. Risk
factors include environmental factors as

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 adenomas are more common in Displacement of the
Etiology industrialized nations, obesity, tobacco use, dysplastic
dietary factors including high-fat and low- epithelium into the
fiber diets, and inherited syndromes such as submucosal tissue
familial adenomatosis polyposis coli due to
mutations in the APC gene and hereditary
nonpolyposis colorectal cancer
1. Any size polyp;
usually associated
with a polyp that
has a prominent
stalk (Fig. 4.36.5)
2. Low-grade
dysplasia is
characterized by a
proliferation of
pseudostratified
cells with enlarged,
elongated, and
cigar-shaped nuclei;
1. More commonly seen in larger polyps prominent nucleoli;
(>2 cm), polyps with villous morphology, loss of apical mucin;
and left-sided polyps prominent apoptotic
2. Low-grade dysplasia is characterized by bodies; and
a proliferation of pseudostratified cells with scattered mitoses
enlarged, elongated, and cigar-shaped (Fig. 4.36.6)
nuclei; prominent nucleoli; loss of apical 3. High-grade
mucin; prominent apoptotic bodies; and lesions demonstrate
scattered mitoses (Fig. 4.36.1) greater nuclear
3. High-grade lesions demonstrate greater pleomorphism and
nuclear pleomorphism and show show architectural
Histology architectural changes including glandular changes including
crowding, cribriform glands, and loss of glandular crowding,
nuclear polarity cribriform glands,
4. Neoplastic glands infiltrate through the and loss of nuclear
muscularis mucosae into the submucosa polarity
with an associated desmoplastic reaction 4. Neoplastic glands
(Figs. 4.36.2 and 4.36.3) displaced into the

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 5. Invasive glands are predominantly submucosa and
angulated (Fig. 4.36.4) surrounded by
6. Some have hemosiderin or hemosiderin- lamina propria
laden macrophages (Figs. 4.36.7 and
4.36.8)
5. Neoplastic glands
generally have
rounded contours
and a similar
cytoarchitecture as
the in situ glands
(Fig. 4.36.9)
6. Background
hemosiderin and/or
hemosiderin-laden
macrophages (Fig.
4.36.10)
Not
Special Not generally performed generally
studies performed

Simple
polypectomy
Endoscopic polypectomy; surgical resection
Treatment followed by routine
for high-risk tumors
screening
surveillance
Fair; the risk of recurrence of lymph node
metastases varies. Poor prognostic factors
are high tumor grade including poorly
differentiated adenocarcinoma, signet-ring
cell carcinoma, small cell carcinoma and
undifferentiated carcinoma, tumor <1 mm Good; polypectomy
Prognosis
from the resection margin, and involvement is generally curative
of small vessels. Patients with one or more
of these findings have an increased risk of
recurrence of metastases of 10%–25%.
Patients with none of these factors have
minimal to no risk of adverse outcomes

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Figure 4.36.1 Low-grade dysplasia in an adenoma characterized by elongated,
hyperchromatic, and pseudostratified nuclei.

Figure 4.36.2 Invasive carcinoma arising in the background of an adenoma

with low-grade dysplasia.

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Figure 4.36.3 Invasive glands surrounded by desmoplastic reaction.

Figure 4.36.4 Angulated gland in invasive carcinoma surrounded by

desmoplasia.

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Figure 4.36.5 Large polyp with displaced glands within the submucosa.

Figure 4.36.6 Low-grade dysplasia in an adenoma characterized by elongated,

hyperchromatic, pseudostratified cells with prominent apoptotic bodies.

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Figure 4.36.7 Displaced glands in an adenoma with pseudoinvasion
surrounded by lamina propria with vascular congestion and hemorrhage.

Figure 4.36.8 Lamina propria surrounding displaced glands with an admixture

of lymphocytes, plasma cells, and extravasated red blood cells.

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Figure 4.36.9 Displaced glands in an adenoma with pseudoinvasion showing
predominantly rounded contours.

Figure 4.36.10 Hemorrhage and hemosiderin-laden macrophages seen adjacent

to displaced glands in an adenoma with pseudoinvasion.

4.37 Neuroendocrine tumors vs.

Colorectal carcinoma

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 Carcinoid
Older adults (60s–70s); males >
Age/Gender
females
Predominantly in the rectum; a
Location subset occur in the right colon
(12%)
Usually asymptomatic incidental
findings; some present with
Symptoms nonspecific abdominal pain, weight
loss, GI bleeding, rectal pain,
diarrhea
Few, if any; positive fecal occult
Signs blood test; carcinoid syndrome is
rare
Neoplasm that arises from the cells
of the diffuse neuroendocrine
Etiology
system and are often seen in
association with MENI
1. Uniform cells with small,
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Colorectal Carcinoma
Typically older adults
(70s); males > females
More common in the left
colon, but can occur at any
location. Proximal lesion is
associated with younger
age, female gender, and
microsatellite instability
Few to vague and
nonspecific; abdominal
pain, diarrhea, constipation,
tenesmus, rectal bleeding
Positive fecal occult blood
test, iron deficiency anemia
Malignant transformation
of colorectal epithelium
that occurs both
sporadically in association
with mutations in APC,
KRAS, p53, and
microsatellite stability
genes and in association
with inherited syndromes
including hereditary
nonpolyposis colon cancer,
which accounts for up to
10% of cases. Patients with
inflammatory bowel
disease are at increased risk
1. Most are well- to
moderately differentiated
tumors of angulated glands
(Fig. 4.37.6) composed of
hyperchromatic,
 uniform, round nuclei; central
prominent nucleoli; and speckled
chromatin (“salt and pepper”); and
eosinophilic cytoplasm (Fig. 4.37.1)
2. No necrosis
3. Cells arranged in variable
architectural patterns including
trabecular, solid, acinar, and nested
(Fig. 4.37.2)
4. Delicate intervening capillary
network (Fig. 4.37.3)
5. Variable mitotic rate: low grade
(<2/10 hpf) and intermediate grade
(2–20/10 hpf).
Histology 6. High grade has small and/or large
pleomorphic cells with prominent
nucleoli and speckled chromatin
(“salt and pepper”) and eosinophilic
cytoplasm
7. Extensive necrosis and apoptosis
8. Cells arranged in solid sheets
9. Delicate intervening capillary
network
10. High mitotic rate (>20/hpf)
11. Often extensive lymphovascular
invasion
12. Often seen in association with an
adenoma or adenocarcinoma
13. Not associated with
desmoplastic stroma
They show
immunolabeling for
synaptophysin (Fig.
4.37.4) and NSE and
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pleomorphic cells with
moderate to marked
pleomorphism with
variable loss of nuclear
polarity (Fig. 4.37.7)
2. Poorly differentiated
tumors show minimal gland
formation consisting of
sheets and clusters of
markedly pleomorphic
cells, which have lost
nuclear polarity
3. Mucinous carcinomas
account for 10% of tumors
characterized by abundant
extracellular mucin and
mucin pools often with a
signet-ring cell morphology
4. Usually seen in
association with an in situ
adenomatous component
(Fig. 4.37.8)
5. Abundant intraluminal
brightly eosinophilic
acellular necrotic debris is
common (Fig. 4.37.9)
6. Neoplastic cells through
the muscularis mucosae
into the submucosa and are
surrounded by dense
desmoplastic stroma (Fig.
4.37.10)
7. Scattered neuroendocrine
cells
Not generally
performed. The
cells show
immunolabeling
 variably positive for EMA for CK20,
and/or other endocrine AE1/AE3,
markers including CDX2, and CEA.
chromogranin (Fig. They are negative
4.37.5), serotonin, for CK7.
Special glucagon, gastrin, and Neuroendocrine
studies somatostatin. The Ki-67 markers highlight
proliferative index is used scattered
to classify grade—grade 1 neuroendocrine
tumors have an index of cells. The Ki-67
<2%, grade 2 tumors have proliferative
an index of 3%–20%, and index varies, and
grade 3 tumors have an most well-
index of >20%. Distal differentiated
tumors of the rectum are tumors have a
often positive for PSAP low mitotic rate

For small tumors (1–2 cm),

endoscopic polypectomy is
Surgical resection with
recommended for tumors limited to
Treatment chemotherapy for
the mucosa and submucosa and
advanced-stage disease
transanal excision for tumors with
muscularis propria invasion
Variable; well-differentiated tumors
have a favorable prognosis with a 5-
year survival rate of 90%. The most
important prognostic factors include
tumor size, invasion of the
muscularis propria, and tumor Good to fair; the 5-year
location as tumors of the right colon survival rate is 55%–60%;
Prognosis are usually metastatic at the time of mucinous carcinomas have
diagnosis and up to 1/3 of patients a worse prognosis
present with metastatic disease.
Poorly differentiated tumors are
very aggressive with a median
survival of 16 months. The overall
survival rate is 42%–72%

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Figure 4.37.1 Well-differentiated neuroendocrine (carcinoid) tumor composed
of uniform, small, round cells with “salt-and-pepper” chromatin and variable
eosinophilic cytoplasm.

Figure 4.37.2 Well-differentiated neuroendocrine tumor arranged in a nested

architecture with intervening capillaries.

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Figure 4.37.3 Delicate intervening capillary network separating nests of cells
in well-differentiated neuroendocrine tumor.

Figure 4.37.4 Synaptophysin stain in neuroendocrine tumor.

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Figure 4.37.5 Chromogranin stain in neuroendocrine tumor.

Figure 4.37.6 Moderately differentiated colorectal carcinoma infiltrating as

angulated glands within the submucosa.

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Figure 4.37.7 Moderately differentiated colorectal carcinoma showing glands
with enlarged, hyperchromatic cells with marked loss of nuclear polarity and
conspicuous mitoses arranged in complex formations.

Figure 4.37.8 Background adenoma with high-grade dysplasia adjacent to

infiltrating carcinoma seen infiltrating beneath the muscularis mucosae.

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Figure 4.37.9 Intraluminal necrotic debris “dirty necrosis” associated with
infiltrating colorectal carcinoma.

Figure 4.37.10 Colorectal carcinoma. Infiltrating glands set in a desmoplastic

stroma.

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4.38 Sessile serrated adenoma vs.
Hyperplastic polyp
Sessile Serrated Adenoma
Typically older adults (mean
Age/Gender
age 70s); female > male
Predominantly proximal colon,
Location but can occur throughout the
colon
Symptoms Few, usually asymptomatic
Few; colonoscopy shows a
Signs
sessile polyp
Unknown; though has been
shown to be related to sporadic
Etiology microsatellite instability, they
also commonly show mutations
in BRAF
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Hyperplastic Polyp
Older adults; male >
female
Typically in the
rectosigmoid colon, but
can occur in any location
Usually none, incidental
findings
Usually none; incidental
findings at routine
screening colonoscopy
Thought to be a
metaplastic transformation
of normal colonic
epithelium. However,
most microvascular
polyps have mutations in
BRAF, and KRAS
mutations are commonly
identified in goblet cell–
rich polyps
1. Serrated architecture
with serrations limited to
the upper portion of the
crypts, which are narrow
at the base (Fig. 4.38.5)
Three histologic types:
a. Microvesicular:
prominent
serrations
 composed of
small, round,
basally located
nuclei with
ample bubbly
apical
1. Serrated architecture (Fig.
cytoplasm,
4.38.1) with serrations
which imparts a
extending from the upper
frothy
Histology portion of the crypts to the base
appearance
(Fig. 4.38.2) with widened
(Fig. 4.38.6)
crypt bases that resemble “duck
b. Goblet cell rich:
feet” (Fig. 4.38.3)
serrations
minimal and
predominantly
at the surface
composed of
predominantly
goblet cells
c. Mucin poor:
prominent
serrations
composed of
small cells with
scant
intracytoplasmic
mucin

2. Loss of
2. Prominent neuroendocrine
neuroendocrine
cells (Fig. 4.38.7)
cells
3. Nuclear atypia
characterized by
enlarged nuclei
with prominent
nucleoli and
asymmetric
3. Rare pleomorphic and
proliferation,
atypical cells limited to the base

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which extends of the crypts
from the base to
the mid- and
upper crypt;
dysplasia and
carcinoma can be
seen (Fig. 4.38.4)
4. Thin basement 4. Often associated with a
membrane thickened basement membrane
Not generally
performed. The cells
show moderate
Not generally
immunolabeling for
performed. The
CDX2, which is
cells show
predominantly in the
diffuse
crypt bases. Some
immunolabeling
show loss of
for CDX2. The
immunolabeling for
cells show no
MLH1 in areas of
staining for
Special studies dysplasia. A majority
beta-catenin. A
of cases (67%) show
Ki-67
aberrant nuclear
immunostain
expression of beta-
shows increased
catenin. A Ki-67 stain
expression,
shows asymmetric
which is regular
and irregular
and symmetric
expression variably
expressed along the
length of the crypts

Simple polypectomy with

Polypectomy, followed by
Treatment
colonoscopy surveillance
Generally good, though patients lesions are benign, but a
are at increased risk for
colorectal carcinoma as the
Prognosis
lesions are the precursors to
routine follow-up
screening colonoscopy
Generally good; most
subset of lesions,
particularly lesions larger
than 1 cm, are associated

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 tumor that are microsatellite with an increased risk of
unstable carcinoma

Figure 4.38.1 Serrated architecture of sessile serrated adenoma.

Figure 4.38.2 Sessile serrated adenoma. Serrations extending from the surface
to the base of crypts.

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Figure 4.38.3 Sessile serrated adenoma. Expanded and transverse-lying crypts
at the base resembling “duck feet.”

Figure 4.38.4 High-grade dysplasia in sessile serrated adenoma.

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Figure 4.38.5 Serrated epithelium of hyperplastic polyp with serrations limited
to the superficial epithelium.

Figure 4.38.6 Microvesicular hyperplastic polyp with prominent serrations and

ample mucinous cytoplasm.

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Figure 4.38.7 Scattered neuroendocrine cells in hyperplastic polyp.

4.39 Sessile serrated adenoma vs.

Traditional serrated adenoma
Traditional Serrated
Sessile Serrated Adenoma
Adenoma
Typically older adults (mean age 70s); Adults (mean age 65); no
Age/Gender
female > male gender predominance
Predominantly distal left
Location Predominantly proximal right colon
colon
None; usually an
Symptoms Few; usually asymptomatic
incidental finding
None; usually an
Few; colonoscopy shows a sessile
Signs incidental finding at
polyp
screening colonoscopy
Unknown; nearly all show
Unknown; though has been shown to CpG island mutation,
be related to sporadic microsatellite most have mutations in
Etiology instability, they also commonly show KRAS (80%), and a subset

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 mutations in BRAF (20%) have mutations in
BRAF
1. Usually pedunculated
(Fig. 4.39.7)
2. Proliferation of
epithelial cells with
elongated nuclei and
1. Always sessile ample, dense eosinophilic
2. Proliferation of cells with small, cytoplasm and minimal to
round nuclei and ample apical mucin; no mucin (Fig. 4.39.8)
eosinophilic change of the cytoplasm 3. Complex villous
is focal or absent (Fig. 4.39.1) architecture (Fig. 4.39.9)
3. Serrated crypt architecture (Fig. with randomly oriented
4.39.2), which extends from the top to crypts that do not extend
the base of crypts (Fig. 4.39.3) with to the muscularis mucosae
widened crypt bases oriented parallel (“ectopic crypt
to the muscularis mucosae that formation”) (Fig. 4.39.10)
Histology
resemble “duck feet” (Fig. 4.39.4); no a. Filiform
villiform architecture or ectopic serrated
crypts adenoma is a
4. Focal nuclear atypia to dysplasia variant with
and intramucosal carcinoma markedly
characterized by enlarged nuclei with elongated
prominent nucleoli and asymmetric complex
proliferation, which extends from the villiform
base to the mid- and upper crypt projections and
(Figs. 4.39.5 and 4.39.6) edematous
stroma

4. Cytologic dysplasia is
distributed throughout the
lesion (Fig. 4.39.11)
Not generally
performed.
They show
Not generally performed; retained staining
some show loss of for
immunolabeling for MLH1 microsatellite

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Special in areas with dysplasia. A markers
studies stain for Ki-67 shows including
patchy, variable, irregular MLH1. A stain
staining throughout the for Ki-67 shows
crypts staining
primarily
localized to
ectopic crypts

Simple polypectomy
Surgical excision, followed by routine
Treatment followed by routine
colonoscopy surveillance
screening colonoscopy
Generally good, though patients are at
Generally good, though
increased risk for colorectal
the lesion is considered to
Prognosis carcinoma as the lesions are the
be a precursor of
precursors to tumor that are
carcinoma
microsatellite unstable

Figure 4.39.1 Proliferative epithelium in sessile serrated adenoma.

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Figure 4.39.2 Serrated crypt architecture of sessile serrated adenoma.

Figure 4.39.3 Serrations extending from the surface to the base of crypts.

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Figure 4.39.4 Expanded and transverse-lying crypts at the base resembling
“duck feet.”

Figure 4.39.5 Focal nuclear atypia and conspicuous mitoses in sessile serrated
adenoma.

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Figure 4.39.6 High-grade dysplasia in sessile serrated adenoma.

Figure 4.39.7 Pedunculated traditional serrated adenoma.

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Figure 4.39.8 Low-grade dysplasia in traditional serrated adenoma.

Figure 4.39.9 Complex villous architecture of traditional serrated adenoma.

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Figure 4.39.10 Randomly oriented ectopic crypt formation.

Figure 4.39.11 Traditional serrated adenoma. Low-grade dysplasia distributed

throughout the lesion. Note the prominent apoptosis.

4.40 Smooth muscle tumors vs.

Gastrointestinal stromal tumor

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 Smooth Muscle
Gastrointestinal Stromal Tumor
Tumors
Adults (median age
Older adults (mean age 60s); no gender
Age/Gender 62 years); males >
predominance
females (2.4:1)
Predominantly
Location Predominantly rectosigmoid
rectosigmoid
None; usually Nonspecific abdominal pain, abdominal
Symptoms
incidental findings distension
None; usually
incidental finding of Palpable abdominal mass, abdominal
Signs
a small polyp seen at tenderness
colonoscopy
Derived from the interstitial cells of Cajal,
Derived from which regulate motility. Most cases have
smooth muscle cells mutations in the CKIT (70%) or PDGFRA
Etiology
located within the (20%) gene, and a subset are associated
bowel wall with syndromic conditions including NF1
and Carney triad
1. Perpendicularly
oriented fascicles
(Fig. 4.40.1) of
bland, uniform
spindle cells with
elongated, blunt-
ended (cigar-shaped)
nuclei and abundant
1. Proliferation of predominantly uniform
brightly eosinophilic
spindle cells with pale indistinct
cytoplasm (Fig.
eosinophilic cytoplasm (Fig. 4.40.7)
4.40.2)
arranged in varying architectures from
2. Intimately
fascicular to storiform and set in a variably
associated with the
hyalinized and edematous stroma (Fig.
muscularis mucosae
4.40.8); some cases show epithelioid
3. Cells occasionally
Histology morphology (Fig. 4.40.9)
have paranuclear
2. Rarely limited to the muscularis
vacuoles
mucosae; nearly always transmural
4. Some have
3. Cells occasionally have paranuclear

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 3. Cells occasionally have paranuclear
intracellular and vacuoles
interstitial 4. Extracellular collagen globules
eosinophilic globules (skeinoid fibers) are variably present
5. Most have no 5. Few to numerous mitoses
mitoses; rare cases
show malignant
features of
leiomyosarcoma
characterized by
increased nuclear
pleomorphism and
mitoses (Fig. 4.40.3)
The cells
are
universally
positive for
smooth Most cases show
muscle immunolabeling for CD117
actin (Fig. (80%, Fig. 4.40.10) and DOG1
4.40.4) and (90%). The cells are also positive
Special desmin and for CD34 (60%). They can be
studies negative focally positive for desmin.
for CD117 Molecular analysis shows
(Fig. mutations in the c-kit gene in
4.40.5), many cases
CD34
(Fig.
4.40.6),
and DOG1

Primary therapy is surgical resection.

Patient with mutations in the CKIT gene
Treatment Simple polypectomy
are treated with Gleevec/imatinib, a
tyrosine kinase inhibitor
Fair; risk of metastasis or death is related
Excellent; to tumor size and mitotic activity—tumors
leiomyomas are <5 cm with fewer than 5 mitoses per 50
considered benign HPF are considered low risk, while tumors

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 with no risk of over 10 cm with >5 mitoses per 50 HPF
Prognosis recurrence; rare are high risk. Many tumors are classified
cases of as high risk, and up to 60% of cases
leiomyosarcoma develop metastases. The 5-year survival
portend a much rate is 50%, and the 10-year survival rate is
worse prognosis 20%

Figure 4.40.1 Smooth muscle tumor. Spindle cells oriented in tight

perpendicular fascicles.

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Figure 4.40.2 Smooth muscle tumor. Uniform “cigar-shaped” spindle cells
with abundant eosinophilic cytoplasm.

Figure 4.40.3 Focal atypia and prominent mitoses in leiomyosarcoma.

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Figure 4.40.4 A smooth muscle actin stain showing positive labeling in
leiomyoma.

Figure 4.40.5 Negative CD117 stain in leiomyoma.

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Figure 4.40.6 Negative CD34 stain in leiomyoma.

Figure 4.40.7 Gastrointestinal stromal tumor. Proliferation of spindle cells with

pale indistinct cytoplasm.

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Figure 4.40.8 Gastrointestinal stromal tumor. Spindle to epithelioid cells
arranged in loose fascicles.

Figure 4.40.9 Focal epithelioid morphology in GIST.

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Figure 4.40.10 CKIT stain in GIST.

4.41 Granular cell tumor vs.

Gastrointestinal stromal tumor
Granular Cell Tumor Gastrointestinal Stromal Tumor
Adults (mean age 50
Older adults (mean age 60s); no
Age/Gender years); no gender
gender predominance
predominance
Predominantly right
Location colon, but can occur any Predominantly rectosigmoid
location
Nonspecific abdominal pain,
Symptoms None; incidental findings
abdominal distension
None; most are detected
Palpable abdominal mass, abdominal
Signs incidentally via
tenderness
colonoscopy
Derived from the interstitial cells of
Cajal, which regulate mobility. Most
cases have mutations in the CKIT
Derived from Schwann

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Etiology cells of peripheral nerves (70%) or PDGFRA (20%) gene, and a
subset are associated with syndromic
conditions including NF1 and Carney
triad
1. Proliferation of large
1. Proliferation of predominantly
round to oval cells with a
uniform spindle to epithelioid cells
round centrally placed
with pale eosinophilic cytoplasm
nucleus, inconspicuous
(Fig. 4.41.4) arranged in varying
nucleoli, ample granular
architectures from fascicular to
eosinophilic cytoplasm,
storiform (Fig. 4.41.5) and set in a
and distinct cell borders
variably hyalinized and edematous
(Fig. 4.41.1)
Histology stroma
2. Centered in the mucosa
2. Nearly all are transmural; small
and/or submucosa and are
tumors may be confided to the serosa
often localized around
3. Cells occasionally have paranuclear
nerves (Fig. 4.41.2)
vacuoles
3. Occasionally associated
4. Extracellular collagen globules
with lymphoid cuff (Fig.
(skeinoid fibers) are variably present
4.41.2)
5. Few to numerous mitoses
4. No mitoses or necrosis
The cells are
positive for
S100 (Fig.
4.41.3), and the
cytoplasmic
granules are
PAS Most cases show
positive/diastase immunolabeling for CD117
resistant. They (Fig. 4.41.6) and DOG1.
are negative for The cells are also positive
Special CD117, DOG1, for CD34 (60%). They are
studies and CD34. negative for S100.
While not Molecular analysis may
generally show mutations in the CKIT
performed, gene
electron
microscopy
shows abundant

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 cytoplasmic
lysosomes

Primary therapy is surgical resection.

Patient with mutations in the CKIT
Treatment Simple surgical excision
gene are treated with Gleevec, a
tyrosine kinase inhibitor
Fair; risk of metastasis or death is
related to tumor size and mitotic
activity—tumors <5 cm with fewer
than 5 mitoses per 50 HPF are
Good; some cases recur
considered low risk, while tumors
after excision, but the
Prognosis over 10 cm with >5 mitoses per 50
lesions are generally
HPF are high risk. Many tumors are
considered benign
classified as high risk, and up to 60%
of cases develop metastases. The 5-
year survival rate is 50%, and the 10-
year survival rate is 20%

Figure 4.41.1 Granular cell tumor. Large cells with ample granular
eosinophilic cytoplasm and indistinct cell borders.

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Figure 4.41.2 Lymphoid aggregate at the perimeter of a well-circumscribed
granular cell tumor.

Figure 4.41.3 S100 stain in granular cell tumor.

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Figure 4.41.4 Gastrointestinal stromal tumor. Predominantly epithelioid cells
to focal spindle cells with pale eosinophilic cytoplasm.

Figure 4.41.5 Spindle to epithelioid cells of GIST arranged in loose fascicles.

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Figure 4.41.6 CKIT stain in GIST.

4.42 Ganglioneuroma vs. Schwann

cell hamartoma
Ganglioneuroma Schwann Cell Hamartoma
Sporadic: middle-aged adults
(mean age 48 years); no gender
Typically adults; no gender
Age/Gender predominanceSyndromic: Younger
predominance
adults (mean age 35 years), no
gender predominance
Rectosigmoid most
Location Usually, left colon common, but can occur in
any location
Sporadic: most are asymptomatic,
incidental findingsSyndromic: most
None; usually an incidental
Symptoms are symptomatic; present with
finding
constipation, diarrhea, vomiting,
abdominal pain
Most lesions are detected via Few; other than
Signs colonoscopy, which shows a

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 colonoscopy small polyp
Both sporadic and syndromic forms
of disease include
ganglioneuromatous polyposis
Unknown; all sporadic
associated with FAP, Cowden
Etiology lesions; no association with
disease, tuberous sclerosis, and
syndromic conditions
juvenile polyposis and
ganglioneuromatosis associated
with MEN2B and NF1
1. Sporadic lesions:
a. Usually solitary
b. Lamina propria
expanded by spindle
Schwann cells nestled in
a fibrillary matrix (Figs.
4.42.1 and 4.42.2).
Adjacent to irregular
clusters of ganglion cells
(Fig. 4.42.3)

2. Syndromic lesions:
a. Generally multiple
b. Ganglioneuromatosis 1. Usually solitary lesion
polyposis shows 2. Diffuse proliferation (Fig.
multiple exophytic 4.42.5) of bland spindle cells
polyps characterized a with wavy nuclei, ample
lamina propria expanded eosinophilic cytoplasm, and
Histology by spindle cells nestled indistinct cell borders
in a fibrillary matrix centered in the lamina
adjacent to numerous propria (Fig. 4.42.6), which
clusters of ganglion cells entraps residual crypts
arranged in a filiform 3. No ganglion cells
architecture 4. Axons rare to absent
c. Ganglioneuromatosis
shows ill-defined
transmural lesions
characterized by
confluent and fusiform

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 expansions of
ganglioneuromatous
proliferations centered
around the myenteric
plexus (Fig. 4.42.4)

3. Axons present

Not generally performed.

The cells are
The spindle cells show
diffusely positive
immunolabeling for
for S100 (Fig.
S100, and the ganglion
Special 4.42.7). They are
cells are positive for
studies negative for NSE,
NSE, synaptophysin, and
synaptophysin and
neurofilament protein.
neurofilament
Clinical history can be
protein
important

Sporadic: polypectomy is curative,

Polypectomy is usually
and follow-up screening is not
curative; no surveillance
Treatment recommended.Syndromic: routine
screening follow-up is
follow-up screening surveillance is
necessary
recommended
Generally good; the lesion itself is
benign, and few sporadic cases
recur. Syndromic cases however
Excellent; lesions are
are associated with an increased
Prognosis considered benign and rarely
risk of transformation to malignant
recur
neoplasms including endocrine
neoplasms and malignant
peripheral nerve sheath tumors

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Figure 4.42.1 Ganglioneuroma centered in the lamina propria.

Figure 4.42.2 Ganglioneuroma. Proliferation of Schwann cells set in a

fibrillary eosinophilic matrix.

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Figure 4.42.3 Irregular clusters of ganglion cells adjacent to spindle cells in
ganglioneuroma.

Figure 4.42.4 Ganglioneuromatosis involving the muscularis propria of the

bowel wall.

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Figure 4.42.5 Diffuse proliferation of Schwann cell hamartoma within the
lamina propria.

Figure 4.42.6 Schwann cell hamartoma. Proliferation of spindle cells with

wavy nuclei, eosinophilic fibrillary cytoplasm, and indistinct cell borers.

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Figure 4.42.7 S100 stain in Schwann cell hamartoma.

4.43 Neuroma vs. Schwann cell

hamartoma
Neuroma Schwann Cell Hamartoma
Children to young adults; no Typically adults; no gender
Age/Gender
gender predominance predominance
Rectosigmoid most common,
Location Any location
but can occur in any location
Nonspecific abdominal pain,
abdominal distension, None; usually an incidental
Symptoms
constipation, diarrhea, vomiting, finding
dysphagia
Abdominal tenderness;
radiographic studies often show
intestinal dilatation and
Few; other than colonoscopy,
Signs megacolon; most patients present
which shows a small polyp
with mucosal neuromas of the
oral cavity and have skeletal
abnormalities

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 Lesions of the myenteric plexus,
which are seen in association
with MEN2B, an inherited
Unknown; all sporadic lesions;
disorder due to mutations in the
Etiology no association with syndromic
RET protooncogene on
conditions
chromosome 10q11.2, which
often develop diffuse GI
ganglioneuromatosis
1. Usually solitary lesion
2. Diffuse proliferation of
1. Often multiple
bland spindle cells with wavy
2. Hyperplastic expansions of
nuclei, ample eosinophilic
poorly organized, coiled, and
cytoplasm, and indistinct cell
Histology twisted nerve bundles
borders (Fig. 4.43.4) centered
surrounded by perineurium
in the lamina propria, which
(Figs. 4.43.1 and 4.43.2)
entraps residual crypts (Fig.
3. Numerous axons
4.43.5)
3. Axons rare to absent
The cells are
The cells show only
diffusely positive for
focal immunolabeling
S100 (Fig. 4.43.6).
Special for S100 (Fig. 4.43.3).
They are negative for
studies A neurofilament
NSE, synaptophysin,
protein stain highlights
and neurofilament
associated axons
protein

Polypectomy is usually
Simple polypectomy to wide
curative; no surveillance
Treatment excision depending on the extent
screening follow-up is
of involvement
necessary
Good; lesions are considered
benign. However, patients often
have diffuse disease requiring
Excellent; lesions are
multiple excisions. The overall considered benign and rarely
Prognosis
prognosis is related to morbidity recur
associated with the severity of
the underlying syndrome

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Figure 4.43.1 Neuroma. Hyperplastic expansions of nerve bundles surrounding
crypts.

Figure 4.43.2 Neuroma. Proliferation of spindle cells with wavy nuclei,

amphophilic cytoplasm, and indistinct cell borders.

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Figure 4.43.3 S100 stain in neuroma.

Figure 4.43.4 Schwann cell hamartoma centered in the lamina propria.

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Figure 4.43.5 Proliferation of cells with wavy nuclei, eosinophilic cytoplasm,
and indistinct cell borders.

Figure 4.43.6 S100 stain in Schwann cell hamartoma.

4.44 Perineurioma/fibroblastic polyp

vs. Schwann cell hamartoma

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 Schwann Cell
Perineurioma/Fibroblastic Polyp
Hamartoma
Older adults (mean age 50s–60s); Typically adults; no
Age/Gender
male = female gender predominance
Rectosigmoid most
Location Usually rectosigmoid common, but can occur in
any location
None; usually an
Symptoms None; usually an incidental finding
incidental finding
Few; other than
None; colonoscopy shows small,
Signs colonoscopy, which
solitary polyp
shows a small polyp
Unknown; a majority of associated
serrated polyps show mutations in Unknown; all sporadic
BRAF and KRAS similar to those lesions; no association
Etiology
found in hyperplastic polyps but the with syndromic
spindle cell component lacks the conditions
mutations.
1. Usually solitary 1. Usually solitary lesion
2. Well-circumscribed expansion of 2. Diffuse ill-defined
the lamina propria by a population of proliferation (Fig. 4.44.6)
bland, monomorphic spindle cells of bland spindle cells with
with scant eosinophilic cytoplasm wavy nuclei, ample
(Fig. 4.44.1), which encircle vessels eosinophilic cytoplasm,
Histology
and crypts in a concentric fashion and indistinct cell borders
(Fig. 4.44.2) (Fig. 4.44.7) centered in
3. Seen in association with sessile the lamina propria, which
serrated adenomas or hyperplastic entraps residual crypts
polyps in up to 50%–70% of cases 3. No association with
(Fig. 4.44.3) hyperplastic epithelium
The cells are positive for The cells are
few immunohistochemical diffusely
markers but show staining positive for
for perineural markers S100 (Fig.
including GLUT-1 (Fig. 4.44.8). They
4.44.4), EMA (usually, are negative for
Special focal weak staining; Fig. NSE,

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 NSE,
studies 4.44.5 ) , collagen type IV, synaptophysin,
and claudin. They are neurofilament
negative for S100 and protein, and
neuroendocrine markers GLUT1 (Fig.
including synaptophysin 4.44.9).
and NE.

Polypectomy is usually
Polypectomy is curative, and no
Treatment curative; no follow-up is
follow-up is necessary
necessary
Excellent; lesions are
Excellent; benign lesions cured with
Prognosis considered benign and
simple excision
rarely recur

Figure 4.44.1 Fibroblastic polyp/Perineurioma. Proliferation of bland, spindle

cells with scant eosinophilic cytoplasm.

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Figure 4.44.2 Fibroblastic polyp/Perineurioma. This example is associated with
a serrated polyp and shows spindle cell arranged in a concentric fashion
around crypts.

Figure 4.44.3 Perineurioma in association with a sessile serrated adenoma.

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Figure 4.44.4 GLUT-1 stain in perineurioma.

Figure 4.44.5 EMA stain in perineurioma.

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Figure 4.44.6 Schwann cell hamartoma. Diffuse ill-defined proliferation within
the lamina propria.

Figure 4.44.7 Schwann cell hamartoma. Bland spindle cells with wavy nuclei
and ample eosinophilic fibrillary cytoplasm.

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Figure 4.44.8 S100 stain in Schwann cell hamartoma.

Figure 4.44.9 GLUT1 stain in Schwann cell hamartoma.

4.45 Benign epithelioid nerve sheath

tumor vs. Melanoma
Benign Epithelioid Nerve

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 Sheath Tumor Melanoma
Adults (mean age 59
Age/Gender years); no gender Adults (mean age 60s); women > men
predominance
Most occur in the left Commonly in the right colon, but can
Location
colon occur in any location
Most present with GI bleeding; other
Symptoms None; incidental findings symptoms include abdominal pain,
constipation, diarrhea, weight loss
None, though
colonoscopy shows a Few if any; most lesions detected via
Signs
moderate sized polyp colonoscopy
usually up to 1 cm
Most are metastatic; rare cases
represent primary disease. Primary
Unknown; sporadic
disease develops from neural crest
Etiology lesions with no syndromic
cells located within the bowel wall.
associations
Many of the tumors have mutations in
the BRAF gene
1. Proliferation of
predominantly epithelioid
cells with uniform round 1. Sheets of epithelioid to spindled
to oval nuclei, fibrillary cells with enlarged, pleomorphic
eosinophilic cytoplasm nuclei, prominent, often cherry-red,
(Fig. 4.45.1) arranged in nucleoli and ample eosinophilic
nests and whorls (Fig. cytoplasm (Figs. 4.45.10 and 4.45.11)
4.45.2); some cases have 2. Pseudoinclusions—intranuclear
a spindle cell component cytoplasmic invaginations (Fig.
(Fig. 4.45.3) 4.45.11)
2. Pseudoinclusions— 3. Mitoses are usually conspicuous to
intranuclear cytoplasmic prominent (Fig. 4.45.10)
invaginations (Fig. 4. Moderate to marked pleomorphism
4.45.4) (Figs. 4.45.10 and 4.45.11)
3. Few to no mitoses 5. Usually centered in the lamina
Histology 4. Minimal to no atypia or propria but extends into the
pleomorphism submucosa and muscularis propria
5. Usually centered in the (Fig. 4.45.12)

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 lamina propria, but can 6. Pagetoid spread is common, and an
extend into the in situ component is usually seen in
submucosa and rarely into primary lesions
the muscularis propria 7. Infiltrative growth pattern with
(Fig. 4.45.5) destruction of background mucosa
6. Infiltrative growth 8. Pigment is often present (50%)
pattern, which entraps characterized by intracytoplasmic fine
crypts (Fig. 4.45.1) dusty, brown pigment or refractile
7. Overlying mucosa globules of pigment within histiocytes
histologically (Fig. 4.45.13)
unremarkable (Fig.
4.45.6)
The cells show They show diffuse
diffuse immunolabeling for S100
immunolabeling (Fig. 4.45.14) and are
for S100 (Fig. positive for melanocytic
4.45.7) and are markers including Melan-A
variably (Mart1) (Fig. 4.45.15),
positive for HMB-45 (Fig. 4.45.16),
CD34, but are SOX10, and MITF (Fig.
negative for 4.45.17), though spindle
Special melanoma cell melanomas may be
studies markers negative. The Ki-67
including proliferative index is
Melan-A (Fig. generally moderate to high.
4.45.8), MITF, Electron microscopy is not
and HMB-45. generally performed but
The Ki-67 shows characteristic
proliferative premelanosomes. Clinical
index is history can be important to
universally low differentiate primary and
(Fig. 4.45.9) metastatic disease

Surgical resection with wide excision

Simple polypectomy is
Treatment margins followed by chemotherapy
curative
and/or radiation for metastatic disease
Poor; most patients present with
metastatic disease and develop

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 metastatic disease and develop
Prognosis Excellent; benign lesions systemic recurrent disease. The 5-year
with no risk of recurrence survival rate varies from 5% to 25%

Figure 4.45.1 Epithelioid nerve sheath tumor. Epithelioid cells with round
nuclei and ample eosinophilic cytoplasm encircling and entrapping
histologically unremarkable crypts.

Figure 4.45.2 Epithelioid nerve sheath tumor. Epithelioid cells arranged in

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loose nests and whorls.

Figure 4.45.3 Epithelioid nerve sheath tumor. Focal spindle cell component of
benign epithelioid nerve sheath tumor.

Figure 4.45.4 Epithelioid nerve sheath tumor. Intranuclear pseudoinclusion in

benign epithelioid nerve sheath tumor.

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Figure 4.45.5 Benign epithelioid nerve sheath tumor centered in the lamina
propria.

Figure 4.45.6 Histologically unremarkable overlying mucosa.

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Figure 4.45.7 S100 stain in benign epithelioid nerve sheath tumor.

Figure 4.45.8 Negative Melan-A stain in benign epithelioid nerve sheath

tumor.

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Figure 4.45.9 Ki-67 stain in benign epithelioid nerve sheath tumor showing a
very low proliferative index.

Figure 4.45.10 Melanoma. Markedly atypical spindled to epithelioid cells with

prominent nucleoli, ample cytoplasm, and conspicuous mitoses.

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Figure 4.45.11 Intranuclear pseudoinclusions in malignant melanoma.

Figure 4.45.12 Malignant melanoma centered in the submucosa.

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Figure 4.45.13 Markedly pleomorphic cells of malignant melanoma associated
with pigmented macrophages containing fine dusty brown pigment.

Figure 4.45.14 Positive S100 stain in melanoma.

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Figure 4.45.15 Positive Mart-1 (red) stain in melanoma.

Figure 4.45.16 Positive HMB-45 stain in melanoma.

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Figure 4.45.17 Positive MITF stain in melanoma.

4.46 Kaposi sarcoma vs. Lamina

propria
Kaposi Sarcoma Lamina Propria
Age/Gender Any age; no gender predominance Any age; any gender
Location Any location Any location
Usually asymptomatic; some patients
Symptoms present with GI bleeding, abdominal None
pain, nausea, vomiting, diarrhea
Signs Few, if any None
Unknown; the malignant cells are
thought to arise from the endothelium
of lymphatics, and all four variants of
disease are associated with HHV-8
infection, which is currently
considered to be the cause of disease.
The most common variant in the
United States is the epidemic form,

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Etiology which is associated with AIDS. The None
classical variant usually occurs in
elderly men from Eastern Europe. The
endemic form (also known as
lymphadenopathy-associated form)
occurs in young children from South
Africa. The transplant- or
immunosuppression-associated form
occurs in the setting of posttransplant
immunosuppressive therapy
1. Variable cellularity;
more cellular in the
proximal colon
1. Expansion of the lamina propria 2. Mixture of plasma
(Fig. 4.46.1) by a population of cells, lymphocytes, and
spindle cells that form slit-like spaces eosinophils; plasma cells
(Fig. 4.46.2) filled with extravasated limited to the superficial
red blood cells and plasma cells (Fig. mucosa in the distal colon
4.46.3) (Fig. 4.46.6)
Histology
2. Infiltrative lesion with destruction 3. Scattered macrophages;
of background intestinal glands may be occasional
3. Associated hemosiderin-laden hemosiderin-laden
macrophages and hyaline bodies (Fig. macrophages or other
4.46.4) pigmented macrophages
4. Conspicuous mitoses (Fig. 4.46.5) 4. No hyaline bodies or
extravasated red blood
cells (Fig. 4.46.6)
5. Few to no mitoses
The cells show
immunolabeling for CD31,
CD34, factor VIII, and
Immunostaining
Special HHV-8. They are negative
for HHV8 is
for CD10, ER, and PR. A
studies negative
PAS stain highlights the
hyaline globules. Clinical
history is important.

Supportive and symptomatic

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 treatment depending on the form of
Treatment disease including chemotherapy None
and/or radiation therapy. Patients with
HIV are managed with antiretroviral
therapy
Prognosis Generally poor None

Figure 4.46.1 Kaposi sarcoma. Expansion of the lamina propria by a

population of spindle cells with associated hemorrhage.

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Figure 4.46.2 Kaposi sarcoma. Proliferation of spindle cells arranged around
slit-like spaces.

Figure 4.46.3 Kaposi sarcoma. Prominent plasma cells and extravasated red
blood cells in the lamina propria.

Figure 4.46.4 Intracytoplasmic hyaline bodies within spindle cells of Kaposi

sarcoma.

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Figure 4.46.5 Prominent mitoses in Kaposi sarcoma.

Figure 4.46.6 Normal lamina propria.

4.47 Mantle cell lymphoma vs.

Reactive lymphoid hyperplasia
Mantle Cell Lymphoma Reactive Lymphoid Hyperplasia

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 Older adults (mean age 55
Children to young adults; no gender
Age/Gender years); males > females
predominance
(2:1)
Usually at the edges of the More common in the right colon, but
Location
specimen can occur in any location
Abdominal pain, diarrhea, Usually none; however, some
Symptoms GI bleeding, weight loss, patients present in the setting of GI
fatigue infection, which may cause diarrhea
Abdominal tenderness;
radiologic studies may
show intestinal wall
thickening or a mass
lesion; colonoscopy often None; colonoscopy may show a
Signs
shows solitary or multiple “polyp”
small masses
(lymphomatous polyposis,
2 mm–2 cm) but can also
be negative
Transformation of mature Unknown; often seen in association
B cells due to a t(11;14) with infection including Giardia and
(q13;132) translocation viral infection as well as
Etiology
involving the Ig heavy immunodeficiency disorders such as
chain gene and the BCL-1 common variable immunodeficiency
gene and IgA deficiency
1. Proliferation of a
population of monotonous
small to medium-sized
cells with irregularly
shaped nuclei, 1. Prominent well-formed germinal
inconspicuous nucleoli, centers (Fig. 4.47.7), which consist
and scant cytoplasm (Fig. of (1) a pale central germinal center
4.47.1) zone composed of polymorphous B
2. Most cases show diffuse and T cells with intervening larger
infiltration, but the cells follicular dendritic cells and tangible
can adopt a nodular body macrophages (Fig. 4.47.8), (2)
architecture or proliferate a mantle zone composed of a rim of
primarily within the mantle small sized B lymphocytes with

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Histology zone of germinal centers scant cytoplasm, and (3) a marginal
(Fig. 4.47.2) zone composed of loosely associated
3. Residual background B cells with moderate cytoplasm
germinal centers may be (Fig. 4.47.9)
present, but the 2. Germinal centers are of variable
architecture is often size and shape and often polarized
distorted due to (Fig. 4.47.9)
compression by the 3. Mitotic figures may be present but
proliferation of malignant are not numerous (Fig. 4.47.10)
cells 4. Background glands are intact
4. Mitotic figures are (Fig. 4.47.7)
conspicuous (Fig. 4.47.3)
5. Displacement and
obliteration of glands may
be present
The malignant
cells are B cells,
which show
immunolabeling There is a mixed
for CD19 and population of B cells,
CD20 (Fig. which show
4.47.4), as well immunolabeling for CD19
as aberrant and CD20 (Fig. 4.47.11),
expression of but are negative for CD5
CD5 (Fig. and CD43. They are
4.47.5) and universally negative for
CD43. They are cyclin D1 (Fig. 4.47.12). A
universally CD10 stain highlights cells
positive for within the germinal center,
Special cyclin D1 (Fig. and CD23 stain highlights
studies 4.47.6) and follicular dendritic cells.
negative for Stains for CD3 and CD5
CD10 and CD23. (Fig. 4.47.13) highlight
Immunostains for background T cells.
kappa and Immunostains for kappa
lambda light and lambda light chains
chains usually show a mixed population
show lambda with no light chain

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 light chain restriction. Cytogenetic
restriction. studies show no
Cytogenetic rearrangements
analysis shows a
t(11;14)
translocation

Systemic chemotherapy;
surgery is reserved for
Treatment None
complications due to
obstruction or perforation
Poor; most patients have
advanced disease at the
time of diagnosis and do Related to any other pathology
Prognosis
not respond to present in the specimen
chemotherapy. The median
survival is 3–5 years

Figure 4.47.1 Mantle cell lymphoma composed of monocytoid cells with

irregularly shaped nuclei and scant cytoplasm.

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Figure 4.47.2 Mantle cell lymphoma infiltrating the submucosa.

Figure 4.47.3 Conspicuous mitoses in mantle cell lymphoma.

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Figure 4.47.4 CD20 stain in mantle cell lymphoma highlighting malignant B
cells.

Figure 4.47.5 CD5 stain in mantle cell lymphoma showing aberrant expression
by the malignant B cells.

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Figure 4.47.6 Cyclin D1 stain in mantle cell lymphoma showing nuclear
staining in the malignant B cells.

Figure 4.47.7 Well-formed reactive follicle centered in the mucosa.

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Figure 4.47.8 Germinal center composed of various sized B cells, scattered T
cells, and tangible body macrophages.

Figure 4.47.9 Well-formed and polarized germinal center.

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Figure 4.47.10 Scattered mitoses present within the germinal center of a
reactive follicle.

Figure 4.47.11 CD20 stain in reactive lymphoid hyperplasia highlighting B

cells within the germinal center.

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Figure 4.47.12 Lymphocytes in lymphoid hyperplasia showing no staining for
cyclin D1.

Figure 4.47.13 CD3 stain in reactive lymphoid hyperplasia highlights

background T cells.

4.48 Metastatic carcinoma vs.

Colorectal carcinoma

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 Metastatic Carcinoma
Age/Gender Older adults (50s–70s); males = females
Location Any location
Nonspecific abdominal pain, fatigue,
Symptoms
weight loss, GI bleeding
Nonspecific abdominal tenderness, iron
Signs
deficiency anemia
Lymphovascular spread to the colon from p53, and microsatellite
an extracolonic primary. The most
Etiology common metastatic tumors include
breast, stomach, ovary, prostate, and
melanoma
Colorectal Carcinoma
Typically older adults
(70s); males > females
More common in the left
colon but can occur at any
location. Proximal lesion
is associated with younger
age, female gender, and
microsatellite instability
Few to vague and
nonspecific; abdominal
pain, diarrhea,
constipation, tenesmus,
rectal bleeding
Positive fecal occult
blood test, iron deficiency
anemia
Malignant transformation
of colorectal epithelium
that occurs both
sporadically in
association with
mutations in APC, KRAS,
stability genes and in
association with inherited
syndromes including
hereditary nonpolyposis
colon cancer, which
accounts for up to 10% of
cases. Patients with
inflammatory bowel
disease are at increased
risk
1. Most are well- to
moderately differentiated
tumors of angulated

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 glands (Fig. 4.48.7)
composed of
hyperchromatic,
pleomorphic cells with
moderate to marked
pleomorphism with
variable loss of nuclear
polarity (Fig. 4.48.8)
2. Poorly differentiated
tumors show minimal
gland formation
1. Various histologic patterns; many are consisting of sheets and
poorly differentiated (Figs. 4.48.1 and clusters of markedly
4.48.2) pleomorphic cells, which
2. No background in situ component have lost nuclear polarity
though often there is a bottom-up 3. Mucinous carcinomas
Histology infiltration of the submucosa and mucosa account for 10% of
(Figs. 4.48.3 and 4.48.4) tumors characterized by
3. Usually centered in the muscularis abundant extracellular
propria and serosa (Figs. 4.48.5 and mucin and mucin pools
4.48.6) often with a signet-ring
4. Desmoplastic response less prominent cell morphology
4. Usually seen in
association with an in situ
adenomatous component
(Fig. 4.48.9)
5. Abundant intraluminal
brightly eosinophilic
acellular necrotic debris is
common (Fig. 4.48.10)
6. Neoplastic cells
through the muscularis
mucosae into the
submucosa and are
surrounded by dense
desmoplastic stroma (Fig.
4.48.11)
Site-specific

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 immunohistochemical markers Not generally
include performed. The
ER/PR/mammaglobin/GCDFP- cells show
15/CK7 for breast, PSAP and immunolabeling
Special NKX-3.1 for prostate, HMB- for CK20,
studies 45/Melan-A/SOX10/S100 for AE1/AE3,
melanoma, CDX2, and
CK7/ER/PR/WT1/PAX8 for CEA. They are
ovary, and CK7 for stomach. negative for
The cells are negative for CK7
CK20 and CDX2. Clinical
history is important

Chemotherapy and surgical resection for Surgical resection with

Treatment complications including obstruction,
strictures, perforation
Poor; metastatic disease to the colon is
associated with systemic spread of
Prognosis
disease that is often resistant to
chemotherapy
chemotherapy for
advanced-stage disease
Good to fair; the 5-year
survival rate is 55%–60%;
mucinous carcinomas
have a worse prognosis

Figure 4.48.1 Metastatic moderately to poorly differentiated pancreatic

adenocarcinoma.

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Figure 4.48.2 Metastatic sarcomatoid carcinoma of the lung.

Figure 4.48.3 Histologically unremarkable adjoining mucosa in metastatic

carcinoma.

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Figure 4.48.4 Infiltration of the mucosa by metastatic lobular breast carcinoma
in a bottom-up fashion.

Figure 4.48.5 Metastatic sarcomatoid carcinoma of the lung centered in the

muscularis propria.

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Figure 4.48.6 Metastatic pancreatic adenocarcinoma centered in the
submucosa.

Figure 4.48.7 Infiltrating moderately differentiated colorectal adenocarcinoma

seen as angulated glands set in a desmoplastic stroma.

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Figure 4.48.8 Moderately differentiated adenocarcinoma showing enlarged,
hyperchromatic nuclei with loss of nuclear polarity and prominent mitoses.

Figure 4.48.9 Background adenoma with high-grade dysplasia associated with

infiltrating colorectal carcinoma.

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Figure 4.48.10 Intraluminal necrotic debris associated with infiltrating
malignant glands of colorectal carcinoma.

Figure 4.48.11 Moderately differentiated colorectal carcinoma set in a marked

desmoplastic stroma.

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 5
Appendix

5.1 Granulomatous appendicitis vs. Crohn disease of the appendix

5.2 Interval appendix vs. Crohn disease of the appendix
5.3 Infectious appendicitis with granulomas vs. Crohn disease of
the appendix
5.4 Low-grade appendiceal mucinous neoplasm vs. Appendiceal
diverticulum
5.5 Low-grade appendiceal mucinous neoplasm vs. Sessile
serrated adenoma
5.6 Low-grade appendiceal mucinous neoplasm vs.
Tubular/tubulovillous adenoma
5.7 Low-grade appendiceal mucinous neoplasm vs. Well-
differentiated adenocarcinoma
5.8 Low-grade appendiceal mucinous neoplasm vs. High-grade
mucinous neoplasm
5.9 Well-differentiated neuroendocrine (carcinoid) tumor vs.
Goblet cell carcinoid
5.10 Tubular carcinoid vs. Adenocarcinoma
5.11 Goblet cell carcinoid vs. Adenocarcinoma ex goblet cell
carcinoid
5.12 Goblet cell carcinoid vs. Adenocarcinoma

5.1 Granulomatous appendicitis vs.

Crohn disease of the appendix

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 Granulomatous
Appendicitis
Typically young adults; more Typically young adults (20s–30s);
Age/Gender
common in males no gender predominance
Location Any location
Right lower quadrant
Symptoms abdominal pain, nausea,
vomiting, loss of appetite
Abdominal tenderness,
Signs elevated white blood cell
count, fever
Unknown; some cases have
been associated with Yersinia
infection; other associations
include foreign body
Etiology
reactions, interval
appendicitis, Mycobacterium
tuberculosis, Enterobius
vermicularis, and sarcoidosis
1. Foci of inflammation
characterized by neutrophils
within the epithelium
(cryptitis) and crypts (crypt
abscesses) (Fig. 5.1.1)
2. Transmural lymphoid
aggregates
Histology 3. Numerous (Fig. 5.1.2)
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Crohn Disease of the Appendix
Any location
Depends on site of involvement;
usually present with abdominal
pain, diarrhea, fever, dyspepsia,
weight loss
Depends on severity of underlying
Crohn disease, including anemia
and failure to thrive. CT scan
shows mural thickening extending
from the appendix into the ileum
and/or cecum
Unknown; chronic relapsing and
remitting inflammatory disease,
which can affect any segment of
the GI tract but commonly
involves the terminal ileum and
proximal colon
1. Discrete foci of inflammation
characterized by neutrophils
within the epithelium (cryptitis)
(Fig. 5.1.4) and crypts (crypt
abscesses) (Fig. 5.1.5) adjacent to
normal epithelium (“skip
lesions”—variability of
inflammation along the GI tract)
2. Aphthous ulcers characterized
by focal epithelial necrosis
associated with a mixed acute and
chronic inflammatory infiltrate
and an underlying lymphoid
aggregate (Fig. 5.1.6)
 well-formed granulomas (Fig. 3. Prominent submucosal chronic
5.1.3)—20 granulomas per inflammation
tissue section 4. Transmural lymphoid
4. Few chronic changes, if aggregates arranged in a “string of
any pearls” (Fig. 5.1.7)
5. Occasional fissures and 5. Only occasional poorly formed
fistulae granulomas—0.3 granulomas per
tissue section (Fig. 5.1.8)
6. Chronic changes include
pyloric metaplasia (Fig. 5.1.9) and
crypt distortion (Fig. 5.1.10)
7. Fissures, fistulae, and
longitudinal ulcers are common
Not generally
Not generally
performed. Clinical
Special performed. Clinical
history is most
studies history is critical to
important to document a
diagnosis
history of Crohn disease

The primary treatment is

immunomodulation with a variety
of agents including steroids and
Appendectomy is generally
Treatment TNF-alpha inhibitors. Surgical
definitive therapy
resection for severe complications
including obstruction or
hemorrhage
Variable; related to the extent and
severity of the underlying Crohn
Very good; few patients have
disease. Appendiceal involvement
recurrent disease though a
Prognosis usually indicates extensive
subset are later diagnosed
ileocolic disease and thus is
with Crohn disease
associated with more severe
disease and a worse prognosis

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Figure 5.1.1 Granulomatous appendicitis. Focal cryptitis with infiltrating
neutrophils.

Figure 5.1.2 Granulomatous appendicitis. Transmural granulomatous

inflammation.

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Figure 5.1.3 Granulomatous appendicitis. Well-formed noncaseating
granulomas.

Figure 5.1.4 Cryptitis in Crohn colitis.

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Figure 5.1.5 Crypt abscess in Crohn colitis.

Figure 5.1.6 Aphthous ulcer consisting of a mucosal lymphoid aggregate with

a surface erosion.

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Figure 5.1.7 Transmural lymphoid aggregates in Crohn colitis.

Figure 5.1.8 Crohns appendicitis. Rare poorly formed granuloma.

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Figure 5.1.9 Pyloric metaplasia in Crohn appendicitis.

Figure 5.1.10 Crypt distortion in Crohn appendicitis.

5.2 Interval appendix vs. Crohn

disease of the appendix
Interval Appendix Crohn Disease of the Appendix

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 Children to early adults (5– Typically young adults (20s –30s);
Age/Gender 20 years); male
no gender predominance
predominance
Location Any location Any location
Depends on site of involvement,
Acute right lower quadrant
usually present with abdominal pain,
Symptoms abdominal pain, nausea,
diarrhea, fever, dyspepsia, weight
vomiting
loss
Depends on severity of underlying
Fever, elevated white blood Crohn disease, including anemia and
cell count, abdominal failure to thrive. CT scan shows
Signs
tenderness, rebound mural thickening extending from the
tenderness appendix into the ileum and/or
cecum
Chronic reparative
response to ruptured acute Unknown; chronic relapsing and
appendicitis, which is remitting inflammatory disease,
Etiology usually treated with which can affect any segment of the
antibiotic therapy prior to GI tract but commonly involves the
appendectomy several terminal ileum and proximal colon
weeks later
Two histologic patterns:
1. Usual pattern
a. Transmural acute
and chronic
inflammation
(Figs. 5.2.1 and
5.2.2)
b. Foreign body
giant cells
c. Granulation
tissue and
hemosiderin 1. Transmural lymphoid aggregates
deposition (Fig. arranged in a “string of pearls” (Fig.
5.2.3) 5.2.6)
d. Moderate serosal 2. Discrete foci of inflammation
fibrosis and characterized by neutrophils within

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 serositis the epithelium (cryptitis) (Fig. 5.2.7)
e. Transmural and crypts (crypt abscesses) (Fig.
mucin extrusion 5.2.8) adjacent to normal epithelium
Histology (“skip lesions”—variability of
2. Xanthogranulomatous inflammation along the GI tract)
pattern 3. Only occasional poorly formed
a. Foam cells granulomas—0.3 granulomas per
b. Scattered tissue section (Fig. 5.2.9)
multinucleated 4. Fissures, fistulae, and longitudinal
histiocytes ulcers are common
c. Hemosiderin 5. Dense concentric fibrosis of the
deposition subserosa
d. Luminal
obliteration with
sparing of
lymphoid
follicles (Figs.
5.2.1 and 5.2.4)

3. Up to two-thirds of cases
have prominent
granulomas (Fig. 5.2.5)
4. No fissures
Generally not
performed. AFB
and GMS stains
are helpful to
rule out
Not generally performed.
granulomatous
Special Clinical history is most
infection.
important to document a
studies Clinical history
history of Crohn disease
of acute
appendicitis with
subsequent
treatment is
helpful

The primary treatment is

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 Surgical resection with immunomodulation with a variety of
Treatment supportive care and agents including steroids and TNF-
antibiotic therapy alpha inhibitors. Surgical resection
for severe complications including
obstruction or hemorrhage
Variable; related to the extent and
severity of the underlying Crohn
Very good; complications
disease. Appendiceal involvement
are rare and most
Prognosis usually indicates extensive ileocolic
commonly associated with
disease and thus is associated with
rupture
more severe disease and a worse
prognosis

Figure 5.2.1 Transmural acute and chronic inflammation with luminal

obliteration and sparing of lymphoid follicles in interval appendicitis. Note the
linear arrangement of lymphoid aggregates in the serosa at the right part of the
field.

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Figure 5.2.2 Mixed acute and chronic inflammation in interval appendicitis.

Figure 5.2.3 Granulation tissue in interval appendicitis.

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Figure 5.2.4 Interval appendix. Reactive follicle with prominent germinal
center.

Figure 5.2.5 Prominent transmural granulomatous inflammation in interval

appendicitis.

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Figure 5.2.6 Transmural chronic inflammation and lymphoid aggregates in
Crohn appendicitis.

Figure 5.2.7 Focal cryptitis in Crohn appendicitis.

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Figure 5.2.8 Crypt abscess in Crohn appendicitis.

Figure 5.2.9 Rare poorly formed granuloma in Crohn appendicitis.

5.3 Infectious appendicitis with

granulomas vs. Crohn disease of the
appendix

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 Infectious Appendicitis
Crohn Disease of the Appendix
with Granulomas
Typically young adults (20s–30s); no
Age/Gender Any age; male = female
gender predominance
Location Any location Any location
Nonspecific abdominal
Depends on the site of involvement;
pain, diarrhea, vomiting,
Symptoms usually present with abdominal pain,
fatigue, weight loss, GI
diarrhea, fever, dyspepsia, weight loss
bleeding
Depends on severity of underlying
Crohn disease, including anemia and
Abdominal tenderness,
Signs failure to thrive. CT scan shows mural
fever
thickening extending from the
appendix into the ileum and/or cecum
Granulomatous response
associated with certain Unknown; chronic relapsing and
infections including remitting inflammatory disease, which
Etiology Mycobacteria sp., can affect any segment of the GI tract
Yersinia sp., and fungal but commonly involves the terminal
infections such as ileum and proximal colon
Histoplasma capsulatum
1. Background often
shows marked acute and
chronic inflammation
primarily involving the
lamina propria with 1. Discrete foci of inflammation
focal erosion and/or characterized by neutrophils within the
ulceration (Fig. 5.3.1) epithelium (cryptitis) (Fig. 5.3.5) and
2. Numerous, large, crypts (crypt abscesses) (Fig. 5.3.6)
well-formed, often adjacent to normal epithelium (“skip
necrotizing granulomas lesions”—variability of inflammation
(Fig. 5.3.2) along the GI tract)
3. Granulomas often 2. Only rare occasional poorly formed,
centered within nonnecrotizing granulomas (Fig. 5.3.7)
Histology
lymphoid follicles (Fig. 3. Granulomas randomly distributed;
5.3.3) no association with lymphoid follicles
4. Multinucleated (Fig. 5.3.7)

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 Langhans-type giant 4. No multinucleated giant cells
cells occasionally 5. Dense concentric fibrosis of the
present (Fig. 5.3.4) subserosa
5. Bowel wall thickening 6. Background shows chronic changes
and ulceration can be including basal plasmacytosis (Fig.
seen particularly in 5.3.8) and crypt distortion (Fig. 5.3.9)
Yersinia infection
6. No significant crypt
distortion; plasma cells
are not increased
AFB and GMS
are generally
performed. Not generally performed.
Special Culture and Clinical history is most
studies clinical history important to document a
can be history of Crohn disease
important to
diagnosis

The primary treatment is

Supportive care and/or
immunomodulation with a variety of
antibiotics. Surgery for
agents including steroids and TNF-
Treatment complications including
alpha inhibitors. Surgical resection for
perforation and
severe complications including
obstruction
obstruction or hemorrhage
Variable; related to the extent and
severity of the underlying Crohn
Generally good; most
disease. Appendiceal involvement
infections resolve
Prognosis usually indicates extensive ileocolic
spontaneously or with
disease and thus is associated with
antibiotic therapy
more severe disease and a worse
prognosis

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Figure 5.3.1 Marked acute and chronic inflammation in infectious appendicitis.

Figure 5.3.2 Multiple, large necrotizing granulomas in Yersinia infectious

appendicitis.

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Figure 5.3.3 Obliteration of the appendiceal mucosa and lumen by large,
coalescent necrotizing granulomas centered within lymphoid follicles in
Yersinia infectious appendicitis.

Figure 5.3.4 Prominent Langhans-type giant cells in infectious appendicitis.

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Figure 5.3.5 Focal cryptitis in Crohn appendicitis.

Figure 5.3.6 Crypt abscess in Crohn appendicitis.

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Figure 5.3.7 Poorly formed Granuloma in Crohn appendicitis.

Figure 5.3.8 Basal plasmacytosis in Crohn disease.

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Figure 5.3.9 Crypt distortion and marked mucosal chronic inflammation with
an associated lymphoid aggregate in Crohn appendicitis.

5.4 Low-grade appendiceal mucinous

neoplasm vs. Appendiceal
diverticulum
Low-Grade Appendiceal
Appendiceal Diverticulum
Mucinous Neoplasm
Typically adults (60s); female Typically adults (50s –60s); no
Age/Gender
predominance gender predominance
Location Any location in appendix Any location in appendix
Most patients are symptomatic
and present with right lower
quadrant pain. Occasionally, Most are asymptomatic and
patients present with abdominal discovered either incidentally or
Symptoms

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 distension due to rupture and in association with acute
subsequent extrusion of mucus appendicitis
into the peritoneal cavity
(pseudomyxoma peritonei)
Abdominal tenderness, dullness Nonspecific, vague abdominal
Signs
to abdominal percussion pain; nausea
Unknown; usually an acquired
defect thought to be due to wall
weakness and increased
Unknown; most common
intraluminal pressure;
mucinous neoplasm of the
associated with cystic fibrosis;
Etiology appendix. Some cases are
up to 14% of patients develop
associated with colonic
diverticula and can be markers
adenomas
of local or regional neoplasms
including low-grade epithelial
neoplasms of the appendix
1. Usually, multiple diverticula,
<5 mm
2. Herniation of the mucosa and
muscularis mucosae through the
submucosa and muscularis
1. Flat to villiform intestinal- propria longitudinally parallel to
type epithelium lined by basally vessels (Figs. 5.4.3 and 5.4.4)
located to pseudostratified 3. Free-floating periappendiceal
elongated and hyperchromatic mucin, which can be associated
nuclei with prominent apical with eversion of the diverticular
mucin (Fig. 5.4.1) epithelium onto the serosal
2. Up to 42% are associated surface mimicking serosal
with diverticula periappendiceal involvement by tumor (Figs.
Histology
serosal mucin deposits 5.4.5 and 5.4.6)
3. Back-to-back crypts with 4. Preserved architecture—
minimal intervening lamina background mucosa is
propria (Fig. 5.4.2) hyperplastic with focal villous
4. No association with architecture, mild reactive
neuromas and few regenerative atypia (Fig. 5.4.7), and crypt
changes other than those distortion, and the changes are
associated with extruded mucin most prominent in the

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 superficial mucosa sparing the
crypts
5. Often associated with
mucosal neuromas and other
reparative changes
Not generally
performed. In certain
cases, a panel of
immunostains can be
helpful to
differentiate a
primary from
metastasis or
Special Not generally
involvement from an
studies performed
ovarian tumor. The
cells show
immunolabeling for
CK20 and CDX-2
and are generally
negative for CK7,
ER, PR, WT1, and
PAX8

Primary treatment is surgical
Treatment
excision
Generally good; limited disease
is considered clinically benign.
Clinical history of
pseudomyxoma peritonei
Prognosis
portends a worse outcome.
Five-year survival rate for
tumors with spread beyond the
appendix is 86%
Appendectomy is curative;
standard therapy or any
underlying neoplasm identified
Excellent; nearly universally
benign. The prognosis of cases
associated with cystic fibrosis or
neoplasm varies depending on
the extent of the underlying
pathology

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Figure 5.4.1 Low-grade dysplasia in low-grade appendiceal mucinous
neoplasm characterized by elongated, hyperchromatic pseudostratified nuclei.

Figure 5.4.2 Proliferative epithelium of low-grade mucinous neoplasm with

minimal intervening lamina propria.

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Figure 5.4.3 Diverticulum herniating through the bowel wall.

Figure 5.4.4 Flat epithelium in appendiceal diverticulum with submucosal

edema.

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Figure 5.4.5 Extruded mucin without epithelial cells.

Figure 5.4.6 Ruptured diverticulum with mucin extrusion and mucous cells.

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Figure 5.4.7 Reactive epithelial changes in appendiceal diverticulum.

5.5 Low-grade appendiceal mucinous

neoplasm vs. Sessile serrated
adenoma
Low-Grade Appendiceal
Sessile Serrated Adenoma
Mucinous Neoplasm
Typically adults (60s); female Adults (60s); no gender
Age/Gender
predominance predominance
Any location in the appendix;
Typically involve the entire
Location typically involves the entire
luminal circumference
luminal circumferences
Most patients are symptomatic
and present with right lower
quadrant pain. Occasionally,
patients present with abdominal
Symptoms distension due to rupture and
subsequent extrusion of mucus
into the peritoneal cavity

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 (pseudomyxoma peritonei)
Abdominal tenderness, dullness
Signs Few, if any
to abdominal percussion
Unknown; a subset have loss of
Unknown; most common
microsatellite instability and
mucinous neoplasm of the
mutations in BRAF (29%) and
Etiology appendix. Some cases are
KRAS (34%) though the
associated with colonic
biologic significance of these
adenomas
mutations is unknown (19%)
1. Prominent architectural
distortion characterized by
serrated crypts, which extend
1. Flat to villiform intestinal-
toward the crypt base; crypt
type epithelium lined by basally
dilation; crypt branching with
located to pseudostratified
transverse-lying/lateral
elongated and hyperchromatic
branching crypts at the base
nuclei with prominent apical
(“duck feet”) (Figs. 5.5.4 and
mucin (Figs. 5.5.1 and 5.5.2)
5.5.5)
Histology 2. Mucous cells present at the
2. Differentiated mucous cells
tips of villi form structures
located at the crypt base (Fig.
3. Mild to moderate cytologic
5.5.6)
atypia present (Fig. 5.5.3)
3. No to minimal cytologic
4. Back-to-back crypts with
atypia in early lesions; late
minimal to no intervening
lesions can show moderate
lamina propria
cytologic atypia
4. Villiform architecture is not
prominent
Not generally Not generally
Special
performed performed
studies
Surgical resection;
Primary treatment is surgical appendectomy is usually
Treatment
excision curative. Routine colonoscopy
is recommended
Generally good; limited disease
is considered clinically benign.
Clinical history of

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 pseudomyxoma peritonei Generally good, though the
Prognosis
portends a worse outcome. malignant potential of SSA in
Five-year survival rate for the appendix is still unknown
tumors with spread beyond the
appendix is 86%

Figure 5.5.1 Cystic low-grade appendiceal mucinous neoplasm.

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Figure 5.5.2 Undulating epithelium of low-grade appendiceal mucinous
neoplasm with low-grade dysplasia. Note the absence of lamina propria.

Figure 5.5.3 Reactive epithelial changes in low-grade appendiceal mucinous

neoplasm in association with ulceration and acute inflammation.

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Figure 5.5.4 Sessile serrated adenoma. Serrated epithelium along the entire
length of the epithelium.

Figure 5.5.5 Sessile serrated adenoma. Prominent crypt dilation at the base
with transverse-lying crypts (“duck feet”).

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Figure 5.5.6 Sessile serrated adenoma. Differentiated mucous cells at the crypt
base.

5.6 Low-grade appendiceal mucinous

neoplasm vs. Tubular/tubulovillous
adenoma
Low-Grade Appendiceal
Mucinous Neoplasm
Typically adults (60s); female
Age/Gender
predominance
Any location in appendix;
typically involves the entire
Location
luminal circumference (Fig.
5.6.1)
Most patients are symptomatic
and present with right lower
quadrant pain. Occasionally,
patients present with abdominal
Symptoms distension due to rupture and
Tubular/Tubulovillous
Adenoma
Typically adults (60s); female
predominance
Any location in appendix;
typically involves the entire
luminal circumferences
Most patients are symptomatic
and present with right lower
quadrant pain. Occasionally,
patients present with
abdominal distension due to

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 subsequent extrusion of mucus rupture and subsequent
into the peritoneal cavity extrusion of mucus into the
(pseudomyxoma peritonei) peritoneal cavity
(pseudomyxoma peritonei)
Abdominal tenderness,
Abdominal tenderness, dullness
Signs dullness to abdominal
to abdominal percussion
percussion
Unknown; the tumors often
Unknown; most common
have KRAS mutations similar
mucinous neoplasm of the
to conventional colon
Etiology appendix. Some cases are
adenomas, but they have not
associated with colonic
been shown to have mutations
adenomas
in APC, or BRAF
1. Flat to villiform intestinal-
1. Flat to villiform intestinal-
type epithelium lined by basally
type epithelium (Fig. 5.6.4)
located to pseudostratified
lined by basally located to
elongated and hyperchromatic
pseudostratified elongated and
nuclei with prominent apical
hyperchromatic nuclei with
mucin (Fig. 5.6.2)
abundant intracytoplasmic
2. Often associated with cystic
mucin (Fig. 5.6.5)
dilation with flatting and partial
2. Often associated with cystic
denudation of the epithelium
dilation with flatting and
Histology (Fig. 5.6.3)
partial denudation of the
3. Variable patterns of invasion
epithelium
including direct extension and
3. No invasion—confined to
extension along diverticula
the mucosa with the muscularis
4. Fibrosis, hyalinization, and
mucosae intact
calcification of the muscularis
4. Bowel wall histologically
propria are common
unremarkable
5. Often present with prominent
5. No mucin on the peritoneal
periappendiceal serosal mucin
surface
deposits
Not generally
Not generally performed. The cells
performed. The cells show
show immunolabeling immunolabeling for
Special
studies for CK20, CDX-2, and CK20, CDX-2, and
MUC-2 and variable

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 labeling for MUC-1 MUC-2 and are
negative for MUC-1

Primary treatment is surgical Surgical resection via

Treatment
excision appendectomy
Generally good; limited disease
is considered clinically benign.
Clinical history of
pseudomyxoma peritonei
Prognosis portends a worse outcome and Excellent; clinically benign
requires close clinical follow-up.
Five-year survival rate for
tumors with spread beyond the
appendix is 86%

Figure 5.6.1 Low-grade appendiceal neoplasm involving the entire appendiceal

circumference with associated intraluminal debris.

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Figure 5.6.2 Villiform architecture of low-grade appendiceal neoplasm
composed of cells with elongated, hyperchromatic nuclei, which are variably
pseudostratified.

Figure 5.6.3 Flat epithelium of low-grade appendiceal neoplasm seen in

association with cystic dilation.

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Figure 5.6.4 Pedunculated villous adenoma extending into the appendiceal
lumen.

Figure 5.6.5 Low-grade dysplasia in an adenoma showing elongated,

hyperchromatic pseudostratified cells with prominent apoptotic bodies and
mitoses.

5.7 Low-grade appendiceal mucinous

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neoplasm vs. Well-differentiated
adenocarcinoma
Low-Grade Appendiceal Mucinous Well-Differentiated
Neoplasm Adenocarcinoma
Typically adults (60s); female Older adults (50s–70s);
Age/Gender
predominance male predominance
Any location in the appendix; More common in the
Location typically involves the entire luminal proximal third of the
circumferences appendix
Most patients are symptomatic and Most present with
present with right lower quadrant symptoms of acute
pain. Occasionally, patients present appendicitis including
Symptoms with abdominal distension due to right lower quadrant
rupture and subsequent extrusion of abdominal pain, nausea,
mucus into the peritoneal cavity vomiting, fever, and
(pseudomyxoma peritonei) gastrointestinal bleeding
Abdominal tenderness,
Abdominal tenderness, dullness to palpable abdominal pass,
Signs
abdominal percussion bowel obstruction,
hematochezia
Unknown; many tumors
Unknown; most common mucinous
have mutations in KRAS,
neoplasm of the appendix. Some
Etiology DPC4, and p53 as well as
cases are associated with colonic
allelic loss of chromosome
adenomas
18q
1. Most are mucinous
adenocarcinomas (40%)
characterized by
infiltrating glands
composed of mucous cells
1. Flat (Fig. 5.7.1) to villiform (Fig. with hyperchromatic and
5.7.2) intestinal-type epithelium lined pleomorphic nuclei (Fig.
by basally located to pseudostratified 5.7.3)
2. Variable cytologic

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 elongated and hyperchromatic nuclei
with prominent apical mucin
2. Low-grade cytologic atypia
3. Variable patterns of invasion
Histology including direct extension and
extension along diverticula in a
pushing growth pattern
4. Fibrosis, hyalinization, and
calcification of the muscularis
propria are common
5. Often present with prominent
periappendiceal serosal mucin
deposits
atypia—low to high grade
(Fig. 5.7.4)
3. Irregular infiltration into
the submucosa and
muscularis propria (Fig.
5.7.5)
4. Desmoplastic stroma
(Fig. 5.7.3)
5. Dissecting pools of
mucin with entrapped
malignant cells are
common (Fig. 5.7.6)
6. Transmural rupture is
common resulting in
extrusion of mucin into the
peritoneal cavity
7. Background adenoma
usually present (Fig. 5.7.7)

Special Not generally

Not generally performed
studies performed

Surgical resection via right

hemicolectomy.
Oophorectomy is
Treatment Primary treatment is surgical excision recommended for women.
Advanced-stage disease is
treated with peritonectomy
and chemotherapy
Generally good; limited disease is Fair; poor prognostic
considered clinically benign. Clinical factors include
history of pseudomyxoma peritonei nonmucinous histology,
portends a worse outcome and stage, grade, and
Prognosis
requires close clinical follow-up. peritoneal carcinomatosis
Five-year survival rate for tumors at the time of diagnosis.
with spread beyond the appendix is The 5-year survival rate
86% varies from 19% to 55%

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Figure 5.7.1 Low-grade appendiceal mucinous neoplasm with flat architecture
showing elongated, hyperchromatic, and crowded nuclei.

Figure 5.7.2 Low-grade appendiceal mucinous neoplasm with undulating

architecture showing elongated, hyperchromatic, and crowded, pseudostratified
nuclei.

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Figure 5.7.3 Infiltrating moderately differentiated adenocarcinoma composed
of irregular-shaped glands set in a desmoplastic stroma.

Figure 5.7.4 Moderately differentiated adenocarcinoma characterized by a

gland with elongated, hyperchromatic nuclei with prominent mucinous
infiltrating the soft tissues.

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Figure 5.7.5 Irregular infiltration of adenocarcinoma seen as pools of mucin
with epithelium dissecting into the muscularis propria.

Figure 5.7.6 Dissecting pools of mucin with floating malignant cells in

invasive adenocarcinoma.

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Figure 5.7.7 Background adenoma with focal invasion of adenocarcinoma.

5.8 Low-grade appendiceal mucinous

neoplasm vs. High-grade mucinous
neoplasm
Low-Grade Appendiceal High-Grade Mucinous
Mucinous Neoplasm Neoplasm
Typically adults (60s); female Older adults; no gender
Age/Gender
predominance predominance
Any location in appendix;
Any location; often involves the
Location typically involves the entire
tip of the appendix
luminal circumference
Most patients are symptomatic
and present with right lower
Most common cause of
quadrant pain. Occasionally,
pseudomyxoma peritonei; many
patients present with
patients present with
Symptoms abdominal distension due to constipation, abdominal
rupture and subsequent
distension, vague abdominal
extrusion of mucus into the

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 peritoneal cavity pain
(pseudomyxoma peritonei)

Abdominal tenderness, Abdominal distension,

Signs dullness to abdominal abdominal tenderness, palpable
percussion abdominal mass
Unknown; most common
mucinous neoplasm of the
appendix. Some cases are
Etiology Unknown
associated with ovarian
mucinous cystadenoma and
colonic adenomas
1. Flat to villiform intestinal-
1. Flat to villiform to cribriform
type epithelium lined by
intestinal-type epithelium lined
basally located to
by hyperchromatic cells, which
pseudostratified elongated and
show loss of nuclear polarity and
hyperchromatic nuclei with
irregular nuclear contours
prominent apical mucin (Figs.
2. High-grade cytologic atypia
5.8.1 and 5.8.2)
with frequent mitoses (Fig.
2. Low-grade cytologic atypia
5.8.3)
(Fig. 5.8.1)
3. Variable patterns of invasion
3. Variable patterns of invasion
including direct extension and
including direct extension and
Histology extension along diverticula in a
extension along diverticula in a
pushing growth pattern as well
pushing growth pattern
as spread along the peritoneal
4. Fibrosis, hyalinization, and
surface
calcification of the muscularis
4. Fibrosis, hyalinization, and
propria are common
calcification of the muscularis
5. Often presents with
propria are common
prominent periappendiceal
5. Often presents with prominent
serosal mucin deposits, which
periappendiceal serosal mucin
are usually acellular or contain
deposits, which contain
entrapped bland-appearing
entrapped high-grade epithelium
low-grade epithelium
Not generally
performed.
Immunohistochemistry
can be used to

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 differentiate a GI vs.
Not generally ovarian primary. The
Special
performed cells show
studies
immunolabeling for
CK20, CDX-2, and
CEA and are negative
for ER, PR, WT1, and
PAX 8

Primary treatment is surgical

Primary treatment is surgical
Treatment
excision
Generally good; limited disease
is considered clinically benign.
Clinical history of
pseudomyxoma peritonei
Prognosis portends a worse outcome and
requires close clinical follow-
up. Five-year survival rate for
tumors with spread beyond the
appendix is 86%
excision. Extensive peritoneal
involvement is sometimes
treated with peritonectomy
and/or intraperitoneal
chemotherapy
Fair; best considered as
peritoneal mucinous
adenocarcinomas as they are
more likely to spread to the
peritoneum, portending a worse
prognosis. The 5-year survival
rate is approximately 30%

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Figure 5.8.1 Low-grade appendiceal neoplasm with villiform architecture
characterized by undulating epithelium composed of elongated,
hyperchromatic, crowded, and pseudostratified nuclei.

Figure 5.8.2 Low-grade appendiceal neoplasm with flat architecture

characterized by elongated, hyperchromatic cells.

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Figure 5.8.3 High-grade dysplasia in high-grade mucinous neoplasm
characterized by enlarged, hyperchromatic, pleomorphic nuclei with loss of
polarity, mucin loss, and conspicuous mitoses.

5.9 Well-differentiated
neuroendocrine (carcinoid) tumor vs.
Goblet cell carcinoid
Well-Differentiated
Neuroendocrine (Carcinoid) Goblet Cell Carcinoid
Tumor
Typically young adults (20–
Typically older adults (50s –60s);
Age/Gender 40 years); females more
no gender predominance
common than males
Location Appendix, usually at the tip Tip of the appendix
Usually asymptomatic; most
are discovered incidentally. Most patients present with
Some patients present with symptoms of acute appendicitis
symptoms of acute
Symptoms appendicitis including right including right lower quadrant
abdominal pain, nausea, vomiting,

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 lower quadrant abdominal loss of appetite
pain, nausea, vomiting, loss
of appetite
Few; nonspecific. Some
present with fever, elevated
Fever, elevated white blood cell
white blood cell count,
count, abdominal tenderness,
Signs abdominal tenderness,
rebound tenderness, occasional
rebound tenderness,
palpable abdominal mass
occasional palpable
abdominal mass
Unknown; arise from
primitive neuroendocrine Unknown; arises from pluripotent
cells within the bowel wall. stem cells located in the crypts of
Most are serotonin- the intestinal epithelium and
Etiology producing enterochromaffin develops a mixed mucinous and
cell carcinoids, and a subset neuroendocrine phenotype. It has
are glucagon-like peptide been associated with
and PP/PYY-producing L- schistosomiasis
cell carcinoids
1. Goblet cells, which appear as
1. Cells with small, round,
signet ring cells with bland nuclei
uniform centrally located
arranged in nests and tubules
nuclei with stippled
separated by intervening bands of
chromatin and conspicuous
smooth muscle and stroma (Fig.
small nucleoli (“salt and
5.9.5)
pepper”) (Fig. 5.9.1)
2. Predominantly infiltrates the
arranged in various growth
lamina propria and submucosa, but
patterns including trabecular,
usually extends into the muscularis
solid, and acinar (Fig. 5.9.2)
propria and periappendiceal fat in
2. No intracellular mucous
a circumferential pattern (Figs.
vacuoles (goblet cells or
5.9.6 and 5.9.7)
signet ring cells) (Fig. 5.9.1)
3. Pools of extracellular mucin,
Histology 3. Arise in the mucosa but
which often dissect through the
usually extend through the
muscularis propria and serosal soft
muscularis propria into
tissues
periappendiceal soft tissues;
4. Occasional to numerous Paneth
infiltrates as a mass (Fig.
cells (Fig. 5.9.8)
5.9.3)
5. Carcinomatous growth pattern

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 4. No pools of extracellular
mucin
5. No Paneth cell
differentiation
6. Mitoses are rare
7. Vascular and perineural
invasion is common
shows predominantly sheets of
single cells and cribriform growth;
marked nuclear pleomorphism
with conspicuous mitoses
6. Vascular perineural invasion is
common (Fig. 5.9.9)
7. Mucosa usually uninvolved

The cells are

diffusely and The cells show
strongly positive immunolabeling for
for neuroendocrine CEA (Fig. 5.9.10), CAM
markers including 5.2, CDX-2, and CK20
synaptophysin and are variably positive
(Fig. 5.9.4), for chromogranin and
chromogranin, synaptophysin (Fig.
neuron-specific 5.9.11) and, when
enolase, CD57, and positive, typically show
Special CD56. They show focal and patchy
studies immunolabeling staining. Mucin stains
for CDX-2. An are positive (Fig.
immunostain for 5.9.12). Cytogenetic
S100 highlights analysis shows genetic
intervening changes similar to
sustentacular cells. carcinoid tumors of the
They are negative small intestine including
for CEA, and loss of chromosomes
stains for mucin 11q, 16q, and 18q
are negative

Primary therapy is surgical Primary therapy is surgical

excision with resection of the
appendix and/or portions of
Treatment the colon if the tumor is >2
cm or there is extensive
periappendiceal involvement
excision with resection of the
appendix and/or portions of the
colon if the tumor extends beyond
the appendix. Adjuvant
chemotherapy in some cases

Generally good. Approximately

20% of tumors extend beyond the

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 Metastasis is rare, occurring
in up to 9% of cases. The
greatest risk of metastasis is
tumor size (>2 cm). For
Prognosis tumors <2 cm, the presence
of mesoappendiceal invasion
is a poor prognostic factor.
Five-year survival rate is
85%
appendix, and up to 10% of tumors
metastasize, and the 5-year
survival rate is approximately
75%. The most important
prognostic factor is stage; other
poor prognostic factors include a
predominantly solid or
carcinomatous pattern, perineural
invasion, lymphovascular
invasion, and extraappendiceal
spread

Figure 5.9.1 Well-differentiated neuroendocrine tumor composed of small,

round cells with prominent nucleoli and “salt-and-pepper chromatin.”

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Figure 5.9.2 Well-differentiated neuroendocrine tumor involving the mucosa
and submucosa infiltrating in a predominantly trabecular pattern.

Figure 5.9.3 Well-differentiated neuroendocrine tumor involving the mucosa

with extension into the submucosa.

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Figure 5.9.4 Synaptophysin stain in well-differentiated neuroendocrine tumor.

Figure 5.9.5 Goblet cell carcinoid composed of signet ring cells infiltrating the
muscularis propria as clusters of cells.

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Figure 5.9.6 Goblet cell carcinoid involving the submucosa and muscularis
propria and infiltrating in a circumferential pattern.

Figure 5.9.7 Goblet cell carcinoid infiltrating in a circumferential pattern

parallel to smooth muscle bundles in the muscularis propria.

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Figure 5.9.8 Goblet cell carcinoid with scattered Paneth cells.

Figure 5.9.9 Perineural invasion in goblet cell carcinoid.

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Figure 5.9.10 pCEA immunostain in goblet cell carcinoid.

Figure 5.9.11 Synaptophysin stain in goblet cell carcinoid.

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Figure 5.9.12 Mucin stain in goblet cell carcinoid.

5.10 Tubular carcinoid vs.

Adenocarcinoma
Tubular Carcinoid Adenocarcinoma
Typically adults; females Older adults (60s); more common n
Age/Gender
more common than males males
Appendix, usually at the
Location Any location
tip
Most are symptomatic and present
Usually asymptomatic;
with vague abdominal pain and an
most are discovered
abdominal mass; some patients
incidentally. Some
present with symptoms of acute
patients present with
appendicitis including right lower
Symptoms symptoms of acute
quadrant abdominal pain, nausea,
appendicitis including
vomiting, loss of appetite, or
right lower quadrant
abdominal distension due to
abdominal pain, nausea,
pseudomyxoma peritonei. Up to 25%
vomiting, loss of appetite
are discovered incidentally
Few, nonspecific. Some

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 present with fever,
elevated white blood cell Palpable abdominal mass, abdominal
Signs count, abdominal tenderness
tenderness, rebound
tenderness, occasional
palpable abdominal mass
Unknown; many cases are associated
Unknown; arises from with inflammatory bowel disease,
Etiology neuroendocrine stem cells specifically ulcerative colitis. Patients
present in the bowel wall with familial adenomatous polyposis
are also at increased risk
1. Most are well-differentiated
mucinous adenocarcinomas
histologically similar to those found
1. Bland-appearing cells
elsewhere in the colon characterized
with round to oval basally
by well-formed glands (Fig. 5.10.5)
located nuclei, indistinct
composed of mucinous cells with
nucleoli, and eosinophilic
uniform basal to pseudostratified
cytoplasm arranged in
nuclei (Fig. 5.10.6)
small glands and tubules
2. Pools of dissecting mucin with or
with rare solid nests
without neoplastic cells are common
(Figs. 5.10.1 and 5.10.2)
Histology (Fig. 5.10.7)
2. Intraluminal inspissated
3. Mucosa is usually involved, and
mucin
there is usually background dysplasia
3. Scattered Paneth cells
and/or intramucosal carcinoma (the
and goblet cells (Fig.
mucosa may be uninvolved in cases
5.10.3)
of metastatic adenocarcinoma, but the
4. Mucosa usually
lesion is generally located in the
uninvolved (Fig. 5.10.4)
serosa and subserosa) (Fig. 5.10.8)
5. Mitoses rare
4. Mitoses common
5. Often cystic and mimics a
mucocele
The cells are
positive for
CEA and The cells show
universally immunolabeling for CK20,
positive for CDX-2, and CEA. Stains
glucagon. They for glucagon and

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Special show variable neuroendocrine markers
studies immunolabeling including synaptophysin
for and chromogranin are
synaptophysin negative
and
chromogranin

Surgical resection with appendectomy

Surgical resection via
Treatment with or without right hemicolectomy
appendectomy
depending on the extent of disease
Variable; poor prognostic factors
include advanced stage, high-grade
cytology, the presence of
Excellent. There is no
nonmucinous features, spread of
metastatic potential, and
Prognosis mucus beyond the lower right
the lesions are considered
quadrant of the abdomen, and cells
clinically benign
outside the visceral peritoneum of the
appendix. The 5-year survival rate is
80%–95% for localized disease

Figure 5.10.1 Tubular carcinoid composed of small, round cells with rare
nucleoli and eosinophilic cytoplasm.

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Figure 5.10.2 Tubular carcinoid arranged in clusters and cords of cells
infiltrating through the muscularis propria.

Figure 5.10.3 Tubular carcinoid with scattered Paneth cells.

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Figure 5.10.4 Tubular carcinoid infiltrating the submucosa with the mucosa
uninvolved.

Figure 5.10.5 Infiltrating moderately to well-differentiated adenocarcinoma

composed of well-formed glands set in a desmoplastic stroma.

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Figure 5.10.6 Malignant glands in adenocarcinoma showing elongated,
hyperchromatic nuclei, which are crowded and pseudostratified with prominent
mitoses.

Figure 5.10.7 Infiltrating adenocarcinoma associated with dissecting pools of

mucin.

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Figure 5.10.8 Background high-grade dysplasia intramucosal carcinoma
showing markedly enlarged, pleomorphic cells with loss of nuclear polarity and
prominent mitoses.

5.11 Goblet cell carcinoid vs.

Adenocarcinoma ex goblet cell
carcinoid
Adenocarcinoma Ex Goblet
Goblet Cell Carcinoid
Cell Carcinoid
Typically older adults (50s–60s); Older adults (50s–60s); no
Age/Gender
no gender predominance gender predominance
Location Appendix Any location
Most patients present with
Mostly present with acute
symptoms of acute appendicitis
appendicitis including right
Symptoms including right lower quadrant
lower quadrant abdominal
abdominal pain, nausea,
pain, nausea, vomiting
vomiting, loss of appetite
Abdominal tenderness,
Fever, elevated white blood cell palpable abdominal mass;

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 count, abdominal tenderness,
Signs
rebound tenderness, occasional
palpable abdominal mass
Unknown; arises from
pluripotent stem cells located in
the crypts of the intestinal
Etiology epithelium and develops a mixed features of both mucinous and
mucinous and neuroendocrine
phenotype. It has been associated
with schistosomiasis
1. Goblet cells, which appear as scattered Paneth cells (Fig.
signet ring cells with bland
nuclei arranged in nests and
tubules separated by intervening either as (a) signet-ring cell
bands of smooth muscle and
stroma (Fig. 5.11.1)
2. Minimal to no atypia; no
Histology
adenomatous glandular
component
3. Infiltrates the bowel wall as
clusters of cells rather than single characterized by a focus
cells (Fig. 5.11.1)
4. No desmoplastic response
(Fig. 5.11.1)
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some patients present with
ovarian masses, bowel
obstruction, and
gastrointestinal bleeding
Unknown; the tumor has
neuroendocrine differentiation
Biphasic histology with
characteristics of both
adenocarcinoma and goblet
cell carcinoid (Fig. 5.11.4)
1. Features of goblet cell
carcinoid are at least focally
present including cohesive
clusters of goblet cells with
5.11.5)
2. Adenocarcinoma is present
type with individual
dyscohesive signet ring cells
with hyperchromatic,
markedly atypical nuclei (Fig.
5.11.4) or (b) poorly
differentiated type
greater than one low-power
field or 1 mm2 of conventional
poorly differentiated
adenocarcinoma or sheets of
markedly atypical cells (Fig.
5.11.6)
3. Infiltrates the bowel wall as
single cells
 4. Prominent desmoplastic
response
The cells show
The immunostaining
immunolabeling for
profile mirrors the
CEA, CAM 5.2, CDX-
biphasic nature of
2, and CK20 and are
the tumor. The areas
variably positive for
of goblet cell
chromogranin and
carcinoid show
synaptophysin (Fig.
immunolabeling for
5.11.2) and, when
chromogranin and
positive, typically
synaptophysin, while
Special show focal and patchy
the areas of
studies staining. Mucin stains
carcinoma are
are positive (Fig.
negative. Both areas
5.11.3). Cytogenetic
show labeling for
analysis shows genetic
CK20, CEA, and
changes similar to
CDX-2. Mucin
carcinoid tumors of the
stains are positive in
small intestine
the areas of signet
including loss of
ring cell and goblet
chromosomes 11q,
cytology
16q, and 18q

Primary treatment is surgical

Primary therapy is surgical
excision with resection of the
appendix and/or portions of the
Treatment
colon if the tumor extends
beyond the appendix. Adjuvant
chemotherapy in some cases
Generally good. Approximately
20% of tumors extend beyond
the appendix, and up to 10% of
tumors metastasize, and the 5-
year survival rate is
approximately 75%. The most
important prognostic factor is
resection including right
hemicolectomy and
appendectomy with debulking
surgery and oophorectomy for
peritoneal involvement. Most
patients are treated with
chemotherapy
Poor; most (88%–100%)
present with metastatic disease
and extraappendiceal

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Prognosis stage; other poor prognostic extension is common. The 5-
factors include a predominantly year survival rate ranges from
solid or carcinomatous pattern, 36% to 0%
perineural invasion,
lymphovascular invasion, and
extraappendiceal spread

Figure 5.11.1 Goblet cell carcinoid infiltrating the muscularis propria.

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Figure 5.11.2 Synaptophysin stain in goblet cell carcinoid.

Figure 5.11.3 Mucin stain in goblet cell carcinoid.

Figure 5.11.4 Biphasic histology of adenocarcinoma ex goblet cell carcinoid

with focal goblet cell carcinoid and moderately differentiated adenocarcinoma.

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Figure 5.11.5 Infiltrating goblet cell carcinoid.

Figure 5.11.6 Infiltrating poorly differentiated signet-ring cell carcinoma.

5.12 Goblet cell carcinoid vs.

Adenocarcinoma
Goblet Cell Carcinoid Adenocarcinoma
Typically older adults (50s–60s); Older adults (60s); males >
Age/Gender
no gender predominance females
Location Appendix Any location

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 Most are symptomatic and
present with vague abdominal
pain and an abdominal mass;
some patients present with
Most patients present with symptoms of acute
symptoms of acute appendicitis appendicitis including right
Symptoms including right lower quadrant lower quadrant abdominal
abdominal pain, nausea, vomiting, pain, nausea, vomiting, loss
loss of appetite of appetite, or abdominal
distension due to
pseudomyxoma peritonei. Up
to 25% are discovered
incidentally
Fever, elevated white blood cell
count, abdominal tenderness, Palpable abdominal mass,
Signs
rebound tenderness, occasional abdominal tenderness
palpable abdominal mass
Unknown; arises from pluripotent Unknown; many cases are
stem cells located in the crypts of associated with inflammatory
the intestinal epithelium and bowel disease, specifically
Etiology develops a mixed mucinous and ulcerative colitis. Patients
neuroendocrine phenotype. It has with familial adenomatous
been associated with polyposis are also at
schistosomiasis increased risk
1. Most are well-
differentiated mucinous
adenocarcinomas
histologically similar to those
found elsewhere in the colon
(Fig. 5.12.4) characterized by
well-formed glands
composed of mucinous cells
with uniform basal to
1. Goblet cells, which appear as
pseudostratified nuclei (Fig.
signet ring cells with bland nuclei
5.12.5)
arranged in nests and tubules,
2. Infiltrates the bowel wall
which can occasionally become
as a mass with spider-like
focally dilated and irregular (Fig.
extensions (Fig. 5.12.6)

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 5.12.1)
2. Predominantly infiltrates the
bowel wall in a circumferential
pattern as groups separated by
intervening bands of smooth
muscle and stroma (Fig. 5.12.2)
3. No desmoplastic response (Fig.
Histology 5.12.2)
4. Pools of extracellular mucin,
which often dissect through the
muscularis propria and serosal
soft tissues; glands within the
mucin are clustered with
conspicuous lumina
5. Mucosa usually uninvolved
6. Occasional to numerous Paneth
cells
7. Few to no mitoses (Fig. 5.12.1)
8. Only mild pleomorphism (Fig.
5.12.1)
9. No precursor component
The cells show
immunolabeling for
CEA, CAM 5.2, CDX-
2, and CK20 and are
variably positive for
Special chromogranin and
studies synaptophysin (Fig.
5.12.3) and, when
positive, typically show
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3. Prominent desmoplastic
response (Fig. 5.12.7)
4. Pools of dissecting mucin
are common; neoplastic cells
are often present arranged in
solid masses of cribriform
glands without distinct
lumina
5. Mucosa is usually
involved, and there is usually
background dysplasia and/or
intramucosal carcinoma (the
mucosa may be uninvolved in
cases of metastatic
adenocarcinoma, but the
lesion is generally located in
the serosa and subserosa)
(Figs. 5.12.6 and 5.12.8)
6. No interspersed Paneth
cells, but occasional
neuroendocrine cells
7. Mitoses common (Fig.
5.12.5)
8. Mild pleomorphism; often
shows moderate to severe
pleomorphism (Fig. 5.12.5)
9. Often seen in association
with an in situ precursor
component (Fig. 5.12.6)
The cells show
immunolabeling for
CK20, CDX-2, and
CEA. Stains for
glucagon and
neuroendocrine
markers including
synaptophysin and
chromogranin are
 focal and patchy generally negative
staining

Primary therapy is surgical

Surgical resection with
excision with resection of the
appendectomy with or
appendix and/or portions of the
Treatment without right hemicolectomy
colon if the tumor extends beyond
depending on the extent of
the appendix. Adjuvant
disease
chemotherapy in some cases
Generally good. Approximately
Variable; poor prognostic
20% of tumors extend beyond the
factors include advanced
appendix, and up to 10% of
stage, high-grade cytology,
tumors metastasize, and the 5-year
the presence of nonmucinous
survival rate is approximately
features, spread of mucus
75%. The most important
beyond the lower right
Prognosis prognostic factor is stage; other
quadrant of the abdomen, and
poor prognostic factors include a
cells outside the visceral
predominantly solid or
peritoneum of the appendix.
carcinomatous pattern, perineural
The 5-year survival rate is
invasion, lymphovascular
80%–95% for localized
invasion, and extraappendiceal
disease
spread

Figure 5.12.1 Goblet cell carcinoid arranged in small clusters of signet ring
cells with minimal atypia and few to no mitoses.

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Figure 5.12.2 Goblet cell carcinoid infiltrating as small clusters of cells parallel
to smooth muscle fibers in the muscularis propria.

Figure 5.12.3 Synaptophysin stain in goblet cell carcinoid.

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Figure 5.12.4 Moderately differentiated adenocarcinoma composed of back-to-
back glands with elongated, hyperchromatic, crowded, and pseudostratified
nuclei with prominent mitoses and intraluminal “dirty necrosis.”

Figure 5.12.5 Moderately to poorly differentiated adenocarcinoma showing

glands with markedly atypical, enlarged, pleomorphic cells with loss of nuclear
polarity and mucin loss.

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Figure 5.12.6 Background dysplasia with infiltrating carcinoma seen as
irregular-shaped glands extending into the submucosa and muscularis propria.

Figure 5.12.7 Infiltrating moderately differentiated adenocarcinoma set in a

desmoplastic stroma.

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 Figure 5.12.8 Background high-grade dysplasia seen at the surface in
infiltrating adenocarcinoma.

SUGGESTED READINGS
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Appelman HD . Epithelial neoplasia of the appendix. In: Norris HT , ed.
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Livingstone, 1991:263–303.
Ariel I , et al. Crohn's disease isolated to the appendix: truths and fallacies. Hum
Pathol. 1986;17(11):1116–1121.
Basturk O , et al. Dedifferentiated goblet cell carcinoid (adenocarcinoma ex-
GCC) is a morphologically distinctive and aggressive neoplasm with
peritoneal dissemination: an analysis of 35 cases (Abstract). Mod Pathol.
2010;23:137A.
Bellizzi AM , et al. Serrated lesions of the appendix: a morphologic and
immunohistochemical appraisal. Am J Clin Pathol. 2010;133:623–632.
Bronner MP . Granulomatous appendicitis and the appendix in idiopathic
inflammatory bowel disease. Semin Diagn Pathol. 2004;21(2):98–107.
Burke AP , et al. Goblet cell carcinoid and related tumors of the vermiform
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Cappell MS , et al. Gastrointestinal histoplasmosis. Dig Dis Sci.

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 1998;33:353–360.
Carr N , Montgomery E . Patterns of healing in the appendix. The morphologic
changes in resolving primary acute appendicitis and a comparison with
Crohn disease. Int J Surg Pathol. 1994;2:23–30.
Carr NJ , Sobin LH . Unusual tumors of the appendix and pseudomyxoma
peritonei. Semin Diagn Pathol. 1996;13:314–325.
Carr NJ , et al. Epithelial noncarcinoid tumors and tumor-like lesions of the
appendix. A clinicopathologic study of 184 patients with a multivariate
analysis of prognostic factors. Cancer. 1995;75:757–768.
Cerame MA . A 25-year review of adenocarcinoma of the appendix. A
frequently perforating carcinoma. Dis Colon Rectum. 1988;31:145–150.
Chang P , Attiyeh FF . Adenocarcinoma of the appendix. Dis Colon Rectum.
1981;24:176–180.
Cortina R , et al. Management and prognosis of adenocarcinoma of the
appendix. Dis Colon Rectum. 1995;38:848–852.
Dudley TH , Dean PJ . Idiopathic granulomatous appendicitis, or Crohn's disease
of the appendix revisited. Hum Pathol. 1993;34:595–601.
El-Maraghi NRH , Mair N . The histopathology of enteric infection with Yersinia
pseudotuberculosis. Am J Clin Pathol. 1979;71:631–639.
Flint FB , et al. Adenocarcinoma of the appendix. Am J Surg.
1970;120:707–709.
George DH . Diverticulosis of the vermiform appendix in patients with cystic
fibrosis. Hum Pathol. 1987;18(1):75–79.
Gilhome RW , et al. Primary adenocarcinoma of the vermiform appendix: a
report of a series of ten cases and review of the literature. Br J Surg.
1984;71:553–555.
Gleason TH , Patterson SD . The pathology of Yersinia enterocolitica ileocolitis.
Am J Surg Pathol. 1982;6:347–355.
Guo G , Greenson JK . Histopathology of interval (delayed) appendectomy
specimens: strong association with granulomatous and xanthogranulomatous
appendicitis. Am J Surg Pathol. 2003;27:1147–1151.
Harris GJ , et al. Adenocarcinoma of the vermiform appendix. J Surg Oncol.
1990;44:218–224.
Horvath KD , Whelan RL . Intestinal tuberculosis: return of an old disease. Am J
Gastroenterol. 1998;93:692–696.
Hsu M , et al. Ruptured appendiceal diverticula mimicking low-grade
appendiceal mucinous neoplasms. Am J Surg Pathol.

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 2009;33(10):1515–1521.
Huang JC , Appelman HD . Another look at chronic appendicitis resembling
Crohn disease. Mod Pathol. 1996;9:975–981.
Isaacson P . Crypt cell carcinoma of the appendix (so-called adenocarcinoid
tumor). Am J Surg Pathol. 1981;5(3):213–224.
Jiang Y , et al. Schistosomiasis may contribute to goblet cell carcinoid of the
appendix. J Parasitol. 2012;98(3):565–568.
Kallenbach K , et al. Significant of acquired diverticular disease of the
vermiform appendix: a marker of regional neoplasms? J Clin Pathol.
2012;65(7):638–642.
Klein HZ . Mucinous carcinoid tumor of the vermiform appendix. Cancer.
1974;33:770–777.
Klemi PJ , et al. The histogenesis of mucinous cystadenoma of the appendix.
Arch Pathol Lab Med. 1980;104:162–163.
Lamps LW , et al. The coexistence of low-grade mucinous neoplasms of the
appendix and appendiceal diverticula: a possible role in the pathogenesis of
pseudomyxoma peritonei. Mod Pathol. 2000;13(5):495–501.
Lamps LW , et al. The role of Yersinia enterocolitica and Yersinia
pseudotuberculosis in granulomatous appendicitis: a histologic and
molecular study. Am J Surg Pathol. 2001;25:508–518.
Lamps LW , et al. The pathologic spectrum of gastrointestinal and hepatic
histoplasmosis. Am J Clin Pathol. 2000;113:64–72.
MacGillivary DC , et al. Distant metastasis from a carcinoid of the appendix less
than 1 cm in size. Surgery. 1992;111:466–471.
Marshall JB . Tuberculosis of the gastrointestinal tract and peritoneum. Am J
Gastroenterol. 1993;88:989–999.
Maru D , et al. Loss of chromosome 18q and DPC4 (Smad4) mutations in
appendiceal adenocarcinomas. Oncogene. 2004;23: 859–864.
Matsukuma KE , Montgomery EA . Tubular carcinoids of the appendix: the
CK7/CK20 immunophenotype can be a diagnostic pitfall. J Clin Pathol.
2012;65:666–668.
Misdraji J , et al. Appendiceal mucinous neoplasms: a clinicopathologic analysis
of 107 cases. Am J Surg Pathol. 2003;27(8): 1089–1103.
Moertel CG , et al. Carcinoid tumor of the appendix: treatment and prognosis. N
Engl J Med. 1987;317:1699–1701.
Nitecki SS , et al. The natural history of surgically treated primary
adenocarcinoma of the appendix. Ann Surg. 1994;219:51–57.

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Pai RK , et al. Appendiceal mucinous neoplasms: a clinicopathologic study of
116 cases with analysis of factors predicting recurrence. Am J Surg Pathol.
2009;33(10):1425–1439.
Park K , et al. Goblet cell carcinoid of the appendix. Gut. 1990;31:322–324.
Pham TH , et al. Surgical and chemotherapy treatment outcomes of goblet cell
carcinoid: a tertiary cancer center experience. Ann Surg Oncol.
2006;13(3):370–376.
Qizilbash AH . Mucoceles of the appendix. Their relationship to hyperplastic
polyps, mucinous cystadenomas, and cystadenocarcinomas. Arch Pathol Lab
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disease, atypical Crohn or not Crohn at all? J Am Coll Surg. 1997;185:13–17.
Ronnett BM , et al. Disseminated peritoneal adenomucinosis and peritoneal
mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with
emphases on distinguishing pathologic features, site of origin, prognosis, and
relationship to “pseudomyxoma peritonei.” Am J Surg Pathol. 1995;19(12):
1390–1408.
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Sugarbaker PH , Jablonski KA . Prognostic features of 51 colorectal and 130
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proteins, p53 and neuroendocrine cell markers in epithelial neoplasm of the
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Yantiss RK , et al. A comprehensive study of nondysplastic and dysplastic
serrated polyps of the vermiform appendix. Am J Surg Pathol.
2007;31:1742–1753.
Yantiss RK , et al. Prognostic significance of localized extra-appendiceal mucin
deposition in appendiceal mucinous neoplasms. Am J Surg Pathol.
2009;33:248–255.
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2011;46:869–874.

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 6
Anal Canal

6.1 Papillary endothelial hyperplasia in hemorrhoidal vessels vs.

Angiosarcoma
6.2 Condyloma lata vs. Squamous cell carcinoma
6.3 Condyloma vs. Fibroepithelial polyp (anal tag)
6.4 Stromal changes in fibroepithelial polyp vs. Sarcoma
6.5 Reactive squamous changes vs. Anal intraepithelial neoplasia
6.6 Anal intraepithelial neoplasia extending into colorectal glands
vs. Invasive squamous cell carcinoma
6.7 Sexually transmitted proctitis vs. Inflammatory bowel disease
involving the anus
6.8 Hidradenoma papilliferum vs. Adenocarcinoma, especially of
female genital tract
6.9 Squamous cell carcinoma vs. Pseudoepitheliomatous
hyperplasia
6.10 Squamous cell carcinoma vs. Skin appendage tumors
6.11 Paget disease vs. Pagetoid extension of colorectal carcinoma
6.12 Anal duct carcinoma vs. Spread of tumors from other sites
6.13 Melanoma vs. Gastrointestinal stromal tumor

6.1 Papillary endothelial hyperplasia

in hemorrhoidal vessels vs.
Angiosarcoma

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 Papillary Endothelial
Hyperplasia in Angiosarcoma
Hemorrhoidal Vessels
Any age but usually in
Age/Gender adults in hemorrhoids. Adults; male predominance
No gender predominance
In large hemorrhoidal
vessels that have Very rare in the anal canal and in the
thrombosed. Sometimes, gastrointestinal (GI) tract in general—
radiation treatment most cases reported have been
Location
prompts this response in associated with the small bowel and
patients with rectal, are deep lesions that extend into the GI
gynecologic, or prostate tract. These tend to be epithelioid
cancers
For the rare anal area examples, a
mass is usually detected but in general
Symptoms Anal pain angiosarcomas of the gastrointestinal
tract affect the small bowel and present
with symptoms of obstruction
Cherry-like mass in anal Nonspecific and related to the site of
Signs
canal the mass
Some cases associated with ionizing
Papillary endothelial
radiation and some with various toxins
hyperplasia is an
Etiology (polyvinyl chloride, arsenic
exaggerated form of
compounds, thorium compounds), but
organization in thrombi
these tend to be in the liver
1. Enlarged vessels
containing thrombi (Fig.
6.1.1)
2. Areas of endothelial
1. Overtly malignant proliferation with
cells coating fibrin cores
variable vasoformation (Fig. 6.1.6)
in a monolayer (Figs.
2. Can be solid sheets of cells and
6.1.2–6.1.4)
areas of epithelioid features (Figs.
Histology 3. In radiated patients,
6.1.7–6.1.9)
the presence of abundant
3. Multilayered endothelial cells (Fig.
fibrinoid change of the
6.1.10)
stroma is a clue that the

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 changes are radiation
induced rather than
neoplastic (Fig. 6.1.5)
Immunolabeling for various
vascular markers (CD31,
CD34, ERG) can be useful
for confirmation. Epithelioid
Special None angiosarcomas and
studies hemangioendotheliomas can
show keratin labeling.
CD117 can be reactive in
angiosarcomas, a pitfall

Removal of the
hemorrhoids if they are
Treatment symptomatic or Surgery and sometimes chemotherapy
interfering with personal
hygiene
Generally poor. Some low-grade
Prognosis Benign process lesions can be treated with good
outcome

Figure 6.1.1 Papillary endothelial hyperplasia. This lesion arose in a

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hemorrhoidal area in a patient who had undergone radiation treatment for
cervical squamous carcinoma. There is hemorrhage and amorphous debris.

Figure 6.1.2 Papillary endothelial hyperplasia. There is abundant fibrin

deposition.

Figure 6.1.3 Papillary endothelial hyperplasia. There are cores of fibrin coated
by a monolayer of endothelial cells.

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Figure 6.1.4 Papillary endothelial hyperplasia. At high magnification, the
endothelial cells are not large. Compare them to the lymphocyte at the upper
right.

Figure 6.1.5 Papillary endothelial hyperplasia. The amorphous fibrin debris in

this field probably reflects prior radiation treatment.

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Figure 6.1.6 Angiosarcoma. This is a solid proliferation of atypical cells.

Figure 6.1.7 Angiosarcoma. There is some vasoformation, but the nuclei are
enlarged compared to the adipocyte nuclei in the field.

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Figure 6.1.8 Angiosarcoma. This example extends along a preexisting vessel.
The malignant cells are hyperchromatic.

Figure 6.1.9 Angiosarcoma. Note the hyperchromatic nuclei.

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Figure 6.1.10 Angiosarcoma. The nuclei form a monolayer on the right but are
“piled up” on the left.

6.2 Condyloma lata vs. Squamous cell

carcinoma
Condyloma Lata Squamous Cell Carcinoma
Adults. A male predominance
reflects the proclivity for human
Male predominance, usually
Age/Gender immunodeficiency virus (HIV)-
middle-aged males
infected persons to also harbor
syphilis
Location Anorectum and genital region Anal canal or perianal area
Mass effect, anal pain, pain
Symptoms Mass, anal discharge, anal pain while defecating, local
hemorrhage
Mass, friable hemorrhagic
Signs Mass lesion
mucosa or perianal skin. Ulcers
Infection with Treponema Most cases associated with
Etiology
pallidum human papillomavirus (HPV)

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1. Rich lymphoplasmacytic
infiltrate with striking
pseudoepitheliomatous
Histology
hyperplasia (Fig. 6.2.1)
2. Mild squamous atypia (Fig.
6.2.2)
Serologic studies are
important. Serologic
studies for syphilis
should be performed.
Immunolabeling is of
Special
interest (Fig. 6.2.3)
studies
only for research since
it is specific but not
sensitive, and a
negative study does not
exclude infection
Treatment Antibiotics
Excellent with treatment. Masses
and ulcers disappear with
Prognosis
treatment, but the underlying
HIV must still be managed
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1. Marked squamous atypia
with desmoplastic response
but limited inflammation
(Figs. 6.2.4–6.2.6)
2. Abnormal keratinization
3. Adjoining squamous
mucosa may show HPV-
related changes
In basaloid cases,
performing
CK5/CK6 can
confirm a squamous
lesion and help
distinguish it from
neuroendocrine
carcinoma. HPV
studies can be of
interest. A pitfall is
that some examples
express CD117
Chemoradiation
Overall good and stage
dependent. Patients tend to
present early with low-stage
lesions because of early
symptoms. Remember that
anal lesions are staged by size
rather than depth of invasion
Figure 6.2.1 Condyloma lata. The eye-catching feature in this image is the
dense chronic inflammation. Even at this magnification, it appears
lymphoplasmacytic. There is pseudoepitheliomatous hyperplasia at the right.

Figure 6.2.2 The squamous epithelium appears reparative, and intercellular

bridges can be seen in the basal layer.

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Figure 6.2.3 Condyloma lata. This is an immunostain for treponemal
organisms. It is fairly specific (it also reacts with the organisms responsible for
intestinal spirochetosis) but not terribly sensitive. As such, patients should be
tested serologically, and the immunostain is not necessary.

Figure 6.2.4 Squamous cell carcinoma. There is ulceration but little chronic
inflammation. There is desmoplasia in this field.

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Figure 6.2.5 Squamous cell carcinoma. There is no in situ component in this
example, but it shows necrosis. There is minimal chronic inflammation.

Figure 6.2.6 Squamous cell carcinoma. This basaloid example has invaded
through the muscularis mucosae. There is some colorectal-type mucosa at the
left. Many squamous cell carcinomas of the anal region arise at the junction of
the squamous and columnar mucosa.

6.3 Condyloma vs. Fibroepithelial

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polyp (anal tag)
Fibroepithelial Polyp (anal
Condyloma
tag)
Typically adults, no gender
Age/Gender Adults/male predominance
predilection
At the junction between the anal
Location Anal canal and perianal skin
canal and the skin
Patient notes small masses.
Patients note exophytic lesion
Removal is suggested when
Symptoms or lesions. May interfere with
they interfere with hygiene
hygiene
since removal is painful
Signs Cauliflower-like lesions May be local hemorrhage
May be related to mucosal
prolapse, constipation, and anal
Etiology Human papillomavirus (HPV) fissures. More common in obese
patients and persons with Crohn
disease
1. The subepithelial layer shows
prominent proliferation and
1. Exophytic polypoid lesions mild inflammation, but the
with proliferation of the overlying squamous epithelium
epithelium with atypical nuclei forms a monolayer (Fig. 6.3.4)
restricted to the bottom half of 2. Generally, the squamous
Histology the epithelium (Fig. 6.3.1) epithelium appears reactive
2. Koilocytic atypia in nuclei (Fig. 6.3.5)
(Fig. 6.3.2) 3. Of course, these polyps
3. Minimal stromal proliferation should be examined carefully as
(Fig. 6.3.3) they occasionally display flat
intraepithelial neoplasia (Fig.
6.3.6)
P16, HPV testing, and
Ki- 67 labeling can all
be used to confirm an
Special impression of
None

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studies condyloma, but most
cases are readily
diagnosed on H&E

Removal if they interfere with

Excisional biopsy, cryotherapy,
Treatment hygiene or are embarrassing to
chemical ablation
the patient
Overall good. Only a small
Prognosis minority progress to squamous Excellent
cell carcinoma

Figure 6.3.1 Condyloma. Note that most of the lesion is composed of

epithelium rather than stroma. The epithelium is quite thick.

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Figure 6.3.2 Condyloma. This image shows enlarged nuclei and koilocytic
atypia in which there is a large perinuclear halo around many nuclei.
Condyloma acuminatum is equivalent to anal intraepithelial neoplasia
(AIN1/low-grade AIN/mild dysplasia).

Figure 6.3.3 Condyloma. As noted above, the stromal component is a minor

one.

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Figure 6.3.4 Fibroepithelial polyp (anal tag). This lesion is “all stroma,” with a
coating of reactive squamous epithelium.

Figure 6.3.5 Fibroepithelial polyp (anal tag). These are reactive surface
changes. The vacuoles around some of the squamous cells are small compared
to the perinuclear halos that characterize condylomas.

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Figure 6.3.6 Fibroepithelial polyp (anal tag). This example had a focus of
AIN3, high-grade AIN on its surface. It is important to check the surface of
even the most mundane-appearing squamous areas in the anus, including the
surface of hemorrhoids.

6.4 Stromal changes in fibroepithelial

polyp vs. Sarcoma
Stromal
Changes in
Sarcoma
Fibroepithelial
Polyps
Typically
adults, no Adults—overall anal area sarcomas are extremely
Age/Gender
gender rare and can be associated with perianal skin
predilection
At the junction
between the
Location Anal canal or perianal skin
anal canal and
the skin
Patient notes

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 small masses.
Removal is
suggested
Symptoms when they Pain while defecating or patient notes mass
interfere with
hygiene since
removal is
painful
May be local
Signs Mass
hemorrhage
May be related
to mucosal
prolapse,
constipation,
and anal
Various but generally not known, depending on
Etiology fissures. More
sarcoma type
common in
obese patients
and persons
with Crohn
disease
1. The
subepithelial
layer shows
prominent
proliferation
and mild
inflammation,
but the
overlying
squamous
epithelium
forms a
monolayer.
There are
enlarged
atypical nuclei 1. Variable according to sarcoma type but more
Histology
in the cellular than stroma of anal tag (Figs. 6.4.4–6.4.6)

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 subepithelial
tissue (Fig.
6.4.1)
2. The atypical
stromal cells
are scattered
throughout an
otherwise
edematous
stroma, and
there is not
much mitotic
activity (Figs.
6.4.2 and
6.4.3)
Depending on type on sarcoma
considered. This example of an
epithelioid sarcoma–like
hemangioendothelioma/pseudomyogenic
Special hemangioendothelioma was CD31+,
None
studies CD34−, ERG+, keratin+. Other
encountered sarcomas would be GIST,
Kaposi sarcoma. In a child,
rhabdomyosarcoma would be of import
but not in an adult

Removal if
they interfere
with hygiene
Treatment Depends on sarcoma type
or are
embarrassing
to the patient
Prognosis Excellent Depends on sarcoma type

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Figure 6.4.1 Stromal changes in fibroepithelial polyps. Since such lesions are
constantly traumatized, they are prone to both reparative epithelial changes as
well as reactive stromal changes. This lesion has squamous epithelial edema
and a cellular stroma.

Figure 6.4.2 Stromal changes in fibroepithelial polyps. Higher magnification

of the lesion shown in Figure 6.4.1.

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Figure 6.4.3 Stromal changes in fibroepithelial polyps. This polyp has rather
striking changes, but there is no mitotic activity, and the peculiar large
fibroblasts have low nuclear-to-cytoplasmic ratios.

Figure 6.4.4 Kaposi sarcoma involving the anal canal. The hemosiderin and
cellularity are both clues.

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Figure 6.4.5 Epithelioid sarcoma–like
hemangioendothelioma/pseudomyogenic hemangioendothelioma involving the
anal area. Even if one is not familiar with this rare tumor, it clearly is far more
cellular than the pseudosarcomatous change seen in Figure 6.4.3.

Figure 6.4.6 Epithelioid sarcoma–like

hemangioendothelioma/pseudomyogenic hemangioendothelioma involving the
anal area. Higher magnification of the tumor shown in Figure 6.4.5.

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6.5 Reactive squamous changes vs.
Anal intraepithelial neoplasia
Reactive Squamous
Anal Intraepithelial Neoplasia (AIN)
Changes
Adults, male predominance since so
Age/Gender Typically adult common in HIV-positive men who have
sex with men
Most examples are found at the junction
Anal canal or perianal
Location between the squamous mucosa and the
area
rectal-type mucosa
None attributable to
the reactive changes
Symptoms per se. The underlying None attributable to AIN
etiology that caused
the changes
Can appear as a red plaque at
colonoscopy but in high-risk patients,
Signs Not applicable some undergo periodic anal screening
with anal cytology. Reddish plaques can
be seen that fail to retain Lugol iodine
Etiology Various causes Human papillomavirus (HPV)
1. There is variable thickness
replacement of the normal squamous
epithelium with squamous epithelial cells
1. The squamous displaying nuclear hyperchromasia (Figs.
epithelium may be 6.5.4–6.5.6). The borders between the
inflamed, and there dysplastic cells are not sharp (squamous
may be erosions or bridges not seen well). Most examples
ulcers (Fig. 6.5.1) lack nucleoli in the cells in question
2. At high 2. AIN can be graded by dividing the
magnification, it is thickness of the neoplasia into the thirds
Histology usually possible to see of the thickness of the epithelium (AINI,
intercellular bridges AIN2, AIN3). There is controversy over
(Fig. 6.5.2) whether to include AIN2 in low- or high-

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 3. Cytoplasm is grade intraepithelial neoplasia or high-
usually apparent with grade neoplasia. P16 immunolabeling
gradual maturation to may be useful to stratify AIN2 into low-
the surface (Fig. 6.5.3) and high-risk groups (such that reactive
cases be included in high-grade
dysplasia). In our practice, we include
AIN2 in high-grade AIN
Negative
P16 and/or
negative
HPV viral Positive P16 and/or positive
Special studies can HPV viral studies can be
studies be confirmatory in occasional
confirmatory difficult cases
in occasional
difficult
cases

Treatment None Cryotherapy, chemical ablation

Progression to invasive squamous cell
Prognosis Generally excellent carcinoma is uncommon, but patients are
at risk for progression

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Figure 6.5.1 Reactive squamous changes. The nuclei lack hyperchromasia and
mature toward the surface.

Figure 6.5.2 Reactive squamous changes. Well-glycogenized mucosa showing

maturation.

Figure 6.5.3 Reactive squamous changes. The basal layer is expanded and
mitotically active as part of reactive changes, but note that there is edema such
that the intercellular bridges are readily apparent. They are difficult to see in
nonreparative basal cells.

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Figure 6.5.4 Anal intraepithelial neoplasia. This example is at the transition
with colorectal-type mucosa. In this example of low-grade dysplasia, enlarged
nuclei are easily identified even at low magnification.

Figure 6.5.5 Anal intraepithelial neoplasia. This high-grade example is quite

hyperchromatic.

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Figure 6.5.6 Anal intraepithelial neoplasia. At high magnification, it is
impossible to see squamous bridges.

6.6 Anal intraepithelial neoplasia

extending into colorectal glands vs.
Invasive squamous cell carcinoma
Anal Intraepithelial
Invasive Squamous Cell
Neoplasia (AIN) Extending
Carcinoma
into Colorectal Glands
Adults with male
predominance since so
Age/Gender Adults with male predominance
common in HIV-positive men
who have sex with men
Most examples are found at
the junction between the
Location Anal canal
squamous mucosa and the
rectal-type mucosa
Symptoms None attributable to AIN Anal pain, blood in stool
Can appear as a red plaque at

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 colonoscopy but in high-risk
patients, some undergo
Signs periodic anal screening with Anal mass
anal cytology. Reddish
plaques can be seen that fail
to retain Lugol iodine
Human papillomavirus
Etiology
(HPV)
1. The lesion is usually high-
grade AIN, and a sharp
demarcation between the AIN
and the colorectal-type
epithelium is apparent (Figs.
Histology
6.6.1 and 6.6.2)
2. The lamina propria is not
sclerotic, and there is no
typical keratinization in the
AIN (Fig. 6.6.3)
Positive P16 and/or
positive HPV viral
studies can be
Special
studies confirmatory in
occasional difficult
cases
Cryotherapy, chemical
Treatment
ablation
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Most anal squamous cancers are
related to human papillomavirus
(HPV)
1. Anal squamous carcinomas
appear similar to squamous
cancers elsewhere
2. They are associated with
desmoplasia and “paradoxical
maturation with nucleoli and
abnormal keratinization” (Figs.
6.6.4 and 6.6.5). The lamina
propria is sclerotic and “overrun”
by the tumor
3. Basaloid examples can be
difficult to recognize but are
associated with a desmoplastic
response (Fig. 6.6.6)
In basaloid examples,
performing CK5/CK6 to
confirm squamous
differentiation can be
helpful to exclude
neuroendocrine
carcinomas (small cell
type). A pitfall is that
these lesions can
express CD117
Chemoradiation. Often, surgery is
not needed
Overall, good and stage
 Progression to invasive
squamous cell carcinoma is
Prognosis uncommon, but patients are at
risk for progression
dependent. Patients tend to
present early with low-stage
lesions because of early
symptoms. Remember that anal
lesions are staged by size rather
than depth of invasion

Figure 6.6.1 Anal intraepithelial neoplasia extending into colorectal glands.

This low-grade lesion shows abrupt transition where it has extended into
colorectal glands. It remains restricted to the basement membrane of the
colorectal glands.

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Figure 6.6.2 Anal intraepithelial neoplasia extending into colorectal glands.
This high-grade example has sharp demarcations from the colorectal glands.
There is abundant lamina propria.

Figure 6.6.3 Anal intraepithelial neoplasia extending into colorectal glands. It

is easy to see the intact basement membrane around the involved glands.
Lamina propria is also easy to identify, and there is no desmoplasia.

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Figure 6.6.4 Squamous cell carcinoma. Note the necrosis in the nests of
invasive carcinoma, which are separated by desmoplastic stroma.

Figure 6.6.5 Squamous cell carcinoma. The lamina propria is effaced and
scarred (desmoplastic).

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Figure 6.6.6 Squamous cell carcinoma. This basaloid example forms sheets.
There is an in situ component at the upper left of the field.

6.7 Sexually transmitted proctitis vs.

Inflammatory bowel disease involving
the anus
Inflammatory Bowel Disease
Sexually Transmitted Proctitis
Involving the Anus
Wide age range but two peaks
Adults, usually men who have sex
Age —late adolescence and early
with men
20s and 50–60 years
Location Anal canal and rectum Anal canal
Abdominal pain, blood in
Anal pain, anal discharge, stool. Patient may have an
Symptoms
hemorrhage established history of Crohn
disease or fissuring disease
Cobblestoned anal canal
Signs Mass, ulcer, erythema mucosa, fissures, fistula
formation

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 Crohn disease. Crohn disease
is poorly understood but can
Chlamydia (lymphogranuloma be regarded as an immune
venereum) and Treponema alteration that results in an
Etiology pallidum (syphilis). Some cases abnormal response to
attributable to gonorrhea but these organisms that unaffected
can be difficult to diagnose persons are able to tolerate as
components of their
gastrointestinal tracts
1. There is chronic inflammation
out of proportion to acute
inflammation (Fig. 6.7.1). Plasma
1. Neutrophils in proportion to
cells are the key element with most
chronic inflammatory cells and
cases showing only a few
plenty of histiocytes and
eosinophils and histiocytes
Histology eosinophils (Figs. 6.7.4 and
2. If there is colorectal mucosa on
6.7.5)
the slide, it lacks prominent basal
2. Granulomas not infrequently
plasmacytosis (Fig. 6.7.2)
encountered (Fig. 6.7.6)
3. Rare examples show positive
syphilis immunolabeling (Fig.
6.7.3)
Serologic studies are
important. Serologic and
swab testing for syphilis
and Chlamydia should be
None. However, it is
performed.
worth adding stains
Immunolabeling is of
Special for microorganisms
studies interest (Fig. 6.2.3) only
if granulomas are
for research since it is
necrotizing
specific but not sensitive,
and a negative study
does not exclude
infection

Immune modulators, steroids,

anti–tumor necrosis factor
alpha preparations. Note that
these medications can reduce

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Treatment Antibiotics
Excellent with treatment. Masses
and ulcers disappear with
Prognosis
treatment, but the underlying HIV
must still be managed
inflammation substantially and
reduce the number of
granulomas detected. A subset
of cases require surgery
There is no cure for
inflammatory bowel disease,
but patients can be managed
with medications

Figure 6.7.1 Sexually transmitted disease proctitis. Note the

pseudoepitheliomatous hyperplasia and striking plasmacytic infiltrate. This
lesion is at the anal opening onto the skin. There are a few hair follicles.

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Figure 6.7.2 Sexually transmitted disease proctitis. The plasmacytic
inflammation is striking. Histiocytes are scarcely present.

Figure 6.7.3 Sexually transmitted disease proctitis. This is a syphilis

immunostain. However, many lesions are negative, and virtually identical
lesions can be caused by chlamydia (lymphogranuloma venereum), so
laboratory testing is usually indicated.

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Figure 6.7.4 Inflammatory bowel disease involving the anus. This biopsy is
from a patient with Crohn disease. There is an ulcer and chronic inflammation.
It is histiocyte rich and has granulomas. Usually, anal disease in patients
known to have Crohn disease is not biopsied as this is very uncomfortable for
the patient.

Figure 6.7.5 Inflammatory bowel disease involving the anus. Aside from the
obvious granulomas, this process lacks striking plasmacytosis.

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Figure 6.7.6 Inflammatory bowel disease involving the anus. Nonnecrotizing
granulomas.

6.8 Hidradenoma papilliferum vs.

Adenocarcinoma, especially of female
genital tract
Adenocarcinoma,
Hidradenoma Papilliferum Especially of Female
Genital Tract
Middle-aged to elderly
Age/Gender Middle-aged women
women
Usually perineum and not actually
Location Cervix, uterus
in the anal canal
Patient notes a nodule on her
Symptoms Blood per vagina
perineum
Variable—mass in cervix or
uterus (or ovary if the
Signs Occasional surface erosion
patient presents with a skin
metastasis)

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 Unknown in general; HPV is
associated with endocervical
adenocarcinomas, whereas
Etiology Unknown
obesity and Lynch syndrome
are associated with
endometrial carcinomas
1. More atypia than
1. Well-marginated small (a cm or
hidradenoma papilliferum
less) lesion composed of complex
and only one layer of cells in
tubules (Figs. 6.8.1–6.8.4). No
zones in which glands are
Histology necrosis or desmoplasia
formed (Figs. 6.8.9–6.8.12)
2. The tubules have stratified nuclei
2. Necrosis and desmoplasia
but have a basal layer (two cell
may be present (Figs.
layers) (Figs. 6.8.5–6.8.8)
6.8.13–6.8.16)
These cause trouble if the
pathologist does not
recognize the lesion.
These tumors are CK7+ ER, PR, often
Special and CK20− and often CK7+, CK20−,
studies express hormone PAX8+
receptors (ER, PR). No
data on PAX8 at this
writing

Variable depending on type.

Treatment Local excision
Surgery generally indicated
Variable depending on type
Prognosis These are benign
and grade

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Figure 6.8.1 Hidradenoma papilliferum. At low power, the lesion is well
marginated.

Figure 6.8.2 Hidradenoma papilliferum. The nuclei are small and not
hyperchromatic.

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Figure 6.8.3 Hidradenoma papilliferum. Papillary structures are present.

Figure 6.8.4 Hidradenoma papilliferum.

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Figure 6.8.5 Hidradenoma papilliferum. The process forms cribriform
structures, but they are separated by bland stromal cells rather than by
desmoplasia. There is no necrosis.

Figure 6.8.6 Hidradenoma papilliferum. The two cell layers are apparent.

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Figure 6.8.7 Hidradenoma papilliferum. Another example. The nuclei have
smooth nuclear membranes.

Figure 6.8.8 Hidradenoma papilliferum. High magnification shows a papillary

structure and bland nuclei.

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Figure 6.8.9 Adenocarcinoma. This is a papillary serous carcinoma of the
endometrium that spreads to the anus. Abundant necrosis is seen.

Figure 6.8.10 Adenocarcinoma. The lesion is overtly malignant.

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Figure 6.8.11 Adenocarcinoma. The papillary structures are lined by
hyperchromatic nuclei.

Figure 6.8.12 Adenocarcinoma.

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Figure 6.8.13 Adenocarcinoma. This is a clear cell carcinoma of the
endometrium that has spread to the anorectal junction. It is composed by
markedly atypical clear cells.

Figure 6.8.14 Adenocarcinoma. In contrast to hidradenoma papilliferum, the

tumor infiltrates the tissue.

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Figure 6.8.15 Adenocarcinoma. Higher magnification of the lesion shown in
Figure 6.8.14.

Figure 6.8.16 Adenocarcinoma. Note the overtly carcinomatous irregular

nuclei.

6.9 Squamous cell carcinoma vs.

Pseudoepitheliomatous hyperplasia

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Squamous Cell Carcinoma
Age/Gender Adults with male predominance
Location Anal canal
Symptoms Anal pain, blood in stool
Signs Anal mass
Most anal squamous cancers are
Etiology related to human papillomavirus
(HPV)
1. Anal squamous carcinomas
appear similar to squamous
cancers elsewhere
2. They are associated with
desmoplasia and “paradoxical
maturation with nucleoli and
abnormal keratinization” (Figs.
Histology
6.9.1–6.9.3). The lamina propria
is sclerotic and “overrun” by the
tumor
3. Basaloid examples can be
difficult to recognize but are
associated with a desmoplastic
response
In basaloid examples,
performing CK5/CK6
to confirm squamous
differentiation can be
helpful to exclude
Special neuroendocrine
studies carcinomas (small cell
type). A pitfall is that
these lesions can
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Pseudoepitheliomatous
Hyperplasia
No specific age. A reparative
response of squamous mucosa
to any stimulus
Anal canal or perianal skin
None attributable to the
pseudoepitheliomatous
hyperplasia
Nothing specific
Reparative response to many
types of injury
1. The squamous epithelium
shows thickening and may
display hyperkeratosis and
parakeratosis but not typically
the bright pink abnormal
keratin pattern of squamous
cell carcinoma (Fig. 6.9.4)
2. Inflammation may be a
prominent feature, but
desmoplasia is not (Fig. 6.9.5)
3. Intercellular bridges are
usually apparent (Fig. 6.9.6)
None. If p16 is
performed, it may
show focal staining
but not strong
diffuse staining
 express CD117

Chemoradiation. Often, surgery

Treatment None
is not needed
Overall, good and stage
dependent. Patients tend to
present early with low-stage
Excellent. This is a reparative
Prognosis lesions because of early
response
symptoms. Remember that anal
lesions are staged by size rather
than depth of invasion

Figure 6.9.1 Squamous cell carcinoma. The malignant cells have overrun the
lamina propria.

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Figure 6.9.2 Squamous cell carcinoma. Zones of necrosis are present.

Figure 6.9.3 Squamous cell carcinoma. There are markedly atypical nuclei,
and squamous bridges are not identifiable.

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Figure 6.9.4 Pseudoepitheliomatous hyperplasia. This example is associated
with a granular cell tumor toward the right of the field. The squamous
epithelium forms jagged nests, but each has a rim of basal cells.

Figure 6.9.5 Pseudoepitheliomatous hyperplasia. Intercellular bridges can be

seen at this magnification.

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Figure 6.9.6 Pseudoepitheliomatous hyperplasia. There is striking edema
between the squamous cells. The granular cells tumor is seen nicely at the
bottom of the field.

6.10 Squamous cell carcinoma vs.

Skin appendage tumors
Skin Appendage
Squamous Cell Carcinoma
Tumors
Adults in general.
Many are
Age/Gender Adults with male predominance hidradenoma
papilliferum (female
predominance)
Location Perianal skin or anal canal Perianal skin
Patient notes a nodule
Symptoms Anal pain, blood in stool
in the perianal zone
Tumors may have
Signs Anal mass crusting and
hemorrhage

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 Unknown. Some are
Most anal squamous cancers are related to estrogen receptor
Etiology human papillomavirus (HPV), as are most reactive, but the
carcinomas of perianal skin
significance of this is
not clear
1. Anal squamous carcinomas appear
similar to squamous cancers elsewhere 1. Variable depending
2. They are associated with desmoplasia on type. Many have
and “paradoxical maturation with nucleoli two cell layers, and
and abnormal keratinization” (Figs. some are associated
6.10.1–6.10.3). The lamina propria is with skin appendages
Histology
sclerotic and “overrun” by the tumor. themselves. All types
Some can have unusual features including can display zones of
clear cells or a basaloid appearance. squamous
These variants have no influence on differentiation (Figs.
outcome, which is driven only by stage 6.10.4–6.10.6)
(tumor size)
Often CK7+
and often
CK5/CK6+,
both of
which are
positive in
In basaloid examples,
squamous
performing CK5/CK6 to
cells
confirm squamous
carcinomas.
differentiation can be helpful to
Special However,
studies exclude neuroendocrine
they are
carcinomas (small cell type). A
HPV ISH
pitfall is that these lesions can
negative,
express CD117
and
squamous
cell
carcinomas
are often
HPV+

Treatment Chemoradiation. Often, surgery is not Excision

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 needed
Overall, good and stage dependent.
Patients tend to present early with low-
Prognosis stage lesions because of early symptoms. Most are benign
Remember that anal lesions are staged by
size rather than depth of invasion

Figure 6.10.1 Squamous cell carcinoma. This unusual case has clear cell
features and has provoked a desmoplastic response at the right side of the
image.

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Figure 6.10.2 Squamous cell carcinoma. Both desmoplasia and abnormal
keratinization are evident.

Figure 6.10.3 Squamous cell carcinoma. Note the abnormal bright pink keratin
on the left half of the field.

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Figure 6.10.4 Skin appendage tumors. This is a hidradenoma papilliferum. It
lacks desmoplasia and is unassociated with the squamous epithelium.

Figure 6.10.5 Skin appendage tumors. This lesion is inflamed but still lacks
desmoplasia. It is not clear how to classify this example, but it appears benign.

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Figure 6.10.6 Skin appendage tumors. There are two cell layers.

6.11 Paget disease vs. Pagetoid

extension of colorectal carcinoma
Pagetoid Extension of
Paget Disease Colorectal Carcinoma
into Perianal Skin
Adults, 50+ years, far less
It is most common in the sixth and
female predominance than
Age/Gender seventh decades, usually in
for skin appendage–type
postmenopausal Caucasian females
Paget disease
Location Anal area, perianal skin Perianal skin
Perianal itching or rash
Perianal itching or rash that does not that does not respond to
respond to local therapy. Some local therapy. Some
Symptoms
patients describe a burning sensation, patients describe a
oozing, and bleeding burning sensation, oozing,
and bleeding
Eczematous perianal
Eczematous perianal patch with well- patch with well-defined

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Signs defined borders, moist and reddish, borders, moist and
and scaling or macerated extending to reddish, and scaling or
the anal canal margin macerated extending to
the anal canal margin
Not clear. It can be regarded as an
intraepithelial skin appendage Associated with a peculiar
carcinoma. In contrast to mammary pattern of spread of
Paget disease, it is not usually colorectal-type
Etiology
associated with a mass. If a mass is adenocarcinoma or
present, the lesion is more likely a adenoma in occasional
reflection of pagetoid extension from instances
colorectal carcinoma
1. Similar to skin
appendage–type Paget
1. Large cells with clear cytoplasm
disease but cells often
are seen within the squamous
somewhat smaller (Figs.
epithelium. They sometimes coalesce
Histology 6.11.9 and 6.11.10)
into nests (Figs. 6.11.1 and 6.11.2)
2. A colorectal carcinoma
2. Some contain obvious mucin (Figs.
or, occasionally, adenoma
6.11.3 and 6.11.4)
may also be present (Figs.
6.11.11 and 6.11.12)
In the type that is a skin Immunolabeling
appendage tumor, the cells is that of
express keratin using cam colorectal
5.2, CEA, GCDFP, and carcinoma. The
CK7 but not CK20 (Figs. cells are
Special 6.11.5–6.11.8). CK20+,
studies Occasionally, AIN can CDX2+, and
appear similar to Paget usually CK7−,
disease; it lacks cam 5.2 and they lack
staining as well as CEA and GCDFP (Figs.
GCDFP 6.11.13–6.11.16)

Surgery and
chemotherapy, depending
on the stage of any
Treatment Local excision associated colorectal
carcinoma. Excision of

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 the intraepithelial
component
Recurrences are common, but the
disease can be managed with repeat
excisions. However, some cases Depends on the stage of
Prognosis
associated with an advanced/invasive any invasive carcinoma
skin appendage–type tumor behave
aggressively

Figure 6.11.1 Paget disease. Note the single pink cells and the plump clusters
of pink cells in the darker squamous epithelium.

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Figure 6.11.2 Paget disease. The pink cells contain mucin.

Figure 6.11.3 Paget disease. In this field, the Paget cells are present in an area
that also shows pseudoepitheliomatous hyperplasia.

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Figure 6.11.4 Paget disease. The nests of cells have very similar appearances
to those of breast carcinoma.

Figure 6.11.5 Paget disease, CK7 stain. Strong diffuse staining is typical.

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Figure 6.11.6 Paget disease. CK20 staining is negative.

Figure 6.11.7 Paget disease. GCDFP is reactive.

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Figure 6.11.8 Paget disease. An S100 protein stain highlights dendritic cells
but not the Paget cells.

Figure 6.11.9 Pagetoid extension of colorectal carcinoma. Many older studies

have “lumped” these cases in with the form that is an intraepithelial carcinoma
similar to sweat duct carcinoma. Their appearances are similar, and
immunolabeling can be helpful in sorting out the types.

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Figure 6.11.10 Pagetoid extension of colorectal carcinoma. The cells are often
slightly smaller than Paget cells, but in any given case, it is important to
correlate with other findings.

Figure 6.11.11 Pagetoid extension of colorectal carcinoma. In this example, an

adjoining colorectal-type adenoma is apparent.

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Figure 6.11.12 Pagetoid extension of colorectal carcinoma. Note the adenoma
on the right.

Figure 6.11.13 Pagetoid extension of colorectal carcinoma. This example

mimics squamous intraepithelial neoplasia.

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Figure 6.11.14 Pagetoid extension of colorectal carcinoma. Negative high-risk
human papillomavirus in situ hybridization on the area seen in Figure 6.11.13.
This can also be an issue in the differential diagnosis of classic anal Paget
disease.

Figure 6.11.15 Pagetoid extension of colorectal carcinoma. This is CDX2

labeling on the area seen in Figure 6.11.13.

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Figure 6.11.16 Pagetoid extension of colorectal carcinoma. CDX2 labeling in
the adjoining adenoma.

6.12 Anal duct carcinoma vs. Spread

of tumors from other sites
Spread of Tumors
Anal Duct Carcinoma
from Other Sites
Older persons. Gender
depends on tumor
type. Prostate cancer
and lower female
Also known as anal gland carcinoma.
genital tract tumors
Age/Gender Very rare without apparent gender
can spread to the anal
predominance in older persons
area in men and
women, respectively,
as can bladder cancer
in either gender
Where anal ducts are found, so quite
Location Anal canal
distal in anus
Blood per rectum, sensation of Blood per rectum,

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Symptoms incomplete evacuation when defecating mass sensation

Anal mass. May be ulcerated but

Signs Mass
sometimes covered by intact mucosa
Associations are those
for prostatic,
Etiology Unknown. No particular associations
gynecologic, and
bladder cancer
1. Prostate carcinomas
1. These lesions consist of tubules and tend to have large
ducts that open onto the mucosal surface nucleoli and lack
but without a luminal in situ component mucin, whereas
Histology (Figs. 6.12.1 and 6.12.2) gynecologic
2. There may be pagetoid extension of neoplasms may
single cells into the overlying surface display a variety of
epithelium (Fig. 6.12.3) appearances (Figs.
6.12.6–6.12.8)
Depending
on type, ER,
These are CK7+ and CK20−
PR, PAX8
(Figs. 6.12.4 and 6.12.5). In
(gynecologic
contrast to normal anal ducts,
tumors),
these tumors lack reactivity
PSA, PSAP,
with CK5/CK6 and p63. Most
P501S
cases seem to be CDX2
(prostate),
negative. In men, it is
GATA3
Special worthwhile to exclude prostate
(bladder),
studies carcinoma with pertinent
and HPV
immunolabeling, whereas in
studies
women, it is important to
(uterine
exclude gynecologic cancers.
cervix) can
In our hands, these tumors
all be useful
lacked hormone receptors and
markers
prostatic markers
(Figs. 6.12.9
and 6.12.10)

Treatment Excision As per the primary site

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Prognosis Locally aggressive and prone to local As per the primary site
metastases and grade

Figure 6.12.1 Anal duct carcinoma. At low magnification, the carcinoma is

beneath the squamous epithelium.

Figure 6.12.2 Anal duct carcinoma. The carcinoma is composed of small

tubules.

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Figure 6.12.3 Anal duct carcinoma. There is focal pagetoid extension into the
overlying squamous epithelium.

Figure 6.12.4 Anal duct carcinoma. This is a CK7 stain.

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Figure 6.12.5 Anal duct carcinoma. This is a CK7 stain showing the area of
pagetoid extension seen in Figure 6.12.3.

Figure 6.12.6 Spread of tumors from other sites. This is a high-grade prostatic
carcinoma that has extended into the anorectal area.

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Figure 6.12.7 Spread of tumors from other sites. Higher magnification of the
tumor shown in Figure 6.12.6.

Figure 6.12.8 Spread of tumors from other sites. This is a bladder carcinoma
that has extended into the anus.

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Figure 6.12.9 Spread of tumors from other sites. This is a prostate-specific
acid phosphatase stain of a prostatic carcinoma that has spread to the
anorectal area.

Figure 6.12.10 Spread of tumors from other sites. This is a GATA3 stain of the
bladder carcinoma seen in Figure 6.12.8.

6.13 Melanoma vs. Gastrointestinal

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stromal tumor
Gastrointestinal
Melanoma
Stromal Tumor
Extremely rare in
Anal melanoma usually affects white adults
the anus and
but, as for subungual and esophageal
Age/gender reported in adults.
melanoma, sometimes persons with
No clear gender
pigmented skin are also affected
predominance
Location Anal canal or perianal skin Anal canal
Mass lesion,
Symptoms Blood per rectum and anal mass sensation
bleeding per rectum
A mass lesion is seen. Some examples are
Signs pigmented. Amelanotic examples often Mass lesion
mistaken for hemorrhoids
Associated with
Etiology
KIT mutations
1. Spindle cell or
epithelioid tumors
1. Easy to recognize if an in situ component without pigment or
is present or there is abundant pigment in situ component
(Figs. 6.13.1 and 6.13.2). Nuclear (Figs. 6.13.7 and
pleomorphism and large nucleoli are 6.13.8)
Histology
common 2. Nuclei are
2. Some lesions are spindled and thus typically
difficult to recognize (Figs. 6.13.3 and monotonous rather
6.13.4) than pleomorphic
(Figs. 6.13.9 and
6.13.10)
CD117+,
DOG1+,
and often
S100 protein is the best stain (and CD34+.
more recently SOX10) (Fig. Can be
6.13.5). Remember that S100

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 melanomas often express CD117, reactive
and some mucosal melanomas but
Special even have KIT mutations (Fig. usually
studies 6.13.6). Spindle cell melanomas not as
often lack expression on so-called strongly
“melanoma markers.” Melanomas reactive
seem to lack DOG1 expression. as
Melanomas usually lack CD34 melanoma
expression (Figs.
6.13.11
and
6.13.12)

Resection, targeted
Treatment Surgery and various types of chemotherapy
therapy
Depends on size
Prognosis Poor
and mitotic counts

Figure 6.13.1 Melanoma. There is pigment as an in situ component.

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Figure 6.13.2 Melanoma. Higher magnification of the zone seen in Figure
6.13.1.

Figure 6.13.3 Melanoma. This spindle cell melanoma has the appearances of a
high-grade sarcoma. However, sarcomas of the anal canal are far rarer than
melanomas.

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Figure 6.13.4 Melanoma. Nests showing pigment appear at the top of the field,
but the deeper component shows purely spindled morphology.

Figure 6.13.5 Melanoma. Note the strong nuclear and cytoplasmic labeling for
S100.

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Figure 6.13.6 Melanoma. This is a CD117 stain. Melanomas are often
CD117+, and some mucosal melanomas harbor KIT mutations.

Figure 6.13.7 Gastrointestinal stromal tumor. This example is composed of

uniform spindle cells. They are less atypical than the cells in spindle cell
melanoma.

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Figure 6.13.8 Gastrointestinal stromal tumor. This epithelioid example shows
uniform nuclei.

Figure 6.13.9 Gastrointestinal stromal tumor. This example shows monotonous

spindle cells.

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Figure 6.13.10 Gastrointestinal stromal tumor. This example shows
monotonous epithelioid cells with cytoplasmic vacuoles.

Figure 6.13.11 Gastrointestinal stromal tumor. Some examples, like this one,
show focal S100 protein expression.

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Figure 6.13.12 Gastrointestinal stromal tumor. Most examples are CD117+.

SUGGESTED READINGS
Antonescu CR, Busam KJ, Francone TD, et al. L576P KIT mutation in anal
melanomas correlates with KIT protein expression and is sensitive to specific
kinase inhibition. Int J Cancer. 2007;121(2):257–264. PubMed PMID:
17372901.
Arnold CA, Limketkai BN, Illei PB, et al. Syphilitic and lymphogranuloma
venereum (LGV) proctocolitis: clues to a frequently missed diagnosis. Am J
Surg Pathol. 2013;37(1):38–46. doi: 10.1097/PAS.0b013e31826a523e.
PubMed PMID: 23095509.
Arnold CA, Montgomery EA, Voltaggio L. From the pathologist: review of
sexual behaviors should be a routine component of clinical histories.
Gastrointest Endosc. 2013;78(2): 385–386. doi: 10.1016/j.gie.2013.03.1323.
PubMed PMID: 23867380.
Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like
hemangioendothelioma. Am J Surg Pathol. 2003;27(1):48–57. PubMed
PMID: 12502927.
Carvalho N, Albergaria D, Lebre R, et al. Anal canal gastrointestinal stromal
tumors: case report and literature review. World J Gastroenterol.
2014;20(1):319–322. doi: 10.3748/wjg.v20.i1.319. Review. PubMed PMID:
24415888; PubMed Central PMCID: PMC3886026.

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Clearkin KP, Enzinger FM. Intravascular papillary endothelial hyperplasia. Arch
Pathol Lab Med. 1976;100(8):441–444. PubMed PMID: 947306.
Cotter M, Kelly M, O'Connell P, et al. Anal intraepithelial neoplasia: single
centre 19 year review. Colorectal Dis. 2014. doi: 10.1111/codi.12679.
PubMed PMID: 24888873.
Hobbs CM, Lowry MA, Owen D, et al. Anal gland carcinoma. Cancer.
2001;92(8):2045–2049. PubMed PMID: 11596018.
Hornick JL, Fletcher CD. Pseudomyogenic hemangioendothelioma: a
distinctive, often multicentric tumor with indolent behavior. Am J Surg
Pathol. 2011;35(2):190–201. doi: 10.1097/PAS.0b013e3181ff0901. PubMed
PMID: 21263239.
Kutlubay Z, Engin B, Zara T, et al. Anogenital malignancies and
premalignancies: facts and controversies. Clin Dermatol. 2013;31(4):
362–373. doi: 10.1016/j.clindermatol.2013.01.003. Review. PubMed PMID:
23806153.
Kyriazanos ID, Stamos NP, Miliadis L, et al. Extra-mammary Paget's disease of
the perianal region: a review of the literature emphasizing the operative
management technique. Surg Oncol. 2011;20(2):e61–e71. doi:
10.1016/j.suronc.2010.09.005. Review. PubMed PMID: 20884199.
Meriden Z, Montgomery EA. Anal duct carcinoma: a report of 5 cases. Hum
Pathol. 2012;43(2):216–220. doi: 10.1016/j.humpath.2011.04.019. PubMed
PMID: 21820151.
Satzger I, Küttler U, Völker B, et al. Anal mucosal melanoma with KIT-
activating mutation and response to imatinib therapy—case report and
review of the literature. Dermatology. 2010;220(1):77–81. doi:
10.1159/000265558. Review. PubMed PMID: 19996579.
Satzger I, Schaefer T, Kuettler U, et al. Analysis of c-KIT expression and KIT
gene mutation in human mucosal melanomas. Br J Cancer.
2008;99(12):2065–2069. doi: 10.1038/sj.bjc.6604791. PubMed PMID:
19018266; PubMed Central PMCID: PMC2607233.
Schaeffer DF, Walsh JC, Kirsch R, et al. Distinctive histopathologic phenotype
in resection specimens from patients with Crohn's disease receiving anti-
TNF-α therapy. Hum Pathol. 2014;45:1928–1935. pii: S0046–
8177(14)00236-6. doi: 10.1016/j.humpath.2014.05.016 PubMed PMID:
25022570.
Schim van der Loeff MF, Mooij SH, Richel O, et al. HPV and anal cancer in
HIV-infected individuals: a review. Curr HIV/AIDS Rep. 2014. PubMed

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 PMID: 24990810.
Sobinsky JD, Giannotti G, Podbielski FJ, et al. Anal melanoma: a rare and
aggressive malignancy. Am Surg. 2014;80(7):213–214. PubMed PMID:
24987890.
Voltaggio L, Montgomery EA, Ali MA, et al. Sex, lies, and gastrointestinal tract
biopsies: a review of selected sexually transmitted proctocolitides. Adv Anat
Pathol. 2014;21(2):83–93. doi: 10.1097/PAP.0000000000000014. PubMed
PMID: 24508691.

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 Index

Chapter 1 (Esophagus)
Actin
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
Adenocarcinoma, intramucosal
vs. high-grade columnar epithelial dysplasia
AE1/AE3 keratins
sarcomatoid squamous cell carcinoma
Alcianophilic foveolar cells
vs. goblet cells of Barrett mucosa
AMACR
adenocarcinoma, intramucosal vs. high-grade columnar epithelial
dysplasia
high-grade columnar epithelial dysplasia vs. low-grade columnar
epithelial dysplasia
reactive epithelial changes vs. columnar epithelial dysplasia
Atypical stromal cells in ulcers
vs. sarcomatoid squamous cell carcinoma
Barrett esophagus, goblet cells of
vs. multilayered epithelium
Barrett mucosa
goblet cells of
vs. alcianophilic foveolar cells
vs. esophageal submucosal glands
vs. carryover of small bowel mucosa, esophageal sample
BRAF mutations

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 melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Caldesmon
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
Calponin
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
CAM5.2
sarcomatoid squamous cell carcinoma
Carryover of small bowel mucosa, esophageal sample
vs. Barrett mucosa
CD10
incomplete intestinal metaplasia vs. complete intestinal
metaplasia
CD34
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
CD117
melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
CDx2
alcianophilic columnar cells vs. goblet cells of Barrett esophagus
Barrett mucosa
incomplete intestinal metaplasia vs. complete intestinal
metaplasia
multilayered epithelium vs. goblet cells of Barrett esophagus
squamous dysplasia vs. multilayered epithelium
Columnar epithelial dysplasia

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 high-grade, vs. intramucosal adenocarcinoma
vs. reactive epithelial changes
vs. taxane effect
Columnar-lined esophagus, submucosa in
vs. lamina propria in columnar-lined esophagus
Complete intestinal metaplasia
vs. incomplete intestinal metaplasia
Cytomegalovirus esophagitis
vs. reactive stromal changes
Desmin
smooth muscle tumors, esophageal vs. esophageal
gastrointestinal stromal tumors
Eosinophilic esophagitis
vs. reflux esophagitis
Esophageal gastrointestinal stromal tumor
vs. esophageal smooth muscle tumors
vs. melanoma
Esophageal sample, small bowel mucosa, carryover of
vs. Barrett mucosa
Esophageal smooth muscle tumors
vs. esophageal gastrointestinal stromal tumors
Esophageal submucosal glands
vs. goblet cells of Barrett mucosa
Esophagitis dissecans
vs. esophageal pemphigus vulgaris
Feline esophagus
Gastrointestinal stromal tumors, esophageal
vs. esophageal smooth muscle tumors
vs. melanoma
Goblet cells of Barrett esophagus
vs. multilayered epithelium

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Goblet cells of Barrett mucosa
vs. alcianophilic foveolar cells
vs. esophageal submucosal glands
Herpes simplex esophagitis
vs. reactive multinucleated squamous cells
High-grade columnar epithelial dysplasia
vs. intramucosal adenocarcinoma
vs. low-grade columnar epithelial dysplasia
HMB45
melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Incomplete intestinal metaplasia
vs. complete intestinal metaplasia
Intramucosal adenocarcinoma
vs. high-grade columnar epithelial dysplasia
Iron pill esophagitis
vs. squamous dysplasia
Ki-67
adenocarcinoma, intramucosal vs. high-grade columnar epithelial
dysplasia
high-grade columnar epithelial dysplasia vs. low-grade columnar
epithelial dysplasia
reactive epithelial changes vs. columnar epithelial dysplasia
squamous dysplasia vs. multilayered epithelium
taxane effect vs. squamous and columnar epithelial dysplasia
Lamina propria in columnar-lined esophagus
vs. submucosa in columnar-lined esophagus
Lichenoid esophagitis
vs. reflux change
Low-grade columnar epithelial dysplasia
vs. high-grade columnar epithelial dysplasia

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MART1
melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Melan A
melanosis vs. melanoma
Melanocytosis. See Melanoma
Melanoma
vs. esophageal gastrointestinal stromal tumor
vs. melanosis
Melanosis
vs. melanoma
MUC2
Barrett mucosa
esophageal submucosal glands vs. goblet cells of Barrett
esophagus
goblet cells of Barrett esophagus vs. alcianophilic columnar cells
incomplete intestinal metaplasia vs. complete intestinal
metaplasia
multilayered epithelium vs. Barrett esophagus, goblet cells of
squamous dysplasia vs. multilayered epithelium
MUC5AC
Barrett mucosa
goblet cells of Barrett esophagus vs. alcianophilic columnar cells
incomplete intestinal metaplasia
Mucin
multilayered epithelium vs. Barrett esophagus, goblet cells of
Multilayered epithelium
vs. goblet cells in Barrett esophagus
vs. squamous dysplasia
Oncocytic change of submucosal glands
vs. pyloric gland adenoma

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p53
adenocarcinoma, intramucosal vs. high-grade columnar epithelial
dysplasia
columnar epithelial dysplasia vs. reactive epithelial changes
high-grade columnar epithelial dysplasia vs. low-grade columnar
epithelial dysplasia
reactive epithelial changes vs. columnar epithelial dysplasia
p63
multilayered epithelium
sarcomatoid squamous cell carcinoma
squamous dysplasia vs. multilayered epithelium
PAS/AB
Barrett mucosa
esophageal submucosal glands vs. goblet cells of Barrett
esophagus
squamous dysplasia vs. multilayered epithelium
Pseudoepitheliomatous hyperplasia
vs. squamous cell carcinoma
Pyloric gland adenoma
vs. oncocytic change of submucosal glands
Reactive epithelial changes
vs. columnar epithelial dysplasia
Reactive multinucleated squamous cells
vs. herpes simplex esophagitis
Reactive stromal changes
vs. cytomegalovirus esophagitis
Reflux change
vs. lichenoid esophagitis
Reflux esophagitis
vs. eosinophilic esophagitis
S100

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 melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Sarcomatoid squamous cell carcinoma
vs. stromal cells in ulcers, atypical
Sloughing esophagitis. See Esophagitis dissecans vs. esophageal
pemphigus vulgaris
Small bowel mucosa, carryover of
vs. Barrett mucosa
Smooth muscle tumors, esophageal
vs. esophageal gastrointestinal stromal tumors
SOX10
melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Sox2
multilayered epithelium
squamous dysplasia vs. multilayered epithelium
Squamous cell carcinoma
vs. pseudoepitheliomatous hyperplasia
sarcomatoid See (Sarcomatoid squamous cell carcinoma)
Squamous dysplasia
vs. iron pill esophagitis
vs. multilayered epithelium
Stromal cells in ulcers, atypical
vs. sarcomatoid squamous cell carcinoma
Submucosa in columnar-lined esophagus
vs. lamina propria in columnar-lined esophagus
Submucosal glands, oncocytic change of
vs. pyloric gland adenoma
Taxane effect
vs. squamous and columnar epithelial dysplasia
Tyrosinase

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 melanoma vs. esophageal gastrointestinal stromal tumor
melanosis vs. melanoma
Vimentin
reactive stromal changes vs. cytomegalovirus esophagitis
squamous cell carcinoma, sarcomatoid vs. stromal cells in ulcers,
atypical
vs. taxane effect

Chapter 2 (Stomach)
Adenocarcinoma vs. well-differentiated neuroendocrine tumor
Adenoma
gastric foveolar-type vs. pyloric gland adenoma
intestinal-type vs. pyloric gland adenoma
Alizarin red
mucosal calcinosis
Antrum
vs. body
vs. cardia
Autoimmune gastritis vs. environmental gastritis
B-cell lymphoma, diffuse large vs. carcinoma
Body vs. antrum
C79a
Russell body gastritis vs. signet-ring cell carcinoma
Carcinoid vs. type 2 neuroendocrine tumor
Carcinoma
vs. diffuse large B-cell lymphoma
vs. epithelioid gastrointestinal tumor
CD10
gastrointestinal stromal tumor (GIST), pediatric type vs.
plexiform fibromyxoma
CD34

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 gastrointestinal stromal tumor (GIST) vs. schwannoma
CD117
carcinoma vs. epithelioid gastrointestinal tumor
CD138
russell body gastritis vs. signet-ring cell carcinoma
CDH1
reactive changes, of stress gastritis vs. in situ signet-ring cell
carcinoma
CEA
body
Chemical gastropathy
vs. gastric antral vascular ectasia See (Watermelon stomach vs.
chemical gastropathy)
vs. watermelon stomach
Chromogranin A
type 1 neuroendocrine tumor
type 2 neuroendocrine tumor
type 3 neuroendocrine tumor
well-differentiated neuroendocrine tumor
Chronic gastritis vs. malt lymphoma
CK7
signet-ring cell carcinoma
signet-ring cell gastric carcinoma vs. metastatic lobular breast
carcinoma
in situ signet-ring cell carcinoma, in patients with CDH1
germline mutations
Colchicine and taxol–associated gastropathy vs. dysplasia
Crush artifact vs. signet-ring cell carcinoma
Cytokeratin markers
lymphoepithelial-like carcinoma
Diffuse large B-cell lymphoma vs. carcinoma

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DOG1
gastrointestinal stromal tumor (GIST)
Dysplasia
vs. colchicine and taxol–associated gastropathy
vs. iron pill gastritis
vs. taxol-associated gastropathy and colchicine
EBV
lymphoepithelial-like carcinoma
E-cadherin
reactive changes of stress gastritis
signet-ring cell change
signet-ring cell gastric carcinoma
EMA
body
Environmental gastritis vs. autoimmune gastritis
Epithelioid gastrointestinal tumor vs. carcinoma
Fundic gland polyp
vs. oxyntic gland polyp/adenoma
vs. proton pump inhibitor effect
Gastric antral vascular ectasia vs. chemical gastropathy. See
Watermelon stomach vs. chemical gastropathy
Gastric foveolar-type gastric adenoma vs. pyloric gland adenoma
Gastrin
antrum
autoimmune gastritis
Gastrointestinal stromal tumor (GIST)
vs. glomus tumor
vs. inflammatory fibroid polyp
pediatric type vs. plexiform fibromyxoma
vs. schwannoma
GFAP

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 schwannoma
GIST. See Gastrointestinal stromal tumor (GIST)
Glomus tumor vs. gastrointestinal stromal tumor (GIST)
H. pylori
environmental gastritis
Hyperplastic polyp
vs. menetrier disease
vs. Peutz-Jeghers polyposis
vs. polyposis
vs. syndromic polyps
In situ signet-ring cell carcinoma, in patients with CDH1 germline
mutations vs. reactive changes of stress gastritis
Inflammatory fibroid polyp
vs. gastrointestinal stromal tumor
Iron pill gastritis
vs. dysplasia
vs. gastric siderosis
Kaposi sarcoma vs. lamina propria
Ki-67
well-differentiated neuroendocrine tumor
Lamina propria vs. kaposi sarcoma
Lymphoepithelial-like carcinoma vs. lymphoma
Lymphoma vs. lymphoepithelial-like carcinoma
MALT lymphoma vs. chronic gastritis
Menetrier disease
vs. hyperplastic polyp
vs. Zollinger-Ellison syndrome
Metastatic lobular breast carcinoma vs. signet-ring cell gastric
carcinoma
Micrococcus vs. sarcina gastropathy
Mucin stains

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 carcinoma
metastatic lobular breast carcinoma
Mucosal calcinosis vs. parasitic gastritis
Neuronspecific enolase (NSE)
type 1 neuroendocrine tumor vs. type 2 neuroendocrine tumor
type 3 neuroendocrine tumor
well-differentiated neuroendocrine tumor
Oxyntic gland adenoma
polyp vs. fundic gland polyp
Oxyntic gland polyp
adenoma vs. fundic gland polyp
vs. proton pump inhibitor effect
Parasitic gastritis vs. mucosal calcinosis
PAS
signet-ring cell gastric carcinoma
in situ signet-ring cell carcinoma in patients with CDH1 germline
mutations
Pepsinogen-I
oxyntic gland polyp/adenoma
Peutz-Jeghers polyposis vs. hyperplastic polyp
Plexiform fibromyxoma
vs. gastrointestinal stromal tumor (GIST), pediatric type
Polyposis vs. hyperplastic polyp
Proton pump inhibitor effect vs. fundic gland polyp
Pyloric gland adenoma
vs. gastric foveolar-type gastric adenoma
vs. intestinal-type adenoma
Reactive changes, of stress gastritis vs. in situ signet-ring cell
carcinoma
Russell body gastritis vs. signet-ring cell carcinoma
S100

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 schwannoma vs. gastrointestinal stromal tumor (gist)
Sarcina gastropathy vs. micrococcus
Schwannoma vs. gastrointestinal stromal tumor (GIST)
Siderosis, gastric vs. iron pill gastritis
Signet-ring cell carcinoma
vs. crush artifact
vs. reactive changes of stress gastritis
vs. russell body gastritis
vs. signet-ring cell change
vs. xanthoma
Signet-ring cell change vs. signet-ring cell carcinoma
Signet-ring cell gastric carcinoma vs. metastatic lobular breast
carcinoma
Smooth muscle actin
gastrointestinal stromal tumor (GIST), pediatric type
Synaptophysin
type 1 neuroendocrine tumor vs. type 2 neuroendocrine tumor
type 3 neuroendocrine tumor
well-differentiated neuroendocrine tumor
Syndromic polyps vs. hyperplastic polyp
Taxol-associated gastropathy and colchicine vs. dysplasia
Type 1 neuroendocrine tumor
type 2 neuroendocrine tumor See (Carcinoid vs. type 2
neuroendocrine tumor)
type 3 neuroendocrine tumor
Type 2 neuroendocrine tumor
vs. type 1 neuroendocrine tumor
Type 3 neuroendocrine tumor
vs. type 1 neuroendocrine tumor
von Kossa stain
mucosal calcinosis

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Watermelon stomach vs. chemical gastropathy
Well-differentiated neuroendocrine tumor vs. adenocarcinoma
Xanthoma vs. signet-ring cell carcinoma
Zollinger-Ellison syndrome vs. Menetrier disease

Chapter 3 (Small Intestine)

Abetalipoproteinemia vs. chronic duodenitis
Atypical stromal cells, in ulcers vs. small bowel sarcomas
Autoimmune enteropathy
vs. common variable immunodeficiency
vs. normal small bowel
B-cell lymphoma, diffuse large vs. Burkitt lymphoma
BCL2
small bowel follicular lymphoma vs. mantle cell lymphoma
Behcet syndrome affecting small bowel vs. Crohn disease
Burkitt lymphoma vs. diffuse large B-cell lymphoma
Calcifying fibrous tumors vs. mesenteric fibromatosis
Carcinoma vs. epithelioid small bowel gastrointestinal stromal tumor
CD10
small bowel follicular lymphoma vs. mantle cell lymphoma
CD19
B-cell lymphoma, diffuse large vs. burkitt lymphoma
mantle cell lymphoma vs. small bowel follicular lymphoma
CD20
diffuse large B-cell lymphoma vs. Burkitt lymphoma
mantle cell lymphoma vs. small bowel follicular lymphoma
CD22
diffuse large B-cell lymphoma vs. burkitt lymphoma
mantle cell lymphoma vs. small bowel follicular lymphoma
CD23
small bowel follicular lymphoma vs. mantle cell lymphoma

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CD79a
diffuse large B-cell lymphoma vs. burkitt lymphoma
Celiac disease
vs. common variable immunodeficiency
vs. enteropathy-associated T-cell lymphoma
vs. small bowel bacterial overgrowth, of enteric contents
Chronic duodenitis
vs. abetalipoproteinemia
vs. intracytoplasmic lipid
Clear cell sarcoma–like tumor
vs. melanoma
vs. small bowel gastrointestinal stromal tumor
Collagenous sprue/enteritis vs. radiation change
Common variable immunodeficiency
vs. autoimmune enteropathy
vs. celiac disease
vs. normal small intestine
Crohn disease
vs. Behcet syndrome affecting small bowel
vs. infectious enteritis
requiring surgery vs. NSAID-associated injury requiring surgery
Cronkhite-Canada polyps vs. juvenile polyps
Crushed Brunner glands
vs. mesenchymal lesions, in small bowel mucosa
vs. whipple disease
Diffuse large B-cell lymphoma vs. burkitt lymphoma
Duodenal well-differentiated neuroendocrine carcinoid tumor vs.
duodenitis
Duodenitis vs. duodenal well-differentiated neuroendocrine carcinoid
tumor
Enteropathy disease vs. enteropathy-associated T-cell lymphoma

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Enteropathy-associated T-cell lymphoma vs. enteropathy/celiac
disease
Epithelioid small bowel gastrointestinal stromal tumor vs. carcinoma
Infectious enteritis vs. Crohn disease
Inflammatory fibroid polyp vs. small bowel gastrointestinal stromal
tumor
Intracytoplasmic lipid
vs. cronkhite-canada
vs. microvillus inclusion disease
Juvenile polyp
vs. Cronkhite-Canada polyps
vs. Peutz-Jeghers polyp
Langerhans cell histiocytosis vs. systemic mastocytosis
Leiomyosarcoma vs. small bowel gastrointestinal stromal tumor
Malignant gastrointestinal neuroectodermal tumor. See Clear cell
sarcoma-like tumor vs. melanoma; clear cell sarcoma-like tumor
vs. small bowel gastrointestinal stromal tumor
Mantle cell lymphoma vs. small bowel follicular lymphoma
Melanoma
vs. clear cell sarcoma–like tumor
vs. malignant gastrointestinal neuroectodermal tumor
vs. small bowel gastrointestinal stromal tumor
Mesenchymal lesions, in small bowel mucosa vs. crushed brunner
glands
Mesenteric fibromatosis
vs. calcifying fibrous tumors
vs. sclerosing mesenteritis
vs. small bowel gastrointestinal stromal tumor
Metastases, to small bowel vs. primary small bowel cancer
Microvillus inclusion disease
vs. intracytoplasmic lipid

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 vs. tufting enteropathy
Mucosa-associated lymphoid tissue (MALT) lymphoma vs. small
bowel follicular lymphoma
Mycobacterium avium complex vs. Whipple disease
Nodular duodenitis vs. tubular/tubulovillous adenoma
Nonsteroidal anti-inflammatory drug (NSAID)–associated injury
requiring surgery. See NSAID-associated injury requiring surgery
Normal small bowel vs. autoimmune enteropathy
Normal small intestine vs. common variable immunodeficiency
NSAID-associated injury requiring surgery vs. Crohn disease
requiring surgery
PAS
mesenchymal lesions, in small bowel mucosa
PAX5
mantle cell lymphoma vs. small bowel follicular lymphoma
Peutz-Jeghers polyp vs. juvenile polyp
Primary small bowel cancer vs. metastases, to small bowel
Pyloric gland adenoma vs. tubular adenoma
Radiation change vs. collagenous sprue/enteritis
Reactive lymphoid hyperplasia vs. small bowel follicular lymphoma
S100
clear cell sarcoma-like tumor vs. small bowel gastrointestinal
stromal tumor
melanoma vs. clear cell sarcoma–like tumor
Sclerosing mesenteritis
vs. mesenteric fibromatosis
Small bowel bacterial overgrowth, of enteric contents vs. celiac
disease
Small bowel follicular lymphoma
vs. mantle cell lymphoma
vs. mucosa-associated lymphoid tissue (MALT) lymphoma

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 vs. reactive lymphoid hyperplasia
Small bowel gastrointestinal stromal tumor
vs. clear cell sarcoma–like tumor
vs. inflammatory fibroid polyp
vs. leiomyosarcoma
vs. melanoma
vs. mesenteric fibromatosis
Small bowel mucosa
mesenchymal lesions in vs. crushed brunner glands
Small bowel sarcomas vs. atypical stromal cells, in ulcers
SOX10
clear cell sarcoma–like tumor vs. melanoma
clear cell sarcoma-like tumor vs. small bowel gastrointestinal
stromal tumor
Systemic mastocytosis vs. Langerhans cell histiocytosis
Tubular/tubulovillous adenoma
vs. nodular duodenitis
vs. pyloric gland adenoma
Tufting enteropathy vs. microvillus inclusion disease
Whipple disease
vs. crushed Brunner glands
vs. mycobacterium avium complex

Chapter 4 (Colon)
Actin
smooth muscle tumors vs. gastrointestinal stromal tumor
Adenoma
vs. colitis-associated dysplasia
with invasive carcinoma vs. pseudoinvasion
vs. juvenile polyps
vs. reparative changes

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Amyloidosis
vs. collagenous colitis
vs. radiation colitis
vs. thick basement membrane
Anti-Saccharomyces cerevisiae antibody (ASCA)
Crohn colitis
vs. collagenous colitis
vs. diverticular-associated colitis
vs. ulcerative colitis
granulomas typical, of Crohn disease vs. normal macrophages
inflammatory bowel disease vs. sexually transmitted disease–
associated proctocolitis
Atypical stromal cells, in polyps and ulcers vs. sarcoma
Autoimmune colopathy vs. normal colon
Benign epithelioid nerve sheath tumor vs. melanoma
Bile sequestratants, cholestyramine vs. kayexalate injury
CD5/43
mantle cell lymphoma vs. reactive lymphoid hyperplasia
CD19/20
mantle cell lymphoma vs. reactive lymphoid hyperplasia
CD34
gastrointestinal stromal tumor vs. granular cell tumor
melanoma vs. benign epithelioid nerve sheath tumor
smooth muscle tumors vs. gastrointestinal stromal tumor
Cholestyramine, bile sequestratants vs. kayexalate injury
Chronic granulomatous disease vs. melanosis coli
CK7 for stomach
colorectal carcinoma vs. metastatic carcinoma
Colitis-associated dysplasia
vs. adenoma
vs. reactive changes

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Collagenous colitis
vs. amyloidosis
vs. Crohn colitis
vs. mastocytosis
vs. radiation colitis
vs. thick basement membrane
Colorectal carcinoma
vs. metastatic carcinoma
vs. neuroendocrine tumors
Common variable immunodeficiency vs. normal colon
Crohn colitis
vs. collagenous colitis
vs. diverticular-associated colitis
vs. ulcerative colitis
Crohn disease
granulomas typical of vs. normal macrophages
Cronkhite-Canada polyp
vs. juvenile polyps
Cyclin D1
mantle cell lymphoma vs. reactive lymphoid hyperplasia
Diversion colitis
vs. pouchitis
vs. ulcerative colitis
Diverticular colitis vs. Crohn colitis
D816V KIT mutation
mastocytosis
vs. collagenous colitis
vs. Langerhans cell histiocytosis
EMA
Schwann cell hamartoma vs. perineurioma/fibroblastic polyp
Endometriosis vs. sarcoma

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Eosinophilic colitis vs. mastocytosis
ER
colorectal carcinoma vs. metastatic carcinoma
endometriosis vs. sarcoma
Fibroblastic polyp vs. Schwann cell hamartoma
Foreign body granulomas vs. granulomas typical, of Crohn disease
Ganglioneuroma vs. Schwann cell hamartoma
Gastrointestinal stromal tumor
vs. granular cell tumor
GCDFP-15/CK7 for breast
colorectal carcinoma vs. metastatic carcinoma
GLUT-1
Schwann cell hamartoma vs. perineurioma/fibroblastic polyp
Granular cell tumor
vs. gastrointestinal stromal tumor
Granulomas typical, of Crohn disease vs. normal macrophages
HMB-45
colorectal carcinoma vs. metastatic melanoma
melanoma vs. benign epithelioid nerve sheath tumor
Hyperplastic polyp
vs. sessile serrated adenoma
Inflammatory bowel disease vs. sexually transmitted disease–
associated proctocolitis
Invasive carcinoma
adenoma with vs. pseudoinvasion
Ischemic colitis
vs. pseudomembranous colitis
vs. squeeze artifact
vs. thick basement membrane
Juvenile polyps
vs. adenomas

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 vs. Cronkhite-Canada polyp
vs. mucosal prolapse polyps
vs. Peutz-Jeghers polyps
Kaposi sarcoma vs. lamina propria
Kayexalate injury vs. cholestyramine
Lamina propria vs. kaposi sarcoma
Langerhans cell histiocytosis
vs. mastocytosis
Mammaglobin
colorectal carcinoma vs. metastatic carcinoma
Mantle cell lymphoma vs. reactive lymphoid hyperplasia
Mastocytosis
vs. collagenous colitis
vs. eosinophilic colitis
vs. Langerhans cell histiocytosis
Melan-A (Mart1)
colorectal carcinoma vs. metastatic carcinoma
melanoma vs. benign epithelioid nerve sheath tumor
Melanoma vs. benign epithelioid nerve sheath tumor
Melanosis coli vs. chronic granulomatous disease
Metastatic carcinoma vs. colorectal carcinoma
MITF
melanoma vs. benign epithelioid nerve sheath tumor
Mucosal prolapse polyps
vs. juvenile polyps
vs. Peutz-Jeghers polyps
vs. sessile serrated adenoma
Neuroendocrine tumors vs. colorectal carcinoma
Neuroma vs. Schwann cell hamartoma
NKX-3.1 for prostate
carcinoma vs. colorectal carcinoma

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Normal colon
vs. autoimmune colopathy
vs. common variable immunodeficiency
Normal macrophages vs. granulomas typical, of Crohn disease
p53
colitis-associated dysplasia vs. adenoma
PAS
granular cell tumor
PAX8 for ovary
carcinoma vs. colorectal carcinoma
Perineurioma vs. Schwann cell hamartoma
Peutz-Jeghers polyps
vs. juvenile polyps
vs. mucosal prolapse polyps
Pouchitis vs. diversion colitis
PR
colorectal carcinoma vs. metastatic carcinoma
endometriosis vs. sarcoma
Proctocolitis, sexually transmitted disease-associated vs. inflammatory
bowel disease
PSAP
carcinoid vs. colorectal carcinoma
colorectal carcinoma vs. metastatic carcinoma
Pseudoinvasion
vs. adenoma, with invasive carcinoma
Pseudomembranous colitis
vs. ischemic colitis
Radiation colitis
vs. amyloidosis
vs. collagenous colitis
Reactive changes

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 vs. colitis-associated dysplasia
Reactive lymphoid hyperplasia vs. mantle cell lymphoma
Reparative changes
vs. adenoma
S100
colorectal carcinoma vs. metastatic carcinoma
granular cell tumor
melanoma vs. benign epithelioid nerve sheath tumor
Schwann cell hamartoma
vs. ganglioneuroma
vs. perineurioma/fibroblastic polyp
Sarcoma
vs. atypical stromal cells, in polyps and ulcers
vs. endometriosis
Schwann cell hamartoma
vs. ganglioneuroma
vs. neuroma
vs. perineurioma/fibroblastic polyp
Self-limiting colitis vs. ulcerative colitis
Sessile serrated adenoma
vs. hyperplastic polyp
vs. mucosal prolapse polyps
vs. traditional serrated adenoma
Sexually transmitted disease–associated proctocolitis vs. inflammatory
bowel disease
Signet-ring cell carcinoma vs. signet-ring cell change
Signet-ring cell change vs. signet-ring cell carcinoma
Smooth muscle tumors
vs. gastrointestinal stromal tumor
SOX10
colorectal carcinoma vs. metastatic melanoma

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 melanoma vs. benign epithelioid nerve sheath tumor
Squeeze artifact vs. ischemic colitis
Thick basement membrane
vs. amyloidosis
vs. collagenous colitis
vs. ischemic colitis
Traditional serrated adenoma
vs. sessile serrated adenoma
Ulcerative colitis
vs. Crohn colitis
vs. diversion colitis
vs. self-limiting colitis
WT1
colorectal carcinoma vs. metastatic carcinoma

Chapter 5 (Appendix)
Adenocarcinoma
ex goblet cell carcinoid vs. goblet cell carcinoid
vs. goblet cell carcinoid
vs. tubular carcinoid
Appendiceal diverticulum vs. low-grade appendiceal mucinous
neoplasm
CAM 5.2
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
goblet cell carcinoid vs. adenocarcinoma
Carcinoid tumor vs. goblet cell carcinoid. See Well-differentiated
neuroendocrine tumor vs. goblet cell carcinoid
CD56/57
well-differentiated neuroendocrine tumor vs. goblet cell carcinoid
CDX-2
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid

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 goblet cell carcinoid vs. adenocarcinoma
CEA
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
adenocarcinoma vs. tubular carcinoid
goblet cell carcinoid vs. adenocarcinoma
Chromogranin
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
goblet cell carcinoid vs. adenocarcinoma
well-differentiated neuroendocrine tumor vs. goblet cell carcinoid
CK20
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
goblet cell carcinoid vs. adenocarcinoma
Crohn disease
vs. granulomatous appendicitis
vs. infectious appendicitis, with granulomas
vs. interval appendix
Ex goblet cell carcinoid, adenocarcinoma vs. goblet cell carcinoid
Glucagon
adenocarcinoma vs. tubular carcinoid
Goblet cell carcinoid
vs. adenocarcinoma
vs. adenocarcinoma ex goblet cell carcinoid
Granulomas vs. Crohn disease
Granulomatous appendicitis vs. Crohn disease
High-grade appendiceal mucinous neoplasm
vs. low-grade appendiceal mucinous neoplasm
Infectious appendicitis, with granulomas vs. Crohn disease
Interval appendix vs. Crohn disease
Low-grade appendiceal mucinous neoplasm
vs. appendiceal diverticulum
vs. high-grade mucinous neoplasm

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 vs. sessile serrated adenoma
vs. tubular/tubulovillous adenoma
vs. well-differentiated adenocarcinoma
Mucin stains
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
well-differentiated neuroendocrine tumor vs. goblet cell carcinoid
Neuron-specific enolase
well-differentiated neuroendocrine tumor vs. goblet cell carcinoid
Sessile serrated adenoma vs. low-grade appendiceal mucinous
neoplasm
Synaptophysin
adenocarcinoma ex goblet cell carcinoid vs. goblet cell carcinoid
goblet cell carcinoid vs. adenocarcinoma
well-differentiated neuroendocrine tumor vs. goblet cell carcinoid
Tubular carcinoid vs. adenocarcinoma
Tubular/tubulovillous adenoma
vs. low-grade appendiceal mucinous neoplasm
Well-differentiated adenocarcinoma
vs. low-grade appendiceal mucinous neoplasm
Well-differentiated neuroendocrine tumor
vs. goblet cell carcinoid

Chapter 6 (Anal Canal)

Adenocarcinoma, of female genital tract vs. hidradenoma papilliferum
Anal duct carcinoma vs. spread of tumors, from other sites
Anal intraepithelial neoplasia (AIN)
extending into colorectal glands vs. invasive squamous cell
carcinoma
vs. reactive squamous changes
Angiosarcoma
vs. papillary endothelial hyperplasia, in hemorrhoidal vessels

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Colorectal carcinoma, pagetoid extension of vs. Paget disease
Colorectal glands vs. invasive squamous cell carcinoma
Condyloma
vs. fibroepithelial polyp (anal tag)
lata vs. squamous cell carcinoma
Fibroepithelial polyp
vs. condyloma
stromal changes in vs. sarcoma
Gastrointestinal stromal tumor vs. melanoma
Hidradenoma papilliferum vs. adenocarcinoma, of female genital tract
HPV
anal intraepithelial neoplasia (AIN)
Inflammatory bowel disease vs. sexually transmitted proctitis
Invasive squamous cell carcinoma vs. colorectal glands
Melanoma vs. gastrointestinal stromal tumor
P16
anal intraepithelial neoplasia (AIN)
Paget disease vs. pagetoid extension, of colorectal carcinoma
Pagetoid extension, of colorectal carcinoma vs. Paget disease. See
Colorectal carcinoma, pagetoid extension of vs. Paget disease
Papillary endothelial hyperplasia, in hemorrhoidal vessels vs.
angiosarcoma
Pseudoepitheliomatous hyperplasia vs. squamous cell carcinoma
Reactive squamous changes vs. anal intraepithelial neoplasia
Sarcoma vs. fibroepithelial polyp, stromal changes in
Sexually transmitted proctitis vs. inflammatory bowel disease
Skin appendage tumors vs. squamous cell carcinoma
Spread of tumors, from other sites vs. anal duct carcinoma
Squamous cell carcinoma
vs. condyloma lata
invasive vs. colorectal glands

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 vs. pseudoepitheliomatous hyperplasia
vs. skin appendage tumors
Stromal changes, in fibroepithelial polyp vs. sarcoma

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