Atlas

of Gastrointestinal Pathology
A Pattern Based Approach to Non-Neoplastic Biopsies

CHRISTINA A. ARNOLD, MD
Assistant Professor Department of Pathology Division of Gastrointestinal
and Liver Pathology Division of Bone and Soft Tissue Pathology The
Ohio State University Wexner Medical Center Columbus, Ohio

DORA M. LAM-HIMLIN, MD
Assistant Professor Department of Laboratory Medicine and Pathology
Mayo Clinic
Scottsdale, Arizona 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
Acquisitions Editor: Ryan Shaw Product Development Editor: Kate Marshall Marketing Manager: Dan
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Library of Congress Cataloging-in-Publication Data

Arnold, Christina A., author.

Atlas of Gastrointestinal Pathology: A Pattern Based Approach to Non-Neoplastic Biopsies /
Christina A. Arnold, Dora M. Lam-Himlin, Elizabeth A. Montgomery.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4511-8810-3 (hardback) I. Lam-Himlin, Dora M., author. II. Montgomery,
Elizabeth (Elizabeth A.), 1958-author. III. Title.
[DNLM: 1. Gastrointestinal Diseases–pathology–Atlases. 2. Gastrointestinal Tract–pathology–
Atlases. WI 17]
RC802.9
616.3′307–dc23

2014017635
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 To Michael, my always best friend.
To Madelyn and Jackson, Dream Big!
Christina A. Arnold, MD

To Matt, for being there.

To Madeline, for your big questions.
To Matthew, for wanting to eat a juvenile polyp.
Dora M. Lam-Himlin, MD

To the fresh ideas and success of all past, present, and future
gastrointestinal pathology fellows.
Elizabeth A. Montgomery, MD
 CONTRIBUTORS

MICHAEL A. ARNOLD, MD, PhD

Assistant Professor
Department of Pathology and Laboratory Medicine Nationwide
Children’s Hospital Department of Pathology The Ohio State University
Wexner Medical Center Columbus, Ohio

BERKELEY N. LIMKETKAI, MD
Assistant Professor
Department of Medicine Division of Gastroenterology and Hepatology
Stanford University
Stanford, California CHRISTINA A. ARNOLD, MD
Assistant Professor
Department of Pathology Division of Gastrointestinal and Liver
Pathology Division of Bone and Soft Tissue Pathology The Ohio State
University Wexner Medical Center Columbus, Ohio

DORA M. LAM-HIMLIN, MD
Assistant Professor
Department of Laboratory Medicine and Pathology Mayo Clinic
Scottsdale, Arizona

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
 PREFACE

As soon as a junior trainee opens a textbook, he/she quickly realizes that

most traditional text books rarely capture the true spectrum of pathology
encountered through routine sign-out. The pathology that exists in
textbooks is beautiful, perfect, and free from distracting artifacts. No
doubt, these perfect examples facilitate the teaching process. The
pathology that exists in real life, however, is messy. The tissue is often
scanty, squashed, burnt, and cursed with artifacts. In real life, we have
to search for “red flags” in the clinical chart, hidden clues in the slides,
and discern an exacting diagnosis despite sometimes disabling artifacts.

This book project grew out of a need to teach pathology in a format that
more closely mirrors daily sign-out. More than 1,100 images are
included to illustrate the full morphologic spectrum of the major
patterns of non-neoplastic gastrointestinal tract injury. Instead of one
picture to illustrate chronic colitis, for example, this book includes over
eighty; each image captioned with a careful description. The
corresponding text details how to recognize the chronic colitis pattern
and then how to translate the vague diagnosis of “chronic colitis” into
the clinically meaningful diagnosis of “syphilitic proctitis,” for example,
and how to avoid the diagnostic pitfall of inflammatory bowel disease.

In this book, disease processes are grouped by their histologic pattern of

injury, an approach which closely approximates the method by which
experienced pathologists mentally approach daily sign-out. Because the
luminal gastrointestinal tract has a limited repertoire of responses to
injury, one need master only a limited number of histologic patterns in
order to elaborate the differential diagnoses. Organized by these major
injury patterns, each chapter details etiologic considerations for the
esophagus, stomach, small intestine, and colon.
Key structural elements are included throughout to enable the reader to
quickly segregate specific patterns of injury, link the injury patterns with
particular etiologies, and to emphasize important teaching points. The
text is high yield and focused on checklists, key features, diagnostic
pearls and pitfalls, frequently asked questions, and sample notes, see
descriptions below. We hope this collective experience leaves the reader
with a familiarity of the major patterns of non-neoplastic injury in the
gastrointestinal tract and confidence in navigating through the
clinicopathologic clues and pitfalls to arrive swiftly at the correct
diagnosis. Select structural elements are briefly introduced below.

• Each chapter opens with a “Chapter Checklist” that outlines the

enclosed structure and allows the reader to quickly hone in on select
patterns and pertinent differential considerations. Similar “Checklists”
are found throughout the chapter to neatly organize complicated
topics.
• “The Unremarkable X”: Normal histology is sometimes overlooked in
textbooks because it is assumed to be widely understood, much to the
frustration of junior trainees. A firm understanding of normal is
essential to recognizing subtle injury patterns. As such, each chapter
begins with a brief discussion of normal histology to contrast to the
succeeding mucosal injury patterns and to highlight helpful diagnostic
clues.
• The “Pearls & Pitfalls” sections include lessons from real life sign-out
experience with an emphasis on important diagnostic clues, mimics,
and hazards.
• The “Frequently Asked Questions” sections stem from our busy consult
service and teaching sessions. In this section, we discuss real life
diagnostic dilemmas and offer diagnostic tips and tools to sort through
commonly encountered sign-out challenges.
• All major topics close with a “Key Features” section that summarizes
the essential elements of the subtopic for handy reference.
• A “Sample Note” section accompanies the more challenging topics. In
these sections, an example pathology report is included with the top-
line diagnosis, pertinent discussion, and salient references. These
 “Notes” offer a template of how to synthesize complicated topics and
are based on real life cases and interactions with clinicians. The select
references are included for those interested in further reading, but also
can be included in pathology reports to help guide clinical
management.
• Each chapter features a corresponding “Quiz” section online to
emphasize important teaching points. These sections offer the reader
experience and confidence with high-yield teaching topics. Questions
are in the format of the board type examinations, and can also serve as
useful board preparatory materials.
 ACKNOWLEDGMENTS

We thank our institutions, colleagues, and trainees for invaluable

resources and support. We are indebted to our inquisitive trainees and
clinicians whose fresh perspectives and lively discussions drove the
direction of this book. We particularly thank our families for
understanding the numerous late night, early morning, and weekend
marathon writing sessions.

We thank our Acquisition Editor, Ryan Shaw, for taking a chance on this
project, and our Product Development Editor, Kate Marshall, for working
diligently with us to develop the format. We thank Rick Marshall for
computer assistance in identifying pertinent teaching material, Shawn
Scully for photography editing on select topics, and the following
physician assistants for the enclosed gross photographs: Sandra Banky,
PA (ASCP), Andrew B. Mcloughlin, MS, PA (ASCP), Kjirsten R. Kellogg,
MS, PA (ASCP), Marlene M. Parker, PA (ASCP), and Jeff Purcell, PA
(ASCP). We acknowledge the Research Institute at Nationwide Children’s
Hospital Biopathology Center Biomedical Imaging Team for the
preparation of virtual microscopy slides for select portions of the small
intestine chapter.
 CONTENTS

1. ESOPHAGUS
The Unremarkable Esophagus
Acute Esophagitis Pattern
Eosinophilic Pattern
Parakeratotic Pattern
Esophageal Lymphocytosis Pattern
Pigments
Near Misses

2. STOMACH
The Unremarkable Stomach
Reactive Gastritis/Gastropathy Pattern
Acute Gastritis Pattern
Chronic Gastritis Pattern
Lymphocytic Gastritis Pattern
Collagenous Gastritis Pattern
Gastric Eosinophilia Pattern
Hyperplastic Pattern
Granulomatous Gastritis Pattern
Vascular and Hemorrhagic Changes Pattern
Pigments and Extras
Near Misses

3. SMALL BOWEL
 The Unremarkable Small Bowel
Acute Duodenitis Pattern
Acute Ileitis Pattern
Chronic Inflammation Pattern
Crypt Architectural Disturbance Pattern
Eosinophilia Pattern
Malabsortion Pattern
Foamy Macrophage Pattern
Dilated Lacteal Pattern
Metaplasia and Heterotopia
Pigments and Extras
Near Misses

4. COLON
The Unremarkable Colon
Focal Active Colitis Pattern
Acute Colitis Pattern
Ischemic Colitis Pattern
Pseudomembranous Pattern
Chronic Colitis Pattern
Lymphocytic Pattern
Eosinophilia Pattern
Granulomatous Pattern
Pigments and Extras
Near Misses

Index
 ESOPHAGUS 1

CHAPTER OUTLINE

The Unremarkable Esophagus

1% Alcian Blue, pH 2.5 Recipe
PAS/AB pH 2.5 Recipe
Acute Esophagitis Pattern
• Gastroesophageal Reflux Disease
• Infections
• Medications
• Other
Eosinophilic Pattern
• Gastroesophageal Reflux Disease
• Eosinophilic Esophagitis
• Drug Reaction
• Allergy
• Photodynamic Therapy
• Systemic Collagen Vascular Disorders
Parakeratotic Pattern
• Gastroesophageal Reflux Disease
• Candida
• Leukoplakia/Epidermoid Metaplasia
• Esophagitis Dissecans Superficialis Pattern/Sloughing Esophagitis
Esophageal Lymphocytosis Pattern
• Gastroesophageal Reflux Disease
• Crohn Disease
• Contact Mucositis
• Lichen Planus/“Lichenoid” Pattern
• Common Variable Immunodeficiency
• Graft Versus Host Disease
• Infection
• Other
Pigments
• Iron Pill
• Resins
Near Misses
• Gastric Inlet Patch/Heterotopic Gastric Mucosa
• Pancreatic Heterotopia/Metaplasia
• Glycogenic Acanthosis
• Squamous Papilloma
• Multilayered Epithelium
• Amyloid
• Granular Cell Tumor
• Granulomata
• Apoptotic Body Prominence
• Ring Mitoses
• Malignancy

THE UNREMARKABLE ESOPHAGUS

Endoscopically, the unremarkable esophagus has smooth, homogenous
pink-tinged mucosa (Fig. 1.1). Clinicians often label the biopsy location
in centimeters, which refers to the distance from the patient’s incisors to
the biopsy site (Fig. 1.2). Consequently, the gastroesophageal junction
varies with the patient’s height and anatomy, although it is most
typically at 40 cm in men. Histologically, the esophagus can be
compartmentalized into four layers (mucosa, submucosa, muscularis
propria, and adventitia) (Fig. 1.3). The mucosa consists of epithelium,
lamina propria, and muscularis mucosae. Lamina propria is a loose
fibroconnective tissue rich in inflammatory cells, lymphovascular
channels, and esophageal glands and ducts. It spans the space between
the epithelium and the muscularis mucosae. Proceeding deeper into the
esophageal wall, the submucosa is the next encountered layer. It sits
between the muscularis mucosae and the muscularis propria and it
consists of loose fibroconnective tissue and lymphovascular channels.
The muscularis propria constitutes the largest portion of muscle in the
esophageal wall. It consists of inner circular and outer longitudinally
oriented muscle fibers. In the proximal esophagus, the muscularis
propria is composed of skeletal muscle and in the distal esophagus, it is
composed of smooth muscle. The outermost layer is the adventitia,
which lacks serosa, facilitating potentially rapid spread of infectious
agents and malignancy.
Normal esophageal epithelium is stratified squamous epithelium (Fig.
1.4). The basal layer is 1 to 2 cells thick and the vascular papillae are
within the lower one-third of the epithelium. Esophageal biopsies can
also contain cardiac mucosa, which is almost always chronically
inflamed (Fig. 1.5). As a result, it is not necessary to routinely diagnose
“chronic inflammation” in the cardia. Since many specimens are
submitted with a request to “rule-out Barrett esophagus,” diagnoses
specifically including phrases such as “no goblet cells are seen” can be
helpful to clinicians in unremarkable esophageal biopsies from adult
patients.

Figure 1.1 Unremarkable endoscopic appearance of the esophagus. The pink-tinged mucosal
surface appears relatively smooth and homogenous throughout the esophagus. There are no
visible plaques, nodules, masses, ulcers, erythema, blood, varices, stenoses, or diverticula.
Variations of luminal caliber in the image may stem from esophageal peristalsis, anatomic bends,
and constriction points.
Figure 1.2 Anatomic esophageal constriction points include the esophageal inlet, crossing of the
aortic arch, left main bronchus, and diaphragmatic hiatus. These sites are prone to narrowing
and can lead to pill impaction and associated local tissue damage.

Figure 1.3 This resection specimen illustrates the four main layers of the esophagus: Mucosa,
submucosa, muscularis propria, and adventitia. The mucosa consists of epithelium (E), lamina
propria (L), and muscularis mucosae (MM). The submucosa sits between the muscularis mucosae
 and the muscularis propria (MP) and it consists of loose fibroconnective tissue and
lymphovascular channels. The MP consists of inner circular and outer longitudinally oriented
muscle fibers. Finally, the outermost layer is the adventitia. The esophagus lacks a serosa.

Figure 1.4 Unremarkable esophageal squamous mucosa. Note the basal layer is only a few cell
layers thick (bracket) and the vascular papillae are confined to the lower one-third of the
epithelial thickness (arrowheads).

Figure 1.5 Unremarkable cardiac mucosa at the gastroesophageal junction. The columnar cells
are of foveolar type, with apical intracytoplasmic neutral mucin that would be magenta on a
PAS/AB.
 Figure 1.6 Pseudogoblet cells. Pseudogoblet cells are important mimics of true goblet cells of
Barrett esophagus and are typically found in clusters. They can be mistaken for true goblet cells
due to their abundant cytoplasmic mucin.

PEARLS & PITFALLS

Beware of pseudogoblet cells, which are important mimics of true
goblet cells. Pseudogoblet cells are foveolar epithelial cells with
prominent cytoplasmic distention and key distinctions from true
goblet cells include the following: (1) Pseudogoblets tend to aggregate
in clusters, whereas true goblet cells are more sparsely distributed
among absorptive cells (complete metaplasia) or foveolar cells
(incomplete metaplasia). (2) Pseudogoblet cells have predominantly
neutral mucin (magenta, PAS/AB) in contrast to the acid mucin of a
true goblet cell (deeply basophilic, PAS/AB) (Figs. 1.6–1.10).
Figure 1.7 Pseudogoblet cells (PAS/AB). On PAS/AB stain, the neutral mucin in the pseudogoblet
cells is magenta. True goblet cells contain acidic mucin, and are deeply basophilic on PAS/AB.

Figure 1.8 Pseudogoblet cells (arrowhead).

 Figure 1.9 True goblet cells. In contrast to pseudogoblet cells, true goblet cells are sparsely
distributed (arrowheads).

Figure 1.10 True goblet cells (PAS/AB). In contrast to pseudogoblet cells, true goblet cells
(arrowheads) have a deeply basophilic appearance on a PAS/AB.

FAQ: What is the utility of and recipe for Periodic acid

Schiff/alcian blue, pH 2.5 special stain (PAS/AB)?
Answer: The combination PAS/AB allows for simultaneous evaluation
of a number of important diagnostic features, such as fungal forms
(magenta), goblet cells (deeply basophilic), an intact small bowel
brush border (crisp and uniform stain condensation). The stain also
highlights the mucin of sneaky adenocarcinomas.
1% ALCIAN BLUE, pH 2.5 RECIPE*
Alcian blue 8GX……..5 g
Acetic acid, 3% solution….500 mL
Adjust the pH to 2.5. Filter and add a few crystals of thymol.
*This solution is commercially available.

PAS/AB pH 2.5 RECIPE

1. Deparaffinize and hydrate to distilled water.
2. One minute in 3% acetic acid. Do not rinse.
3. Stain in Alcian Blue pH 2.5 for 30 minutes.
4. Rinse in tap, then distilled water.
5. Oxidize in 0.5% periodic acid solution for 10 minutes.
6. Rinse in distilled water.
7. Place slides in Schiff reagent for 20 minutes.
8. Wash in running tap water for 5 minutes, or until water is clear and
sections are pink.
9. Stain in Harris hematoxylin for 3 minutes.
10. Wash in tap water.
11. Clarifier for 1 minute.
12. Wash in tap water for 1 minute.
13. Bluing reagent for 1 minute.
14. Wash in running water for 1 minute.
15. Dehydrate through 95% alcohol, absolute and clear in xylene.
16. Mount.
Recipe courtesy of Deborah Duckworth, Johns Hopkins Hospital, Histology
Laboratory.

FAQ: Are there histologic clues that confirm the biopsy site as
esophagus (and not cardia, for example)?
Answer: Yes. Establishing the tissue origin as esophagus is critical for
the diagnosis of Barrett mucosa, a diagnosis that necessitates periodic
surveillance based on an increased risk of neoplasia. Usually
correlation with the endoscopic report provides the most effective
means to determining the tissue site of origin. Unfortunately, detailed
reports are not always provided, and clinicians may not be confident
that they are in the tubular esophagus, especially if a patient has a
sliding hiatal hernia. Since esophageal ducts transmit secretions from
the esophageal submucosal glands to the luminal surface, their
histologic identification can establish the tissue site as esophagus,
providing helpful diagnostic clues (Figs. 1.11–1.20).

Figure 1.11 Esophageal ducts. Esophageal ducts confirm the site of origin as esophageal (arrow).
If goblet cells were present on this tissue fragment, they would signify Barrett esophagus,
assuming an abnormal endoscopic examination.
Figure 1.12 Esophageal duct. Higher power of previous figure. Periductal chronic inflammation is
a typical finding. Squamoid metaplasia of the ducts is not uncommon.

Figure 1.13 Esophageal ducts. This esophageal duct is present in the lamina propria, amidst a
background of lymphovascular spaces. The overlying squamous epithelium can be seen (top).
 Figure 1.14 Esophageal ducts (arrows).

Figure 1.15 Esophageal duct. Higher power of previous figure.

Figure 1.16 Esophageal ducts. These ducts are traversing the muscularis mucosae en route from
 submucosal glands. Their presence indicates that the tissue origin is esophageal.

Figure 1.17 Esophageal duct (arrowhead). This biopsy predominantly consists of oxyntic-type
glandular mucosa. An esophageal duct (arrowhead) signifies that this biopsy was taken from the
tubular esophagus. The proximity to gastric oxyntic glands emphasizes the variability of gastric
cardia length among patients; while some patients may demonstrate several centimeters of
gastric cardiac-type mucosa, others transition directly from esophagus to oxyntic mucosa, like
this patient.

Figure 1.18 Esophageal duct. Higher power of previous figure.

Figure 1.19 Esophageal glands. Esophageal glands produce mucoprotective products that help
lubricate the passage of food and, at the same time, protect the integrity of the esophageal
mucosa.

Figure 1.20 Esophageal glands (PAS/AB). The esophageal glands stain deeply basophilic on
PAS/AB. In contrast, cardiac-type mucosal glands would appear magenta on PAS/AB (Fig. 1.7).

ACUTE ESOPHAGITIS PATTERN

 Figure 1.21 CMV esophagitis. This example of acute esophagitis shows prominent ulceration,
mixed inflammation, and reactive endothelial and stromal cells. A CMV immunostain confirmed
a diagnosis of CMV esophagitis.

Acute esophagitis describes an injury pattern that includes intraepithelial

neutrophils, erosions, and/or ulcerations (Fig. 1.21). This pattern of
injury is entirely nonspecific, but is most commonly caused by
gastroesophageal reflux disease (GERD), infections, and medications.
Malignancy, amyloidosis, radiation injury, and vasculitis are also
potential causes of acute esophagitis, particularly if erosions and
ulcerations are present. While findings in ulcer debris are easy to
overlook since ulcers have a “busy” visual appearance, the cause of the
ulcer can occasionally be identified by careful inspection.

CHECKLIST: Etiologic Considerations for the Acute

Esophagitis Pattern
Gastroesophageal Reflux Disease
Infections
Medications
Other
Figure 1.22 Erosion. The surface epithelium is eroded and accompanied by fibroinflammatory
debris (bracket). By definition, an erosion is confined to the mucosa (arrowheads highlight the
muscularis mucosae). Ulcerations, in contrast to erosions, extend through the mucosa and
involve at least the submucosa.

Figure 1.23 Erosion versus ulceration. This resection specimen illustrates the compartments of
the esophageal wall. Note that erosions are limited to the mucosa (epithelium, lamina propria,
and muscularis mucosae), while ulcerations extend through the mucosa into at least the
submucosa.

PEARLS & PITFALLS

 The distinction between erosion and ulceration occasionally presents a
point of confusion. Erosions are denudations limited to the mucosa
(epithelium, lamina propria, and muscularis mucosae).
Characteristically erosions are accompanied by a rind of fibrin and
inflammatory debris, allowing distinction of a true erosion from an
artifactual epithelial denudation that occurs with aggressive tissue
handling. In contrast, ulcerations extend through and beyond the
muscularis mucosae and involve at least the submucosa (Figs. 1.22
and 1.23).

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

GERD is a common cause of inflammation of the distal esophagus
epithelium, caused by reflux of the acidic gastric contents into the
tubular esophagus, discussed in detail in GERD subsection, Lymphocytic
Pattern, this chapter. Histologically, it is comprised by a constellation of
features, including dilatation of intercellular spaces, basal hyperplasia,
elongation of the vascular papillae, intraepithelial eosinophils, vascular
lakes, increased intraepithelial T lymphocytes, and balloon cells
(epithelial cells with abundant pale cytoplasm). Of these features,
dilation of intercellular spaces was most consistently reported, seen in
41% to 100% of patients with GERD and 0% to 30% of control patients.1
Papillary elongation is also a prominent finding, seen in up to 85% of
those with GERD and 20% of control patients. GERD can further be
stratified into three categories to more accurately describe the degree of
pathology: Mild (subtle findings, including rare intraepithelial
eosinophils), moderate (conspicuous findings), or marked GERD (striking
findings) (Figs. 1.24–1.32). GERD is important to recognize owing to its
association with strictures, Barrett mucosa, and malignancy. At this time
there are no official consensus recommendations on biopsy protocol for
GERD uncomplicated by Barrett esophagus or eosinophilic esophagitis
(EoE). Treatment typically includes lifestyle modification and proton-
pump inhibitors, with surgical procedures reserved for severe, refractory
cases.

KEY FEATURES OF GERD (some, not all, of the following features are
required):
• Dilatation of intercellular spaces
• Basal hyperplasia, >15% of epithelial thickness
• Elongation of the vascular papillae, top half of epithelium thickness
• Intraepithelial eosinophils
• Vascular lakes
• Increased intraepithelial T lymphocytes (squiggle cells)
• Balloon cells (epithelial cells with abundant pale cytoplasm)

Figure 1.24 Balloon cells (arrowheads). Balloon cells are seen throughout this biopsy as large
squamous cells with abundant pale eosinophilic/smudgy cytoplasm.

Figure 1.25 Balloon cells. This example shows the balloon cells’ smudgy cytoplasm is similar to
frosted glass.
 Figure 1.26 Balloon cells. Higher power of previous figure.

Figure 1.27 Mild GERD. The descriptor “mild” can be used in GERD cases with rare
intraepithelial eosinophils (arrowhead). Also depicted are basal hyperplasia and vascular papillae
elongation.
 Figure 1.28 Mild GERD. In this example, a single degranulated intraepithelial eosinophil is
identified (arrowhead) along with mild basal hyperplasia.

Figure 1.29 Moderate GERD refers to more conspicuous GERD histologic changes. This case
shows more readily identifiable intraepithelial eosinophils (no arrowhead is needed to appreciate
the scattered intraepithelial eosinophils). Also note the basal hyperplasia&emdash;the basal 12
layers are expanded from the 1 to 2 cell thickness expected in a normal esophagus.

Figure 1.30 Moderate GERD. The easily identified intraepithelial eosinophils, basal hyperplasia,
and elongation of vascular papillae meet the criteria for GERD. However, the findings are
nonspecific and in the absence of clinical information, eosinophilic diseases of the esophagus
should be considered.
Figure 1.31 Marked GERD shows striking histologic changes, easily appreciated at low power, as
in this case. This epithelium is “too blue” due to the prominent basal hyperplasia. In addition,
the vascular papillae are approaching the midpoint of the thickness (papillae should normally be
confined to the lower third of the epithelial thickness). Eosinophils are abundant. Amyloidosis is
also seen (arrowhead).

Figure 1.32 Marked GERD.

FAQ: Could the findings in Figure 1.32 represent eosinophilic

esophagitis (EoE) instead of marked GERD?
Answer: Absolutely. It is clinically important to distinguish EoE from
GERD because of differing etiologic specific therapies. In general,
features favoring EoE include superficial eosinophilic microabscesses,
eosinophil counts greater than 50/HPF, and basal hyperplasia greater
than 50%. Since an unmapped biopsy of EoE can be histologically
indistinguishable from GERD, clinicopathologic correlation and
mapping of tandem proximal and distal esophageal biopsies are
necessary to more definitively distinguish EoE from GERD. See also
Eosinophilic pattern, this chapter.
INFECTIONS
Candida Esophagitis
Candida esophagitis appears endoscopically as scattered yellow plaques,
patches, exudates, and ulcerations (Figs. 1.33–1.34). These endoscopic
appearances can overlap with those of glycogenic acanthosis, esophageal
leukoplakia/epidermoid metaplasia, lichen planus/“lichenoid” pattern,
making correlation with biopsy findings essential to arrive at the correct
diagnosis. Brushing samples sent to the microbiology or cytology
laboratories may be more sensitive than biopsies alone.2,3 A history of
HIV/AIDS is an important red flag to this diagnosis. In one study of 110
patients with HIV, 51.8% of patients were found to have candidiasis.3
The plaques histologically correlate with desquamated debris, which can
coalesce to form extensive exudates and/or ulcerations in severe cases
(Fig. 1.34).4 Histologically, acute inflammation in the squamous
epithelium and hyperkeratosis are red flags and prompt a thorough high-
power examination for the pseudohyphae forms characteristic of
candidiasis (Figs. 1.35 and 1.36). Importantly, a complete absence of
inflammation can be seen in immunosuppressed patients. A low
threshold for ordering special stains such as PAS/D or Grocott
methenamine-silver stain (GMS) is advised (Fig. 1.37). See also
Parakeratotic pattern, this chapter.

Figure 1.33 Candida esophagitis often appears as scattered yellow plaques on endoscopy.
Figure 1.34 Candida esophagitis. In severe cases of candida esophagitis, the plaques coalesce to
form confluent exudates and ulceration, as in this case.

Figure 1.35 Candida esophagitis. This biopsy is “too blue” because of marked inflammation and
reactive squamous epithelium. Acute inflammation in the esophagus is often caused by GERD,
but should also serve as a red flag to search carefully for Candida and viral cytopathic effect.
 Figure 1.36 Candida esophagitis. Indeed, the diagnostic fungal forms were identified with a
PAS/AB (magenta, circle). They would appear black on GMS.

FAQ: Do budding yeast signify Candida esophagitis?

Answer: No. Budding yeast often represent oral contamination.
Pseudohyphal forms, in contrast, signify tissue invasion and are
required for the diagnosis of Candida esophagitis.

Figure 1.37 Candida esophagitis (GMS). True hyphae are defined by the presence of septa, an
uncommon finding in Candida. Pseudohyphae, in contrast, are composed of budding yeast-like
forms (blastoconidia) joined end to end. The constrictions formed by the buds give the
appearance of septations (pseudohyphae) (arrow).

FAQ: How are PAS, PAS/AB, or GMS special stains utilized in the
 evaluation of pseudohyphae?
Answer: PAS, PAS/AB, and GMS special stains highlight fungal forms
and are advised in the following cases, assuming the fungal forms are
not present on H&E: • Clinical impression of candidiasis
• Striking acute inflammation
• Prominent parakeratosis
• Refractory GERD or EoE

Cytomegalovirus (CMV)
KEY FEATURES of CMV Esophagitis:
• Endoscopic findings are typically linear, serpiginous ulcerations with
a propensity for the distal esophagus (Fig. 1.38) • CMV viral
cytopathic effect can be seen in endothelial cells, columnar
epithelium, and stromal cells; biopsy of the ulcer base is critical for
complete evaluation • CMV viral cytopathic effect includes nuclear and
cellular enlargement, smudged chromatin, and nuclear (“owl’s eye”)
and/or cytoplasmic inclusions • The inflammatory backdrop shows a
prominence of mononuclear inflammation (Figs. 1.39–1.44)

Figure 1.38 CMV esophagitis. Discrete erosive changes and ulcerations are seen in the distal
esophagus. These ulcers sometimes coalesce to broadly involve large regions of the esophagus,
although small solitary ulcers are most commonly found.
 Figure 1.39 CMV esophagitis. CMV viral cytopathic effect is identified with nuclear and
cytoplasmic viral inclusions (arrowhead) and is sufficient for the diagnosis of CMV esophagitis: A
CMV immunostain was not required for this diagnosis.

Figure 1.40 CMV esophagitis. Higher power of previous figure. Note the characteristic smudgy
nuclear and coarse cytoplasmic inclusions with a deep magenta tinctorial quality.
Figure 1.41 CMV esophagitis (CMV immunostain). Although the H&E impression was diagnostic
of CMV infection, less obvious cases often require a CMV immunostain. Note the nuclear
reactivity in a large (“megalic”) cell.

Figure 1.42 CMV esophagitis (arrowhead). The affected cells are “megalic” or enlarged at low
power and typically found in the endothelial or stromal cells at the ulcer base. The background
shows prominent mixed inflammation with reactive endothelial cells, important red flags to the
diagnosis.
 Figure 1.43 CMV esophagitis. In this example, the indicated cell (arrowhead) is a markedly
enlarged endothelial cell with prominent glassy and smudged cytoplasm. The features are highly
suspicious for CMV infection but the nuclear detail is unclear and the characteristic deep
magenta inclusion is not seen in this plane.

Figure 1.44 CMV esophagitis (CMV immunostain). Although CMV immunostains can be tricky to
evaluate when there is high background or a suboptimal specimen, look for nuclear reactivity in
“megalic” cells, as seen in this case.

Herpes simplex virus (HSV)

KEY FEATURES of HSV Esophagitis:
• Endoscopic findings include well-circumscribed ulcerations with raised
yellow edges (“volcano ulcers”) which can be seen in any region of
the esophagus (Fig. 1.45) • HSV infects squamous epithelium; biopsy
of the edge of the ulcer is recommended to ensure squamous
epithelium is present5
• The classic nuclear features include molding of nuclear contours,
margination of chromatin, and multinucleation (referred to as the
“three M’s”) (Figs. 1.46–1.55) • Cowdry A: Intranuclear inclusions
with a clear halo
• Cowdry B: Intranuclear inclusions lacking a clear halo

PEARLS & PITFALLS

In Figure 1.49, the subtle HSV diagnosis could be easily overlooked if
the “rule-out EoE” request narrowed the evaluation to counting
eosinophils only, rather than taking a more open, systematic approach
to the tissue. This case highlights the importance of always looking for
the second and less obvious diagnosis. While examining the requisition
is always worthwhile, it is more important to avoid being blinded by
the history and endoscopic findings.

Figure 1.45 HSV esophagitis. This endoscopic image shows ulcerations, patchy erosions, and
white exudates. HSV cannot be reliably distinguished from CMV or Candida by endoscopic
evaluation. A complete evaluation should therefore include biopsy of the ulcer base (for CMV)
and ulcer edge (for HSV).
Figure 1.46 HSV esophagitis. An HSV immunostain is not necessary because the classic diagnostic
features are present (the three “M’s”): (1) Molding of nuclear contours; (2) margination of
chromatin to the periphery of the nucleus resulting in a pale nuclear center and darkened
peripheral rim; (3) multinucleation.

Figure 1.47 HSV esophagitis. This case of acute esophagitis features a rare cell suspicious for HSV
viral cytopathic effect with multinucleation and equivocal molding (arrowhead). Since similar
findings are occasionally seen in degenerating, reactive squamous cells, an HSV immunostain
was performed.
 Figure 1.48 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain
highlights more virally infected squamous epithelium than apparent on H&E.

Figure 1.49 HSV esophagitis. This case was from a patient with a history of eosinophilic
esophagitis (EoE), although characteristic features of EoE are not seen in this field. Note the
subtle viral cytopathic effect in the basal aspect of the squamous epithelium (arrowheads
highlight nuclear molding and chromatin margination).
 Figure 1.50 HSV esophagitis. Subtle viral cytopathic effect is seen in the lateral aspects of this
specimen and in the free-floating fragment at the top right.

Figure 1.51 HSV esophagitis. Careful examination of ulcer debris can provide valuable clues to
the etiology of the ulcer. In this example, viral cytopathic effect diagnostic of HSV esophagitis is
identified within the ulcer debris. Numerous multinucleated cells show molding of nuclear
contours and margination of chromatin. An HSV immunohistochemical stain is not necessary for
these unequivocal morphologic features.
Figure 1.52 HSV esophagitis. This example shows a rare cell with equivocal HSV viral cytopathic
effect (arrowhead) and background ulceration (not shown).

Figure 1.53 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain confirms
HSV esophagitis, and emphasizes that a low threshold for CMV, HSV, and PAS stains is prudent
in the case of esophageal ulcerations.

Figure 1.54 HSV esophagitis. Cells suspicious for HSV viral cytopathic effect are seen at the base.
 Figure 1.55 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain
highlights the virally infected cells.

FAQ: Does HSV2 infection in a child imply sexual activity/abuse?

Answer: No. Historically, the HSV1 serotype has been associated with
oral ulcerations and HSV2 with genital ulcerations. Studies that are
more recent suggest these historic associations may no longer be
relevant.6,7 As a result, it is not necessary to routinely determine
serotypes nor to suggest sexual abuse for HSV2 reactive cases,
although the testing is technically feasible with HSV1-or HSV2-specific
immunohistochemical stains or molecular-based assays.

FAQ: Does a positive HSV immunohistochemical stain exclude

varicella-zoster virus (VZV)?
Answer: No. VZV is the causative agent of varicella (chickenpox) and
herpes zoster (shingles). Both HSV and VZV belong to the
Herpesviridae family, show identical viral cytopathic effect, and react
identically with an HSV immunohistochemical stain. HSV can be
distinguished from VZV by a specific VZV immunohistochemical stain,
culture methods, or molecular assays.

FAQ: How are CMV, HSV immunostains utilized?

Answer: If the diagnosis can be made on H&E due to classic viral
 cytopathic effect, additional immunostains are not necessary.
However, a low threshold for requesting CMV and HSV immunostains
(and fungal special stains) is recommended in the setting of
esophageal ulcerations because the diagnostic features can be easily
obscured by the intense background inflammation.

Helicobacter
Whereas acute inflammation in the esophagus is most associated with
GERD, inflamed cardia biopsies (which can be present in biopsies
containing esophagus) are associated with Helicobacter infections in the
majority of cases (78% to 97.7%).8,9 The concept of the cardia as a
normal anatomic landmark is debated but, in general, the cardia is
defined as the small segment of stomach between the distal esophagus
and proximal stomach with oxyntic mucosa. Red flags to the diagnosis of
Helicobacter infection include recognition of acute and chronic
inflammation, superficial lymphoplasmacytosis, and lymphoid
aggregates (Figs. 1.56–1.61), as discussed in detail in Acute Gastritis,
Stomach chapter.

Figure 1.56 Helicobacter. Esophageal biopsies with columnar mucosa offer an opportunity to
make additional diagnoses, such as Helicobacter carditis, as in this case. On low power, the active
chronic inflammation, prominent lymphoid aggregate with a well-formed germinal center, and
superficial lymphoplasmacytic inflammation strongly suggest Helicobacter infection.
Figure 1.57 Helicobacter pylori. The organisms were found in mucin-rich foci (arrowheads) and in
gland lumina (not shown). Their wide one-and-a-half-turn spiral gives them a slightly bent
appearance.

Figure 1.58 Helicobacter pylori (Diff-Quik). A Diff-Quik special stain highlights the Helicobacter
pylori organisms (special stains are not necessary if the organisms are apparent on H&E).
Figure 1.59 Helicobacter pylori (Warthin–Starry). A Warthin–Starry special stain highlights the
Helicobacter pylori organisms. This silver-based stain coats the organisms, making them slightly
larger and easier to identify than the previous Diff-Quik stain.

Figure 1.60 Helicobacter heilmannii organisms are more slender and tightly spiraled than
Helicobacter pylori organisms.
 Figure 1.61 Helicobacter heilmannii (Diff-Quik). A Diff-Quik special stain highlights the tightly
spiraled Helicobacter heilmannii organisms embedded within the surface mucus.

MEDICATIONS
Medication-related injury is seen with some regularity in centers
enriched for elderly patients, and in the setting of polypharmacy. The
resulting injury pattern can include a wide range of histologic findings
including nonspecific reactive changes, prominent apoptotic bodies,
intraepithelial lymphocytosis, mild acute esophagitis, eosinophilia,
and/or marked ulceration. Medication injury can be seen throughout the
GI tract, but in the esophagus so-called “pill esophagitis” is most
common at the anatomic constriction points (Fig. 1.62).
Select Medications Considerations
• Iron
• Resins (Kayexalate, sevelamer, bile acid sequestrants)
• Bisphosphonates
Iron
Ferrous sulfate-mediated corrosive injury is seen in approximately 1% of
individuals undergoing upper endoscopy and is associated with erosions
and ulceration.10 The pigment can have a coarse, crystalline, or subtle
brown hue on H&E, and it is blue on a Prussian blue iron special stain
(Figs. 1.62–1.66). Recognition is important to help prevent further injury
and potential stricture formation. These patients benefit from behavioral
modifications such as maintaining upright posture for 30 minutes after
taking the pill and/or taking the pill with ample liquids or food. See also
Pigments and Extras, Stomach Chapter.

Figure 1.62 Iron pill esophagitis. This dramatic example features the pigmented crystalline form
of iron pill deposition in a background of ulceration.

Figure 1.63 Iron encrustation, ulcerative esophagitis. Some cases of iron encrustation are quite
subtle. In this case, a superficial rind of light brown suggests iron, but a confirmatory iron stain
was required to arrive at the correct diagnosis.
 Figure 1.64 Iron encrustation, ulcerative esophagitis (Prussian blue special stain). The iron
pigment appears as a faint blue hue on a Prussian blue special stain.

Figure 1.65 Iron pill esophagitis. Iron pill esophagitis with a rind of coarse brown pigmentation
admixed in ulcer debris. A Prussian blue iron special stain was reactive, confirming the above
diagnosis.
Figure 1.66 Iron pill esophagitis. Iron pill esophagitis with coarse crystalline pigment deposition
and ulcer debris. The patient endorsed a history of taking her iron pill with a few sips of water
right before time. She was encouraged to take her pill with generous amounts of yogurt a few
hours before bedtime, and her symptoms quickly resolved.

PEARLS & PITFALLS

Iron pill esophagitis occasionally raises concern for invasive carcinoma
based on the sometimes ominous endoscopic appearance and
prominent reactive changes seen in the corresponding biopsies.
Recognition of the iron pigment is critical and, when in doubt, an iron
special stain can be helpful. Alternatively, mass lesions constrict the
esophageal lumen and can result in entrapped iron encrustation
overlying the mass lesion. If the clinical suspicious for malignancy is
high, deeper sections and repeat biopsy are often worthwhile.

Resins
Resins are nonabsorbable medications that exchange ions as they course
through the GIT; they are often referred to as “medication crystals.” The
three most common include Kayexalate, sevelamer, and the bile acid
sequestrants. The resins can usually be confidently identified on H&E
and confirmed with a quick review of the medication list. Awareness of
these resins and comfort in discriminating between them is essential
because the first two are associated with mucosal injury. This section
will focus on red flags in the chart and distinctive features of the crystal
morphology to quickly navigate to the correct diagnosis.
Kayexalate
Also known as sodium polystyrene sulfonate, Kayexalate was introduced
in 1958 as a cation exchange resin used to treat hyperkalemia in renal
failure patients.11–13 When administered via the upper tract, the resin
releases sodium ions and becomes protonated in the acidic milieu of the
stomach. As the resin traverses the bowel, the hydrogen is subsequently
exchanged for potassium. The potassium bound resin is then released in
the feces, thereby lowering serum potassium levels. Kayexalate was
initially administered in an aqueous solution but initial reports found an
association with constipation and, sometimes lethal, bezoar
formation.13–15 As a result, Kayexalate was combined with a sorbitol
diluent that effectively reduced these side effects but, unfortunately has
been linked to ischemic and ulcerative GIT injury. Historically, these
changes have been attributed to the hyperosmotic sorbitol diluent,
although some suggest the resin itself may be a contributing
factor.11,13,14 Today, the sorbitol diluent is strongly discouraged in favor
of emulsifying the medication directly into food or drink.16 The resin can
lodge anywhere along the GI tract since it can be administered via a
nasogastric tube, orally, or a rectal enema. Kayexalate displays a so-
called “fish-scale” or “mosaic” appearance due to regular, narrow
cracking lines. It is purple on H&E, black-green on AFB, and hot pink on
PAS/AB (Figs. 1.67–1.77).

KEY FEATURES of Kayexalate:

• Also known as sodium polystyrene sulfonate
• Administered via nasogastric tube, orally, or rectal enema (can be seen
anywhere in the GIT)
• Used to treat hyperkalemia in renal failure patients
• The hyperosmotic sorbitol diluent is blamed for ischemic and
ulcerative GIT injury
• Resin has narrow, regular “fish-scale” pattern
• Resin is purple on H&E, black-green on AFB, and hot pink on
PAS/D (Figs. 1.67–1.77)
 Figure 1.67 Kayexalate (sodium polystyrene sulfonate). Alternate case showing Kayexalate’s
characteristic purple color on H&E and narrow, regularly positioned “fish-scales.”

Figure 1.68 Kayexalate (sodium polystyrene sulfonate). Note the necrotic background. This resin
was identified in a perforated colon with transmural necrosis and inflammation. Kayexalate was
concentrated in the necrotic bowel, and was the likely cause of the perforation.
Figure 1.69 Kayexalate (sodium polystyrene sulfonate). Alternate field. Identification of these
crystals in the perforated bowel resulted in immediate contact with the clinician. As a result,
Kayexalate was discontinued and the patient had an uneventful recovery.

Figure 1.70 Kayexalate (sodium polystyrene sulfonate). Alternate case. The purple color and
narrow, regular “fish-scales” are consistent with Kayexalate.
 Figure 1.71 Kayexalate (sodium polystyrene sulfonate). Alternate field. Note the
fibrinoinflammatory background.

Figure 1.72 Kayexalate (sodium polystyrene sulfonate) (AFB). Kayexalate is dark black with a
hint of green on AFB, similar to the skin of the wicked witch of the west in “The Wizard of Oz.”
Figure 1.73 Kayexalate (sodium polystyrene sulfonate) (PAS/D). Kayexalate is bright pink on
PAS/D. These additional stains are not necessary on classic cases, but can be helpful if the
specimen is suboptimal.

Figure 1.74 Iron pill esophagitis with Kayexalate. This case shows a rare Kayexalate resin
(arrowhead) in a background of abundant iron pill and ulceration.
Figure 1.75 Iron pill esophagitis with Kayexalate. Higher-power view of previous figure. Note the
characteristic purple hue and “fish-scale” appearance of the Kayexalate resin (arrowhead).

Figure 1.76 Iron pill esophagitis with Kayexalate. The corresponding Prussian blue stain
highlights the background iron pigment.
 Figure 1.77 Kayexalate (sodium polystyrene sulfonate). Kayexalate resins appear purple with a
mosaic “fish-scale” appearance on H&E. These resins are often seen in association with ulcer
debris, which has been historically attributed to the hyperosmotic sorbitol diluent.

PEARLS & PITFALLS

Identification of Kayexalate is a medical emergency, particularly if an
ulcerated or ischemic background is seen. Kayexalate has been linked
to fatality cases and the clinicians should be alerted to its presence
and educated about its notorious association with GIT injury. If
mucosa injury is seen, the patient should be closely monitored and or
the medication list safely adjusted. Accurate diagnosis of this crystal
and communication with the clinician is one way pathologists can
potentially save a life without directly interacting with the patient.

SAMPLE NOTE: KAYEXALATE

Esophageal, Biopsy:
• Squamous mucosa with Kayexalate resins concentrated within
ulceration and necroinflammatory debris.
Note: The history of renal failure and esophageal ulcerations is noted.
The biopsy shows Kayexalate resins concentrated within the
necroinflammatory and ulcer debris and are likely a contributing factor
to this injury pattern. This information was verbally shared with Dr.
Anderson by Dr. Arnold on 08/12/2013, 1613. CMV and HSV
immunostains are negative. A PAS/D for fungal organisms is negative.

References
Lillemoe KD, Romolo JL, Hamilton SR, et al. Intestinal necrosis due to
sodium polystyrene (Kayexalate) in sorbitol enemas: Clinical and
experimental support for the hypothesis. Surgery. 1987;101:267–272.
Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic
patients as a result of sodium polystyrene sulfonate (Kayexalate) in
sorbitol: An underrecognized condition. Am J Surg Pathol. 1997;21:60–
69.
Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract
injury in patients receiving Kayexalate (sodium polystyrene sulfonate)
in sorbitol: Clinical, endoscopic, and histopathologic findings. Am J
Surg Pathol. 2001;25:637–644.

Sevelamer
Sevelamer is a recently introduced, orally administered, ion-exchange
resin. It lowers phosphate levels in patients with chronic kidney disease;
therefore, its clinical presentation overlaps with Kayexalate. It was
introduced in the tablet form as Renagel (sevelamer hydrochloride) in
2000 and in tablet and powder form as Renvela (sevelamer carbonate) in
2007.17,18 Both formulations show similar efficacy, but sevelamer
carbonate (Renvela) is marketed as the preferred form based on a
decreased incidence of metabolic acidosis.19–22 We recently reported the
first morphologic description of sevelamer and found a provocative
association with mucosal injury, which we relay to the clinicians in
pertinent cases, similar to our approach to Kayexalate.23 We also
disclose that the initial report is small and further studies are needed to
fully clarify the possibility of sevelamer-mediated injury. The core
histologic features of the sevelamer resins include broad, curved, and
irregularly spaced “fish-scales” with a variable color.23 Whereas, most
resins displayed a two-toned color imparted by bright pink linear
accentuations and a rusty yellow background, those crystals embedded
in extensive ulcer, ischemia, or necrotic debris acquired a deep
eosinophilia or rusty brown color. Sevelamer crystals are magenta on
AFB and lavender on PAS/D (Figs. 1.78–1.86).

KEY FEATURES of Sevelamer:

• Also known as Renagel (sevelamer hydrochloride) and Renvela
(sevelamer carbonate)
• Administered orally (can be seen anywhere along the GIT)
• Lowers phosphate levels in patients with chronic kidney disease
• May be associated with mucosal injury
• Resins show broad, curved, and irregularly spaced “fish-scales”
• Resins are two-toned color (bright pink linear accentuations and a
rusty yellow background) on H&E, magenta on AFB, and lavender on
PAS/D
• Resins embedded in extensive ulcer, ischemia, or necrotic debris
acquired a deep eosinophilia or rusty brown color

Figure 1.78 Sevelamer resins characteristically display broad, curved, and irregularly spaced
“fish-scales” with a variable color. Like this example, most have a two-toned color imparted by
bright pink linear accentuations and a rusty yellow background.
 Figure 1.79 Sevelamer. This resin features all the usual features of Sevelamer: Two-toned color
with bright pink lines amidst a rusty yellow background. Compared to Kayexalate, note these
“fish-scales” are more broad and irregular.

Figure 1.80 Sevelamer. Sevelamer and Kayexalate are both seen in the setting of renal failure and
both have been associated with mucosal injury. Awareness of their distinctive morphology is key
to the right diagnosis.
 Figure 1.81 Sevelamer. Note the prominent background fibrinoinflammatory debris. Close
examination of ulcer debris is always worthwhile because it may contain “hidden” clues to the
underlying etiology, such as sevelamer resins in this case.

Figure 1.82 Sevelamer. In cases of severe mucosal injury, the characteristic two-toned color of
sevelamer transitions to deep eosinophilia or rusty brown color. Note the “fish-scale” pattern is
consistent, providing helpful diagnostic clues to the diagnosis of sevelamer.
 Figure 1.83 Sevelamer. This is a biopsy of a large esophageal ulcer. Note the sevelamer resin
displays its usual “fish-scale” pattern but the color is rusty brown instead of the more typical
two-toned color. This color shift has been described in the setting of severe background mucosal
injury and may relate to varying binding capacity and pH properties of the entrapped resin.

Figure 1.84 Sevelamer. This resin was identified in an ischemic and perforated small bowel.
While the characteristic “fish-scale” pattern is seen, the resin is deeply eosinophilic, typical of
resins entrapped in severe background mucosal injury.
 Figure 1.85 Sevelamer is magenta on AFB. Note the typical broad, irregular “fish-scale” pattern
characteristic of sevelamer. Sevelamer is also known by its trademark names Renvela (sevelamer
carbonate) and Renagel (sevelamer hydrochloride).

Figure 1.86 Sevelamer is lavender on PAS/D, helpful distinguishing features from Kayexalate and
the bile acid sequestrants.

PEARLS & PITFALLS

Sevelamer is most commonly misdiagnosed as Kayexalate.
Unfortunately, the medication list is almost guaranteed to be missing
from the disclosed requisition. “Renal failure”, however, is a common
accompanying comment and should invoke the possibility of both
Kayexalate and sevelamer. Accurate discernment of sevelamer from
 Kayexalate relies on recognition of their distinct morphologic features
(sevelamer: broad, curved, and irregularly spaced “fish-scales,” two-
toned on H&E, magenta on AFB, and lavender on PAS/D; Kayexalate:
narrow, regular “fish-scales,” purple on H&E, black-green on AFB, and
hot pink on PAS/D).

SAMPLE NOTE: SEVELAMER

Esophageal, Biopsy:
• Squamous mucosa with sevelamer resins concentrated within
ulceration and necroinflammatory debris.
Note: The history of renal failure and esophageal ulcerations is noted.
The biopsy shows sevelamer resins concentrated within the
necroinflammatory and ulcer debris. In the one small study available,
sevelamer was associated with mucosal injury in a dose-dependent
manner, suggesting sevelamer may be a contributing factor to the above
pathology. Of note, the referenced study is small and no definitive
conclusions can be drawn at until larger studies are available. This
information was verbally shared with Dr. Anderson by Dr. Arnold on
08/12/2013, 1613. CMV and HSV immunostains are negative. A PAS/D
for fungal organisms is negative.

Reference
Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the
gastrointestinal tract (GIT): A new entity associated with mucosal
injury. Am J Surg Pathol. 2013;37(11):1686–1693.

Bile Acid Sequestrants

Cholestyramine (LoCholest, Prevalite, Questran) was introduced in 1973
and is the most commonly encountered bile acid sequestrant. Others in
this family include colestipol (Colestid) and colesevelam (WelChol).
Familiarity with these names, while cumbersome, makes confirmatory
chart review a cinch. These medications are available in powder form for
oral administration. The nonabsorbable resins bind negatively charged
anions, such as bile acids, which are then eliminated in the feces.24–26 It
is primarily used to lower serum cholesterol levels but can additionally
be used to treat pruritus in patients with biliary tract disease or to treat
bile acid–mediated diarrhea in patients with decreased bile acid
absorption due to ileal resection (e.g., in Crohn disease). Historically,
bile acid sequestrants are thought to be biologically inert and not
associated with causing mucosal injury, unlike Kayexalate and
sevelamer. Cholestyramine can be readily identified based on its unique
morphology. The resin is smooth and glassy in texture because it lacks
an internal “fish-scale” pattern, unlike Kayexalate and sevelamer. Bile
acid sequestrants are bright orange on H&E, neon green on AFB, and
variable gray or hot pink color on PAS/D (Figs. 1.87–1.94).

Figure 1.87 Cholestyramine resins are smooth and glassy in texture; they lack a “fish-scale”
pattern. They are bright orange on H&E.
Figure 1.88 Cholestyramine. This resin is surrounded by ulcer debris. Cholestyramine crystals are
biologically inert and do not cause mucosal injury; therefore, a search for the underlying
etiologic agent of the ulcer debris is necessary. In this case, the background mucosa showed
prominent CMV viral cytopathic effect. Therefore, the resin was an “innocent bystander” trapped
within the CMV ulcer debris.

Figure 1.89 Cholestyramine. Alternate field. The clinician later called to ask if the cholestyramine
should be discontinued based on the severe mucosal injury. We explained that cholestyramine
does not cause mucosal injury; there was no need to adjust the medication injury. The patient
had an uneventful recovery following antiviral therapy.
Figure 1.90 Cholestyramine. Note the characteristic smooth and glassy texture, and bright orange
color on H&E. Bile acid sequestrants are known by many names: Cholestyramine (LoCholest,
Prevalite, Questran); colestipol (Colestid); colesevelam (WelChol).

Figure 1.91 Cholestyramine. Bile acid sequestrants reduce bile acid levels and are most
commonly used to treat hypercholesterolemia, pruritus, and bile acid–mediated diarrhea.
 Figure 1.92 Cholestyramine.

Figure 1.93 Cholestyramine is neon green on AFB.

 Figure 1.94 Cholestyramine resins display both gray or hot pink color on PAS/D.

KEY FEATURES of Bile Acid Sequestrants:

• Cholestyramine (LoCholest, Prevalite, Questran); colestipol
(Colestid); colesevelam (WelChol) • Lowers bile acids, most
commonly used to treat hypercholesterolemia, pruritus, and bile acid–
mediated diarrhea
• Not associated with mucosal injury
• Resins are smooth and glassy in texture (lacks a “fish-scale” pattern)
• Resins are bright orange on H&E, neon green on AFB, and variable
gray or hot pink color on PAS/D

PEARLS & PITFALLS

While the bile acid sequestrants are generally smooth in texture, larger
resins can have occasional, irregular “fracture” lines, which are a knife
artifact from histologic processing of larger, thicker resins. Such cases
are occasionally misdiagnosed as Kayexalate or sevelamer if the
irregular fracture lines are mistaken for a “fish-scale” pattern. A true
“fish-scale” pattern, however, shows geometric, predictable, internal
structures. Examples of true “fish-scales” are illustrated in Figures
1.67–1.86.
 FAQ: What should I report if I see a luminal resin but have no
access to the medical chart to confirm the resin identity?
Answer: If the resin morphology is classic, chart review is not essential
for diagnosis. In suboptimal cases, AFB and PAS/D special stains can
help clarify the identity of the resin. If neither the medication list nor
special stains are available, a careful descriptive note is most prudent.

SAMPLE NOTE: LUMINAL CRYSTAL, NOS

Esophagus, Biopsy:
• Ulcer debris with entrapped luminal crystals.
• Negative for fungal elements and viral cytopathic effect (H&E).
Note: The history of esophageal ulceration is noted. Entrapped luminal
crystals are identified which are not further classifiable based on
pronounced histologic artifact. The differential diagnoses include
Kayexalate (sodium polystyrene sulfonate), sevelamer (Renagel,
Renvela) and the bile acid sequestrants (cholestyramine [LoCholest,
Prevalite, Questran]); colestipol (Colestid); colesevelam (WelChol). The
former two are associated with mucosal injury. Correlation with the
medication list is required for further identification.

References
Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic
patients as a result of sodium polystyrene sulfonate (Kayexalate) in
sorbitol: An underrecognized condition. Am J Surg Pathol. 1997;21:60–
69.
Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract
injury in patients receiving Kayexalate (sodium polystyrene sulfonate)
in sorbitol: Clinical, endoscopic, and histopathologic findings. Am J
Surg Pathol. 2001;25:637–644.
Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the
gastrointestinal tract (GIT): A new entity associated with mucosal
injury. Am J Surg Pathol. 2013;37(11):1686–1693.
Bisphosphonates
Bisphosphonates are medications that prevent bone reabsorption and are
commonly used in the treatment of osteoporosis. Examples of
bisphosphonates include Alendronate (Fosamax), Ibandronate (Boniva),
and Risedronate (Actonel), among others. These medications are linked
to acute esophagitis and ulcerations through direct mucosal irritation
from the impacted pill and toxicity through the pill itself.27 While these
polarizable pill fragments are capable of causing ulceration, they are not
histologically specific and cannot be reliably distinguished from
“bystander” pill fragments incidentally trapped within the ulcer debris
(Fig. 1.95). Chart review and/or communication with the clinician can
be helpful.

Figure 1.95 Ulcerative esophagitis seen in the setting of bisphosphonate usage. In this example of
ulcerative esophagitis, no specific etiologic clues are apparent such as polarizable pill fragments.
However, a careful chart review revealed usage of a bisphosphonate, a class of medications
notorious for causing esophageal injury.

OTHER (MALIGNANCY, AMYLOIDOSIS, RADIATION

INJURY, AND VASCULITIS)
Esophageal ulcerations can also be caused by any infiltrative process or
any process that comprises the regional blood supply, such as
malignancy, amyloidosis, radiation injury, or vasculitis (Figs.
1.96–1.102). Careful inspection of the ulcer, ulcer debris, and adjacent
tissue is imperative for complete evaluation. Note, vasculitis is best
evaluated in resection specimens.
Figure 1.96 Poorly differentiated squamous cell carcinoma. This patient had a history of
esophageal squamous cell carcinoma status post resection and radiation. The endoscopic
examination identified an ulcer, and histologic sections show markedly atypical cells with
prominent nuclear pleomorphism and hyperchromasia.

Figure 1.97 Poorly differentiated squamous cell carcinoma and ulcer debris (p63). A p63
immunostain confirms the squamous origin of the malignant cells, supporting the above
diagnosis.
 Figure 1.98 Diffuse large B cell lymphoma (DLBCL) arising in a background of Barrett mucosa.
This biopsy was adjacent to an ulcer and shows large, monomorphic lymphocytes arranged in
sheets. Immunohistochemical studies confirmed the indicated malignant cells as B-lineage cells
(CD20 reactive) with a Ki-67 proliferation index of 80%. Additional immunohistochemical stains
were performed for prognostic information. The lesional cells were confirmed to be germinal
center derived (CD10, Bcl-6 reactive, MUM1 nonreactive) which carries a better prognosis than
nongerminal center-derived DLBCL. Bcl-2 is an independent prognostic marker that can confer a
relatively worse prognosis, and was nonreactive in this case. The finding of both Barrett mucosa
and DLBCL is thought to be coincidental.

Figure 1.99 Amyloidosis. Amyloidosis can have a varied endoscopic appearance. In this case, an
esophageal nodule was seen (arrowhead).
Figure 1.100 Amyloidosis. Considerable bleeding was noted after nodule removal, and this post-
biopsy image shows hemorrhagic mucosa. Patients with amyloidosis often bleed easily due to the
fragile nature of the amyloid-laden vessels.

Figure 1.101 Amyloidosis. At low power the squamous mucosa has prominent hemorrhage and
abundant amorphous eosinophilic material in the lamina propria. The deposition was bright
orange on Congo red with direct light, and apple-green under polarized light, confirming the
diagnosis of amyloidosis.
 Figure 1.102 Amyloidosis. Higher power of the previous figure. The lamina propria shows
abundant eosinophilic material with cracking and tissue tears. This characteristic artifact is
produced when tissue sections containing amyloid are sectioned on a microtome in the histology
laboratory. This is a helpful clue in identifying this subtle and easily missed entity.

EOSINOPHILIC PATTERN

Figure 1.103 Esophageal eosinophilia. Numerous eosinophils are present in the squamous
epithelium. This change is frequently, but not always, accompanied by basal compartment
hyperplasia, elongation of the vascular papillae, and widened intercellular spaces (sometimes
referred to as intercellular edema or spongiosis). In the absence of clinical history, the findings
are nonspecific.

Eosinophils are a normal constituent of some mucosal real estate in the

gastrointestinal tract, such as the lamina propria of the small intestine
and colon (Fig. 1.103). However, the esophagus is unique in being
devoid of eosinophils under normal conditions. While some disease
entities are practically defined by a minimum number of eosinophils, the
category “eosinophilic pattern of injury” is intended to capture the full
spectrum of intraepithelial eosinophilia in the esophagus, whether there
is only a single intraepithelial eosinophil, or >100 eosinophils in one
high power field (HPF). Analogous to the other patterns of injury in this
book, the differential diagnoses considered in the following pages are
most applicable if eosinophilia is the primary pattern of injury. The
presence of eosinophils is often, but not always, accompanied by
additional findings including basal layer hyperplasia, elongation of the
vascular papillae, intercellular edema or “spongiosis,” lamina propria
sclerosis, acute inflammation, and intraepithelial lymphocytosis. These
ancillary features may influence the priority order of the differential
diagnoses, but none are specific. The end result is that the presence of
eosinophils in the esophagus is a nonspecific finding, and is best
regarded simply as a pattern of injury requiring correlation with clinical
information.

FAQ: What are the constituents of the eosinophil’s cytoplasmic

granules?
Answer: Eosinophils are distinctive white blood cells with bilobed
nuclei and cytoplasm that contains numerous eosinophilic secondary
granules composed of cytotoxic molecules (eosinophil peroxidase,
major basic protein, eosinophil cationic protein, and eosinophil-
derived neurotoxin).

CHECKLIST: Eosinophilic Pattern of Injury in the

Esophagus
Gastroesophageal Reflux Disease
Idiopathic Eosinophilic Esophagitis
Drug Reaction
Food Allergy
Photodynamic Therapy
Systemic Collagen Vascular Disorders (Scleroderma)
GASTROESOPHAGEAL REFLUX DISEASE
GERD is a condition in which the stomach contents backflow into the
esophagus leading to esophageal damage and, when longstanding and
severe, can eventually lead to metaplasia and neoplasia.28–34 Clinically,
patients may present with odynophagia, heartburn, chest pain,
regurgitation, hoarseness, or chronic cough. Treatment includes lifestyle
modifications, such as weight loss and avoidance of citrus foods, spices,
caffeine, alcohol, chocolate, and smoking. Medications to neutralize or
inhibit acid production, including antacids, proton pump inhibitors
(PPIs), H2-receptor blockers, and mucoprotective agents are common
treatments. Surgical procedures such as endoscopic injection of the
lower esophageal sphincter or Nissen fundoplication are effective
alternatives for patients’ refractory to medical management.
Endoscopically, esophageal erythema, erosions, and/or ulcerations can
be seen. The severity of injury can vary greatly, but reflux disease
typically affects the distal esophagus, starting at the gastroesophageal
junction (Z-line) and extending proximally with tapering of
inflammation. When proximal endoscopic irregularities are seen,
iatrogenic or infectious etiologies are more likely.

KEY FEATURES of GERD (Figs. 1.104–1.108):

• Dilatation of intercellular spaces
• Basal hyperplasia, >15% of epithelial thickness
• Elongation of the vascular papillae, extending to top half of
epithelium thickness
• Intraepithelial eosinophils
• Vascular lakes
• Increased intraepithelial T lymphocytes (squiggle cells)
• Balloon cells (epithelial cells with abundant pale cytoplasm)
 Figure 1.104 Eosinophilic pattern, GERD. This example of GERD shows mild hyperplasia of the
basal cell compartment, elongation of the vascular papillae, and scattered eosinophils in the
squamous epithelium. Lamina propria is present in this biopsy, and it does not contain
inflammatory cells or show evidence of sclerosis.

Figure 1.105 Eosinophilic pattern, GERD. This biopsy demonstrates characteristic reactive
epithelial changes of basal cell hyperplasia, elongation of vascular papillae, and prominent
intercellular edema (spongiosis). The inflammatory infiltrate is predominantly eosinophils. In the
absence of clinical information, the findings of this biopsy are nonspecific. GERD, EoE, and other
eosinophilic diseases of the esophagus are in the differential diagnosis.
 Figure 1.106 Eosinophilic pattern, GERD. The biopsy fragment on the left of this field shows
squamous epithelium with markedly increased eosinophils (arrowhead), intercellular edema
(spongiosis), elongation of the vascular papillae, and basal cell hyperplasia (basal zone
expansion). Alone, these findings are nonspecific and require clinical correlation for
interpretation. However, the biopsy fragment on the right of the field clearly shows numerous
goblet cells with bluish cytoplasmic mucin (arrow). The presence of intestinal metaplasia is
consistent with Barrett esophagus and serves as histologic evidence of reflux disease, suggesting
that the prominent eosinophilia seen in the squamous epithelium is secondary to reflux changes
and not EoE.

Figure 1.107 Eosinophilic pattern, severe GERD. A single high-powered field in this biopsy shows
>50 eosinophils in one high-powered field. Superficial layering of eosinophils toward the
luminal surface (arrowhead) is also seen-–a feature that is more commonly seen in EoE than
GERD. However, this biopsy comes from a patient with known severe reflux esophagitis, and it
emphasizes the nonspecific nature of the histologic findings in both GERD and EoE. The
parakeratotic debris seen on the surface is the result of adjacent ulceration and should not be
 mistaken for epithelial sloughing secondary to food impaction.

Figure 1.108 Eosinophilic pattern, severe GERD. Higher power of the previous figure. Careful
examination of the background shows scattered eosinophil granules throughout this biopsy. This
is a feature more commonly seen in EoE, but may also be seen GERD. The presence of
neutrophils (arrowheads) is unusual for EoE, and these microabscesses may provide a clue that
the histologic changes are secondary to GERD, despite the prominent eosinophilia and
degranulation.

PEARLS & PITFALLS

When the eosinophils are few in number, limited to the distal
esophagus, and are accompanied by a mixed inflammatory infiltrate,
GERD is a more likely cause than eosinophilic esophagitis (EoE).
However, in severe GERD, eosinophils can become a prominent
finding, exceeding 15 eosinophils/HPF. As a result, histologic findings
alone are not sufficient to discriminate eosinophilic esophagitis from
GERD, and correlation with the clinicopathologic setting is important.

SAMPLE NOTE: NO CLINICAL HISTORY PROVIDED

Esophagus, Distal, Biopsy:
• Squamous esophageal mucosa with reactive epithelial changes and
increased intraepithelial eosinophils (up to 20 intraepithelial
 eosinophils in one high-powered field).
Note: The biopsy shows prominent reactive changes and intraepithelial
eosinophils. These findings are etiologically nonspecific and can be seen
in the setting of GERD and/or EoE, among others. Correlation with the
clinical information is necessary. In addition, if the possibility of EoE is a
clinical consideration, tandem biopsies of the distal and mid- (or
proximal-)esophagus are recommended.

EOSINOPHILIC ESOPHAGITIS (EOE)

EoE is defined as a clinicopathologic disease entity that is immune
mediated (Figs. 1.109–1.122).28–34 It is characterized clinically by
symptoms related to esophageal dysfunction and histologically by
eosinophil-predominant inflammation. Clinically, patients commonly
have concurrent allergic diatheses, especially food sensitization
compared with the general population. Symptoms in the adult patient
include dysphagia, chest pain, food impaction, and upper abdominal
pain. In contrast, children tend to present with food aversion and
vomiting. Frequently seen endoscopically are esophageal rings, either
fixed or transient, which have also been described as corrugated rings,
trachealization, or felinization of the esophagus (Fig. 1.109). Other
findings include white exudates, longitudinal furrows (Fig. 1.110),
edema, esophageal narrowing, and esophageal lacerations induced by
passage of the endoscope (Fig. 1.111). The last finding, when severe,
gives the esophagus the endoscopic appearance of crepe paper, and is
thought to be a manifestation of mucosal fragility. However, all of these
endoscopic features have been described in other conditions, and none
can be considered pathognomonic for EoE. Histologically, one or more
biopsy specimens must show a minimal peak value of 15 intraepithelial
eosinophils/HPF, with few exceptions. For optimal pathologic
evaluation, multiple biopsy specimens from both the proximal and distal
esophagus should be obtained, as the distribution of eosinophils can be
patchy. Unlike for reflux esophagitis, the presence of increased
intraepithelial eosinophils proximally makes EoE more likely. EoE
should remit with treatments of dietary exclusion, topical
corticosteroids, or both (Table 1.1).
 Figure 1.109 Endoscopic esophageal rings in EoE. Subtle circumferential rings are seen in the
esophageal mucosa of this patient with eosinophilic esophagitis. This finding often raises the
clinical suspicion of eosinophilic esophagitis, but only about one-third of patients with
esophageal rings are confirmed to have esophageal eosinophils on biopsy.

Figure 1.110 Endoscopic esophageal furrows in EoE. Linear furrows and whitish exudates can be
seen in EoE. In the proper clinical setting, this finding can support but not establish a diagnosis
of EoE.
Figure 1.111 Endoscopic esophageal trachealization in EoE. This dramatic endoscopic example
shows fixed rings, or “trachealization,” and deep linear furrows in the esophagus of a patient
with EoE. A mucosal laceration has been induced by the passage of the endoscope (arrow).

Figure 1.112 Feline esophagus. A cat esophagus from a veterinary necropsy shows the ridged
esophageal mucosa from which the term “felinization” emerged to describe the endoscopic
findings in EoE. (Photograph courtesy of Dr. Lysandra Voltaggio, Johns Hopkins Hospital.)

Figure 1.113 Eosinophilic pattern, basal cell hyperplasia in EoE. Although eosinophils may be
difficult to readily identify at this low magnification, the presence of basal cell hyperplasia and
 elongation of the vascular papillae are striking, and are often the first clues to diagnosis. Also
note the intercellular edema or “spongiosis,” which appears as a white lattice-like network.

Figure 1.114 Eosinophilic pattern, EoE. Higher magnification of a different EoE case shows
similar features of basal cell hyperplasia, elongation of the vascular papillae, and spongiosis, as
well as prominent intraepithelial eosinophils. The small amount of attached lamina propria at the
base shows a suggestion of sclerosis, although it is difficult to confidently assess given the limited
sample.

Figure 1.115 Eosinophilic pattern, eosinophilic microabscess in EoE. Some studies have shown
that superficial layering of eosinophils toward the luminal surface and eosinophilic
microabscesses (arrow) (defined as ≥4 eosinophils clustered together) are more common in EoE
than in GERD.
 Figure 1.116 Eosinophilic pattern, EoE. This example of EoE shows prominent eosinophils, but
the additional features of basal cell hyperplasia, elongation of vascular papillae, and spongiosis
are not as prominent, emphasizing that the histologic features exist along a spectrum, and may
be patchy in the esophagus. Some superficial parakeratotic cells are shedding in this photo and is
likely secondary to food impaction.

Figure 1.117 Eosinophilic pattern, EoE. Characteristic features of EoE are present, including
prominent intraepithelial eosinophils, eosinophilic microabscesses, basal compartment
hyperplasia, elongation of vascular papillae, and mild spongiosis. Careful examination of the
photo will show numerous extracellular eosinophilic granules, evidence of eosinophil
degranulation.
 Figure 1.118 Eosinophilic pattern, eosinophil degranulation in EoE. At high magnification,
eosinophil degranulation can be appreciated as a prominent feature in this case of EoE.
Numerous superficial eosinophils and eosinophilic microabscesses are present, as well as
prominent spongiosis. The surface squamous epithelial cells have faded nuclei or a “mummified”
appearance. These squamous reactive changes are secondary to food impaction, which led to this
patient’s endoscopy and diagnosis.

Figure 1.119 Eosinophilic pattern, food impaction in EoE. Characteristic low power features of
basal compartment hyperplasia, elongation of vascular papillae, and spongiosis are present in
this example. Intraepithelial eosinophils are present, as well as superficial reactive squamous
epithelial changes. The faded appearance of some squamous epithelial cells and superficial
parakeratosis are secondary to this patient’s food impaction.
 Figure 1.120 Eosinophilic pattern, food impaction in EoE. Superficial parakeratosis and faded
“mummified” squamous epithelial cells are present in this example of EoE with food impaction.
The background epithelium shows markedly increased intraepithelial eosinophils and prominent
spongiosis. Note the superficial eosinophilic microabscess (arrowhead).

Figure 1.121 Eosinophilic pattern, food impaction in EoE. Superficial parakeratosis is present in
this biopsy from a patient with EoE and food impaction. The background epithelium shows mild
spongiosis and increased eosinophils. The absence of lamina propria is common in esophageal
biopsies.

Figure 1.122 Eosinophilic pattern, lamina propria sclerosis in EoE. Lamina propria is not
frequently present in esophageal biopsies. However, this example shows abundant lamina propria
with scattered eosinophils and densely pink collagenized stroma. This lamina propria sclerosis is
a common finding in patients with EoE, and is not seen in patients with GERD. Compare the
lamina propria in this photo with that seen in the photo of GERD (Fig. 1.104).

TABLE 1.1: Common Features of Eosinophilic Esophagitis (EoE) and

Gastroesophageal Reflux Disease (GERD)
PEARLS & PITFALLS
Highlights of the 2011 Updated Consensus Recommendations31
• EoE is now the preferred abbreviation; EE has historically been
reserved for erosive esophagitis.
• Definition: “EoE represents a chronic, immune/antigen-mediated,
esophageal disease characterized clinically by symptoms of
dysfunction and histologically by eosinophil-predominant
inflammation.”
• EoE is a disease that is isolated to the esophagus, by definition. The
presence of increased eosinophils in other areas of the
gastrointestinal tract suggests the possibility of other disease entities,
such as peripheral hypereosinophilic syndrome, idiopathic
eosinophilic enteritis, connective tissue disease (particularly
scleroderma), vasculitides, drug reaction, inflammatory bowel
disease, and malignancies.
• There are no pathognomonic features of EoE, including no absolute
lower limit of eosinophilia. However, a minimum peak value of 15
eosinophils/HPF is seen in the majority of cases.
• PPI-responsive esophageal eosinophilia is recommended to describe
 patients with eosinophilic-predominant esophageal disease who
completely respond to PPI therapy.

FAQ: How does one quantify intraepithelial eosinophils for cases

of “rule-out EoE”?
Answer: EoE is a clinicopathologic diagnosis and requires the presence
of both pertinent clinical and histologic features: Neither component is
diagnostic of EoE in isolation. The ideal practice pattern is to integrate
the clinical setting, the endoscopic impression, and the morphologic
findings of both the mid-or proximal esophagus and those at the distal
esophagus to distinguish GERD from EoE. Specifically, the following
elements can be included in reports.
• Approximate peak value eosinophil count of one HPF
• Presence of additional findings (microabscesses, surface layering,
extracellular eosinophil granules, lamina propria fibrosis, and basal
hyperplasia) • Distribution of changes (e.g., proximal vs. distal
esophagus)
• A comparison of these findings to previous material is often clinically
requested, although its utility in the management of EoE remains
unclear

FAQ: Eosinophilic infiltrates are seen in parasitic infections.

Should the differential diagnosis of parasitic infection be raised
when there is esophageal eosinophilia?
Answer: No. Parasitic infections essentially never affect the esophagus,
and this does not need to be included in the differential diagnosis of
esophageal eosinophilia unless prominent mucosal eosinophilia is also
seen in other parts of the GI tract. In addition, while eosinophils may
be part of the infiltrate of fungal or viral infections, the main injury
pattern for these entities is typically acute esophagitis.
Figure 1.123 Eosinophilic pattern, pill esophagitis. An ibuprofen pill was lodged in this patient’s
esophagus, resulting in an eosinophilic infiltrate (arrow), spongiosis and edema, mild
parakeratosis, and reactive epithelial changes.

Figure 1.124 Eosinophilic pattern, pill esophagitis. This patient had an ibuprofen pill lodged in
the esophagus. The resulting injury is interesting in its “tide-line” pattern (highlighted by
arrowheads). Rare eosinophils may be found (between the two bottommost arrowheads).

SAMPLE NOTE: CLINICAL IMPRESSION SUGGESTIVE OF

EOE
Esophagus, Mid, Biopsy:
• Squamous esophageal mucosa with markedly increased intraepithelial
eosinophils (focally up to 35 eosinophils in one HPF).
Note: The history of food allergies, food impaction, and the clinical
impression of esophageal linear furrows and trachealization is noted.
The biopsies show a patchy increase in intraepithelial eosinophils with
the peak eosinophil count at 35 eosinophils in one HPF. Additional
findings include basal cell hyperplasia, elongation of the vascular
papillae, and eosinophilic microabscesses. Changes in the midesophagus
are more prominent than those in the distal esophagus. These findings
would support a clinicopathologic diagnosis of eosinophilic esophagitis if
in the proper clinical setting.

DRUG REACTION
Esophageal intraepithelial eosinophils can be seen in rare cases of drug
reactions. It is unclear whether the eosinophilic inflammation is
secondary to contact injury or a direct effect of the medication (Figs.
1.123–1.124).

ALLERGY
IgE-mediated food hypersensitivity has been implicated as an etiology
for eosinophilic infiltrates in the esophagus. Allergic rhinitis, asthma,
seasonal allergies, and eczema are also commonly seen in patients with
high eosinophil counts in the esophagus. The distinction between known
food allergies and EoE is not entirely clear, especially as the current
etiology of EoE is also believed to be an antigen-driven process.31,33,35,36
However, identification and elimination of known allergens, such as
food hypersensitivities, can resolve patient symptoms and esophageal
eosinophilia. Thorough evaluation by an allergist or immunologist with
evaluation of serum IgE levels and skin testing for immediate-type food
allergy is warranted to identify food-induced allergic disease in patients
with esophageal eosinophilia prior to diagnosis of idiopathic EoE (Fig.
1.125).

PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT) is an endoscopic method of treatment for
Barrett esophagus and associated dysplasia or early carcinoma.37 It was
commonly used in the past and has largely been replaced by
radiofrequency ablation (RFA). Many patients who have been treated
with PDT remain under surveillance so their biopsies may be
encountered. PDT uses a light source to activate an applied
photosensitizing drug, resulting in activated oxygen molecules that
ablate targets of interest. A small subset (3.4%) of patients who undergo
PDT for Barrett esophagus demonstrate eosinophilic infiltrates that
histologically resemble the changes seen in EoE. This eosinophilic
infiltrate may present anywhere from several months to years following
PDT, and the histologic features can include eosinophil degranulation,
spongiosis, increased papillary height, and basal zone thickening (Figs.
1.126–1.128). However, unlike those with EoE, these patients do not
have dysphagia.

Figure 1.125 Eosinophilic pattern, food allergy. Occasional scattered eosinophils (arrowheads) are
seen in the esophageal biopsy of a patient with documented food allergies.
 Figure 1.126 Eosinophilic pattern, photodynamic therapy (PDT). This esophageal biopsy shows
basal zone expansion, elongation of the vascular papillae, marked intercellular edema, and
prominent eosinophilic infiltrates, including superficial eosinophilic microabscess (arrowhead).
While the histologic features are similar to those seen in EoE, this biopsy was obtained for
follow-up of Barrett esophagus following photodynamic therapy. Importantly, this patient did not
have clinical complaints of dysphagia, which essentially excludes EoE.

Figure 1.127 Eosinophilic pattern, PDT. This biopsy was taken from a patient who had received
photodynamic therapy for dysplasia in Barrett esophagus. Note the intense eosinophilic infiltrate.

Figure 1.128 Eosinophilic pattern, PDT. This biopsy shows superficial layering of eosinophils,
with eosinophilic microabscess formation and degranulation of eosinophils. These nonspecific
features may raise the possibility of EoE, but correlation with clinical information is always a
must. This patient had a history of photodynamic therapy for dysplasia in Barrett esophagus, a
known cause of esophageal eosinophilia.
 Figure 1.129 Eosinophilic pattern, scleroderma: An esophageal biopsy from a patient with
scleroderma shows marked basal zone expansion and marked elongation of vascular papillae that
nearly reach the surface epithelium (arrowheads). Scattered eosinophils are present throughout
the biopsy, and a background of intraepithelial lymphocytes is also present. The presence of
eosinophils in the esophagus is a nonspecific finding, and raises the possibility of collagen
vascular disorders.

SYSTEMIC COLLAGEN VASCULAR DISORDERS

(SCLERODERMA)
Systemic collagen vascular disorders, particularly scleroderma, have
been reported to demonstrate increased mucosal eosinophils.38 While
this finding is more common distally in the GI tract, some patients may
demonstrate esophageal eosinophilia (Fig. 1.129).

PARAKERATOTIC PATTERN
 Figure 1.130 Parakeratosis. Parakeratosis consists of squamous epithelial cells with brightly
eosinophilic cytoplasm and retained nuclei, sometimes with sloughing of epithelial cells
(arrowheads).

Figure 1.131 Parakeratosis, Candidiasis. In this case, the fungal forms of Candida are seen
admixed in the parakeratotic debris (arrowheads).

Parakeratosis describes abnormal retention of the nuclei in the most

superficial squamous layers, superficial keratinization, and individual
cell desquamation into the lumen. Parakeratosis is a nonspecific injury
pattern seen most commonly in the following settings (Figs. 1.130 and
1.131).

CHECKLIST: Parakeratotic Pattern

 Gastroesophageal Reflux Disease
Candida Esophagitis
Orthokeratosis is seen in Esophageal Leukoplakia/Epidermoid
Metaplasia
Esophagitis Dissecans Superficialis/Sloughing Esophagitis

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Parakeratosis is commonly seen in the setting of GERD (Figs.
1.132–1.137). See also GERD, Acute Esophagitis and Lymphocytic
Pattern, this chapter.

CANDIDA
Sometimes parakeratosis is the only clue to candidiasis (Figs.
1.138–1.146). Candida infections can occur in the complete absence of
background inflammation, particularly in immunosuppressed individuals
(elderly, pregnant, status post transplant, HIV/AIDS, patients on
immunosuppressive therapies, and even children with EoE taking oral
steroids). Identification of parakeratosis should always prompt a diligent
high-power examination for the pseudohyphal forms of Candida,
particularly when single-cell shedding or “flaking” of the surface
epithelium is seen.

Figure 1.132 Parakeratosis, GERD. Parakeratosis in a patient with a longstanding history of

 GERD. The surface squamous cells shows brightly eosinophilic cytoplasm, indicative of
keratinization, while intact nuclei are retained.

Figure 1.133 Parakeratosis, GERD. Parakeratosis in a patient with a longstanding history of reflux
disease.

Figure 1.134 Parakeratosis, GERD. Parakeratosis in a patient with a longstanding history of reflux
disease.
Figure 1.135 Parakeratosis, GERD. Parakeratosis can often be picked up at low power due to the
brightly eosinophilic cytoplasm of the surface squamous cells undergoing keratinization.

Figure 1.136 Parakeratosis, GERD. Higher power of previous figure. Retained nuclei are present
in squamous cells undergoing keratinization of the cytoplasm, seen as brightly eosinophilic
change.
Figure 1.137 Parakeratosis, GERD. Small focus of parakeratosis is seen among squamous balloon
cells.

Figure 1.138 Severe candidiasis. The endoscopic image shows a coalescing of white plaques that
correspond histologically to parakeratotic debris.

Figure 1.139 Parakeratosis, candidiasis. The corresponding biopsy shows mats of parakeratotic
debris and embedded fungal forms. Note how the parakeratotic cells desquamate in a single cell
pattern. This “flakiness” is a very helpful red flag to the underlying diagnosis and it is easily
spotted at low power.
 Figure 1.140 Parakeratosis, candidiasis. A PAS/AB highlights the long fungal pseudohyphae
(arrowheads), a requirement for diagnosis. In contrast, the neighboring rounded fungal yeast
forms can be seen with oral contamination and are not indicative of candidiasis (circles).

Figure 1.141 Parakeratosis, candidiasis. The “flakiness” seen at low power is the single cell
desquamation of parakeratotic cells (arrowheads), a finding which may be the only clue in subtle
cases of candidiasis. This patient had a history of eosinophilic esophagitis treated with diet
modification and topical steroids. Note the complete absence of acute inflammation, which can
be seen in candidiasis from patients on oral steroids, or otherwise immunosuppressed.
 Figure 1.142 Parakeratosis, candidiasis (PAS/AB). A PAS/AB highlights both fungal
pseudohyphae and rounded yeast forms. Again, take note of the flaky background appearance
due to single cell desquamation of parakeratotic squamous cells.

Figure 1.143 Parakeratosis, candidiasis. Although there is no background inflammation in this

biopsy, the single cell flaking (parakeratosis) almost certainly indicates Candida lurking within
the parakeratotic debris.
 Figure 1.144 Parakeratosis, candidiasis (PAS/AB). A PAS/AB highlights the rare fungal
pseudohyphae.

Figure 1.145 Parakeratosis, candidiasis. The presence of parakeratosis and single cell detachment
of the surface epithelium is highly suspicious for involvement by Candida.
Figure 1.146 Parakeratosis, candidiasis. (PAS/AB). A PAS/AB highlights the rare fungal hyphae
(arrowheads).

LEUKOPLAKIA PATTERN/EPIDERMOID METAPLASIA

At scanning magnification, the superficial hypereosinophilia of
leukoplakia (epidermoid metaplasia) can appear similar to the
parakeratotic pattern described above. Esophageal
leukoplakia/epidermoid metaplasia is a clinicopathologic diagnosis that
requires satisfaction of clinical criteria (endoscopically apparent white
plaque) and histologic criteria (orthokeratosis and hypergranulosis)
(Figs. 1.147–1.153).39–42 Orthokeratosis describes anucleated
keratinization, whereas, parakeratosis refers to keratinization with
retained nuclei. This uncommon finding is associated with scleroderma,
distal esophageal dysmotility disorders, and factors associated with oral
leukoplakia (including tobacco and alcohol usage and head and neck
pathology). Endoscopically, it appears as a white plaque (similar
endoscopic images can be seen with candidiasis, glycogenic acanthosis,
and lichen planus). Histologically, basal hyperplasia, an acanthotic
midzone, superficial hyperkeratosis, and hypergranulosis characterize
the lesion. Candida or bacterial colonization is seen in 45% of cases.
Recent reports show patients with esophageal leukoplakia/epidermoid
metaplasia have an increased risk of squamous cell dysplasia and
squamous cell carcinoma, suggesting affected patients may benefit from
surveillance, although as of this writing, no official consensus guidelines
exist.
 Figure 1.147 Esophageal leukoplakia pattern/epidermoid metaplasia. The endoscopic image
shows scattered white plaques.

Figure 1.148 Esophageal leukoplakia pattern/epidermoid metaplasia. The corresponding

histologic sections show squamous mucosa with hyperkeratosis, hypergranulosis, and bacterial
colonization. No dysplasia is seen.
Figure 1.149 Esophageal leukoplakia pattern/epidermoid metaplasia. This striking low-power
example shows hyperkeratosis and prominent hypergranulosis. No dysplasia is seen.

Figure 1.150 Esophageal leukoplakia pattern/epidermoid metaplasia. Higher power of previous

figure. The presence of a granular layer and keratinization in the esophageal mucosa is never
normal and should prompt consideration of esophageal leukoplakia/epidermoid metaplasia, as
well as a close examination for associated squamous dysplasia.
 Figure 1.151 Esophageal leukoplakia pattern/epidermoid metaplasia. Keratinization of the
surface epithelium and the presence of a granular layer are seen. These features are more subtle;
the granular layer is attenuated, making high-power evaluation necessary. No dysplasia is
present.

Figure 1.152 Dysplasia arising in a background of esophageal leukoplakia/epidermoid

metaplasia. Note the jumbled appearance to the squamous epithelium with scattered large,
pleomorphic squamous cells and a focal loss of maturation.

Figure 1.153 Dysplasia arising in a background of esophageal leukoplakia. Higher power of

 previous figure.

SAMPLE NOTE: ESOPHAGEAL LEUKOPLAKIA/EPIDERMOID

METAPLASIA
Proximal Esophageal Plaque, Biopsy:
• Esophagus with orthokeratosis, hypergranulosis, and bacterial
overgrowth (esophageal leukoplakia/epidermoid metaplasia pattern).
• Negative for dysplasia.
Note: Esophageal leukoplakia/epidermoid metaplasia pattern appears to
arise in patients with similar risk factors for squamous cell carcinoma to
those associated with oral leukoplakia. Periodic follow-up of this process
is recommended, although there are no guidelines for surveillance
intervals at this time.

References
Taggart MW, Rashid A, Ross WA, et al. Oesophageal hyperkeratosis:
Clinicopathological associations. Histopathology. 2013;63(4):463–473.
Singhi AD, Arnold CA, Crowder CD, et al. Esophageal leukoplakia or
epidermoid metaplasia: A clinicopathological study of 18 patients. Mod
Pathol. 2013;27(1):38–43.
ESOPHAGITIS DISSECANS SUPERFICIALIS/SLOUGHING
ESOPHAGITIS
This is an unusual endoscopic finding of epithelial sloughing that has
been associated with medications (bisphosphonates and NSAIDs), heavy
smoking, alcohol use, bullous skin disorders (such as pemphigus
vulgaris), autoimmune diseases, celiac disease, motility disorders, and
physical or thermal injury.43–47 However, many cases lack a recognized
clinical association. The clinical presentation ranges from asymptomatic
to dysphagia with stricture formation. The endoscopic impression can be
dramatic with vertical fissures and intervening patches of peeling and
sloughed epithelium (Fig. 1.154). Histologically, on low power, long
detached fragments of superficial squamous epithelium are typically
present. Most cases demonstrate some degree of intraepithelial splitting
at varying intervals above the basal layer. Various stages of splitting can
be seen, with some cases demonstrating distinct bullae. Earlier stages
may show intraepithelial splitting with fluid-containing and cell-
containing cysts in the upper third of the epithelium. Parakeratosis is a
consistent and prominent feature in all cases. Other characteristic
features include a superficial “mummified” layer (anucleated squamous
mucosa), variable necrosis, and bacterial colonization with minimal
inflammation (Figs. 1.155–1.160). A study by Carmack et al. showed that
four of five patients had complete resolution of endoscopic and
histologic findings following PPI therapy, suggesting this could be a
potential treatment. There have been no reports of neoplasia associated
with esophagitis dissecans superficialis.
 Figure 1.154 Endoscopic appearance of esophagitis dissecans superficialis (sloughing
esophagitis). The esophageal squamous epithelium has a distinct white appearance with
fissuring. Some areas have shed off in sheets, exposing the underlying tissue (arrow). With
endoscopic maneuvering, the residual epithelium may lift off with a crepe paper-like quality
(arrowhead).

Figure 1.155 Esophagitis dissecans superficialis. The histologic findings from the previous
endoscopic photo show features of esophagitis dissecans superficialis (sloughing esophagitis).
This entity uniformly demonstrates parakeratosis; retained nuclei (arrowheads) are present in the
superficial and keratinizing squamous cells. An intraepithelial split is often frequently seen, but
no inflammatory cells are present. Bacterial overgrowth is visualized as a fuzzy basophilic lining
along the superficial epithelium. It can also be seen as detached basophilic clusters (arrow), and
is a common finding in sloughing esophagitis.

Figure 1.156 Esophagitis dissecans superficialis. A different example of sloughing esophagitis

shows an early intraepithelial split above the basal layer. This case shows fluid-containing cysts
(arrowheads) within the epithelium, another common finding. Although difficult to visualize at
this power, the surface epithelium shows bacterial colonization and parakeratosis. Note the
absence of inflammation.
 Figure 1.157 Esophagitis dissecans superficialis. This example of esophagitis dissecans
superficialis shows a prominent intraepithelial split, with residual fluid-filled cysts (arrowhead),
prominent parakeratosis (arrow), and a total lack of inflammation. The etiology of sloughing
esophagitis is frequently unidentifiable.

Figure 1.158 Esophagitis dissecans superficialis. Another example of esophagitis dissecans

superficialis with an intraepithelial split and small fluid-filled cysts (arrowhead). The lack of
inflammation is characteristic for this entity.

Figure 1.159 Esophagitis dissecans superficialis. This example of esophagitis dissecans

 superficialis shows the characteristic parakeratosis, with development of fluid-filled cyst-like
spaces. An intraepithelial split has not yet developed. Note the lack of inflammation.

Figure 1.160 Severe reflux with features of esophageal sloughing. This esophageal biopsy shows
sloughed squamous epithelium with parakeratosis and surface bacterial colonization. However,
the presence of the intense acute inflammation found at the base of the epithelial split is unusual
for esophagitis dissecans superficialis (sloughing esophagitis). Investigation into the clinical and
endoscopic findings yielded a history of severe reflux esophagitis.

KEY FEATURES of Esophagitis Dissecans Superficialis/Sloughing

Esophagitis:
• The endoscopic appearance can be dramatic, with sloughing or
peeling squamous mucosa
• Histology shows a preserved basal layer with mummified and often
a splitting superficial layer with “ghost” nuclei, parakeratosis, and
fragmentation
• Inflammation is not prominent
• The etiology is usually unknown, but the condition has been associated
with some medications, bullous dermatoses, motility disorders,
physical/thermal injury, and autoimmune diseases

PEARLS & PITFALLS

Although most cases of esophagitis dissecans superficialis (sloughing
esophagitis) will not yield an identifiable etiology, if bullae and
epithelial clefting are prominent features, skin disorders that have
similar esophageal manifestations should be excluded, such as
Stevens–Johnson syndrome, pemphigus and pemphigoid, and
dermatitis herpetiformis. In such cases, consultation with a
dermatopathologist and biopsy with fresh tissue (tissue not fixed in
formalin) submitted for pertinent immunofluorescent studies (IgG,
IgM, IgA, C3, fibrinogen) is recommended.

PEARLS & PITFALLS

Detached or split squamous epithelium, alone, does not qualify a
diagnosis of esophagitis dissecans superficialis (sloughing esophagitis),
as this can result from biopsy trauma or processing artifact (Fig.
1.161). In addition, dilated intercellular spaces (spongiosis) are not
seen in this entity; when this feature is seen, other etiologies, such as
reflux or changes secondary to a stricture should be considered.

Figure 1.161 Normal esophagus with artifactual split. This intraepithelial split is the result of
processing and cutting artifact. While an intraepithelial split is characteristic of esophagitis
dissecans superficialis (sloughing esophagitis), this biopsy lacks parakeratosis, fluid-or cell-filled
cysts, bacterial overgrowth, or other abnormalities to suggest esophagitis dissecans superficialis.
In addition, the endoscopic impression was unremarkable and not suggestive of a esophagitis
dissecans superficialis (sloughing esophagitis) pattern of injury.

ESOPHAGEAL LYMPHOCYTOSIS PATTERN

 Figure 1.162 Lymphocytic esophagitis pattern. Lymphocytic esophagitis pattern features a
prominence of peripapillary intraepithelial lymphocytes and marked spongiosis.

Figure 1.163 Lymphocytic esophagitis pattern, GERD. The biopsy shows intraepithelial
lymphocytosis in a patient with a long-standing history of GERD.

While the normal esophageal biopsy may contain occasional

intraepithelial lymphocytes, “lymphocytic esophagitis pattern” refers to
a relative prominence of peripapillary intraepithelial lymphocytes and
marked spongiosis (Fig. 1.162).48–50 In one recent large study, this
pattern was reported in up to 0.1% of material and was most often
encountered in elderly female patients with dysphagia, odynophagia,
and motility disorders.50 Endoscopically, features typically associated
with EoE have been reported, including esophageal felinization, rings,
furrows, and plaques. Consequently, up to one-third of these cases were
submitted with the clinical impression of EoE.50 These patients can show
improvement with PPIs, but it is unclear if this is due to direct treatment
of the lymphocytic esophagitis or indirect treatment of the background
GERD.49 Importantly, this histologic pattern of intraepithelial
lymphocytosis can be patchy. Since there is no minimum numerical
requirement for the diagnosis of lymphocytic esophagitis, providing
numerical values in reports is not required (thankfully). The literature on
lymphocytic esophagitis is evolving and no particular underlying
etiology has yet emerged. This pattern of injury has been associated
most commonly in the following settings.

CHECKLIST: Lymphocytic Esophagitis Pattern

Gastroesophageal Reflux Disease
Crohn Disease
Contact Mucositis (Nonspecific Allergy: Seasonal, Food, Medication)
Lichen Planus/“Lichenoid” Pattern
Common Variable Immunodeficiency
Graft Versus Host Disease
Infection (candidiasis, Helicobacter)
Other (dysmotility disorders, gastroduodenitis, celiac disease,
malignancy, hiatal hernia, Hashimoto thyroiditis, gastric
ulcer/asthma/hypertension, cirrhosis/diabetes)

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Lymphocytic esophagitis pattern is commonly seen in the setting of
GERD. It is unclear if this association is merely coincidental simply
because GERD is one of the most common esophageal diagnoses (and so
would be common in any unrelated scenario), or if lymphocytic
esophagitis could be a direct manifestation of GERD (Fig. 1.163).
 Figure 1.164 Lymphocytic esophagitis pattern, Crohn disease. Squamous mucosa with
intraepithelial lymphocytosis and lamina propria granulomata (arrowheads) in a patient with
established upper tract Crohn disease. AFB and GMS special stains for microorganisms were
negative.

Figure 1.165 Lymphocytic esophagitis pattern, Crohn disease. Higher power of the previous
figure. The granulomata in Crohn disease are often poorly formed and sometimes challenging to
identify.

CROHN DISEASE
The relationship between lymphocytic esophagitis and Crohn disease is
controversial and may be population specific. In Rubio’s initial report,
40% of the pediatric lymphocytic esophagitis cases were associated with
Crohn disease,48 a finding which has not been reproduced in other
studies of adult patients (Figs. 1.164 and 1.165).49–51

PEARLS & PITFALLS

Careful inspection of the lamina propria will occasionally uncover
poorly formed granulomata, a finding highly suggestive of Crohn
disease.

FAQ: How are AFB/GMS special stains utilized in Crohn disease

cases with granulomata?
Answer: Routine AFB/GMS special stains are not necessary on all
Crohn cases with granulomata. Select examples where careful
evaluation of AFB/GMS stains are recommended include the
following.
• Newly diagnosed Crohn disease cases with granulomata
• Necrotizing granulomata
• Established cases with refractory symptoms
• Cases with a strong clinical suspicion for an infectious component
(fevers, etc.)

“CONTACT MUCOSITIS”
Similarities have been noted between the histologic appearance of
lymphocytic esophagitis and contact dermatitis.51 As such, lymphocytic
esophagitis may be a generalized response to mucosal injury, for
example, an unspecified allergy (drug or nondrug) or a related mucosal
injury. Select medications implicated in lymphocytic esophagitis include
gold, antimalarials, and thiazides, although the literature on this topic is
very limited.

LICHEN PLANUS/“LICHENOID” PATTERN

Lichen planus/“lichenoid” pattern is a chronic and relapsing
inflammatory condition that most typically afflicts the middle-aged to
elderly women. These patients present with dysphagia, have proximal
esophageal strictures, and generally benefit from immunosuppressive
therapy. However, a subset of patients poorly tolerate the
immunosuppressive therapy, and these patients instead opt for periodic
dilatations of their esophageal strictures. Endoscopic images show white
plaques or streaks (similar endoscopic findings can be seen with
candidiasis, glycogenic acanthosis, and leukoplakia). Similar to
cutaneous sites, the common histologic features of esophageal lichen
planus/“lichenoid” pattern include a band-like lymphocytic infiltrate
involving the interface of the basal epithelium and the lamina propria (T
lymphocytes predominate), parakeratosis, intraepithelial lymphocytosis,
acanthosis, and single dyskeratotic keratinocytes (“Civatte bodies”)
(Figs. 1.166–1.181). Importantly, squamous dysplasia and carcinoma
have been described in association with lichen planus/“lichenoid”
pattern and, consequently, periodic surveillance may be of value.52–58 At
this time, no evidence-based surveillance guidelines have been
established. The histologic features of lichen planus/“lichenoid” pattern
are characteristic but nonspecific and, consequently, some advocate
usage of the term “lichenoid” pattern to describe this histologic injury
pattern and reserve “lichen planus” for those cases with the appropriate
clinical history, endoscopic impressions, and histologic findings.

Figure 1.166 Lichen planus. Endoscopically, lichen planus often appears as white plaques or
streaks.
Figure 1.167 Lichen planus. Lichen planus is associated with squamous dysplasia and carcinoma
and can have a dramatic endoscopic appearance as shown here with a marked granulonodular
appearance, polypoid lesions, white papules, and erosive changes.

Figure 1.168 Lichen planus. Lichen planus of the esophagus form another patient, revealing a
granulonodular appearance, polypoid lesions, and white papules on endoscopy.
 Figure 1.169 Lichenoid pattern of lymphocytic esophagitis. This biopsy shows a band-like
lymphocytic infiltrate involving the interface of the basal epithelium and the lamina propria,
parakeratosis, intraepithelial lymphocytosis, acanthosis, and single dyskeratotic keratinocytes
(“Civatte bodies”). In addition, the surface shows acute inflammation and necrotic debris,
features attributed to the superimposed candidiasis. No dysplasia is seen.

Figure 1.170 Lichenoid pattern of lymphocytic esophagitis. Higher power of previous figure.
Correlation with clinical information is necessary for a diagnosis of esophageal lichen planus,
else “lichenoid pattern” is the preferred terminology because this nonspecific injury pattern can
be caused by varying etiologies.
Figure 1.171 Lichenoid pattern of lymphocytic esophagitis. These histologic images show the
characteristic but nonspecific features of lichen planus/“lichenoid” pattern and also squamous
dysplasia.

Figure 1.172 Lichenoid pattern of lymphocytic esophagitis.

Figure 1.173 Lichenoid pattern of lymphocytic esophagitis.

 Figure 1.174 Lichen planus. Not all cases showing a lichenoid pattern are straightforward,
especially those cases lacking lamina propria because they preclude evaluation of the epithelial–
lamina propria interface. While this case of lichen planus lacks lamina propria, prominent
intraepithelial lymphocytes and dyskeratotic keratocytes (“Civatte” bodies) are seen
(arrowheads). The patient had a long-standing history of oral lichen planus and proximal
esophageal strictures.

Figure 1.175 Treated lichen planus with sloughing. This biopsy comes from a patient with a
known clinical history of esophageal involvement by lichen planus. During endoscopic
manipulation, the esophageal epithelium of patients with lichen planus may slough. The tissue
split in lichen planus is typically at the junction of the epithelium and lamina propria, as
compared to esophagitis dissecans superficialis (“sloughing esophagitis”) in which the split is
intraepithelial. The lack of a prominent lichenoid infiltrate in this case is likely the result of
steroid treatment.
 Figure 1.176 Sloughing epithelium in lymphocytic esophagitis. This biopsy was sent with an
endoscopic impression of “sloughing” epithelium. Further clinical history was not available, but
histologic sections showed a junctional split between squamous epithelium and lamina propria,
excluding esophagitis dissecans superficialis. Also notable in this biopsy is the intraepithelial
lymphocytes, or lymphocytic esophagitis pattern.

Figure 1.177 Lichenoid pattern of lymphocytic esophagitis. Same patient as previous. Additional
biopsies of the previous showed a lichenoid pattern of low-lying lymphocytes.

Figure 1.178 Lichenoid pattern of lymphocytic esophagitis. Same patient as previous. Other areas
showed a lichenoid infiltrate of lymphocytes and single hypereosinophilic dyskeratotic cells,
similar to Civatte bodies (arrow). While the histologic findings are compatible with lichen planus,
in the absence of clinical information, the findings are nonspecific. This case was signed out with
 a differential diagnosis of lichen planus, viral infection, contact injury, and drug reaction.

Figure 1.179 Lichenoid pattern of lymphocytic esophagitis in ulcerative colitis. This esophageal
biopsy comes from a patient with a known history of ulcerative colitis (UC). Upper tract
involvement by UC is rare, but can manifest as a lymphocytic esophagitis. This case shows an
intense low-lying infiltrate of lymphocytes at the basal layer, emphasizing the nonspecific nature
of lymphocytic esophagitis, even when a lichenoid pattern is present.

Figure 1.180 Lichenoid pattern of lymphocytic esophagitis. Esophageal biopsies from a man with
recurrent oral mucosal lesions and esophageal stricture. The esophageal sections show an intense
low-lying lymphocytic infiltrate with a single hypereosinophilic dyskeratotic cell (center left).

Figure 1.181 Lichenoid pattern of lymphocytic esophagitis. Same patient as previous. Additional
biopsies of the esophagus show similar features of an intense lichenoid infiltrate. Tissue from the
oral biopsies was sent for immunofluorescence studies, which excluded specific dermatoses
(bullous pemphigoid, dermatitis herpetiformis, pemphigus, lupus erythematosus, etc.). The
findings alone are nonspecific, but would support a clinical impression of esophageal
involvement by lichen planus.

KEY FEATURES of Lichen Planus/“Lichenoid” Pattern:

• Most common in the proximal esophagus of middle-aged and elderly
women
• Endoscopic images show white plaques or streaks
• Histologic features include a band-like lymphocytic infiltrate,
parakeratosis, intraepithelial lymphocytosis, acanthosis, and
Civatte bodies
Associations with Esophageal Lichen Planus/“Lichenoid” Pattern
• Esophageal manifestation of oral/cutaneous lichen planus (examination
for oral, cutaneous, or vulvar lesions recommended).
• Medication effect (including antimalarial drugs, gold, nonsteroidal anti-
inflammatory drugs, thiazides, and amalgam).
• Viral infections (viral hepatitis, human immunodeficiency virus).
• Upper tract Crohn disease.
• Mucosa physically damaged by nearby “pill esophagitis.”

SAMPLE NOTE: LICHEN PLANUS/“LICHENOID” PATTERN

Proximal Esophagus, Biopsy:
• Squamous mucosa with lichenoid injury pattern (prominent band-like
lymphocytic infiltrate) involving the interface of the basal epithelium
and the lamina propria, parakeratosis, intraepithelial lymphocytosis,
acanthosis, and dyskeratotic keratinocytes (“Civatte bodies”).
• Negative for dysplasia and viral cytopathic effect.
Note: The biopsies show a “lichenoid” pattern of injury. This is an
etiologically nonspecific finding that can be seen as an esophageal
manifestation of lichen planus, or association with medications
(antimalarial drugs, nonsteroidal anti-inflammatory drugs,
antihypertensive agents, and dental materials such as amalgam), viral
infections (especially viral hepatitis and human immunodeficiency
virus), Crohn disease, or “pill esophagitis.” Careful correlation with the
patient’s medication history and clinical examination with particular
attention to any cutaneous, oral, or genital lesions is advised. If lichen
planus is a consideration, some patients improve with
immunosuppressive therapy, while others opt for periodic esophageal
dilatations if strictures are present. Importantly, some authors have
reported an association with squamous cell dysplasia and carcinoma,
suggesting periodic surveillance may be of value. CMV, HSV, and EBV
immunostains are nonreactive. No dysplasia or carcinoma is seen.

References
Abraham SC, Ravich WJ, Anhalt GJ, et al. Esophageal lichen planus:
Case report and review of the literature. Am J Surg Pathol.
2000;24:1678–1682.
Chandan VS, Murray JA, Abraham SC. Esophageal lichen planus. Arch
Pathol Lab Med. 2008;132:1026–1029.
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.

Figure 1.182 Lymphocytic esophagitis pattern, common variable immunodeficiency (CVID).

Squamous mucosa with a mild prominence of intraepithelial lymphocytes overlying a lymphoid
aggregate. Plasma cells are absent. CVID was clinically confirmed through documentation of low
levels of serum immunoglobulins. A CMV immunostain was nonreactive.

COMMON VARIABLE IMMUNODEFICIENCY

Common variable immunodeficiency (CVID) is another (uncommon)
etiologic consideration when a lymphocytosis is seen in the esophageal
squamous epithelium. CVID is clinically characterized by
hypogammaglobulinemia, a lack of functional plasma cells, impaired
response to vaccinations, and chronic infections (including Giardia
lamblia and bacterial infections). A lack of plasma cells is a helpful clue
to the diagnosis (Fig. 1.182), but this finding is seen in only one-half to
two-thirds of cases.59 Clinicopathologic correlation is essential for the
diagnosis, particularly if plasma cells are present. Additional ancillary
testing includes titration of serum immunoglobulins. CVID is a widely
heterogeneous disease that can appear normal or can mimic the
following entities.
• Graft Versus Host Disease
• Lymphocytic Gastritis Pattern
• Malabsorption Pattern
• Lymphocytic Colitis Pattern
• Collagenous Colitis Pattern
• Granulomatous Pattern
• Inflammatory Bowel Disease (IBD)

GRAFT VERSUS HOST DISEASE

Although intraepithelial lymphocytes are not a diagnostic criteria for
Graft Versus Host Disease (GVHD), this injury pattern can be a red flag
to consider GVHD, in the appropriate clinical setting. GVHD is an attack
on host tissues by donor T lymphocytes, seen most commonly in stem
cell transplants but also rarely seen in solid organ transplants
(particularly liver) and blood transfusions.60,61 The tubular GIT is a
common site of GVHD involvement, as is the hepatobiliary system, skin,
and lung. GVHD is critical to recognize because it is linked to significant
morbidity and mortality in the transplant setting, and patients often
benefit from immunosuppressive therapy. Patients with GI GVHD
commonly present with a skin rash and GI-related complaints, such as
nausea, vomiting, and watery diarrhea. The endoscopic findings in
GVHD are nonspecific and insensitive; biopsies from up to 65.8% of
unremarkable endoscopic examinations fulfill the histologic criteria for
GVHD.62–64 Nonspecific endoscopic abnormalities include loss of
vascular pattern, erythema, edema, erosions, ulcerations, and exudates.
More recently, experts have found severe endoscopic findings correlate
better with severe GVHD (grade III and IV).64 The optimal site of tissue
biopsy has been debated. In a recent study of 112 patients, rectosigmoid
biopsies were shown to have the highest sensitivity, specificity, and
positive and negative predicative values for diagnosing GI GVHD, when
compared to biopsies of the stomach and duodenum.65 Others have
reported the stomach as the optimal biopsy site for evaluation of
GVHD.66,67 As a result, some advise a two-step approach: An initial
rectal biopsy is preferred based on ease of access, followed by an upper
tract biopsy if the clinical concern for GVHD is high and the rectal
biopsy is unremarkable.68 The most common histologic grading scheme
for GVHD was developed by Lerner et al.69 and is detailed below (Table
1.2). More recently, the National Institutes of Health (NIH) defined the
minimal criteria for active GIT GVHD as at least one crypt apoptotic
bodies per tissue fragment (Fig. 1.183–1.185).70 While not a part of the
NIH grading scheme, other histologic features enriched in the GVHD
setting include eosinophilia, lymphocytic infiltration, glandular or crypt
destruction, crypt abscess filled with apoptotic debris, focally enhanced
gastritis, and endocrine cell nests.68,70,71 Moreover, features that can be
seen with any chronic injury (features not specific for chronic GVHD)
include glandular destruction, ulceration, or submucosal fibrosis.70 The
NIH working group recommends the following standard comments to
simplify the diagnostic process; these comments can be used for any
tissue site (Table 1.3).70

TABLE 1.2: GVHD Histologic Grading

Adapted from Lerner KG, Kao GF, Storb R, et al. Histopathology of graft-vs.-host reaction (GvHR)
in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc.
1974;6(4):367–371.
 Figure 1.183 Lymphocytic esophagitis pattern, mild GVHD (grade I). This biopsy shows
conspicuous intraepithelial lymphocytes, rare dyskeratotic keratinocytes (arrowhead), and
scattered apoptotic bodies (circles). A CMV immunostain was nonreactive.

Figure 1.184 Lymphocytic esophagitis pattern, moderate GVHD (grade II). Prominent
intraepithelial lymphocytes and apoptotic bodies (circles) are seen. A CMV immunostain was
nonreactive.
 Figure 1.185 Lymphocytic esophagitis pattern, moderate GVHD (grade II). Higher power of
previous figure. Prominent intraepithelial lymphocytes and apoptotic bodies (circles) are seen. A
CMV immunostain was nonreactive.

PEARLS & PITFALLS

Application of the NIH and Lerner GVHD histologic grading scheme
relies on counting crypt apoptotic bodies (at least one apoptotic body
per tissue fragment qualifies as abnormal).70 Importantly, apoptotic
bodies in the superficial colonic mucosa may be secondary to bowel
preparation and should be disregarded in the evaluation of apoptotic
body prominence.68 Because apoptotic bodies can be patchy, the
current recommendation is to examine at least eight serial sections for
complete evaluation.70 There is no role for immunostains in the
counting of apoptotic bodies at this time.

PEARLS & PITFALLS

Unfortunately, the characteristic findings of GVHD can also be seen
with medication injury (particularly CellCept/mycophenolate mofetil
[MMF]) and infections, making clinicopathologic correlation
imperative. We recommend a low threshold for CMV immunostains in
biopsies from transplant patients, particularly in the following
 settings: Acute and/or chronic inflammatory injury, increased
apoptotic bodies, or upon clinical request.

TABLE 1.3: Recommended Standard Reporting of GVHD

Adapted from Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-
versus-host disease: National Institutes of Health Consensus Development Project on criteria for
clinical trials in chronic graft-versus-host disease: II. Pathology Working Group Report. Biol Blood
Marrow Transplant. 2006;12(1):31–47.

FAQ: What is the distinction between acute versus chronic

GVHD?
Answer: Historically, acute and chronic GVHD were histologically
indistinguishable and were separable only by the time interval from
transplant: Acute GVHD occurring before 100 days, and chronic GVHD
occurring after 100 days. Both are essential to recognize because of
their association with morbidity and mortality in the transplant
setting.72–74 Chronic GVHD is seen in 6% to 80% of transplant patients
and is enriched in those who have had acute GVHD. In 2005, the NIH
released consensus guidelines for the classification of chronic GVHD
for clinical trials.73 In their report, a new scoring system was
developed that defines chronic GVHD based on a more global clinical
assessment, regardless of the interval time since transplant. This
algorithm assesses number of organs and degree of functional
impairment to arrive at the diagnosis of chronic GVHD. Diagnostic
features of chronic GVHD in the GIT include esophageal web,
stricture, or concentric rings in the middle third of the esophagus as
documented on endoscopy or barium contrast radiograph. Other
clinical associations indicate but are not diagnostic of chronic GVHD,
 include pancreatic exocrine insufficiency. Nonspecific features that
can be seen in (acute and chronic) GVHD, infection, and medication
injury include anorexia, nausea, vomiting, diarrhea, weight loss, and
failure to thrive.

The working group further defined grading of chronic GVHD as mild,

moderate, and severe. Mild chronic GVHD involves one or two organs
with no significant impairment; treatment is local therapies alone.
Moderate chronic GVHD involves at least one organ with significant
impairment OR three or more organs involved with no significant
impairment; treatment may include systemic immunosuppression. Severe
chronic GVHD involves major impairment; recommendations are to
intensify immunosuppression in those already on immunosuppressive
therapy with infection prevention measures initiated. A recent reprisal of
chronic GVHD grading schemes found no statistically significant
association with survival, regardless of the presence or absence of either
NIH criteria or historically defined criteria for chronic GVHD.72 The
utility of the NIH grading scheme in the routine clinical practice has not
been fully established.

PIGMENTS
A variety of colorful entities can be seen in esophageal biopsies. Iron pill
and resins are among the more common (Kayexalate, sevalamer, and bile
acid sequestrants). These entities are discussed at length in the Acute
Esophagitis subsection at the beginning of this chapter.

NEAR MISSES
 Figure 1.186 Inlet patch/gastric heterotopic mucosa. The biopsy shows oxyntic mucosa in a
biopsy labeled as “proximal esophagus.” These findings are consistent with the clinicopathologic
diagnosis of gastric inlet patch.

Figure 1.187 Inlet patch/heterotopic gastric mucosa. The corresponding endoscopic image shows
a pink patch of mucosa (arrowheads) in the proximal esophagus.

The seemingly normal esophageal biopsy can hold clues to tricky

diagnoses. Some of these entities are critical for patient care while others
are more for academic interest and proper clinicopathologic agreement.
While this list is by no means exhaustive, consider the following before
releasing the apparent unremarkable esophageal biopsy.

GASTRIC INLET PATCH/HETEROTOPIC GASTRIC MUCOSA

Gastric inlet patches are most commonly found in the proximal,
posterior cervical esophageal mucosa (Fig. 1.186). Some observers
believe they are congenitally acquired through the incomplete
replacement of the embryologic columnar esophageal epithelium by
squamous epithelium, although others argue they are metaplastic
growths in response to acid secretion.75–77 Gastric inlet patches were
found in 0.18% of patients in a study of over 487,000 patients in tertiary
centers.77 Most of the patients were men with a history of Barrett
mucosa and, unexpectedly, they had an increased risk of
adenocarcinoma arising in Barrett mucosa when compared to those
without gastric inlet patches. These patients presented with dysphagia,
odynophagia, globus sensation, hoarseness, cough, stridor, and asthma,
and these symptoms correlated with the size of the lesion. The most
common type of heterotopic gastric mucosa identified was oxyntic
mucosa and up to 1% of gastric inlet patches contained intestinal
mucosa (Figs. 1.186–1.187). Helicobacter infections were encountered in
the gastric inlet patches, and these infections correlated with
corresponding Helicobacter gastritis. Dysplasia and malignancy arising in
the gastric inlet patch itself are exceedingly rare.

FAQ: What is the HGM classification scheme?

Answer: In 2004 von Rahden proposed a clinicopathologic
classification scheme for esophageal heterotopic gastric mucosa
(HGM) (inlet patch).75 While subclassification is not required in
pathology reports, awareness of this scheme is worthwhile since it is
occasionally encountered in clinical reports.
HGM I Asymptomatic
HGM II Symptomatic without pathologic findings
HGM III Symptomatic with morphologic changes
HGM IV Dysplasia present
HGM V Malignancy present

PANCREATIC HETEROTOPIA/METAPLASIA
Figure 1.188 Pancreatic heterotopia/metaplasia (PAS/AB). This focus was mistakenly diagnosed
as Barrett esophagus because the pancreatic heterotopia/metaplasia (arrowheads) displayed
alcianophilia on PAS/AB, mimicking the staining pattern of goblet cells.

Figure 1.189 Pancreatic heterotopia/metaplasia. Comparison to the corresponding H&E reassures

that there are no goblet cells. The pancreatic cells do not have distinct cytoplasmic distention
(arrowheads), as would be expected for goblet cells.

Pancreatic acinar tissue occasionally raises concerns for goblet cells.

Particularly challenging cases are those in which the pancreatic acinar
tissue acquires an alcianophilia reminiscent of the deep basophilia of a
goblet cell (Figs. 1.188 and 1.189). In such cases, it is worth noting that
acinar cells lack distinct cytoplasmic distention and uniform strong
purple staining, findings characteristic of goblet cells. Pancreatic
heterotopia/metaplasia and oxyntic mucosa are also occasionally
confused because, at low power, both entities have a similar two-toned
admixture of cells displaying pink and purple staining. Pancreatic
heterotopia, however, shows zonal distribution of color confined within
an individual cell: The cytoplasm nearest the nucleus is purple, and the
opposite is pink (Figs. 1.190–1.196). Oxyntic-type mucosa, in contrast,
owes its two-toned appearance to a mixture of two distinct cell types
(chief cells are purple and parietal cells are pink).

Figure 1.190 Pancreatic heterotopia/metaplasia. Pancreatic heterotopia/metaplasia can

occasionally appear polypoid/nodular.

Figure 1.191 Pancreatic heterotopia/metaplasia (PAS/AB). Pancreatic heterotopia/metaplasia

appears a dull blue (arrows) compared to the intermixed magenta cardiac glands (arrowheads).
Figure 1.192 Pancreatic heterotopia/metaplasia (PAS/AB). Higher power of previous figure.

Figure 1.193 Pancreatic heterotopia/metaplasia.

Figure 1.194 Pancreatic heterotopia/metaplasia. Higher power of previous figure. As shown here,
pancreatic acinar cells show a zonal distribution of color with the cytoplasm nearest the nucleus
purple, and the opposite pink. Oxyntic-type mucosa, in contrast, owes its two-toned appearance
to a mixture of two distinct cell types (chief cells are purple and parietal cells are pink).

Figure 1.195 Pancreatic heterotopia/metaplasia.

 Figure 1.196 Pancreatic heterotopia/metaplasia. Higher power of previous figure. Note the
abundant eosinophilic zymogen granules, characteristic of pancreatic acinar cell differentiation.

GLYCOGENIC ACANTHOSIS

Figure 1.197 Glycogenic acanthosis. Low power shows characteristic epithelial hyperplasia with
enlargement of mid-to-superficial cells. These cells of glycogenic acanthosis have abundant
cytoplasm with a frosted-glass appearance, and they show no nuclear atypia. The basal
compartment is unaffected.

Glycogenic acanthosis is a common esophageal lesion with a reported

incidence 3% to 40% (Fig. 1.197).78–83 This benign hyperplasia of the
squamous epithelium appears endoscopically as a gray-white mucosal
plaque. The lesion is usually discrete with well-circumscribed borders,
oval to round, and slightly raised (Figs. 1.197–1.209). The distal third of
the esophagus is the most common site and lesions are usually multiple.
Biopsies are often submitted to exclude Candida infection or neoplasia;
the endoscopic appearance is indistinguishable from Candida,
leukoplakia/epidermoid metaplasia, and lichen planus/“lichenoid”
injury. Histologically, prominent cytoplasmic glycogen is seen, which
distends the squamous epithelial cells and has a pale pink, frosted-glass
texture. Typically, the basal layer is spared. PAS/D is helpful in
equivocal cases and highlights a two-toned appearance of affected cells
(Figs. 1.200 and 1.209). Glycogenic acanthosis is benign and clinical
follow-up or treatment is not necessary. Its diagnostic importance is in
providing helpful feedback to the endoscopist to account for their
abnormal clinical impression. Although rare associations with Cowden
syndrome and celiac disease have been reported, the exact etiology of
glycogenic acanthosis is not known.78,79 Some have postulated a
relationship to GERD due to the predilection for the distal esophagus.

Figure 1.198 Glycogenic acanthosis nodule in the setting of Barrett esophagus. A well-
circumscribed, raised white nodule (arrowhead) is present in the distal esophagus along with a
salmon-colored patch (arrows) that is suggestive of Barrett esophagus. Glycogenic acanthosis
typically shows multiple grey-white nodules or plaques.
Figure 1.199 Endoscopic view of glycogenic acanthosis. A discrete oval, gray-white plaque is
seen in the distal esophagus (arrows). Endoscopically, the lesion can raise concern for Candida
esophagitis.

Figure 1.200 Glycogenic acanthosis (PAS/D). A PAS/D stain from the previous case highlights
the characteristic two-toned appearance with magenta accumulating on one aspect of the cell,
the remaining cytoplasm cleared, and the basal layers uninvolved.

Figure 1.201 Glycogenic acanthosis (PAS/D). Higher power of previous. On PAS/D stain, the
two-toned appearance is easily seen. Note the magenta stain marginalized to the superficial
aspect of the cell and the remaining cytoplasm clear.
 Figure 1.202 Raised nodule of glycogenic acanthosis. This lesion appeared as a nodule
endoscopically, and was biopsied to exclude a neoplasm. The low-power view shows the
epithelial hyperplasia that imparted that raised endoscopic appearance. The affected cells contain
abundant pale cytoplasm, and the basal layer is unaffected.

Figure 1.203 Raised nodule of glycogenic acanthosis (PAS/D). A PAS/D stain highlights the two-
toned appearance of the affected cells.
 Figure 1.204 Raised nodule of glycogenic acanthosis (PAS/D). Higher power of previous. The
two-toned appearance is the result of aggregation or marginalization of glycogen particles
(magenta on PAS/D) and cytoplasmic clearing.

Figure 1.205 Focal glycogenic acanthosis. The abrupt transition between the lesion and the
uninvolved epithelium is appreciated in this image. The enlarged cells have abundant pale
cytoplasm with a frosted-glass texture.

Figure 1.206 Diffuse glycogenic acanthosis. In contrast to the previous image, this example shows
 diffusely involved epithelium. These cases can be subtle to the eye, as quick perusal might give
the impression of normal or ballooned squamous cells. The clue to diagnosis is the abundant pale
pink cytoplasm with a ground-glass or frosted-glass texture.

Figure 1.207 High power of glycogenic acanthosis cells: Higher power of previous. Unlike
ballooned squamous cells, the cells of glycogenic acanthosis show abundant pale pink cytoplasm
with a frosty appearance.

Figure 1.208 Glycogenic acanthosis with ballooned squamous cells. Epithelial hyperplasia and
sparing of the basal compartment are characteristically present, as in this low-power view of
glycogenic acanthosis. However, note that only the superficial most cells show the abundant pale
pink and frosted-glass cytoplasm of glycogenic acanthosis (ovals). The remaining cells with
cytoplasmic clearing have a hard basket weave appearance of ballooned squamous cells.
 Figure 1.209 Glycogenic acanthosis with ballooned squamous cells. Only focal areas of this
biopsy show cells affected by glycogenic acanthosis. These cells have abundant pale pink
cytoplasm with a frosted-glass appearance (far left, and superficially) with rounded cytoplasmic
borders. By comparison, the remaining cleared-out cells have dense, angulated cytoplasmic
borders and a hard basket weave pattern.

FAQ: How can glycogenic acanthosis be distinguished from a

balloon cell?
Answer: Glycogenic acanthosis shows pale pink, frosted-glass
cytoplasm in distended squamous cells, and endoscopically presents as
a nodule or plaque. A PAS/D confirms a two-tone appearance and the
basal layer is uninvolved. Balloon cells are seen in a background of
GERD-type changes and lack the above features.

SQUAMOUS PAPILLOMA
 Figure 1.210 Squamous papilloma. Squamous papillomas are characterized by bland polypoid
squamous mucosa overlying fibrovascular cores.

In the United States, squamous papillomas are rare lesions, seen in

0.07% of endoscopic material (Fig. 1.210). They are most often detected
incidentally as a solitary nodule in the distal esophagus, more commonly
in females (Fig. 1.211).84–87 Histologic sections show bland polypoid
squamous mucosa with fibrovascular cores (Figs. 1.212–1.220). The
majority of cases lack human papilloma viral cytopathic effect
(koilocytosis, binucleation, hyperchromatic nuclei). The underlying
etiology of these neoplasms is controversial. Some experts suggest
squamous papillomas arise as a reparative response to chronic reflux
disease based on their distal esophageal predominance. Others have
suggested a possible role for human papillomavirus (HPV), particularly
in the case of multiple, proximal papillomas with viral cytopathic effect.
The inconsistent findings regarding an established link between
squamous papilloma and HPV likely reflect variable population and
assay technique. In general, the isolated squamous papilloma seldom
progresses to dysplasia or carcinoma, and does not recur. Extensive
papillomatosis, however, is even more rare with only few reports in the
literature. This condition should prompt extensive sampling to exclude
an underlying malignancy. Some experts include a comment on the
presence or absence of viral cytopathic effect, dysplasia assessment, and
HPV testing; however, this practice is not required, and is not
universally adopted. A line-diagnosis “squamous papilloma” is sufficient,
and inclusion of dysplasia assessment and viral cytopathic effect is
necessary only when these features are present. HPV testing when viral
cytopathic effect is present may be of academic interest, but is not
currently a requirement. Importantly, correlation with the endoscopic
impression is often worthwhile since tangential embedding of normal
squamous mucosa can show similar features.

Figure 1.211 Squamous papilloma. Two smooth pink nodular lesions are seen just proximal to
the gastroesophageal junction.

Figure 1.212 Squamous papilloma.

Figure 1.213 Squamous papilloma. Similar to this image, the majority of papillomas do not show
viral cytopathic effect. The linkage between HPV and squamous papillomas of the esophagus
varies among different patient populations.

Figure 1.214 Squamous papilloma.

 Figure 1.215 Squamous papilloma.

Figure 1.216 Squamous papilloma. Poor embedding or tangential sections can make squamous
papillomas more difficult to recognize. This example does not show the typical papillary
architecture, but the fibrovascular cores are present. The radiating pattern is a clue to the
diagnosis of squamous papilloma.
Figure 1.217 Squamous papilloma.

Figure 1.218 Squamous papilloma.

Figure 1.219 Squamous papilloma.

 Figure 1.220 Squamous papilloma with glycogenic acanthosis.

MULTILAYERED EPITHELIUM

Figure 1.221 Multilayered epithelium. Multilayered epithelium is a commonly encountered

mimic of intestinal metaplasia. The epithelium shows a mixture of both squamoid and columnar
features.
 Figure 1.222 Multilayered epithelium (PAS/AB). A PAS/AB can be especially helpful in
distinguishing the pseudogoblet cells of multilayered epithelium from the goblet cells of Barrett
mucosa. The tinctorial properties of the mucin in multilayered mucosa (arrowheads) are a cross
between those of goblet cells (purple) and foveolar mucosa (magenta).

Multilayered epithelium bears resemblance to both squamous and

columnar mucosa with pseudogoblet cells (Figs. 1.221 and 1.222).
Multilayered epithelium can appear quite atypical with complicated
architecture and a striking resemblance to true goblet cells.
Consequently, multilayered epithelium commonly raises concern for
Barrett mucosa, or dysplasia arising in Barrett mucosa. Some experts
regard multilayered mucosa as the precursor to Barrett mucosa.88–90
Literature in this area is limited and there are no official
recommendations on the diagnosis or management of multilayered
epithelium at this time. Consequently, this finding is nondiagnostic of
Barrett mucosa and is not a required or recommended element of the
pathology report.

PEARLS & PITFALLS

A PAS/AB can be quite helpful in distinguishing multilayered
epithelium from Barrett mucosa: The tinctorial properties of the mucin
in multilayered mucosa are a cross between those of goblet cells and
foveolar epithelium (Fig. 1.222).

AMYLOID
Figure 1.223 Amyloidosis. Routine inspection of the lamina propria can lead to the recognition of
subtle amyloid deposition. The lamina propria appears slightly glassy from the deposition of
amyloid proteins. The characteristic cracking artifact is a helpful clue. A Congo red special stain
confirmed the H&E diagnosis.

Abnormal deposition of amyloid proteins can occur anywhere along the

GIT (Fig. 1.223). Deposition may occur within the lamina propria,
muscularis mucosae, or vascular walls. The material appears glassy,
amorphous, and occasionally fibrillary on routine H&E stain. The pale
eosinophilic material may blend into the background appearing similar
to collagen, but a characteristic cracking or “chatter” artifact is often
present. Always consider the possibility of amyloid!

PEARLS & PITFALLS

Amyloid is one of the easiest findings to miss because of the subtle
appearance of the deposition. In the esophagus, the diagnosis is
especially challenging because the lamina propria is rarely provided in
abundance. Routine inspection of the lamina propria, however, will
forestall overlooking amyloid deposition.

GRANULAR CELL TUMOR

 Figure 1.224 Granular cell tumor. Note the lamina propria at the far right aspects of this slide,
which appears a bit smoother and more homogenous than the typical lamina propria. At this
power, it is impossible to distinguish a granular cell tumor from amyloidosis or a sclerotic lamina
propria.

Two percent of granular cell tumors originate in the esophagus, most in

the distal esophagus (Fig. 1.224). Endoscopically, they appear as a well-
marginated, submucosal nodule. Histologically, the neoplastic cells have
abundant lightly pink, granular cytoplasm and small, pyknotic nuclei
(Figs. 1.225–1.233). The cytoplasm contains abundant lysosomes,
explaining the strong CD68 immunoreactivity despite their schwannian
differentiation (GCT are also S100 immunoreactive). The cytoplasmic
granules show retention upon periodic acid-Schiff staining with diastase
digestion (PAS/D). Some lesions are associated with
pseudoepitheliomatous hyperplasia, which can mimic invasive squamous
cell carcinoma. While esophageal granular cell tumors are typically
unifocal, benign lesions, rare reports of multicentricity and malignant
transformation exist.91,92

Figure 1.225 Granular cell tumor. Higher power of previous figure. At higher power, rare cells
with abundant eosinophilic cytoplasm and small pyknotic nuclei are seen (arrowhead). These
cells showed strong and diffuse S100 protein reactivity. The overlying squamous mucosa shows
striking pseudoepitheliomatous hyperplasia. This benign reactive epithelial change is
characterized by irregular acanthosis with downward squamous proliferation that can mimic
squamous cell carcinoma.

Figure 1.226 Granular cell tumor. Arrowheads highlight striking pseudoepitheliomatous

hyperplasia. The surrounding lamina propria is expanded by a granular cell tumor.

Figure 1.227 Granular cell tumor. Higher power of previous figure. On higher power, the cells of
the granular cell tumor show pale granular cytoplasm and mild nuclear atypia. Ultrastructural
studies have shown these cells are filled with lysosomes. The pseudoepitheliomatous hyperplasia
is seen extending downward, but the squamous cells lack prominent atypia or other features
concerning for neoplasia.
 Figure 1.228 Granular cell tumor. The pseudoepitheliomatous hyperplasia of this consultation
case had been interpreted as invasive squamous cell carcinoma based on the infiltrative
architecture of the squamous epithelium. However, examination of the underlying lamina
propria shows numerous spindled and epithelioid eosinophilic cells with abundant granular
cytoplasm. Recognition of the surrounding granular cell neoplasm was critical for arriving at the
correct diagnosis.

Figure 1.229 Granular cell tumor. Higher power of previous figure. While the infiltrative
squamous architecture is an eye-catching feature, always remember to check the underlying
lamina propria before diagnosing a squamous cell carcinoma in the esophagus.
 Figure 1.230 Granular cell tumor (S100 protein immunostain). Strong and diffuse S100 protein
nuclear and cytoplasmic reactivity is seen in the granular tumor cells.

Figure 1.231 Granular cell tumor. This low-power view shows an unencapsulated submucosal-
based mass extending upward to the epithelium and downward to the muscularis propria. The
overlying squamous epithelium shows pseudoepitheliomatous hyperplasia with small finger-like
projections downward. The finding should not be mistaken for invasive squamous cell carcinoma.
 Figure 1.232 Granular cell tumor with prominent pseudoepitheliomatous hyperplasia. Higher
power of previous figure. Irregular downward extension of squamous mucosa with mild reactive
atypia. Never forget to examine the underlying lamina propria when this pattern is seen! The
granular tumor cells in this example are slightly spindled, and should not be mistaken for lamina
propria fibroblasts. When in doubt, an S100 protein immunostain is prudent, and can be
especially helpful in small biopsies.

Figure 1.233 Granular cell tumor with prominent pseudoepitheliomatous hyperplasia. Higher
power of previous figure.

PEARLS & PITFALLS

Granular cell tumor is yet another example of an entity that can be
easily overlooked when only wisps of lamina propria are available.
 Typically, pseudoepitheliomatous hyperplasia is seen overlying the
neoplasm, and this can serve as an important clue to the diagnosis. In
addition, awareness of these benign epithelial changes is critical to
avoid overdiagnosing invasive squamous cell carcinoma.

GRANULOMATA

Figure 1.234 Lamina propria granulomata. Poorly formed granulomata are important examples
of other critical clues that can be hidden in the lamina propria.

Figure 1.235 Lamina propria granulomata. Higher power of previous case.

Poorly formed granulomata are important examples of other critical

clues that can be hidden in the lamina propria (Fig. 1.234). This subtle
finding is highly suggestive of Crohn disease and can be reliably
identified if critical inspection of the lamina propria is routine (Figs.
1.235–1.239). AFB and GMS special stains for microorganisms are
worthwhile.

Figure 1.236 Lamina propria granuloma. A poorly formed lamina propria granuloma in a patient
ultimately diagnosed with Crohn disease.

Figure 1.237 Lamina propria granuloma. Higher power of previous case. AFB and GMS special
stains were nonreactive.
 Figure 1.238 Lamina propria granulomata. Poorly formed lamina propria granulomata in a
patient with established Crohn disease.

Figure 1.239 Lamina propria granulomata. Higher power of previous case. AFB and GMS special
stains were nonreactive.

APOPTOTIC BODY PROMINENCE

Figure 1.240 Apoptotic bodies. This esophageal biopsy features numerous apoptotic bodies. Upon
chart review, the patient was a bone marrow recipient who presented with a cutaneous rash,
fever, nausea, and vomiting. The patient was not taking mycophenolate mofetil and infectious
etiologies had been excluded clinically. In this case, the prominent apoptotic bodies (arrowheads)
were a manifestation of mild GVHD (grade I).

Figure 1.241 Apoptotic bodies associated with CMV infection. CMV esophagitis can also show a
prominence of apoptotic bodies (arrowheads). In the setting of immunosuppression, a low
threshold for ordering CMV immunohistochemistry is warranted.
Figure 1.242 CMV esophagitis. The corresponding CMV immunostain was reactive. In this case,
increased apoptotic bodies was an important red flag to the underlying diagnosis of CMV
esophagitis.

One apoptotic body per tissue fragment is permissible in the normal

esophageal biopsy (Fig. 1.240). Conspicuous apoptotic bodies, however,
can be clues to crucial diagnosis, listed below (Figs. 1.241 and 1.242).
See also, GVHD, Lymphocytic pattern, this chapter.
• GVHD93
• Medication (i.e., NSAIDs, CellCept [MMF], among others)94–96
• CMV infection97
• Immunodeficiency disorders59

RING MITOSES (TAXOL AND COLCHICINE)

 Figure 1.243 Taxane effect. Ring mitoses (arrowheads) can indicate taxane effect or colchicine
toxicity; the latter is a clinical emergency requiring immediate notification of the clinician.

Figure 1.244 Taxane effect. Alternate field.

Taxanes (Taxol or paclitaxel, and Taxotere or docetaxel) are

chemotherapeutic agents used in the treatment of breast, ovarian, and
lung cancer, as well as Kaposi sarcoma (Figs. 1.243 and 1.244).98,99
Their mechanism of action involves stabilization of microtubules,
resulting in mitotic ring forms and mitotic arrest. Importantly, recent
taxane administration may cause changes that mimic high-grade
dysplasia; therefore, biopsy immediately after Taxol administration
should be avoided, if possible. In the setting of taxane administration,
these histologic changes are indicative of taxane effect (not toxicity). In
contrast, identical findings seen in the setting of colchicine usage would
indicate colchicine toxicity, requiring immediate clinician notification.99

MALIGNANCY

Figure 1.245 Metastatic lobular breast carcinoma. This case featured an ulceration with nearby
infiltration of cells with a “single file” configuration, occasional cytoplasmic vacuoles, scanty
eosinophilic cytoplasm, and a mucinous background. The indicated cells were reactive for
mammoglobulin and GCDFP-15, supporting the above diagnosis.

Certainly, complete evaluation always includes inspection for sneaky

malignancies (Fig. 1.245).

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 STOMACH 2

CHAPTER OUTLINE

The Unremarkable Stomach

Reactive Gastritis/Gastropathy Pattern
• Bile Reflux
• Medications
• Alcohol
• Portal Hypertensive Gastropathy
• Gastric Antral Vascular Ectasia
• Autoimmune Metaplastic Atrophic Gastritis
Acute Gastritis Pattern
• Medications
• Helicobacter
• Cytomegalovirus
• Focally Enhanced Gastritis
• Inflammatory Bowel Disease
Chronic Gastritis Pattern
• Autoimmune Metaplastic Atrophic Gastritis
• Environmental Metaplastic Atrophic Gastritis
• A Patterns-Based Approach to Chronic Gastritis
• Superficial Plasmacytic Infiltrate
• Basal Lymphocytic Infiltrate
• Atrophic
• Metaplasia
• Lymphoid Aggregates
Lymphocytic Gastritis Pattern
• Infections
• Immune-Mediated Disorders
• Medications
• Lymphoma
Collagenous Gastritis Pattern
• Immune-Mediated Disorders
• Collagenous Enteritis/Colitis
• Helicobacter
• Medications
Gastric Eosinophilia Pattern
• Idiopathic Eosinophilic Gastritis and Gastroenteritis
• Medications
• Allergy
• Helicobacter
• Parasites
• Inflammatory Bowel Disease
• Connective Tissue Disorders and Vasculitis
• Neoplasia
Hyperplasia Pattern
• Oxyntic Gland Hyperplasia
• Fundic Gland Polyps
• Familial Adenomatous Polyposis Syndrome
• Attenuated Familial Adenomatous Polyposis Syndrome
• MutYH-Associated Polyposis
• Sporadic Fundic Gland Polyposis Syndrome
• Zollinger–Ellison Syndrome
• Foveolar Hyperplasia
• Gastric Hyperplastic Polyp
• Gastric Juvenile Polyp
• Gastric Peutz–Jeghers Polyp
• PTEN Syndromes
• Cowden Syndrome
• Bannayan–Riley–Ruvalcaba Syndrome
• Adult Lhermitte–Duclos Disease
• Cronkhite–Canada Syndrome
• Ménétrier Disease
Granulomatous Gastritis Pattern
• Crohn Disease
• Sarcoidosis
• Infection
• Medication
• Foreign Body Reaction
• Nearby Neoplasm
• Vasculitis
• Common Variable Immunodeficiency
• Chronic Granulomatous Disease
Vascular and Hemorrhagic Changes Pattern
• Portal Hypertensive Gastropathy
• Gastric Antral Vascular Ectasia
• Amyloid
• Radiation Gastritis Pattern
Pigments and Extras
• Iron
• Gastric Pseudomelanosis
• Calcinosis
• Resins
• 90Yttrium-Labeled Microspheres
Near Misses
• Amyloidosis
• Apoptotic Body Prominence
• Poorly Differentiated Adenocarcinoma with Signet Ring Cell Features
• Russell Body Gastritis
• Mucus Neck Cells
• Sarcina
• Bezoar and other Foreign Material
• Mast Cell Disease

THE UNREMARKABLE STOMACH

The stomach is functionally a more complex organ than the rest of the
luminal gastrointestinal tract, with variable histology based on anatomic
location and physiologic function. Based purely on anatomic landmarks,
the stomach can be divided into the cardiac opening, fundus, body,
antrum, and pylorus (Fig. 2.1). To a pathologist, however, the organ is
best compartmentalized based on physiologic function of the mucosa,
which does not always correspond with anatomic landmarks. A basic
understanding of gastric mucosal physiology will aid in the diagnosis
and understanding of common gastritides.1–14

LAYERS
The layers of the stomach are structurally similar to the rest of the
luminal gastrointestinal tract and can be divided into the gastric mucosa,
submucosa, muscularis propria, and serosa (Fig. 2.2). The mucosa
consists of epithelium, lamina propria, and muscularis mucosae. The
epithelial component includes superficial pits (foveolae) that are lined
by mucus-secreting foveolar epithelium and line the entire surface of the
stomach, regardless of site. Deep to these pits are the gastric glands,
which differ in function and epithelial cell type depending on location,
and are discussed in detail later (Histology and Function, next
subsection). The lamina propria between the pits and glands contains
lymphovascular spaces and is normally nearly devoid of inflammatory
cells. The muscularis mucosae is composed of a thin layer of smooth
muscle cells, separating the mucosa from the underlying submucosa that
contains abundant lymphatic and vascular structures. The muscularis
propria of the stomach is composed of three sets of smooth muscle
fibers&emdash;longitudinal, circular, and oblique. The serosa is derived
from the peritoneum and surfaced by mesothelial cells.

FAQ: Are there lymphatic spaces in the gastric lamina propria? Is

a gastric intramucosal carcinoma capable of metastasizing to
lymph nodes?
Answer: Yes. Lymphatic channels are present in the lamina propria of
the gastric mucosa. They are found directly superficial to the
muscularis mucosae and connect to larger efferent channels in the
submucosa. Even an early gastric carcinoma without submucosal
invasion can have lymphatic metastasis, although such superficial
tumors usually do not.
 Figure 2.1 Anatomic compartments of the stomach. Although the stomach can be
compartmentalized based on anatomic landmarks, the histologic compartmentalization of the
stomach is based on physiologic function. The gastric fundus and corpus (body) are composed of
oxyntic mucosa, whereas the pyloric antrum and pylorus contain pyloric glands.

Figure 2.2 Layers of the stomach. This resection specimen illustrates the four main layers of the
stomach: mucosa, submucosa, muscularis propria, and serosa. The mucosa consists of epithelium
(E), lamina propria (L), and muscularis mucosae (MM). The submucosa sits between the
muscularis mucosae and the muscularis propria (MP). The MP consists of three muscle layers: the
inner oblique, middle circular and outer longitudinal, which function in gastric contraction and
peristalsis. The outermost layer is the serosa.

HISTOLOGY AND FUNCTION

Body/Corpus and Fundus (“Oxyntic Mucosa”)
The largest histologic compartment is the gastric body and fundus,
comprising 90% of the gastric mucosa (Fig. 2.1). They share similar
histology and function as both contain oxyntic (or fundic) glands and
have shallow pits that extend less than 25% of the distance to the base
(Fig. 2.3). The superficial isthmus contains intensely pink acid-secreting
parietal cells that also produce intrinsic factor, important for absorption
of vitamin B12 (Fig. 2.4). By comparison, the base of the glands contains
bluish-purple pepsinogen-secreting chief cells and scattered
enterochromaffin-like (ECL) endocrine cells. The intervening neck area
contains a mixture of chief, parietal, and mucus neck cells, the latter of
which are important in mucosal regeneration (Figs. 2.5 and 2.6) and
should not be mistaken for signet ring cells.

Figure 2.3 Pits and glands in oxyntic mucosa. The gastric pits are lined by foveolar epithelium, a
finding that is common throughout the gastric mucosa, independent of site. The deeper glands of
the oxyntic mucosa can be divided into (1) the superficial isthmus, composed primarily of the
bright pink parietal cells, (2) the transitional neck area, containing a mixture of parietal cells,
mucus neck cells, and chief cells, and (3) the base, composed almost entirely of the more
basophilic chief cells.
Figure 2.4 Physiology of the parietal cell. The parietal cell has a number of important functions,
including production of intrinsic factor (IF) which binds vitamin B12 (cobalamin), thus, allowing
the complex to be transported across the small bowel wall. In addition, parietal cells are
stimulated to produce acid (H+) by gastrin (produced in the antrum by the “G” cell) and
histamine (secreted predominantly in the oxyntic mucosa by ECL cells). Whereas high acid levels
inhibit gastrin secretion, conversely, hypoacidic states, such as those with parietal cell atrophy or
loss, result in uninhibited secretion of gastrin.

Figure 2.5 Neck of oxyntic glands. There are three cells types within the neck area of the oxyntic
glands. The pink parietal cells and the blue chief cells are easily discernible on routine H&E.
Harder to appreciate are the mucous neck cells (arc), which are the proliferative stem cell of the
gastric glands.
 Figure 2.6 Normal oxyntic mucosa cut in cross section. In tissue sections that are oriented
tangentially, the oxyntic glands have a mixture of pink parietal and blue chief cells arranged
around a central lumen (arrows). Note the abundant capillaries (arrowheads) at the basal aspect
of each gland, and the scant lamina propria.

Figure 2.7 Normal antral mucosa. The pits of the antrum are much deeper as compared to the
oxyntic mucosa, comprising sometimes greater than 50% of the mucosal thickness. The deeper
pyloric glands are composed of mucus secreting cells.
 Figure 2.8 Pyloric glands. The pyloric glands are composed of mucus secreting cells with
abundant clear foamy cytoplasm and basally located nuclei, which are sometimes flattened,
similar to those seen in Brunner glands and the gastric cardia.

Figure 2.9 G cells (gastrin immunostain). A gastrin immunohistochemical stain highlights a band
of G cells, which are exclusively found in the gastric antrum. Their presence can be exploited to
identify site of tissue origin.

Antrum and Pylorus (“Antral Mucosa”)

The antrum and pylorus comprise the second largest histologic
compartment, and most practitioners regard them as interchangeable, as
they are histologically similar (Fig. 2.1). The pits of the gastric antrum
comprise approximately 50% of the distance to the base of the glands
(Fig. 2.7). Abundant lamina propria separates the purely mucus-
secreting tortuous glands of the antral mucosa. These cells have
abundant frothy cytoplasm with nuclei that appear flattened against the
basal aspect (Fig. 2.8), similar to those seen in Brunner glands and
gastric cardiac glands. Importantly, gastrin-producing G cells are
exclusively found in the gastric antral glands, and they can be
highlighted with a gastrin immunohistochemical stain (Fig. 2.9).

FAQ: Why does my “antrum” biopsy frequently look like oxyntic

mucosa?
Answer: More than 90% of the gastric mucosa is oxyntic type, leaving
only the distal-most portion of the stomach as true antral-type mucosa.
It is not unusual for endoscopists to capture transition zone, or even
distal corpus when targeting the gastric antrum.

PEARLS & PITFALLS

By comparison, it would be highly unusual for the endoscopist to miss
a targeted biopsy of the body or fundus. If a specimen labeled as
“body” or “fundus” shows antral-type histology, consider one of the
following scenarios: • Atrophy of the gastric corpus, such as in
autoimmune metaplastic atrophic gastritis
• Mixed specimen or carryover
An immunohistochemical stain for gastrin can be helpful in this
scenario by highlighting the antral restricted “G” cells; biopsies from
the antrum would have a prominent band of G cells, and those from
the body/fundus are nonreactive for gastrin (Figs. 2.10–2.13). See also
Chronic Gastritis subsection, this chapter.
Figure 2.10 Gastric antrum mislabeled as gastric body. This tissue was received in a jar labeled
“stomach, body.” There is a complete lack of oxyntic glands, suggesting this tissue likely
originated from the gastric antrum.

Figure 2.11 Gastric antrum mislabeled as gastric body (gastrin immunostain). A gastrin stain of
the previous figure highlights a band of G cells, confirming the antral origin of this tissue
(oxyntic mucosa lacks G cells).
Figure 2.12 Gastric body with total oxyntic gland atrophy. This tissue fragment was received in a
jar labeled “stomach, body.” Similar to the previous case (Fig. 2.10), there is a total lack of
oxyntic glands. Note the extensive background intestinal metaplasia.

Figure 2.13 Gastric body with total oxyntic gland atrophy (gastrin immunostain). A gastrin stain
of the previous figure fails to highlight any G cells, confirming that this biopsy fragment
originated from the gastric body or fundus. The total atrophy of oxyntic glands and presence of
intestinal metaplasia raises the suspicion for autoimmune metaplastic atrophic gastritis (AMAG).
See also Chronic Gastritis, this chapter.
Figure 2.14 Transitional mucosa. The junction of the body and antrum contains a transition zone
that includes a mixture of both the clear pyloric glands of the antrum (left bracket), and the
mixed pink and blue oxyntic glands of the body (right bracket).

Figure 2.15 Gastric cardia. The gastric cardia is lined by surface foveolar epithelium and the
glands are composed of mucous-secreting cells which are histologically identical to those found
in the gastric antrum. It is not unusual to see some inflammatory cells in the lamina propria of
the gastric cardia.

Transition Zone (“Transitional Mucosa”)

Histologically, the transition between the oxyntic and antral mucosa is
gradual, spanning 1 to 2 centimeters. The histology shows mixed glands
in varying proportions (Fig. 2.14).
Cardia
The smallest gastric compartment, the gastric cardia, is composed of
mucus-secreting cells and is devoid of acid-secreting chief cells and
parietal cells. Histologically, the surface epithelium is lined by foveolar
cells and the pits and glands are composed of pyloric-type glandular
epithelium. In the absence of a biopsy location provided by the
endoscopist, the histology is nearly indistinguishable from that of the
gastric antrum (Fig. 2.15).

FAQ: Why do my gastric cardia biopsies frequently contain

oxyntic mucosa?
Answer: The length of cardiac mucosa is variable. The cardia typically
spans only 1 to 4 mm in most adults. It was originally believed that
the gastric cardia developed as people aged; however, autopsy studies
have disproven this idea, as some infants have cardiac glands and
some elderly persons have none, transitioning directly from squamous
mucosa to acid-secreting mucosa (Fig. 2.16). Although controversial,
the presence of gastric cardiac-type mucosa has also been regarded by
some as a purely metaplastic condition secondary to gastroesophageal
reflux, Helicobacter infection, and autoimmune gastritis.

PEARLS & PITFALLS

Chronic inflammation is so ubiquitous a finding in the gastric cardia
that many practitioners do not mention this finding in their reports;
however, the gastric cardiac mucosa may harbor Helicobacter
organisms (Fig. 2.17). It is prudent to examine closely or perform
staining for Helicobacter organisms in the following scenarios: • If the
pattern of the infiltrate is characteristic of Helicobacter infection;
specifically active chronic inflammation, superficial
lymphoplasmacytic inflammation, and or prominent lymphoid
aggregates with well-formed germinal centers, or • If the inflammation
is exuberant and no additional gastric biopsies were obtained from the
gastric antrum and body. In this scenario, careful examination of the
cardia might be the only opportunity to diagnose an underlying
Helicobacter infection.
Figure 2.16 Minimal gastric cardia. Seen here is the gastroesophageal junction, with squamous
epithelium on the far left, gastric cardiac mucosa composed of a few clear pyloric-like glands
(arrow) and an immediate transition into the mixed pink and blue oxyntic glands (arrowhead) of
the fundus. The cardia differs from the antrum in lacking G cells.

Figure 2.17 Helicobacter pylori carditis. This biopsy of the gastric cardia was performed in
evaluation of Barrett esophagus. Although the gastric cardia may have some mild chronic
inflammation, the presence of a lymphoid aggregate, expanded lamina propria, and superficial
infiltrate should prompt a careful search for Helicobacter organisms. Indeed, Helicobacter
organisms were identified on H&E (not shown).

REACTIVE GASTRITIS/GASTROPATHY PATTERN

 Figure 2.18 Reactive gastritis/gastropathy pattern. Reactive gastritis/gastropathy is another
example of an entity that is best appreciated at scanning magnification. At low power, the
surface epithelium appears dark because of the mucin loss, and it is easy to appreciate the
corkscrew-like appearance of the gastric pits (arrowheads). As true for most cases of reactive
gastritis/gastropathy, the background inflammation is minimal.

Figure 2.19 Reactive gastritis/gastropathy pattern. On higher power, the mucin loss is apparent:
the surface foveolar epithelium has tiny apical caps of mucin, instead of the normal tall mucin-
rich cytoplasm seen in normal apical epithelium. At this power, it is also easy to appreciate the
smooth muscle bundles (arrows) between the corkscrew-like gastric pits (arrowheads) which
extend toward the surface.

CHECKLIST: Etiologic Considerations for the Reactive

Gastritis/Gastropathy Pattern
 Bile Reflux
Medications
Alcohol
Portal Hypertensive Gastropathy
Gastric Antral Vascular Ectasia
Autoimmune Metaplastic Atrophic Gastritis

Reactive gastritis/gastropathy constitutes the most common gastric

injury pattern (Figs. 2.18 and 2.19). In a recent study of over 500,000
gastric specimens, reactive gastritis/gastropathy was reported in up to
15.6% of cases.15 There is no geographic predilection, and its incidence
increases with patient age, seen in only 2% of patients under 10 years
and in greater than 20% of patients over 80 years.15 Histologically, this
injury pattern refers to foveolar mucin cell depletion, a corkscrew-like
appearance of the gastric pits, lamina propria edema, smooth muscle
fibers extending between the pits and toward the surface, and little to no
inflammation (Figs. 2.20–2.23).
Reactive gastritis/gastropathy is another example of a nonspecific
injury pattern. In the majority of cases, no precise etiology can be
established.16 Of those with identifiable causes, bile reflux, medications
(e.g., NSAIDs), alcohol, portal hypertensive gastropathy, gastric antral
vascular ectasia, and autoimmune metaplastic atrophic gastritis have
been implicated.15,17–22 Although the etiologic possibilities are broad,
the previously mentioned etiologies are thought to induce a chemical-
type damage, which result in this characteristic gastric injury pattern.
Reactive gastritis is most commonly seen in the gastric antrum,
supporting the theory that bile reflux is an important contributing factor.
In severe cases, this injury pattern can extend into the oxyntic mucosa,
sometimes even involving the cardiac mucosa. These cases must be
diligently inspected for dysplasia, intestinal metaplasia, and neoplasia
because chronic mucosal injury of any sort can increase a patient’s risk
of neoplasia. Specimens should be carefully inspected for congested
mucosal vessels (which can be seen with portal hypertensive
gastropathy) and thrombosed mucosal vessels, which would suggest a
diagnosis of gastric antral vascular ectasia (GAVE), in the appropriate
clinical setting. See also Vascular and Hemorrhagic Injury pattern in this
chapter.

Figure 2.20 Reactive gastritis/gastropathy pattern. Again, the key features of reactive
gastritis/gastropathy “jump off the slide” at scanning magnification: gastric surface foveolar
mucin cell depletion, a corkscrew-like appearance of the gastric pits, lamina propria edema,
smooth muscle bundles splaying foveolar epithelium, and little to no inflammation. If you have
to go to 40× to appreciate the key features of reactive gastritis/gastropathy, it is not reactive
gastritis/gastropathy! These features should be apparent at scanning magnification.

Figure 2.21 Reactive gastritis/gastropathy pattern. This case manifests all the key features of
reactive gastritis/gastropathy: surface foveolar mucin cell depletion, a corkscrew-like appearance
of the gastric pits, lamina propria edema, smooth muscle bundles extending to toward the
surface, and little to no inflammation.
 Figure 2.22 Reactive gastritis/gastropathy pattern. This case is a bit more subtle than the
previous cases (Figs. 2.18–2.21) since the gastric foveolar epithelium is not quite as dark or
corkscrew-like and lamina propria edema is not seen. Instead, this case features prominent
smooth muscle hypertrophy (arrowheads) as it splays and envelopes the involved gastric pits.
Gastric foveolar mucin cell depletion and a smattering of chronic inflammation are seen.

Figure 2.23 Reactive gastritis/gastropathy pattern with occasional congested vessels. This case
illustrates that congested vessels are occasionally seen in the reactive gastritis/gastropathy
pattern (arrowheads). In this case, a quick chart review was helpful to assess for a history of
portal hypertension (as would be expected if these congested vessels were a part of portal
hypertensive gastropathy) or if a striped watermelon endoscopic appearance was seen (to suggest
a diagnosis of gastric antral vascular ectasia). A chart review was noncontributory in this case.

Despite its relatively high prevalence, the terminology surrounding

reactive gastritis/gastropathy is a bit contentious. Equivalent terms
include “chemical gastritis,” and “chemical gastropathy.” In 1996, a
diverse group of gastrointestinal pathology experts convened to discuss
key issues related to the classification and grading of gastritis,
culminating in the updated Sydney system recommendations.16 Some
preferred “chemical” since it more explicitly states the mechanism of
injury; some advocated for “gastropathy” instead of “gastritis” since
most cases lack clinically significant inflammation to warrant a
“gastritis” designation. This nomenclature controversy is trivial and only
important in so far as the reader knows that these terms all refer to the
same injury pattern.

KEY FEATURES of the Reactive Gastritis/Gastropathy Pattern:

• Reactive gastritis/gastropathy is the most common gastric injury
pattern.
• Morphologic features include gastric surface foveolar mucin cell
depletion, a corkscrew-like appearance of the gastric pits, lamina
propria edema, smooth muscle bundles extending toward the surface,
and little to no inflammation.
• Implicated etiologies include bile reflux, medications (NSAIDs, e.g.,),
alcohol, portal hypertensive gastropathy, gastric antral vascular
ectasia, and autoimmune metaplastic atrophic gastritis.

PITFALLS & PEARLS

Reactive gastritis/gastropathy pattern can “jump off the slides” and be
so eye-catching that it is easy to overlook other important diagnoses.
Remember to look at every biopsy for the following sneaky entities,
which can be easily obscured by a marked reactive
gastritis/gastropathy pattern.

CHECKLIST: Select Diagnoses Not To Miss

Erosion (Figs. 2.24 and 2.25)
 Ulceration (Fig. 2.26)
Iron Pill Gastritis (Figs. 2.27 and 2.28)
Intestinal Metaplasia
Portal Hypertensive Gastropathy (Fig. 2.29)
Gastric Antral Vascular Ectasia (Fig. 2.30)
Dysplasia
Sneaky Malignant Neoplasms (including Signet Ring and
Neuroendocrine Tumors)
Autoimmune Metaplastic Atrophic Gastritis
Granulomata
Amyloid
Lymphocytic Gastritis Pattern

Figure 2.24 Reactive gastritis/gastropathy pattern and erosion. Erosions (blue bracket) are
denudations limited to the mucosa and are often accompanied by fibrino-inflammatory debris.
The fibrin deposition is “biologic proof” that true tissue damage has occurred prior to the biopsy,
that is this is not a histologic artifact of tissue mishandling. The mucosa consists of the E,
epithelium; L, lamina propria; MM, muscularis mucosae.
 Figure 2.25 Reactive gastritis/gastropathy pattern with erosion. This example of reactive
gastritis/gastropathy features an erosion with focal fibrin deposition (arrowhead).

Figure 2.26 Reactive gastritis/gastropathy pattern and ulceration. In contrast to erosions which
are confined to the mucosa, ulcerations extend through and beyond the muscularis mucosae and
involve at least the submucosa (red bracket). The mucosa consists of the E, epithelium; L, lamina
propria; MM, muscularis mucosae and the submucosa is between the muscularis mucosae and the
muscularis propria.
Figure 2.27 Reactive gastritis/gastropathy pattern, iron deposition. Reactive gastritis/gastropathy
is a nonspecific injury pattern, that can be caused by a variety of unrelated entities. Careful
scrutiny of the background can occasionally uncover clues to the etiologic injury, such as iron
deposition in this case.

Figure 2.28 Reactive gastritis/gastropathy pattern, iron deposition (Prussian blue). A Prussian
blue iron stain highlights the iron deposition.
 Figure 2.29 Reactive gastritis/gastropathy pattern, portal hypertensive gastropathy. This case
shows the usual features of reactive gastritis/gastropathy in addition to a prominence of
congested mucosal vessels. A careful chart review uncovered the red flags of cirrhosis, portal
hypertension, and endoscopic abnormalities suggestive of portal hypertensive gastropathy. These
features support the clinicopathologic diagnosis of portal hypertensive gastropathy.

Figure 2.30 Reactive gastritis/gastropathy pattern, gastric antral vascular ectasia. Reactive
gastritis/gastropathy can be an important clue to the diagnosis of gastric antral vascular ectasia.
Other diagnostic features include mucosa thrombi (arrowhead) and an endoscopic image showing
a striped-watermelon-like pattern.

FAQ: What is the preferred terminology for cases of reactive

gastritis/gastropathy with prominent acute and chronic
inflammation (Figs. 2.31 and 2.32)?
Answer: Historically, only minimal chronic inflammation was typical
of reactive gastritis/gastropathy; however, an occasional case will
feature slightly more acute and chronic inflammation. If the
predominant pattern is reactive gastritis/gastropathy, the preferred
terminology is “active chronic reactive gastritis/gastropathy.” The
alternative wording, “reactive gastritis/gastropathy with acute and
chronic inflammation” is often translated by clinicians as “Helicobacter
infection.” Certainly, a Helicobacter special stain can be easily
performed, although it is almost always negative owing to the
microenvironment shifts common to this injury pattern.

Figure 2.31 Active chronic reactive gastritis/gastropathy. In exceptionally striking examples of

reactive gastritis/gastropathy, sometimes a prominence of acute and chronic inflammation is
seen, as in this case.
 Figure 2.32 Active chronic reactive gastritis/gastropathy. The acute inflammation is best
appreciated on higher power (arrowheads). The prominent pattern is reactive
gastritis/gastropathy with a minimal amount of acute and chronic inflammation.

ACUTE GASTRITIS PATTERN

Figure 2.33 Acute gastritis example. An acute gastritis pattern refers to neutrophils in the gastric
epithelium of the stomach (arrows). Acute gastritis pattern is an etiologically nonspecific pattern.
This case features a single epithelial cell with nuclear and cytomegaly and smudged chromatin
(arrowhead). A confirmatory CMV immunostain was reactive (not shown).

An acute gastritis pattern refers to neutrophils in the epithelium of the

stomach (Fig. 2.33). This pattern can be accompanied by erosions,
ulcerations, and marked reactive epithelial change. Although this injury
pattern is etiologically nonspecific, it is most commonly seen in the
setting of medication injury, infections (Helicobacter and CMV), and
inflammatory bowel disease. This injury pattern can also be seen with
iatrogenic injury (gastrotomy tube, postsurgical setting,
chemoradiation), alcohol, and in association with polyps and infiltrating
processes such as amyloidosis and neoplasms. This section will discuss
the most common etiologies of the acute gastritis pattern and will
present practical tips to sort out the individual etiologies.

CHECKLIST: Etiologic Considerations for the Acute

Gastritis Pattern
Medications
Helicobacter
Cytomegalovirus
Focally Enhanced Gastritis
Inflammatory Bowel Disease

MEDICATIONS
Medication related gastritis is increasingly common as the population
ages and our pharmaceutical repertoire expands. The resultant injury
pattern is entirely nonspecific and can include a range of pathology,
including the reactive gastritis/gastropathy, prominent apoptotic bodies,
chronic gastritis with or without acute inflammation, mildly prominent
eosinophils, intraepithelial lymphocytosis, granulomata, erosions,
ulceration, and vascular degeneration with microthrombi and ischemic
damage.23–27 In only a small percentage of cases will the medication be
identified. The far more typical scenario is identification of a nonspecific
injury pattern, although occasionally refractile or polarizable pill
fragments of unclear significance can be seen (Figs. 2.34–2.36). The
mechanism of injury may be related to the mechanical damage of the
pill as it is “stuck” in the mucosa and causes local physical trauma, or
through the resultant downstream chemical effects of the pill itself.
Certainly, the most notorious medication culprits include the
nonsteroidal anti-inflammatory drugs (NSAIDs) by way of their
nonselective inhibition of the cyclooxygenase isoenzymes, resulting in
decreased production of mucosal protectant products, such as
prostaglandins, mucin, bicarbonate, and dampened microcirculation.28
More recently gastric (and esophageal) mucosal injuries secondary to
doxycycline have been described.25–27 Characteristic presentations
include severe chest pain shortly after tablet ingestion that is postulated
to be related to underlying nerve or vascular ischemia. Endoscopic
abnormalities include erosions, ulcerations, friability, and
circumferential white “coated”, “hard-to-peel-off” lesions.27 Typical
histologic findings include erosions, ulcerations, necrosis, reactive
gastritis/gastropathy, and vasculitis with microthrombi. Some advocate
referring to these constellation of findings as “toxic-ischemic pattern”
(TIP)26 and others advocate the term perivascular “halos” or
perivascular zones of edema, reactive myofibroblasts, and
lymphoblasts.25 Other medications associated with acute gastritis
include potassium chloride in heart failure patients, bisphosphonates in
patients with pathologic bone reabsorption, iron, resins, and a variety of
chemoradiation therapeutic agents. See also Pigments and Extras
subsection, this chapter.

Figure 2.34 Nonspecific pill fragments. Pill fragments not otherwise specified can be easy to miss
on H&E because of their transparent appearance (arrowheads).

Figure 2.35 Nonspecific pill fragments. When the substage condenser is flipped, the outline of the
 pill fragments is often better appreciated (arrowheads) due to increased light refraction.
Occasionally, pill fragments are refractile.

Figure 2.36 Nonspecific pill fragments (PAS). Often, these pill fragments are bright pink on PAS
staining, which sometimes raises concern for swallowed parasitic ova; however, parasitic ova are
exceptionally uncommon, if not reportable. Moreover, parasitic ova are expected to be more
uniform is size and shape, associated with a tissue reaction, and seen in the clinical setting of
pertinent clinical symptoms.

CHECKLIST: Select Medications Commonly Associated with

the Acute Gastritis Pattern:
Nonsteroidal Anti-Inflammatory Drugs
Doxycycline
Potassium Chloride
Bisphosphonates
Iron
Resins
Various Chemoradiation Therapeutic Agents

HELICOBACTER PYLORI
Helicobacter pylori is a gram-negative helical or curved bacillus known to
colonize more than half of the human population,29 and is found in up to
20% of gastric biopsies in North America.30 Fecal–oral contamination is
the major mode of transmission, although the organisms have also been
cultivated from vomitus and saliva.29,31–34 Dyspepsia is the most
common presenting symptom and endoscopic abnormalities can include
gastric and or peptic ulcerations. Recognition of the organism is
important for symptom resolution and to prevent infection related
neoplasia, such as gastric mucosa-associated lymphoid tissue (MALT)
lymphoma, glandular dysplasia, and adenocarcinoma.35–37 In addition,
Helicobacter pylori infections have been associated with iron deficiency
anemia, idiopathic thrombocytic purpura, and have an inverse
relationship with asthma, allergy, atopic disease, and gastroesophageal
reflux disease.32
In classic examples of Helicobacter pylori gastritis, the diagnosis can
almost be made at scanning magnification owing to its characteristic
histologic findings: a superficial lymphoplasmacytic inflammation that
often appears band-like and snug beneath the surface foveolar
epithelium, brisk acute inflammation, and prominent lymphoid
aggregates (Figs. 2.37–2.39). Occasionally, a lymphocytic gastritis
pattern can also be seen (Figs. 2.40–2.42).38,39 See Lymphocytic Gastritis
Pattern in this chapter. The Helicobacter pylori organisms can be easily
spotted on H&E without the use of ancillary stains.30 Efficient “bug
hunts” target mucin-rich foci near the surface, particularly those that are
acutely inflamed (Figs. 2.43–2.45). Characteristically, the organisms
appear as curved rods (Figs. 2.46 and 2.47). Occasionally, normal oral
and gastrointestinal flora can raise concerns for Helicobacter. Important
points of distinction from oral and gastrointestinal flora include the
following:

Figure 2.37 Acute gastritis pattern, Helicobacter pylori. This prototypic example of Helicobacter
pylori gastritis shows prominent lymphoid aggregates with a germinal center and a superficial
lymphoplasmacytosis that appears band-like and snug beneath the surface foveolar epithelium
(bracket). These characteristic features are highly suggestive of Helicobacter gastritis at scanning
magnification. Helicobacter pylori was identified on higher-power (not shown).

Figure 2.38 Acute gastritis pattern, Helicobacter pylori. This example shows features highly
suggestive of Helicobacter gastritis at scanning magnification: prominent lymphoid aggregates
and a band-like superficial lymphoplasmacytosis (bracket) are seen.

Figure 2.39 Acute gastritis pattern, Helicobacter pylori. On high power, a superficial
lymphoplasmacytosis is seen along with scattered pockets of acutely inflamed pits (arrowheads).
This histologic appearance is highly suggestive of Helicobacter, requiring a thorough “bug hunt”
for the organism. Helicobacter pylori were identified on higher-power (not shown).
Figure 2.40 Lymphocytic gastritis pattern, Helicobacter pylori. A lymphocytic gastritis pattern can
be an important red flag to the diagnosis of Helicobacter gastritis, as seen in this case. This case
also features the usual characteristics of Helicobacter, namely a band-like superficial
lymphoplasmacytosis and scattered pockets of acute inflammation (arrowheads). Intestinal
metaplasia is seen at the far right (arrow).

Figure 2.41 Lymphocytic gastritis pattern, Helicobacter pylori. On higher power, the
intraepithelial lymphocytosis is easily appreciated. Also seen are the superficial
lymphoplasmacytosis and pockets of acute inflammation (arrowheads) characteristic of
Helicobacter. Helicobacter pylori was identified on higher-power (not shown).
Figure 2.42 Lymphocytic gastritis pattern, Helicobacter pylori. This case originated from a patient
with Celiac disease. A Helicobacter immunostain was negative.

1. Location: Helicobacter pylori prefer close association with the surface

epithelium, unlike the normal oral and gastrointestinal flora, which
are found farther from the surface epithelium and often admixed
with luminal debris (Fig. 2.44 vs. Fig. 2.48). It is worthwhile to note
that occasionally the Helicobacter organisms can be found in gastric
pits and glands, a finding not typical of oral and gastrointestinal flora
(Figs. 2.49 and 2.50).40

Figure 2.43 Acute gastritis pattern, Helicobacter pylori. Unfortunately, most of the time the
diagnosis of Helicobacter requires usage of the dreaded 40× objective. Thankfully, only one
organism is needed for the diagnosis, and efficient “bug hunts” can speed the diagnostic process
by targeting acutely inflamed tissue fragments, particularly those cases that feature superficial,
 mucin-rich foci, as seen here (arrowheads). Characteristically, the bacilli are helical, slightly
curved, or cinched in the midpoint.

Figure 2.44 Acute gastritis pattern, Helicobacter pylori. Note the close association of the
Helicobacter pylori organisms to the foveolar epithelium (arrowheads) and their position within
the gastric pit (arrow); these are important points of distinction from the normal gastrointestinal
tract and oral flora to be discussed below.

Figure 2.45 Acute gastritis pattern, Helicobacter pylori (arrowheads).

Figure 2.46 Acute gastritis pattern, Helicobacter pylori (Warthin-Starry). The organisms appear a
bit plumper on a Warthin-Starry since this process coats the organism with the silver compound.

Figure 2.47 Acute gastritis pattern, Helicobacter pylori (Diff–Quik). A Diff–Quik special stain can
highlight the organisms (arrowheads).
Figure 2.48 Gastrointestinal tract and oral bacteria. Unlike H. pylori, the gastrointestinal tract and
oral bacteria are not found in intimate association with the surface epithelium, and, instead, are
more commonly found amidst luminal debris and mixed bacterial flora with rods and cocci, as
seen here (arrowheads). Compare with Figure 2.44.

Figure 2.49 Acute gastritis pattern, Helicobacter pylori. Unlike the gastrointestinal tract and oral
bacteria, Helicobacter pylori can be found within the gastric pits (arrowheads).

Figure 2.50 Acute gastritis pattern, Helicobacter pylori (Diff–Quik).

2. Associated bacteria: Helicobacter pylori clusters have nearly identical

similarly shaped organisms, whereas the normal oral and
gastrointestinal flora are found as mixed flora composed of a mixed
population of rods and cocci (Figs. 2.43–2.45 vs. Fig. 2.48).
3. Background: Lastly, Helicobacter pylori is almost always found
suspended within a background of active chronic inflammation, as
outlined earlier. In contrast, the normal oral and gastrointestinal
flora show no consistent relationship with mucosal injury since they
are swallowed, endogenous flora. In challenging cases, the
Helicobacter pylori immunostain can be helpful.
In general, Helicobacter organisms and their related pathology are most
easily seen in the antrum; however, in cases of intestinal metaplasia or
marked reactive gastritis/gastropathy involving the antrum, the resultant
microenvironment changes are thought to cause the organisms to shift to
the oxyntic mucosa or even cardia, underscoring the importance of
looking at every stomach biopsy carefully for Helicobacter.
Unfortunately, sometimes the Helicobacter organisms can be difficult to
find, especially in treated cases that usually show small, rounded, and
rare organisms (Figs. 2.51 and 2.52). In such cases, the Helicobacter
immunostain is recommended.30

Figure 2.51 Acute gastritis pattern, partially treated Helicobacter pylori (Helicobacter pylori
immunostain). In partially treated cases, the organisms can be exceedingly difficult to find
because of their altered morphology. In this case, the organisms appear small and rounded,
requiring the aid of the Helicobacter pylori immunohistochemical stain for confirmation.
 Figure 2.52 Acute gastritis pattern, partially treated Helicobacter pylori (Helicobacter pylori
immunostain). Note the coccoid morphology, which results from partial treatment effect. These
organisms are usually rare and almost impossible to detect on H&E alone.

PEARLS & PITFALLS

Highlights from the 2013 Rodger C. Haggitt Gastrointestinal
Pathology Society Recommendations for the Appropriate Use of
Special Stains for Helicobacter Detection:30
• The Helicobacter immunostain is the recommended stain of choice
based on its superior sensitivity in comparison to histologic stains,
and its enhanced ability to detect Helicobacter with treatment effect
(coccoid forms) and rare organisms present deep in the glands or
intracellular locations • Indications for the Helicobacter immunostain
include the following, assuming no Helicobacter organisms are seen
on H&E:
• Inflamed gastric biopsies, including cardiac mucosa and cases of
reactive gastritis/gastropathy, although the yield is low (less than
10%) in the absence of moderate-marked acute and chronic
inflammation • Lymphocytic gastritis pattern
• Chronic inactive gastritis with concomitant positive Helicobacter
serologies, gastroduodenal ulcers, gastric MALT-type lymphoma or
adenocarcinoma, duodenal lymphocytosis, prior Helicobacter
infection, and or high-risk demographics • Inflamed or ulcerated
 duodenal biopsies with gastric foveolar metaplasia
• Contraindications to Helicobacter immunostains include the
following:
• Cases with Helicobacter organisms present on H&E
• Background normal mucosa
• Reactive gastritis/gastropathy lacking inflammation
• Uninflamed gastric polyps
• A clinical request to “rule-out” Helicobacter; thorough histologic
examination of the H&E slide is up to 95% sensitive for
Helicobacter detection, particularly if greater than five high-power
fields (HPFs) are examined • The society argues against “up-front”
Helicobacter immunostains on all esophageal, gastric, and small
bowel biopsies, citing insufficient evidence for reduced turnaround
time • No current recommendations were provided for
granulomatous gastritis and eosinophilic gastritis

PEARLS & PITFALLS

A lymphocytic gastritis pattern refers to an intraepithelial
lymphocytosis that is most easily seen in the superficial foveolar
epithelium (Figs. 2.40–2.42). Helicobacter infections and celiac disease
are the most common association with this injury pattern.38,39 If
Helicobacter is not identified on H&E, a Helicobacter immunostain is
recommended.30 Biopsy material negative for Helicobacter should be
accompanied by recommendations to exclude Helicobacter with
pertinent clinical studies, such as serology, urease breath test, or stool
antigen studies. Similarly, celiac disease should be considered when
examining any tandem small bowel specimens. If a small bowel
specimen is not provided, it is worthwhile to recommend exclusion of
celiac disease with pertinent clinical serologies. See also Lymphocytic
Gastritis Pattern in this chapter.
PEARLS & PITFALLS
One of the most challenging aspects of pathology is recognizing that a
single biopsy can have more than one important diagnosis; for
example, Helicobacter gastritis can have such striking histologic
findings that other key diagnoses can be easily overlooked. Routine
consideration of these select diagnoses will avoid such missteps.

CHECKLIST: Select Diagnoses Not To Miss on Busy

Helicobacter Gastritis Cases:
Granulomata
Amyloid
Lymphocytic Gastritis Pattern
Intestinal Metaplasia
Glandular Dysplasia
Mucosa-Associated Lymphoid Tissue Lymphoma
Infiltrating Adenocarcinoma and Sneaky Signet-Ring Cells

FAQ: What is the best way to approach cases with morphologic

features strongly suggestive of Helicobacter infection but in which
no organisms are found?
Answer: In challenging cases, a recommendation to clinically exclude
Helicobacter with pertinent clinical studies may be prudent (serology,
urease breath test, or stool antigen studies). Helicobacter cases can be
among the most satisfying because they provide an etiology for the
histologic findings and clinical symptoms, and effective treatment can
result in symptomatic relief and decreased incidence of gastric MALT
lymphoma, glandular dysplasia, and adenocarcinoma. What could be
better?! On the other hand, cases with morphology provocative for
Helicobacter and no obvious organisms are among the most frustrating
because an unrecognized infection can lead to persistent symptoms
 and increased risk for gastric MALT lymphoma, glandular dysplasia,
and adenocarcinoma. What could be worse?! These cases are
unavoidably time-consuming and require diligent inspection of
multiple HPFs as well as usage of the Helicobacter pylori immunostain.
When the classic features of Helicobacter are seen but the organisms
are not apparent with the Helicobacter immunostain, a standard note
to encourage additional clinical studies is of use. Note, this approach
should not be applied to every “juicy” case of chronic gastritis, else it
would be overused and its value would be lost. This note is
recommended for cases with a minimum of brisk acute and chronic
gastritis and superficial lymphoplasmacytic inflammation, with or
without prominent lymphoid aggregates and lymphocytic gastritis
pattern.

Sample Note: Active Chronic Gastritis Suspicious for

Helicobacter
Stomach, Biopsy:
• Antral mucosa with marked active chronic gastritis and superficial
lymphoplasmacytosis.
Note: The biopsy shows marked active chronic gastritis with superficial
lymphoplasmacytic inflammation. These features are very suspicious for
a Helicobacter infection. Although no organisms were identified on the
Helicobacter immunostain, clinical exclusion of a Helicobacter infection is
recommended with pertinent clinical studies (serology, urease breath
test, or stool antigen studies).

HELICOBACTER HEILMANNII
Not every Helicobacter gastritis case is caused by Helicobacter pylori. To
date, phylogenetic studies have identified more than 50 species within
the Helicobacter genus. The most familiar of these is Helicobacter
heilmannii which itself refers to at least five different species, leading
some experts to advocate for the more precise nomenclature of
“Helicobacter heilmannii-like organisms”. Unfortunately, much less is
known about Helicobacter heilmannii-like infections owing to their rarity.
The available literature has shown important similarities with
Helicobacter pylori, including shared symptomatology (abdominal pain,
nausea, and vomiting), antral predominant active chronic inflammation
with prominent lymphoid aggregates (Figs. 2.53–2.56), gastric and
duodenal ulcerations, and suggest an increased risk for gastric MALT
lymphoma and adenocarcinoma, underscoring their biologic
importance.41–44 Limited anecdotal evidence has shown Helicobacter
heilmannii–like infections respond to the same treatment regime as
Helicobacter pylori infections. Important points of distinction of
Helicobacter heilmannii–like infections from Helicobacter pylori include the
following:

Figure 2.53 Acute gastritis pattern, Helicobacter heilmannii. At low power, Helicobacter heilmannii
and Helicobacter pylori gastritis look similar with antral predominant active chronic inflammation
and prominent lymphoid aggregates. Helicobacter heilmannii was identified on higher power (not
shown). Compare with Figure 2.37.
Figure 2.54 Acute gastritis pattern, Helicobacter heilmannii. This example originates from a 2-year-
old boy, emphasizing that Helicobacter heilmannii is more common in children. This example
features prominent superficial and deep lymphoid aggregates. Helicobacter heilmannii was
identified on higher-power (not shown).

Figure 2.55 Acute gastritis pattern, Helicobacter heilmannii. In this example, the lymphoid
aggregates are not quite as prominent, but nevertheless they are red flags to the underlying
diagnosis. Helicobacter heilmannii was identified on higher power (not shown).

Figure 2.56 Acute gastritis pattern, Helicobacter heilmannii. This biopsy originated from a 1-year-
old boy with food avoidance. The chronic inflammation was a useful red flag to the underlying
Helicobacter heilmannii infection. This example also features atrophy (the normal back to back
gastric gland architecture is absent). After treatment, the clinical symptoms resolved and the
gastric mucosa reverted to normal.

1. Helicobacter heilmannii infections are relatively rare. In a study of

5,985 consecutive gastric biopsies in Korea, Helicobacter pylori was
identified in 54.9% (n = 3,285) compared to only 0.17% (n = 10)
cases of Helicobacter heilmannii.43
2. The mode of transmission for Helicobacter heilmannii is through direct
contact with animals, particularly dogs, cats, rabbits, primates, cattle,
and swine.
3. Children constitute the most common demographic.
4. The background mucosa shows less acute inflammation than for
Helicobacter pylori (Figs. 2.57–2.59).
5. The organisms are elongated and spiraled, less numerous, and not
typically adherent to the foveolar epithelium (Figs. 2.60–2.63).

Figure 2.57 Acute gastritis pattern, Helicobacter heilmannii. Typically, Helicobacter heilmannii
gastritis feature less acute inflammation than Helicobacter pylori gastritis.

Figure 2.58 Acute gastritis pattern, Helicobacter heilmannii. Again, note the characteristic chronic
inflammation prominence with minimal acute inflammation in this case of Helicobacter heilmannii
gastritis. Helicobacter heilmannii was identified on higher power.

Figure 2.59 Acute gastritis pattern, Helicobacter heilmannii. This typical example of Helicobacter
heilmannii gastritis involves transitional mucosa. A prominent lymphoid aggregate and brisk
chronic inflammation is seen and acute inflammation is minimal. Helicobacter heilmannii was
identified on higher power (not shown).

Figure 2.60 Acute gastritis pattern, Helicobacter heilmannii. In contrast to Helicobacter pylori,
Helicobacter heilmannii organisms are more elongated, slender, and spiraled. As seen in this
figure, Helicobacter heilmannii organisms are not typically adherent to the foveolar epithelium,
unlike Helicobacter pylori. Compare to Figure 2.44.
Figure 2.61 Acute gastritis pattern, Helicobacter heilmannii (Diff–Quik). This exceptional example
features numerous long, slender, and spiraled organisms diagnostic of Helicobacter heilmannii. In
most cases, the organisms are far less numerous.

Figure 2.62 Acute gastritis pattern, Helicobacter heilmannii (Diff–Quik). This example is far more
typical of Helicobacter heilmannii. Only occasional rare forms are seen in an isolated gastric gland
(arrowhead). This diagnosis would have been nearly impossible without the Diff–Quik stain.
 Figure 2.63 Acute gastritis pattern, Helicobacter heilmannii (Diff–Quik). In this spectacular
example, note how the organisms almost stream over the foveolar surface. Their elongated,
slender, spiraled forms are easily seen.

FAQ: Can the Helicobacter pylori immunostain detect Helicobacter

heilmannii?
Answer: Yes.
Conveniently, the Helicobacter pylori immunostain cross reacts with the
antigens of Helicobacter heilmannii, and is the preferred method of
detecting organisms not apparent on H&E.30,45 In contrast, the Diff–
Quik and Warthin–Starry special stains are special stains that
nonspecifically highlight all bacteria including Helicobacter pylori,
Helicobacter heilmannii, and the normal oral and gastrointestinal flora.
As a result, these nonspecific special stains can highlight bacteria, in
general, but the diagnosis of Helicobacter gastritis relies on familiarity
with the characteristic shape and distribution.

CYTOMEGALOVIRUS INFECTION
Endoscopic images of cytomegalovirus infection (CMV) are variable and
can include normal, erythema, erosions, or ulcerations (Fig. 2.64).46
Similar to that seen with CMV infections of other sites, the characteristic
inflammatory backdrop shows a prominence of mononuclear cells
(lymphocytes, macrophages, lymphocytes, and plasma cells), increased
apoptotic bodies, erosions, ulcers, and acute inflammation (Figs. 2.65
and 2.66). The classic viral cytopathic effect includes nuclear
enlargement, prominent nuclear inclusions (with an “owls’ eye”
appearance), and nuclear and or cytoplasmic inclusions (Fig. 2.67).
These changes are predominantly seen in stromal and endothelial cells;
hence, biopsy of the ulcer base is critical for complete evaluation. Often
times, viral cytopathic effect in the stomach is sneaky and may only
include scattered enlarged cells with slightly smudged chromatin and
prominent apoptotic bodies (Figs. 2.68 and 2.69). Unlike in other sites,
CMV gastritis (and enteritis) can feature viral cytopathic effect in
epithelial cells, although the key features are generally very subtle (Fig.
2.70). As these features can also be seen in regenerative atypia, a low
threshold for a CMV immunostain is worthwhile. Importantly,
sometimes the only clue to CMV gastritis is prominent foveolar
hyperplasia reminiscent of a gastric hyperplastic polyp (Figs.
2.71–2.75).47,48 This pattern is particularly common in
immunocompromised individuals and can be seen with a complete lack
of acute and chronic inflammation. See also Hyperplasia Pattern, this
chapter.

Figure 2.64 Cytomegalovirus (CMV) ulceration, endoscopic image. This example of CMV gastritis
shows a deep ulceration (arrowheads).
 Figure 2.65 Acute gastritis pattern, CMV. Like that in any other site, the characteristic
inflammatory backdrop of CMV infection includes a prominence of mononuclear inflammation,
composed of lymphocytes, macrophages, lymphocytes, and plasma cells, in addition to acute
inflammation. Whenever this pattern is seen, careful examination for CMV is required; a CMV
immunostain is recommended if diagnostic cells are not apparent on H&E.

Figure 2.66 Acute gastritis pattern, CMV. Higher power of previous case (Fig. 2.65). CMV
infected cells were detected with CMV immunostain (not shown).
 Figure 2.67 Acute gastritis pattern, CMV. This case features a single cell diagnostic of CMV
gastritis (arrowhead): cytomegaly, nuclear enlargement, a prominent nuclear inclusion (with an
“owls’ eye” appearance), and bright-red, globular cytoplasmic inclusions. In addition,
mononuclear inflammation and scattered apoptotic bodies (circles) are seen in the background.
CMV immunostain was not necessary in this case.

Figure 2.68 Acute gastritis pattern, CMV. Gastric CMV viral cytopathic effect can be easy to miss
and sometimes the only clue to the diagnosis is prominent mononuclear inflammation, scattered
enlarged atypical cells with slightly smudged chromatin (arrowhead), or prominent apoptotic
bodies (circles), as seen in this case of CMV gastritis. CMV infected cells were seen with a CMV
immunostain.
 Figure 2.69 Acute gastritis pattern, CMV. Note the striking mononuclear backdrop, scattered
atypical stromal cells with prominent nucleoli (arrowheads), and prominent apoptotic bodies
(circles) in this case of CMV gastritis. CMV infected cells were seen with CMV immunostain.

Figure 2.70 Acute gastritis pattern, CMV. In most other sites, CMV infection is predominantly
seen in stromal cells and endothelial cells. Gastric (and small bowel) CMV infection is unique,
however, in that epithelial cells can display CMV viral cytopathic effect. In this example, an
epithelial cell displays equivocal features of CMV gastritis with slight nucleomegaly, a prominent
nuclear inclusion, and quasi-chromatin smudging (arrowhead); however, the neighboring stromal
cells show more classic features with unequivocal cytomegaly, nuclear enlargement, nuclear
inclusions, smudged chromatin, and cytoplasmic inclusions (arrows). CMV infected cells were
also seen with CMV immunostain.
 Figure 2.71 CMV. Foveolar hyperplasia can sometimes be the only clue to a CMV infection,
particularly in immunosuppressed patients. This biopsy of flat gastric mucosa originated from a
bone marrow transplant patient with vomiting. Prominent foveolar hyperplasia is seen,
reminiscent of a gastric hyperplastic polyp. A CMV immunostain was reactive, despite the
complete absence of acute inflammation or ulceration.

Figure 2.72 CMV gastritis. This biopsy is from flat gastric mucosa in a patient status post
chemoradiation for metastatic breast cancer. The biopsy shows foveolar hyperplasia with lamina
propria chronic inflammation.
Figure 2.73 CMV gastritis. Higher power of the previous case (Fig. 2.72). The corresponding CMV
immunostain was focally reactive. Foveolar hyperplasia in an immunosuppressed patient should
raise consideration of CMV.

Figure 2.74 CMV. In this case, the only clue to the diagnosis of CMV gastritis was the prominent
foveolar hyperplasia. This was a biopsy of flat mucosa (no polyp was endoscopically
appreciated).
Figure 2.75 CMV (CMV immunostain). CMV immunostain from the previous case (Fig. 2.74). A
single CMV immunostain reactive cell is seen.

FAQ: How are CMV immunostains utilized?

Answer: If the diagnosis can be made on H&E owing to classic viral
cytopathic effect, a CMV immunostain is not required; however, a low
threshold for ordering a CMV immunostain is recommended in
immunocompromised patients because the histologic findings can be
subtle, easily hidden by obscuring inflammation, or can be
accompanied by a complete lack of acute inflammation. The CMV
immunostain is recommended in the following settings:

CMV Immunostains Are Recommended in the Following Stomach

Biopsies:
• Prominent Apoptotic Bodies
• Atypical Stromal, Endothelial, or Epithelial Cells
• Ulceration
• Prominent Foveolar Hyperplasia in Immunosuppressed Patients
• At the Request of the Clinician

FAQ: How should I approach a case with one equivocal CMV

labeled cell?
 Answer: Recommend correlation with pertinent clinical studies.
Like all ancillary stains, the CMV immunostain is imperfect and can
suffer from high background artifacts, making interpretation
challenging. Moreover, the immunostain cannot distinguish an active
CMV infection from a latent infection and viral therapy is poorly
tolerated in some patients. If equivocal or rare CMV labeling is seen,
correlation with the clinical picture and CMV amplification based
studies is recommended.

FOCALLY ENHANCED GASTRITIS

The term “focally enhanced gastritis” (FEG) was introduced in 1997 and
refers to focally injured gastric glands surrounded by a cuff of
inflammation (Figs. 2.76–2.78).49 Acute inflammation is not a
requirement for this feature, although it is sometimes encountered; thus,
FEG is included in the discussion of the acute gastritis pattern. In a
recent study of 31 cases of pediatric FEG, 48% contained eosinophils,
30% contained neutrophils, 10% contained granulomas, and 44% cases
were multifocal.50 The clinical significance of FEG has been
controversial. Some have reported FEG as a nonspecific finding in adults,
with only a 5.9% positive predictive value of inflammatory bowel
disease.51 Interestingly, these same experts subsequently reported a
significant association of FEG and inflammatory bowel disease in
children (p ≤ 0.001).50 This association has been demonstrated by
others with a positive predictive value of inflammatory bowel disease up
to 94%.49 FEG is most common in Crohn disease (up to 76%), but also
occurs in ulcerative colitis (up to 30%); therefore, it cannot reliably
distinguish Crohn, ulcerative colitis, or type indeterminate.49–53 More
recently, experts have found that FEG in the pediatric setting also
correlates with active ileitis and granulomata formation.53
Figure 2.76 Acute gastritis pattern, focally enhanced gastritis (FEG). This stomach biopsy is from
a 13-year-old girl with Crohn disease. The tissue fragments were fairly unremarkable except for a
focally injured pit surrounded by lymphocytes, macrophages, eosinophils, and neutrophils
(arrowhead).

Figure 2.77 Acute gastritis pattern, FEG. The scattered acute inflammation is more apparent on
higher power. Although the significance of FEG in adults is not entirely clear, FEG in children is
more commonly associated with inflammatory bowel disease (Crohn disease > ulcerative
colitis). An Helicobacter pylori immunostain was negative.
 Figure 2.78 Acute gastritis pattern, FEG. This example shows a gland encircled by lymphocytes
and macrophages (arrowhead). NSAID injury was the likely culprit in this case originating from a
44-year-old athlete with an extensive history of NSAIDs. An Helicobacter pylori immunostain was
negative.

FAQ: How is FEG incorporated into diagnostic reports?

Answer: The significance of FEG in adults is not entirely established,51
and reporting of such is for academic purposes; however, it may be
worthwhile to report FEG in the pediatric population based on its
more common association with inflammatory bowel disease.50,52,53 If
acute inflammation is seen, a Helicobacter pylori immunostain is
recommended, if the organisms are not obvious on H&E.

SAMPLE NOTE: FEG, PEDIATRIC SETTING

Stomach, Biopsy:
• Antral mucosa with focal enhanced gastritis.
• A Helicobacter immunostain is nonreactive.
Note: The history of bloody diarrhea is noted. The stomach biopsy shows
focal enhanced gastritis. This finding has been associated with
inflammatory bowel disease (Crohn disease > ulcerative colitis) in the
pediatric setting. Correlation with biopsies of the terminal ileum, right
colon, left colon, and rectum recommended, based on the clinical history
of bloody diarrhea. A Helicobacter immunostain is nonreactive.

References:
Ushiku T, Moran CJ, Lauwers GY. Focally enhanced gastritis in newly
diagnosed pediatric inflammatory bowel disease. Am J Surg Pathol.
2013;37(12):1882–1888.
McHugh JB, Gopal P, Greenson JK. The clinical significance of focally
enhanced gastritis in children. Am J Surg Pathol. 2013;37(2):295–299.
Sharif F, McDermott M, Dillon M, et al. Focally enhanced gastritis in
children with Crohn’s disease and ulcerative colitis. Am J
Gastroenterol. 2002;97(6):1415–1420.

CHRONIC GASTRITIS PATTERN

Figure 2.79 Chronic gastritis pattern. Chronic gastritis refers to a heterogeneous group of diseases
characterized by chronic inflammation of the gastric mucosa. This is a completely nonspecific
injury pattern that relies on clinicopathologic red flags to uncover the underlying etiology.

Gastritis refers to a heterogeneous group of diseases characterized by

inflammation of the gastric mucosa (Fig. 2.79). “Chronic gastritis” is
arguably one of the more common diagnoses but, unfortunately, also is
among the most meaningless. The role of the pathologist is to not only
confirm the presence of chronic inflammation but also determine the
etiology such that directed therapeutic measures can be taken. As such,
“chronic gastritis” may be accurate, but of limited value to clinician and
patient. Instead, recognizing different patterns of “chronic gastritis” can
provide clues to the pathogenesis and, in doing so, provide useful
information that can impact patient management. In this section, the
discussion will center on the injury patterns important for determination
of the two most common causes of chronic gastritis: autoimmune
metaplastic atrophic gastritis (AMAG) and environmental metaplastic
atrophic gastritis (EMAG).11,12,16,54–88

AUTOIMMUNE METAPLASTIC ATROPHIC GASTRITIS

(AMAG)
An Overview
AMAG is also commonly referred to as “autoimmune gastritis (AIG),”
“autoimmune atrophic gastritis,” “type A gastritis,” or “diffuse corporal
atrophic gastritis (DCAG).”4,11,12,89 AMAG is critical to recognize
because these patients are at an increased risk for dysplasia, a threefold
increased risk of gastric carcinomas, and at 13-fold increased risk of
gastric neuroendocrine tumors (formerly “carcinoids”) as well as at risk
for pernicious anemia. Physiologically, AMAG is the immune-mediated
destruction of gastric parietal cells and the late clinical result is vitamin
B12 deficiency (clinically pernicious anemia). Briefly, antibody mediated
loss of parietal cells and chief cells results in decreased parietal cellular
products, such as decreased intrinsic factor (IF) and decreased acid
production (increased pH). In an attempt to replenish these cellular
products, antral G cells increase gastrin secretion and ECL cells increase
histamine secretion (Figs. 2.80–2.82). Over many years to decades,
reduced vitamin B12 absorption will eventually lead to pernicious
(megaloblastic) anemia. In addition, over long periods of time, persistent
ECL cell hyperplasia can lead to neuroendocrine tumors (formerly
“carcinoids”) (Figs. 2.83 and 2.84).
AMAG characteristically shows body/fundus-predominant injury and
demonstrates a combination of the following morphologic features (Figs.
2.85–2.89).
• Basal Lymphocytic Infiltrate of Oxyntic Mucosa
• Atrophy of Oxyntic Mucosa (Patchy or Complete)
• Intestinal and Pyloric Metaplasia of Oxyntic Mucosa
• Lymphoid Aggregates in Oxyntic Mucosa

Figure 2.80 Normal physiology of the parietal cell. The parietal cell is stimulated by gastrin that
is produced by the G cells found exclusively in the gastric antrum, and by histamine produced by
ECL cells found preferentially in oxyntic mucosa. The parietal cell secretes intrinsic factor, which
plays a critical role in the transport of vitamin B12 in the small bowel. In addition, the parietal
cell is responsible for secretion of acid, resulting in feedback inhibition of the G cell.
 Figure 2.81 Physiology of autoimmune metaplastic atrophic gastritis (AMAG). Autoantibodies
attack parietal cells resulting in decreased acid and loss of feedback inhibition of the antral G
cells. The increased gastrin secretion causes elevated serum gastrin as well as hyperplasia of ECL
cells. Furthermore, the lack of intrinsic factor results in the inability to absorb dietary vitamin
B12.

Figure 2.82 Normal gastric cell populations compared to autoimmune metaplastic atrophic
gastritis (AMAG). The normal gastric body and fundus is composed of oxyntic mucosa containing
abundant parietal cells with scattered ECL cells. The acid secreted by the parietal cells serves as
feedback inhibition to turn off gastrin secretion by the antral G cells. By comparison, the
autoimmune-mediated loss of parietal cells in AMAG results in loss of feedback inhibition of the
G cells. The resulting unchecked gastrin secretion causes ECL cell hyperplasia in a background of
oxyntic gland atrophy.
Figure 2.83 Chronic gastritis pattern, well-differentiated neuroendocrine (carcinoid) tumor (type
I). Prolonged and unchecked gastrin stimulation of the ECL cells can lead to transformation of
ECL cell hyperplasia into neuroendocrine tumors (type I, when in the setting of AMAG). One
should always carefully evaluate of the background gastric mucosa in all cases of gastric
neuroendocrine tumors to aid in classification, treatment, and prognosis.

Figure 2.84 Chronic gastritis pattern, well differentiated neuroendocrine (carcinoid) tumor (type
I) (chromogranin immunostain). Previous case (Fig. 2.83). The distinction between reversible
nodular ECL cell hyperplasia and neuroendocrine neoplasm is somewhat arbitrary. The College of
American Pathologists suggests a size threshold of ≥0.5 mm for neuroendocrine tumors, whereas
smaller nodules are considered ECL cell hyperplasia (or “dysplasia”).
 Figure 2.85 Chronic gastritis pattern, antral histology of autoimmune metaplastic atrophic
gastritis (AMAG). The gastric antrum has minimal histologic change, with mild reactive
gastritis/gastropathy (tortuosity of antral pits, foveolar hyperplasia, loss of apical mucin,
minimal background chronic inflammation, and smooth muscle streaming in the lamina propria).

Figure 2.86 Chronic gastritis pattern, body/fundus histology of well-developed autoimmune

metaplastic atrophic gastritis (AMAG). The autoimmune destruction of parietal cells results in
total loss of oxyntic glands in the late stages of AMAG. Characteristic features of intestinal
metaplasia, pyloric metaplasia (arrowhead), and low-lying lymphoid aggregates (arrow) are seen
in this gastric biopsy. In the complete absence of oxyntic mucosa, it would be easy to mistake
this biopsy for antral mucosa with intestinal metaplasia and chronic inflammation.
 Figure 2.87 Chronic gastritis pattern, comparison of G cell location autoimmune metaplastic
atrophic gastritis (AMAG) (gastrin immunostain). Utilization of a gastrin stain can aid in
identifying the gastric compartment (body/fundus vs. antrum) from which tissue fragments were
obtained. Gastrin stains G cells which are found exclusively in the antrum (right), whereas tissue
fragments obtained from the body/fundus contain no G cells (left). This immunostain can be
useful when there is total atrophy of the oxyntic glands and the compartment of origin is
uncertain, such as in the previous figure. Photograph courtesy of Dr. Lysandra Voltaggio, Johns
Hopkins.

Figure 2.88 Chronic gastritis pattern, linear ECL cell hyperplasia (chromogranin immunostain).
The uninhibited gastrin secretion in autoimmune metaplastic atrophic gastritis (AMAG) results in
ECL cell hyperplasia (≥5 ECL cells arranged together). This example shows a linear
configuration (arrow) of ECL cell hyperplasia&emdash;at least five ECL-consecutive cells
arranged in a row.
Figure 2.89 Chronic gastritis pattern, nodular ECL cell hyperplasia (chromogranin immunostain).
ECL cell hyperplasia can progress to nodular form (≥5 or more ECL cells arranged in a nodule).
At low magnification, the small nodular aggregates of ECL cells are evident (arrowheads). ECL
cell hyperplasia, by definition, is reversible with the interruption of gastrin stimulation.

FAQ: What constitutes ECL cell hyperplasia?

Answer: By definition, ECL cell hyperplasia refers to five or more ECL
cells arranged in a back-to-back configuration, either grouped in a row
(linear ECL cell hyperplasia) (Fig. 2.88) or in a cluster (nodular ECL
cell hyperplasia) (Fig. 2.89). ECL cell hyperplasia is seen in 33% to
100% of patients with AMAG and is best visualized with a
chromogranin immunostain.

FAQ: What are the size criteria for neuroendocrine tumors? When
does ECL cell hyperplasia become a neuroendocrine tumor?
Answer: The practical answer is that if the endoscopist can see a
“bump,” it should be considered an endoscopically resectable lesion,
and therefore a neuroendocrine tumor. The technical answer is that
both terminology and size criteria for neuroendocrine tumors vary
depending on which standards are followed:
 PEARLS & PITFALLS
It is important to identify the background gastric changes whenever a
neuroendocrine tumor is encountered in the stomach. Like tumors that
arise in the setting of Zollinger–Ellison syndrome (type II) but in
contrast to those sporadically (type III), those that arise in the setting
of AMAG (type I) have excellent prognoses and low rates of metastatic
disease. For patients with extensive neuroendocrine tumors,
antrectomy to remove the stimulatory G cells has been successful.

ENVIRONMENTAL METAPLASTIC ATROPHIC GASTRITIS

(EMAG)
An Overview
EMAG is also commonly referred to as “multifocal atrophic gastritis
(MAG),” or “type B gastritis.” EMAG characteristically shows antral-
predominant injury and demonstrates a combination of: • Superficial
Plasmacytic Infiltrate
• Atrophy of Antral Mucosa (Early) and Oxyntic Mucosa (Late)
• Intestinal Metaplasia of Antrum (Early) and Oxyntic Mucosa (Late)
• Lymphoid Aggregates of Antrum (Early) and Oxyntic Mucosa (Late)
The term EMAG refers to environmental insult, but necessarily
implicates Helicobacter, which is discussed in greater detail in the acute
gastritis section. When the previously mentioned subpatterns are seen in
combination, the findings are fairly specific for Helicobacter; however,
antral-predominant disease that includes only one of these subpatterns of
injury may be the result of other “environmental” or chemical etiologies,
such as bile reflux, NSAIDs, and other direct toxins (i.e., smoking,
alcohol); therefore, it is helpful to look for additional patterns of injury
in the background. For example, the presence of intestinal metaplasia
limited to the gastric antrum could be the result of any of the previously
listed environmental factors, but the additional presence of a superficial
plasmacytic infiltrate suggests Helicobacter. In comparison, if the antral-
predominant intestinal metaplasia is paired with a hyperplastic or
reactive gastropathy pattern, a chemical injury (bile reflux, NSAIDs) is
more likely.

A PATTERNS-BASED APPROACH TO CHRONIC GASTRITIS

CHECKLIST: The Five Major Chronic Gastritis Subpatterns

Superficial Plasmacytic Infiltrate
Basal Lymphocytic Infiltrate
Atrophic
Metaplastic
Lymphoid Aggregates

This section discusses five key injury patterns; all can be identified at
scanning magnification. Proper awareness and understanding of these
features can be used to construe the etiology of the chronic gastritis,
thereby providing useful information for clinicians and patients. Using
the framework prescribed herein, the majority of cases can be ascribed
an etiology of either autoimmune metaplastic atrophic gastritis (AMAG)
or environmental metaplastic atrophic gastritis (EMAG). As one can
discern from the AMAG and EMAG overview discussions earlier, the
compartment in which the predominant injury pattern is found (i.e.,
antral vs. oxyntic mucosa) is a critical factor in distinguishing these
entities. For example, AMAG is a body/fundus predominant disease,
with the immune-mediated loss of parietal cells (Fig. 2.90), whereas
EMAG is antral-predominant in its early stages, and more diffuse and
multifocal in the late stages (Fig. 2.91). As such, the discussion that
follows will include a section on compartments for each injury pattern,
to further underscore the importance of compartment/location in
determining the etiology of the chronic gastritis. In addition, it is
necessary to evaluate tissue from both antral and oxyntic mucosa to fully
assess the etiology of the gastritis. Recommended biopsy protocols exist,
the most widely accepted of which is the Sydney System protocol (Fig.
2.92) which includes five samples: two each from greater and lesser
curvatures (to include both antrum and body) and one from incisura
(transition zone). It must be noted that, unfortunately, not all cases of
chronic gastritis can be neatly stratified into AMAG or EMAG. Despite
the pathologist’s best efforts, there will remain a number of cases that
retain a nonspecific diagnosis of “chronic gastritis” for which an etiology
cannot be determined. This could be attributed to limited tissue
sampling, nonspecific etiologies, or as-yet uncharacterized forms of
gastritis.

Figure 2.90 Chronic gastritis pattern, compartment of injury in autoimmune metaplastic atrophic
gastritis (AMAG). The autoimmune destruction of parietal cells in AMAG results in injury limited
to the body and fundus, with sparing of the gastric antrum. Note how this pattern of
compartmental injury is reversed in EMAG (see Fig. 2.91).

Figure 2.91 Chronic gastritis pattern, compartment of injury in environmental metaplastic

atrophic gastritis (EMAG). The preference of Helicobacter for the antral mucosa in EMAG results
in injury limited to the antrum during the early stages. There is relative sparing of the gastric
 body until late in the disease. By comparison, AMAG is limited to the gastric body/fundus.

Figure 2.92 Biopsies of the gastric mucosa, Sydney protocol. Evaluation of both the antrum and
body/fundus are necessary to appreciate the extent of disease and whether the changes are
limited to a particular compartment. The Sydney protocol is widely accepted and requires five
biopsies: two each from the greater and lesser curvature (to include both body and antrum) and
one from the incisura (stars).

SUPERFICIAL PLASMACYTIC INFILTRATE SUBPATTERN

This subpattern of chronic gastritis is defined as an expansion of the
lamina propria just below the surface epithelium by an inflammatory
infiltrate composed predominantly of plasma cells, and produces a
characteristic “band-like” quality at scanning magnification. (Figs.
2.93–2.96). Examination at higher power shows that other inflammatory
cells, such as lymphocytes and eosinophils, are often admixed, but the
dominant cell type is plasma cells. This subpattern of injury is frequently
a dominant pattern, and is so highly characteristic of EMAG’s
Helicobacter infection, that Helicobacter gastritis can essentially be
diagnosed on a 2× objective, much to the amazement of novice trainees.
In the absence of demonstrable organisms on higher power or special
stains, this subpattern of injury should still be considered Helicobacter
infection until excluded clinically with additional testing (i.e., serum
antibody, urease breath test, stool antigen). Of note, superficial
plasmacytic infiltrates are not commonly seen in AMAG.
 Figure 2.93 Chronic gastritis pattern, superficial plasmacytic infiltrate subpattern. At scanning
magnification, this oxyntic mucosa shows a single dominant subpattern, with a band-like
infiltrate expanding the lamina propria between the surface epithelium and the superficial
glands. Even at this magnification, the main differential diagnosis is Helicobacter gastritis.

Figure 2.94 Chronic gastritis pattern, superficial plasmacytic infiltrate subpattern. Higher
magnification of previous figure. At higher magnification, one can appreciate that the superficial
band is composed of a mixture of chronic inflammatory cells, but the predominant cell type is
plasma cells.
 Figure 2.95 Chronic gastritis pattern, Helicobacter pylori gastritis. The superficial plasmacytic
infiltrate subpattern of injury is highly associated with Helicobacter pylori infection. These spiral
organisms (arrowheads) can be found in the mucin of gastric pits.

Figure 2.96 Chronic gastritis pattern, Helicobacter pylori (Warthin–Starry special stain). This
silver-based Warthin-Starry stain coats the Helicobacter organisms, and enhances their
morphologic features, including their short, tight spirals, and curved appearance.

Compartment, Superficial Plasmacytic Infiltrate Subpattern

The superficial plasmacytic infiltrate subpattern is most commonly seen
in the gastric antrum, the preferential site of residence for Helicobacter
organisms. Importantly, this pattern can also be seen in the gastric body,
particularly in the setting of proton pump inhibitor (PPIs) use, which
decrease the gastric acidity and, thereby, foster a more hospitable local
environment for Helicobacter.

PEARLS & PITFALLS

In addition to facilitating proximal migration of Helicobacter
organisms, PPIs or concurrent antibiotics can decrease Helicobacter
bacterial load so that organisms may not be visible or may acquire an
altered morphology to a more coccoid form, and facilitate the survival
of non-Helicobacter bacteria, making diagnosis challenging. As such, if
the pattern of injury is characteristic, but there are no demonstrable
organisms, additional clinical workup (i.e., serum antibody, breath
test, and stool antigen testing) can be worthwhile.

BASAL LYMPHOCYTIC INFILTRATE SUBPATTERN

This subpattern of chronic gastritis is defined by a low-lying lymphocytic
infiltrate that expands the lamina propria between the base of the gastric
glands and the muscularis mucosae. The prototypical case shows a
“band-like” infiltrate hugging the muscularis mucosae at scanning
magnification. High-power examination shows admixed plasma cells and
occasional eosinophils, but the dominant cell type is lymphocytes (Figs.
2.79, 2.97 and 2.98).
Compartment, Basal Lymphocytic Infiltrate Subpattern
Recognizing the compartment in which this pattern arises can aid in
determining the etiology of the chronic gastritis. For example, when
found isolated to the gastric body/fundus, the changes are more likely
related to AMAG, and further identification of additional AMAG patterns
of injury can be helpful. In contrast, involvement limited to the antrum
(or mixed antral and oxyntic involvement) suggests the etiology may be
related to EMAG; however, identification of other concurrent patterns of
injury is necessary.
 Figure 2.97 Chronic gastritis pattern, basal lymphocytic infiltrate subpattern, early AMAG. The
dominant pattern of injury in this tissue fragment is a low-lying lymphocytic infiltrate that hugs
the muscularis mucosae and expands the lamina propria below the base of the glands (arrow).
The oxyntic glands (bracket) indicate that the compartment of injury is body/fundus. Further
investigation reveals an area of oxyntic gland atrophy (arrowheads), suggesting early AMAG.

Figure 2.98 Chronic gastritis pattern, basal lymphocytic infiltrate subpattern, AMAG. At scanning
magnification, this tissue fragment shows a chronic inflammatory infiltrate that is bottom-heavy
(arrow). Whereas this pattern in the body/fundus suggests AMAG, this finding in the antrum
suggests EMAG. Awareness of the compartment is critical for determining the underlying etiology
of the chronic gastritis pattern.

PEARLS & PITFALLS

Beware the monomorphic lymphocytic infiltrate that is gland-
destructive or that traverses the muscularis mucosae. These two
features should raise suspicion for a malignant lymphocytic infiltrate
 and further immunohistochemical workup would be prudent.

ATROPHIC
The definition of “atrophy” is the loss of appropriate glands, and atrophy
can be scored according to the degree of severity as mild, moderate, or
marked (Figs. 2.99–2.105). Atrophy can be divided into antral/pyloric
gland atrophy, and oxyntic gland atrophy. By definition, both AMAG and
EMAG have glandular atrophy, but in differing compartments.

Figure 2.99 Chronic gastritis pattern, antral pyloric gland atrophy, EMAG. Antral atrophy has
poor interobserver concordance and can be difficult to evaluate; however, this example shows a
marked reduction in the pyloric glands (bracket) as compared to the full thickness of the biopsy.
Isolated antral atrophy is commonly associated with Helicobacter. Not the top-heavy superficial
plasmacytic infiltrate in this case.
Figure 2.100 Chronic gastritis pattern, antral pyloric gland atrophy, EMAG. This example shows
atrophy of pyloric glands (residual pyloric glands in brackets). The findings of atrophy and
lymphoid aggregates in this antral biopsy suggest EMAG or Helicobacter infection.

Figure 2.101 Chronic gastritis pattern, antral pyloric gland atrophy, EMAG. This biopsy shows
atrophic mucosa with lymphoid aggregates. A few residual pyloric glands are present (arrow).

Figure 2.102 Chronic gastritis pattern, antral pyloric gland atrophy, EMAG (gastrin
immunostain). The gastrin immunostain from the previous case (Fig. 2.101) highlights a residual
band of G cells, thereby confirming this as antral mucosa.
Figure 2.103 Chronic gastritis pattern, partial oxyntic gland atrophy, early AMAG. This inflamed
mucosa can appear quite “busy”, but careful examination reveals areas of oxyntic gland
loss/atrophy (arrowheads; residual oxyntic glands in bracket). Patchy atrophy of oxyntic glands
such as this should raise suspicion for early AMAG.

Figure 2.104 Chronic gastritis pattern, total atrophy of gastric glands, AMAG. This biopsy shows
marked atrophy. In addition, the background mucosa also shows a subpattern of a bottom-heavy
basal lymphocytic infiltrate. Correctly identifying the compartment (antral vs. body) of this
biopsy is critical in the distinction of AMAG versus. EMAG. A gastrin immunohistochemical stain
is necessary (see next figure).
 Figure 2.105 Chronic gastritis pattern, total atrophy of gastric glands (gastrin immunostain),
AMAG. A negative gastrin immunostain from the previous case (Fig. 2.105) indicates that the
tissue originates from the gastric body/fundus. In this compartment, the findings suggest AMAG.
This case underscores the importance of compartment awareness for arriving at the correct
underlying etiology.

Compartment, Atrophic Subpattern

Since AMAG is the result of oxyntic gland atrophy from antibodies
against parietal cells, this disease process is, necessarily, limited to
oxyntic mucosa. In contrast, EMAG is an antral-predominant disease
process and results in antral atrophy before extending multifocally into
the gastric body and fundus. Late stage disease for both entities provides
some challenges, since total atrophy of oxyntic glands in late AMAG can
deceive one into accepting the tissue as antrum. Alternatively, the late
stage of EMAG can also show atrophy of oxyntic glands, misleading one
into thinking there is an autoimmune process. Immunostaining for
gastrin is a quick, and sometimes necessary, method to identify the site
of origin for a biopsy fragment (the gastric antrum displays a band of G
cells, and the gastric body/fundus lacks G cells). Identification of other
compartment-restricted patterns of injury is necessary to establish a
diagnosis.

METAPLASIA
The two most common types of metaplasia seen in the stomach include
intestinal metaplasia (IM) and pyloric metaplasia (Figs. 2.106–2.109).
Both are the result of chronic gastritis, and consequently both are more
frequently encountered in elderly individuals. A third, less common form
of metaplasia is pancreatic metaplasia (Figs. 2.110–2.113).
 Figure 2.106 Chronic gastritis pattern, intestinal metaplasia, complete, with villiform change,
AMAG. This biopsy was removed from the gastric body of a patient with well-developed AMAG.
The intestinal metaplasia includes intensely pink Paneth cells at the bases of the pits (arrowhead),
indicating complete intestinal metaplasia. Further evidence of advanced intestinal metaplasia can
be seen in the villiform architecture of the pits and glands.

Figure 2.107 Chronic gastritis pattern, intestinal and pyloric metaplasia, AMAG. This biopsy from
the gastric body shows both intestinal metaplasia (arrow) and pyloric metaplasia (arrowhead). In
the setting of total oxyntic atrophy, such as this, a gastrin stain can confirm that this tissue as
body/fundus in origin.
 Figure 2.108 Chronic gastritis pattern, intestinal and pyloric metaplasia, AMAG (gastrin
immunostain). This negative gastrin immunostain from the previous case (Fig. 2.107) verifies the
absence of G cells and confirms gastric body/fundus origin, further substantiating an
interpretation of AMAG.

Figure 2.109 Chronic gastritis pattern, linear and nodular enterochromaffin cell (ECL) cell
hyperplasia, AMAG (chromogranin immunostain). This chromogranin immunostain of the
previous figure highlights both linear (arrowhead) and nodular (arrow) ECL cell hyperplasia. The
finding of either linear or nodular ECL cell hyperplasia confirms the diagnosis of AMAG.
 Figure 2.110 Chronic gastritis pattern, pancreatic metaplasia/heterotopia. Pancreatic
differentiation (arrowhead) is seen as a lobule of pancreatic acinar cells and is etiologically
nonspecific. The background in this example is unremarkable oxyntic mucosa. In normal
stomachs, this finding is probably heterotopic rather than metaplastic whereas in stomachs with
autoimmune gastritis, pancreatic type tissue is probably metaplasic.

Figure 2.111 Chronic gastritis pattern, pancreatic metaplasia. Higher magnification of previous
case (Fig. 2.110). This focus shows pancreatic acinar cells (arrow) which are wider at the base
than at the luminal apex. Brightly eosinophilic, coarse zymogen granules fill the cytoplasm and
the cells have basally located small, uniform nuclei. By comparison, parietal cells (arrowhead) are
polygonal with finely granular eosinophilic cytoplasm. The nuclei may be centrally or basally
located, and are larger by comparison. A trypsin stain may be useful in difficult cases (pancreatic
cells would display trypsin reactivity and oxyntic cells would be trypsin nonreactive).
 Figure 2.112 Chronic gastritis pattern, pancreatic metaplasia, AMAG. Lobules of pancreatic
metaplasia (arrowheads) are present in this gastric body biopsy of a patient with AMAG.
Intestinal metaplasia and total atrophy of oxyntic glands are present in a background of a chronic
inflammatory infiltrate. Based on the presence of damaged background mucosa, this pancreatic
tissue is best regarded as metaplastic.

Figure 2.113 Chronic gastritis pattern, pancreatic metaplasia, AMAG. Higher magnification of
previous case (Fig. 2.112). The pancreatic acinar cell (arrow) is seen in the same field as Paneth
cells (arrowhead) in the background of complete intestinal metaplasia. By comparison, the Paneth
cells have coarser and more brightly eosinophilic zymogen granules.

Pyloric metaplasia is the replacement of the oxyntic mucosa with

pyloric glands. Although this finding is highly characteristic of AMAG, it
is not always a dominant pattern of injury. More often, adjoining
intestinal metaplasia (IM) is far more prominent, particularly at low
power. With IM, the cells of the surface and pit epithelium change such
that they morphologically and histochemically resemble the small or
large bowel, a finding that can be categorized as complete (type I) or
incomplete (type II). Complete IM resembles normal small bowel
epithelium with fully developed goblet cells, enterocytes with a brush
border, and Paneth cells. In advanced cases, the contour of the mucosa
develops villiform architecture and crypts. In contrast, incomplete IM
(type II) has a mixture of goblet cells and normal gastric epithelium, and
it lacks a brush border, Paneth cells, and absorptive cells. IM (complete
or incomplete) may be seen in both AMAG and EMAG. Finally, the less
common pancreatic acinar metaplasia is found in over 20% of AMAG
cases and is frequently seen in conjunction with pyloric or intestinal
metaplasia. These nested or lobulated collections of pancreatic acinar
cells stain with amylase (75%).
Compartment, Metaplasia Subpattern
In AMAG, IM is a prominent finding in the gastric body/fundus in
combination with oxyntic gland atrophy, pyloric metaplasia, and
pancreatic metaplasia. By comparison, in EMAG, IM is a prominent
finding in the gastric antrum and does not extend to the body/fundus
until late in the disease. When IM is limited to the antral mucosa,
diagnostic considerations include EMAG (Helicobacter, bile reflux,
nonsteroidal anti-inflammatory medication injury, and other direct
mucosal toxins [i.e., smoking, alcohol]). Inspection for other
concomitant patterns or subpatterns of injury may help suggest the
etiology; for example, the presence of antral-based IM with acute
gastritis is likely Helicobacter, whereas antral-based IM with
reactive/chemical gastropathy is more likely related to bile reflux or
other chemical agents.

LYMPHOID AGGREGATES
Lymphoid aggregates subpattern is defined as the presence of benign
lymphoid aggregates or lymphoid follicles involving the mucosa (Figs.
2.114–2.119). This subpattern is perhaps the least specific of the chronic
gastritis subpatterns, but one of the most common, and most easily
identifiable at low power. Lymphoid aggregates can be seen in any form
of chronic gastritis, regardless of etiology, and are commonly associated
with EMAG’s Helicobacter infection and treated Helicobacter. These
aggregates can be antral predominant, or extend into the gastric body
and fundus in EMAG.
Compartment, Lymphoid Aggregates Subpattern
Because of the nonspecific nature of lymphoid aggregates, the
compartment in which this finding is seen is not particularly helpful.
Rather, one should carefully examine for other features of AMAG and
EMAG (Tables 2.1 and 2.2).

Figure 2.114 Chronic gastritis pattern, lymphoid aggregate subpattern, late EMAG. At scanning
magnification, the prominent lymphoid aggregate is eye catching. Lymphoid aggregates are not
always helpful in differentiating AMAG from EMAG. For example, this lymphoid aggregate is
seen in the body compartment, but the superficial band-like inflammatory infiltrate (arrowheads)
indicates this is most likely Helicobacter related (late EMAG).

Figure 2.115 Chronic gastritis pattern, lymphoid aggregate, treated H. pylori gastritis. In cases of
eradicated Helicobacter infection, such as this, lymphoid aggregates may persist for up to a year.
The persistent lymphoid aggregate is not a sign of active infection.
 Figure 2.116 Chronic gastritis pattern, lymphoid aggregate subpattern, AMAG. At scanning
magnification, a prominent lymphoid aggregate is present in this body biopsy. Given the location
of injury and the combination of background intestinal metaplasia and the total lack of oxyntic
glands, the etiology is likely AMAG.

Figure 2.117 Chronic gastritis pattern, lymphoid aggregate, AMAG. Another example of
prominent lymphoid aggregates at scanning magnification. Although this biopsy is labeled
“body”, no oxyntic glands are present.
 Figure 2.118 Chronic gastritis pattern, lymphoid aggregate, AMAG (gastrin immunostain). A
gastrin immunostain of the previous figure is devoid of G cells, confirming the tissue originated
from the gastric body.

Figure 2.119 Chronic gastritis pattern, lymphoid aggregate, AMAG. Higher magnification of
previous figure reveals intestinal metaplasia (top bracket), pyloric metaplasia (lower bracket), and
total atrophy of oxyntic glands. The findings are strongly suggestive of AMAG.

FAQ: If lymphoid aggregates and follicles persist following

Helicobacter treatment, does this mean treatment failed?
Answer: No.
In cases of treated Helicobacter, the gastric mucosa shows various
degrees of chronic gastritis, possibly with some lymphoid follicles, but
no active inflammation. These chronic changes can persist for months
 following eradication of the organism.

FAQ: Are lymphoid aggregates ever normal in the stomach?

Answer: Yes.
Although MALT is limited to the oropharynx, terminal ileum and
appendix of the alimentary tract, isolated lymphoid aggregates can be
present in the otherwise normal gastric mucosa of both pediatric and
adult patients.90

TABLE 2.1: Comparison of Early and Late AMAG and EMAG by

Compartment and Potential Neoplasia

TABLE 2.2: Comparison of AMAG versus EMAG by Patterns of Injury

KEY FEATURES of Autoimmune Metaplastic Atrophic Gastritis (AMAG):
• AMAG is also known as autoimmune gastritis (AIG), type A gastritis,
autoimmune atrophic gastritis, diffuse corporal atrophic gastritis
(DCAG).
• Autoantibodies cause loss of oxyntic glands and intrinsic factor.
• Histologically, this is a body-predominant disease characterized by
intestinal metaplasia, pyloric metaplasia, oxyntic gland atrophy, and
ECL cell hyperplasia.
• Long term clinical sequelae include pernicious anemia, elevated
serum gastrin, achlorhydria, and neuroendocrine tumors (type I).
• Antrectomy to remove the stimulatory G cells has proven useful in
treatment of neuroendocrine tumors.

KEY FEATURES of Environmental Metaplastic Atrophic Gastritis

(EMAG):
• EMAG is also known as: multifocal atrophic gastritis (MAG) or type B
gastritis.
• The most common etiologic cause is Helicobacter. Other
associations included dietary factors (high-salt smoked foods,
 nitrates, lack of intake of fruit and vegetables).
• Histologically, this is an antral-predominant disease with variable
histologic appearances.
• Long term clinical sequelae may include mucosa associated lymphoid
tissue (MALT) lymphoma, glandular dysplasia, and adenocarcinoma.
• Most patients respond to treatment of their associated condition

LYMPHOCYTIC GASTRITIS PATTERN

Figure 2.120 Lymphocytic gastritis pattern. This pattern of injury characteristically includes a
mononuclear infiltrate in the lamina propria, but it differs from other types of chronic gastritis by
the presence of increased intraepithelial lymphocytes (IELs), defined as >25 IELs per 100
epithelial cells.

CHECKLIST: Etiologic Considerations for the Lymphocytic

Gastritis Pattern
Infectious: Helicobacter, HIV
Celiac Disease
Other Immune-Mediated Disorders: CVID, Crohn Disease, Lymphocytic
Enterocolitis
Medications: Ticlopidine, Olmesartan (Benicar)
Neoplasia: Lymphoma
Lymphocytic gastritis differs from chronic gastritis by the presence of
increased intraepithelial lymphocytes (IELs), defined as more than 25
intraepithelial lymphocytes per 100 epithelial cells (Figs.
2.120–2.126).38,91–97 The term “lymphocytic gastritis” was originally
used to describe the histologic counterpart to “varioliform” gastritis (i.e.,
thickened rugal folds and erosions), but subsequent studies have shown
this association in only 3.9% to 30% of cases. More commonly, the
endoscopic image shows erythema but up to 50% of patients have a
normal endoscopic appearance. Although the etiology of the
inflammation remains unknown in up to 20% of cases, common
associations include infection (e.g., Helicobacter, HIV), celiac disease and
other immune-mediated disorders (common variable immunodeficiency,
Crohn disease, lymphocytic enterocolitis), medications, and neoplasia
(Figs. 2.127–2.142).98 As a result, recognition of the lymphocytic
gastritis pattern can serve as an important red flag to the underlying
diagnosis and, consequently, lead to effective therapy with resolution of
symptoms. The changes affect the entire stomach, but intraepithelial
lymphocytes are most evident in the oxyntic mucosa, and are more
prominent in the superficial epithelium than the glands. Most cases show
expansion of the lamina propria with a mixed lymphoplasmacytic
inflammatory infiltrate, in addition to the intraepithelial lymphocytosis
(Fig. 2.121). Regenerative and hyperplastic changes in the surface
epithelium may be present, analogous to the surface changes seen with
intraepithelial lymphocytosis of the small and large bowel.
Immunolabeling identifies these as CD3+ T cells, with about 80%
showing a cytotoxic/suppressor CD8+ phenotype. Most patients respond
to treatment of their associated condition, when a known etiology is
present (i.e., successful eradication of Helicobacter usually leads to
reduced symptoms and decreased inflammation in biopsies, and
adherence to a gluten-free diet typically results in clinical and histologic
improvement in patients with celiac disease). Others advocate empiric
Helicobacter eradiation, even in Helicobacter-negative patients. In general,
immunosuppressive medications are reserved for those who fail gluten
withdrawal and whose intraepithelial lymphocytosis involves the
stomach, small, and large bowel. Untreated lymphocytic gastritis may
persist for years, although spontaneous remission has been reported.
 Figure 2.121 Lymphocytic gastritis pattern. The changes of lymphocytic gastritis are often
prominent enough that they can be identified at scanning magnification, obviating the need for
intraepithelial lymphocyte counts. The IELs usually affect the entire stomach but are more
evident in the oxyntic mucosa and are more prominent in the superficial epithelium as compared
to the deeper glands. Note the diffuse mixed inflammatory infiltrate in the lamina propria.

Figure 2.122 Lymphocytic gastritis pattern. There is a prominence of IELs in the surface
epithelium, with expansion of the lamina propria by a mixed chronic inflammatory infiltrate that
is plasma cell rich. This case had no demonstrable Helicobacter organisms, but additional clinical
testing was suggested based on histologic findings.
 Figure 2.123 Lymphocytic gastritis pattern (CD3 immunostain). The corresponding CD3
immunostain from the previous case (Fig. 2.122) confirms that the intraepithelial lymphocytes
are predominantly CD3+ T-cells. Immunophenotyping the IELs is not required for diagnosis.

Figure 2.124 Lymphocytic gastritis pattern (CD4 immunostain). The corresponding CD4
immunostain highlights a small population of CD4+ T-cells.
 Figure 2.125 Lymphocytic gastritis pattern (CD8 immunostain). The corresponding CD8
immunostain highlights shows that the majority of the IELS are CD8+ T-cells.

Figure 2.126 Intraepithelial lymphocytes of lymphocytic gastritis. High-power examination of the

IELs shows that each lymphocyte has a clear halo surrounding it, likely a processing artifact. The
IEL cell sizes are generally uniform and similar to those of the neighboring lymphocytes and
plasma cells in the lamina propria (circles). These findings are useful if one is considering
apoptotic injury in the differential diagnosis, which would show greater variability in the nuclear
fragments.
 Figure 2.127 Lymphocytic gastritis pattern, Helicobacter. In addition, in this case, scanning
magnification shows a superficial band-like infiltrate in gastric oxyntic mucosa. Whereas
lymphocytic gastritis is most commonly associated with celiac disease, the superficial band-like
infiltrate should indicate Helicobacter infection until proven otherwise, and should prompt higher
power investigation for the organisms.

Figure 2.128 Lymphocytic gastritis pattern, Helicobacter. Higher power of previous case. There
are intraepithelial lymphocytes present (arrows), and the lamina propria is expanded by a plasma
cell predominant mixed chronic inflammatory infiltrate. Careful examination also reveals focal
active inflammation (arrowheads). This combination of patterns are most suggestive of
Helicobacter infection.
 Figure 2.129 Lymphocytic gastritis pattern, Helicobacter (Helicobacter immunostain). The
Helicobacter immunostain highlights numerous spiral organisms within a gastric gland,
confirming the H&E impression. Note, the organisms are most easily found in the superficial
foveolar epithelium, in mucin rich foci.

Figure 2.130 Lymphocytic gastritis pattern, Helicobacter. This oxyntic mucosa shows a superficial
band-like chronic inflammatory infiltrate, suggesting Helicobacter. At this magnification, the
surface epithelium appears “busy”, requiring high-power examination.
 Figure 2.131 Lymphocytic gastritis pattern, Helicobacter. Higher power of previous figure. The
surface foveolar epithelium shows abundant IELs, and the inflammatory cells found in the lamina
propria are plasma cell predominant. This combination of lymphocytic gastritis pattern and
superficial plasmacytic infiltrate is highly suggestive of Helicobacter.

Figure 2.132 Lymphocytic gastritis pattern, celiac disease. This patient has an established history
of celiac disease with poor adherence to a gluten-free diet. The IELs seen in the gastric mucosa
are believed to result from the same immunologic process as seen in the duodenum. Some studies
have correlated more severe small bowel disease in patients who demonstrate lymphocytic
gastritis.
 Figure 2.133 Small-bowel biopsy correlating with previous figure. The patient’s small bowel
biopsy shows marked intraepithelial lymphocytosis and mild villous blunting, in keeping with
partially treated celiac disease.

Figure 2.134 Lymphocytic gastritis pattern, common variable immunodeficiency (CVID).

Lymphocytic gastritis is associated with a number of immune mediated disorders. In this
example, the gastric biopsy is from a patient with CVID. Mild intraepithelial lymphocytosis and
intestinal metaplasia are seen (bracket). Careful examination of the lamina propria reveals a
marked paucity of plasma cells, consistent with the established diagnosis of CVID.
Figure 2.135 Lymphocytic gastritis pattern, Crohn disease. Upper tract involvement of Crohn
disease is not uncommon. This gastric biopsy from a patient with established Crohn disease
features intraepithelial lymphocytosis.

Figure 2.136 Lymphocytic gastritis pattern, lymphocytic gastroenteritis. This gastric biopsy
shows numerous IELs, and tandem biopsies of the lower gastrointestinal tract showed similar
findings. Although etiologically nonspecific, this case highlights that intraepithelial
lymphocytosis can diffusely involve the luminal gastrointestinal tract.
 Figure 2.137 Lymphocytic colitis, tandem colon biopsy correlation of previous figure. Colon
biopsies also show abundant IELs. The diffuse gastric and colonic nature of this process is
unusual.

Figure 2.138 Lymphocytic/collagenous gastritis pattern, olmesartan. The superficial epithelium

in this antral biopsy shows increased IELs and the subepithelial collagen layer is prominent. This
patient had reported watery diarrhea while on olmesartan (Benicar), an angiotensin two receptor
inhibitor.
 Figure 2.139 Lymphocytic/collagenous gastritis pattern, olmesartan. Biopsies of the gastric
oxyntic mucosa corresponding to previous figure show a similar pattern of injury. There are
increased IELs, a mixed chronic inflammatory infiltrate in the lamina propria, and a prominent
subepithelial collagen table.

Figure 2.140 Lymphocytic/collagenous gastritis pattern, olmesartan (Masson’s trichrome). A

Masson’s trichome stain confirms that the subepithelial band is composed of abnormal collagen
deposition and not simply edema. Note the entrapped inflammatory cells and small vessels
within the collagen. Discontinuation of olmesartan resulted in clinical improvement of
symptoms.

Figure 2.141 Lymphocytic gastritis pattern, lymphoepithelial lesion, mucosa associated lymphoid
tissue (MALT) lymphoma. These gastric glands have been damaged by intraepithelial
lymphocytes. This pattern of injury is termed lymphoepithelial lesion (LEL), composed of three
or more lymphocytes within the gland epithelium. Note the smaller gland that has been almost
entirely obliterated by these LELs (arrowhead), and the background intense lymphocytic infiltrate
in the lamina propria. By comparison, lymphocytic gastritis is composed of a mixed
inflammatory infiltrate in the lamina propria and single, scattered intraepithelial lymphocytes.
 Figure 2.142 Lymphocytic gastritis pattern, mucosa-associated lymphoid tissue (MALT)
lymphoma. The low power appearance shows a prominent expansion of the lamina propria by a
monomorphic population of cells that has overrun the glandular architecture and has infiltrated
through the muscularis mucosae. Intraepithelial lymphocytes are hard to appreciate at this
power, and although a benign-appearing lymphoid follicle is present, the overall findings suggest
lymphoma.

FAQ: How many intraepithelial lymphocytes are too many? Am I

supposed to count the lymphocytes?
Answer: More than 25 intraepithelial lymphocytes per 100 epithelial
cells are considered abnormal, but counting is rarely necessary. Most
cases contain sufficient numbers of intraepithelial lymphocytes such
that the pattern of lymphocytic gastritis can be identified at scanning
magnification, obviating the need for intraepithelial lymphocyte
counts.

KEY FEATURES of the Lymphocytic Gastritis Pattern:

• The endoscopic appearance most commonly shows erythema.
• The two most common associations are Helicobacter infection and
celiac disease.
• IELs are most prominent in the superficial epithelium of the oxyntic
mucosa.
• The intraepithelial lymphocytes are most commonly CD8+
cytotoxic/suppressor T cells.
• Most patients respond to treatment of their associated condition.
PEARLS & PITFALLS
Be aware that medications can be an important cause of both
lymphocytic gastritis and celiac disease-like changes of the small
bowel (Figs. 2.138–2.140).99,100 For example, ticlopidine, a platelet
aggregation inhibitor, and olmesartan, an angiotensin II receptor
antagonist, have been implicated in intraepithelial lymphocytosis. In
particular, olmesartan has been shown to cause a severe sprue-like
small bowel enteropathy in some patients, who present with chronic
diarrhea and weight loss, and whose biopsies show villous blunting
and prominent intraepithelial lymphocytosis. Histologically, a subset
(32%) of these patients additionally shows a lymphocytic or
collagenous pattern gastritis. Clinical or histologic improvement
occurs in all patients following discontinuation of the medication. See
also Malabsorption pattern, Duodenum Chapter.

FAQ: How frequently is lymphocytic gastritis associated with H.

pylori infection?
Answer: Up to 85% of patients with lymphocytic gastritis have
positive IgG antibodies against Helicobacter, but only 27% of these
have identifiable organisms on mucosal biopsy.38,92,96,101–104 Thus, the
absence of demonstrable organisms does not entirely exclude
Helicobacter infection. Additional clinical testing is recommended in
this situation, such as serology for Helicobacter IgG antibody, urea
breath test, and stool antigen testing, each of which has relatively high
sensitivity and specificity (ranging from 89% to 100% and 76% to
100%, respectively).

FAQ: How frequently is lymphocytic gastritis associated with

celiac disease?
Answer: Up to one third of adult patients and 60% to 100% of
pediatric patients have underlying celiac disease (Figs. 2.132 and
2.133).91,102,105–108 Presumably, the mechanism of gastric
intraepithelial lymphocytosis in patients with celiac disease is similar
 to the immune response seen in the small bowel whereby lymphocytes
develop gluten sensitivity. Increased severity of small intestinal
disease has been observed in patients with lymphocytic gastritis.
Treatment with gluten withdrawal frequently results in improvement
of clinical symptoms and resolution of histologic lesions.

SAMPLE NOTE: LYMPHOCYTIC GASTRITIS PATTERN, NOS

Stomach, Antrum and Body, Biopsy:
• Gastric antral and oxyntic mucosa with lymphocytic gastritis pattern.
• A Helicobacter immunostain is nonreactive.
Note: The lymphocytic gastritis pattern is etiologically nonspecific. It is
an uncommon injury pattern that has been associated with various
conditions, most notably celiac disease and Helicobacter infection. Other
less common associations include other infections, other immune
mediated disorders (lymphocytic enterocolitis, Crohn disease, common
variable immunodeficiency), and medication effect (ticlopidine and
olmesartan). Approximately 20% of cases are idiopathic. Although a
Helicobacter immunostain is nonreactive, in this case it would be
worthwhile to correlate with Helicobacter serologies, breath test, or stool
antigen study, in addition to consideration of celiac disease.

COLLAGENOUS GASTRITIS PATTERN

Figure 2.143 Collagenous gastritis pattern, olmesartan. At scanning magnification, this gastric
biopsy has a prominent pink band below the surface epithelium. Focal areas of surface
epithelium have also sheared off (far left), a characteristic finding in collagenous enteritis. Most
cases are not as obvious as this example, and may require confirmation with a Masson’s
 trichrome stain to highlight the collagen deposition.

CHECKLIST: Clinical Associations in Adults with the

Collagenous Gastritis Pattern
Immune-Mediated Conditions: Celiac Disease, Hashimoto Thyroiditis,
Sjögren Syndrome, Polymyositis
Collagenous Enteritis/Colitis
Helicobacter
Medications (i.e., Olmesartan)

Collagenous gastritis is characterized by the deposition of a subepithelial

collagen band and accompanying inflammatory infiltrate (Fig.
2.143).99,109–112 The pathogenesis of this rare disease remains unclear.
The disease is more common in adults (range from 1 to 77 years), in
whom associations include lymphocytic gastritis (33%), celiac disease or
collagenous enteritis (25%), collagenous colitis, other immune-mediated
disorders (such as Hashimoto thyroiditis, Sjögren syndrome, and
polymyositis), Helicobacter, and medication injury (i.e., olmesartan). In
contrast, associated intestinl and autoimmune diseases are not reported
in children with collagenous gastritis. In the pediatric setting,
endoscopic findings include a nodular, erythematous mucosa, and these
findings are usually limited to the stomach. By comparison, endoscopic
findings in adults typically include gastric atrophy with diffuse
involvement of the gastrointestinal tract. Histologically, lamina propria
lymphoplasmacytosis, patchy subepithelial collagen deposition of
variable thickness, injury to and detachment of the surface epithelium,
and glandular atrophy are seen (Figs. 2.143–2.151). Because the
pathogenesis of collagenous gastritis is so poorly understood in children,
treatment remains challenging and poorly defined. For adults, treatment
of any underlying associated diseases is recommended, such as a gluten-
free diet in patients with celiac disease, steroids in patients with
collagenous colitis, and discontinuation of offending medications (i.e.,
olmesartan).
Figure 2.144 Collagenous gastritis pattern, olmesartan. This antrum biopsy shows intraepithelial
lymphocytosis and a markedly abnormal subepithelial collagen table. The pink band is seen right
beneath the surface epithelium and the lamina propria contains increased chronic inflammation.
This patient was taking olmesartan, an antihypertensive drug known to cause collagenous
gastritis and sprue-like enteropathy.

Figure 2.145 Collagenous gastritis pattern, olmesartan, (Masson’s trichrome). A trichrome stain
of the previous case confirms that the pink band is composed of collagen. The surface epithelium
has sheared away from the collagen in this deeper level, a finding highly characteristic of
collagenous enteritis/colitis and not seen as often in the stomach. Note how the deep border of
the collagen band is markedly irregular, appearing to seep between the glands as if the collagen
were candle wax drippings.
 Figure 2.146 Collagenous gastritis pattern. A biopsy of the gastric body shows a thickened
subepithelial collagen table that has entrapped inflammatory cells and small vessels. The
background mucosa shows a mild chronic inflammatory infiltrate in the lamina propria and mild
intraepithelial lymphocytosis of the surface epithelium. This example is not as obvious as
previous figures, and some observers might suggest that the findings represent merely lamina
propria edema.

Figure 2.147 Collagenous gastritis pattern (Masson’s trichrome). A Masson’s trichrome stain of
the previous case highlights the irregularly expanded subepithelial collagen table. Again, note
the entrapped inflammatory cells and small vessels. The trichrome stain accentuates tendrils of
“candle wax drippings” percolating downward between the glands, a finding highly characteristic
of collagenous enteritis. The etiology of the collagenous gastritis in this case is unknown.
Figure 2.148 Collagenous gastritis pattern. Collagenous gastritis can be a patchy finding in the
stomach. This high-power field is adjacent to the one shown in the previous figure, and
abnormalities of the collagen table are not as appreciable on routine H&E examination.

Figure 2.149 Collagenous gastritis pattern (Masson’s trichrome). A Masson’s trichrome stain
highlights the irregular subepithelial collagen thickening. Not the entrapped inflammatory cells
and small vessels, as well as the background IELs.
Figure 2.150 Collagenous gastritis pattern. Another example has an irregular collagen table with
entrapped cells and small vessels, evident on H&E.

Figure 2.151 Collagenous gastritis pattern (Masson’s trichrome). A trichrome stain of the
previous case accentuates the irregular collagen tendrils similar to “candle wax drippings”.

GASTRIC EOSINOPHILIA PATTERN

Figure 2.152 Gastric mucosal eosinophilia pattern. When eosinophils extend into the glandular or
surface epithelium (arrowheads), the muscularis mucosae, or submucosa, this finding should be
considered abnormal and reported; however, there is currently no standard accepted threshold
for increased eosinophils of the gastric mucosa limited to the lamina propria.

CHECKLIST: Etiologic Considerations for the Gastric

Eosinophilia Pattern
Idiopathic Eosinophilic Gastritis and Gastroenteritis
Medications
Allergy
Helicobacter
Parasites
Inflammatory Bowel Disease
Connective Tissue Disorders and Vasculitis
Neoplasia

“Eosinophilic gastritis” is a designation reserved for cases in which

eosinophils infiltrate the surface or foveolar epithelium, the muscularis
mucosae or submucosa, or cases in which other mucosal damage (e.g.,
foveolar hyperplasia, architectural distortion, significant chronic or
active inflammation) is present (Figs. 2.152–2.156). By contrast, the
presence of increased eosinophils limited to the lamina propria is
referred to as “mucosal eosinophilia,” and has been associated with
numerous etiologies. This section briefly discusses several major
etiologic considerations of gastric eosinophilia pattern, including
idiopathic eosinophilic gastritis, medication injury, allergy, parasitic
infections, inflammatory bowel disease, connective tissue disorders and
vasculitis, and neoplasia.16,101,113–119

Figure 2.153 Gastric mucosal eosinophilia pattern, peripheral eosinophilia. At scanning

magnification, one can appreciate the expanded lamina propria with an eosinophilic hue in this
antral biopsy (bracket). This patient is known to have peripheral eosinophilia and increased
eosinophils in the small bowel and colon, as well, with an established diagnosis of idiopathic
eosinophilic gastroenteritis.

Figure 2.154 Gastric mucosal eosinophilia pattern, peripheral eosinophilia. Higher power of
previous case (Fig. 2.153). Numerous eosinophils are present in the lamina propria (arrowheads),
with clusters of eosinophils extending to the just below the surface epithelium. The exact
etiology of this patient’s diffuse eosinophilic gastroenteritis is unknown.
 Figure 2.155 Gastric mucosal eosinophilia pattern, eosinophilic esophagitis (EoE). Numerous
eosinophils (arrowheads) are percolating between the oxyntic glands of this gastric biopsy. This
patient has an established diagnosis of EoE. Gastric mucosal eosinophilia in association with EoE
has been reported, but is relatively uncommon. The association between these two entities is
unclear.

Figure 2.156 Gastric mucosal eosinophilia pattern. Increased numbers of eosinophils are present
in the lamina propria of this gastric biopsy. An etiology for this finding was not apparent, and a
list of differential diagnoses was given to aid in clinical correlation.

FAQ: How many eosinophils are too many?

Answer: The normal number of eosinophils in the stomach continues
to undergo modification and may be influenced by geographic
location and seasonal variation, among other variables; however,
studies on normal numbers of gastric eosinophils show concordance,
despite different mechanisms for counting: Some have reported
 between 8 and 11 eosinophils per HPF, whereas others have reported
12 per HPF, averaged over five fields, and still others report <38
eosinophils per square millimeter. Despite the lack of a widely
accepted methodology for reporting numbers of eosinophils in the
stomach, the updated Sydney system suggests that the presence of
intraepithelial eosinophils is always abnormal.

FAQ: Is there significance to eosinophil degranulation?

Answer: Yes.
Some experts believe that specific histopathologic findings are more
suggestive of eosinophilic mediated pathology, such as
• Degranulated Eosinophils
• Increased Eosinophils
• Intraepithelial Eosinophils
• Eosinophil Gland/Crypt Abscesses
• Epithelial Degenerative and Regenerative Changes
• Foveolar/Crypt Hyperplasia
• Eosinophils in the Muscularis Mucosae or Submucosa
• Minimal Acute or Chronic Inflammation

IDIOPATHIC EOSINOPHILIC GASTRITIS AND

GASTROENTERITIS
Isolated (idiopathic) eosinophilic gastritis is rare and poorly understood.
This diagnosis presupposes that other causes of gastric eosinophilia have
been excluded. Some authors suggest consideration of idiopathic
eosinophilic gastritis when the following criteria are met113,115,120–122: 1.
The gastric biopsies show an average density of ≥127 eosinophils/mm2
(or ≥30 eosinophilia per HPF on microscopes equipped with wide-lens
oculars) in at least five separate HPFs.
2. Other potential causes of eosinophilia have been excluded (i.e.,
Helicobacter, Crohn disease, parasitic infections, and hematologic or
lymphoid disorders).
SAMPLE NOTE: ISOLATED EOSINOPHILIC GASTRITIS
GASTRIC EOSINOPHILIA, NOS
Stomach, Antrum and Body, Biopsy:
• Gastric antral and oxyntic mucosa with histologic eosinophilic gastritis.
• Negative for Helicobacter.
Note: The histologic sections show intraepithelial eosinophils in addition
to increased lamina propria eosinophils (eosinophils per HPF, averaged
over five fields). Eosinophils in the stomach are a nonspecific finding
and have been associated with food allergy, medication injury,
Helicobacter infection or treatment, parasitic infection, Crohn disease,
hematologic or lymphoid disorders, and connective tissue disorders.
Some cases remain idiopathic, and exclusion of involvement of other
sites in the gastrointestinal tract (i.e., the small bowel and colon) may be
of interest. Correlation with clinical and serologic information is
suggested.

MEDICATIONS
Medication induced eosinophilia of the gastrointestinal tract has been
described more fully in colonic mucosa (Figs. 2.157–2.160). See also
Eosinophilia Pattern, Colon Chapter. A laundry list of medications has
been implicated, including: aspirin, clozapine, carbamazepine,
diclofenac, enalapril, gemfibrozil, ibuprofen, nimesulide, rifampicin,
tacrolimus, ticlopidine, and therapeutic gold compounds.123–132 Note
that a number of these are NSAIDs, a commonly implicated drug in
various mucosal injuries of the gastrointestinal tract; however,
documentation of medication injury in the stomach is limited to case
reports. Practically speaking, an effort to review the patient’s medication
list for known offenders and other pertinent clinical findings (such as
concurrent dermatitis that might suggest medication injury) may be
helpful to include in the note.
Figure 2.157 Gastric mucosal eosinophilia pattern, medication injury. This gastric biopsy shows
numerous eosinophils (arrowheads). In the absence of clinical history, this finding would be
entirely nonspecific; however, investigation into this patient’s chart showed that he had history
significant for chronic lymphocytic leukemia and was experiencing abdominal distress, diarrhea,
and dermatitis which were temporally related to the start of chemotherapy. The overall clinical
findings in combination with the histology strongly suggest medication injury.

Figure 2.158 Small bowel eosinophilia pattern, medication injury. This small bowel biopsy
corresponds to the previous case (Fig. 2.157). Note the increased eosinophils both in the lamina
propria and within the glandular epithelium (arrowhead). The finding of eosinophilia in multiple
GI sites suggests that the disease process is more diffuse or systemic in nature. The patient had
concurrent dermatitis, in keeping with medication injury.
 Figure 2.159 Gastric mucosal eosinophilia pattern, medication injury. This gastric biopsy was
obtained as part of a graft versus host disease (GVHD) protocol in a patient who had received a
bone marrow transplant. At low power, damaged glands (arrow) suggest an element of GVHD,
but the eosinophilic gastritis seen in the background is uncharacteristic for GVHD. Investigation
into the patient’s drug list revealed administration of mycophenolate mofetil, an
immunosuppressant that has been associated with gastrointestinal mucosal eosinophilia.

Figure 2.160 Gastric mucosal eosinophilia pattern, medication injury. Higher magnification of
previous case (Fig. 2.159). Eosinophilic abscesses (arrowheads) are also present, an uncommon
finding in eosinophilic gastritis.

SAMPLE NOTE: GASTRIC EOSINOPHILIA IN A PATIENT

WITH CLINICAL FEATURES SUGGESTING MEDICATION
INJURY
Stomach, Antrum and Body, Biopsy:
• Gastric antral and oxyntic mucosa with erosion and lamina propria
eosinophils with focal clustering.
• Negative for Helicobacter.
Note: Noted is the patient’s history of chronic lymphocytic leukemia on
chemotherapy with complaints of abdominal pain and dermatitis. The
histologic sections of the gastric mucosa show scattered eosinophils in
the lamina propria, and focal clustering of eosinophils. The prominence
of eosinophils in this particular clinical setting raises the possibility of
medication injury, particularly in light of the concurrent dermatitis.
Parasitic infection is also a consideration in a patient who may be
immunocompromised. Other etiologies of eosinophilia in the
gastrointestinal tract include food allergies, idiopathic eosinophilic
gastroenteritis, and connective tissue disorders, among others.
Correlation with clinical information is recommended.

ALLERGY
The diagnosis of allergic eosinophilic gastritis remains clinical and the
patients are often evaluated by an allergy specialist to identify specific
food allergens.133,134 Eosinophilia may be seen in any of the gastric
layers, including the muscularis propria and serosa. Mucosal
involvement is the most common, reported to occur in 25% to 100% of
cases. Patients typically present with nausea, vomiting, diarrhea, and
abdominal pain. Some patients show occult blood loss, anemia, and
protein-losing enteropathy. Involvement of the muscularis propria can be
associated with gastric outlet obstruction or stricture, whereas patients
with serosal involvement can present with bloating and ascites. Allergic
eosinophilic gastrointestinal disorders can cause failure to thrive or food
refusal in infants and toddlers. Peripheral eosinophilia occurs in 50% to
60% of cases and the sedimentation rate is elevated in approximately
25% of cases, both return to normal with effective diet modification.
Other medical treatments include montelukast (a leukotriene receptor
antagonist), cromolyn sodium (a mast cell stabilizer), and oral steroids
such as budesonide.

Figure 2.161 Gastric mucosal eosinophilia pattern, parasitic infection. This gastric biopsy shows
an intense and striking diffuse eosinophilia. Note the background acute inflammation, as well.
The presence of acute inflammation should prompt a search for infectious etiologies.

Figure 2.162 Gastric mucosal eosinophilia pattern, parasitic infection. Additional field of
 previous case (Fig. 2.161). Numerous cross sections of adult Strongyloides stercoralis are seen in
association with an intense acute and eosinophilic inflammatory infiltrate. Photograph courtesy
of Dr. Fabio Tavora, Argos Laboratories, Fortaleza, Brazil.

PARASITIC INFECTION
Eosinophilic infiltrates and peripheral eosinophilia are common signs of
helminthic infection, particularly Anisakis spp. Larvae.135,136 Helminthic
infection is most commonly seen in the small intestine, but can
occasionally be seen in the stomach. Focal dense eosinophilic infiltrates
can be found adjacent to worms, larvae, or eggs (Figs. 2.161 and 2.162).
See also Eosinophilia Pattern, Small Bowel Chapter.

INFLAMMATORY BOWEL DISEASE

Eosinophils are characteristic in the inflammatory infiltrates of
inflammatory bowel disease.115,137,138 Other characteristic histologic and
clinical findings, however, are necessary to establish this diagnosis; for
example, isolated mucosal eosinophilia in the absence of granulomata,
established active chronic inflammatory injury, or lower gastrointestinal
tract disease is purely nonspecific, but may be listed among the
differential diagnoses of otherwise idiopathic gastric eosinophilia.

CONNECTIVE TISSUE DISORDER AND VASCULITIS

Although better described in the colon, the presence of eosinophils in the
stomach should still raise the differential diagnosis of connective tissue
disorders such as systemic lupus erythematosus, scleroderma,
dermatomyositis, and polymyositis.139–142 The gastrointestinal findings
in connective tissue disorders are nonspecific but may prompt a note
suggesting ancillary studies for serum autoantibodies. By comparison,
specific histologic features of vasculitis may be found in the submucosa,
which contains abundant blood vessels and lymphatics; for example,
Churg–Strauss syndrome shows systemic necrotizing vasculitis, and the
gastrointestinal tract is affected in 30% of patients. Eosinophil-rich
granulomas with necrosis involving medium to small sized vessels are
characteristic findings. Another systemic necrotizing inflammatory
disease of small and medium sized arteries is polyarteritis nodosa, and it
affects the GI tract in up to 25% of cases. These lesions often involve
bifurcations of arteries that lead to aneurysm, thrombosis or rupture of
vessels. Although endoscopic biopsies provide limited submucosa,
careful review of this layer when increased eosinophils are present
should be performed.

NEOPLASIA
Systemic mastocytosis, Langerhans cell histiocytosis, inflammatory
fibroid polyp, melanoma and Hodgkin lymphoma are a few examples of
neoplastic processes that can induce an eosinophilic infiltrate. In
general, careful consideration of neoplasia is worthwhile in cases of
eosinophilia.

KEY FEATURES of the Gastric Eosinophilia Pattern:

• Eosinophilic gastritis refers to eosinophilia in conjunction with
mucosal damage.
• Mucosal eosinophilia refers to eosinophilia in the absence of mucosal
damage.
• Common etiologic considerations include idiopathic eosinophilic
gastritis, medication injury, allergy, Helicobacter infection, parasitic
infections, inflammatory bowel disease, connective tissue disorders and
vasculitis, and neoplasia.
• The threshold for increased eosinophils is suggested at >30
eosinophils per HPF, averaged over five fields.
HYPERPLASTIC PATTERN

Figure 2.163 Gastric hyperplasia pattern example, Ménétrier disease. A gastrectomy was
performed in this patient with Ménétrier disease for intractable protein losing gastropathy and
worsening anasarca. Grossly, the body and fundus had innumerable giant hyperplastic folds (not
shown). Histologically, the folds consisted of prominent foveolar hyperplasia with oxyntic gland
loss, in keeping with the clinicopathologic diagnosis of Ménétrier disease. CMV immunostain was
negative.

Gastric hyperplasia can be difficult to appreciate in a mucosal biopsy

specimen, but the findings can appear dramatic to the endoscopist (Fig.
2.163). Clinicians often use the following common red flags to describe
this sometimes striking finding: “gastric hyperplasia,” “thickened gastric
folds,” or “giant folds.” Accurate diagnosis is facilitated by first
segregating the hyperplastic pattern according to the constituents of the
hyperplasia: oxyntic gland hyperplasia versus foveolar hyperplasia.

CHECKLIST: Etiologic Considerations for the Gastric

Hyperplasia Pattern
Oxyntic Gland Hyperplasia
Sporadic
Sporadic Fundic Gland Polyps (favor related to proton pump
 inhibitors)
Syndromic
Familial Adenomatous Polyposis Syndrome
Attenuated Familial Adenomatous Polyposis Syndrome
MutYH-Associated Polyposis
Sporadic Fundic Gland Polyposis Syndrome
Zollinger–Ellison syndrome, sporadic or familial
Foveolar Hyperplasia
Sporadic
Sporadic Gastric Hyperplastic Polyp
Gastric Juvenile Polyp
Gastric Peutz–Jeghers Polyp
Syndromic
Gastric Juvenile Polyp
Gastric Peutz–Jeghers Polyp
PTEN syndromes (Cowden syndrome, Bannayan–Riley–Ruvalcaba
syndrome, Adult Lhermitte–Duclos disease)
Cronkhite–Canada Syndrome
Ménétrier Disease

OXYNTIC GLAND HYPERPLASIA

Oxyntic gland hyperplasia can result in either discreet gastric fundic
polyps or giant gastric folds. Fundic gland polyps are the most common
gastric polyp, comprising 77% of all gastric polyps in a study of over
120,000 patients.143 They are seen in up to 5.9% of adults undergoing
upper-tract endoscopy.144 In the sporadic setting, they are linked to
proton pump inhibitor usage, and they regress with proton pump
inhibitor cessation.145 Whether sporadic or syndromic, all fundic gland
polyps consist of dilated cystic oxyntic glands with hypertrophic parietal
cells whose luminal surface is often protuberant or “snout”-like (Figs.
2.164–2.173). Noted clinical associations include gastroesophageal
reflux disease, gastric heterotopia, hyperplastic polyps (in men) and
adenomas (in women) of the colon. They are inversely associated with
Helicobacter infection, active gastritis, and neoplasia.144 In a study of
over 100,000 patients in North America, there were no cases of high-
grade dysplasia or carcinoma, suggesting the progression to carcinoma is
uncommon in the sporadic setting.144 However, associations with high-
grade dysplasia and carcinoma exist; these reports are predominantly in
the syndromic setting.146,147 When the fundic gland polyps are
innumerable or dysplastic, syndromic polyposis should be considered.
Syndromic etiologies include familial adenomatous polyposis syndrome,
attenuated familial adenomatous polyposis syndrome, MutYH-associated
polyposis, and sporadic fundic gland polyposis syndrome.148 Sorting
through these possibilities requires correlation with family history,
physical examination, endoscopic appearance, and, in challenging cases,
genetic studies: familial adenomatous polyposis syndrome and
attenuated familial adenomatous polyposis syndrome are characterized
by APC mutations; MutYH-associated polyposis is characterized by
MutYH mutations; sporadic fundic gland polyposis syndrome is
characterized by β-catenin mutations (Table 2.3).

Figure 2.164 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. This fundic gland
polyp was incidentally found in a 55 year-old man taking proton pump inhibitors for
gastroesophageal reflux disease. Histologically, the polyp consists of dilated oxyntic glands.
Figure 2.165 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. There is no reliable
histologic means to distinguish a sporadic fundic gland polyp from a fundic gland polyp due to
familial adenomatous polyposis. The diagnostic distinction rests entirely on the associated
clinical setting, gross findings, and, sometimes, genetic studies. In this case, the patient was
taking proton pump inhibitors for Barrett esophagus, and an isolated gastric body polyp was seen
consisting of dilated oxyntic glands. These clinical features are in keeping with a sporadic fundic
gland polyp.

Figure 2.166 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp.
 Figure 2.167 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. Note the
characteristic cystically dilated oxyntic glands of this sporadic fundic gland polyp.

Figure 2.168 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp.

Figure 2.169 Oxyntic gland hyperplasia pattern, fundic gland polyp, familial adenomatous
polyposis. This case originated from a young man with innumerable stomach and colonic polyps.
Subsequent APC mutational studies were positive, confirming a diagnosis of familial
adenomatous polyposis.

Figure 2.170 Oxyntic gland hyperplasia pattern, fundic gland polyp, familial adenomatous
polyposis. All of the sampled stomach polyps were fundic gland polyps.

Figure 2.171 Oxyntic gland hyperplasia pattern, fundic gland polyp, sporadic fundic gland
polyposis syndrome. This patient had innumerable fundic gland polyps. Familial adenomatous
polyposis was excluded based on an unremarkable endoscopic examination of the small and large
bowel and normal APC genetic studies. β-catenin mutations were identified, confirming a
diagnosis of sporadic fundic gland polyposis syndrome.
 Figure 2.172 Oxyntic gland hyperplasia pattern, fundic gland polyp, sporadic fundic gland
polyposis syndrome. Under oil immersion, note the protuberant apical snouts pushing into the
cyst lumen. These features can be seen in either the sporadic or syndromic setting.

Figure 2.173 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp with low-grade
dysplasia. Low-grade dysplasia refers to the depicted nuclear enlargement, hyperchromasia, and
pseudostratification. This focus looks distinct and has no associated inflammation to explain the
cytologic atypia. Dysplastic fundic gland polyps occur both in either the sporadic or syndromic
setting.

If massive oxyntic gland hyperplasia is seen, Zollinger–Ellison

syndrome should be considered (Figs. 2.174 and 2.175). This syndrome
describes the association of a gastrinoma of the small bowel (more
common) or pancreas (less common), oxyntic gland hyperplasia, and
gastric and small bowel ulcerations. This constellation of findings is due
to tremendous tumor-mediated hypergastrinemia, which stimulates the
oxyntic mucosa to release tremendous amounts of acid, resulting in
gastric and duodenal ulcerations. The majority of patients with
Zollinger–Ellison syndrome are sporadic, but up to 30% are owing to a
genetic defect in the MEN1 tumor suppressor as part of multiple
endocrine neoplasia type 1 (MEN1). Patients with MEN1 are important
to identify because of the associations with other endocrinopathies (such
as parathyroid and pituitary gland abnormalities) and neoplasia. MEN1
is often referred to as the “3P syndrome” based on its associations with
neoplasms of the Parathyroid, Pituitary, and Pancreas (and small bowel)
neuroendocrine tumors. It is inherited in an autosomal dominant
inheritance pattern and imparts similar risks to the patient’s relatives.
Determination of serum gastrin levels is theoretically helpful with
gastrin levels at least ≥10 times normal suggestive of Zollinger–Ellison
syndrome. Because approximately two-thirds of Zollinger–Ellison
patients have nondiagnostic serum gastrin, other considerations include
Helicobacter, renal failure, gastric outlet obstruction, and short bowel
syndrome.149 In ambiguous cases, correlation with Helicobacter studies,
gastric pH, careful imaging studies of the small bowel and pancreas,
somatostatin receptor scintigraphy, and or MEN1 genetic sequencing
studies are a consideration.

TABLE 2.3: Select Gastric Polyposis Summary

Sources: Adapted from Seshadri D, Karagiorgos N, Hyser MJ. A case of cronkhite-Canada
syndrome and a review of gastrointestinal polyposis syndromes. Gastroenterol Hepatol (N Y).
2012;8:197–201; Lam-Himlin D, Arnold, CA, De Petris G. Gastric polyps and polyposis
syndromes. Diagnostic Histopathology. 2013, http://dx.doi.org/10.1016/j.mpdhp.2013.12.002.

Figure 2.174 Oxyntic gland hyperplasia pattern, Zollinger–Ellison syndrome. This partial gastric
resection originated from a patient with a widely metastatic gastrinoma and clinically significant
GI bleeding. The patient was found to have Zollinger–Ellison syndrome, and a partial gastric
resection and vagotomy were performed to reduce the gastric acid secretion. In Zollinger–Ellison
syndrome, the tumor mediated hypergastrinemia results in overwhelming gastric acid
production, extensive gastric and duodenal ulcerations, and sometimes, as in this case, clinically
significant GI bleeding. The stomach resection had numerous, giant, hyperplastic folds in the
body and fundus. At low power, note that this properly orientated section entirely fills the entire
2× field (!) and scattered dilated oxyntic glands are seen throughout. In the case of an
unremarkable gastric resection, the oxyntic mucosa would take up a fraction of this width.

Figure 2.175 Oxyntic gland hyperplasia pattern, Zollinger–Ellison syndrome. At higher power, a
number of dilated oxyntic glands are seen. The epithelial cells have apical snouts or rounded
luminal surfaces (arrowheads).

KEY FEATURES of Oxyntic Gland Hyperplasia:

• Discreet gastric polyps
• Fundic gland polyps are the most common type of gastric polyp.
• They are most common in the sporadic setting (favored related
to proton pump inhibitors).
• Syndromic settings include familial adenomatous polyposis
syndrome, attenuated familial adenomatous MutYH-associated
polyposis, and sporadic fundic gland polyposis syndrome.
• Dysplastic fundic gland polyps have a negligible rate of
progression (rare case of progression exist, mainly in the
syndromic setting).
• Giant gastric folds
• Zollinger–Ellison syndrome
• Triad of gastrinoma (small bowel >>> pancreas), oxyntic gland
hyperplasia, and gastric and small bowel ulcerations.
 • Secondary to tumor-mediated hypergastrinemia.
• Most are sporadic.
• Thirty percent are familial due to MEN1 tumor suppressor
mutation.

Figure 2.176 Oxyntic gland hyperplasia pattern. This biopsy was of nonpolypoid mucosa and
shows slight oxyntic gland dilatation with mild luminal snouting. This nonspecific pattern can be
seen with any process that interferes with gastric acid production; it is not specific for proton
pump inhibitor usage.

FAQ: If the biopsy is of flat mucosa and slight oxyntic gland

dilatation is seen, is “proton-pump inhibitor change” appropriate
(Fig. 2.176)?
Answer: Probably not.
In the sporadic setting, oxyntic gland hyperplasia is seen with any
etiology characterized by low gastric acid production and,
consequently, hypergastrinemia. Recall, gastric acid inhibits G-cell
mediated production of gastrin and, conversely gastric acid depletion
relieves this negative inhibition and results in enhanced G-cell
mediated release of gastrin, in attempts to restore acid production
(Fig. 2.80). High gastrin levels stimulate the oxyntic mucosa to
produce acid and induce oxyntic gland hyperplasia, resulting in
dilated oxyntic glands and hypertrophic oxyntic epithelium with
protuberant luminal “snouts”. This nonspecific morphology is seen
 with any process that interferes with gastric acid production, such as
proton pump inhibitors, autoimmune metaplastic atrophic gastritis,
and late environmental metaplastic atrophic gastritis (Helicobacter,
medications, reactive gastritis/gastropathy, etc.). To further emphasize
this point, Helicobacter infections were recently found to produce
identical histologic findings in oxyntic mucosa as those seen with
PPIs.150 As a result, describing the histologic features of oxyntic
hyperplasia without presuming the changes are linked to a particular
medication is advised.

FOVEOLAR HYPERPLASIA
Hyperplasia of the superficial gastric foveolar epithelium can result in
either discreet gastric hyperplastic polyps or giant gastric folds. Because
superficial gastric foveolar epithelium lines the entire stomach, this
hyperplastic pattern can be seen in any stomach compartment. Gastric
hyperplastic polyps are the second most common stomach polyp,
comprising 17% of all stomach polyps.143 They are seen in any
compartment of the stomach: antral (56%), oxyntic (60%), and
transitional (60%).151 Earlier work found up to 85% were associated
with background inflammatory injury, such as Helicobacter (25%),
reactive gastritis/gastropathy (21%), autoimmune metaplastic atrophic
gastritis (12%), and environmental metaplastic atrophic gastritis (8%),
suggesting gastric hyperplastic polyps are a marker for nonspecific
gastric mucosal injury, unlike their colonic counterparts.152 As a result,
gastric hyperplastic polyps can be an important red flag for one to
consider other specific etiologic agents of mucosal injury (Figs. 2.177
and 2.178). Histologically, gastric hyperplastic polyps are benign
neoplasms defined by polypoid foveolar hyperplasia, cystic dilatation of
antral and pyloric glands, and increased lamina propria acute and
chronic inflammation. Ulcerations, erosions, increased lamina propria
acute and chronic inflammation, and fibromuscular hyperplasia/prolapse
change are common (Figs. 2.179–2.184).
Figure 2.177 Foveolar hyperplasia pattern, gastric hyperplastic polyp with iron deposition.
Unlike colon hyperplastic polyps, gastric hyperplastic polyps are a result of mucosal injury.
Careful inspection will occasionally uncover the potential injurious agent. In this case, iron
deposition was found (arrowhead), a potential contributor to this injury pattern.

Figure 2.178 Foveolar hyperplasia pattern, gastric hyperplastic polyp with iron deposition.
Higher power of previous figure.
Figure 2.179 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. This antral gastric
hyperplastic polyp appears polypoid at scanning magnification. The characteristic histologic
features include prominent foveolar hyperplasia and an inflammatory rich stroma. Focal
intestinal metaplasia is also seen (arrowhead).

Figure 2.180 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Higher power of
previous case (Fig. 2.179) shows the focal intestinal metaplasia.

Lam-Himlin and colleagues found sporadic gastric hyperplastic polyps

defied reliable distinction from syndromic gastric juvenile polyps (Figs.
2.185–2.189) and syndromic gastric Peutz–Jeghers polyps (Figs. 2.190
and 2.191), despite the latter two polyps’ more characteristic histology
when seen in the small and large bowel.151 Similarly, nearly
indistinguishable morphology is seen in polyps of Cronkhite–Canada
syndrome (Figs. 2.192–2.194) and PTEN-associated hamartomatous
polyps (Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Adult
Lhermitte–Duclos disease) (Figs. 2.195 and 2.196). Although gastric
polyps are themselves benign, if they are linked to a polyposis syndrome
associated with an increased risk of neoplasia or mortality, then they
become important red flags for close clinical follow-up. Since the
histologic features of sporadic and syndromic gastric hyperplastic polyps
are indistinguishable, awareness of these clinical syndromes and
diagnostic criteria is important to assure appropriate clinical follow-up
(Table 2.3).153,154 In challenging cases, correlation with endoscopic
evaluation of the small and large bowel can be helpful to highlight the
syndromic polyps’ more characteristic features, as is molecular
correlation (syndromic juvenile polyposis is characterized by SMAD4,
BMPR1 A mutations; syndromic Peutz–Jeghers is characterized by
STK11/LKB1 germline mutations; Cowden syndrome, Bannayan–Riley–
Ruvalcaba syndrome, Adult Lhermitte–Duclos disease have PTEN
mutations).

Figure 2.181 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. In this polyp,
foveolar hyperplasia and inflammatory stroma is seen. The foveolar epithelium is mucin
depleted, a manifestation of focally reactive and regenerative change typical of this injury
pattern.
 Figure 2.182 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Gastris
hyperplastic polyps are often eroded and ulcerated with acute and chronically inflamed lamina
propria, as in this case.

Figure 2.183 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Higher power.
The intact epithelium shows foveolar hyperplasia and cystic dilatation of the antral/pyloric
glands.
 Figure 2.184 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Note the
prominent foveolar hyperplasia and cystic dilatation of the antral/pyloric glands.

Figure 2.185 Foveolar hyperplasia pattern, juvenile polyposis syndrome, gastric resection. This
partial gastric resection was for gastric obstruction secondary to innumerable gastric polyps in a
patient with established juvenile polyposis syndrome.
 Figure 2.186 Foveolar hyperplasia pattern, juvenile polyposis syndrome, gastric resection.
Juvenile polyposis syndrome is characterized by SMAD4 and BMPR1 A mutations.

Figure 2.187 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Corresponding

histologic sections of the polyps show indistinguishable morphology from sporadic gastric
hyperplastic polyps: foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and an
inflamed lamina propria.
 Figure 2.188 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Alternate field.

Figure 2.189 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Higher power. Foveolar
hyperplasia, cystic dilatation of the antral/pyloric glands, and an inflamed lamina propria is
seen. This gastric juvenile polyp is indistinguishable from a sporadic gastric hyperplastic polyp.

Figure 2.190 Foveolar hyperplasia pattern, Peutz–Jeghers polyp. This gastric polyp features
foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and an inflamed lamina
propria. Scattered smooth bundles are seen (arrowheads), a feature which can be seen as a
manifestation of prolapse injury in large polyps of any sort, and also in gastric Peutz–Jeghers
polyps. In the small bowel and colon, these lesions are more easily recognized based on the
prominent arborizing smooth muscle fibers enveloping large groups of unremarkable mucosa.
Analogous findings in the stomach are minimal and nonspecific.
Figure 2.191 Foveolar hyperplasia pattern, Peutz–Jeghers polyp. Higher power of previous case
(Fig. 2.190). Patients with syndromic Peutz– Jeghers have germline STK11/LKB1 mutations and
a 93% lifetime risk for malignancy, including carcinomas of the gastrointestinal tract, breast,
ovary, and testis. Sporadic Peutz–Jeghers polyps have a similar lifetime risk of malignancy, and
require similarly close surveillance.

Figure 2.192 Foveolar hyperplasia pattern, Cronkhite–Canada syndrome. In Cronkhite–Canada

syndrome, both the polyp and intervening nonpolypoid mucosa show similar features to a
sporadic gastric hyperplastic polyp, as seen here. Note the foveolar hyperplasia, cystic dilatation
of the antral/pyloric glands, and the inflamed lamina propria.
 Figure 2.193 Foveolar hyperplasia pattern, Cronkhite–Canada syndrome. Cronkhite-Canada is a
noninherited clinical condition characterized by gastrointestinal hamartomatous polyposis,
diarrhea, and dermatologic abnormalities (alopecia, onychodystrophy, and hyperpigmentation).

Figure 2.194 Foveolar hyperplasia pattern, Cronkhite-Canada syndrome. Despite this bland
appearance, only 55% of patients are alive at 5 years after diagnosis; accurate, timely diagnosis is
critical to ensure appropriate supportive therapy. In isolation, these features are indistinguishable
from a gastris hyperplastic polyp.
Figure 2.195 Foveolar hyperplasia pattern, Cowden syndrome. Gastric polyps of PTEN syndromes
are indistinguishable from those of sporadic gastric hyperplastic polyps. PTEN syndromes of
interest include Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, and adult Lhermitte–
Duclos disease.

Figure 2.196 Foveolar hyperplasia pattern, Cowden syndrome. Higher power. The PTEN pathway
negatively regulates the phosphatidylinositol 3-kinase-AKT and mammalian target of rapamycin
(mTOR) signaling pathways, thereby, leading to tumorigenesis through interfering with cell
proliferation, cell cycle progression, and apoptosis.

If diffuse changes are seen involving both the polypoid and

nonpolypoid mucosa, Cronkhite–Canada should be considered. It is an
exceptionally rare, nonfamilial syndrome characterized by the triad of
alopecia, onychodystrophy, and hyperpigmentation.155,156 Patients
present with altered taste, diarrhea, nutritional deficiency, and
generalized edema. Histologic sections of both the polyp, and,
importantly, the nonpolypoid mucosa show features indistinguishable
from gastric hyperplastic polyps with foveolar hyperplasia, cystic
dilatation of antral and pyloric glands, increased lamina propria acute
and chronic inflammation, and fibromuscular hyperplasia/prolapse
change (Figs. 2.192–2.194). The 5-year mortality rate is 55%,
underscoring the importance of recognizing this pattern so that
appropriate supportive measures can be taken with electrolyte
stabilization and immunosuppression.

Figure 2.197 Foveolar hyperplasia pattern, Ménétrier disease. Note the prominent foveolar
hyperplasia and cystic dilatation of the superficial glands. The oxyntic glands are relatively
attenuated (bracket). Superficial biopsy of this lesion would be indistinguishable from a sporadic
gastric hyperplastic polyp.

Another consideration for massive foveolar hyperplasia is Ménétrier

disease. It is another rare syndrome (so an extremely popular subject for
examinations!) seen in the foveolar hyperplasia pattern. In biopsy
material, it is indistinguishable from sporadic gastric hyperplastic
polyps, but clinically it is characterized by gigantic gastric folds that
histologically consist of dramatic foveolar hyperplasia and oxyntic gland
loss (Fig. 2.197). Clinically, patients have protein losing enteropathy,
peripheral edema, and hypochlorhydria (increased pH) secondary to the
massive mucus secretion that impairs normal absorption and alters the
local microenvironment.157 In adults, the disease is chronic, progressive,
and associated with TGFα overexpression.158 Transgenic mice with TGFα
overexpression show Ménétrier disease–like findings, suggesting this
molecule may be play a central role in Ménétrier disease, at least in the
adult setting.159 In children, Ménétrier disease is associated with CMV
infection and can spontaneously regress.160 Treatment is generally
supportive with a high-protein diet, although some patients ultimately
require gastrectomies for intractable symptoms. Newer studies show
promising success with EGF receptor inhibitors, which competitively
inhibit TGFα binding and activation of the EGF receptor.161–163

KEY FEATURES of the Foveolar Hyperplasia Pattern:

• Discrete gastric polyps
• Sporadic gastric hyperplastic polyps indicate background mucosal
injury.
• They can be seen in any gastric compartment.
• Sporadic gastric hyperplastic polyps are histologically
indistinguishable from the syndromic counterparts (Gastric
Juvenile Polyp, Gastric Peutz–Jeghers Polyp, Cronkhite–Canada
Syndrome, PTEN syndromes (Cowden syndrome, Bannayan–Riley–
Ruvalcaba syndrome, Adult Lhermitte–Duclos disease), and
Ménétrier disease.
• Awareness of the syndromic associations is critical because of the
increased risk of neoplasia and mortality
• Giant gastric folds
• Cronkhite–Canada is characterized by the triad of alopecia,
onychodystrophy, and hyperpigmentation.
• Patients present with altered taste, diarrhea, nutritional deficiency,
and generalized edema.
• Histologic sections of both the polyp and nonpolypoid mucosa
show features indistinguishable from gastric hyperplastic polyps.
• The 5-year mortality rate is 55%.
• Treatment is supportive.
• Ménétrier disease is characterized by protein losing enteropathy,
peripheral edema, and hypochlorhydria (increased pH).
• Biopsy is indistinguishable from gastric hyperplastic polyp but the
clinical presentation consists of dramatic, giant gastric folds.
• Associated with TGFα overexpression in adults, and CMV in
 children.

PEARLS & PITFALLS

Patients with syndromic Peutz–Jeghers have germline STK11/LKB1
mutations and a 93% lifetime risk for malignancy, including
carcinomas of the gastrointestinal tract, breast, ovary, and testis.
Sporadic Peutz–Jeghers polyps have a similar lifetime risk of
malignancy, and require similarly close surveillance.164

GRANULOMATOUS GASTRITIS PATTERN

Figure 2.198 Granulomatous gastritis pattern. The granulomatous gastritis pattern is best
appreciated at low power. In this spectacular example, numerous large granulomata are seen
deep in the mucosa (arrowheads). This patient had a history of sarcoidosis, was status post
pancreatoduodenectomy for pancreatic adenocarcinoma, and was on chemotherapy.
Consequently, this patient had numerous potential causes for this nonspecific injury pattern.

CHECKLIST: Etiologic Considerations for the

Granulomatous Gastritis Pattern
Crohn Disease
Sarcoidosis
 Infection (Helicobacter, Mycobacterial, Fungal)
Medication
Foreign Body Reaction
Nearby Neoplasm
Vasculitis (Best Assessed on Resection Specimens)
Common Variable Immunodeficiency
Chronic Granulomatous Disease

Granulomata are collections of epithelioid histiocytes admixed with

lymphocytes and plasma cells (Fig. 2.198). They are occasionally
accompanied by foreign body-type giant cells (Figs. 2.199–2.205). The
morphology of the granulomata can offer some clues to a specific
etiology based on subtle histologic features: poorly formed granulomata
are commonly seen in Crohn disease, tight granulomata are common in
sarcoidosis, and uniformly sized granulomata with caseating necrosis
suggest an infection. Unfortunately, these subtle histologic clues are not
reliable enough for a confident etiologic diagnosis. Indeed, the
granulomatous gastritis pattern may be one of the best examples of a
patterns based approach because the identical injury pattern can be seen
with an expansive list of varied clinical settings. In the largest series of
the granulomatous gastritis pattern (n = 71 patients), most cases
showed a single granuloma and most granulomas (64%) were located in
the antrum. Careful clinical correlation determined an association with
Helicobacter (92%, n = 64), Crohn disease (52%, n = 37), foreign body
reaction (10%, n = 7), neoplasms (7%, n = 4), sarcoidosis (1%, n = 1),
Whipple disease (1%, n = 1), and vasculitis (1%, n = 1).165 Similar
associations have been reported by others.166,167 The granulomatous
gastritis pattern can also be a red flag to consider rare immune-mediated
diseases such as common variable immunodeficiency (CVID)98 and
chronic granulomatous disease (CGD),168 making it worthwhile to
evaluate for apoptotic body prominence and paucity of plasma cells
(CVID) and a careful chart review for clinical stigmata of CGD,
particularly in the pediatric setting. Some suggest that idiopathic
granulomatous gastritis is rare, if it exists at all, and should be surmised
only if a thorough and exhaustive exclusion of all possible diagnoses
have been confidently excluded.166 This leaves the pathologist with a
fair amount of detective work, including careful scrutiny of the
background mucosa, a detailed clinical chart review, and often a
conversation with the clinician to frame this peculiar finding in its
appropriate clinicopathologic context. Acid fast bacillus (AFB) and
Gomori methenamine silver (GMS) special stains are worthwhile to
exclude mycobacteria and fungal organisms, respectively, in all cases of
granulomatous gastritis, although most are negative.

Figure 2.199 Granulomata. Higher power of the previous case (Fig. 2.198). A granuloma is a
collection of epithelioid histiocytes admixed with lymphocytes and plasma cells. As seen here,
epithelioid histiocytes are characterized by “slipper-shaped” nuclei or nuclei with oblong, thin
nuclei (arrowheads). Special stains for Helicobacter, fungi (GMS), and mycobacteria (AFB) were
negative.
 Figure 2.200 Granulomata, foreign body reaction. In this classic example of a granuloma, the
epithelioid histiocyte collection is surrounded by lymphocytes, plasma cells, and scattered
foreign body-type giant cells (arrowheads). This patient had a history of a gastrostomy tube
placement and mucosal erythema was endoscopically identified in association with the
instrument tip. In the absence of other contributing factors, iatrogenic injury was the likely nidus
for the associated granulomatous inflammation. Special stains for microorganisms were negative.

Figure 2.201 Granulomatous gastritis pattern, sarcoidosis. This case originated from a patient
with sarcoidosis. Special stains for microorganisms were negative.
Figure 2.202 Granulomatous gastritis pattern, Crohn disease. Although the prior cases feature
spectacular teaching examples of the granulomatous gastritis pattern, in actuality, gastric
granulomata are usually much harder to identify. This more typical example originated from a
patient with a long-standing history of upper-tract Crohn disease. A small, poorly formed
granuloma is identified (arrowhead) in a background of active chronic gastritis.

Figure 2.203 Granulomatous gastritis pattern, Crohn disease. On higher power, the epithelioid
appearance of the histiocytes is better appreciated (arrowhead), as is the background active
chronic inflammation. Special stains for microorganisms were negative, suggesting this injury
pattern was most likely a manifestation of upper-tract Crohn disease.
Figure 2.204 Granulomatous gastritis pattern, Crohn disease. This case features another sneaky
granuloma (arrowhead) in a patient with a history of upper-tract Crohn disease. This type of
subtle granuloma is best appreciated on scanning magnification: at low power, a “hole”-like
appearance is due to local displacement of the neighboring gastric pits. A background of active
chronic inflammation is also seen.

Figure 2.205 Granulomatous gastritis pattern, Crohn disease. It would be easy to miss this tiny
granuloma (arrowhead) with such prominent background active chronic inflammation:
granulomata are typically best seen at lower power (compare to previous figure). Special stains
for microorganisms were negative.

FAQ: What is the significance of an isolated foreign body giant

cell in the stomach (Fig. 2.206)?
Answer: An isolated foreign body giant cell is abnormal but this
finding is etiologically nonspecific. Deeper sections may be
worthwhile to see if the foreign body giant cell is part of a deeper
granuloma. Such cases are signed out descriptively with a note
addressing the most likely possibilities after careful chart review; for
example, in the context of a patient with established sarcoidosis, this
isolated finding is most likely compatible with the history of
sarcoidosis, whereas in patient status post chemotherapy for widely
metastatic carcinoma, a medication injury would be favored, assuming
infection has been excluded. For the clinician, an isolated foreign body
giant cell can sometimes raise concerns for Crohn disease, in which
case correlation with the clinical history and biopsies of the terminal
ileum, right colon, left colon, and rectal biopsies may be worthwhile,
in the appropriate clinicopathologic setting.

Figure 2.206 An isolated foreign body-type giant cell in a background of active chronic gastritis
(arrow). Although an isolated foreign body giant cell is abnormal, it does not imply a specific
etiology.

FAQ: What is the best approach for a case with a vaguely

granuloma-like focus that is exhausted on deeper sections?
Answer: Beware of crushed gastric epithelium, cauterized muscularis
mucosae, and scattered histiocytes that can look vaguely like
epithelioid granulomata in suboptimal specimens. In questionable
cases, deeper sections and a CD68 immunostain can be helpful, if the
indicated focus is present on deeper sections. In cases in which
collections of histiocytes are seen but the histiocytes lack both the
 epithelioid morphology and granuloma type architecture, “focal
histiocyte aggregates” or “focal histiocyte collections” are satisfactory
to document the findings without glorifying these ambiguous findings
with the clinically charged term “granuloma”.

VASCULAR AND HEMORRHAGIC CHANGES

PATTERN

Figure 2.207 Vascular changes, portal hypertensive gastropathy (PHG). This example illustrates a
vascular pattern of injury: a number of congested mucosal vessels are seen in a background of
reactive gastritis/gastropathy. This patient was known to have cirrhosis and portal hypertension;
these histologic findings support the clinicopathologic diagnosis of PHG.

A prominent vascular and or hemorrhagic pattern of gastric injury can

be seen with a variety of entities (Fig. 2.207). In especially satisfying
cases, the underlying etiology can be established such as the
identification of amyloid deposits in systemic amyloidosis or 90Yttrium-
labeled microspheres in radiation gastritis; however, more common is
the scenario in which identification of this injury pattern prompts a
careful examination of the background mucosa and chart review. Portal
hypertensive gastropathy, for example, is a diagnosis seen with some
regularity and yet the characteristic features can be subtle, requiring a
careful chart review for the requisite history of portal hypertension.
Similarly, the characteristic features of GAVE can be almost miss-able in
mild cases, requiring correlation with the clinical history and the
characteristic endoscopic image showing a striped watermelon-like
pattern. This section discusses the most common causes of vascular and
hemorrhagic pattern of gastric injury.

CHECKLIST: Etiologic Considerations for Vascular and or

Hemorrhagic Pattern
Portal Hypertensive Gastropathy
Gastric Antral Vascular Ectasia
Amyloid
Radiation Gastritis Pattern

PORTAL HYPERTENSIVE GASTROPATHY

Portal hypertension is an increase in the pressure of the venous system,
seen most commonly in cirrhotic patients. In healthy patients, the veins
that drain the stomach, intestines, spleen, and pancreas merge into the
portal vein, which then drains into the liver. In cirrhotic patients, the
advanced liver fibrosis creates a high-resistance, high-pressure venous
system, also termed “portal hypertension.” As a result, blood backs up
into the low-resistance, low-pressure system of the collateral circulation,
manifesting as esophageal varices (or collateral circulation through the
esophageal veins), caput medusa (or collateral circulation through the
periumbilical and abdominal wall veins), and hemorrhoids (or collateral
circulation through the perirectal veins). These congested, engorged
vessels are prone to significant clinical bleeding with up to 25% of
cirrhotic patients succumbing to a fatal gastrointestinal hemorrhage.169
After variceal bleeding, portal hypertensive gastropathy (PHG) and
peptic ulcer disease are the next commonest causes of gastrointestinal
bleeding in cirrhotic patients.170,171 PHG is seen in 20% to 98% of
cirrhotic patients.172–174 Endoscopically, PHG consists of a snake skin
mosaic-like pattern (as seen in mild cases) or bulging red or brown
marks (as seen in marked cases) that predominantly affects the body and
fundus (Figs. 2.208 and 2.209).169,172 Histologically, variably prominent
congested vessels are seen (Figs. 2.210–2.213). The findings can be very
subtle and easy to miss, but careful attention to the requisition often
uncovers the red flags of “esophageal varices” or “cirrhotic patient with
upper gastrointestinal bleeding.” Treatment efforts are aimed at reducing
the portal hypertension with medications, such as beta-blockers.

Figure 2.208 PHG, endoscopic appearance. PHG shows a snake skin, mosaic-like pattern on
endoscopy.

Figure 2.209 Snake skin. This photograph of a snake’s skin shows smooth scales positioned in an
almost perfect geometric configuration, features similar to those seen endoscopically in PHG.
 Figure 2.210 PHG. At low power, the predominant finding is that of reactive
gastritis/gastropathy pattern of injury: gastric foveolar mucin cell depletion, a corkscrew-like
appearance of the foveolar epithelium, lamina propria edema, and little to no inflammation. The
reactive gastritis/gastropathy pattern can be a red flag to a variety of additional diagnoses. In
this case, scattered congested vessels are seen (arrowheads).

Figure 2.211 PHG. On higher power, the congested vessels are more easily seen. A chart review
revealed a history of portal hypertension, and a diagnosis of portal hypertensive gastropathy was
rendered. This case is an excellent example of pushing through the first obvious diagnosis
(reactive gastritis/gastropathy pattern) and thoroughly searching for other important diagnoses
(portal hypertensive gastropathy).
 Figure 2.212 PHG.

Figure 2.213 PHG. This case was submitted to us in consultation with a concern for dysplasia.
The requisition detailed a history of portal hypertension and the biopsy shows reactive
gastritis/gastropathy and congested mucosal vessels, supporting a diagnosis of portal
hypertensive gastropathy. Although the epithelium in reactive gastritis/gastropathy can be
atypical, it is important to interpret the changes in the context of the clinicopathologic setting. In
this case, the reactive epithelial changes (a bit of hyperchromasia and nuclear enlargement) are
diffuse, a finding that supports the diagnosis of a reactive change. In contrast, dysplasia has
abrupt and discreet transitions. This case was signed out as “portal hypertensive gastropathy with
reactive epithelial change, negative for dysplasia.”

KEY FEATURES of Portal Hypertensive Gastropathy:

• Clinical red flags include cirrhosis, portal hypertension, and esophageal
varices.
• Endoscopically, a snake-skin mosaic-like pattern or red marks are seen.
• Histologically, the mucosa shows variably prominent congested vessels
in the body and fundus.
• Treatment efforts are aimed at reducing portal hypertension with beta-
blockers.

GASTRIC ANTRAL VASCULAR ECTASIA

GAVE shares many important clinical features with PHG (Table 2.4).
Both entities can occur in patients with background liver disease and
chronic gastrointestinal bleeding, and whose gastric endoscopic images
show red spots.175 Distinction is important, however, since the
treatments are unique: GAVE is treated with endoscopic techniques,
whereas PHG is predominantly treated with medications to reduce the
portal hypertension, such as beta-blockers. Distinguishing features of
GAVE include that it is much less common, has a less stringent
association with portal hypertension, and, instead, has associations with
chronic renal failure, autoimmune connective tissue diseases, and bone
marrow transplantation.176–178 In addition, GAVE is typically antral
predominant, unlike PHG which is classically described as body/fundus
predominant. Occasionally GAVE diffusely involves the stomach, in
which case the preferred terminology is diffuse gastric vascular ectasia.
Although both entities can have similar endoscopic images with gastric
red spots, in GAVE, the red spots coalesce, imparting a striped
watermelon-like appearance (Figs. 2.214 and 2.215). Histologically,
GAVE and PHG can both show a background of reactive
gastritis/gastropathy and prominent ectatic, congested vessels. GAVE,
however, also shows prominent mucosal thrombi (Figs.
2.216–2.220).179,180 Endoscopic therapy remains the mainstay of GAVE
treatment with argon plasma coagulation being the most common
thermoablative based technique. Unfortunately, some GAVE cases are
refractory to standard endoscopic intervention and, consequently,
(partial) gastric resection is sometimes required.
TABLE 2.4: Gastric Antral Vascular Ectasia versus Portal Hypertensive
Gastropathy

CRF, chronic renal failure; MCT, mixed connective tissue disease; BMT, bone marrow transplant.

KEY FEATURES of Gastric Antral Vascular Ectasia:

• Associations include patients with liver disease, chronic renal failure,
autoimmune connective tissue diseases, and bone marrow
transplantations.
• Endoscopic images include gastric red spots which can coalesce into a
striped watermelon-like appearance.
• Histologically, a background of reactive gastritis/gastropathy,
congested, ectatic vessels, and prominent mucosal vascular thrombi
are characteristic and most typically seen in the antrum.
• Treatment includes endoscopic therapy such as argon plasma
coagulation and surgical resection in cases refractory to endoscopic
management.
Figure 2.214 Gastric Antral Vascular Ectasia (GAVE). This endoscopic image shows a stripped
watermelon-like appearance characteristic of GAVE.

Figure 2.215 Watermelon. The watermelon’s alternating yellow and green stripes decorate the
stem remnant, and mirror the mucosal changes seen in GAVE.
Figure 2.216 GAVE. In this remarkable case, a partial gastric resection was performed for GAVE
refractory to endoscopic management. Numerous foci of hemorrhage and thrombi are seen at
scanning magnification (brackets).

Figure 2.217 GAVE. On higher power, intravascular thrombi are seen along with pools of
hemorrhage. The corresponding endoscopic image showed the characteristic striped watermelon-
like appearance consistent with the clinicopathologic diagnosis of GAVE.
Figure 2.218 GAVE. This spectacular example of GAVE shows a number of intravascular thrombi
(arrowheads). Note, fibrin is hot-pink with a homogenous appearance. In contrast, the nearby
congested vessels are engorged with red blood cells (not thrombi) and appear a bolder shade of
red (arrows).

Figure 2.219 GAVE. The diagnosis of GAVE can be easy to miss at low power, unless the mucosal
vessels are diligently inspected in each stomach biopsy. Often times, the mucosal thrombi are
best appreciated on higher power, as in this case (arrowhead).
 Figure 2.220 GAVE. This case originated from a 55-year-old women with a mixed connective
tissue disease, emphasizing the known association of GAVE with autoimmune diseases.

Figure 2.221 Amyloidosis. This stomach biopsy shows a prominent pink infiltrate that displaces
the normal back-to-back pit pattern (arrowheads).
 Figure 2.222 Amyloidosis. On higher power, the pink material is seen between stromal cells.

Figure 2.223 Amyloidosis (Congo Red). A Congo Red confirms the presence of amyloid, which is
orange on direct light and bright green under polarized light (not shown). This patient was seen
for workup of gastrointestinal bleeding and was found to have amyloidosis involving all GI
biopsies (esophagus, stomach, and colon).

AMYLOID
A hemorrhagic gastritis pattern can also be seen in the setting of
systemic amyloidosis. On mucosal biopsies, the deposition is most
commonly seen within the lamina propria, muscularis mucosae, or
vascular walls. Deposition within vascular walls compromises the
vessel’s structural integrity and can result in hemorrhage and or
ischemia to the downstream mucosa. Unfortunately, the deposition can
be focal and subtle, and so requires diligent inspection. On H&E,
amyloid appears glassy and amorphous with a characteristic cracking or
“chatter” artifact (Figs. 2.221–2.223). The amyloid appears orange under
direct light on a Congo red special stain and bright-apple green under
polarized light.

RADIATION GASTRITIS PATTERN

Radiation gastritis pattern is similar to radiation injury seen elsewhere in
the gastrointestinal tract.181,182 Endoscopically, erythema, erosions,
ulcerations, and friability can be seen (Fig. 2.224). Histologically, lamina
propria hyalinization, atypical stromal, endothelial, and epithelial cells,
and prominence of ectatic, and damaged vessels are seen (Figs.
2.225–2.227). Occasionally the radiation damage is seen in association
with radiation microspheres, such as 90Yttrium-labeled microspheres.
See also Pigments & Extras subsection, this chapter. Radiation gastritis
has some overlap with CMV infections, making routine CMV
immunostains worthwhile in these cases. The atypical stromal cells
characteristic of radiation gastritis can also raise concern for infiltrating
carcinoma. In such cases a cytokeratin and smooth muscle actin stain
can be reassuring (the atypical stromal cells are cytokeratin negative and
sometimes smooth muscle actin positive).

Figure 2.224 Radiation gastritis pattern. This patient had a history of radiation for esophageal
adenocarcinoma. The endoscopic image is dramatic with erosive changes, erythema, superficial
ulceration, mucosal sloughing, and friability.

Figure 2.225 Radiation gastritis pattern. The corresponding stomach biopsy has more subtle
findings than the endoscopic image. The radiation gastritis pattern refers to the lamina propria
 hyalinization and scattered ectatic vessels that are parallel to the surface epithelium
(arrowheads). Inactive chronic gastritis, including increased eosinophils, and glandular atrophy
are also seen.

Figure 2.226 Radiation gastritis pattern. On higher power, scattered atypical stromal cells are
seen that are hyperchromatic and a bit pleomorphic (arrow). The background shows scattered,
thin walled ectatic vessels (arrowhead) and stromal hyalinization that appears pink. Occasionally
stromal hyalinization raises concerns for amyloidosis, but amyloidosis would not have atypical
stromal cells nor thin walled ectatic vessels (recall amyloidosis typically infiltrates the vessel
walls, resulting in a thick, smudgy, vascular wall). In challenging cases, a Congo Red special stain
to evaluate for amyloid is worthwhile. A CMV immunostain was negative.

Figure 2.227 Radiation gastritis pattern. This alternate field shows stromal hyalinization (or
lamina propria expanded by pink material), scattered ectatic vessels which that parallel to the
 surface, and chronic inflammation, including increased eosinophils.

PEARLS & PITFALLS

Since radiation is administered to manage neoplasms, recognition of
this injury pattern is an important red flag to look carefully for
residual/recurrent neoplasms.

PIGMENTS AND EXTRAS

Figure 2.228 Iron pattern B/“iron pill gastritis”. Pigment in the stomach can herald a variety of
etiologies and consumables. In this example, the golden pigment of iron is seen embedded in the
superficial mucosa and within the luminal debris. This case was submitted as “rule-out
carcinoma” based on the ominous endoscopic impression.

CHECKLIST: Etiologic Considerations for Pigments and

Extras
Iron
Gastric pseudomelanosis
Calcinosis
Resins
 90Yttrium (90Y)-labeled microspheres

IRON
Gastric iron deposition is seen in up to 3.8% of upper tract biopsies (Fig.
2.228).23,24,183–185 In a study of 500 gastric biopsies, the deposition was
demonstrated in three generalized patterns. Pattern A (also referred to as
“nonspecific gastric siderosis”) was the most common subpattern and
involved 2.2% of specimens (Figs. 2.229 and 2.230). This subpattern was
associated with prior mucosal microhemorrhages, and the subtle
depositions were predominantly identified within macrophages and
stromal cells of the lamina propria. Pattern B (also referred to as “iron
pill gastritis”) was seen in 0.8% of the biopsies and was consistently
associated with ferrous sulfate therapy. This deposition was coarse and
crystalline and predominantly identified in the extracellular and most
superficial aspect of the biopsy (Figs. 2.231–2.234). In this subpattern,
the background mucosa had a reactive gastritis/gastropathy pattern with
erosions, ulcerations, and fibrino-inflammatory exudate common. In a
separate study of 1,300 gastric biopsies, a similar “iron pill gastritis”
injury pattern was detailed.184 This latter group reproduced the identical
iron deposits in the laboratory by oxidizing ferrous sulfate tablets,
providing clear evidence for the iron origin of these deposits. The
mechanism of injury is a bit unclear in this subpattern. Some speculate
that the iron pill has a direct caustic effect on the adjacent mucosa,
whereas others suggest that the iron deposits may simply colonize
previously injured mucosa. Pattern C (also referred to as “gastric
glandular siderosis”) was the least common pattern, involving 0.6% of
the specimens. This subpattern was associated with iron overload
settings, such as hereditary hemochromatosis and multiple blood
transfusions. The characteristic deposits were subtle, uniform, and
identified in the deep antral and oxyntic glands (Figs. 2.235–2.239). The
iron deposits can be highlighted blue with a Prussian blue iron special
stain. Recognition is important to help prevent further injury and
potential stricture formation (pattern B), to suggest pertinent iron
overload evaluation (pattern C), and to avoid overdiagnosing the marked
reactive epithelial change as dysplasia.
Figure 2.229 Iron pattern A/“nonspecific gastric siderosis”. This is the most common iron pattern
of injury, and it can be easy to miss on low power. Scattered pigment laden macrophages and
stromal cells are seen (arrowheads), characteristic of the iron pattern A/nonspecific gastric
siderosis pattern. Prior mucosal damage and microhemorrhages account for these findings.

Figure 2.230 Iron pattern A/“nonspecific gastric siderosis” (Prussian Blue). The iron is blue on a
Prussian Blue special stain, supporting the previously mentioned diagnosis.
Figure 2.231 Iron pattern B/“iron pill gastritis”. In this dramatic case, coarse crystalline iron
deposits are seen on the mucosa and within the luminal debris (arrowheads). A prominent
reactive gastritis/gastropathy pattern is also seen in the background.

Figure 2.232 Iron pattern B/“iron pill gastritis” (Prussian blue). A Prussian blue highlights the
iron. As characteristic for pattern B, the iron is predominantly extracellular, embedded in the
superficial mucosa, and within the luminal space.
Figure 2.233 Iron pattern B/“iron pill gastritis”. Iron is seen encrusted in the superficial foveolar
epithelium.

Figure 2.234 Iron pattern B/“iron pill gastritis” (Prussian blue). A Prussian blue highlights the
iron.
 Figure 2.235 Iron pattern C/“gastric glandular siderosis”. This iron pattern can be one of the
more difficult to recognize because of the subtle and uniform findings that are not very apparent
at low power (bracket). Nonetheless, it can be critical to appreciate since it indicates iron
overload and may prompt genetic testing for hereditary hemochromatosis, in the appropriate
clinical setting. The more common setting, however, is a transfusion dependent patient, as in this
case. This patient had a history of lymphoma, bone marrow transplant, and was known to have
iron overload syndrome based on the history of extensive blood transfusions.

Figure 2.236 Iron pattern C/“gastric glandular siderosis” (Prussian blue). The iron is highlighted
by the Prussian blue stain. In this pattern, the characteristic deposits are uniform and generally
restricted to the deep gastric glands and occasional deep stromal cells.
 Figure 2.237 Iron pattern C/“gastric glandular siderosis”. On high power, it is easier to
appreciate the fine golden pigment uniformly distributed in the deep gastric glands (arrowhead)
and occasional stromal cells (arrows).

Figure 2.238 Iron pattern C/“gastric glandular siderosis”.

 Figure 2.239 Iron pattern C/“gastric glandular siderosis” (Prussian blue). The iron stain
highlights the uniform iron deposits restricted to the deep gastric glands and rare stromal cells.

KEY FEATURES of Iron Pigment Deposition:

• Gastric iron deposition is seen in up to 3.8% of upper tract biopsies.
• Pattern A/“nonspecific gastric siderosis” is associated with prior
mucosal microhemorrhages; the depositions are in the lamina
propria macrophages and stromal cells.
• Pattern B/“iron pill gastritis” features coarse, crystalline deposits in
the extracellular space and most superficial aspects of the biopsy.
• Pattern C/“gastric glandular siderosis” is associated with iron
overload; the deposits are subtle, uniform, and identified in the deep
antral and oxyntic glands.

PEARLS & PITFALLS

Anecdotally, iron pill gastritis is not an uncommon specimen rushed
for a clinical concern for carcinoma. The endoscopic and histologic
features can appear equally ominous, making it easy to misdiagnosis
malignancy if the associated iron pill injury pattern is not recognized.
In general, before diagnosing malignancy, always scrutinize the tissue
and surrounding luminal debris for any benign excuse that might
account for the horrendous atypia. When in doubt, a Prussian blue
 iron special stain can be reassuring.

GASTRIC PSEUDOMELANOSIS
Gastric pseudomelanosis is a rare entity described in only a handful of
case reports, but its identification tends to elicit a bit of anxiety from
both the clinician and pathologist.186–188 The endoscopic appearance is a
patchy dark mucosal pigmentation and the corresponding requisitions
are sometimes accompanied by “rule-out melanoma” (Fig. 2.240). The
histologic sections show patchy, coarse dark pigmentation within the
cytoplasm of scattered macrophages in the superficial lamina propria,
similar to that seen with pseudomelanosis intestinalis or that seen with
tattoo ink (Figs. 2.241–2.243). The lack of cytologic atypia is reassuring
that this is a benign process, and a CD68 will confirm the histiocytic
nature of the indicated cells. Some cases show reactivity with the
Prussian blue special stain for iron, but most do not. Although no
consistent etiology has been identified, it may be an ingestant, or
perhaps as part of a reparative response to local hemorrhage or injury.
Regardless, it is thought to be a benign, self-limited finding requiring no
specific surveillance or treatment. See also Pigments and Extras, Small
Bowel Chapter.

Figure 2.240 Gastric pseudomelanosis. This case originated from a 42-year-old woman with an
extensive psychiatric disorder. Following a suicide attempt with a toxic ingestant, the patient
developed abdominal pain. Black mucosal pigmentation was seen in the stomach (arrowheads),
and the requisition detailed “rule-out melanoma”.
Figure 2.241 Gastric pseudomelanosis. The corresponding biopsy is almost normal at first glance.
Careful scrutiny of the lamina propria reveals a few rare pigment laden-macrophages
(arrowheads). Certainly, this finding would have been miss-able had the clinician not detailed her
clinical impression of mucosal pigmentation.

Figure 2.242 Gastric pseudomelanosis. Elsewhere, more obvious pigmentation was seen. Note the
fine black pigment in the cytoplasm of the macrophages (arrowheads). Importantly, also note the
benign cytology of the host nuclei-no pleomorphism, hyperchromasia, or mitotic figures are seen
to suggest a malignant process.
 Figure 2.243 Gastric pseudomelanosis. No special stains are required for this diagnosis. Some
have found the pigment can occasionally react with iron special stains. In our experience, it
appears most similar to tattoo pigment.

CALCINOSIS
Mucosal calcium deposition is classified as metastatic, dystrophic, or
idiopathic.189–192 Metastatic calcinosis is the most common subtype and
refers to calcium deposition in normal tissues in the setting of calcium
dysregulation. Other reported associations include hyperphosphatemia
associated tumor lysis syndrome, atrophic gastritis, hypervitaminosis A,
organ transplantation, gastric neoplasia, uremia with
eucalcemia/euphosphatemia, and the use of aluminum-containing
antacids, citrate-containing blood products, isotretinoin, and
sucralfate.191,192 Dystrophic calcification refers to calcium deposition in
damaged tissues in the setting of a normal serum biochemical
environment. The incidence of mucosal calcinosis is unknown, but it is
seen with some regularity in patients with renal failure or parathyroid
dysregulation. Endoscopically, mucosal calcinosis appears as small white
flecks, plaques, or nodules (Fig. 2.244). Histologically, the coarse black
pigmentation is usually superficial and extracellular (Figs. 2.245–2.248).
On histologic grounds alone, the calcium pigment can be difficult to
distinguish from iron pill pigment since both can have brown-black
tinctorial properties, and they both show a predilection for the
superficial extracellular compartment. In difficult cases, a von Kossa
special stain for calcium (calcium appears black) and a Prussian blue
special stain for iron (iron appears blue) can be helpful. Not surprisingly,
in this age of polypharmacy and an aging baby-boom population, some
patients are found to have a conglomerate of both calcium and iron,
making it worthwhile to perform both special stains when in doubt.
Recognition of this deposit is important because “metastatic calcinosis”
can indicate the patient is at risk for cardiac calcium deposits, which can
be fatal. In addition, this diagnosis should prompt the clinician to search
for causes of calcium dysregulation which can sometimes be obvious (as
in the case of renal failure) but can occasionally be sneaky (as in the
case of an occult parathyroid neoplasm or surreptitious antacid abuse).

Figure 2.244 Mucosal calcinosis, endoscopic image. Mucosal calcinosis can appear as small white
flecks (arrowheads), plaques, or nodules.

Figure 2.245 Mucosal calcinosis. This case originated from a 79-year-old diabetic patient with
 renal failure and abdominal pain. Focal calcium deposition is seen (arrowheads); they appear
chunky and deeply purple. Occasionally, the calcifications present a problem for the histology
technicians: the tissue blocks can be especially difficult to cut and, consequently, “tissue holes”
result from calcifications lost during processing. A confirmatory von Kossa special stain was
positive, supporting the previously mentioned diagnosis.

Figure 2.246 Mucosal calcinosis. This is a more typical case of mucosal calcinosis with the faint
purple mineralization difficult to appreciate on low power. The “tissue hole” artifacts help to
hide the mineral in the background tissue (arrowheads).

Figure 2.247 Mucosal calcinosis. On higher power, the faint purple mineralization is seen
hugging the base of the foveolar epithelium (arrowheads).
Figure 2.248 Mucosal calcinosis (von Kossa). A confirmatory von Kossa special stain was positive
in the indicated focus from the previous case (Fig. 2.247). Note the calcium appears black on a
von Kossa special stain.

KEY FEATURES of Calcinosis:

• Mucosal calcium deposition is classified as metastatic, dystrophic, or
idiopathic.
• Metastatic calcinosis is the most common subtype and refers to calcium
deposition in normal tissues in the setting of calcium dysregulation.
• Dystrophic calcification refers to calcium deposition in damaged tissues
with normal serum calcium levels.
• Endoscopically, mucosal calcinosis appears as small white flecks,
plaques, or nodules.
• Histologically, the variably purple-to-black-pigmentation on H&E is
usually superficial and extracellular.
• A von Kossa special stain confirms the calcium deposition (calcium
appears black).

RESINS
Resins are colorful crystals not uncommonly encountered in the
gastrointestinal tract (Figs. 2.249 and 2.250). For a thorough discussion,
see also Resins Subsection, Acute esophagitis, Esophagus Chapter.
Figure 2.249 Kayexalate. Kayexalate is used in renal failure patients to reduce potassium levels.
Importantly, the osmotic effects of the diluent can result in ulcerations and ischemia to the
background tissue. The resin is purple on H&E with a characteristic “fish-scale” or “mosaic”
appearance due to intersecting “cracking lines”.

Figure 2.250 Cholestyramine. Cholestyramine is a bile acid sequestrant and it is used in

hyperlipidemic patients to lower lipid levels. In contrast to Kayexalate, these resins are not seen
in association with mucosal injury. Cholestyramine is bright orange on H&E and typically
appears smooth with no “cracking lines” in the small crystals (arrowheads), although some
irregular wave-like lines can be seen in the larger fragments (arrow).

90YTTRIUM-LABELED MICROSPHERES

90Yttrium-labeled microspheres are used in the targeted treatment of

unresectable primary and metastatic hepatic malignancies, a process
termed “selective internal radiation therapy.” The microspheres are
delivered via catheter into the hepatic artery to preferentially target the
neoplastic cells since the neoplastic cells derive most of their blood
supply from the hepatic artery and the nonneoplastic hepatocytes derive
the majority of their blood supply from the portal vein. This targeted
nature of delivery allows for a higher dosage of radiation than that
which would be tolerable under systemic radiation therapy, and
theoretically minimizes the toxic effects of the radiation to uninvolved
organs; however, when the 90yttrium-labeled microspheres inadvertently
enter the arteries supplying the stomach, duodenum, or pancreas, they
can cause unintended radiation damage to nontargeted organs at
relatively high doses of radiation. Recall, radiation injury consists of
lamina propria hyalinization, atypical stromal, endothelial, and
epithelial cells, and prominence of ectatic, damaged vessels. See also
Radiation Gastritis Pattern, Vascular and or Hemorrhagic Pattern in this
chapter (Figs. 2.224–2.227). 90Yttrium-labeled microsphere-related
esophagitis, gastritis, duodenitis, pancreatitis, and cholecystitis have
been reported.181,182,193,194 The microspheres are 30 to 40 μm in
diameter with a maximum penetration of 11 mm, a half-life of 2.5 days,
and emissions can occur as far out as 14 days postdelivery (Figs.
2.251–2.254).193,194

Figure 2.251 90Yttrium-labeled microsphere gastritis. At scanning magnification, this biopsy

features foveolar hyperplasia, patchy chronic inflammation, and scattered 90yttrium-labeled
microspheres deep in the mucosa (arrowheads). The microspheres are perfectly round, uniformly
 opaque, and deep dark purple.

Figure 2.252 90Yttrium-labeled microsphere gastritis. On higher power, these microspheres can
look like little else, they are so characteristic. Of course, they have raised concerns for
Schistosomiasis, psammoma bodies in association with neuroendocrine tumors, dystrophic
calcifications, and embolization material. In this example, the microspheres (arrowheads) are
surrounded by a pool of brisk chronic inflammation.

Figure 2.253 90Yttrium-labeled microsphere gastritis. In this example, prominent ulceration and
granulation tissue are seen. Careful drudging through the necroinflammatory debris reveals the
etiology of the findings: 90Yttrium-labeled microspheres are seen embedded within the ulcer
debris (arrowheads).
 Figure 2.254 90Yttrium-labeled microsphere gastritis.

PEARLS & PITFALLS

90Yttrium-labeled microspheres are usually seen in association with an
alarming endoscopic appearance (Fig. 2.224), radiation injury pattern,
and horrendous epithelial change. These changes can be so concerning
that dysplasia or carcinoma are often diagnostic considerations. In
these cases, recognition of the background radiation injury pattern
and the characteristic microspheres are essential to arriving at the
correct diagnosis. In addition, a CMV immunostain is worthwhile in all
cases, as the diagnostic CMV-infected cells can be easily obscured by
the radiation injury.

PEARLS & PITFALLS

Anecdotally, 90yttrium-labeled microspheres can be confused for
Schistosomiasis, psammoma bodies in association with neuroendocrine
tumors, dystrophic calcifications, and embolization material. In these
types of cases, careful attention to the background radiation injury
pattern serves as important red flags for the correct diagnosis.
KEY FEATURES of 90Yttrium-Labeled Microspheres:
• Used in the targeted treatment of unresectable primary and metastatic
hepatic malignancies.
• Seen in association with radiation injury: lamina propria
hyalinization, atypical stromal, endothelial, and epithelial cells, and
prominence of ectatic, damaged vessels.
• Inadvertent delivery to nontarget organs can result in 90yttrium-labeled
microsphere-related esophagitis, gastritis, duodenitis, pancreatitis, and
cholecystitis.
• The characteristic microspheres are 30 to 40 um in diameter, are
uniformly opaque, deep purple and perfectly round, and emissions
occur as far out as 14 days postdelivery.
• CMV immunostains are recommended in all cases.

NEAR MISSES
AMYLOIDOSIS

Figure 2.255 Amyloidosis involving antral mucosa. At low power, slight eosinophilic material
focally expands the lamina propria.
 Figure 2.256 Amyloidosis involving antral mucosa. Higher power shows the acellular
eosinophilic material.

Figure 2.257 Amyloidosis involving antral mucosa (Congo Red). Amyloid is orange on direct
light and apple green with polarized light (Congo Red) (not shown).

Amyloidosis is notoriously easy to miss, unless carefully searched for on

every biopsy (Figs. 2.255 and 2.256). On low power, this antral biopsy
looks almost normal, but on high power a subtle amorphous pink deposit
is focally seen. The corresponding Congo red is positive for amyloid,
confirming the H&E impressions (Fig. 2.257). This patient was
ultimately found to have a plasma cell dyscrasia.

APOPTOTIC BODY PROMINENCE

Figure 2.258 Apoptotic gastropathy. Apoptotic bodies are tiny bits of nuclear debris or dust that
are often variably sized (arrowheads), in contrast to lymphocytes (arrows).

As with every biopsy, apoptotic body evaluation is part of the routine

biopsy assessment and requires at least a few fields with the 40×
objective (Fig. 2.258). In the stomach, one apoptotic body per 100
glands is normal, so it takes very few apoptotic bodies to cross the
required threshold for apoptotic gastropathy. Occasionally, lymphocytes
can raise concerns for apoptotic bodies, but with experience the
distinction is more easily made: apoptotic bodies are tiny bits of nuclear
debris or dust that are often variably sized; lymphocytes are larger and
more uniform in size (Figs. 2.258 and 2.259). Apoptotic gastropathy is
most commonly seen in the following settings:
 Figure 2.259 Apoptotic gastropathy. CMV viral cytopathic effect is seen (arrow) with nuclear
megaly and prominent nucleoli, in addition to a mild prominence of apoptotic bodies
(arrowheads). A CMV immunostain was positive. In this case, the patient had a history of
Hodgkin lymphoma, bone marrow transplant, and febrile diarrhea. Excess apoptotic bodies can
be a valuable red flag to the underlying (treatable) diagnosis.

• Infection (Helicobacter, CMV, among others)

• Medication (i.e., NSAIDS and CellCept (Mycophenolate) injury, among
others)195–197
• Graft versus Host Disease (See also Graft versus Host Disease,
Lymphocytic Esophagitis Pattern, Esophagus Chapter)
• Immune-Mediated Disease

POORLY DIFFERENTIATED ADENOCARCINOMA WITH

SIGNET RING CELL FEATURES

Figure 2.260 Metastatic lobular breast carcinoma.

 Figure 2.261 Metastatic lobular breast carcinoma. Atypical stromal cells are seen (bracket).

Figure 2.262 Metastatic lobular breast carcinoma. Pleomorphic cells are seen with abundant pink
cytoplasm (arrowheads).

This specimen is from a gastric resection for gastric bypass surgery (Figs.
2.260–2.262). The surgeon detected a firm focus at the proximal margin
which she submitted for frozen section analysis. At low power,
unremarkable oxyntic-type mucosa is seen in the upper left corner, in
addition to fragments of squamous mucosa (Fig. 2.260). At higher
power, the lamina propria appears a bit more cellular than usual,
prompting closer inspection (bracket) (Fig. 2.261). On highest power,
the nuclei have approximately the same appearance as those of the
neighboring endothelial cells (not particularly hyperchromatic and not
particularly large); however, histiocytes do not have such an infiltrative
architecture (arrowheads) (Fig. 2.262). A CAM5.2 IHC highlights all of
the indicated cells, supporting a diagnosis of poorly differentiated
adenocarcinoma with signet ring cell features (Fig. 2.263). But the story
does not conclude here. Every poorly differentiated adenocarcinoma with
signet ring cell features in a woman must be accompanied by breast markers
to exclude a metastatic lobular carcinoma. In this case, the atypical cells
also show strong nuclear positivity for progesterone receptor, supporting
the diagnosis of metastatic lobular carcinoma (Fig. 2.264). The patient
ultimately was found to have a breast mass requiring subsequent
mastectomy.

Figure 2.263 Metastatic lobular breast carcinoma (CAM5.2). The atypical cells are diffusely
cytokeratin reactive, supporting the diagnosis of poorly differentiated carcinoma with signet ring
cell features.
 Figure 2.264 Metastatic lobular breast carcinoma (Progesterone receptor). Every poorly
differentiated carcinoma with signet ring cell features in a woman should be evaluated with
breast markers. This case was PR reactive, and a subsequent breast mass was found.

RUSSELL BODY GASTRITIS

Figure 2.265 Russell body gastritis.

 Figure 2.266 Russell body gastritis.

Figure 2.267 Russell body gastritis (PAS).

This case represents a not uncommon consultation case, typically

submitted with a concern for poorly-differentiated adenocarcinoma
(Figs. 2.265–2.267). At lowest power, the gastric mucosa shows peculiar
cells just below the surface epithelium and dispersed between gastric
pits. These cells have brightly eosinophilic cytoplasm (Fig. 2.265). On
higher power, the pink cytoplasmic inclusions are smooth and
homogenous, and the nuclear cytology is bland: no hyperchromasia,
pleomorphism, nor mitotic figures are seen (Fig. 2.266). Under oil
magnification, the bland nature of the nuclear cytology is best
appreciated (PAS). Note, the nuclei of the indicated cells are much
smaller than those in the adjoining foveolar epithelium and the
cytoplasmic inclusions are PAS reactive (Fig. 2.267). This case is an
example of Russell body gastritis. Russell bodies are bright pink
cytoplasmic inclusions derived from entrapped immunoglobulins that
are lodged in the rough endoplasmic reticulum of plasma cells.
Supporting their benign nature, Russell bodies display a mixed kappa
and lambda light chain distribution. When plasma cells acquire
prominent Russell bodies, as in this case, they are termed “Mott cells.” In
the stomach, Russell bodies are commonly associated with Helicobacter
gastritis, but they can theoretically be seen with any type of long-
standing chronic inflammation. Importantly, Mott cells can be mimics of
poorly differentiated adenocarcinoma since both can be sparsely
distributed in a quasi-infiltrative pattern and have PAS+ cytoplasmic
inclusions (Figs. 2.266 and 2.267 vs. Figs. 2.268–2.269); however, Mott
cells display a uniformly bland cytology. In Figure 2.267, for example,
note that the Mott cell nuclei are smaller than those of the neighboring
foveolar epithelium nuclei. In comparison, the nuclei of poorly
differentiated adenocarcinoma are typically larger than normal cells and
display irregular nuclear contours, prominent nucleoli, and
hyperchromasia (Figs. 2.268 and 2.269). In challenging cases, a
cytokeratin stain can be helpful (the Mott cells are cytokeratin
nonreactive, whereas the adenocarcinoma is cytokeratin reactive).

Figure 2.268 Poorly differentiated adenocarcinoma.

 Figure 2.269 Poorly differentiated adenocarcinoma (PAS).

MUCUS-NECK CELLS

Figure 2.270 Mucus neck cells (arrowheads).

 Figure 2.271 Mucus neck cells.

Figure 2.272 Mucus neck cells (PAS, arrowheads).

This near miss case highlights another common mimic of poorly

differentiated adenocarcinoma with signet ring cell features (Figs.
2.270–2.272). Mucus neck cells are normal cellular constituents and, as
their name implies, they are mucus secreting cells found at the neck of
the gastric pits. Occasionally, these cells become dislodged, dispersed, or
crushed, in which case their eccentrically placed nuclei can raise
concerns for a signet ring cell adenocarcinoma. In this case, the abused
tissue fragment features quite a few dislodged mucus neck cells in the
luminal space (Fig. 2.270). Oil immersion is necessary to detect the
miniscule nucleoli of mucus neck cells (unlike adenocarcinoma); at this
power the nuclear contours are smooth and uniform, the chromatin is
fine, and no mitotic figures are seen, all features supporting a benign
diagnosis (Fig. 2.271). These cells display cytoplasmic PAS reactivity,
but again the nuclear cytologic features are bland (Fig. 2.272). In
addition to the histology, the clinical setting is also
reassuring&emdash;the biopsy originated from an 8-year-old boy with
eosinophilic esophagitis who had an unremarkable endoscopic
examination.

SARCINA

Figure 2.273 Sarcina. Luminal debris is often ignored, but this example shows a mixture of
Sarcina (arrow) and Micrococcus (arrowheads) organisms. Both Sarcina and Micrococcus can be
found in tetrad formations, but Micrococcus grows in dense bacterial microcolonies clusters and
each organism is smaller.
Figure 2.274 Sarcina in a gastric ulcer. These Sarcina tetrads are embedded within a gastric ulcer
of a patient with delayed gastric emptying. Treatment of the gastric ulcer, such as with
sucralfate, is reasonable given the rare reported cases of emphysematous gastritis and gastric
perforation associated with Sarcina.

Sarcina is a Gram-positive anaerobic bacteria with carbohydrate

fermentative metabolism as the sole energy source (Figs. 2.273 and
2.274).198 Although the organism is ubiquitous in the environment and
is not invasive, Sarcina can cause deadly gaseous bloat in livestock and
rare cases of emphysematous gastritis and gastric perforation have been
described in humans. The organism is found most commonly in patients
with delayed gastric emptying (gastroparesis, nearby mass, obstruction).
The presence of an underlying mucosal defect, such as an erosion or
ulceration, may predispose patients to more serious sequelae from this
otherwise ubiquitous and noninvasive organism. The characteristic
tetrad or octet packets of Sarcina organisms are approximately 10
microns across, or the size of a lymphocyte nucleus, and are typically
found intermixed with luminal debris. The unusual morphology is the
result of cell division in at least two planes of growth, and this
morphologic finding is diagnostic for the organism on routine H&E stain.
Micrococcus species also forms a tetrad and, consequently, is an
important Sarcina mimic. Micrococcus, however, clusters in dense
bacterial microcolonies and is considerably smaller (0.5 micron
individual compared to Sarcina’s larger three micron size).
 FAQ: What are Sarcina treatment recommendations?
Answer: At this time, there are no recommended guidelines for Sarcina
treatment. In patients without underlying mucosal defects, there is no
evidence to show that eradication of the bacteria with antibiotics is
effective or necessary. Because the organism can be found in vegetable
matter, air, soil, and the feces of healthy humans, it is unlikely that
Sarcina causes injury in the absence of an underlying mucosal defect;
however, treatment of any underlying mucosal erosion or ulceration, if
present, would be reasonable. The role of antibiotics in humans has
not been fully investigated.

BEZOAR AND OTHER FOREIGN MATERIAL

Figure 2.275 Trichobezoar. This is a gross photograph of a hair bezoar removed from the
stomach of a patient who was ingesting hair.

A “bezoar” is a ball of swallowed foreign material that collects in the

stomach and fails to pass through the intestines (Fig. 2.275). Common
examples include hair, fiber, food, or medication. Often, these are
recognized at the time of endoscopy and are simply documented as a
gross finding. Occasionally, however, undigested material can pose
unusual challenges by mimicking other disease entities (Figs. 2.276 and
2.277). An important histologic clue to look for is whether there is tissue
reaction or inflammation, the absence of which should raise suspicion
that the findings may represent inert luminal debris.
 Figure 2.276 Ingested mushroom. These fungal hyphae were seen in the duodenal biopsy of a
patient who had undergone bone marrow transplantation for chronic lymphocytic leukemia. In
the clinical setting of immunosuppression, it is reasonable to consider an fungal infection;
however, the endoscopic impression was that of foreign material, such as ingested food.

Figure 2.277 Ingested mushroom. Lower power of previous figure. The lack of tissue invasion
and tissue inflammation is a strong indicator that the fungal elements in the field are not
pathogenic. Indeed, further investigation revealed this patient had an omelet with mushrooms
prior to endoscopy.

MAST CELL DISEASE

 Figure 2.278 Gastric involvement by systemic mastocytosis. At scanning magnification, this
gastric oxyntic mucosa might appear to have a mere superficial erosion (arrow); however, this
patient has a significant past medical history for systemic mastocytosis.

Figure 2.279 Gastric involvement by systemic mastocytosis. Higher magnification corresponding

to the area of “erosion” seen in previous figure. Even with the knowledge of the patient’s clinical
history, and high-power examination, this case is challenging on routine H&E stain.

Figure 2.280 Gastric involvement by systemic mastocytosis. Oil immersion 100×

photomicrograph of mast cells within the “erosion” seen in previous figures. The mast cells have
 clear to eosinophilic granular cytoplasm with centrally located nuclei. These mast cells show
some nuclear atypia with mild hyperchromasia and spindle cell morphology.

Figure 2.281 Gastric involvement by systemic mastocytosis (CD117 immunostain). A CD117

immunostain of the case shown in the previous figure highlights clusters of mast cells in the area
of erosion.

Figure 2.282 Gastric involvement by systemic mastocytosis (CD25 immunostain). A CD25

immunostain of the case shown in the previous figures shows aberrant expression within the
mast cells. This presence of mast cell clusters in an extracutaneous site that express CD25 fulfills
the criteria for diagnosis of systemic mastocytosis (World Health Organization: one major and
one minor criterion).

Mastocytosis refers to a group of disorders characterized by excessive

mast cell accumulation in one or multiple tissues (Figs.
2.278–2.280).199–201 Involvement of neoplastic mast cells in the
gastrointestinal tract fulfills one major criterion of the World Health
Organization (WHO) diagnostic criteria for systemic mastocytosis. In
addition, abnormal expression of CD2 or CD25 by
immunohistochemistry in these cells satisfies one minor criterion and
fulfills the diagnosis of systemic mastocytosis (Figs. 2.281 and 2.282).

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 SMALL BOWEL 3

CHAPTER OUTLINE

The Unremarkable Small Bowel

Acute Duodenitis Pattern
• Peptic Injury
• Reactive Duodenitis
• Peptic Ulcer Disease
• Infection
• Medication
• Cigarette Smoking
• Zollinger–Ellison Syndrome
• Inflammatory Bowel Disease
• Infiltrative Processes
• Radiation Injury
• Ischemia
• Vasculitis
Acute Ileitis Pattern
• Medications
• Infection/Inflammatory Bowel Disease
• Infiltrative Processes
• Radiation injury
• Ischemia
• Vasculitis
Chronic Inflammation Pattern
• Reactive Duodenopathy
• Inflammatory Bowel Disease
• Infection
• Inflammatory or Immune-Regulated Disorders
Crypt Architectural Disturbance Pattern
• Inflammatory Bowel Disease
• Diaphragm Disease
• Ischemia
• Graft Versus Host Disease
• Medication
• Allograft Rejection
• Radiation Enteritis
• Pouchitis and Pouch-Related Changes
Eosinophilia Pattern
• Idiopathic Eosinophilic Enteritis
• Medications
• Allergy
• Parasitic Infection
• Inflammatory Bowel Disease
• Connective Tissue Disorders and Vasculitis
Malabsorption Pattern
• Medications
• Reactive Duodenopathy
• Small Intestinal Bacterial Overgrowth
• Gluten Sensitive Enteropathy
• Nongluten Protein Sensitivity
• Tropical Sprue
• Common Variable Immunodeficiency
• Autoimmune Enteropathy
• Collagenous Duodenitis
Foamy Macrophage Pattern
• Mycobacterium avium intracellulare
• Whipple Disease
• Nonspecific Scattered Macrophages
• Others
Dilated Lacteal Pattern
• Primary Lymphangiectasia
• Secondary Lymphangiectasia
• Obstruction
• Adjacent Neoplasm
• Adhesions
• Strictures
• Fistulas
• Inflammatory Bowel Disease
• Previous Operations
• Infection
• Whipple Disease
• Radiation Injury
Metaplasia and Heterotopia
• Reactive Duodenopathy
• Gastric Heterotopia
• Pancreatic Heterotopia
• Meckel Diverticulum
Pigments and Extras
• Titanium
• Tattoo Pigment
• Pseudomelanosis Duodeni
• Formalin Pigment
• Melanoma
• 90Yttrium-Labeled Microspheres
Near Misses
• Sneaky Adenocarcinoma
• Isospora
• Giardia
• Common Variable Immunodeficiency
• Collagenous Enteritis
• Sneaky Neuroendocrine Tumor
• Pyloric Metaplasia

THE UNREMARKABLE SMALL BOWEL

Endoscopically, the unremarkable small bowel shows a homogeneous
pink mucosa with permanent circular folds (plicae circulares) and a
dense carpet of villi. These plicae are an architectural adaptation to
augment the absorptive surface area in the small bowel, and correspond
histologically to reduplication of the mucosa, which is held together by a
submucosa core (Fig. 3.1).
The layers of the small bowel are divided into the mucosa, submucosa,
muscularis propria, and serosa (Fig. 3.2). Designed for absorption of
ingested nutrients, the mucosa is composed of an epithelial component,
lamina propria, and muscularis mucosae. The surface epithelium and
lamina propria form intraluminal projections called villi; these
microscopic fingerlike and leaflike projections cover the entire luminal
surface of the small bowel and further enhance surface area for
absorption.1 Each villus is covered by a single layer of epithelial cells of
varying types (see below), under which sits the epithelial basement
membrane and lamina propria. This lamina propria core contains a
blind-ended lymphatic channel (lacteal), capillary network, and
migratory inflammatory cells.2. Although the villi are extensions above
the surface architecture, the crypts (of Lieberkühn) are depressions
below that extend from the lumen to the muscularis mucosae. The ratio
of crypt height to villous length in the normal small bowel varies from
1:3 to 1:5 (Figs. 3.3–3.5).3
The villous epithelium is lined by tall columnar absorptive epithelial
cells, each of which contains an apical brush border composed of
microvilli (Figs. 3.6–3.8). These minute projections further augment the
surface area of the small bowel. Interspersed between the absorptive
cells are goblet cells, which secrete both neutral and acid mucins. These
sialomucins stain blue-purple on a combined Alcian blue-PAS stain.
Scattered endocrine cells are present within the villous epithelium, but
they are more abundant within the crypts. Intraepithelial lymphocytes
(IELs) are normally present as one per five epithelial cells. The deep
crypts additionally contain abundant Paneth cells (Fig. 3.9). The lamina
propria rests on the muscularis mucosae, surrounds the crypts, and
extends upward into the core of the intestinal villi. It serves as an
immunologic organ and contains plasma cells, lymphocytes, eosinophils,
histiocytes, and mast cells. Plasma cells are the most abundant cellular
lamina propria constituent. Most contain IgA but some contain IgM; in
contrast to their abundance in extraintestinal sites, IgG secreting plasma
cells are scarce. Lymphocytes of both B-and T-lineage are common. The
only granulocytes normally found in the lamina propria are eosinophils
and mast cells. The muscularis mucosae is composed of a thin layer of
smooth muscle cells separating the mucosa from the underlying
submucosa. Tufts of smooth muscle radiate from the muscularis mucosae
into the lamina propria and extend into the villi (Figs. 3.10–3.12).

Figure 3.1 Normal small bowel, endoscopic findings in the normal duodenum. A fine carpet of
villi lines the duodenal lumen. The circular folds (plicae) of the small bowel have smooth
borders.

Figure 3.2 Normal small bowel, layers of the small intestine. This resection specimen illustrates
the four main layers of the small bowel: mucosa, submucosa, muscularis propria, and serosa. The
mucosa consists of epithelium (E), lamina propria (L), and muscularis mucosae (MM). The
submucosa sits between the muscularis mucosae and the muscularis propria (MP) and it consists
of loose fibroconnective tissue and lymphovascular channels. The MP consists of two muscle
layers: an inner circular and outer longitudinal. The outermost layer is the serosa. Note the plicae
 circulares are composed of a reduplication of mucosa held together by a submucosa core.

Figure 3.3 Normal small bowel. The crypt to villous ratio in the normal small bowel ranges from
1:3 to 1:5. The epithelial cells lining the villi are tall columnar absorptive cells and are
intermittently punctuated by goblet cells. The base of the crypts contains visible bright pink
Paneth cells with scattered endocrine cells (unperceivable at this magnification).

Figure 3.4 Normal small bowel, lacteals. The core of the villi are composed of lamina propria
containing migratory chronic inflammatory cells, blood vessels, lymphatic channels, and smooth
muscle cells. This example shows dilated lacteals in the tips of the villi, a finding that indicates
lymphatic blockage of lymphatic flow of unclear significance.
 Figure 3.5 Normal small bowel, cross section of villous projection. Higher magnification of a
villous core highlights a dilated lymphatic space containing pale eosinophilic serum. Separate
capillary vessels contain red blood cells, and scattered chronic inflammatory cells are present in
the supporting substance.

Figure 3.6 Normal small bowel, villous tip. The villous tip is lined by columnar cells with an
absorptive brush border composed of microvilli. On H&E stain, this can be visualized as an
eosinophilic “fuzzy” border. These absorptive columnar cells are punctuated by goblet cells
(arrowhead), and small numbers of lymphocytes (arrows) may be seen traversing between them.
Figure 3.7 Normal small bowel, villous tips (PAS special stain). The microvillous brush border is
crisp and deeply eosinophilic on a PAS special stain, which also highlights the goblet cells.
Defective, broken, or smudgy brush borders should prompt consideration of microvillous
inclusion disease, especially in infants. The cytoplasm of the columnar cells appears pale and
homogeneous.

Figure 3.8 Normal small bowel, lipid “hang-up” (PAS special stain). This PAS stain of a villous tip
reveals vacuolated cytoplasm of the absorptive columnar cells (compare to previous figure). This
finding indicates lipid within the cytoplasm of the epithelial cells and is commonly seen among
patients who have ingested food or drink prior to endoscopy. When severe, diffuse, or present in
the pediatric population, it is worthwhile to consider a lipid transport disorder.
Figure 3.9 Normal small bowel, crypt base. Paneth cells (arrowheads) contain abundant brightly
eosinophilic coarse granules that face the gland lumen. By comparison, enteroendocrine cells
(arrows) have deeper red and smaller granules that face the basement membrane.

Figure 3.10 Normal small bowel, smooth muscle within villous core. Delicate tufts of smooth
muscle (arrows) extend from the muscularis mucosae along the core of the villi. When cut in
cross section (arrowheads), these can be mistaken for histiocytes, signet ring cell carcinoma, or
infectious diseases (such as Mycobacterium avium intracellulare).
Figure 3.11 Normal small bowel, normal variant morphology in small intestine. Remember that
the slide is a two-dimensional representation of three-dimensional tissues. Villi may be truncated
if they extend out of the plane of section, as seen here. The adjoining long, slender villi reassure
observers that there is not true villous atrophy.

Figure 3.12 Normal small bowel, normal variant morphology in small intestine. Villi may vary
from slender and fingerlike to broad and leaflike depending on geographic region or specific
diets. Other variations, such as bridging villi (seen here) may also be seen in healthy patients.

The submucosa of the duodenum contains ganglion cells of Meissner’s

plexus, lymphatic and vascular structures, and is one of only two sites in
the gastrointestinal tract that contains submucosal glands (the other
being the esophagus). These Brunner glands are lobular collections of
tubuloalveolar glands that are limited to the submucosa of the
duodenum; however, up to one third of them can reside within the deep
mucosa in the absence of pathology (Fig. 3.13).4 These glands are most
concentrated at the gastro–duodenal junction and gradually decrease in
number distally (Figs. 3.14 and 3.15). The glands are lined by cells (Fig.
3.16) that contain PAS positive and diastase-resistant neutral mucins,
and scattered endocrine cells that secrete somatostatin, gastrin, and
peptide YY. Secretions empty into the luminal crypt spaces by way of
small ducts. Distally, the jejunum and ileum lack Brunner glands.

Figure 3.13 Normal small bowel, proximal duodenum with Brunner glands. Brunner glands are
found exclusively in the proximal duodenum. Although their bulk lies in the submucosa,
extension above the muscularis mucosae is not uncommon, even under normal conditions, as
seen here.

Figure 3.14 Normal small bowel, Brunner glands. Brunner glands are lined by cuboidal to
columnar cells with pale, uniform cytoplasm and oval, basally located nuclei.
 Figure 3.15 Normal small bowel, crushed Brunner glands. Crushed Brunner glands may
sometimes take on a neural appearance, raising the differential diagnosis of a neural tumor.

Figure 3.16 Normal small bowel, Brunner glands (PAS special stain). Brunner glands contain PAS
positive and diastase-resistant cytoplasmic mucin. This staining pattern can be helpful in
differentiating crushed Brunner glands from a neural tumor.

The muscularis propria surrounds the submucosa and is composed of

an inner circular and outer longitudinal layer of smooth muscle.
Between these layers lies the myenteric plexus of Auerbach, a major
neural plexus of the enteric nervous system. Externally, the bowel is
enveloped by subserosal connective tissue and the mesothelial-derived
serosa.
PEARLS & PITFALLS
Distinctive Differences Among Regions of Small Bowel
Duodenum: Contains submucosal Brunner glands, more abundant
proximally
Villi range from slender and fingerlike to broad and
leaflike.
Jejunum: Prominent, tall plicae circulares
Villi are uniformly slender and fingerlike.
Ileum: Submucosal adipose tissue may be present, especially
near the ileocecal valve
Shorter and fewer plicae circulares
Increased proportion of goblet cells
Presence of Peyer patches (abundance of lymphoid
aggregates) (Fig. 3.17)

Figure 3.17 Normal small bowel, terminal ileum. Unencapsulated organized lymphoid nodules
are found within the mucosa and submucosa of the terminal ileum. These Peyer patches are
found exclusively in the ileum, which functions as an immunologic organ.
FAQ: My terminal ileum biopsy shows prominent lymphoid
aggregates. How can I be sure I am not missing a sneaky
hematolymphoid malignancy?
Answer: You are not alone! Prominent lymphoid aggregates can be
especially alarming in the terminal ileum and, thus, are a common
source of consultation. The small bowel serves as an essential
component of the immune system through its perpetual surveillance of
the passing luminal contents. Diligent immunosurveillance is
facilitated through specialized epithelial cells (M-cells) that transport
luminal antigens to the lymphoid aggregates (designated “Peyer
patches” when seen in the terminal ileum). Hyperplastic lymphoid
aggregates can be sufficiently large as to be visualized endoscopically
and can also serve as intussusception lead points, especially in young
children.5,6 The epicenter of lymphoid aggregates is in the mucosa but
especially prominent cases can feature extension into the submucosa,
raising concerns for a hematolymphoid malignancy. Histologic
features reassuring for a benign, reactive process include the presence
of germinal centers, tingible body macrophages, and a polymorphous
constituent lymphoid population (i.e., a variety of cell sizes
represented); however if the focus in question seems at all concerning,
a quick immunohistochemical panel may be worthwhile (Figs.
3.19–3.37) (Table 3.1).

PEARLS & PITFALLS

CD43 also highlights plasma cells.

Lymphomas treated with Rituximab (anti-CD20) can be CD20 negative

(use PAX5 to confirm B lymphocytes in these cases).

PEARLS & PITFALLS

For those of us who do not routinely evaluate hematopathology
 specimens, it can be difficult to remember the significance of several
of the similarly sounding hematopathology markers, particularly BCL-
2, BCL-6, and CD10. If you relate to these challenges, consider this
dartboard analogy as a handy learning tool (Figs. 3.18 and 3.19). In
the game of darts, a player is awarded more points for landing a dart
at the prized center bull’s eye due to the challenging nature of this
difficult shot, and fewer points for landing a dart in the periphery of
the dart board. In this analogy, imagine the center bull’s eye as a
germinal center with the highest points awarded (BCL-6 and CD10). In
contrast, the peripheral location outside of the germinal center is
awarded fewer points (BCL-2). Importantly, this analogy only works
for normal lymphoid aggregates! Follicular lymphoma, for example, is
characterized by BCL-2 reactive germinal centers due to the t(14;18)
rearrangement of BCL-2 and the immunoglobin heavy chain (IgH). See
also Table 3.1.

TABLE 3.1: Quick and Dirty Immunohistochemical Panel for Prominent

Lymphoid Aggregates versus Select Hematolymphoid Malignancies
 Figure 3.18 Dart game analogy. If it is difficult to remember the significance of BCL-2, BCL-6,
and CD10 as they relate to normal lymphoid aggregate architecture, consider this dartboard
analogy. In the game of darts, a player is awarded more points for landing a dart at the center
bull’s eye as compared to the periphery of the dartboard. In this analogy, imagine the bull’s eye
 as a germinal center with the highest points awarded (BCL-6 and CD10). In contrast, the
peripheral location is outside of the germinal center and fewer points are awarded for these less
challenging shots (BCL-2).

Figure 3.19 Normal lymphoid aggregate, illustration. In a normal lymphoid aggregate, the
germinal center is highlighted by BCL-6 and CD10 (analogous to a dartboard’s prized bull’s eye)
and is negative for BCL-2. Recall, normal B lymphocytes in the mantle zone surrounding the
germinal center and normal T lymphocytes express BCL-2 (analogous to a dartboard’s periphery).
Therefore, interpretation of BCL-2 always requires concomitant interpretation of CD20 B
lymphocyte marker and CD3 T lymphocyte marker.

Figure 3.20 Normal terminal ileum. The overlying villi of the terminal ileum are
characteristically shorter than those seen in the duodenum and jejunum (Figs. 3.3 and 3.13). At
low power, the prominent lymphoid aggregate is seen confined within the mucosa (arrowheads
highlight the narrow wisp of muscularis mucosae). Although the crypts are not identical copies of
each other (the crypts are variably sized with varying amounts of intervening lamina propria),
these slight differences are due to the prominent lymphoid aggregate and are entirely within the
spectrum of normal terminal ileum histology. The lymphoid aggregate gently pushes the crypts
apart; there is neither acute inflammation actively destroying the epithelium nor features of
chronic injury (such as pyloric gland metaplasia). As a result, the superficial epithelium could be
theoretically pulled off the lymphoid aggregate since there is no destructive inflammatory injury
tethering the epithelium to the lymphoid aggregate. See figures 3.64, 3.66–3.70 to contrast this
normal architecture with features of established active chronic injury.

Figure 3.21 Normal terminal ileum. As this case illustrates, large lymphoid aggregates can
occasionally extend below the muscularis mucosae (bracket) into the submucosa. Features in
support of a benign process include variably sized lymphoid aggregates, germinal centers (arcs),
tingible body macrophages (macrophages containing apoptotic debris in the cytoplasm,
arrowheads), and a polymorphous lymphoid population (variably sized lymphocytes, best seen at
high-power, Figures 3.29–3.30).
 Figure 3.22 Normal terminal ileum. Note how the overlying epithelium could be theoretically
“peeled” off the lymphoid aggregates since the large lymphoid aggregates are seen gently
pushing aside the epithelium and not associated with active chronic inflammatory injury. Note
the features of benignity: variably-sized lymphoid aggregates, germinal centers, and tingible
body macrophages.

Figure 3.23 Normal terminal ileum. With such large prominent aggregates, the ever so slight
scattered appearance to the crypts is entirely within the spectrum of normal terminal ileum
architecture. Note that the overlying epithelium could be theoretically “peeled” off the lymphoid
aggregates since there is no active chronic inflammatory injury linking the lymphoid aggregates
to the epithelium.
Figure 3.24 Normal terminal ileum with variably sized lymphoid aggregates, germinal centers,
and tingible body macrophages.

Figure 3.25 Normal terminal ileum. Crushed lymphoid tissue traversing the muscularis mucosae
can raise concerns for a malignant hematolymphoid process (bracket). In this case, however, the
intact lymphoid aggregate shows germinal centers (arc), tingible body macrophages
(arrowheads), and a polymorphous lymphoid population, all features of a benign lymphoid
process.
 Figure 3.26 Normal terminal ileum. On higher power, a germinal center with tingible body
macrophages is seen. Note that increased IELs are a normal finding in epithelium overlying
lymphoid aggregates (brackets).

Figure 3.27 Normal terminal ileum. On higher power, the increased IELs are better appreciated
(brackets). Recall, increased IELs are a normal finding in epithelium overlying lymphoid
aggregates.
Figure 3.28 Normal terminal ileum. This high power view features a reactive germinal center
with numerous tingible body macrophages (arrowheads). Tingible body macrophages harbor
engulfed apoptotic debris, accounting for their characteristic cytoplasmic morphology.

Figure 3.29 Normal terminal ileum. This focus illustrates important features of a benign
lymphoid aggregate: a germinal center (arc), tingible body macrophages (arrowheads), and
variably sized lymphocytes (small, medium, and large lymphocytes).
Figure 3.30 Normal terminal ileum. The polymorphous nature of this benign lymphoid aggregate
is best seen at high power (note the various sized and shaped lymphocytes). A rare mitotic body
is seen (arrowhead), a feature not unusual for reactive lymphoid aggregates.

Figure 3.31 Normal terminal ileum. Prominent lymphoid aggregates can be alarming and,
consequently, are a common source of consultation. Most typically, recognition of the key H&E
features of benignity is sufficient to render a diagnosis of an unremarkable lymphoid aggregate:
as in this case, germinal centers, tingible body macrophages, and variably sized lymphocytes are
seen. Sometimes, however, a quick immunostain panel approach can be reassuring.
 Figure 3.32 Normal terminal ileum (CD23 immunostain). A CD23 highlights the follicular
dendritic cell meshwork surrounding the germinal centers, a feature of intact (normal) lymphoid
aggregate architecture.

Figure 3.33 Normal terminal ileum (CD3 immunostain). A CD3 highlights T lymphocytes, which
are predominantly seen surrounding the germinal center. On H&E, these lymphocytes were
uniform and small, no atypical cytologic features were seen.
 Figure 3.34 Normal terminal ileum (CD20 immunostain). A CD20 highlights B lymphocytes,
which are the majority of the lymphoid constituents.

Figure 3.35 Normal terminal ileum (BCL-6 immunostain). Various artifacts occasionally make
germinal centers difficult to discern. In such cases, BCL-6 and CD10 are equally helpful markers
that highlight germinal centers.
 Figure 3.36 Normal terminal ileum (CD10 immunostain). Like BCL-6, CD10 also highlights
germinal centers. Of note, CD10 also highlights a crisp/intact brush border characteristic of
normal small bowel mucosa (bracket). Defective, broken, or smudgy brush borders should prompt
consideration of microvillous inclusion disease, especially in infants.

Figure 3.37 Normal terminal ileum (BCL-2 immunostain). Normal germinal centers are BCL-2
negative. If the germinal center is BCL-2 reactive, consider follicular lymphoma, which is
characterized by the t(14;18) rearrangement of BCL-2 and the immunoglobin heavy chain (IgH).
Importantly, recall that normal B lymphocytes in the mantle zone surrounding the germinal
center and normal T lymphocytes express BCL-2. Therefore, interpretation of BCL-2 always
requires concomitant interpretation of CD20 B lymphocyte marker, CD3 T lymphocyte marker,
and a germinal center marker (BCL-6 or CD10).
ACUTE DUODENITIS PATTERN

Figure 3.38 Acute duodenitis pattern. Acute duodenitis refers to acute inflammation in the
duodenal epithelium (arrowheads). In this particular example, infiltrating pancreatic
adenocarcinoma (not shown) was identified lurking within the acute inflammation, underscoring
the importance of recognizing seemingly bland clues, such as acute duodenitis, to help uncover
critical diagnoses.

CHECKLIST: Etiologic Considerations for the Acute

Duodenitis Pattern (Fig. 3.38)
Peptic Injury (due to excess acid)
Reactive Duodenitis (mild histologic changes)
Peptic Ulcer Disease (marked histologic changes)
Infection
Medication (NSAIDs)
Cigarette Smoking
Zollinger–Ellison Syndrome
Inflammatory Bowel Disease
Infiltrative Processes
Radiation Injury
Ischemia
 Vasculitis

The acute duodenitis pattern refers to acute inflammation in the

epithelium of the duodenum. This injury pattern is most commonly seen
in the setting of peptic injury, infection, and medication injury, but can
also be a clue to inflammatory bowel disease (IBD), infiltrative
processes, ischemia, radiation injury, and others. Careful attention to the
clinical presentation and scrutiny of the surrounding mucosa is critical to
arriving at the correct diagnosis. Acute duodenitis can be further
classified as “mild,” “moderate,” or “marked” based on the qualitative
distribution of the acute inflammation; counting neutrophils is not
necessary. For a simple rule of thumb, “mild” includes villitis and
cryptitis, “moderate” is indicated by crypt abscesses, and “marked” is
indicated by sheets of neutrophils with or without erosion/ulceration. By
definition, histologic features of chronic injury are absent, that is,
architectural distortion, gastric foveolar metaplasia, and pyloric gland
metaplasia are not seen with simple acute duodenitis. When features of
chronic damage are established, the injury has occurred over a longer
time period and the differential diagnostic considerations expand to
include chronic injury of any sort (i.e., chronic peptic injury, chronic
infections, chronic medication injury, in addition to IBD and others).

PEPTIC INJURY
Peptic injury describes a broad morphologic range of duodenal injury
ranging from spotty acute inflammation to deep, penetrating ulcers. At
the mild end of the spectrum, peptic injury manifests with the following
histologic features:
1. Increased plasma cell infiltration
2. Neutrophils in the lamina propria or epithelium (or in both) (Figs.
3.39 and 3.40)
3. Reactive epithelial changes including villous blunting
4. Gastric foveolar (mucin cell) metaplasia
This mild injury pattern is interchangeably referred to as “reactive
duodenopathy,” “gastric foveolar metaplasia,” “chronic peptic
duodenopathy,” “chronic peptic duodenitis” and “peptic-type
duodenopathy.” Based on the variable villous blunting, the pattern is
more extensively discussed in the Malabsorption Pattern, this chapter.
Briefly, this pattern is historically associated with excessive gastric acid
production coupled with insufficient protective effects of bicarbonate.
Strong links with Helicobacter are not seen in reactive duodenopathy, in
contrast to peptic ulcer disease (PUD). PUD represents the extreme range
of peptic injury characterized by ulcerations, marked acute and chronic
inflammation, mucin attenuation, and reactive changes. PUD is
attributable to Helicobacter in the majority of cases, although
nonsteroidal anti-inflammatory drugs (NSAIDs) and cigarette smoking
are also implicated. Recurrent, multifocal, or marked peptic ulcer disease
may serve as an important red flag to Zollinger–Ellison syndrome. Recall
that Zollinger–Ellison syndrome is characterized by gastrinoma (and
tumor-mediated hypergastrinemia), hyperplasia of the oxyntic
compartment, increased gastric acid production, and gastric and small
bowel ulcerations. See also Hyperplasia Pattern, Stomach Chapter.

Figure 3.39 Acute duodenitis pattern, peptic injury. Acute duodenitis is an etiologically
nonspecific injury pattern most commonly seen in the setting of peptic injury, infection, and
medication injury. Neutrophils are seen in the epithelium (arrowhead) and lamina propria
(asterisk).
 Figure 3.40 Acute duodenitis pattern, peptic injury. Under oil immersion, the neutrophils are
more easily seen in the epithelium (arrowhead) and lamina propria (asterisk). The cause of the
injury is unknown.

INFECTION

Figure 3.41 Acute duodenitis pattern, Helicobacter pylori. This case of Helicobacter pylori
duodenitis shows similar features to Helicobacter pylori gastritis. At low power, increased acute
and chronic inflammation is seen, which is particularly prominent toward the superficial mucosa.
Gastric foveolar metaplasia (bracket) provides a hospitable environment for Helicobacter and
should always be carefully checked for organisms.
 Figure 3.42 Acute duodenitis pattern, Helicobacter pylori. At higher power, intraepithelial acute
inflammation (arrowheads) and prominent superficial plasma cells provide helpful red flags to the
underlying Helicobacter infection. A rare Helicobacter organism is seen (arrow). Since this case had
no corresponding stomach biopsy, the only opportunity to diagnosis and treat the infection
stemmed from recognizing this injury pattern and carefully searching for the rare Helicobacter
organisms.

Figure 3.43 Acute duodenitis pattern, Helicobacter pylori. This low power image shows features
highly suspicious for a Helicobacter infection with a prominent superficial lymphoplasmacytic
infiltrate, acute inflammation (not seen at this power), and gastric metaplasia (brackets). The
organisms were seen in abundance on a Diff–Quik special stain (not shown) in the gastric
metaplastic zones.
 Figure 3.44 Acute duodenitis pattern, Helicobacter pylori. This low power image shows features
reminiscent of those of exuberant Helicobacter gastritis. Note the prominent superficial
lymphoplasmacytic infiltration and gastric metaplasia (brackets). Brisk acute inflammation and
Helicobacter organisms were seen on higher power (not shown).

Figure 3.45 Acute duodenitis pattern, gastric foveolar metaplasia (PAS/AB). A PAS/Alcian blue
pH 2.5 special stain highlights the neutral mucin characteristic of gastric foveolar metaplasia
(bracket), similar to native stomach mucosa. In contrast, goblet cells display basophilia because of
acidic mucin (arrowhead).
 Figure 3.46 Acute duodenitis pattern, gastric foveolar metaplasia (PAS/AB). Gastric foveolar
metaplasia appears eosinophilic because of neutral mucin (bracket); goblet cells are basophilic
because of acidic mucin (arrowhead). Note the abundant superficial plasma cells with a sprinkling
of acute inflammation, features suggestive of Helicobacter duodenitis (organisms not shown).

Figure 3.47 Acute duodenitis pattern, adenovirus infection. Prominent apoptotic bodies
(arrowheads) and scattered intraepithelial neutrophils serve as helpful red flags to the
characteristic adenovirus inclusions (bracket). Note the glassy and eosinophilic intranuclear
inclusions typical for adenovirus. Since similar findings can be seen with degenerative change, a
confirmatory adenovirus immunostain was performed and was reactive (not shown).
 Figure 3.48 Acute duodenitis pattern, CMV infection. In this case, a smattering of acute
inflammation and increased apoptotic bodies (arrowheads) serve as important clues to the
diagnosis of CMV enteritis.

Figure 3.49 Acute duodenitis pattern, CMV infection. Careful inspection of the nearby mucosa
revealed abundant Brunner epithelium with classic CMV viral cytopathic effect (arrowheads):
cytolomegaly, prominent nucleoli, and both nuclear and cytoplasmic viral inclusions are seen. In
the stomach and small bowel, viral cytopathic effect is often more conspicuous in the epithelium
than the stromal and endothelial cells. These viral inclusions were diagnostic (a CMV
immunostain was not required).
Figure 3.50 Acute duodenitis pattern, CMV infection. Higher power of another field shows classic
CMV viral cytopathic effect with cytolomegaly and prominent nuclear and cytoplasmic viral
inclusions (arrowheads). Although not included on the requisition, chart review revealed a history
of febrile diarrhea, metastatic colorectal carcinoma, and concurrent chemotherapy. This case
underscores the importance of recognizing this acute enteritis pattern, even when the history of
immunosuppression is not apparent on the requisition.

Helicobacter remains a leading contender in infectious agents associated

with the acute duodenitis pattern. Its histology can show similar features
to the analogous gastric process with brisk acute and chronic
inflammation and conspicuous superficial plasma cells (Figs. 3.41–3.46).
If not apparent on H&E, a Helicobacter immunostain can be utilized for
suspicious cases.7 Not to be missed, adenovirus and CMV are similarly
important infectious agents, particularly in immunocompromised
patients. The characteristic intranuclear adenovirus inclusions are glassy
eosinophilic, and can be highlighted with an adenovirus immunostain
(Fig. 3.47). Adenovirus treatment involves lowering immunosuppressive
agents, making the distinction from graft versus host disease (GVHD)
critical because GVHD therapy requires increased immunosuppressive
therapy. See also GVHD, Lymphocytic Pattern, Esophagus Chapter.
Similar to CMV infections of other sites, the characteristic inflammatory
backdrop shows a prominence of mononuclear inflammation
(lymphocytes, macrophages, lymphocytes, and plasma cells), in addition
to active background injury and increased apoptotic bodies. The classic
CMV viral cytopathic effect includes nuclear enlargement, prominent
nuclear inclusions (with an “owl’s eye” appearance), and cytoplasmic
inclusions (Figs. 3.48–3.50). In the stomach and small bowel, CMV viral
cytopathic changes can be more prominent in the epithelium rather than
the stromal and endothelial cells; the latter changes more common in
CMV esophagitis, colitis, and proctitis.

KEY FEATURES of the Acute Duodenitis Pattern:

• Acute duodenitis refers to acute inflammation in the epithelium of the
duodenum.
• The most common etiologies include peptic injury, infection, and
medication injury.
• Reactive duodenopathy shows mild mucosal damage and is due to
excess gastric acid; it has no strong association with Helicobacter.
• Peptic ulcer disease is due to Helicobacter in the majority of cases,
although NSAIDs and cigarette smoking also play a causal role.
• Helicobacter remains the most common identifiable infectious etiology
of the acute duodenitis pattern.

ACUTE ILEITIS PATTERN

Figure 3.51 Acute ileitis pattern. Acute ileitis refers to acute inflammation in the epithelium of
the ileum (arrowheads). It is most commonly caused by medication, infection, and inflammatory
bowel disease.

Similar to that in the acute duodenitis pattern, acute inflammation in the

epithelium of the ileum can qualitatively be scored “mild,” “moderate,”
or “marked” based on the relative prominence of acute inflammation in
the epithelium (Figs. 3.51–3.55). Comparatively, the acute ileitis pattern
is associated with a slightly modified differential diagnostic list of
etiologic considerations. In this section, the discussion emphasizes
etiologic considerations particularly important to the ileum.

Figure 3.52 Acute ileitis pattern, aphthoid lesion. The diagnosis of acute ileitis implies the
absence of chronic injury, as seen in this figure). Although the lymphoid aggregate is gently
pushing apart the crypts, there is no chronic injury of the epithelium (note the epithelium could
be theoretically peeled off the lymphoid aggregate since the epithelium is not tethered to the
lymphoid aggregate by destructive inflammatory injury).

Figure 3.53 Acute ileitis pattern, aphthoid lesion. Higher power of previous case. An aphthoid
 lesion/ulcer refers to acute inflammation in the epithelium overlying a lymphoid aggregate. In
the appropriate clinicopathologic context, an aphthoid lesion can lend support to the diagnosis of
Crohn disease.

Figure 3.54 Acute ileitis pattern. A pocket of luminal neutrophils is seen (bracket) along with
acute inflammation in the epithelium (arrowheads).

Figure 3.55 Acute ileitis pattern, prominent ulceration. Acute ileitis refers to a fairly wide range
of mucosal injury patterns ranging from scattered neutrophils in the epithelium to deep
penetrating ulcerations and fissures. In this example, a prominent ulceration is featured
(arrowhead), while the background mucosa is essentially unremarkable at this power. The
terminal ileum findings were attributed to the established history of excessive NSAID usage.
CHECKLIST: Etiologic Considerations for the Acute Ileitis
Pattern
Medications (i.e., NSAIDs, ipilimumab, other chemotherapeutic agents)
Infection (CMV, Adenovirus, and Typical Stool Pathogens, including
Yersinia, Salmonella, others)
Inflammatory Bowel Disease
Infiltrative Processes (i.e., Amyloidosis or Malignancy)
Radiation Injury
Ischemia
Vasculitis

MEDICATIONS
Medication-related injury constitutes the most common cause of the
acute ileitis pattern of injury, particularly in adults. In an endoscopic
study of long-term NSAID users, up to 71% showed distal small bowel
mucosal injury compared to only 10% of non-NSAID users (p < 0.001).8
NSAIDs mediate injury via nonselective inhibition of cyclooxygenase
isoenzymes resulting in decreased production of mucosal protectant
products, such as prostaglandins, mucin, and bicarbonate, and
dampened microcirculation. The injury pattern can range from mild
acute ileitis to erosions, deep-penetrating ulcerations, perforations, and
necrosis (Fig. 3.55). The so-called diaphragm disease is a rare but
clinically significant consequence seen in up to 2% of patients with
chronic NSAID usage and is presumed to be pathognomonic for NSAID-
related injury. See also Diaphragm Disease, Chronic Ileitis, this chapter.
Although NSAID-related injury can occur at any point along the tubular
GI tract, the terminal ileum is particularly vulnerable because of the
increased popularity of extended release formulations that delay release
of NSAIDs (and the associated mucosal damage) from the stomach to
distal bowel segments, including the terminal ileum9 and even the
colon.10,11 Other proposed factors include the geographic specific
constraints of the terminal ileum; the prominent lymphoid aggregates
and narrowed ileocecal valve may result in increased tablet-mucosal
contact and related physical and or chemical injury.9

INFLAMMATORY BOWEL DISEASE

The acute ileitis pattern can also herald inflammatory bowel disease
(IBD). Although IBD is discussed at length in Inflammatory Bowel
Disease, Chronic Colitis, Colon Chapter, a few comments pertaining to
the terminal ileum are warranted. Importantly, terminal ileal injury is
not restricted to Crohn disease. Up to 17% of ulcerative colitis cases are
associated with acute ileitis via a process termed “backwash ileitis.”12
“Backwash ileitis” occurs in a background of marked pancolitis whereby
the inflammatory rich luminal contents in the colon are refluxed into the
contiguous terminal ileum segment, causing associated inflammatory and
reactive changes. The degree of terminal ileum injury is usually mild, or
no greater than that in the cecum, and features of chronic mucosal
injury are uncommon (Figs. 3.56 and 3.57).12 If terminal ileum restricted
injury is present and the adjoining colon shows unremarkable mucosa,
medication injury, infection, or Crohn disease would figure a more likely
etiology.
When assessing the acute ileitis pattern, it is worthwhile to carefully
scrutinize the background mucosa for any additional diagnostic clues
that might help refine the diagnosis. For example, aphthoid
lesions/ulcers consist of acute inflammation in the epithelium overlying
lymphoid aggregates and their presence can lend support to a
clinicopathologic diagnosis of Crohn disease (Figs. 3.52–3.54). Although
granulomata can be difficult to detect in the normally busy-appearing
terminal ileum biopsies, their presence can also be helpful when
considering the possibility of Crohn disease, infection, sarcoidosis, or
medication injury (Figs. 3.58–3.65). Features of chronic mucosal injury
are also important to identify, such as pyloric gland metaplasia and
architectural distortion, although these features can be seen with chronic
injury of any sort, such as chronic NSAID-associated injury or chronic
infections (Figs. 3.58–3.73). Histologic features of chronic mucosal
injury are extensively discussed in Chronic Colitis, Colon Chapter. Based
on the overlapping features between IBD, chronic medication injury, and
chronic infection, IBD is remains a clinicopathologic diagnosis that must
encompass all available clinicopathologic features (clinical
symptomatology, disease course, disease distribution pattern, pertinent
microbiologic studies, and family history, etc.).13

KEY FEATURES of the Acute Ileitis Pattern:

• Medication-related injury constitutes the most common etiology,
followed by infection and IBD (Crohn disease > ulcerative colitis).
• This injury pattern ranges from mild acute ileitis to erosions, deep-
penetrating ulcerations, perforations, and necrosis.
• Diaphragm disease is a rare consequence of chronic NSAID usage and
refers to mucosal strictures that concentrically involve the bowel wall,
narrowing the lumen to a pinhole size, resulting in obstruction.
• Assess the background mucosa for clues such as aphthoid lesions,
granulomata, features of chronic mucosal injury, radiation injury,
amyloidosis, and neoplasia, in attempts to uncover the etiology.

Figure 3.56 Acute ileitis pattern, backwash ileitis, ulcerative colitis. This ileal biopsy was taken
from a patient with well-established ulcerative colitis.
Figure 3.57 Acute ileitis pattern, backwash ileitis, ulcerative colitis. Higher magnification of the
previous figure reveals mild focal acute inflammation (arrowheads) that should not be mistaken
for Crohn disease.

Figure 3.58 Granulomatous pattern (brackets), terminal ileum, sarcoidosis. This terminal ileum
resection originated from a 58-year-old woman with an extensive history of sarcoidosis who
presented with a small bowel obstruction. The background mucosa was unremarkable. AFB and
GMS special stains were negative.
 Figure 3.59 Acute ileitis pattern, granuloma, Crohn disease. This sneaky granuloma is almost
miss-able on low power (arrowhead). This biopsy originated from a patient with a history of
Crohn disease and scattered mucosal granulomata were seen throughout representative upper
and lower gastrointestinal tract biopsies.

Figure 3.60 Acute ileitis pattern, granuloma, Crohn disease. On higher power, the granuloma is
more easily spotted (arrowhead) as is the focal acute inflammation in the adjoining epithelium
(bracket). AFB and GMS special stains were negative.
 Figure 3.61 Acute ileitis pattern, erosive active chronic granulomatous ileitis, Crohn disease.
Active chronic inflammation refers to acute injury (i.e., acute inflammation in the epithelium or
crypt lumens, erosions, and or ulcerations) and chronic injury. In this case, an erosion is seen
(arrowhead) along with an expansion of the lamina propria by a lymphohistiocytic inflammation
(brackets).

Figure 3.62 Acute ileitis pattern, erosive active chronic granulomatous ileitis, Crohn disease. On
intermediate power, a foreign body giant cell is more easily seen (arrowhead) in addition to
vague granulomatous inflammation (brackets). Granulomata in Crohn disease are often poorly
formed, as in this case.

Figure 3.63 Acute ileitis pattern, erosive active chronic granulomatous ileitis, Crohn disease. On
highest power, the epithelioid morphology characteristic of granulomatous inflammation is seen
(bracket). AFB and GMS special stains were negative.
 Figure 3.64 Acute ileitis pattern, active chronic granulomatous ileitis, Crohn disease. At low
power, crypt shortfall with basal lymphoplasmacytosis is seen: note that the crypts fall short of
the muscularis mucosae (arrowheads) because of a basal layer of lymphoplasmacytic
inflammation (bracket). Granulomata in Crohn disease (asterisk) can be notoriously difficult to
appreciate in intensely inflamed specimens, as in this case. In contrast to normal terminal ileum
architecture, note that it would be impossible to strip off the overlying epithelium in this case
since the epithelium is inseparably melded to the associated active chronic inflammatory injury.
Contrast this image with normal architecture (Figs. 3.20–3.25).

Figure 3.65 Acute ileitis pattern, active chronic granulomatous ileitis, Crohn disease. On higher
power a granuloma with foreign body giant cells is more easily appreciated (bracket). AFB and
GMS special stains were negative.
 Figure 3.66 Acute ileitis pattern, active chronic ileitis, Crohn disease. Active chronic injury
implies both acute and chronic inflammatory injury. Although acute inflammation is not
apparent at this magnification, features of established chronic injury (chronicity) include pyloric
gland metaplasia (best appreciated at higher power) and architectural distortion (note the
variably sized crypts with variable intervening lamina propria). Also note the transmural fibrosis
and chronic inflammation, and subserosal lymphoid aggregates (brackets), features compatible
with the history of established Crohn disease.

Figure 3.67 Acute ileitis pattern, ulcerative active chronic ileitis, Crohn disease. This resection is
from a patient with a history of terminal ileum-restricted Crohn disease. The image features both
acute injury (ulceration (arrowhead) and acute inflammation in the epithelium (not shown)) and
chronic injury (gastric foveolar metaplasia [brackets], pyloric gland metaplasia [asterisks], and
slight architectural distortion with variably sized crypts, variable intervening lamina propria,
 minimal crypt shortfall, and basal lymphoplasmacytosis [arrows]).

Figure 3.68 Acute ileitis pattern, ulcerative active chronic ileitis, Crohn disease. Alternate field.
Luminal ulcer debris is seen along with features of chronic mucosal injury (gastric foveolar
metaplasia and architectural distortion).

Figure 3.69 Acute ileitis pattern, active chronic ileitis, Crohn disease. Alternate field.
Architectural distortion is often best seen at low power: note the variably sized crypts with
variable intervening lamina propria.
Figure 3.70 Acute ileitis pattern, active chronic ileitis, Crohn disease. Architectural distortion can
also be appreciated on small bits of biopsy material, as this case. Note the central bizarrely
shaped crypt with greater than seven branches, and the variable amount of intervening lamina
propria throughout, both features of chronic mucosal injury. Acute ileitis was also seen (not
shown).

Figure 3.71 Acute ileitis pattern, active (arrow) chronic (arrowheads) ileitis, Crohn disease.

Figure 3.72 Acute ileitis pattern, active chronic ileitis, Crohn disease. Pyloric gland metaplasia is
evidence of chronic mucosal injury (brackets). Pyloric gland metaplasia of the ileum is
histologically identical to the pyloric-type glands of the gastric cardia and antrum and to Brunner
glands of the duodenum. These glands are composed of mucus secreting cells with abundant
clear foamy cytoplasm and basally located nuclei. A PAS/AB special stain would highlight
eosinophilic neutral mucin (not shown).
 Figure 3.73 Acute ileitis pattern, active chronic ileitis, Crohn disease. Higher power of previous
case.

CHRONIC INFLAMMATION PATTERN

Figure 3.74 Chronic inflammation, nonspecific. Not uncommonly, small bowel biopsies show a
chronic inflammatory infiltrate without other specific features. Following systematic review of all
tissue compartments for clues, and chart review for clinical correlates, some cases just remain
“nonspecific.”

CHECKLIST: Etiologic Considerations for the Chronic

Inflammation Pattern
Reactive Duodenopathy
 Inflammatory Bowel Disease
Infection
Inflammatory or Immune-Regulated Disorders (i.e., Psoriasis)

The chronic inflammation pattern is defined by mild expansion of the

lamina propria with mononuclear cells or lymphoid aggregates in the
absence of villous blunting or intraepithelial lymphocytosis (Fig. 3.74).
This is the most nonspecific of the small bowel patterns, but also among
the most common. Etiologic considerations include reactive
duodenopathy (see Malabsorption Pattern, this chapter), infection, and
upper tract involvement by IBD (Figs. 3.75 and 3.76). Up to 40% of
patients with Crohn disease may show active, chronic, and
granulomatous inflammation in varying proportions.14 By comparison,
ulcerative colitis is typically limited to the lower gastrointestinal tract,
although up to 10% of ulcerative colitis patients may demonstrate a
diffuse chronic duodenitis.15 Keep in mind, however, that IBD is a
primary consideration only when the changes are “focally enhanced”
(Figs. 3.77 and 3.78) (See Focally Enhanced Gastritis, Stomach Chapter)
or are accompanied by mucosal granulomata, or if lower gastrointestinal
tract disease is present. Sampling error in the duodenum may result in
the lack of specific features, and this can raise a host of other differential
diagnoses, such as medication-induced changes, upstream gastric
disease, and other inflammatory or immune-regulated disorders. One
such example is psoriasis, which may show mild duodenal inflammation
and mast cell infiltration.16–18 It is perhaps, therefore, best not to
speculate on the etiology of a mild nonspecific duodenitis in the absence
of clinical information. Rather, simple documentation of the mild
abnormality and acknowledgement of pertinent negatives are sufficient.
Figure 3.75 Chronic inflammation, nonspecific, duodenal giardiasis. Chronic inflammation in the
small bowel is often nonspecific, but routine careful examination of all the tissue compartments
may yield diagnostic findings. This example shows a prominent lymphoid aggregate and some
dilated lacteals (arrow) in this duodenal biopsy. The tissue findings are nonspecific, but the
diagnosis resides in the space between the villi (arrowhead).

Figure 3.76 Chronic inflammation, nonspecific, duodenal giardiasis Higher magnification of the
indicated area in the previous figure reveals the protozoa Giardia.
Figure 3.77 Chronic inflammation, focally enhanced, duodenal Crohn disease. This biopsy shows
a pattern of focally enhanced inflammation in a patient with duodenal Crohn disease. The
findings are nonspecific and consist of localized inflammation, which should be interpreted in the
proper clinical setting.

Figure 3.78 Chronic inflammation, nonspecific, duodenal Crohn disease. Higher magnification of
the previous figure shows cryptitis (arrowheads) consistent with the patient’s known history of
duodenal involvement by Crohn disease.

SAMPLE NOTE: SMALL BOWEL WITH MILD CHRONIC

INFLAMMATION, BUT NO OTHER SPECIFIC FEATURES:
Small Bowel, Biopsy:
• Small intestinal mucosa with mildly increased lamina propria chronic
inflammation, nonspecific.
• Negative for intraepithelial lymphocytosis or villous blunting.

CRYPT ARCHITECTURAL DISTURBANCE

PATTERN

Figure 3.79 Crypt architectural disturbance pattern. This pattern encompasses the general
features of “chronicity” including crypt distortion and branching (pictured here), crypt dropout,
crypt shortfall, and pyloric metaplasia.

CHECKLIST: Etiologic Considerations for the Architectural

Disturbance Pattern
Inflammatory Bowel Disease
Diaphragm Disease
Ischemia
Graft Versus Host Disease
Acute Medication Reaction (Mycophenolate Mofetil and Mycophenolic
Acid)
Allograft Rejection
Radiation Duodenitis
Pouchitis and Pouch-Related Changes
At scanning magnification, the appearance of crypt architectural
disturbance can be seen as: crypt distortion, crypt dropout, crypt
shortfall with or without basal lymphoplasmacytosis, or microcrypt
formation (Fig. 3.79). Note that this pattern is exclusive of villous
architectural changes (i.e., villous blunting), which, instead, is a feature
of malabsorption pattern and confers a different group of differential
diagnoses. Although some might consider villous blunting a feature of
chronic injury, isolated architectural disturbances of the villi should be
investigated as a malabsorption pattern. Furthermore, although many of
these features indicate chronic injury, this pattern spans a histologic
spectrum from subtle to striking, encompassing features from the earliest
crypt disturbance (a single withered crypt) to marked crypt distortion.
Crypt architectural disturbance is a nonspecific pattern of injury, the
etiology of which encompasses IBD, mesenteric ischemia, graft versus
host disease, allograft rejection, short gut syndrome, radiation
duodenitis, and (ileal) pouchitis. Incisive readers will note that crypt
disturbances are a minor histologic pattern in many of these entities, and
indicate chronic injury. Accordingly, examination for other primary
features (e.g., increased apoptotic bodies in graft vs. host disease) and
correlation with clinical circumstances are required to arrive at an
etiology.

INFLAMMATORY BOWEL DISEASE

Crohn disease is a chronic idiopathic inflammatory disorder
characteristically involving the distal 15 to 25 cm of the terminal ileum;
however the gastrointestinal manifestations of Crohn disease are
remarkably diverse and may include variations such as ileocolic Crohn
disease (30% to 50% of patients with Crohn disease), localized or
extensive disease of the small bowel (25% to 50%), isolated Crohn colitis
(15% to 30%), anorectal Crohn disease (5% to 19%), or gastric,
esophageal and duodenal Crohn disease (5% to 30%).19–22
Histologically, the disease manifests in a patchy distribution with a
combination of activity (cryptitis, crypt abscess, erosion, and ulceration)
and chronicity (villous blunting, crypt architectural distortion, crypt
dropout, crypt shortfall, basal lymphoplasmacytosis, increased lamina
propria chronic inflammation, pyloric metaplasia, transmural lymphoid
aggregates, and neuromuscular hyperplasia&emdash;with or without
granulomata). For an expanded discussion on the general features of
Crohn disease, see also Inflammatory Bowel Disease, Chronic Colitis
Pattern, Colon Chapter.
In the duodenum, Crohn disease produces typical lesions in
approximately 0.5% to 4% of patients.23 These lesions usually coexist
with ileal involvement, and may extend proximally and distally to
involve the stomach or jejunum. By comparison, “regional jejunitis”
rarely coexists with duodenal disease and may locally or diffusely
involve the jejunum. Progressive transmural inflammation with scarring
and deep ulceration may ultimately lead to symptoms associated with
intestinal obstruction, perforation, bleeding, or fistula formation. When
obstruction develops, it usually does so in the distal ileum, and deep
linear ulcers or fistulae may give rise to profound gastrointestinal
bleeding. Gross and full-thickness microscopic examination of the small
bowel are considered the gold standard for diagnosis. Gross pathology
shows thickening of the bowel wall, fistula formation, strictures,
serpiginous ulcers, aphthous ulcers, and creeping mesenteric fat. The
corresponding histology shows a combination of variable activity
(cryptitis, villitis, crypt abscess, erosion, and ulcer) and chronicity
(villous blunting, crypt architectural distortion, crypt dropout, crypt
shortfall, basal lymphoplasmacytosis, increased lamina propria chronic
inflammation, pyloric metaplasia, transmural lymphoid aggregates, and
neuromuscular hyperplasia&emdash;with or without granulomata) (Figs.
3.80–3.87).

FAQ: What is “creeping fat?”

Answer: The antimesenteric serosal surface of the small bowel and
colon is usually smooth and devoid of adipose tissue. In Crohn disease,
repeated cycles of transmural damage can result in an irregular
antimesenteric serosal surface composed of prominent fibrosis and fat
(“creeping fat”). This creeping fat is used by surgeons to identify the
extent of affected bowel for resection. In addition, this finding should
be documented at the grossing bench as it can help differentiate Crohn
disease from ulcerative colitis.
Figure 3.80 Crypt architectural disturbance, Crohn disease. The crypt architectural disturbances
are evident at low magnification. Normally, the crypts rest directly on the muscularis mucosae.
In this example, the base of a crypt falls short of touching the muscularis mucosae. This gap
between the muscularis mucosae and the crypt is called “crypt shortfall” (arrow). Also, note the
irregularly shaped crypts, or abnormal crypt configuration, in addition to areas of total glandular
loss, or “crypt dropout.”

Figure 3.81 Crypt architectural disturbance, Crohn disease. Crypt architectural disturbances are
seen with irregularly shaped crypts and bifid branching crypts (arrowhead). Note also the
presence of cryptitis within this same crypt and the loosely-formed granuloma (arrow).
 Figure 3.82 Crypt architectural disturbance, Crohn disease. Residual villous projections are
present, but the major pattern here is crypt architectural disturbances, including crypt distortion,
crypt shortfall, and crypt dropout. The lamina propria is expanded with increased chronic
inflammation and prominent pyloric metaplasia (arrowheads) is present.

Figure 3.83 Crypt architectural disturbance, pyloric metaplasia. Pyloric-type glands are normally
limited to the pylorus at the junction of the stomach and small bowel. When seen in the terminal
ileum, these metaplastic glands indicate chronicity.
 Figure 3.84 Crypt architectural disturbance, pyloric metaplasia. These pyloric glands have
abundant foamy-to-clear cytoplasm and small, round or ovoid nuclei that may be flattened
against the basement membrane.

Figure 3.85 Crypt architectural disturbance, pyloric metaplasia. Although pyloric metaplasia
(arrowhead) indicates chronicity, it is not specific for Crohn disease, and can be found in other
chronic conditions, such as diaphragm disease of the terminal ileum.
Figure 3.86 Crypt architectural disturbance, Crohn disease. This example shows crypt distortion
and expansion of the lamina propria with an inflammatory infiltrate. Areas of pyloric metaplasia
(arrow) are also present.

Figure 3.87 Crypt architectural disturbance, Crohn disease. Although chronic injury features are
evident at low power, higher magnification is required to see areas of active inflammation
(activity) indicated by neutrophils. Seen here are cryptitis (arrow) and lamina propria acute
inflammation (arrowhead).

FAQ: Does involvement of resection margins by Crohn disease

have prognostic significance?
Answer: No.
The status of resection margins is not predictive of disease
recurrence.24 Postoperative recurrence of Crohn disease is more
common in patients with greater disease extent, perforating disease,
and medically refractory Crohn disease.25
DIAPHRAGM DISEASE
NSAIDs cause a wide spectrum of histologic changes in the small bowel,
some of which are segment specific, such as diaphragm disease of the
terminal ileum. Mild lesions consist of superficial erosions with
nonspecific neutrophilic, eosinophilic and plasmacytic infiltrates. These
erosions may be multiple, can coalesce forming deep ulcers, and may
result in hemorrhage. Repeat cycles of ulceration and healing can cause
submucosal scarring and web-like mucosal septa that project into the
lumen. These resulting circumferential stenosing lesions appear as
multiple diaphragm-like narrowings and are more commonly seen in the
distal small bowel, particularly the terminal ileum (Figs. 3.88 and 3.89).
Accordingly, the patients often present with a surgically emergent
obstruction. This so-called diaphragm disease can be accompanied by a
wide array of additional abnormalities, including crypt architectural
disturbances mimicking IBD, eosinophilic enteritis, enteritis cystica
profunda, and neuromuscular and vascular hamartoma-like changes
(Figs. 3.90–3.92).26 By comparison, NSAID injury in the proximal small
bowel often results in subtle and nonspecific reactive duodenopathy-type
changes, rather than chronic architectural changes. See also
Malabsorption Pattern, this chapter. A diagnosis of diaphragm disease
can be suggested by the endoscopic or pathologic findings but requires
correlation with the patient’s medication list for definitive diagnosis.
Distinction from ileal Crohn disease can be particularly challenging if a
history of NSAID use cannot be documented; in general, there is minimal
chronic inflammation in NSAID-associated injury, whereas it is abundant
in Crohn enteritis. Anecdotally, we have seen surreptitious NSAID abuse
lead to segmental resection of obstructing diaphragms; family members
of the patients may be able to provide the clinical correlation in these
cases.
Figure 3.88 Diaphragm disease, endoscopic view. Chronic NSAID injury in the distal small bowel
causes cycles of ulceration and healing that result in circumferential stenosing lesions
(“diaphragms”) and can lead to obstruction.

Figure 3.89 Crypt architectural disturbance, diaphragm disease. Low power magnification of the
diaphragm shows raised mucosa pushed upward by a thickened and fibrotic submucosa.
 Figure 3.90 Crypt architectural disturbance, diaphragm disease, submucosal fibrosis. Dense
collagen replaces the normally loose submucosal tissues after repeat cycles of ulceration and
healing.

Figure 3.91 Crypt architectural disturbance, diaphragm disease, pyloric metaplasia. Diaphragm
disease is found almost exclusively in the ileum and can demonstrate chronic injury features such
as crypt architectural distortion and pyloric metaplasia (arrowheads). The main differential
diagnosis is with inflammatory bowel disease.
Figure 3.92 Crypt architectural disturbance, diaphragm disease. Longstanding diaphragm disease
can show mucosal abnormalities similar to those seen in inflammatory bowel disease, and can be
a diagnostic pitfall.

KEY FEATURES of Diaphragm Disease:

• Caused by chronic NSAID use or abuse.
• Repeat cycles of ulceration and submucosal scarring result in
diaphragm-like narrowing of the terminal ileum.
• Features can mimic IBD, with ileal stricturing and histologic features
of chronicity.
• Correlation with clinical use of NSAIDs is required.

ISCHEMIA
Acute insufficiency of mesenteric arterial blood flow accounts for 60% to
70% of cases of mesenteric ischemia, and results in mortality rates
exceeding 60%.27 Severe pain is a common presentation of small bowel
ischemia compared with ischemia of the colon, in which extreme pain is
usually not as prominent a feature. Specific risk factors include advanced
age, atherosclerosis, low cardiac output states, cardiac arrhythmias,
severe cardiac valvular disease, recent myocardial infarction, and intra-
abdominal malignancy.27 The causes of intestinal ischemia are many
(Table 3.2), but can be classified into four major categories28,29:

TABLE 3.2: Causes of Intestinal Ischemia

• Superior mesenteric artery (SMA) embolism (50%):
This is most frequently due to a dislodged thrombus from the left
atrium, left ventricle, or cardiac valves. The SMA is anatomically most
susceptible to embolism due to its large caliber and narrow take-off
angle from the aorta.29 The embolus usually lodges 3 to 10 cm distal to
the origin of the SMA, in a tapered segment distal to the take-off of the
middle colic artery. Concomitant arteriolar vasoconstriction usually
occurs, further impairing splanchnic blood flow and exacerbating
ischemia. The middle segment of the jejunum is most often involved in
the ischemic process, as it is most distant from the collateral
circulation of the celiac and inferior mesenteric arteries.
• Superior mesenteric artery thrombosis (15% to 25%):
Acute thrombosis of the mesenteric circulation usually occurs as a
superimposed phenomenon in patients with a history of chronic
intestinal ischemia from progressive atherosclerotic stenosis, but may
 also happen in the setting of abdominal trauma or infection. There
does not appear to be a significant association between inherited
coagulation defects and mesenteric arterial thrombosis.30,31
• Mesenteric venous thrombosis (5%):
Risk factors include hypercoagulable states, portal hypertension,
abdominal infections, blunt abdominal trauma, pancreatitis,
splenectomy, and malignancy in the portal region.32 Ischemia is due to
the resistance in mesenteric venous blood flow, which subsequently
causes diminished arterial flow.27
• Nonocclusive ischemia (20% to 30%):
This is thought to be caused by splanchnic hypoperfusion and
vasoconstriction,33 and it occurs most frequently in patients with
atherosclerotic vascular disease. Inciting events include aortic
insufficiency, sepsis, cardiac arrhythmias, and medications such as
digoxin and alpha-adrenergic agonists. Ischemia secondary to cocaine
use has also been described.34,35
Mesenteric angiography remains the gold standard diagnostic study,
and most patients do not receive endoscopic examination due to the risk
of bowel perforation. As such, it is quite rare to diagnose small bowel
ischemia by endoscopic biopsy. Naturally, the histologic findings are
similar to those seen in the colon, namely mucosal coagulative necrosis.
Early and minimal injury occurs first at the villous tips due to splanchnic
shunting of blood away from the mucosa. This is noted as degeneration
and sloughing of superficial epithelial cells, edema, and vascular
congestion (Fig. 3.93). Later, the epithelial cells become markedly
attenuated and the crypts appear compressed and atrophic
(“microcrypts”) as the lamina propria swells and hemorrhages (Fig.
3.94). Within 5 hours of total acute occlusion, almost the entire
intestinal wall appears necrotic (Fig. 3.95). These changes are all devoid
of acute inflammation (Fig. 3.96) until reperfusion occurs. And,
paradoxically, reperfusion further injures the tissues by introducing
oxygen free radical formation,36 the severity of which is dependent upon
the duration of the preceding hypoxia (Figs. 3.97–3.100).
Figure 3.93 Crypt architectural disturbance, ischemic enteritis, earliest signs. Marked congestion
of capillaries with sloughing of epithelial cells along the villous surface are present in the
absence of an inflammatory infiltrate. At these earliest stages, the crypts remain intact.

Figure 3.94 Crypt architectural disturbance, ischemic enteritis. The lamina propria has become
hemorrhagic and the crypt architecture is abnormal with areas of crypt dropout and mirocrypt
formation.
 Figure 3.95 Crypt architectural disturbance. End stage ischemic bowel with necrosis.

Figure 3.96 Crypt architectural disturbance, ischemic enteritis. This example lacks the striking
hemorrhage seen previously, but the epithelial cells have sloughed off, leaving slightly necrotic
villous tips and residual microcrypts (arrowheads) at the base.
Figure 3.97 Crypt architectural disturbance, ischemic enteritis. This example shows the marked
crypt architectural disturbance that can accompany ischemic enteritis. The lamina propria has
hemorrhage and hyalinization, yielding an eosinophilic appearance. The crypt lumina have
sloughed degenerated epithelial cells that mimic crypt abscesses (arrowhead).

Figure 3.98 Crypt architectural disturbance, ischemic enteritis. Higher magnification of the
crypts shows that they are filled with karyorrhectic debris from sloughed epithelial cells and not
neutrophils.
 Figure 3.99 Crypt architectural disturbance, ischemic enteritis. There is marked crypt
architectural distortion at low power, and the lamina propria appears hemorrhagic and
hyalinized.

Figure 3.100 Crypt architectural disturbance, ischemic enteritis. Higher magnification of the
previous figure reveals focal microcrypt formation. The abundant fibrin deposition in the lamina
propria imparts a homogenous eosinophilic/hyalinized appearance.

KEY FEATURES of Ischemia:

• Mesenteric ischemia can be clinically categorized as SMA embolism,
SMA thrombosis, mesenteric venous thrombosis, and nonocclusive
ischemia.
• Severe pain is a common presentation in mesenteric ischemia, but not
colonic ischemia.
• Early histologic findings include sloughing of superficial epithelial
cells, edema, and vascular congestion.
• Later stages include lamina propria hemorrhage, hyalinization,
microcrypt formation, followed by coagulative necrosis.
• Acute inflammation is absent unless reperfusion has occurred.
• Beware not to overcall crush artifact from biopsy forceps as ischemic
change.
• Inflammatory changes can mimic vasculitis.

PEARLS & PITFALLS

Crush Artifact from Biopsy Forceps Can Mimic Ischemic Injury
Biopsy forceps may strip epithelial cells from villi and cause crushed
glands that can be mistaken for atrophic microcrypts. True ischemic
injury shows lamina propria hemorrhage and degenerative cellular
changes, such as loss of the apical brush border and ghostlike nuclei
(Figs. 3.101–3.103).

Figure 3.101 Crypt architectural disturbance, ischemic enteritis mimic, crush artifact. Forceps
biopsies can sometimes cause crush artifact that mimics ischemic injury. These crypt epithelial
cells have “popped” out of their rightful place (arrows) as a result of crush injury. Note how the
detached epithelial cells lack degenerative features, and how the lamina propria looks intact,
without hemorrhage, fibrin deposition, hyalinization, or fibrosis.
 Figure 3.102 Crypt architectural disturbance, ischemic enteritis mimic, crush artifact. The
sloughing epithelial cells leave some villi without intact epithelium; however one can be
reassured this is the result of endoscopic (or laboratory) manipulation because the epithelial cells
lack degenerative changes, and the lamina propria of the villi (arrowheads) lack edema,
hemorrhage, fibrin deposition, hyalinization, and fibrosis.

Figure 3.103 Crypt architectural disturbance, ischemic enteritis. A row of microcrypts is present
in a fibrotic lamina propria. Microcrypts are highly specific for ischemic injury. Compare this
Figure to the mimics above.

PEARLS & PITFALLS

Evaluation for Underlying Vasculitis
 Ischemic damage can cause vascular thrombi, and reperfusion injury
may cause inflammatory changes, neither of which should be confused
for an underlying causal vasculitis. Primary vascular injury should
only be evaluated in areas not directly subjacent to ischemia or
ulceration (Figs. 3.104 and 3.105).

Figure 3.104 Crypt architectural disturbance, ischemic enteritis, adjacent vasculitis mimic. When
encountering ischemic enteritis, it is prudent to search for vasculitis as a possible underlying
etiology; however beware as vessels that are directly subjacent to ischemic areas may show
inflammation and occlusion secondary to the mucosal damage (as opposed to the cause of the
mucosal injury). This muscular artery is involved by marked acute inflammation and fibrin
deposition.

Figure 3.105 Crypt architectural disturbance, ischemic enteritis, adjacent vasculitis mimic. This
 higher magnification of the previous Figure shows karyorrhectic debris (arrowhead) and
neutrophils within the smooth muscle wall of the artery. Overinterpretation as vasculitis is a
pitfall. Vasculitis assessment is best performed in areas away from the acute injury.

PEARLS & PITFALLS

Distinction from Infectious Enteritides
There are no reliable histologic features to distinguish ischemic
enteritis from infectious enteritis; correlation with endoscopic
impression, clinical information and microbiologic studies is
imperative. Infectious enteritides that are toxin mediated, such as
Escherichia coli 0157:H7 can cause hemorrhagic enteritis. In addition,
while the pseudomembrane of Clostridium difficile colitis is highly
characteristic, pseudomembranes are also frequently seen in ischemic
enteritis (Fig. 3.106).

Figure 3.106 Crypt architectural disturbance, ischemic enteritis, pseudomembrane formation.

Compare the ischemic right side of this Figure with the intact mucosa on the left. Note the crypt
architectural disturbances on the right, in addition to the hemorrhagic and hyalinized
appearance of the lamina propria. The surface is covered with a pseudomembrane, similar to that
seen in C. difficile colitis.

GRAFT VERSUS HOST DISEASE

Graft versus host disease (GVHD) is the donor T lymphocyte mediated
destruction of host tissues that occurs following allogeneic transplant.
Although allogeneic bone marrow and stem cell transplantation has the
highest frequency of GVHD (40% to 80% of patients), GVHD can also
occur in donor lymphocyte, whole blood, and solid organ
transplantation.37–39 Although in mild cases apoptotic bodies may be the
only morphologic clue to GVHD, in more severe cases cystic dilatation of
glands or crypts lined by regenerative epithelium, crypt abscesses, and
frank epithelial destruction are seen. Thus, scanning magnification view
of the biopsies will show architectural disturbance and loss of crypts that
correlates with severity of histologic grade (Figs. 3.107 and 3.108).
Histologic grading of GVHD is not performed in all transplantation
centers, some preferring to use a qualitative approach by reporting
“mild, moderate, or severe” GVHD, but when used, a modification of the
system for colonic GVHD described by Lerner40 is most common (Figs.
3.109–3.113):
Grade 1: Isolated apoptotic epithelial cells
Grade 2: Loss or damage of isolated crypts with or without crypt
abscesses
Grade 3: Loss of 2 or more contiguous crypts
Grade 4: Extensive crypt loss with mucosal denudation
See also GVHD, Lymphocytic Pattern, Esophagus Chapter.

KEY FEATURES of Graft Versus Host Disease:

• GVHD is an immune-mediated destruction of host tissue following bone
marrow and stem cell transplantation.
• GVHD may also follow solid organ transplantation, donor T lymphocyte
transfusion, and whole blood transfusion.
• Grading of GVHD may be done based on histologic findings (Lerner
system) or on diagnostic confidence (NIH system).
• Crypt architectural disturbance in GVHD indicates at least moderate
GVHD (grade 2 and higher by the Lerner system).
• Crypt apoptotic activity is the histologic hallmark of GVHD, but is
nonspecific.
• The differential diagnosis for apoptotic injury includes infection,
chemotherapeutic condition regimen, and the immunosuppressant
medication mycophenolate mofetil.

Figure 3.107 Crypt architectural disturbance, graft versus host disease. Crypt architectural
disturbance is present in the form of mild crypt distortion and crypt shortfall (arrowhead)
involving at least two contiguous crypts (Lerner grade 2 of 4). In addition, the proliferative
compartment of the crypts appears expanded and hyperchromatic.

Figure 3.108 Crypt architectural disturbance, graft versus host disease (GVHD). This duodenal
biopsy shows marked crypt dropout in this patient with GVHD. The villous architecture remains
relatively intact.
Figure 3.109 Crypt architectural disturbance, graft versus host disease. Marked glandular injury
and dropout have occurred as a result of GVHD in this patient with a bone marrow transplant.

Figure 3.110 Crypt architectural disturbance, graft versus host disease. Residual crypt bases are
seen. Note the relative abundance of enteroendocrine cells (arrowheads), which are not as
affected by apoptotic injury.
Figure 3.111 Crypt architectural disturbance, graft versus host disease. This biopsy shows marked
crypt architectural changes due to graft versus host disease. At this power, it might be easy to
misdiagnose a crypt abscesses.

Figure 3.112 Crypt architectural disturbance, graft versus host disease. Higher magnification of
the previous figure shows sloughed epithelial cells in the crypt lumen (not acute inflammation as
would be expected in a crypt abscess).
 Figure 3.113 Crypt architectural disturbance, graft versus host disease. Complete loss of
epithelium and crypts are seen in this example of severe GVHD (Lerner grade 4 of 4).

PEARLS & PITFALLS

Apoptosis is a Nonspecific Pattern of Injury, and Not Singularly
Diagnostic for GVHD
False positive interpretations may be due to effects of
chemotherapeutic conditioning regimens, concomitant infections, and
medications. As a result of induction chemotherapy, an apoptotic
pattern of injury can be seen within the first 20 days of bone marrow
ablation,41 rendering the diagnosis of acute GVHD difficult. In
addition, apoptoses are commonly seen in cytomegalovirus infection42
and cryptosporidiosis,43 which are prevalent in this
immunocompromised population. Further complicating the picture
may be the use of the immunosuppressant mycophenolate mofetil
posttransplantation, which can cause acute mucosal injury with focal
ulceration and marked crypt cell apoptosis (see below).44

FAQ: How many apoptotic bodies are required for a diagnosis of

GVHD?
Answer: Advances in healthcare allow clinicians to suspect GVHD at
much earlier stages, and morphologic features may be more subtle
than reported in earlier studies. Correspondingly, minimum thresholds
have not been established, but many pathologists require the finding
of at least one apoptotic body per biopsy tissue fragment to suggest
the diagnosis of GVHD.45,46 Other published thresholds include (1) the
total number of apoptotic bodies at least equal to the number of
pieces, or (2) scattered apoptotic bodies in more than one crypt.40,45,47
Take note, however, that surface epithelial apoptoses may occur as the
result of bowel preparatory regimens, and therefore should not be
considered diagnostic for GVHD.

FAQ: How can I tell if this an apoptotic body or a lymphocyte?

Answer: Apoptotic cells contain intracytoplasmic vacuoles filled with
nuclear dust and other karyorrhectic debris. These apoptotic fragments
appear as small, dark, round bodies surrounded by a white halo.
Similarly, IELs may have a clear halo; however by comparison,
lymphocytes retain a uniform size of about 10 microns in diameter. To
differentiate the two, simply identify a lymphocyte or plasma cell
nucleus in the lamina propria and use this as your benchmark for size
comparison. Because of their fragmented nature, apoptotic bodies are
typically much smaller and variably sized (Fig. 3.114).

Figure 3.114 Crypt architectural disturbance, graft versus host disease. At the crypt bases,
numerous apoptotic bodies (circled) are seen. Note how the nuclear fragments have a much
smaller diameter and are more variably sized than the mononuclear cells in the lamina propria.
MEDICATIONS (MYCOPHENOLATE MOFETIL AND
MYCOPHENOLIC ACID)
Mycophenolate mofetil and mycophenolic acid are immunosuppressants
commonly prescribed to transplant recipients and are used in the
treatment of some autoimmune diseases. This reversible inhibitor of
inosine monophosphate dehydrogenase results in inhibition of purine
synthesis and causes a reduction in B and T lymphocytes. At high
dosages, epithelial cell damage can also occur, which leads to clinical
diarrhea and histologic findings of prominent apoptotic injury with crypt
damage and distortion (Figs. 3.115–3.121).44,48 These changes overlap
with Crohn disease, GVHD, and ischemia.44,48–51 Further complicating
the picture, dual pathology is frequently present in patients prescribed
mycophenolate.50 Fortunately, a reduction in dosage or discontinuation
of the medication yields rapid clinical response. In difficult cases, a note
suggesting modification of the medication list may be helpful to
clinicians.

Figure 3.115 Crypt architectural disturbance, mycophenolate-induced injury. This low

magnification view of the duodenum, from a patient with unexplained diarrhea, shows very mild
crypt architectural disturbance with very focal crypt dropout (arrows). Although the villous
architecture is preserved, isolated disturbances of the crypts should prompt further investigation.
 Figure 3.116 Crypt architectural disturbance, mycophenolate-induced injury. An area of crypt
dropout from the previous case is shown at higher magnification and features apoptotic activity
(arrowheads). Although up to 4 apoptoses per 10 duodenal crypts may be considered normal, the
presence of apoptoses in confluent crypts is abnormal.

Figure 3.117 Crypt architectural disturbance, mycophenolate-induced injury. Additional crypts

from the previous case show numerous apoptotic bodies (arrowheads). Investigation into the
patient’s medical record revealed use of mycophenolate mofetil for immunosuppression in the
setting of cardiac transplantation.
Figure 3.118 Crypt architectural disturbance, mycophenolate-induced injury. Additional crypts
from the previous case show contiguous crypts, each containing apoptotic bodies. This finding
should prompt further investigation.

Figure 3.119 Crypt architectural disturbance, mycophenolate-induced injury. This biopsy of the
duodenum is from a kidney transplant patient experiencing unexplained diarrhea. Very focal
dropout of the crypts, crypt shortfall and basal lymphoplasmacytosis (brackets), and a possible
crypt abscess (arrow) are visible at low magnification. Note that the disturbances in this biopsy
are limited to the crypts, while the villi appear intact. These mild disturbances of the crypt
architecture at low magnification should prompt higher magnification examination.
 Figure 3.120 Crypt architectural disturbance, mycophenolate-induced injury. Higher power
magnification of the previous case reveals marked apoptotic destruction of the crypts
(arrowheads) rather than crypt abscesses. This finding should prompt review of the medication
list in any transplant patient.

Figure 3.121 Crypt architectural disturbance, mycophenolate-induced injury. Higher

magnification of other crypts from those in the previous figures reveals confluent apoptotic
activity (arrowhead) with numerous apoptotic bodies in the proliferative compartment (i.e., base)
of the crypts. Cessation of mycophenolate use in this patient resulted in dramatic clinical
improvement within 48 hours.

ALLOGRAFT REJECTION, SMALL BOWEL

Small bowel transplantation is increasingly performed to treat patients
with irreversible intestinal failure. Because the intestine is a lymphoid-
rich organ, intestinal transplantation requires complex immunologic
events to occur for the graft to function; for example, the donor mucosal
immune system must be replaced by the host, and a chimeric state is
essential for allograft function.52 Clinical features of acute rejection
include fever, nausea and vomiting, diarrhea, and abdominal pain and
distension. Severe cases may be accompanied by septic shock, metabolic
acidosis, hypotension, and adult respiratory distress syndrome.
Surveillance endoscopy can be performed through the ileostomy stoma,
and endoscopists should be encouraged to biopsy away from the stoma
since stoma sites contain inflammatory and regenerative changes. In
addition, since features of acute cellular rejection may be patchy,
multiple biopsies should be obtained from both endoscopically normal
and abnormal areas. Diagnosis of acute cellular rejection requires
clinicopathologic correlation, and requires immediate aggressive
immunosuppressive therapy, since progression of allograft rejection can
advance to graft loss or mortality. The histologic diagnosis of acute
intestinal rejection is similar to that of GVHD and is based on a varying
combination of three main features which can be used to determine a
rejection grade (Table 3.3) (Figs. 3.122–3.128)52–55:

TABLE 3.3: Grading Schema for Small Bowel Allograft Acute Cellular
Rejection52
1. Infiltration by a mixed but primarily mononuclear inflammatory
population, including immunoblasts or activated lymphocytes
2. Crypt inflammation and injury, characterized by cytoplasmic
basophilia, nuclear enlargement and hyperchromasia, decreased cell
height and mucin depletion
3. Increase in crypt apoptotic bodies

Figure 3.122 Crypt architectural disturbance, small bowel allograft rejection. This example of
 small bowel allograft rejection shows marked crypt architectural disturbances, such as crypt
distortion and branching with areas of crypt dropout. The lamina propria is markedly expanded
by chronic inflammatory cells.

Figure 3.123 Crypt architectural disturbance, small bowel allograft rejection. Higher
magnification of the previous figure shows abundant apoptotic bodies (circled) within the crypt
epithelium. Note how the nuclear debris is smaller and more irregular than the mononuclear
cells in the adjacent lamina propria.

Figure 3.124 Crypt architectural disturbance, small bowel allograft rejection. This small bowel
allograft shows crypt dropout. Some areas with residual crypt profiles show sloughed epithelial
cells within their lumen (arrowhead).
Figure 3.125 Crypt architectural disturbance, small bowel allograft rejection, moderate to severe.
Although the villous architecture is relatively intact, there is only one residual crypt (bottom
right). The marked crypt loss indicates moderate to severe allograft rejection.

Figure 3.126 Crypt architectural disturbance, indeterminate for small bowel allograft rejection.
There are very mild architectural changes in this biopsy, but the crypt epithelium and villi
appear intact.
 Figure 3.127 Crypt architectural disturbance, indeterminate for small bowel allograft rejection.
Higher magnification of the previous figure shows multiple apoptotic bodies (arrowheads) within
the crypt epithelium. In this setting, the biopsy is best considered indeterminate for acute cellular
rejection and close clinical follow-up is recommended. Comparison of these bodies to a
mononuclear cell (arrow) in the lamina propria emphasizes their small size and helps
differentiate them from IELs.

Figure 3.128 Crypt architectural disturbance, indeterminate for small bowel allograft rejection.
Additional apoptotic body examples (arrowheads).

KEY FEATURES of Allograft Rejection:

• Surveillance of small bowel allografts can be performed endoscopically
through the stoma site.
• Biopsies should be taken away from the stoma to avoid chronic and
 regenerative changes.
• Histologic features are similar to GVHD and include increased
chronic inflammation, crypt inflammation and injury, and
apoptotic activity.
• The presence of crypt injury and crypt architectural disturbance
indicates at least moderate acute rejection.
• Immediate and aggressive immunosuppressive therapy is required
for small bowel allograft rejection to prevent graft loss and mortality.

FAQ: How many apoptotic bodies are required to establish a

diagnosis of acute allograft rejection?
Answer: As many as or more than six apoptotic bodies per 10 crypts in
addition to crypt injury and lymphocytic infiltration. If all three of the
criteria are not met, the case is best considered as indeterminate for
acute rejection.

RADIATION ENTERITIS
Advances in technology allow more precise delivery of radiation dosage
and result in less side scatter damage; however the small bowel remains
more susceptible to radiation injury than the large bowel, and a number
of factors enhance radiation injury, particularly the presence of other
diseases such as diabetes, hypertension, atherosclerosis, prior intestinal
injury, and cardiovascular disease.56 The mechanism of injury is similar
to that of ischemic enteritis whereby endothelial cell damage results in
edema, fibrin deposition, and increases in vascular permeability.56
Correspondingly, the histologic features are similar to those seen in
ischemic mesenteritis and include epithelial degeneration, mucosal
denudation, crypt disintegration, mucosal edema, and necrosis (Figs.
3.129 and 3.130). Features indicating that tissues were within a
radiation field include hyaline sclerosis of small vessels, intimal
thickening and fibrosis of muscular arteries, endarteritis obliterans, and
enlarged bizarre nuclei of endothelial cells and fibroblasts (Figs. 3.131
and 3.132).
Figure 3.129 Crypt architectural disturbance, radiation enteritis. Low magnification shows crypt
architectural disturbances including mild crypt distortion and loss of crypts (arrow). The lamina
propria contains hemorrhage and muscular arteries show congestion (arrowheads). Surface
foveolar gastric metaplasia is also present, but may be unrelated to the radiation changes.

Figure 3.130 Crypt architectural disturbance, radiation enteritis. Higher magnification of the
previous figure highlights congested muscular arteries (arrowhead) and ectatic capillaries in the
lamina propria (arrows).
 Figure 3.131 Crypt architectural disturbance, radiation enteritis. Higher magnification of the
previous figures shows an abnormally prominent muscular artery. Also note the lamina propria
hemorrhage and early hyalinization.

Figure 3.132 Crypt architectural disturbance, radiation enteritis. Higher magnification of the
artery in the previous figures shows enlarged endothelial cells with mild nuclear atypia.

POUCHITIS AND POUCH-RELATED CHANGES

Ileal pouch anal anastomosis (IPAA) is a procedure that consists of a
total colectomy with stripping of the rectal mucosa and preservation of
the anal sphincter. An ileal reservoir/pouch is constructed (sometimes
termed “J-pouch”) and anastomosed either to the residual rectal cuff at
the anus or directly to the anus itself (Fig. 3.133). This procedure is
favored over total proctocolectomy with permanent ileostomy because it
allows patients to retain sphincter function and intestinal continuity; it
has been most often employed in patients with ulcerative colitis and
familial adenomatous polyposis (FAP). Traditionally, the diagnosis of
Crohn disease was an absolute contraindication for an IPAA because of
high rates of pouch complications and failure; however recent studies
have demonstrated good functional outcomes in the majority of Crohn
disease patients, and suggest that trial IPAA may be offered to highly
motivated patients wishing to avoid a permanent stoma.57–59 The most
frequently observed long-term complication of IPAA is “pouchitis,” an
acute and/or chronic inflammation of the ileal reservoir that remains
poorly defined in regards to its true prevalence (reported as 7% to
44%),60–64 etiology, and natural history. Five to 10% of patient with
IPAA develop chronic antibiotic-refractory pouchitis or Crohn disease of
the pouch, both of which are leading causes of permanent diversion or
pouch failure.65,66 Preoperative risk factors for pouchitis include use of
steroids prior to colectomy, severe pancolitis, appendiceal involvement,
extraintestinal manifestations of colitis and primary sclerosing
cholangitis.61,67–69 Postoperative risk factors include bacterial
overgrowth due to stasis, closure of ileostomy site, nonsteroidal anti-
inflammatory drug use, and lack of short chain fatty acids in diet.70,71
Serologic markers show increased risk for pouchitis in patients with
perinuclear anticytoplasmic antibodies (ANCA), whereas positive
antibodies to anti-Saccharomyces cerevisiae (ASCA) have been linked to
developing postoperative fistulas and a change in diagnosis to from
ulcerative colitis to Crohn disease in patients with an IPAA.72
 Figure 3.133 Ileal-pouch anal anastomosis (IPAA). Closure of a total proctocolectomy requires
either an ostomy/stoma site or an IPAA (in this illustration the colon is “greyed out” to represent
removal). IPAA is the preferred surgical approach because it maintains GIT continuity and avoids
the need for a permanent enterostomy bag. IPAA involves anastomosis of the ileum either to the
rectal cuff at the anus or directly to the anus itself. A reservoir is created by stitching two loops
of ileum together and removing the internal walls. The resulting reservoir is in the shape of a “J”
and often termed a “J-pouch.” Historically, IPAA was the standard of care for ulcerative colitis
patients but was generally contraindicated in Crohn cases because of increased risks of disease
flares, a view that has evolved.

Clinical manifestations of pouchitis include increased stool frequency,

urgency, hematochezia, abdominal pain, and fever. These symptoms
trigger biopsy of the pouch to exclude specific infection (such as
cytomegalovirus) and other etiologies. If histologic changes support
pouchitis, antibiotic therapy is instituted (Figs. 3.134 and 3.135). It
should be noted, however, that histologic changes in the pouch are
nonspecific. For example, long-standing pouches invariably contain
chronic inflammation, villous blunting, crypt architectural disturbance
and colonic metaplasia (Figs. 3.136 and 3.137).73,74 Moreover, while
acute inflammation can support a clinical impression of pouchitis,
neutrophils could also indicate residual/recurrent IBD, the histologic
distinction of which should not be attempted without strong clinical
correlation. IBD may be a consideration in the following scenarios:
• Biopsies of the rectal cuff show active chronic features discordant with
those of the pouch proper; consider residual/recurrent ulcerative colitis
(also referred to as “cuffitis”) (Figs. 3.138–3.143).
• Pouchitis has been refractory to multiple rounds of antibiotic therapy;
consider pouch involvement of Crohn disease.

Figure 3.134 Crypt architectural disturbance, pouchitis. Pouchitis refers to acute and/or chronic
inflammation of the ileal reservoir or “pouch” as a result of an ileal pouch anal anastomosis
(IPAA). At low magnification, the mild crypt distortion, crypt dropout, expansion of the lamina
propria with chronic inflammation and loss of villi are apparent.

Figure 3.135 Crypt architectural disturbance, moderate acute pouchitis. The presence of cryptitis
and crypt abscesses (arrow) are consistent with moderate acute pouchitis, in the proper clinical
setting.

Figure 3.136 Crypt architectural disturbance, chronic pouch changes. Over time, all pouches
show chronic injury features, regardless of whether there is a history of acute pouchitis. This
example lacks acute inflammation, but shows some mild crypt distortion and villous blunting.

Figure 3.137 Crypt architectural disturbance, chronic pouch changes mimicking colonic mucosa.
This biopsy of a long-standing pouch shows residual Paneth cells (arrowheads) but no intact villi.
Identical findings could be seen with cuffitis or inflammatory bowel disease involving the
residual colon mucosa. Unfortunately, there are no reliable histologic features to distinguish
pouchitis from cuffitis. In such cases, it is best that the endoscopist separately submit biopsies of
the pouch and the rectal cuff in separate jars.
Figure 3.138 Crypt architectural disturbance, chronic pouch changes mimicking rectal cuff. It can
be difficult to differentiate chronic pouchitis changes from rectal cuff tissue. Histologically, this
biopsy could represent a pouch with chronic changes or rectal cuffitis. Samples from both the
pouch and the rectal cuff sent in separate jars are most helpful in this distinction.

Figure 3.139 Crypt architectural disturbance, rectal cuffitis. This biopsy was taken from the
rectal cuff and shows continued involvement by ulcerative colitis. There is crypt distortion and
cryptitis present in a background of marked chronic inflammation.
 Figure 3.140 Paired intact pouch. This pouch biopsy is paired with the previous cuffitis. The
pouch shows intact architecture and long villi, with only mild expansion of the lamina propria.
The stark contrast between the cuff and the pouch allows for easier distinction of which disease
state is present –pouchitis or cuffitis. Based on separate submission of the pouch and cuff, this
case features cuffitis, or inflammatory bowel disease changes involving the residual rectal cuff.

Figure 3.141 Crypt architectural disturbance, rectal cuffitis. Another example of rectal cuffitis
demonstrates active and chronic features of ulcerative colitis, with crypt distortion and
branching, crypt shortfall/basal lymphoplasmacytosis (arrow), crypt dropout, and marked lamina
propria chronic inflammation. Moderate active and chronic pouchitis can look similar.

Figure 3.142 Crypt architectural disturbance, rectal cuffitis. Higher magnification of the previous
figure shows cryptitis (arrowhead). Paneth cell metaplasia is also seen in the lower left crypt.
 Figure 3.143 Paired intact pouch. This pouch biopsy is paired with the previous cuffitis. The
intact and noninflamed pouch is a striking comparison to the cuffitis seen previously, allowing
for confident differentiation between cuffitis and pouchitis. This case features cuffitis, or
inflammatory bowel disease changes involving the residual rectal cuff.

• Extraintestinal and intestinal manifestations of Crohn disease become

apparent (i.e., mucosal granulomata, uveitis, arthritis, small bowel
stricture or fistula, perianal disease, etc.).

KEY FEATURES of Pouchitis:

• Ileal pouch anal anastomosis (IPAA) is a sphincter-sparing
proctocolectomy that results in a small bowel reservoir (or “pouch”)
attached to either the residual rectal cuff or directly to the anus.
• Pouchitis is a poorly defined inflammatory complication of this
procedure.
• Symptoms include: stool frequency, urgency, hematochezia, abdominal
pain, and fever.
• Biopsies of the pouch are sent to exclude specific infection (e.g.,
cytomegalovirus) and confirm active and chronic inflammation
• Histologic features of activity and chronicity support a clinical
impression of pouchitis, but are nonspecific.
• There are no reliable histologic features to distinguish IBD from
pouchitis.
• Residual or recurrent IBD involving the rectal cuff is known as
“cuffitis.”
• Crohn disease should only be suggested if strong clinical correlation is
available, such as:
• Antibiotic-refractory pouchitis
 • Extraintestinal manifestations of Crohn disease
• Perianal disease
• Small bowel strictures or fistulas

PEARLS & PITFALLS

Recall that a residual cuff of rectal mucosa can remain distal to the
pouch in construction of an IPAA. Detection of residual IBD in this
rectal cuff (“cuffitis”) is important for prognostic and treatment
purposes; however take caution, as metaplastic changes in the pouch
can cause it to appear colonic and thus mistaken for cuffitis. Likewise,
the chronic changes of IBD (i.e., Paneth cell metaplasia) in the rectal
cuff can mimic small bowel mucosa and be mistaken for pouchitis;
thus, ideally rectal cuff and pouch biopsies should be submitted
separately by the endoscopist, and clearly labeled. IBD might be
suggested by the pathologist when there is major histologic
discordance among biopsy samples (i.e., one tissue fragment shows
marked active and chronic changes, while the remaining fragments are
unremarkable); see sample note below (Figs. 3.139 and 3.140).

Figure 3.144 Crypt architectural disturbance, prepouch biopsy with chronic changes. This
prepouch biopsy shows marked lamina propria chronic inflammation, including lymphoid
aggregate formation. Findings such as this may be found in the prepouch small bowel and should
not be over-interpreted as Crohn disease.
Figure 3.145 Crypt architectural disturbance, prepouch biopsy with chronic changes. Another
example of a prepouch biopsy showing chronic features (crypt distortion, dropout, and
shortfall/basal lymphoplasmacytosis). Chronic changes such as this may be found in prepouch
biopsies and do not indicate Crohn disease.

FAQ: Does active and chronic inflammation in the prepouch

biopsy indicate the presence of Crohn disease?
Answer: No.
Inflammation proximal to the pouch, or “prepouch ileitis,” is common
in patients with pouchitis (13%) and does not imply missed Crohn
disease or predict pouch failure.75 The majority of patients (86%) with
prepouch ileitis respond to antibiotic treatment, further supporting
that prepouch ileitis is not a manifestation of Crohn disease.76 A
diagnosis of Crohn disease can only be made in the proper clinical
context; for example, if the patient demonstrates extraintestinal
manifestations of Crohn disease, perianal disease, or small bowel
strictures or fistulas (Figs. 3.144 and 3.145).

FAQ: Is pyloric gland metaplasia in ileal pouch biopsies a

definitive marker for Crohn disease?
Answer: No.
Pyloric gland metaplasia (Fig. 3.146) is more common in patients who
experience complication following an IPAA (55%) as compared to
those who follow a normal postoperative course (12%). The
prevalence is higher in patients with Crohn disease of the pouch
(77%) as compared to ulcerative colitis patients with chronic pouchitis
(22%), but cannot be used as a definitive marker for Crohn disease.77

Figure 3.146 Pyloric metaplasia (arrowheads) in chronic pouch changes does not necessarily
implicate Crohn disease. It is a nonspecific sign of chronic mucosal injury.

FAQ: Can pouchitis be distinguished from IBD histologically?

Answer: No.
The histologic changes of active and chronic pouchitis are nonspecific
and cannot be distinguished from the active and chronic changes seen
in IBD. The function of pouch biopsies is to exclude other etiologies
(e.g., cytomegalovirus infection) and to confirm the clinical
impression of pouchitis. A diagnosis of Crohn disease can only be
made in the proper clinical context (Figs. 3.147–3.152).
 Figure 3.147 Anal transition. A helpful tip can sometimes be found in the biopsy. If biopsies
contain the anal transition (arrowhead) of columnar mucosa to squamous, the biopsy is from the
rectal cuff and not the pouch.

Figure 3.148 Crypt architectural disturbance, pouch with Crohn disease. This pouch shows
nonspecific features of chronicity, including crypt branching and distortion and increased chronic
inflammation. Following an IPAA procedure, this patient developed extraintestinal
manifestations of Crohn disease, including uveitis, iritis, and arthritis. This case illustrates that,
unfortunately, there are no reliable histologic features to distinguish pouchitis from
inflammatory bowel disease: identical findings can be seen in both settings. Correlation with the
clinical setting offers the best means to distinguish pouchitis from inflammatory bowel disease.

Figure 3.149 Crypt architectural disturbance, pouch with Crohn disease. Additional biopsies of
the pouch from the same patient show marked crypt shortfall/basal lymphoplasmacytosis and
chronic inflammation.
Figure 3.150 Crypt architectural disturbance, prepouch biopsies in patient with Crohn disease.
Biopsies of the prepouch small bowel in the same patients show crypt distortion and crypt
abscesses (arrowhead).

Figure 3.151 Crypt abscess in prepouch biopsy from previous case.

 Figure 3.152 Crypt architectural disturbance, prepouch biopsies in patient with Crohn disease.
Additional prepouch biopsies show features of chronicity. In the absence of pertinent clinical
information, the findings are nonspecific.

SAMPLE NOTE: UNCOMPLICATED POUCH BIOPSY WITH

ACUTE INFLAMMATION AND CHRONIC CHANGES FOR
“SUSPECT POUCHITIS”
Ileum, Pouch, Biopsy:
• Mild acute inflammation with chronic mucosal changes, consistent with
clinical impression of mild active chronic pouchitis.

SAMPLE NOTE: POUCH BIOPSY SENT FOR “RULE OUT

CROHN DISEASE”
Ileoanal Pouch, Biopsy:
• Small intestinal mucosa with moderate acute inflammation and chronic
mucosal injury changes.
Note: The histologic sections show small intestinal mucosa with crypt
abscesses and chronic changes (marked villous blunting and increased
lamina propria chronic inflammation) without granulomata. The features
are nonspecific and are compatible with active chronic pouchitis in the
proper clinical setting. Involvement by Crohn disease can show similar
changes and this possibility cannot be entirely excluded. Correlation
with clinical information is recommended.

SAMPLE NOTE: DISTAL POUCH OR RECTAL CUFF BIOPSY

WITH FEATURES SUSPICIOUS FOR INFLAMMATORY
BOWEL DISEASE
Ileum, Distal, and Postpouch Biopsies:
• Intestinal-type mucosa with moderately active chronic inflammatory
disease and patchy ulceration.
Note: Longstanding chronic pouchitis may show metaplastic changes that
mimic colonic mucosa; however, it is suspected this biopsy was taken
from the rectal cuff and the findings represent active IBD (“cuffitis”).
Correlation with endoscopic and clinical findings is suggested. No
dysplasia identified.

EOSINOPHILIA PATTERN

Figure 3.153 Eosinophils in the lamina propria. Eosinophils are bi-lobed leukocytes with
abundant brightly eosinophilic granules that make them easily identifiable at low magnification.
They are a normal inhabitant of the small bowel lamina propria, but areas of intense clustering,
intraepithelial eosinophils, or eosinophilic abscesses may indicate an underlying disease state.
CHECKLIST: Etiologic Considerations for the Eosinophilia
Pattern

Idiopathic Eosinophilic Enteritis

Medications
Allergy
Parasitic Infection
Inflammatory Bowel Disease
Connective Tissue Disorders and Vasculitis
The eosinophilia pattern is broadly defined as excessive numbers of
eosinophils in a normal location (i.e., lamina propria) or any eosinophils
in an abnormal location (i.e., epithelium or muscularis mucosae) (Fig.
3.153). Eosinophil numbers show an upward gradient from the
esophagus to the small bowel.78 Currently, there are no vigorous
standards for the threshold of increased eosinophils in the small bowel,
although some studies employ >20 eosinophils in one high powered
field.79 Low-level eosinophilia is relatively common in routine biopsies
and studies have shown an association with allergy and hypersensitivity
in patients.78–84 Nonetheless, compared to other gastrointestinal sites,
there is a relative paucity of information regarding eosinophilia in the
small bowel, and diagnoses are frequently descriptive and operator-
dependent (Figs. 3.154–3.157). Until further study clarifies the
significance of small bowel eosinophilia, the differential diagnosis
broadly overlaps with that of gastric eosinophilia. For this reason,
readers are referred to the Eosinophilia Pattern, Stomach Chapter.
 Figure 3.154 Mucosal eosinophilia, medication-related (arrowhead). Review of a patient’s
medication list may provide etiologic clues for mucosal eosinophilia. In this example, the patient
was taking the immunosuppressant mycophenolate mofetil, which has a known association with
mucosal eosinophilia.

Figure 3.155 Mucosal eosinophilia, medication-related (arrowheads). Mucosal eosinophilia is

nonspecific without clinical context. This example is from a patient on a chemotherapeutic
regimen for chronic lymphocytic leukemia who presented with a skin rash and gastrointestinal
symptoms. The findings likely represent medication-related mucosal eosinophilia.
 Figure 3.156 Duodenal eosinophilia in a patient with eosinophilic esophagitis. This duodenal
biopsy shows mild villous blunting and marked expansion of the lamina propria by an
inflammatory infiltrate.

Figure 3.157 Duodenal eosinophilia in a patient with eosinophilic esophagitis (EoE). Higher
magnification of the previous figure shows abundant mucosal eosinophils in the lamina propria
(arrows). The patient has an established diagnosis of EoE, and the duodenal findings raise the
possibility of a more generalized idiopathic eosinophilic enteritis.

SAMPLE NOTE: DUODENAL EOSINOPHILIA PATTERN OF

INJURY, MILD, NOS
Duodenum, Biopsy:
• Duodenal mucosa with increased eosinophils.
Note: The presence of eosinophils in the gastrointestinal tract is a
nonspecific finding and has been associated with food allergy,
medication reaction, parasitic infection, Crohn disease, hematologic or
lymphoid disorders, and connective tissue disorders. Some cases remain
idiopathic, and exclusion of involvement of other sites in the
gastrointestinal tract (i.e., stomach and colon) may be of interest.
Correlation with clinical and serologic information is recommended.

MALABSORTION PATTERN

Figure 3.158 Malabsorption pattern of injury in the small intestine. This small bowel biopsy
shows near-complete atrophy of the villi, associated crypt hyperplasia, and marked
intraepithelial lymphocytosis. These three findings may be seen in variable combination in the
malabsorption pattern, but note the intact crypt architecture; crypt architectural distortion is not
a prominent feature of the malabsorption pattern.

CHECKLIST: Etiologic Considerations for the

Malabsorption Pattern
Medications
Reactive Duodenopathy
Small Intestinal Bacterial Overgrowth
Gluten Sensitive Enteropathy (Celiac Disease) and Refractory Sprue.
Nongluten Protein Sensitivity
Tropical Sprue
 Common Variable Immunodeficiency
Autoimmune Enteropathy
Collagenous Duodenitis (Collagenous Sprue)

The malabsorption pattern of injury refers to a combination of

intraepithelial lymphocytosis, crypt hyperplasia, and villous blunting
(Fig. 3.158). This triad is the histologic hallmark of malabsorption in the
small bowel and is frequently accompanied by the clinical symptom of
diarrhea. These features can manifest singly or in combination along a
wide histologic spectrum.
Intraepithelial Lymphocytosis
Intraepithelial lymphocytosis represents an immunologic process of
crosstalk between luminal antigens and mucosal lymphocytes. The
number of IELs in the normal small intestine has been reported as 11 to
23 IELs per 100 enterocytes.85–87 Except in the case of gluten sensitive
enteropathy (celiac disease), there are currently no specific cut-off points
for any the various disease entities. As such, the number of IELs does not
need to be assessed in all cases; however if a reliable objective measure
is needed, a rapid method of counting IELs can be performed by
counting 20 epithelial cells at the distal apex (tip) of each of 5 villi (Fig.
3.159).85,87,88 This number can be expressed as IELs per 100 enterocytes.
Villous Blunting and Crypt Hyperplasia
Crypt hyperplasia is ambiguously defined as the elongation of the crypt
compartment and is difficult to quantify. As such, crypt hyperplasia and
villous blunting are frequently assessed together and can be expressed as
a crypt-to-villous ratio. When the crypt compartment elongates and
blunting of the villi occurs, the normal crypt-to-villous ratio (1:3 to 1:5)
increases (Fig. 3.160).89
Figure 3.159 Counting IELs. One rapid method of counting IELs can be performed by selecting an
enterocyte at one villous tip (center arrow) and counting 10 epithelial cells to either side. This
brackets off 20 epithelial cells (lateral arrows). Count the IELs (arrowheads) in this area. When
this method is performed across five villous tips, the number of IELs can be quantified per 100
enterocytes.

Figure 3.160 Malabsorption pattern, abnormal crypt to villous ratio. This biopsy from the second
portion of the duodenum has a crypt depth to villous height ratio of approximately 1:1 which is
the result of both crypt hyperplasia and villous blunting. Normal crypt to villous ratios range
from 1:3 to 1:5. Compare this figure to Figure 3.3, which has a normal crypt to villous ratio. Care
should be taken not to overcall villous blunting in the bulb, as villi in the bulb are naturally
shorter.

The severity of features, whether manifested singly or in combination,

can serve as diagnostic clues; however the features are nonspecific, and
they may be seen in an ever-increasing list of conditions that require
clinical correlation, as discussed below.

SAMPLE NOTE: INTRAEPITHELIAL LYMPHOCYTOSIS IN

THE ABSENCE OF VILLOUS ATROPHY
Duodenum, Biopsy:
• Duodenal mucosa with mild intraepithelial lymphocytosis and
preserved villous architecture.
Note: The duodenal biopsy shows mild histologic changes including mild
intraepithelial lymphocytosis in the setting of preserved crypt and villous
architecture. The findings are nonspecific and raise a differential
diagnosis including small intestinal bacterial overgrowth (SIBO),
medication-induced injury (NSAIDs and olmesartan), peptic injury,
celiac disease, and sensitivity to nongluten proteins, among others.
Correlation with clinical information is recommended.
A similar approach would be recommended in the case of mild villous
atrophy.

SAMPLE NOTE: MALABSORPTION PATTERN OF INJURY,

SEVERE
Duodenum, Biopsy:
• Duodenal mucosa with near-total villous atrophy, crypt hyperplasia,
and marked intraepithelial lymphocytosis.
Note: Duodenal biopsies show a marked malabsorption pattern of injury
including near-total villous atrophy, crypt hyperplasia, marked
intraepithelial lymphocytosis, and expansion of the lamina propria by
chronic inflammation. The findings are nonspecific, but raise a
differential diagnosis including celiac disease, hypersensitivity reaction
to nongluten proteins, severe bacterial overgrowth, chronic malnutrition,
and immune dysregulation disorders (e.g, common variable
immunodeficiency [CVID], and autoimmune enteropathy [AIE]). Of
note, the normal expected constituents are present (i.e., plasma cells,
goblet cells, Paneth cells, and enteroendocrine cells). Correlation with
clinical, serologic and microbiologic information is necessary.

MEDICATION
NSAIDs cause a wide spectrum of histologic changes in the small bowel,
some of which are segment specific. The frequency of injury is likely
underappreciated, with one study demonstrating 55% to 75% of healthy
volunteers showing small bowel damage after 2 weeks of treatment.90
Mechanistically, the prostaglandin reduction from both selective and
nonselective COX inhibitors alters mucus and bicarbonate secretions,
reduces mucosal blood flow, affects neutrophilic function and alters
endothelial function. Selective COX2 inhibitors reduce, but do not
completely eliminate side effects. Mild lesions may occur along the
length of the small intestine and consist of superficial erosions with
nonspecific neutrophilic, eosinophilic and plasmacytic infiltrates. These
erosions may be multiple, coalesce forming deep ulcers, and result in
hemorrhage. Repeat cycles may result in chronic injury, such as
diaphragm disease in the terminal ileum. See also Diaphragm Disease,
Crypt Architectural Disturbance Pattern, this chapter; however NSAID
injury in the proximal small bowel is typically mild and results in subtle
and nonspecific malabsorption-type changes, such as mild villous
blunting and intraepithelial lymphocytosis (Figs. 3.161 and 3.162).
These cases require correlation with the patient’s medication list to
exclude NSAID injury. Note that severe diffuse villous blunting has not
been reported in association with NSAIDs. In the absence of a definitive
etiology for a mild malabsorption pattern of injury, a descriptive report
listing the differential diagnoses should suffice (see sample note above).
The antihypertensive medication olmesartan (Benicar), an angiotensin
II receptor inhibitor, is associated with lymphocytic gastritis, collagenous
gastritis, and collagenous enteritis.91 These patterns of injury may occur
singly or in combination, and have been described as “sprue-like.”
Patients often present with clinically significant diarrhea and weight loss
and the biopsies can be indistinguishable from those of celiac disease.
Interestingly, these patients do not respond to a gluten-free diet (GFD),
celiac serologies are typically negative, and the histology and
symptomatology reverse upon olmesartan cessation. As such, this pattern
of injury is histologically indistinguishable from celiac disease or other
non–drug-related conditions, making review of the patient’s medication
list an important effort during biopsy review. See also Malabsorption
Pattern, Collagenous Enteritis, this chapter.

KEY FEATURES of Medication Injury:

• NSAIDs are the most common culprits.
• Repeat cycles of ulceration and submucosal scarring can result in
“diaphragm disease” of the terminal ileum.
• The proximal small bowel can show a nonspecific mild malabsorption
pattern of injury.
• Severe diffuse villous blunting is not seen in NSAID-induced
injury.
• Correlation with clinical use of NSAIDs is required.

Figure 3.161 Malabsorption pattern, NSAID injury in the proximal small intestine. Duodenal
changes are typically mild and demonstrate a malabsorption pattern of injury. This example
shows mild villous blunting (crypt to villous ratio of 1:1 to 1:2).
 Figure 3.162 Malabsorption pattern, NSAID injury in the proximal small intestine. Villous tips
may contain mild or prominent intraepithelial lymphocytosis. Although NSAID injury in the
proximal small intestine features a malabsorption pattern, severe atrophic lesions have not been
reported.

REACTIVE DUODENOPATHY
Reactive duodenopathy has been ascribed to chronic exposure to acid,
such as in cases of gastric antral Helicobacter infection, gastric
heterotopia, and Zollinger–Ellison syndrome. Histologic changes are
predominantly limited to the bulb, but are sometimes seen as far as the
second portion of the duodenum. Historically, reactive duodenopathy
has been characterized by three main pathologic features, all of which
may vary in severity, and include (Figs. 3.163–3.169):
1. Increased plasma cell infiltration
2. Neutrophils in the lamina propria or epithelium (or in both)
3. Reactive epithelial changes including villous blunting
Although surface gastric foveolar metaplasia and Brunner gland
hyperplasia are often prominent findings, and are sometimes used as
diagnostic criteria, these are not absolute criteria because they may be
missed due to sampling error, and can be found in cases without
inflammation. Both the surface gastric foveolar metaplasia and villous
blunting are features indicating chronic mucosal injury. When severe,
acid injury can cause duodenal ulcers, resulting in a clinical condition
termed “peptic ulcer disease.” See also Peptic Ulcer Disease, Acute
Duodenitis, this chapter; however while 95% of peptic ulcer disease has
been ascribed to Helicobacter infection, the milder changes of reactive
duodenopathy do not carry this bacterial association. In fact, some
authors argue that there is insufficient evidence to ascribe gastric
foveolar metaplasia to a “peptic” disorder, since only 16.4% of patients
with metaplasia have detectable Helicobacter infection.92 As a result,
there exists some degree of uncertainty regarding diagnostic criteria and
terminology. Alternative nomenclature include gastric foveolar
metaplasia with chronic inflammation, chronic peptic duodenopathy,
active chronic peptic duodenitis (in the presence of acute inflammation),
and peptic-type duodenopathy. Although the later terms containing
“peptic” are discouraged by some due to the inaccurate implication of a
peptic or Helicobacter etiology, these terms are retained by institutional
conventions and often used interchangeably. Regardless of terminology,
the histologic findings overlap with many of the differential diagnoses
found in the malabsorption pattern, and can result in some diagnostic
difficulty. In mild cases, nearly normal mucosa may be seen with only a
borderline increase in plasma cells, intraepithelial lymphocytosis, and
mild villous blunting. When faced with these mild changes, examination
of gastric biopsies can help distinguish upstream Helicobacter infection
from NSAID-induced injury to the proximal duodenum. In the absence of
a definitive etiology for a mild malabsorption pattern of injury, a
descriptive report listing the differential diagnoses should suffice (see the
preceding Sample Note).

Figure 3.163 Malabsorption pattern, reactive duodenopathy. This low power view shows villous
 blunting (crypt to villous ratio 1:1) characteristic of malabsorption pattern of injury; however
further examination reveals intramucosal Brunner glands, increased chronic inflammation in an
expanded lamina propria, surface epithelial damage (arrow), and gastric foveolar metaplasia
(arrowhead). The constellation of findings is consistent with reactive duodenopathy.

Figure 3.164 Malabsorption pattern, reactive duodenopathy. High power view of a villous tip
shows gastric foveolar metaplasia (arrow) and IELs.

Figure 3.165 Malabsorption pattern, reactive duodenopathy. At first glance, this low power view
shows a prominent pattern of villous blunting; however further examination reveals subtle
gastric foveolar metaplasia (arrowheads) arising in a background of exuberant intramucosal
Brunner glands and an expanded lamina propria.
 Figure 3.166 Malabsorption pattern, reactive duodenopathy. On higher power, it is easier to
appreciate the focal gastric foveolar metaplasia (arrow) and mild intraepithelial lymphocytosis
(arrowheads).

Figure 3.167 Malabsorption pattern, reactive duodenopathy. The villi in this example are
blunted. Abundant IELs (arrowheads) are readily identifiable, as is focal gastric foveolar
metaplasia (arrow).
Figure 3.168 Malabsorption pattern, reactive duodenopathy (PAS/AB). A PAS/AB stain highlights
the acidic mucin of the goblet cells (right) blue-purple. The gastric foveolar metaplasia (left)
contains neutral mucins which stain eosinophilic.

Figure 3.169 Malabsorption pattern, gastric heterotopia. Reactive duodenopathy is often an

isolated finding, but do not forget to systematically check for underlying gastric oxyntic gland
heterotopia. The pink and blue mixture of parietal and chief cells may be focal, but these acid-
secreting glands can be the underlying cause of peptic-type injury in adjacent mucosa and result
in misinterpretation unless specifically identified.

KEY FEATURES of Reactive Duodenopathy:

• Reactive duodenopathy is often attributed to increased acid in the
duodenum.
• Causes include increased gastric acid, Helicobacter gastritis, gastric
 heterotopia, NSAID, and Zollinger–Ellison syndrome.
• Pathologic features include: increased lamina propria plasma cells,
neutrophilic infiltration, and reactive epithelial changes.
• Surface gastric foveolar metaplasia and intramucosal Brunner glands
may or may not be present.
• Mild changes may cause a nonspecific malabsorption pattern.
• Severe changes, such as ulceration, may be termed peptic ulcer
disease, which has been associated with Helicobacter infection far
more frequently than the milder peptic duodenitis (95% vs. 16%).

PEARLS & PITFALLS

When available, proximal duodenal or bulb biopsies should be
examined for peptic-type changes, particularly when patchy
intraepithelial lymphocytosis is found in the distal duodenum. The
helpful presence of gastric foveolar metaplasia and peptic-type
changes are found more frequently in the proximal duodenal biopsies,
while downstream changes are often nonspecific.

SMALL INTESTINAL BACTERIAL OVERGROWTH

Small intestinal bacterial overgrowth (SIBO) is defined as excessive
anaerobic enteric bacteria in the small bowel, specifically >100,000
colony forming units per milliliter (CFU/mL) on culture of a duodenal
aspirate. The most common causes for bacterial overgrowth are
diminished gastric acid secretion and small intestine dysmotility; these
lead to disruption of the normal homeostatic mechanisms that control
enteric bacterial populations. Disturbances in gut immune function and
anatomic abnormalities of the GI tract increase the likelihood of
developing SIBO (Table 3.4) and are found in two-thirds of patients.93

TABLE 3.4: Conditions Predisposing to Bacterial Overgrowth

 Deconjugation of bile salts and metabolic breakdown of carbohydrates
by the bacteria cause clinical symptoms of bloating, abdominal
distention, abdominal pain or discomfort, diarrhea, steatorrhea, fatigue,
and weakness. Patients may also present with anemia, deficiency of fat
soluble vitamins (A, D, E, K), and vitamin B12 or protein deficiency.
Local damage and inflammatory changes in the small bowel result in
nonspecific histologic features that vary from normal to a profound
malabsorption pattern. One study found that more than half of biopsies
from SIBO patients were histologically unremarkable, and that villous
blunting (crypt to villous ratio of >3:1) was the only feature more
common as compared to controls (Figs. 3.170–3.176).93 In the absence
of a definitive etiology for a mild malabsorption pattern of injury, a
descriptive report listing the differential diagnoses should suffice.
Culture of a small bowel aspirate obtained during endoscopy is the gold
standard for diagnosis. Antibiotic therapy remains the mainstay of
treatment, the goal of which is to reduce or eliminate bacterial overload
and reverse the mucosal inflammation associated with malabsorption.94
 Figure 3.170 Malabsorption pattern, SIBO. This distal duodenal biopsy shows marked villous
blunting (reversed crypt to villous ratio 3:1) which raises the malabsorption pattern differential
diagnosis. A duodenal aspirate performed at the time of biopsy grew >100,000 CFU/mL,
confirming the presence of SIBO.

Figure 3.171 Malabsorption pattern, SIBO. A high power view of the villous tips from the
previous figure reveals abundant IELs (some of which are highlighted by arrowheads).
Figure 3.172 Malabsorption pattern, SIBO. This example of confirmed SIBO shows mild villous
blunting and marked expansion of the lamina propria with chronic inflammatory cells.

Figure 3.173 Malabsorption pattern, SIBO. A high power view of the villous tips from the
previous figure reveals abundant IELs (some of which are highlighted by arrowheads).
Figure 3.174 Malabsorption pattern, SIBO. Duodenal biopsies frequently arrive at the laboratory
stating “rule out celiac disease.” A quick glance at this biopsy shows features compatible with
celiac disease, such as villous blunting (crypt to villous ratio 1:1), a lamina propria expanded
with chronic inflammatory cells, and intraepithelial lymphocytosis; however culture of a
duodenal aspirate grew >100,000 CFU/mL of anaerobic bacteria, confirming SIBO. Additional
clinical information revealed negative celiac disease specific antibodies.

Figure 3.175 Malabsorption pattern, SIBO. Higher power examination of the previous figure
shows IELs (some of which are highlighted by arrowheads).
Figure 3.176 Malabsorption pattern, SIBO. These villi show intraepithelial lymphocytes (some of
which are highlighted by arrows) that are evenly distributed along the full length of the villi. By
comparison, celiac disease may demonstrate a crescendo of IELs toward the tips of the villi.

KEY FEATURES of Small Intestinal Bacterial Overgrowth:

• SBIO is defined as the growth of anaerobic enteric bacteria >100,000
CFU/mL from a duodenal aspirate.
• Causes include: decreased acid secretion or motility, anatomic
abnormalities, and altered gut immunity.
• Patients experience bloating, diarrhea, steatorrhea, and fat soluble
vitamin deficiency.
• Histology shows a nonspecific malabsorption pattern than can range
from very mild intraepithelial lymphocytosis to total villous atrophy.
• Although radiolabeled carbon and hydrogen breath tests are available,
the gold standard of diagnosis is culture of duodenal aspirates.
• Antibiotics are the mainstay of treatment.

FAQ: What if a small bowel aspirate was not sent for culture at
the time of endoscopy, and a malabsorption pattern is present on
biopsy?
Answer: Culture of small bowel fluid is the preferred method, but
other laboratory tests such as hydrogen breath test, 14C-xylose breath
test, and bile acid breath test are available if an aspirate was not
 performed.95 It is worthwhile to evaluate for SIBO because it is
treatable, and because exclusion of SIBO can narrow the histologic
differential diagnosis.

GLUTEN SENSITIVE ENTEROPATHY (CELIAC DISEASE)

Celiac disease is an immune-mediated systemic disorder caused when
exposure to gluten (found in wheat, barley, and rye) triggers
inflammation in the small intestine in genetically susceptible individuals.
Also known as sprue, nontropical sprue, celiac sprue, gluten sensitive
enteropathy, and gluten-induced enteropathy, the estimated prevalence
of celiac disease approaches 1% in Europe and North America.96,97
Diagnosis requires careful correlation of four main characteristics,
including (1) a variable combination of gluten-dependent clinical
manifestations, (2) celiac disease specific antibodies, (3) genetic
predisposition including HLA-DQ2 or HLA-DQ8 haplotypes, and (4)
histologic features of enteropathy.98–101 A pathologist who understands
the clinical, serologic, and genetic factors of celiac disease provides the
benefit of a more useful and integrated pathology report.
Clinical manifestations are myriad, and most biopsies received in the
laboratory state only “rule out celiac disease.” Table 3.5 provides some
examples of the clinical manifestations, particularly those in which
screening for celiac disease is advantageous. Serologic testing should be
performed while a patient is on a gluten-inclusive diet and calls for
celiac disease specific antibodies, namely, deamidated antigliadin
antibodies (DGP), tissue transglutaminase antibody (TTG-IgA), and
antiendomysial antibody (EMA-IgA), each of which are >90% sensitive
and specific for CD.102–107 Note that antigliadin antibody (AGA-IgA and
AGA-IgG) is no longer recommended due to its comparatively low
sensitivity and specificity (as low as 75% to 80%, each).108; however
testing for IgA deficiency remains essential since this condition can show
false negative serologic results and is found in 2% to 3% of patients with
celiac disease.109,110 As an adjunct to serologic testing, genetic testing
has evolved over the past decade, and may be useful in cases with
equivocal serologic and histologic findings. Haplotypes HLA-DQ2
(encoded by alleles A1*05 and B1*02) or HLA-DQ8 (encoded by alleles
A1*03 and B1*0302) are found in 30% to 40% of the population and are
inherited in families and geographically.111–113 This genetic information
can be exploited since celiac disease develops in a minority of the
population, and nearly all celiac patients have the isoform DQ2 (95%) or
DQ8 (5%).114,115 Thus, the presence of either one of these haplotypes is
permissive for celiac disease, and conversely the absence of both these
haplotypes essentially excludes celiac disease (negative predictive value
99%).116

TABLE 3.5: Conditions in which Celiac Disease Occurs More Frequently

than in the General Population and/or for Whom a Gluten-Free Diet May
Be Beneficial

Despite advances in serologic and genetic testing, adequate small

bowel biopsies for histopathology remain critical for diagnosis and
should similarly be obtained before instituting a GFD. In one study,
when ≥4 duodenal biopsy specimens were submitted from 132,352
patients without known celiac disease, the probability of a new diagnosis
of celiac disease was significantly increased (1.8% vs. 0.7%, p
<0.0001).117 Furthermore, concurrent duodenal bulb biopsies increase
diagnostic yield, since villous atrophy can be found exclusively in the
bulb in 9% to 13% of children and adults with positive celiac disease-
specific serologies.118–120 Consequently, expert recommendations suggest
multiple single-pass biopsies of the duodenum (one or two biopsies of
the bulb and at least four biopsies of the distal duodenum) to confirm
the diagnosis of celiac disease.101,108,121 At the time of biopsy,
endoscopists characteristically find mucosal atrophy, scalloping along
the plicae, or fissuring (Fig. 3.177), but while these endoscopic findings
are highly typical, they are not specific for celiac disease.122 Similarly,
the histologic changes of malabsorption pattern (villous atrophy, crypt
hyperplasia, and intraepithelial lymphocytosis) are required for a
diagnosis of celiac disease, but they are nonspecific and include the wide
differential diagnosis listed within this chapter. Histologic findings can
be classified according to the modified Marsh (Oberhuber) or simplified
Corazza classifications (Figs. 3.178–3.193) (Table 3.6). Note, however,
that these grading systems presuppose a diagnosis of celiac disease and
are best used as a method for assessing histologic improvement in
sequential biopsies, or for research purposes.

Figure 3.177 Celiac disease, endoscopic image. The small bowel mucosa in the proximal
duodenum shows patchy atrophy and fissuring.
Figure 3.178 Malabsorption pattern, celiac disease, modified Marsh 1. Low power magnification
shows intact villous and crypt architecture with a crypt to villous ratio within normal limits (1:3
to 1:5); however note the slightly expanded lamina propria and villi, which should prompt
further investigation for IELs.

Figure 3.179 Malabsorption pattern, celiac disease, modified Marsh 1. Higher magnification of
the previous figure shows markedly increased IELs (some of which are indicated by the
arrowheads). In the absence of clinical and serologic information, this malabsorption pattern is
nonspecific and elicits a lengthy differential diagnosis.
Figure 3.180 Malabsorption pattern, celiac disease, modified Marsh 3a. Low power magnification
shows a decrease in the crypt to villous ratio (about 1:1) that is the result of mild crypt
hyperplasia and mild villous blunting. Crypt hyperplasia precedes villous blunting in celiac
disease, but the purely hyperplastic lesion (Marsh 2) is rarely seen.

Figure 3.181 Malabsorption pattern, celiac disease, modified Marsh 3a. The villous tips show
markedly increase IELs (some of which are indicated by the arrowheads). Even with this degree of
intraepithelial lymphocytosis, the differential diagnosis remains broad and correlation with
clinical and serologic information is required.
 Figure 3.182 Malabsorption pattern, celiac disease, modified Marsh 3b. At low power
magnification, both crypt hyperplasia and moderate villous blunting are present (crypt to villous
ratio 1:1 to 2:1).

Figure 3.183 Malabsorption pattern, celiac disease, modified Marsh 3b. Another example of crypt
hyperplasia and villous blunting that shows reversal of the crypt to villous ratio (3:1). Note the
expansion of the lamina propria with mononuclear cells and the broadening of the villi.
Figure 3.184 Malabsorption pattern, celiac disease, modified Marsh 3b. Higher magnification of
the previous figure shows increased IELs (some of which are indicated by arrowheads). Note the
lamina propria inflammatory cells are predominantly plasma cells, which is quite characteristic.

Figure 3.185 Malabsorption pattern, celiac disease, modified Marsh 3b. Another high
magnification area of the previous figure showing marked intraepithelial lymphocytosis (some
IELs are marked by arrowheads).

Figure 3.186 Malabsorption pattern, celiac disease, modified Marsh 3c. At low power
magnification, the villi are totally atrophic. There is mild expansion of the lamina propria with
mononuclear inflammatory cells. This degree of villous atrophy includes a broad differential
diagnosis, but is almost never seen in NSAID-induced injury.

Figure 3.187 Malabsorption pattern, celiac disease, modified Marsh 3c. Higher magnification of
the previous figure shows marked intraepithelial lymphocytosis (arrowheads).

Figure 3.188 Malabsorption pattern, confounding features in celiac disease. This biopsy shows
crypt hyperplasia and marked villous atrophy in a background of markedly increased lamina
propria chronic inflammation. In addition, intramucosal Brunner glands are present at the base
of the biopsy, raising the possibility of reactive duodenopathy. The histologic findings are
nonspecific, and this biopsy was obtained from a patient with known celiac disease.
 Figure 3.189 Malabsorption pattern, celiac disease, modified Marsh 3b. Another example of
celiac disease shows a crypt to villous ratio of about 1:1 with hypercellularity at the tips of the
villi evident even at low magnification.

Figure 3.190 IELs. Higher magnification of the previous figure shows IELs (some of which are
indicated by the arrowheads). Note how the IELs are concentrated at the villous tip, with fewer
IELs toward the base.
Figure 3.191 Lymphocytic colitis in a patient with celiac disease. This colon biopsy comes from
the same patient as seen in the previous two figures. Lymphocytic colitis has been associated
with celiac disease, along with other nonneoplastic diseases of the GI tract.

Figure 3.192 Malabsorption pattern, celiac disease, modified Marsh 3 c. This biopsy shows
complete atrophy of the villi with marked crypt hyperplasia. There is increased lamina propria
chronic inflammation, but note the preservation of the crypt architecture; there is no evidence of
crypt shortfall, distortion, or dropout. Crypt architectural distortion is not a feature of celiac
disease.
Figure 3.193 Malabsorption pattern, celiac disease, modified Marsh 3c. Higher magnification of
previous figure to demonstrate IELs (arrowheads).

TABLE 3.6: 2013 American College of Gastroenterology

Recommendations for when to Test for Celiac Disease101
 Figure 3.194 Malabsorption pattern, EATCL. EATCL can be a sequela of long-standing celiac
disease, and should always be considered in a patient with refractory sprue. This low power view
shows a diffuse, monomorphic infiltrate of lymphocytes.

Figure 3.195 Malabsorption pattern, EATCL. Higher magnification of the previous figure
highlights the monomorphic T lymphocytes, some of which are intraepithelial (arrowheads).

The treatment for celiac disease is adherence to a GFD. Long term

monitoring of adherence to a GFD can help control symptoms, improve
quality of life, and decrease the risk of complications such as: anemia,
failure to thrive, osteomalacia, peripheral neuropathy, and small bowel
lymphoma. Monitoring is based on a combination of history and
serology; repeat upper endoscopy with intestinal biopsies is
recommended in cases lacking clinical response or showing relapse of
symptoms despite a GFD.101 Patients who fail to respond to a GFD may
have nonresponsive celiac disease (NRCD; failure to respond in the first
6 to 12 months) or refractory celiac disease (RCD; failure to respond for
more than 12 months). These scenarios require diligent reexamination
for alternative diagnoses such as other food intolerances, surreptitious or
inadvertent gluten exposure, SIBO, microscopic colitis, pancreatic
insufficiency, and irritable bowel syndrome.
Diagnosis of RCD requires repeat small bowel biopsy while the patient
adheres to a GFD, and can be further divided into Type I RCD and Type
II RCD based on the histologic findings. Type I RCD shows lymphocyte
infiltration of the small intestinal mucosa similar to that seen in
untreated celiac disease. By comparison, Type II RCD, shows CD3-
positive intraepithelial T cells that exhibit an abnormal lack of CD8
expression. These T cell abnormalities in Type II RCD are associated with
a significantly less favorable prognosis as compared to Type I RCD.123,124
Transformation to enteropathy-associated T-cell lymphoma (EATCL) is a
prominent risk and may require treatment by surgery, chemotherapy, or
bone marrow transplantation (Figs. 3.194 and 3.195).125,126

KEY FEATURES of Celiac Disease:

• Celiac disease is an immune-mediated systemic disorder caused by
exposure to gluten proteins found in wheat, barley and rye.
• It affects up to 1% of North Americans and Europeans.
• Other names include: sprue, nontropical sprue, celiac sprue, gluten
sensitive enteropathy, and gluten-induced enteropathy.
• Diagnosis requires:
1. clinical manifestations,
2. celiac disease–specific antibodies (DGP, TTG-IgA, and EMA-IgA),
3. genetic predisposition (HLA-DQ2 or HLA-DQ8 haplotypes), and
4. histologic features of small bowel enteropathy.
• Presence of either DQ2 or DQ8 is permissive for CD, and absence of
both essentially excludes CD with a negative predictive value of 99%.

TABLE 3.7: Histologic Classification and Grading Systems Used for

Celiac Disease89,127
• Testing guidelines (Table 3.6) are provided by the American College of
Gastroenterology.
• Biopsy recommendations: four single-pass biopsies from the distal
duodenum and two from the bulb, preferably submitted separately.
• Histologic features include: intraepithelial lymphocytosis (>25 IELs
per 100 enterocytes), crypt hyperplasia, and villous atrophy, but are
not diagnostic in isolation.
• A crescendo in the number of IELs from the base of the crypts to the
tips of the villi is characteristic.
• Grading mechanisms exist, including the modified Marsh and Corazza
systems (Table 3.7).
• The presence of neutrophils does not exclude a diagnosis of CD.
• Immunohistochemistry for IELs is not useful if biopsies are otherwise
unremarkable on routine H&E stain.
• Treatment is lifelong adherence to a strict GFD.
• RCD has an increased risk for EATCL.

FAQ: How many IELs are considered “increased” in celiac

disease?
Answer: Original Marsh descriptions of celiac disease did not specify a
cut-off number for IELs, whereas Oberhuber et al.89 suggested that
>40 IELs per 100 enterocytes indicates an ongoing immunologic
process. Since that time, the threshold has dropped, with Corazza et
al.127 supporting a threshold of 25 IELs per 100 enterocytes. For
comparison, the number of IELs in the normal small intestine has been
reported as 11 to 23 IELs per 100 enterocytes.86,87,128

FAQ: Are IELs more prominent at the villous tips vs. the crypts in
celiac disease?
Answer: Yes.
In normal villi, the IELs tend to be more numerous along the lateral
aspects of the villi compared with the tips.129,130 In contrast, the villi
from patients with celiac disease show an escalation in the number of
IELs as one proceeds from the crypts toward the villous tips.87,128,131
This crescendo of IELs toward the tips in celiac disease reflects
immunologic crosstalk between luminal gliadin antigens and the
migratory inflammatory cells of the lamina propria (Fig. 3.196).

Figure 3.196 Malabsorption pattern, crescendo pattern of IELs. This villous tip contains
numerous IELs (some of which are marked by the arrowheads). Note how the number of IELs
drops precipitously as one approaches the base of the villus.

FAQ: How does one count the number of IELs in 100 enterocytes?
Answer: A reliable objective measure is needed in the evaluation of
celiac disease, and a rapid method of counting IELs can be performed
by counting 20 epithelial cells at the distal apex of each of 5 villi (Fig.
 3.197).85,87,88 The number if IELs within this area can be expressed as
IELs per 100 enterocytes.

Figure 3.197 Counting IELs in villous tips. Starting at the centermost enterocyte, count 10
epithelial cells toward either side. Within this span of 20 epithelial cells (bracketed by arrows),
count the IELs (one example is indicated by an arrowhead); this example contains at least 4.
When this process is performed across 5 villous tips, the results can be quantified as IELs per 100
enterocytes.

FAQ: What is the significance of neutrophils in biopsies for CD?

Answer: While the presence of neutrophils in duodenal biopsies can
prompt consideration for Crohn disease and peptic injury, significant
duodenal neutrophilia is reported in celiac patients (56% of pediatric
and 28% of adult) and is associated with more active disease.132 Thus,
the findings of duodenal neutrophils in biopsies otherwise consistent
with celiac disease should not preclude a diagnosis of celiac disease
(Fig. 3.198).
Figure 3.198 Neutrophils in celiac disease (arrowheads). Although neutrophils are not a classic
feature of celiac disease, significant duodenal neutrophilia is reported in celiac patients and has
been associated with more active disease. The finding of neutrophils does not preclude a
diagnosis of celiac disease.

FAQ: Is immunohistochemistry for T-cell markers useful in the

diagnosis of celiac disease?
Answer: No.
The IELs found in celiac disease are predominantly CD8+/CD3+ T-
cells. Accordingly, some authors and practices advocate the use of CD8
and CD3 immunohistochemical stains to improve detection of IELs;
however immunostains for T-cell markers do not improve detection of
gluten-sensitive enteropathy when H&E stained sections are
unremarkable (Fig. 3.199).133
 Figure 3.199 Combined CD3 and CDX2 immunohistochemical stain. This CD3 immunostain
(highlights CD3+ T-cells of celiac disease red) has been overlaid on a CDX2 immunostain
(highlights enterocytes nuclei brown). This practice is employed by some laboratories, but is
unnecessary as studies have shown that immunostains do not improve the detection of celiac
disease.

FAQ: How quickly do clinical and histologic features improve

after a GFD is instituted?
Answer: In most patients, diarrhea responds within days of instituting
a GFD, and mean time to resolution is 4 weeks.99 Within days of
starting a GFD, there is evidence of diminished surface epithelial
damage and a reduction in the number of IELs; however it may be >3
months before normal histology is appreciated, even with adherence
to a strict GFD.

FAQ: What is a gluten challenge, and how quickly do histologic

lesions emerge following institution?
Answer: A gluten challenge is the process whereby a patient with
suspected but unproven celiac disease on a GFD reverts to a normal
gluten-inclusive diet under medical supervision to enable diagnostic
testing. This was routine for diagnosis in the past, but is now less
frequently used because of the high positive predictive value of
specific celiac serology testing. It remains a useful diagnostic test in
patients with permissive haplotypes (HLA-DQ2 or DQ8), but with
 normal serologic and histologic results while on a GFD. A diet
containing at least 10 g of gluten per day for 6 to 8 weeks is the
normal gluten challenge prior to repeat biopsy134,135; however lower
doses of gluten (3 g/day) can produce diagnostic changes in as little as
2 weeks of gluten ingestion.136 This information can be leveraged for
patients who develop severe symptoms following gluten ingestion
(celiac crisis) and cannot tolerate a full gluten challenge. It may also
prove useful for following refractory patients who either
surreptitiously or unintentionally ingest gluten.

NONGLUTEN PROTEIN SENSITIVITY

Sensitivity to nongluten proteins occurs most commonly with cow’s
milk, but soy, egg, and wheat proteins are also culprits. Other types of
food sensitivities, especially among adults, are not well understood.
Infants with cow’s milk or soy sensitivity may present at 1 week to 3
months of age with protracted vomiting, diarrhea, protein-losing
enteropathy, dehydration, anemia from chronic blood loss in the stool,
and failure to thrive.137 Rapid onset reactions can develop within 1 hour
of food ingestion, are IgE mediated, and do not result in histologic
changes.138 Slow onset reactions may be either IgE-or T cell–mediated
immune reactions which can result in macrophage influx and cytokine-
mediated mucosal damage.138 Biopsy specimens show a malabsorption
pattern similar to celiac disease, with patchy areas of villous atrophy,
intraepithelial lymphocytosis, edema, and increased mononuclear cell
infiltrate in the lamina propria (Figs. 3.200 and 3.201). Mild to severe
mucosal eosinophilia and intraepithelial eosinophils can be seen in
nongluten protein sensitivity,139 and can help distinguish these two
entities. In addition, IELs have been reported as fewer than seen in celiac
disease.139 When offending antigens are removed from the diet, the
clinical and histologic abnormalities resolve, and characteristically recur
when challenged.

KEY FEATURES of Nongluten Protein Sensitivity:

• Cow’s milk, soy, egg, and wheat proteins can cause hypersensitivity
reactions in the small bowel.
• Infants commonly present with vomiting, diarrhea, dehydration, and
failure to thrive.
• Histologic features show a patchy malabsorption pattern, similar to
celiac disease.
• Mucosal eosinophilia is more common in nongluten protein
sensitivity than in celiac disease.
• Treatment is avoidance of offending antigens.

Figure 3.200 Malabsorption pattern, nongluten protein sensitivity. Histologic features of

nongluten protein sensitivity are similar to those seen in celiac disease. These include villous
atrophy, crypt hyperplasia, and intraepithelial lymphocytosis.

Figure 3.201 Malabsorption pattern, nongluten protein sensitivity. High magnification of an

intact villous tip from a patient with soy protein allergy showed marked intraepithelial
lymphocytosis.
TROPICAL SPRUE
Tropical sprue is an acquired intestinal malabsorption syndrome of
unknown etiology that affects residents, tourists, and expatriates of
tropical regions specific to West Africa, Central America, South America,
the Caribbean, Puerto Rico, South East Asia, and the Indian
subcontinent. The etiology remains elusive, but most evidence suggests
an infectious cause, and the term “postinfective tropical malabsorption”
is sometimes used.140,141 Symptoms include chronic nonbloody diarrhea,
weight loss, bloating, and abdominal cramping. In severe cases, folate
and vitamin B12 deficiency can lead to anemia and neurologic
symptoms. In the United States, the typical scenario is a patient with
chronic diarrhea who has lived in or recently visited a tropical region.
Travelers returning to nontropical regions generally recover completely
after treatment, which includes antibiotics and restoration of fluids,
electrolytes, and vitamins.142 The entire small bowel including the ileum
is usually affected in tropical sprue. Thus, biopsies from both the
duodenum and the ileum should show similar features of villous
blunting, intraepithelial lymphocytosis, and increased lamina propria
chronic inflammation (Figs. 3.202–3.207). By contrast, celiac disease
primarily affects the proximal small bowel.

Figure 3.202 Malabsorption pattern, duodenum in tropical sprue. This duodenal biopsy shows a
combination of crypt hyperplasia and villous blunting (crypt to villous ratio 1:1) with increased
lamina propria chronic inflammation. The differential diagnosis based on this photo alone is
extensive.
 Figure 3.203 Malabsorption pattern, duodenum in tropical sprue. Higher magnification of the
previous figure shows increased mononuclear cells in the lamina propria and markedly increased
IELs (arrowheads) along the villi.

Figure 3.204 Malabsorption pattern, duodenum in tropical sprue. Higher magnification of the
previous figure highlights the intraepithelial lymphocytosis (arrowheads).
Figure 3.205 Malabsorption pattern, terminal ileum in tropical sprue. Terminal ileal biopsies of
the same patient show similar findings as seen in the duodenum. There is mild villous blunting
and expansion of the lamina propria with chronic inflammatory cells.

Figure 3.206 Malabsorption pattern, terminal ileum in tropical sprue. Higher magnification of
the previous figure shows histology analogous to that seen in the duodenum. There are increased
lamina propria mononuclear cells and IELs (arrowheads). In the absence of any clinical
information, the parallel findings in the duodenum and TI should prompt suspicion for tropical
sprue. Further investigation revealed that symptoms coincided with return from a visit to India 3
months prior; infectious etiologies had been extensively excluded.
 Figure 3.207 Malabsorption pattern, terminal ileum in tropical sprue. The villous tips of the
terminal ileum show marked intraepithelial lymphocytosis (arrowheads) similar to that seen in
the duodenum.

KEY FEATURES of Tropical Sprue:

• Tropical sprue is an acquired malabsorptive syndrome.
• Patients usually report an abrupt onset, associated with travel to the
tropics.
• Histology includes a malabsorptive pattern throughout the small bowel.
• The terminal ileum shows villous blunting and IELs similar to that seen
in the duodenum.
• Exclusion of infectious etiologies and response to treatment are
required for diagnosis.

FAQ: How is a diagnosis of tropical sprue established?

Answer: The diagnostic possibilities in patients with diarrhea acquired
in the tropics are quite extensive and include a large number of
infectious etiologies, including Entamoeba histolytica, Giardia lamblia,
Strongyloides stercoralis, Cryptosporidium parvum, Isospora belli, and
Cyclospora cayetanensis, among others. Exclusion of these causes by
stool and serologic testing is necessary. Upper endoscopy with biopsy
shows a nonspecific malabsorption pattern of injury; tandem ileal
biopsies showing similar changes are strongly suggestive of tropical
sprue; however the diagnosis is ultimately confirmed by a response to
 treatment.

COMMON VARIABLE IMMUNODEFICIENCY

Common variable immunodeficiency (CVID) is a primary
immunodeficiency disorder characterized by impaired B-cell
differentiation with defective immunoglobulin production. It is the most
prevalent severe antibody deficiency affecting both children and adults.
“Variable” refers to the heterogeneous clinical manifestations of this
disorder, which include recurrent infections, chronic lung disease,
autoimmune disorders, gastrointestinal disease, and susceptibility to
lymphoma. CVID is not a single disease, but rather a collection of
hypogammaglobulinemia syndromes resulting from many genetic
defects. The diagnosis of CVID relies on the presence of all four of the
following features:
1. Significantly reduced total serum concentration of IgG
2. Low IgA and/or IgM
3. Poor or absent response to immunization
4. The absence of any other defined immunodeficiency state (i.e., CVID
is a diagnosis of exclusion)
Small bowel biopsies from patients with CVID can display a host of
nonspecific features including villous atrophy, prominent intraepithelial
lymphocytosis, apoptotic activity, acute inflammation and mucosal
granulomata. Because of the immunocompromised status of these
patients, the histologic changes are likely secondary to opportunistic
infections (particularly Giardia), but can raise the differential diagnoses
of celiac disease, Crohn disease, and even autoimmune enteritis.143 The
absence of plasma cells is a helpful specific feature of CVID and
distinguishes it from the aforementioned differential diagnoses (Figs.
3.208–3.210).144 In particular, always consider CVID in patients who
appear to have refractory sprue.
 Figure 3.208 Malabsorption pattern, CVID. This low power view of the duodenum shows a
marked malabsorption pattern of injury with crypt hyperplasia, total atrophy of villi, expansion
of the lamina propria with inflammatory cells, and intraepithelial lymphocytosis. At this
magnification, the differential diagnosis is broad, but if one is in the habit of examining for the
presence of normal cellular constituents, the diagnosis will become apparent.

Figure 3.209 Malabsorption pattern, CVID. Higher magnification of the previous photo highlights
the marked intraepithelial lymphocytosis (arrowheads). The lamina propria contains mixed acute
and chronic inflammatory infiltrate, but a paucity of plasma cells.
 Figure 3.210 Malabsorption pattern, CVID. This higher power view of the lamina propria in
previous figure shows a complete lack of plasma cells, consistent with CVID. Routine
examination of the lamina propria for plasma cells should be performed in all biopsies.

KEY FEATURES of Common Variable Immunodeficiency:

• CVID is the result of ineffective immunoglobulin production.
• Patients often present with recurrent infections, such as Giardia.
• Histologic changes are likely secondary to opportunistic infections and
can mimic other disease entities.
• Patients may show an absence of plasma cells in the lamina propria.
• The presence of plasma cells does not exclude CVID, and can be seen in
up to one third of patients.

PEARLS & PITFALLS

Pathologists have great difficulty noting features that have been
subtracted from normal tissue, such as lack of plasma cells. To alleviate
this blind spot and prevent missed diagnoses, routine identification of
plasma cells, goblet cells, Paneth cells, and enteroendocrine cells
should be performed for every small bowel biopsy. When biopsies are
examined in a systematic and consistent manner, the absence of a
normal constituent will not be overlooked.
 FAQ: Do all patients with CVID lack plasma cells?
Answer: No.
About one third of patients with CVID have plasma cells present,
although hypofunctional. The absence of plasma cells in the small
bowel biopsy is a specific but not sensitive marker for CVID.144

AUTOIMMUNE ENTEROPATHY
Autoimmune enteropathy (AIE) is a rare condition characterized by
intractable diarrhea, is associated with a predisposition to other
autoimmunity and may present with extraintestinal manifestations.
Suggested diagnostic criteria for AIE require all of the following145
although we have encountered adult cases with preserved villous
architecture:
1. Severe villous atrophy not responding to dietary restriction
2. Circulating gut autoantibodies or associated autoimmune conditions
3. Lack of severe immunodeficiencies
This condition is more common in infants, but AIE is increasingly
recognized in adults.146 Patients with AIE may have more systemic forms
of autoimmune disease that can be characterized into syndromes, such
as immunodysregulation, polyendocrinopathy, enteropathy, X-linked
syndrome (IPEX); or autoimmune phenomena, polyendocrinopathy,
candidiasis, and extodermal dystrophy (APECED).147 The majority of
patients with AIE have an alteration in regulatory T-cell function. A
number of gene mutations have been linked to AIE, the most common of
which is found on the FOXP3 gene (responsible for T-regulatory cell
activity) and is seen in up to two-thirds of patients.148 Biopsies from
these patients may demonstrate a malabsorption pattern of injury, but
are particularly striking for the marked reduction in numbers of goblet
or Paneth cells and display of prominent crypt apoptoses (Figs.
3.211–3.215). If one is in the routine habit of searching for these
components in all biopsies, this diagnosis will not be missed.
 Figure 3.211 Malabsorption pattern, AIE. Low magnification shows a severe malabsorption
pattern of injury with crypt hyperplasia, total villous atrophy, and relatively intact crypt
architecture.

Figure 3.212 Malabsorption pattern, AIE. Higher magnification of the previous figure shows
intraepithelial lymphocytosis (arrowheads) in the flattened surface epithelium. In the absence of
clinical and serologic information, the findings are nonspecific, but if one is in the habit of
examining for the presence of normal cellular constituents, the diagnosis will become apparent.
Figure 3.213 Malabsorption pattern, AIE. Higher magnification of the same case shows IELs and
apoptotic activity at the crypt bases (arrowheads). Note the complete absence of Paneth cells.

Figure 3.214 Malabsorption pattern, another example of AIE. This low power view shows marked
crypt hyperplasia and villous atrophy. There is lamina propria expansion, but the crypt
architecture is relatively intact. These features are a nonspecific malabsorption pattern of injury.
 Figure 3.215 Malabsorption pattern, lack of Paneth cells in AIE. Higher power magnification of
the previous figure shows a complete absence of Paneth cells in a patient with AIE.

KEY FEATURES of Autoimmune Enteropathy:

• AIE is characterized by intractable diarrhea, not responsive to dietary
restriction.
• Although primarily a disease of infants, adult onset cases have been
documented.
• AIE is associated with systemic forms of autoimmune disease such as
IPEX and APECED.
• Up to two-thirds of patients have a mutation on the FOXP3 gene, which
is responsible for regulatory T-cell function.
• Absence or reduction in numbers of goblet and/or Paneth cells and the
presence of crypt apoptoses are diagnostic features.
• The presence of antigoblet cell or antienterocyte antibodies is found in
the majority of cases.

PEARLS & PITFALLS

Patients carrying a diagnosis of celiac disease who are nonresponsive
to a GFD should be evaluated for AIE as an alternative diagnosis.
Remember: The malabsorption pattern of injury is nonspecific, and
while celiac disease is more common than AIE, neither of these
 diagnoses can be established on histology alone. Anecdotally, we have
seen several cases of “nonresponsive celiac disease” (NRCD)
subsequently diagnosed as AIE and respond to AIE based therapies
(immunosuppression).

FAQ: How are antigoblet cell and antienterocyte antibodies used

in the diagnosis of AIE?
Answer: The presence of antigoblet cell or antienterocyte antibodies is
supportive of the diagnosis. Antienterocyte antibodies (AEA) have
been detected in 85% to 87% of patients with AIE146,147 but are not
specific for AIE as they may be found in other diseases such as IBD,
HIV infection, and allergic enteropathy. These antibodies have also
been detected in first-degree asymptomatic relatives.145 Thus, the
presence of these antibodies may be helpful in challenging cases, but
should be interpreted in the proper clinical setting.

COLLAGENOUS ENTERITIS
Collagenous enteritis, also known as collagenous sprue, is poorly defined
in the literature due to its infrequency. Best characterized as an easily
overlooked subpattern of malabsorption pattern, collagenous enteritis
exhibits a prominent subepithelial collagen layer in a background of
variable villous blunting and increased lamina propria inflammatory
cells (Figs. 3.216 and 3.217). The use of a histochemical stain such as
Masson trichrome may be helpful in highlighting the collagen deposition
(Figs. 3.218 and 3.219), but careful observation remains the best tool to
prevent overlooking this feature (Figs. 3.220 and 3.221). Additional
helpful histologic characteristics include surface epithelial detachment
and superficial ulceration, similar to that seen in collagenous colitis
(Figs. 3.222 and 3.223).149 IELs are variable and may indicate celiac
disease as the underlying etiology.149 Other reported associations
include collagenous gastritis, collagenous colitis, lymphocytic colitis,
lymphocytic gastritis, ulcerative jejunitis, and medication injury (i.e.,
olmesartan, an angiotensin 2 receptor blocker).91,150 Treatment of
known underlying disease, such as adherence to a GFD in celiac disease
and discontinuation of offending medications in medication injury, is the
mainstay of treatment. Some patients show clinical and histologic
response to immunosuppressive therapy.150

Figure 3.216 Malabsorption pattern, collagenous enteritis in the jejunum. Low magnification
shows a malabsorption pattern, with crypt hyperplasia, villous atrophy, and mild expansion of
the lamina propria. An abnormally thickened collagen band (arrowheads) is present at the
basement membrane. This patient was taking olmesartan, a medication that has been implicated
in collagenous sprue.

Figure 3.217 Malabsorption pattern, collagenous enteritis in the jejunum. Higher magnification
of the previous figure shows entrapped inflammatory cells and small vessels (arrows) in an
irregular collagen band.
Figure 3.218 Malabsorption pattern, collagenous enteritis in the jejunum (Masson’s trichrome). A
trichrome stain of the previous figure highlights the irregular contour of the collagen band. Note
how the collagen percolates downward between the cells of the lamina propria. Entrapped small
vessels (arrows) are also present. Compare with the next figure.

Figure 3.219 Normal basement membrane. A trichrome stain of a normal basement membrane
features a delicate band of collagen with a relatively crisp contour.
Figure 3.220 Malabsorption pattern, collagenous enteritis in the duodenum. Low magnification
shows a severe malabsorption pattern with crypt hyperplasia and villous atrophy. The findings
are nonspecific so far, but if one is in the habit of reviewing all layers of the biopsy, important
clues (e.g., a patchy collagen abnormality) will not be missed.

Figure 3.221 Malabsorption pattern, collagenous enteritis in the duodenum. Higher

magnification of the previous figure shows focal abnormalities of the collagen layer. Entrapped
inflammatory cells and vascular structures (arrows) are present.
 Figure 3.222 Malabsorption pattern, collagenous enteritis in the duodenum. Detachment and
stripping of epithelial cells above the abnormal collagen layer (arrow) is common in collagenous
enteritis, similar to its counterpart in the colon. Note the total lack of villous projections in this
biopsy.

Figure 3.223 Malabsorption pattern, collagenous enteritis in the duodenum. The surface
epithelial cells have stripped off this biopsy. Note the prominent and irregular collagen layer
with entrapped vessels (arrow).

KEY FEATURES of Collagenous Enteritis:

• Collagenous enteritis is also known as collagenous sprue.
• Histologic findings of subepithelial collagen deposition may be
overshadowed by the malabsorption pattern of injury.
• A Masson trichrome stain can help highlight the collagen layer.
• Other histologic findings can include variable villous atrophy,
increased lamina propria inflammatory cells, intraepithelial
lymphocytosis, detachment of strips of epithelial cells, and superficial
ulceration.
• Associated diseases include celiac disease, collagenous gastritis,
collagenous colitis, lymphocytic colitis, lymphocytic gastritis,
ulcerative jejunitis and olmesartan-induced injury.

Figure 3.224 Malabsorption pattern, subepithelial collagen deposition at an ileostomy site. Cycles
of acute or chronic mucosal injury can increase the collagen deposition at the basement
membrane; an expanded subepithelial collagen table alone does not meet the criteria for
collagenous enteritis.

PEARLS & PITFALLS

An altered or thickened collagen table can also occur as a healing
mechanism following erosion or ulceration; for example, a thickened
basement membrane is frequently observed at ileostomy sites.
Remember to consider the clinical context (Fig. 3.224).
FOAMY MACROPHAGE PATTERN

Figure 3.225 Foamy macrophage pattern, Whipple disease. When foamy macrophages are
particularly prominent, Mycobacterium avium-intracellulare infection and Whipple disease are the
front-line differential considerations. This case was ultimately diagnosed as Whipple disease
based on the abundant, coarsely globular, PAS reactive cytoplasmic inclusions, a reactive
Whipple immunohistochemical stain (not shown), and a negative AFB special stain (not shown).

Figure 3.226 Foamy macrophage pattern, Whipple disease. On higher power, the foamy
macrophages are better appreciated. Note the dilated lacteal (arrowhead), a distinctive feature of
Whipple disease.
 Figure 3.227 Foamy macrophage pattern, Whipple disease (PAS/D). The PAS/D special stain
highlights the contents of the foamy macrophages: abundant, coarsely globular, PAS reactive
cytoplasmic inclusions are seen. This patient presented with arthralgias and diarrhea, and all
symptoms responded to antibiotic therapy.

The foamy macrophage pattern in the small bowel primarily invokes the
differential diagnosis of Mycobacterium avium intracellulare, Whipple
disease, and nonspecific histiocytosis (Figs. 3.225–3.227). This pattern
generally refers to sheets of foamy macrophages in the lamina propria,
exclusive of organized epithelioid histiocytes seen in granulomatous
inflammation. If the clinical impression is of a mass lesion, other
neoplastic considerations on H&E include Langerhans cell histiocytosis,
mast cell neoplasms, melanoma, and infiltrating carcinomas. Sorting
through these histologically similar processes usually requires ancillary
special stains and chart review. In this section, the most common and
clinically relevant diagnoses will be discussed.

CHECKLIST: Etiologic Considerations for the Foamy

Macrophage Pattern
Mycobacterium avium intracellulare
Whipple Disease
Nonspecific Histiocytosis
Other considerations, Langerhans Cell Histiocytosis, Mast Cell
Neoplasms, Melanoma, and Carcinomas
MYCOBACTERIUM AVIUM-INTRACELLULARE
Mycobacterium avium and intracellulare are two species of atypical
mycobacterium that are collectively referred to as mycobacterium avium-
intracellulare (MAI), previously termed mycobacterium avium complex
(MAC). MAI is ubiquitous in the environment and the most common
human pathogen of the atypical mycobacteria. It is transmitted by
inhalation into the respiratory tract and by ingestion into the
gastrointestinal tract. MAI is considered an AIDS-defining opportunistic
infection primarily affecting those with CD4 counts less than 50 cells/
μL, but it can also be seen in the non-HIV setting, such as in individuals
otherwise immunocompromised (i.e., patients on chemotherapy or
heavy immunosuppressive agents). Mycobacterium avium accounts for
more than 95% of infections in AIDS patients, whereas Mycobacterium
intracellulare is responsible for 40% of infections in the
immunocompetent. Infection of the bowel most commonly is associated
with weight loss, abdominal pain, and diarrhea. Histologically, MAI is
characterized by variably blunted villi engorged with foamy
macrophages (Figs. 3.228–3.230). In contrast to Whipple disease, MAI
organisms are delicate, uniform rods on both PAS and AFB special stains
(Figs. 3.231 and 3.232). In addition, dilated lacteals and fat droplets are
absent, providing further helpful points of distinction from Whipple
disease. Treatment includes two or three antimicrobials for at least 12
months.

Figure 3.228 Foamy macrophage pattern, Mycobacterium avium-intracellulare (MAI). This biopsy
features blunted villi and an expansion of the lamina propria by abundant foamy macrophages.
Dilated lacteals and fat droplets are absent, features favoring a low power diagnosis of MAI over
Whipple disease. Moreover, chart review revealed a history of HIV/AIDS, a clinical feature more
common to MAI than Whipple disease.

Figure 3.229 Foamy macrophage pattern, Mycobacterium avium-intracellulare (MAI). Higher power
better illustrates the expansion of the lamina propria by numerous foamy macrophages.

Figure 3.230 Foamy macrophage pattern, Mycobacterium avium-intracellulare (MAI). Highest

power reveals a sprinkling of lamina propria neutrophils among the foamy macrophages.
 Figure 3.231 Foamy macrophage pattern, Mycobacterium avium-intracellulare (MAI) (PAS/D). A
PAS/D special stain highlights the red, uniform bacilli characteristic of MAI. They are almost
difficult to appreciate, even on oil magnification, due to their delicate size. Compare to the more
globular and coarse PAS reactive inclusions characteristic of Whipple disease (Fig. 3.236).

Figure 3.232 Foamy macrophage pattern, Mycobacterium avium-intracellulare (MAI) (AFB). An

AFB special stain confirms the mycobacterium infection by highlighting the abundant red bacilli
(Whipple disease is AFB nonreactive).

KEY FEATURES of Mycobacterium avium-intracellulare:

• Mycobacterium avium-intracellulare (MAI) is the most common human
pathogen of the atypical mycobacteria.
• It is transmitted by inhalation into the respiratory tract and by
ingestion into the gastrointestinal tract.
• MAI is considered an AIDS-defining opportunistic infection but also
 affects individuals otherwise immunocompromised.
• Histologically, MAI is characterized by variably blunted villi engorged
with foamy macrophages on H&E.
• In contrast to Whipple disease, MAI organisms are delicate, uniform
rods on both PAS and AFB special stains.
• Dilated lacteals and fat droplets are absent.

PEARLS & PITFALLS

Since MAI is consistently identified in immunocompromised patients,
it serves as an important red flag that the patient is at risk for other
sneaky infectious agents and malignancies. Look twice for these easily
miss-able additional infectious agents in biopsies of the tubular
gastrointestinal tract:
• Cytomegalovirus
• Adenovirus
• Herpes simplex virus
• Cryptosporidium
• Isospora
• Candida
• Spirochetosis
• Syphilitic or Lymphogranuloma venereum proctocolitis

WHIPPLE DISEASE
Whipple disease is very rare and caused by the gram-positive
actinobacterium Tropheryma whipplei. Although the mode of transmission
is not entirely understood, fecal–oral transmission has been postulated
based on an increased incidence among sewage treatment workers and
identification of the organisms in human waste and oral samples.151–153
Despite over a hundred years of experience with Whipple disease, the
core clinical features endure: Whipple disease remains a disease of adult
white men who often report years of arthralgias followed by abdominal
pain, malabsorption, weight loss, and diarrhea.154 More recently, an
association with non-HIV immune-mediated conditions has been
reported, which may reflect overlapping and complicated disease
presentations or perhaps a predisposition to Whipple disease by
particular immunosuppressed hosts, such as those patients on high-dose
steroids for sarcoidosis, ankylosing spondylitis, IBD, or rheumatoid
arthritis. Prior to antibiotics, Whipple disease was universally fatal.
Although antibiotics can lead to rapid resolution of disease symptoms,
unfortunately up to 30% of patients relapse, particularly those with CNS
involvement. Consequently, antibiotic therapy for Whipple disease is
often long term (at least 12 months), and can sometimes be lifelong.
Histologically, classic Whipple disease is characterized by villous
blunting, lamina propria expansion by numerous foamy macrophages,
and scattered dilated lacteals and fat droplets (Figs. 3.233 and 3.234).
The foamy macrophages contain abundant PAS reactive, variably-sized
cytoplasmic inclusions (Figs. 3.235 and 3.236). The organisms can be
confirmed by a T whipplei immunohistochemical stain (Fig. 3.237) or
PCR assay targeting T. whipplei’s 16 S ribosomal genes. Importantly,
direct (inadvertent) antibiotic treatment of Whipple disease can result in
dramatic treatment effects that can resemble normal or near normal
histology, requiring a low-threshold for a careful chart review,
discussion with a clinician, and ordering confirmatory ancillary studies
(Figs. 3.238–3.244).
A summary of the distinguishing features of MAI versus Whipple
disease can be found in Figure 3.245 and Table 3.8.

Figure 3.233 Foamy macrophage pattern, classic Whipple disease. This biopsy originated from a
62-year-old man with a history of arthralgias, diarrhea, and significant weight loss. The small
 bowel biopsy shows blunted villi with prominent foamy macrophages and scattered dilated
lacteals and fat droplets (arrowheads). These clinicopathologic features are highly suggestive of
Whipple disease.

Figure 3.234 Foamy macrophage pattern, classic Whipple disease. This case of Whipple disease
also features blunted villi, prominent foamy macrophages, and scattered dilated lacteals and fat
droplets (arrowheads), histologic features of classic Whipple disease. A PAS/D special stain
highlighted abundant, variably sized cytoplasmic inclusions, a Whipple immunohistochemical
stain was reactive, and an AFB special stain was nonreactive (not shown).

Figure 3.235 Foamy macrophage pattern, classic Whipple disease (PAS/D). A PAS/D special stain
highlights abundant variably-sized cytoplasmic inclusions.
 Figure 3.236 Foamy macrophage pattern, classic Whipple disease (PAS/D). On highest power,
the variably sized cytoplasmic inclusions characteristic of Whipple disease are best appreciated.
The coarse and globular nature of these inclusions contrast with the more delicate and uniform
bacilli seen with MAI (compare with the characteristic inclusions of MAI in Figure 3.231).

Figure 3.237 Foamy macrophage pattern, classic Whipple disease (Whipple

immunohistochemical stain). The Whipple immunostain is diffusely reactive is this classic case of
Whipple disease. Dilated lacteals and fat droplets are also seen (arrowheads). This immunostain is
not widely available, but can be accessed via reference centers and large consultation-based
centers.
 Figure 3.238 Foamy macrophage pattern, Whipple disease with partial histologic treatment
effect. Following 6 months of Whipple-based therapy, the biopsy shows less prominent features
of Whipple disease. Although foamy macrophages (brackets) and scattered dilated lacteals and fat
droplets are still seen on H&E, these features are much less prominent than those seen in classic
Whipple disease histology. Such dampened features have been described with patients early in
their antibiotic course for Whipple disease and are referred to as Whipple disease with partial
histologic treatment effect. Compare this image with classic Whipple disease seen in Figures
3.233–3.234.

Figure 3.239 Foamy macrophage pattern, Whipple disease with partial histologic treatment
effect. Higher power of previous image. Whipple disease with partial histologic treatment effect
refers to cases with attenuated features of Whipple disease on H&E, PAS/D, and a Whipple
immunostain. As seen here, villous blunting, foamy macrophages, dilated lacteals, and fat
droplets (arrowheads) are detectable but not prominent. Compare this image with classic Whipple
disease seen in Figures 3.233–3.234.

Figure 3.240 Foamy macrophage pattern, Whipple disease with partial histologic treatment effect
(PAS/D). Characteristic of Whipple disease with partial histologic treatment effect, cytoplasmic
inclusions (arrowhead) are present on a PAS/D special stain; however they are very subtle
compared to those of classic Whipple disease. Compare this image with classic Whipple disease
in Figure 3.236.
Figure 3.241 Foamy macrophage pattern, Whipple disease with partial histologic treatment effect
(Whipple immunostain). A Whipple immunostain is reactive but shows attenuated reactivity
compared to that seen with classic Whipple disease. Compare this image with classic Whipple
disease (Fig. 3.237).

Figure 3.242 Foamy macrophage pattern, Whipple disease with complete histologic treatment
effect. Of note, Whipple disease can histologically appear as an essentially normal biopsy, as
depicted in this case. When there are no histologic features of Whipple disease on both the H&E
and a PAS/D, and a Whipple immunohistochemical stain is positive, the preferred designation is
Whipple disease with complete histologic treatment effect. Patients with this morphology have often
been on Whipple disease antibiotic therapy for an extended period of time or had a remote
history of Whipple disease therapy. Based on limited long-term clinical follow-up data, the
clinical significance of Whipple disease with histologic treatment effect is unknown.
 Figure 3.243 Foamy macrophage pattern, Whipple disease with complete histologic treatment
effect (PAS/AB). By definition, a PAS/AB fails to demonstrate any characteristic Whipple
cytoplasmic inclusions with complete histologic treatment effect.

Figure 3.244 Foamy macrophage pattern, Whipple disease with complete histologic treatment
effect (Whipple immunostain). The Whipple immunostain is focally positive in rare macrophages
deep in the mucosa. This subtle pattern of reactivity is typical for Whipple disease with complete
histologic treatment effect. If this biopsy had been more superficial, the rare diagnostic
macrophages would have been entirely missed.
Figure 3.245 MAI versus classic Whipple disease. A: MAI, H&E, blunted villi and an expansion of
the lamina propria by abundant foamy macrophages are seen and dilated lacteals and fat
droplets are lacking, features favoring a low power diagnosis of MAI over Whipple disease; B,
MAI, a PAS/D special stain highlights the red, uniform, almost difficult to appreciate bacilli. C:
MAI, an AFB special stain confirms the mycobacterium infection by highlighting the abundant
red bacilli (“red snappers”) within the macrophage cytoplasm. D: Whipple disease, H&E, blunted
villi with prominent foamy macrophages and scattered dilated lacteals and fat droplets favor a
low power diagnosis of Whipple disease over MAI. E: Whipple disease, a PAS/D highlights
abundant, coarsely globular, variably sized cytoplasmic inclusions. F: Whipple disease, the
Whipple immunohistochemical stain is diffusely reactive is this classic case of Whipple disease.
TABLE 3.8: A Comparison of Mycobacterium intracellulare (MAI) versus
Whipple Disease

KEY FEATURES of Whipple Disease:

• Whipple disease is caused by the gram-positive actinobacterium
Tropheryma whipplei.
• It is much less common than MAI.
• Fecal–oral transmission is presumed.
• Adult white men constitute the most common demographic, but it is
also seen enriched in non-HIV immune-mediated conditions.
• Up to 30% of patients relapse, especially those with CNS involvement.
• Histologically, classic Whipple disease is characterized by villous
blunting, lamina propria expansion by numerous foamy
macrophages, and scattered dilated lacteals and fat droplets.
• The foamy macrophages contain abundant PAS reactive, variably-
sized cytoplasmic inclusions.
• Confirmatory tests include the T whipplei immunohistochemical stain or
PCR assay.
• Histologic treatment effects resemble normal or near normal
histology.
• The T. whipplei immunohistochemical stain cannot distinguish
viable from nonviable organisms.
PEARLS & PITFALLS
Whipple disease with histologic treatment effect can be seen in patients
who are not specifically treated for Whipple disease! For example, we
have seen Whipple disease with histologic treatment effect in patients
on broad spectrum antibiotics for myocarditis, urinary tract infections,
and pneumonia. These patients had unrecognized Whipple disease and
were indirectly (and unknowingly) treated for Whipple disease as a
consequence of broad spectrum antibiotics for unrelated medical
conditions. Although the antibiotics resulted in near normal small
bowel histology on H&E, additional studies confirmed the sparsely
distributed PAS/D, T. whipplei reactive cytoplasmic globules,
confirming the diagnosis of Whipple disease with histologic treatment
effect. In summary, a low threshold for routinely considering Whipple
disease is worthwhile, particularly in patients with complicated
clinical presentations.

FAQ: Can the T. whipplei immunostain distinguish viable from

nonviable organisms?
Answer: No.
Unfortunately, this immunostain cannot distinguish viable from
nonviable organisms, and bacterial remnants can persist in
macrophages for years.155–157 Von Herbay et al. found conversion from
positive to negative Whipple PCR results occurred before clearance of
PAS positive foamy macrophages.157 This suggests that DNA
degradation of the organism occurs early in treatment and that
bacterial protein remnants can persist for some time thereafter. As
such, the biologic significance of Whipple disease with histologic
treatment effect is unclear. In these cases, it is worthwhile to correlate
with the patient’s clinical symptoms and PCR studies to help guide
clinical management decisions. For example, in the symptomatic
patient with Whipple disease and histologic treatment effect, resuming
or continuing treatment is required; however in those asymptomatic
patients with histologic treatment effect, close clinical follow-up with
a low threshold to resume Whipple disease therapy may be a
 reasonable approach.

NONSPECIFIC SCATTERED MACROPHAGES

The lamina propria of the normal small bowel is populated by
mononuclear inflammatory cells, such as lymphocytes, plasma cells, and
macrophages. Occasionally macrophages can be mildly increased
(particularly after reading about Whipple disease with treatment effect!),
raising concerns for Whipple disease and or MAI. In general, a chart
review coupled with PAS and AFB special stains can sort through the
majority of these problematic cases. For example, MAI is easy to dismiss
in an immunocompetent individual lacking a history of diarrhea and
where no PAS or AFB positive cytoplasmic inclusions are seen. More
often than not, a slight prominence of macrophages signifies nothing
more than a slight prominence of macrophages. Perhaps their presence
represents a reparative response to a nonspecific, incidental, or incipient
mechanical, medication, or infectious related injury. Regardless, when
this finding is rare or seen in isolation, it carries no specific meaning.

DILATED LACTEAL PATTERN

Figure 3.246 Dilated lacteal pattern, clinically small bowel obstruction. Dilated lacteals
(arrowheads) are most commonly caused by obstructive changes (neoplasms, adhesions,
strictures, and fistulas) and radiation injury.
Lacteals are blind-ended lymphatic channels and normal constituents of
the small bowel lamina propria (Fig. 3.246). Normally these delicate
structures are difficult to discern at low power; on high power they
appear as slightly expanded “slits” containing pale, eosinophilic serum.
When dilated, the engorged structures are more readily apparent and
invoke a variety of etiologic possibilities, as discussed below.

CHECKLIST: Etiologic Considerations for the Dilated

Lacteal Pattern
Primary Lymphangiectasia
Secondary Lymphangiectasia
Obstruction
Adjacent Neoplasm
Adhesions
Strictures
Fistulas
Inflammatory Bowel Disease
Previous Surgeries
Infection
Whipple Disease
Radiation Injury

PRIMARY LYMPHANGIECTASIA
Primary lymphangiectasia (Waldmann disease) was first described in
1961.158 It remains a rare and poorly understood disease clinically
characterized by lymph and albumin leakage into the bowel lumen,
resulting in diarrhea, hypogammaglobulinemia, hypoalbuminemia, and
lower limb edema. Histologically, dilated lymphatics can be seen in the
mucosa or submucosa of the intestines in either a focal or diffuse
distribution.159 Only a few familial cases have been reported, the
majority are presumed sporadic.158 The diagnosis requires
clinicopathologic correlation and, importantly, exclusion of the infinitely
more common secondary forms of lymphectasia. The cornerstone of
management is a lifelong, low-fat diet–enriched with medium-chain
triglycerides, which theoretically minimizes fatty engorgement of the
“leaky” lymphatic system.160 Surgical resection is reserved for those with
both localized disease and symptoms unresponsive to diet management.
Additional clinical associations include malabsorption, osteomalacia
(related to vitamin D deficiency), pleural effusions, iron deficiency
anemia, and “yellow nail syndrome,” or dystrophic ridging of the nail
with loss of the nail lunula.161 Decades of disease have been associated
with B-cell lymphomas in rare cases, although the cases are too few to
establish a meaningful relationship.

SECONDARY LYMPHANGIECTASIA
Identical histologic findings are seen with secondary lymphangiectasia,
or lymphangiectasia secondary to some other etiology; therefore,
identification of the dilated lymphatic injury pattern is only part of the
diagnosis! Meticulous scrutiny of the background mucosa and thorough
chart review may yield clues to the underlying etiology, the most
common of which are obstructive changes (as can be seen with nearby
neoplasms, adhesions, strictures, and fistulas), infections (Whipple
disease), and radiation injury. Obstructive changes in the small bowel
are often seen in association with dilated lymphatics, increased IELs, and
a sprinkling of neutrophils in the lamina propria or epithelium.
Confirmation of a history of small bowel obstruction, such as conclusive
radiographic studies, intraoperative findings, or an extensive history of
adhesions, strictures, or fistulas can be most satisfying when these
histologic features are seen (Figs. 3.247–3.251). Unfortunately, these
same findings can be seen in nonobstructed patients, who may have
partial, subclinical, transient, or evolving obstruction. Difficult cases
such as these require a less dogmatic approach and a careful note
discussing the differential diagnostic considerations. Dilated lacteals can
also be red flags to a diagnosis of radiation enteritis or Whipple disease,
in the appropriate clinical setting.
 Figure 3.247 Dilated lacteal pattern, clinically small bowel obstruction. In this example, dilated
lacteals (arrowheads) were seen secondary to a small bowel obstruction in a patient with a history
of numerous abdominal operations and extensive serosal adhesions.

Figure 3.248 Dilated lacteal pattern, clinically small bowel obstruction. At higher power, a
sprinkling of intraepithelial neutrophils is seen (arrowheads), a finding not uncommon seen in
small bowel obstruction.

Figure 3.249 Dilated lacteal pattern, Crohn disease. This biopsy originated from a patient with an
extensive history of small bowel Crohn disease, strictures, and adhesive disease. Dilated lacteals
 (arrowheads) are seen in addition to gastric foveolar metaplasia (bracket), pyloric gland
metaplasia, mild architectural distortion, and reactive epithelium (mucin attenuation).

Figure 3.250 Dilated lacteal pattern, radiation therapy. Radiation injury in the small bowel,
similar to that in other sites, manifests as ectatic lymphovascular spaces, prominent blood
vessels, lamina propria hyalinization, and stromal atypia. At this power, only scattered dilated
lacteals (arrowheads) are appreciated.

Figure 3.251 Dilated lacteal pattern, radiation therapy. On higher power, the dilated lacteals
(arrowheads) and haphazard blood vessels (asterisks) characteristic of radiation injury are seen.
This patient had a history of radiation therapy for cholangiocarcinoma. Recognition of the
radiation injury pattern is a reminder that the patient has a reasonable risk of harboring a sneaky
malignancy, requiring careful examination of the background mucosa and a low threshold for
ordering deeper sections.

PEARLS & PITFALLS

Occult malignancies occasionally lurk in dilated lacteals. As a result,
 dilated lacteals can serve as precious clues to malignancy in an
otherwise busy-appearing small bowel biopsy. Make sure to routinely
check all lacteals, and make sure to check them twice in those cases
with a history of mass lesion or malignancy (Figs. 3.252–3.254).

Figure 3.252 Dilated lacteal pattern, metastatic alveolar rhabdomyosarcoma. In this example, the
dilated lacteals harbor metastatic alveolar rhabdomyosarcoma (arrowheads) in a patient with a
history of widely metastatic disease and a small bowel obstruction. The malignant cells almost
blend into the normally busy-appearing duodenal mucosa (arrowhead); routine inspection of the
lacteals was critical to arriving at the correct diagnosis.

Figure 3.253 Dilated lacteal pattern, metastatic alveolar rhabdomyosarcoma. A confirmatory

MyoD1 was strongly positive in the indicated cells, supporting the above diagnosis.
Figure 3.254 Dilated lacteal pattern, metastatic melanoma. Melanoma, mammary carcinoma, and
pancreatic adenocarcinoma are notorious for occupying dilated lacteals of the small bowel. This
example features a focus of metastatic melanoma lurking in the engorged lacteal (arrowhead),
underscoring the point that all lacteals should be carefully inspected for metastasis.

FAQ: Is the finding of isolated lymphectasia always clinically

important (Fig. 3.255)?
Answer: No.
In a recent study of 1,866 consecutive endoscopic examinations,
lymphangiectasia was clinically suspected in 3.2% and histologically
confirmed in 1.9%. No clinical evidence of malabsorption was
identified, even in those with subsequent biopsies showing persistent
lymphangiectasia, suggesting lymphangiectasia is often an incidental
or subclinical finding.162

Figure 3.255 Dilated lacteal pattern, not further specified. Dilated lacteals are routinely seen and
 their presence is not always clinically significant.

FAQ: What is the difference between “lymphangiectasia” and

“lymphangioma”?
Lymphangiectasia refers to the dilation of indigenous lacteals in a
typically flat (nonpolypoid) biopsy. In contrast, lymphangioma refers
to a malformation of lymphatic vessels and is more likely to present
endoscopically as a polyp, nodule or mass.

KEY FEATURES of Lymphangiectasia:

• Primary:
• Primary lymphangiectasia is a diagnosis of exclusion.
• Clinically, it is characterized by lymph and albumin leakage into the
bowel lumen, resulting in diarrhea, hypogammaglobulinemia, and
lower limb edema.
• Histologically, dilated lymphatics are seen in the mucosa or
submucosa of the intestines in either a focal or diffuse distribution.
• Predominantly sporadic in nature.
• Treatment is a lifelong low-fat diet–enriched with medium-chain
triglycerides.
• Surgical management is reserved for those unresponsive to diet
management with localized disease.
• Secondary:
• Histologically identical to primary lymphangiectasia.
• Common causes include obstructive changes (neoplasms, adhesions,
strictures, and fistulas), radiation injury, and Whipple disease.
• Lymphangiectasia is most often an incidental or subclinical finding.

METAPLASIA AND HETEROTOPIA

 Figure 3.256 The small bowel mucosa can feature nonnative epithelium, such as in reactive
duodenopathy, gastric heterotopia, pyloric gland metaplasia, and pancreatic heterotopia. The
clinical significance of recognizing these changes varies. For example, a patch of gastric
metaplasia, gastric heterotopia, or pancreatic heterotopia can explain the clinical impression of a
nodule, bump, or polyp. Gastric foveolar metaplasia can serve as a diagnostic clue to carefully
look for Helicobacter, and gastric foveolar metaplasia and pyloric gland metaplasia can serve as
evidence of chronic mucosal injury. In the illustrated example, pyloric gland metaplasia is shown
(asterisks). Pyloric gland metaplasia is histologically identical to pyloric glands of the gastric
cardia and antrum and to Brunner glands of the duodenum. These glands are composed of
neutral mucus-secreting cells with abundant clear foamy cytoplasm and basally located nuclei.

CHECKLIST: Etiologic Considerations for Metaplasia,

Heterotopia, and Ectopias (Fig. 3.256):
Reactive Duodenopathy
Gastric Heterotopia
Pancreatic Heterotopia
Pyloric Gland Metaplasia
Meckel Diverticulum

REACTIVE DUODENOPATHY
As discussed in the malabsorption pattern, reactive duodenopathy refers
to gastric foveolar epithelium in the small bowel mucosa as a result of
chronic acid exposure (Figs. 3.257–3.259). The surface gastric foveolar
metaplasia can be seen on H&E, but subtle cases may be highlighted by a
PAS special stain, staining the neutral mucin eosinophilic. Similarly, if a
combination PAS/Alcian blue stain is employed, the gastric metaplastic
zones still remain eosinophilic, but the acidic mucin of goblet cells stains
basophilic (Figs. 3.260 and 3.261). Histologic changes also include
variable increased plasma cell infiltration, neutrophils, villous blunting,
and Brunner gland hyperplasia. In contrast to peptic ulcer disease, the
histologic findings of reactive duodenopathy are milder and they lack a
strong association with Helicobacter infections. As such, some experts
suggest abandoning the previously interchangeable terms “chronic peptic
duodenopathy,” “active chronic peptic duodenitis, and “peptic-type
duodenopathy” due to their misguided inference of a Helicobacter
etiology. See also Malabsorption Pattern, this Chapter.

Figure 3.257 Reactive duodenopathy refers to metaplastic gastric foveolar epithelium (brackets)
in the small bowel mucosa. It is most commonly associated with excessive acidity, Helicobacter,
or NSAID-related damage. Zones of surface gastric foveolar metaplasia are composed of back-to-
back metaplastic cells that create regions that lack goblet cells or enterocytes. By comparison, the
normal small bowel mucosa is punctuated by goblet cells (arrowheads) that are scattered singly
between enterocytes. Further comparison shows that individual goblet cells contain a voluminous
mucin vacuole, in contrast to the more delicate apical mucin cap seen in the gastric metaplastic
cells (brackets).
 Figure 3.258 Reactive duodenopathy, small bowel obstruction. This case features scattered
dilated lacteals (arrowheads) in addition to gastric foveolar metaplasia.

Figure 3.259 Reactive duodenopathy, small bowel obstruction. Higher power of an alternate field
from the same patient. Note the tiny apical mucin caps in a zone lacking goblet cells.
 Figure 3.260 Metaplastic gastric foveolar epithelium (PAS/AB). For junior trainees, the
distinction between metaplastic gastric foveolar epithelium and goblet cells can be challenging
on H&E. In subtle cases, a PAS/AB can be especially useful. On a PAS/AB, the neutral mucin of
the metaplastic gastric foveolar epithelium appears eosinophilic (bracket); in contrast, the acidic
mucin of the goblet cells appears deeply basophilic (arrowhead). Again, note that metaplastic
gastric foveolar epithelial cells are lined up back to back and create long runs or zones of
metaplasia, as opposed to goblet cells, which are more sparsely distributed among the
enterocytes. Although the distinction between metaplastic gastric foveolar epithelium and goblet
cells is not critical to discern in the small bowel, these distinctions become clinically important
when evaluating for Barrett mucosa in the esophagus, for example.

Figure 3.261 Reactive duodenopathy (PAS/AB). The eosinophilic metaplastic gastric foveolar
epithelium (highlighted by brackets) and the basophilic goblet cell (highlighted by an arrowhead).
This case was complicated by Helicobacter duodenitis, emphasizing the importance of routinely
looking for Helicobacter in gastric metaplastic zones.
KEY FEATURES of Reactive Duodenopathy:
• Reactive duodenopathy is seen in up to 7% of small bowel mucosal
biopsies.
• Alternative terms include gastric foveolar mucin cell metaplasia, active
chronic peptic duodenitis, chronic peptic duodenopathy, and peptic-
type duodenopathy.
• Common causes include excessive acidity, Helicobacter, or NSAID-
related damage.
• Severe cases with ulcerations are termed peptic ulcer disease, which
has a stronger association with Helicobacter.

GASTRIC HETEROTOPIA
Heterotopic tissue refers to histologically normal tissue found in
abnormal anatomic sites. More specifically, gastric heterotopia describes
the presence of both gastric foveolar epithelium and oxyntic glands in the
small bowel mucosa (Figs. 3.262–3.266). Although some experts
advocate this finding is an embryologic remnant, others suggest it is a
metaplastic response to small bowel injury.92,163–166 In the largest study,
gastric heterotopia was identified in 1.9% of over 28,000 duodenal
biopsies and was found in the duodenal bulb in 66% of cases.92 Patients
with gastric heterotopia were 1/5 as likely to have Helicobacter pylori
gastritis, compared to those patients with a normal duodenum,
suggesting this phenomenon is not a metaplastic response to mucosal
injury. Further, this finding was associated with three times the number
of fundic gland polyps, leading the authors to suggest these presumed
congenital patches may be influenced by proton pump inhibitors. Similar
findings were recently replicated by others.166
 Figure 3.262 Gastric heterotopia. On low power, the polypoid nature of this biopsy is
appreciated. Both gastric foveolar epithelium (arrowheads) and oxyntic glands (brackets) are seen
in the small bowel polypectomy specimen, meeting the diagnostic criteria for gastric heterotopia.

Figure 3.263 Gastric heterotopia. On higher power, gastric foveolar epithelium (brackets) and
oxyntic glands are better seen. An area of normal small bowel epithelium is lined by back-to-back
enterocytes punctuated by goblet cells (arrowheads).
 Figure 3.264 Gastric heterotopia (PAS/AB). A PAS/AB easily distinguishes between the diffuse
zones of eosinophilic gastric foveolar epithelium (bracket) and the scattered basophilic goblet
cells (arrowheads).

Figure 3.265 Gastric heterotopia. The nodular nature of this duodenal polyp is easily appreciated
at low power. The diagnosis of gastric heterotopia was rendered based on the identification of
both gastric foveolar epithelial cells (bracket) and oxyntic glands (arrowheads).
Figure 3.266 Gastric heterotopia is generally a low power diagnosis, but some cases require high
power to appreciate the focal oxyntic glands (arrowhead), as in this case.

KEY FEATURES of Gastric Heterotopia:

• Gastric heterotopia is seen in 1.9% of duodenal biopsies.
• It is most common in the duodenal bulb and is associated with fundic
gland polyps.
• Histologically, it consists of gastric foveolar epithelium and oxyntic
glands.
• The histogenesis is controversial; embryologic remnant versus
metaplastic response to injury, possibly responsive to proton-pump
inhibitors.

FAQ: What if only superficial gastric foveolar epithelium is

present and underlying gastric glands are not seen?
Answer: “Reactive duodenopathy” is the preferred term when only
superficial gastric foveolar epithelium is seen.

PANCREATIC HETEROTOPIA
Pancreatic tissue identified at sites not anatomically or vascularly
connected to the pancreas is termed pancreatic heterotopia, also known
as pancreatic rest, or ectopic or aberrant pancreas (Fig. 3.267). The
putative etiologic origin is aberrant embryonic rotation of the dorsal and
ventral buds, such that “pancreas bits” are positioned in nonphysiologic
sites. Although the incidence of pancreatic heterotopia is not well
established, it is seen in 13.7% of autopsies in one small series.167
Pancreatic heterotopia has been reported in a variety of sites, including
the gastrointestinal tract, lung, mediastinum, and fallopian tube.168 It is
most commonly seen in the gastrointestinal tract, particularly in the
stomach and small bowel. Most cases are asymptomatic, especially small
lesions. Symptomatic patients can present with abdominal pain,
gastrointestinal bleeding, pancreatitis, or obstruction.169 Although not
required, nor routinely practiced, pancreatic heterotopia can be stratified
into four types based on the modified Heinrich classification scheme170:
Type 1: Acini, ducts, and islets
Type 2: Ducts only
Type 3: Acini only
Type 4: Islets only

KEY FEATURES of Pancreatic Heterotopia:

• Pancreatic heterotopia is pancreatic tissue at ectopic sites.
• Seen in up to 13.7% of autopsies.
• Sites of involvement include the gastrointestinal tract (most common
in the stomach and small bowel), lung, mediastinum, and fallopian
tube.
• Most cases are asymptomatic.
• Among symptomatic patients, abdominal pain, gastrointestinal
bleeding, pancreatitis, or obstructive symptoms are common.
• Lesions can include clinically significant diagnosis: chronic
pancreatitis, pseudocysts, and neoplasia.
Figure 3.267 Pancreatic heterotopia refers to pancreatic tissue identified at sites not anatomically
or vascularly connected to the pancreas. This high power image reveals the characteristic two-
tone nature of pancreatic acinar cell cytoplasm with peripheral basophilia and centroluminal
eosinophilia.

FAQ: Are there any clinically significant diagnoses linked to

pancreatic heterotopia?
Answer: Yes.
Any diagnosis that occurs in the native pancreas can theoretically
occur in heterotopic pancreas. Be sure to look carefully for chronic
pancreatitis, pseudocysts, and neoplasia.168,171,172

PYLORIC METAPLASIA
Pyloric metaplasia (pseudo-pyloric metaplasia) arises secondary to
chronic mucosal damage and is characterized by the replacement of the
normal mucosal crypts with glands that resemble pyloric glands of the
stomach or Brunner glands of the duodenum. Morphologically, pyloric
metaplasia can be identified by its acinar structure lined by epithelial
cells with abundant clear-to-foamy cytoplasm and small ovoid or round
nuclei which may be flattened against the basement membrane (Figs.
3.268–3.273). These cells which appear adjacent to ulcers and have been
termed ulcer-associated cell lineage (UACL). The UACLs produce
endothelial growth factors and trefoil peptides that promote mucosal
proliferation and healing.173,174 Although pyloric metaplasia has been
cited as highly predictive of Crohn disease,175 it can also be a
nonspecific reparative reaction found in intestinal ulcers, NSAID-induced
injury, or chronic pouchitis.

Figure 3.268 Pyloric metaplasia. This biopsy is from the terminal ileum of a patient with Crohn
disease. Pyloric metaplasia (arrow) is visible from low magnification because the pale cytoplasm
contrasts nicely with the darker inflammatory background. Note also the background crypt
dropout, crypt shortfall, and basal lymphoplasmacytosis, in keeping with the established history
of Crohn disease.

Figure 3.269 Pyloric metaplasia. The pyloric gland (arrowhead) is histologically indistinguishable
from true pyloric glands found in the gastric antrum. The acinar structure is composed of cells
with abundance clear to foamy cytoplasm and small round or ovoid, basally located nuclei. The
base of a small bowel crypt is pictured at right for comparison.
Figure 3.270 Pyloric metaplasia. The glands of pyloric metaplasia (arrowheads) are identical to
those of the gastric antrum. In this example, some of the nuclei are pressed flat against the
basement membrane. This example is from a case of ileal Crohn disease.

Figure 3.271 Pyloric metaplasia. Although pyloric metaplasia is associated with Crohn disease,
the finding is nonspecific and indicates only the presence of chronic injury. This biopsy with
pyloric metaplasia (arrows) is taken from near an ileostomy site. As with most nonneoplastic
biopsies, clinical history is imperative.
 Figure 3.272 Pyloric metaplasia. These pyloric glands (arrow) have replaced the crypts in the
small bowel as a result of chronic injury.

Figure 3.273 Pyloric metaplasia. This biopsy comes from an 83-year-old man with chronic NSAID
use. Note the slight architectural distortion, and the presence of pyloric metaplasia (arrow). This
finding may be subtle in some cases, and the glands are most often found in the deep mucosa, as
seen here.

FAQ: Is pyloric gland metaplasia in ileal pouch biopsies a

definitive marker for Crohn disease?
Answer: No.
Pyloric gland metaplasia is more common in patients who experience
complication following an IPAA (55%) as compared to those who
follow a normal postoperative course (12%). The prevalence is higher
in patients with Crohn disease of the pouch (77%) as compared to
ulcerative colitis patients with chronic pouchitis (22%), but cannot be
used as a definitive marker for Crohn disease.77

PEARLS & PITFALLS

Consider Meckel Diverticulum When Gastric or Pancreatic Tissue
Is Seen in the Small Bowel
Meckel diverticulum is the most common congenital anomaly of the
small bowel. It arises as a result of failure of involution of the
omphalomesenteric duct (also termed “vitelline duct”). The
omphalomesenteric duct connects the embryonic midgut to the yolk
sac ventrally, and normally narrows progressively until its obliteration
by the tenth week of gestation. Failure to involute results in this
congenital outpouch on the antimesenteric border of the ileum (Fig.
3.274). Meckel diverticulum is an example of a true diverticulum
because it contains all layers of the small bowel wall: mucosa,
submucosa, and muscularis propria. It is also described as “the rule of
2’s” because it occurs in approximately 2% of the population, is
located within 2 feet of the ileocecal valve, is 2 inches in length,
presents most commonly at 2 years of age, and has a male:female ratio
of 2:1.176–178 Although most cases are asymptomatic, approximately
2% come to medical attention and require surgical resection based on
obstruction, bleeding, intussusception, volvulus, perforation, or
inflammation. Up to 1/2 of cases contain heterotopic gastric (52%) or
pancreatic tissue (5%) and neoplasia is rare (but can include
gastrointestinal tract stromal tumors, neuroendocrine tumors, and
adenocarcinoma).
 Figure 3.274 Meckel diverticulum. This gross image depicts a congenital outpouching on the
antimesenteric border of the ileum. Although the majority of patients are asymptomatic, common
indications for resection include persistent gastrointestinal bleeding (as in this case), obstruction,
intussusception, volvulus, perforation, or inflammation. Histologically unremarkable small bowel
mucosa is common with heterotopic tissues seen in up to 50% of cases (gastric > pancreas).
Neoplasia is rare.

PIGMENTS AND EXTRAS

Figure 3.275 Pigment example, pseudomelanosis duodeni. Common etiologies of pigment and
pigment-like material in the small bowel include titanium, India ink tattoo, pseudomelanosis
duodeni, formalin, melanoma, and 90yttrium-labeled microspheres. In this example,
pseudomelanosis duodeni was diagnosed based on the brown-black pigment seen in macrophages
located at the villous tips. The patient had a history of renal failure, as is common for patients
 with this finding.

CHECKLIST: Etiologic Considerations for Pigments and

Extras (Fig. 3.275)
Titanium
Tattoo Pigment
Pseudomelanosis Duodeni
Formalin Pigment
Melanoma
90Yttrium-Labeled Microspheres

TITANIUM (“PEYER PATCH PIGMENT”)

Along the tubular gastrointestinal tract, titanium deposition is unique to
the terminal ileum, and can be used to declare the origin of the biopsy
site without looking at the accompanying requisition. This pigment is
fine in texture, dark-brown to black in color, and confined to the
macrophage cytoplasm (Figs. 3.276–3.281). Historical studies using
scanning electron microscopy, backscattered electron imaging, and X-ray
energy spectroscopy of routine histologic sections determined the
pigment represents titanium, aluminum, and
silicon &emdash;although for simplicity’s sake, this pigment is usually
179
referred to as titanium alone. The ingestants originate from food
additives in thickening and whitening agents (e.g., toothpaste) and
arrive in the lymphoid aggregates of the terminal ileum (Peyer patches)
via routine immunosurveillance-related trafficking.
Figure 3.276 Titanium pigment. Without referencing any paperwork, the origin of this tissue is
ileum based on the prominent lymphoid aggregates, relatively short villi, and titanium pigment
(bracket).

Figure 3.277 Titanium pigment. The pigment (arrowheads) is easier to discern on higher power.
The characteristic pigment is fine in texture, dark-brown to black in color, and confined within
the macrophage cytoplasm.
 Figure 3.278 Titanium pigment. In addition to titanium pigment, this image also features air
artifact that was introduced at time of endoscopy (arrowheads). Air artifact is also known as
“pseudolipomatous change” based on its resemblance to mature fat. Although mature fat has
cellular detail such as a nucleus, air artifact lacks cellular detail and a nucleus, and it appears as
variably-sized empty spaces that gently push the lamina propria constituents aside. Air artifact is
frequently found in terminal ileum and colonic mucosal biopsies.

Figure 3.279 Titanium pigment. Historic studies determined this pigment contains variable
amounts of titanium, aluminum, and silicon, although today this pigment is simply referred to as
“titanium.”
 Figure 3.280 Titanium pigment. Titanium pigment originates from ingested thickening and
whitening agents found in toothpaste and other consumables. Under oil immersion, note the fine
quality of the titanium pigment. Compare this image to the coarse pigment seen in tattoo and
melanin pigment (Figs. 3.282–3.287 and 3.300–3.305).

Figure 3.281 Titanium pigment. Note the bland cytologic features of the macrophages: the
chromatin is uniform, the nuclear contours are smooth and regular, and neither pleomorphism,
necrosis, nor atypical mitoses are seen. This case is unlikely to cause concern for melanoma,
based on the bland cytologic features and fine texture of the pigment; however cautious
observers may employ an S100 protein immunostain (remember to use a red chromogen for
easier visibility), which should be negative in titanium pigment and positive in melanomas.

TATTOO PIGMENT
Preoperative tattooing of luminal lesions was introduced in 1958.180 It is
useful for targeted surveillance of endoscopically monitored lesions,
localizing the lesion at time of surgery, and improved local lymph node
dissections. Although a variety of dyes have been used over the years
(e.g., methylene blue, indigo carmine, toluidine blue, lymphazurine,
hematoxylin, eosin, and indocyanine green),181 India ink remains the
most widely employed agent. This tattoo pigment can be easily mistaken
for Titanium since both are dark brown-black and distributed within the
cytoplasm of macrophages (Figs. 3.282–3.287). Helpful clues include
that tattoo pigment is usually very prominently distributed (since its sole
purpose is for gross visibility with the naked eye) and it is not restricted
to the terminal ileum, unlike titanium.

Figure 3.282 Tattoo pigment. Like titanium, India ink tattoo pigment is also dark brown-black
and confined within the cytoplasm of macrophages; however tattoo pigment is typically more
coarse, clumpy, and conspicuous. Compare with the more fine pigment seen in titanium pigment
(Figs. 3.276–3.281).
 Figure 3.283 Tattoo pigment. Tattoo pigment is applied for targeted surveillance of
endoscopically monitored lesions, localizing the lesion at time of surgery, and improved local
lymph node dissections. Since tattoo pigment is intended to help localize lesions at the gross
level (without any visual aids), tattoo pigment is almost always easier to identify than the finer
and sparsely distributed titanium pigment (compare with Figures 3.276–3.281). India ink is the
most commonly used tattoo agent to date.

Figure 3.284 Tattoo pigment. This case features more sparsely distributed tattoo pigment. Such
findings are common at the periphery of the tattoo site or in remotely applied tattoos (greater
than a few months).
 Figure 3.285 Tattoo pigment. Under oil immersion, the dense, clumped tattoo pigment is
apparent.

Figure 3.286 Tattoo pigment. In this field, the tattoo pigment density varies from intense (left) to
more sparsely distributed (right). Note that the pigment is confined to the macrophage
cytoplasm, and the macrophage nuclei are bland and uniform. This case is unlikely to cause
concern for melanoma based on the bland cytologic features of the macrophages and the
intensely black character of the tattoo pigment; however cautious observers may employ an S100
protein immunostain (remember to use a red chromogen for easier visibility), which should be
negative in titanium pigment and positive in melanomas.
 Figure 3.287 Tattoo pigment.

PSEUDOMELANOSIS DUODENI
The first report of pseudomelanosis duodeni emerged in 1976.182 Like
the counterpart in the colon (pseudomelanosis coli), the name is an
unfortunate misnomer. The pigment is not melanin but instead
represents iron with variable amounts of calcium, lipofuscin,
magnesium, aluminum, potassium, silica, and sulfur.183–185 The coarse
and variably brown-black pigment is identified within the cytoplasm of
macrophages, and can usually be highlighted with special stains for iron
(83%) and or calcium (24%).186 The indicated macrophages are most
commonly seen in the villous tips (Figs. 3.288–3.293). Pseudomelanosis
duodeni is associated with hypertension, gastrointestinal bleeding, renal
failure, diabetes, and with particular medications, such as iron and
antihypertensive medications (hydrocholorthiazide, atenolol,
lisinopril/quinapril, and irbesartan).186,187
 Figure 3.288 Pseudomelanosis duodeni. Small bowel biopsies are among the most time
consuming because of the varied diagnoses that can hide in the busy background. As this case
illustrates, the patchy lamina propria pigment deposition (arrowheads) can be difficult to discern
at low power in the normally busy-appearing small bowel mucosa.

Figure 3.289 Pseudomelanosis duodeni. On higher power, the characteristic brown-black

pigment of pseudomelanosis duodeni is better appreciated. Despite the misnomer, the pigment is
not melanin but, instead, is iron with variable amounts of calcium, lipofuscin, magnesium,
aluminum, potassium, silica, and or sulfur. Although acute inflammation is seen, it is unrelated
to the pigment.
 Figure 3.290 Pseudomelanosis duodeni. Pseudomelanosis duodeni is associated with particular
clinical features, such as hypertension, gastrointestinal bleeding, renal failure, diabetes, and with
particular medications, such as iron and antihypertensive medications.

Figure 3.291 Pseudomelanosis duodeni. At higher power, note the coarse nature of this brown-
black pigment confined within the macrophage cytoplasm.
 Figure 3.292 Pseudomelanosis duodeni. Under oil immersion, the pigment is composed of
uniformly sized and uniformly shaped packets of brown pigment.

Figure 3.293 Pseudomelanosis duodeni. Note the uniform and bland cytologic features of the
macrophages; no atypical features are seen.

PEARLS & PITFALLS

Pseudomelanosis duodeni is recognized endoscopically in only 36% of
cases.186 Do not be alarmed if your histologic diagnosis has no
endoscopic counterpart.

FORMALIN PIGMENT (ACID FORMALDEHYDE HEMATIN)

Formalin pigment (acid formaldehyde hematin) is a bothersome tissue
artifact seen in any tissue that is fixed in a formalin tissue preservative.
It carries neither clinical nor pathologic importance. It is a sparsely
distributed, finely granular, dark brown-black, birefringent crystal most
commonly seen in bloody backgrounds (Figs. 3.294–3.299). Unlike
titanium, tattoo, and pseudomelanosis, formalin pigment is not seen in
the confines of a macrophage and is often not even on the same plane as
the examined tissue, features that can serve as helpful clues to the
pigment’s identification. Various experts have noted that formalin
pigment collects in tissues especially rich in fats, such as liver and
kidney,188,189 and theorize that this fatty microenvironment may
promote formalin pigment precipitation through donation of
triglycerides.

Figure 3.294 Formalin pigment. Although this example of formalin pigment originates from the
esophagus, it exemplifies the characteristic features of formalin pigment. On low power, formalin
pigment can look insect-like due to the strange shapes created by the condensed pigmentation.
Figure 3.295 Formalin pigment. On higher power, note that a portion of the formalin pigment is
out of focus (arc). Formalin pigment is typically not entirely on the same plane as the associated
tissue and, consequently, is characteristically partly out of focus, providing a helpful clue to the
identification of formalin pigment.

Figure 3.296 Formalin pigment (arc). Under oil immersion, note that the pigment is finely
granular and dark brown. Features that distinguish formalin pigment from any other pigment
discussed in this section include an extracellular location and its propensity to be only partly in
focus. An arc highlights a portion that is not in the same plane, a reliable feature of formalin
pigment.
 Figure 3.297 Formalin pigment (arc). In this alternate field, the finely granular nature of the
pigment and its extracellular location is better appreciated. An arc highlights a portion of the
pigment that is out of focus.

Figure 3.298 Formalin pigment (arc). There is neither clinical nor pathologic importance to
identification of formalin pigment. The importance of recognizing this pigment is simply not to
confuse it with any of the other pigments discussed in this section. An arc highlights a portion of
the pigment that is out of focus.
 Figure 3.299 Formalin pigment (arc). Formalin pigment is seen entrapped with luminal debris.
An arc highlights a portion of the pigment that is out of focus.

MELANOMA
Of all the pigments in this section, melanoma pigment is the one
pigment that is NOT TO BE MISSED. Whereas the prior mentioned
pigments are found in macrophages with bland nuclear features,
melanoma pigment is seen in unequivocally malignant cells with
prominent nucleoli, pleomorphism, and hyperchromasia. Atypical
mitoses are often easily identified. The pigment itself is coarse, variably
sized, and highlighted by the Fontana–Masson special stain (Figs.
3.300–3.305). Additional special stains and immunostains are often
reassuring (melanoma is S100 protein reactive, variably reactive for
Melan-A and Mart-1, and the pigment is highlighted by the Fontana–
Masson special stain).
Figure 3.300 Melanoma. From low power, coarse brown pigment is seen within the cytoplasm of
overtly malignant cells; benign macrophages would not have such large, pleomorphic nuclei with
prominent nucleoli. Moreover, lymphovascular invasion is demonstrated in a dilated lacteal
(arrowheads). The patient had a history of cutaneous malignant melanoma and was found to have
widely metastatic disease involving the small bowel, liver, and brain.

Figure 3.301 Melanoma. Although no melanin pigment is seen in this figure, other characteristic
features of melanoma are seen, including a packeted or nested architecture (arcs), prominent
nucleoli, and a high nuclear to cytoplasmic ratio. Half of melanomas are amelanotic.
 Figure 3.302 Melanoma. At higher power, pleomorphism is evident with nuclear size varying 3
to 4 times among the malignant cells. Necrosis is also seen along with eccentrically placed nuclei,
prominent nucleoli, and brown pigment.

Figure 3.303 Melanoma. Under oil immersion, the coarsely distributed brown pigment is seen in
cells bearing large nuclei with prominent nucleoli. On H&E, this pigment can be nothing other
than melanin based on the malignant cytologic features. Melanoma immunostains can confirm
this impression.
Figure 3.304 Melanoma. Under oil immersion, again note the cytologically malignant features of
the lesional cells, including large nuclei, prominent nucleoli, and lymphovascular space invasion
(arrowheads highlight the endothelium). Note that the characteristic melanin pigment is coarse,
brown, and variably sized.

Figure 3.305 Melanoma, Fontana–Masson. The melanoma pigment can be confirmed with a
Fontana–Masson special stain, which highlights the melanin pigment black.

90Yttrium-Labeled Microspheres

As mentioned in the Stomach Chapter, Pigments and Extras subsection,

90yttrium-labeled microspheres are used in the targeted treatment of
unresectable primary and metastatic hepatic malignancies. Inadvertent
delivery to nontarget organs can result in unintentional radiation injury.
Affected organs include the esophagus, stomach, small bowel, pancreas,
and gallbladder. The background mucosa shows a radiation pattern of
injury with lamina propria hyalinization, atypical stromal, endothelial,
and epithelial cells, and prominence of ectatic, damaged vessels. The
characteristic microspheres are 30 to 40 μm in diameter, uniformly
opaque, deep purple and perfectly round, and radioactive emissions
occur as far out as 14 days postdelivery (Figs. 3.306–3.311). CMV
immunostains are recommended in all cases since such patients are
typically immunocompromised. Moreover, radiation atypia can obscure
or overlap with CMV viral cytopathic effect.
A comparison summary of the pigments can be found in Figure 3.312.

Figure 3.306 90Yttrium-labeled microspheres and radiation injury. This patient had a history of
unresectable hepatocellular carcinoma treated with selective internal radiation therapy with
90yttrium-labeled microspheres. He presented with nausea and vomiting, and biopsies of

ulcerated small bowel mucosa are shown. Note the focal ulceration with numerous embedded
90yttrium-labeled microspheres (arrowheads). A CMV immunohistochemical stain was negative.

Figure 3.307 90Yttrium-labeled microspheres and radiation injury. Although 90yttrium-labeled

 microspheres are not seen in this field, this image shows the classic features of a radiation
pattern of injury with numerous ectatic, damaged vessels (brackets). Gastric foveolar metaplasia
is also seen, a feature of chronic mucosal injury. A CMV immunohistochemical stain was
negative.

Figure 3.308 90Yttrium-labeled microspheres and radiation injury. Higher power shows the
characteristic 90yttrium-labeled microspheres that are 30 to 40 μm in diameter, uniformly
opaque, deep purple, and perfectly round. The associated mucosa shows a radiation pattern of
injury with lamina propria hyalinization and atypical stromal and epithelial cells.

Figure 3.309 90Yttrium-labeled microspheres and radiation injury. Higher power shows the
90yttrium-labeled microspheres embedded in inflammation, stromal hyalinization, and markedly

atypical stromal and epithelial cells, features characteristic of radiation injury.

 Figure 3.310 90Yttrium-labeled microspheres and radiation injury. Note the associated ectatic
vessels (arrowheads) with atypical endothelial cells resulting from radiation damage.

Figure 3.311 90Yttrium-labeled microspheres and radiation injury. Under oil immersion, the
uniformly opaque, deep purple, and perfectly round structures characteristic of 90yttrium-labeled
microspheres are seen. Also note the background stromal hyalinization and associated epithelial
atypia (arrowhead); both features are secondary to radiation injury. A CMV immunohistochemical
stain was negative.
Figure 3.312 Pigment Composite. This composite image contains the above mentioned pigments
at 100× to best differentiate the morphologic subtleties. A: Titanium pigment is fine in texture,
dark-brown to black in color, and confined within macrophage cytoplasm. B: Tattoo pigment is
also dark brown-black and confined within the cytoplasm of macrophages but, unlike titanium, it
is more coarse, clumpy, and conspicuous since its sole purpose is to be grossly identifiable. C:
Pseudomelanosis pigment consists of coarse brown-black pigment confined within the
macrophage cytoplasm. As shown here, pseudomelanosis pigment is composed of uniformly sized
and uniformly shaped packets of brown pigment that are most typically seen in macrophages in
the villous tips in patients with hypertension, gastrointestinal bleeding, renal failure, diabetes,
and in those with iron and antihypertensive medication therapy. D: Formalin pigment is a
bothersome pigment with neither clinical nor pathologic importance (except to not mistake it for
any of the other pigments discussed here within!). On low it often looks insect-like and on high
power it is finely granular, dark brown, exclusively extracellular, and partially out of focus since
it is on multiple planes. E: Melanin pigment is variably coarse, brown, and within the cytoplasm
of overtly malignant cells. F: 90yttrium-labeled microspheres are 30 to 40 μm in diameter,
uniformly opaque, deep purple, perfectly round, and associated with a radiation pattern of
injury.

KEY FEATURES: Pigments and Extras

• Titanium deposition is unique to the terminal ileum and is likely
introduced through ingested toothpaste.
• Tattoo pigment (usually India ink) is preoperatively applied for lesion
localization in future procedures: targeted surveillance of
endoscopically monitored lesions, localizing the lesion at time of
surgery, and improved local lymph node dissections.
• Pseudomelanosis duodeni consists of iron with variable amounts of
calcium, lipofuscin, magnesium, aluminum, potassium, silica, and or
sulfur and is associated with hypertension, gastrointestinal bleeding,
renal failure, diabetes, and with particular medications.
• Formalin pigment is a tissue artifact with neither clinical nor
pathologic importance; it is not seen in the confines of a macrophage
and is often not even on the same plane as the examined tissue.
• Melanoma pigment is seen in unequivocally malignant cells and
confirmed with the following diagnostic panel (S100 reactive, variably
reactive for Melan-A and Mart-1, and the pigment is highlighted by the
Fontana–Masson special stain).
• 90Yttrium-labeled microspheres are used in the targeted treatment of
unresectable primary and metastatic hepatic malignancies; inadvertent
delivery to nontarget organs can result in inadvertent radiation injury;
CMV immunostains are recommended in all cases.

NEAR MISSES
SNEAKY ADENOCARCINOMA
 Figure 3.313 Acute duodenitis with gastric foveolar metaplasia and reactive epithelial change.
The clinical impression of a mass lesion inspired deeper sections on this busy-appearing biopsy,
although no histologic features of malignancy are readily apparent on this first level.

This case was received as “prominent ampulla, concerning for

malignancy” (Fig. 3.313). The initial sections show duodenal mucosa
with acute and chronic inflammation, gastric foveolar metaplasia, and
marked reactive epithelial change (Fig. 3.313). Although these histologic
features can account for a nodular clinical impression, deeper sections
were pursued based on the clinical suspicion for malignancy. The first
set of deeper sections were similarly concerning, but definitive
malignancy was not seen. Deeper sections were repeated. And repeated.
And repeated. In this case, the tissue block was exhausted and on the
38th level (!!!), clear lymphovascular invasion and infiltrating
adenocarcinoma were seen (Figs. 3.314 and 3.315). When the histology
does not fit the clinical scenario, consider deeper sections. When the
deeper sections are not conclusive, consider repeat deeper sections or
recommend rebiopsy (in this case, the patient was too unstable for a
subsequent biopsy).
 Figure 3.314 Infiltrating poorly-differentiated adenocarcinoma and lymphovascular space
invasion. Deeper sections were performed until the block was exhausted. This photomicrograph
represents the 38th (and final) section, which shows desmoplasia, infiltrating adenocarcinoma
(arrowheads), and lymphovascular space invasion (asterisk). These deeper sections show an
entirely different biopsy compared to the initial sections and were sufficient for chemotherapy
initiation.

Figure 3.315 Sneaky adenocarcinoma involving the duodenal mucosa. Under oil immersion, note
the nuclear irregularities, abundant pink cytoplasm, and cytoplasmic mucin droplet (arrowhead)
characteristic of pancreatobiliary adenocarcinoma. Unfortunately, sometimes 38 levels are
required for the ultimate diagnosis and sometimes only a few malignant cells are present! When
the clinical scenario and the histology are not aligned, deeper sections (and deeper sections and
deeper sections and deeper sections) are often required.

ISOSPORA
Figure 3.316 Isosporiasis. This intermediate power view shows how easy it is to miss Isospora. At
low power, only gastric foveolar metaplasia and perhaps a slight increase in lamina propria
eosinophils is seen. Other fields of this same case were essentially normal, emphasizing that
every biopsy needs a few high power fields of attention for such extremely subtle diagnoses.

Figure 3.317 Isosporiasis. On higher power, a slight prominence of lamina propria eosinophils
serves as a red flag to the diagnosis. Arrowheads highlight the Isospora organisms, which are
obligate intracellular parasites and are found in the paranuclear or subnuclear cytoplasm.
 Figure 3.318 Isosporiasis. On higher power, the Isospora organisms (arrowheads) are seen
embedded within the epithelium. Unless the epithelial compartment is diligently inspected in
every biopsy, these organisms would almost certainly be missed.

Isosporiasis is among the more common protozoan causes of severe

diarrhea in AIDS patients (Figs. 3.316–3.318).190 The Isospora belli
organisms are spread via contaminated water or fecal–oral
contamination. They localize to the small bowel surface and are
exceedingly easy to miss owing to sometimes unremarkable background
mucosa and sparsely distributed organisms (Figs. 3.316–3.321).
Diagnostic confirmation is facilitated through identification of the
oocysts in stool samples or duodenal aspirates.191 Standard therapy
consists of trimethoprim–sulfamethoxazole, which is often long term in
severely immunocompromised patients.
Cryptosporidia and microsporidia infections can manifest with similar
clinical symptoms and are frequent differential considerations, especially
on board examinations! Cryptosporidia are small (2 to 5 μm), rounded
basophilic structures that attach to the small bowel and pancreatobiliary
epithelium (Figs. 3.322–3.326). The organisms can be all too easy to
miss on H&E and are best highlighted by Giemsa, silver, or PAS special
stains. Microsporidium was recently reclassified from a parasite to a
fungus. It is an obligate intracellular organism that is best seen with
electron microscopy.
 Figure 3.319 Isosporiasis (arrowhead). Oil magnification.

Figure 3.320 Isosporiasis. The Isospora organisms are nested within the duodenal epithelium and
have a peripheral clearing (arrowheads) or halo that represents a parasitophorous vacuole only
seen during some stages of development.
 Figure 3.321 Isosporiasis. The large size of Isospora can help distinguish it from other
intracellular protozoa, such as Cyclospora. This Isospora organism is larger than the nucleus of the
neighboring enterocyte. Note that the peripheral clearing or halo is still present. Chart review
revealed the patient was from Cameroon and presented with diarrhea. He was ultimately
determined to have AIDS.

Figure 3.322 Cryptosporidiosis. Cryptosporidiosis is not an infrequent cause of diarrhea in the

immunocompromised patient. At low power, the biopsy shows mild villous blunting and crypt
hyperplasia. There is neither architectural distortion nor inflammatory injury.

Figure 3.323 Cryptosporidiosis. The histologic “chatter” artifact makes this biopsy difficult,
 replicating the “real life” issues practicing pathologists routinely face.

Figure 3.324 Cryptosporidiosis. At high power, the characteristic 2 to 5 μm, rounded basophilic
structures are seen attached to the small bowel epithelium.

Figure 3.325 Cryptosporidiosis. The organisms are best appreciated at high power, underscoring
the difficulty in diagnosis unless “the layers” are diligently inspected in all cases. Although
Cryptosporidia are obligate intracellular organisms, they are extracytoplasmic and live within the
microvilli of the enterocyte, hence their characteristic surface location.
Figure 3.326 Cryptosporidiosis. The organisms are seen “dancing” on the superficial epithelium.
In difficult cases, the organisms can be highlighted by Giemsa, silver, or PAS special stains.

GIARDIA DUODENALIS (GIARDIA LAMBLIA OR GIARDIA

INTESTINALIS)

Figure 3.327 Giardiasis. At low power, the duodenal mucosa looks fairly unremarkable, except
for the haphazardly arranged luminal debris characteristic of giardiasis. This patient was
clinically thought to have an occult malignancy based on the profound weight loss, but all
symptoms resolved with Giardia eradication.

Giardia is the most common intestinal protozoan causing diarrhea in

humans (Fig. 3.327).192 Part of the protozoan’s success stems from its
ability to infect both the immunocompromised and immunocompetent
and its ability to be perpetuated in silent carriers (or asymptomatic
patients). This awareness of asymptomatic Giardia infections is
important such that one is not misled by a lack of diarrhea&emdash;it
happens! Nevertheless, treatment of these asymptomatic cases is critical
for prevention of onward spread. The cyst is transmitted via
contaminated water or via fecal–oral route, and the flagellated
trophozoite adheres to the intestinal epithelium. On duodenal mucosa
biopsies, the organisms haphazardly swirl close to the mucosal surface.
They can bear such a haphazard arrangement that they can be mistaken
for luminal debris to the untrained eye. On closer examination, the
trophozoites have been described as clown-faced or pear-shaped based
on their peculiar binucleate structure (Figs. 3.328–3.332). Diagnosis can
be confirmed with stool smears for the trophozoites or cysts, stool
antigen assays, or serologic studies. The only FDA approved treatment is
furazolidone (Furoxone),190 although metronidazole is the most common
first-line therapy. In the unusual case of recurrent or medically
nonresponsive giardiasis, consider the following immunodeficiencies:

Figure 3.328 Giardiasis. On higher power, the Giardia organisms are better visualized
(arrowheads). Note that the background mucosa is essentially normal and provides no clues to the
infection, making routine inspection for giardiasis critical in every small bowel biopsy. This
patient was an avid hiker and likely contracted the organisms by drinking contaminated water or
through inadequate hygiene practices.
 Figure 3.329 Giardiasis. On highest power, the trophozoites are best seen. Note how the cup-
shaped organisms swirl near the duodenal epithelium.

Figure 3.330 Giardiasis. On a busy day, this low power view might seem less than interesting but
it underscores that examination of the luminal contents is essential for every biopsy! A bracket
highlights the focal collection of Giardia organisms, which are often best appreciated at
intermediate power.
 Figure 3.331 Giardiasis. This patient had recurrent giardiasis that failed medical management
and consequently immunodeficiencies were considered. Although plasma cells were identified, he
was ultimately diagnosed with CVID based on abnormal serum immunoglobulin levels. When
considering immunodeficiencies related to recurrent giardiasis, it is important to assess for goblet
cells and Paneth cells (either can be lost with AIE), plasma cells (up to 67% of those with CVID
show a loss of plasma cells), and increased apoptotic bodies (which are a nonspecific feature of
various immune-mediated processes).

Figure 3.332 Giardiasis. Higher power shows the cup-shaped forms characteristic of giardiasis.

CHECKLIST: Immunodeficiencies Associated with

Giardiasis
IgA Deficiencies
 Common Variable Immunodeficiency (CVID)
Autoimmune Enteropathy
IPEX Syndrome (Immunodysregulation, Polyendocrinopathy,
Enteropathy, X-Linked Inheritance)
APECED Syndrome (Autoimmune phenomena, Polyendocrinopathy,
Candidiasis, and Ectodermal Dystrophy)
X-Linked Agammaglobulinemia

COMMON VARIABLE IMMUNODEFICIENCY

Figure 3.333 Common variable immunodeficiency (CVID). This biopsy originated from a 7-year-
old boy with a history of chronic diarrhea. It would be easy to entertain Celiac disease in this
case based on the villous blunting, crypt hyperplasia, and intraepithelial lymphocytosis (not
appreciated at this power).

Figure 3.334 Common variable immunodeficiency (CVID). Higher power of previous image. At
this power, a complete lack of plasma cells is seen. In other fields, prominent apoptotic bodies
 were also seen, further supporting a pathologic suspicion of CVID. Titration of serum
immunoglobulins was diagnostic of CVID and the patient clinically responded to intravenous
immunoglobulin administration. Importantly, goblet cells and Paneth cells are seen, making
concomitant AIE less likely.

CVID is characterized by hypogammaglobulinemia, a lack of functional

plasma cells, impaired response to vaccinations, and chronic infections
(including Giardia and bacterial infections) (Figs. 3.333 and 3.334). A
lack of plasma cells is helpful, but only seen in two-thirds of cases;
identification of plasma cells cannot exclude CVID.144 Therefore,
clinicopathologic correlation is essential with titration of serum
immunoglobulins serving as an essential component to the diagnosis.

COLLAGENOUS ENTERITIS

Figure 3.335 Collagenous enteritis in a patient with celiac disease. At low power, mild villous
blunting and prominent subepithelial collagen are seen. The most common diagnoses linked to
collagenous enteritis include collagenous colitis, lymphocytic colitis, and celiac disease. In this
case, collagenous enteritis was a manifestation of clinically confirmed celiac disease. The clinical
symptoms and histologic changes abated with adherence to a GFD.

Collagenous enteritis can be easily missed at low magnification,

particularly since the architectural pattern often remains intact (Fig.
3.335). Remember to spend a moment at higher magnification to
routinely inspect all the layers of the small bowel. Doing so may reveal
an altered collagen table or otherwise easily missed diagnoses (Figs.
3.336–3.340).
 Figure 3.336 Collagenous enteritis in a patient with celiac disease. At higher power, the
prominent subepithelial collagen shows an irregular border and contains entrapped capillaries. In
addition, moderate villous blunting and a mild prominence of IELs are seen.

Figure 3.337 Collagenous enteritis in a patient with celiac disease.

Figure 3.338 Collagenous enteritis in a patient with collagenous colitis. This case of collagenous
enteritis originated from a patient with a history of collagenous colitis and shows a prominent,
irregular subepithelial collagen table with entrapped capillaries.

Figure 3.339 Collagenous enteritis in a patient with collagenous colitis.

Figure 3.340 Collagenous enteritis in a patient with collagenous colitis. Prominent entrapped
capillaries are seen within the expanded subepithelial collagen table. Note that intraepithelial
lymphocytosis can be patchy in collagenous enteritis and is not seen in this field.
SNEAKY NEUROENDOCRINE TUMOR

Figure 3.341 Sneaky neuroendocrine tumor. This biopsy was submitted as a duodenal polyp. At
low power, gastric foveolar metaplasia and Brunner gland hyperplasia are seen, findings that
could account for the impression of a polyp; however every biopsy deserves closer inspection.

Small bowel biopsies can be treacherous because of all the potential

hiding places for sneaky diagnoses (Fig. 3.341). Microscopic
neuroendocrine tumors, for example, can be easily obscured by a busy
and “abused” small bowel biopsy (Figs. 3.341–3.345) and yet diligent
inspection is critical as even microscopic neuroendocrine tumors can
behave aggressively. When dealing with a challenging case of crushed
and cauterized tissue, consider a chromogranin and synaptophysin
immunostain, deeper sections, or ask for a repeat biopsy.

Figure 3.342 Sneaky neuroendocrine tumor. At higher power, the gastric foveolar metaplasia and
 crushed lymphoid aggregates are better appreciated.

Figure 3.343 Sneaky neuroendocrine tumor. At this power, note the Brunner glands are pushed
apart by an expansile process, an alarming finding that deserves close inspection. Brackets
highlight pockets of neoplastic cells arranged in nests, suggestive of a neuroendocrine neoplasm.
The diagnosis of this sneaky neuroendocrine tumor is particularly challenging in such a busy
background.

Figure 3.344 Sneaky neuroendocrine tumor. Higher power. The neoplastic cells (brackets) are
poorly preserved, crushed, and could easily be mistaken for crushed lymphocytes if not carefully
inspected at higher power.
 Figure 3.345 Sneaky neuroendocrine tumor (arc). Alternative field.

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 COLON 4

CHAPTER OUTLINE

The Unremarkable Colon

Focal Active Colitis Pattern
• Acute Self-limited Colitis
• Infection
• Medication
• Chemicals or Irritants
• Inflammatory Bowel Disease
• Ischemic Colitis
• Irritable Bowel Syndrome
• Antibiotic-associated Colitis
• Nonsteroidal Anti-inflammatory Drugs
• Bowel Preparatory Artifact
Acute Colitis Pattern
• Infection
• Medication
• Inflammatory Bowel Disease
Ischemic Colitis Pattern
• Ischemia
• Infection
• Medication
Pseudomembranous Pattern
• Ischemia
• Clostridium difficile Colitis and Other Infections
Chronic Colitis Pattern
• Inflammatory Bowel Disease
• Diverticular Disease
• Diversion-associated Colitis
• Syphilitic and Lymphogranuloma Venereum Proctocolitis
• Cord Colitis Syndrome
• Ipilimumab Colitis
• Resins
Lymphocytic Pattern
• Lymphocytic Colitis
• Collagenous Colitis
• Medications
• Viral Infection
Eosinophilia Pattern
• Idiopathic Eosinophilic Colitis
• Inflammatory Bowel Disease
• Allergy
• Medications
• Infection
• Parasite
• Collagen Vascular Disorder and Vasculitis
Granulomatous Pattern
• Inflammatory Bowel Disease
• Nonspecific Mucosal Injury
• Diverticular Disease
• Infections
• Medication
• Sarcoidosis
• Vascular Injury
• Pneumatosis Cystoides Intestinalis
• Autoimmune Diseases
• Cord Colitis Syndrome
• Lymphoproliferative Disorders
Pigments and Extras
• Melanosis Coli
• Tattoo Pigment
• Air Artifact
• Pneumatosis Cystoides Intestinalis
• Muciphages
• Resins
Near Misses
• Endometriosis
• Benign Signet Ring Cell Change
• Pulse Granulomata
• Apoptotic Colopathy
• Spirochetosis

THE UNREMARKABLE COLON

Endoscopically, the unremarkable colon appears as homogeneous pink
mucosa, but regional landmarks allow for reasonably accurate anatomic
localization; for example, proximally, the ileocecal valve and
appendiceal orifice identify the cecum, whereas the appearance of a
triangular lumen signifies entrance into the transverse colon. Moving
distally, the acute bend of the splenic flexure indicates the approach of
the descending colon. Further anatomic localization at the sigmoid and
rectum become more difficult but is aided by luminal narrowing,
thickened mucosal folds, presence of diverticula, and ultimately
calibration marks on the colonoscope.
Histologically, the colon divides into the mucosa, submucosa,
muscularis propria, and serosa (Fig. 4.1). The mucosa is composed of a
single cell layer of columnar cells lining colonic crypts, the investing
lamina propria, and a thin underlying layer of smooth
muscle&emdash;the muscularis mucosae. These mucosal crypts are
oriented parallel to one another and perpendicular to the muscularis
mucosae, such that crypts appear orderly and uniform, like a row of test
tubes when seen on a well-oriented cross section (Figs. 4.2–4.5). When
cut en face, these crypt openings remain orderly and evenly spaced,
providing a top–down view of test tubes in a rack or a “bed of flowers”
architecture (Figs. 4.6 and 4.7). Lining the surface epithelium is a
combination of absorptive columnar cells and mucous-secreting goblet
cells that may be punctuated by very rare intraepithelial eosinophils and
mast cells; neutrophils in the epithelium are never normal. By
comparison, the deep crypt epithelium additionally contains Paneth cells
and endocrine cells (Figs. 4.8 and 4.9). These Paneth cells are normally
limited to the cecum and ascending colon, and their presence distal to
the transverse colon signifies metaplasia, typically due to chronic injury.

Figure 4.1 Normal colon. This resection specimen illustrates the four main layers of the colon:
mucosa, submucosa, muscularis propria, and serosa. The mucosa consists of epithelium (E),
lamina propria (L), and muscularis mucosae (MM). The submucosa sits between the muscularis
mucosae and the muscularis propria, and it consists of loose fibroconnective tissue and
lymphovascular channels. The muscularis propria consists of inner circular and outer
longitudinally orientated muscle fibers. This is covered by subserosal fibroadipose tissue and the
outermost serosa.

Figure 4.2 Test tubes in a rack, profile view. Normal colonic architecture is analogous to a profile
view of test tubes in a rack, with each test tube (or crypt) superimposable upon its neighbor
based on uniform size and distribution.
 Figure 4.3 Normal colon. A well-oriented colonic section illustrates the orderly nature of the
colonic crypts. They are evenly spaced and arranged in parallel, like a row of test tubes in a rack.
The crypt bases extend down to almost touch the muscularis mucosae.

Similarly, the contents of the colonic lamina propria vary depending

on location. This supportive stroma contains a wide variety of cells
arranged among loosely organized strands of collagen, occasional slips of
smooth muscle, nerve twiglets, and small lymphovascular spaces that
lack the potential for lymphovascular spread of tumor.1 The cellular
composition is predominantly lymphocytic and plasmacytic, with
varying numbers of eosinophils and mast cells. This normal complement
of inflammatory cells decreases in concentration approaching the
rectum; knowledge of this prevents overdiagnosis of “chronic colitis”
(Figs. 4.10–4.13). See also Chronic Colitis, this chapter. A rare
neutrophil in the lamina propria or capillary vessel is likely insignificant.
The right colon contains more absorptive cells and fewer goblet cells
than the left colon, a reflection of the differing functions of the right
colon (to absorb excess fluid) versus the left colon (to lubricate the
lumen and facilitate elimination of the luminal contents). Muciphages,
while not native inhabitants, are so commonly found in the rectum that
they are considered by many as normal variants. These colonic
macrophages contain abundant cytoplasmic mucin from “clean up” of
nonspecific mucosal injury (Figs. 4.14 and 4.15)2; when excessive, one
might consider pathologic entities such as metabolic storage disorders or
infection with Mycobacterium avium-intracellulare. See also Muciphages,
Near Misses, this chapter.
 Figure 4.4 Normal colon. An innominate groove in the colon shows crypts branching from a
central lumen (arrows). This is a normal structure in the colon and should not be mistaken for the
crypt distortion seen in chronic colitis.

Figure 4.5 Normal colon. An innominate groove in the colon shows crypts extending away from a
central lumen in an orderly and symmetric fashion. Note that the background crypts are evenly
spaced, indicating a lack of chronic injury (chronicity). This normal structure, seen periodically
along the length of the colonic mucosa, should not be mistaken for the crypt branching of
chronic colitis.
Figure 4.6 Test tubes in a rack, tangential view. When viewed from above, the test tubes are
superimposable upon their neighbors based on uniform size and distribution, analogous to a
tangential view of normal colonic architecture.

Figure 4.7 Normal colon. When cut in cross section, the colonic crypts appear like an evenly
spaced bed of flowers. Even when maloriented, or tangentially sectioned, the normal colonic
mucosa shows an orderly distribution of colonic crypts.
Figure 4.8 Normal colon, Paneth cell versus endocrine cell. Paneth cells (arrowhead) are found in
the crypt bases of the right and transverse colon. Their nuclei abut the basement membrane,
while their coarse, pink cytoplasmic granules polarize toward the crypt lumen. By comparison,
endocrine cells (arrow) are found scattered throughout the crypt bases along the length of the
colon. Their nuclei face the lumen, while their fine, reddish cytoplasmic granules abut the
basement membrane.

Figure 4.9 Normal colon, Paneth cell versus endocrine cell. The Paneth cell (arrowhead) contains
larger, coarse, pink granules released toward the crypt lumen, whereas the endocrine cell (arrow)
contains small, fine, reddish granules released toward the crypt basement membrane. Paneth
cells in the left colon signify evidence of chronic injury.

Figure 4.10 Normal right colon. The right colon is rich in Paneth cells at the crypt bases. In
addition, mixed chronic inflammatory cells are abundant in the lamina propria, including
scattered eosinophils.
 Figure 4.11 Normal right colon. The lamina propria of the right colon contains substantial
numbers of lymphocytes, plasma cells, and eosinophils.

The cellular composition of the submucosa is similar to that of the

lamina propria, but includes larger lymphovascular structures that, in
contrast to those of the lamina propria, can facilitate lymphovascular
spread of tumor cells. Other submucosal cells include adipocytes,
ganglion cells, and nerve axons, the latter two of which compose the
superficial Meissner plexus and the deeper Henle’s plexus. These
ganglion cells are not normally present in the mucosa, and when found
there indicate prior mucosal injury.

Figure 4.12 Normal left colon. Compared to the right colon (Figs. 4.10 and 4.11), the normal left
colon contains fewer lamina propria inflammatory cells. Although eosinophils may be present in
the left colon, they are far less common as compared to the right colon. Note, also, the lack of
 Paneth cells at the crypt bases.

Figure 4.13 Normal rectum. The rectal lamina propria is paucicellular and more goblet cells are
seen compared to their density in proximal sites. Red-colored endocrine cells are normally
present throughout the colon, but note the absence of Paneth cells in the crypt bases.

Figure 4.14 Near-normal rectum, muciphages in the rectum. Muciphages (arrow) may cluster or
can be found dispersed singly in the lamina propria, particularly in the rectum. They are a
nonspecific sign of mucosal injury.
Figure 4.15 Near-normal rectum. Higher magnification of previous figure shows the amphophilic
and bubbly cytoplasm of the muciphages.

The muscularis propria surrounds the submucosa with its inner

circular and outer longitudinal layers of smooth muscle, which sandwich
the myenteric plexus of Auerbach. Externally, the subserosal connective
tissue and the mesothelial-derived serosa encase the bowel. Sites not
entirely covered by serosa include the posterior surface of the ascending
and descending colon and portions of the rectum (posterior aspect of the
upper third, posterior and lateral aspects of the middle third, and the
entire lower third), features important for assessing radial margins in
resection specimens of colonic neoplasms. Grossly visible through the
serosa are the external longitudinal layers of the muscularis propria,
which appear as three distinct bands, or taenia coli, on the right colon
and become confluent on the left.

TABLE 4.1: Distinctive Differences among Regions of the Large Bowel

FOCAL ACTIVE COLITIS PATTERN

Figure 4.16 Focal active colitis pattern. Except for an isolated collection of neutrophils invading
the crypt epithelium (arrow), this colonic biopsy appears essentially normal; the background
crypts are evenly spaced and orderly.

Focal active colitis (FAC) is a histologic pattern characterized by single

foci of neutrophilic crypt injury without features of chronic injury
(chronicity) (Figs. 4.16–4.23). The pattern encompasses a spectrum of
histologic changes, ranging from a single crypt abscess (neutrophils in
the crypt lumen) and single focus of cryptitis (neutrophils in the crypt
epithelium) to multiple discrete foci of cryptitis, or even crypt abscesses
within a series of colorectal biopsies.3 Segmental distribution and
features of architectural distortion and chronicity are absent, by
definition. Similar to most patterns, the FAC pattern does not represent a
discrete disease entity, but instead represents multiple clinical
prodromes that have similar histologic features. These include acute self-
limited colitis, inflammatory bowel disease, ischemic colitis, irritable
bowel syndrome, bowel preparation artifact, antibiotic-associated colitis
(i.e., Clostridium difficile colitis), and medication injury (i.e., nonsteroidal
anti-inflammatory drugs, NSAIDs). Among these patients, clinically
significant diarrhea is the most common indication for colonoscopy;
however, FAC is also an incidental finding in asymptomatic patients
undergoing routine cancer surveillance colonoscopy. As a result,
determining the significance of FAC requires correlation with clinical
and microbiologic information.
Figure 4.17 Focal active colitis pattern. Higher magnification of the previous case shows evenly
spaced and orderly crypt architecture and an isolated focus of acute inflammation in the
epithelium (cryptitis) (arrow).

Figure 4.18 Focal active colitis pattern. Higher magnification of the previous case shows the
single focus of cryptitis (arrow). The surrounding crypts are unaffected.
 Figure 4.19 Focal active colitis pattern. This low magnification emphasizes the orderly
architecture of the colonic crypts. Cut in cross section, they appear like an evenly spaced bed of
flowers. A single isolated focus of acute inflammation (arrow) is present at the surface.

Figure 4.20 Focal active colitis pattern. Higher magnification of the previous case shows an
isolated focus of acute inflammation (arrow) in a background of unremarkable colonic mucosa.
Figure 4.21 Focal active colitis pattern. Higher magnification of the previous case shows a small
neutrophilic abscess at the colonic surface.

Figure 4.22 Focal active colitis pattern. The low-magnification photo emphasizes the focality of
the changes in this biopsy. The background colonic crypts are evenly spaced, and only a single,
isolated focus of acute inflammation (arrow) is present.
 Figure 4.23 Focal active colitis pattern. Higher magnification of the previous case reveals an
isolated crypt abscess with neutrophils and eosinophils in the crypt lumen (arrow).

PEARLS & PITFALLS

A diagnosis of inflammatory bowel disease (IBD) may be rendered if
additional histologic features, such as mucosal distortion, chronic
inflammation of the lamina propria, or epithelioid granulomas are
present.4 Often, however, these additional features are insufficiently
developed to establish a clear-cut diagnosis of IBD. Although FAC may
be a harbinger to IBD, especially in children, there is a preponderance
of acute self-limited colitis, antibiotic-associated colitis, and
medication injury among these patients.

CHECKLIST: Etiologic Considerations for the FAC Pattern

Acute Self-limited Colitis
Infection
Medication
Chemicals or Irritants
Inflammatory Bowel Disease
Ischemic Colitis
 Irritable Bowel Syndrome
Antibiotic-Associated Colitis (Clostridium difficile Colitis)
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Bowel Preparatory Artifact

ACUTE SELF-LIMITED COLITIS

By definition, acute self-limited colitis is one that resolves in less than 4
weeks. An identifiable infectious agent is found in approximately half of
cases, the most common pathogens of which are Campylobacter jejunales,
Salmonella, Shigella, and Yersinia. Clinical clues favoring infectious colitis
include acute onset, fever within the first week of disease onset, and at
least 10 bowel movements in a 24-hour period. By contrast, the majority
of patients eventually diagnosed with IBD have a more insidious onset,
lack a fever within the first week of onset, and have no more than six
bowel movements in a 24-hour period. The remaining cases of acute self-
limited colitis for which stool cultures are negative are the result of viral
infection, parasitic infection, medication reaction, or other chemical
irritants. Histologically, biopsies show a predominantly acute
inflammation restricted to the mucosa in either a patchy or diffuse
fashion. Erosions, ulcerations, and neutrophilic involvement of crypt
epithelium (cryptitis) and crypt lumens (crypt abscesses) may be seen,
but features of chronicity (e.g., crypt distortion, crypt dropout, crypt
shortfall, increased lamina propria chronic inflammation) are absent.

KEY FEATURES of the Focal Active Colitis Pattern:

• FAC refers to individual foci of neutrophilic inflammation in the
absence of chronicity.
• The most common etiology is acute self-limited colitis.
• Acute self-limited colitis is defined as a diarrheal illness less than 4
weeks in duration, and is most commonly attributed to infection
even though half of these patients have negative stool cultures.
• Other associations with FAC include inflammatory bowel disease,
ischemic colitis, irritable bowel syndrome, antibiotic-associated
colitis, and NSAIDs.
• FAC in asymptomatic patients undergoing surveillance endoscopy is
likely of no clinical significance and may be related to bowel
preparation artifact.

ACUTE COLITIS PATTERN

Figure 4.24 Acute colitis pattern. Low magnification reveals abundant crypt abscesses
(arrowheads) in a background of preserved crypt architecture. By definition, acute colitis lacks
features of chronic injury (chronicity).

Acute colitis describes an injury pattern similar to FAC, but more severe
or diffuse, the features of which include cryptitis (acute inflammation in
the crypt epithelium) (Figs. 4.24 and 4.25), crypt abscesses (acute
inflammation in the crypt lumina) (Fig. 4.26), erosions, and ulcerations
in the absence of chronicity. This pattern of injury is entirely
nonspecific, but is most commonly caused by acute viral and bacterial
infections, medications (NSAIDs, Kayexalate, sevelamer, ipilimumab,
etc.) and emerging or partially treated inflammatory bowel disease.
Although ancillary findings of lamina propria hemorrhage or fibrin
deposition may be seen in acute colitis pattern, the distinctive findings of
microcrypts or pseudomembranes raise a unique set of differential
diagnoses, and are therefore discussed as separate patterns within this
chapter. See also Ischemic Colitis Pattern and Pseudomembranous
Pattern, this chapter.
 Figure 4.25 Acute colitis pattern, cryptitis. Neutrophils cross the basement membrane and
infiltrate the crypt epithelium (arrows).

Figure 4.26 Acute colitis pattern, crypt abscess. An aggregate of neutrophils fills a crypt lumen,
forming a crypt abscess.

CHECKLIST: Etiologic Considerations for the Acute Colitis

Pattern
Infection (Cytomegalovirus, Salmonella, Shigella, Campylobacter)
Medication (NSAIDs, Kayexalate, sevelamer, ipilimumab)
Inflammatory Bowel Disease, emerging or partially treated
CYTOMEGALOVIRUS
KEY FEATURES of Cytomegalovirus (CMV) Colitis:
• CMV colitis is most frequently seen among immunocompromised
patients, transplant patients, and the elderly.
• Endothelial cells, macrophages, and stromal cells are
preferentially affected by CMV, although epithelial involvement is
common (Figs. 4.27–4.30)
• The viral cytopathic effect is characterized by cytomegaly (cell
enlargement) containing both nuclear (“owl’s eye”) and cytoplasmic
inclusion bodies that have a distinctive magenta tinctorial quality
(Figs. 4.31–4.34)
• An inflammatory backdrop of mononuclear cells often accompanies
the acute colitis (Figs. 4.35 and 4.36)
• Biopsies of the ulcer base are most likely to yield diagnostic CMV
viral cytopathic effect.
• CMV immunostains are not necessary if classic viral cytopathic effect is
seen on H&E.

Figure 4.27 Acute colitis pattern, Cytomegalovirus. This infected endothelial cell (arrowhead)
bulges into the lumen of a small vascular space. This markedly enlarged cell is easy to spot, even
at low magnification.
Figure 4.28 Acute colitis pattern, Cytomegalovirus. This small vessel shows abnormal hobnail-
like endothelial cells. One cell shows characteristic enlargement with both nuclear and
cytoplasmic expansion (arrowhead). Note the tinctorial change in this CMV infected cell.

Figure 4.29 Acute colitis pattern, Cytomegalovirus. CMV preferentially infects endothelial cells.
This small capillary shows a markedly enlarged endothelial cell with nuclear inclusions
(arrowhead) characteristic of CMV. Note the mononuclear cell infiltrate in the background.
 Figure 4.30 Acute colitis pattern, Cytomegalovirus. The enlarged nucleus in this infected
endothelial cell (arrowhead) shows the characteristic tinctorial change of CMV.

Figure 4.31 Acute colitis pattern, Cytomegalovirus. Viral cytopathic effect of CMV includes
nuclear and cytoplasmic expansion resulting in cellular enlargement (“cytomegaly”), as well as
both nuclear and cytoplasmic inclusion bodies (arrowheads).
 Figure 4.32 Acute colitis pattern, Cytomegalovirus. These enlarged cells (arrowheads) show
characteristic inclusions of cytomegalovirus infection. Note the tinctorial quality of these infected
cells.

Figure 4.33 Acute colitis pattern, Cytomegalovirus. Both cytoplasmic and nuclear inclusions are
evident in these infected cells (arrowheads). The top right cell shows the characteristic “owl’s
eye” nuclear inclusion of CMV.
Figure 4.34 Ganglion cell. Ganglion cells (arrow) can be mistaken for CMV infected cells due to
their amphophilic and voluminous cytoplasm. When in doubt, correlation with a CMV
immunostain may be necessary.

Figure 4.35 Acute colitis pattern, Cytomegalovirus. Although CMV infections (arrowhead) cause
acute inflammation and ulceration of the mucosa, it can be accompanied by a prominent
mononuclear backdrop, as seen here.
 Figure 4.36 Acute colitis pattern, Cytomegalovirus. Higher magnification of the previous case
shows a CMV infected cell (arrowhead) with a prominent mononuclear backdrop composed
primarily of plasma cells and lymphocytes. Scattered neutrophils are also present.

SALMONELLA
KEY FEATURES of Salmonella Infection:
• Salmonella is a gram-negative bacteria transmitted through
contaminated food (meat, dairy, eggs, produce) and water that can
survive partial cooking, freezing, and drying.5
• Infection is divided into two groups:
(1) Typhoid serotypes include S. typhi and S. paratyphi.
(2) Nontyphoid serotypes include S. enteritidis, S. typhimurium, S.
muenchen, S. Newport, and S. paratyphi, among others.5
• Clinical presentation of typhoid species includes fever, abdominal
rash, hepatosplenomegaly, leukopenia, abdominal pain,
headache, watery diarrhea that progresses to hematochezia, and
perforation.
• Nontyphoid species cause less severe illness.
• Treatment is supportive care and antibiotics.
• Histologic features of typhoid fever include involvement of the ileum,
right colon, and appendix with hyperplastic Peyer patches, deep
ulceration, and necrosis (Figs. 4.37–4.41).
• Acute inflammation and a mononuclear backdrop are present.6,7
• Architectural distortion of crypts may raise the question of
inflammatory bowel disease.
• Nontyphoid infection shows an acute colitis, but features can overlap
with typhoid fever.8
• Culture is required for definitive diagnosis.

Figure 4.37 Acute colitis pattern, Salmonella infection. Scanning magnification shows an acute
colitis with prominent crypt abscesses, but relatively preserved crypt architecture. Although
slightly distorted due to the crypt abscesses, these cross-sectioned crypts look like an evenly
spaced bed of flowers.

Figure 4.38 Acute colitis pattern, Salmonella infection. Again, note the relatively preserved crypt
 architecture as the backdrop to this acute colitis with abundant crypt abscesses.

Figure 4.39 Acute colitis pattern, Salmonella infection. This biopsy shows multiple crypt abscesses
and abundant acute inflammation, but no significant crypt architectural changes.

Figure 4.40 Acute colitis pattern, crypt abscess in Salmonella infection. Abundant neutrophils fill
the crypt lumen.
Figure 4.41 Acute colitis pattern, Salmonella infection. Lamina propria hemorrhage and abundant
cryptitis and crypt abscesses are present.

SHIGELLA
KEY FEATURES of Shigella Infection:
• Shigella is an invasive gram-negative bacillus and a major cause of
diarrhea across the world.
• S. dysenteriae is the most virulent and most common, but S. sonnei
and S. flexneri are increasingly reported in the United States.
• Shigella has the highest infectivity rate among all enteric gram-negative
bacteria, with food-and water-borne transmission, as well as the
fecal–oral route; rare instances of sexual transmission are also
reported.
• Outbreaks are associated with crowded living conditions and poor
sanitation, with children less than 6 years most commonly affected.
• Patients present with fever, abdominal pain, and watery diarrhea,
followed by bloody diarrhea with mucus and pus.
• Onset of symptoms begins within 12 to 50 hours after ingestion of
contaminated food or water.
• Medical complications are most commonly seen with S. dysenteriae, and
include severe dehydration, sepsis, toxic megacolon and
perforation. Autoimmune phenomena such as reactive arthritis,
 reactive arthropathy, and hemolytic–anemic syndrome also occur.9
• Treatment is supportive care and antibiotics.
• Histologic findings include a left colon predominant acute colitis,
sometimes with terminal ileum involvement.
• Early changes appear as a diffuse acute colitis, with or without
pseudomembranes (Figs. 4.42–4.45).10
• Later changes may show patchy or segmental involvement, and
concomitant architectural distortion may raise the question of
inflammatory bowel disease.11

Figure 4.42 Acute colitis pattern, Shigella infection. At low magnification, the crypt architecture
is relatively preserved. There is abundant acute inflammation involving both the crypts and the
surface epithelium (arrowheads).

Figure 4.43 Acute colitis pattern, Shigella infection. Higher magnification of the previous case
 shows surface neutrophilic abscess.

Figure 4.44 Acute colitis pattern, Shigella infection. Lamina propria hemorrhage (arrow) and
abundant cryptitis (arrowhead) are present.

Figure 4.45 Acute colitis pattern, Shigella infection. Neutrophils are present within the colonic
epithelium (arrow) and within the crypt lumen (arrowheads).

CAMPYLOBACTER
KEY FEATURES of Campylobacter Infection:
• Campylobacter is a gram-negative food and water-borne bacterium
found in undercooked poultry, raw milk, and untreated water.12
• C. jejuni is most commonly associated with food-borne gastroenteritis,
followed by C. coli and C. laridis.12–14
• Watery diarrhea is the most common presentation, accompanied by
 fever and cramping abdominal pain.12
• Infants, children, and young adults are most commonly affected, and
there is a higher incidence in HIV-positive patients, particularly with
C. fetus.12
• Autoimmune complications such as Guillain–Barré syndrome,
Henoch–Schönlein purpura, and reactive arthropathy are associated.12
• Treatment is supportive care, with resolution within 1 to 2 weeks.
Antibiotics may be needed in immunocompromised patients, or those
with severe, recurrent, or disseminated infection.15
• Histologic features include an acute colitis (Figs. 4.46–4.49) and stool
culture is necessary for definitive diagnosis.15

Figure 4.46 Acute colitis pattern, Campylobacter infection. Abundant crypt abscesses (arrowheads)
indicate the presence of an acute colitis. Note the evenly spaced “bed of flowers” appearance of
the colonic crypts (cut in cross section); there is no evidence of chronicity in this image from the
right colon.
Figure 4.47 Acute colitis pattern, Campylobacter infection. Neutrophils (arrow) have crossed the
crypt basement membrane and are present between the colonic epithelial cells.

Figure 4.48 Acute colitis pattern, Campylobacter infection. Higher magnification of cryptitis
shows neutrophils (arrowheads) within the colonic crypt epithelium.

Figure 4.49 Acute colitis pattern, crypt abscess in Campylobacter infection. A large collection of
 neutrophils is present within this crypt lumen (crypt abscess). Note the neutrophil crossing
through the crypt epithelium (cryptitis) (arrowhead).

ISCHEMIC COLITIS PATTERN

Figure 4.50 Ischemic colitis pattern. This example shows small and withered crypts near the
surface. The surface epithelium has sloughed off in some areas, and lamina propria hemorrhage
and hyalinization are present.

Figure 4.51 Ischemic colitis pattern. The striking finding at low magnification is the presence of
“microcrypts” (arrow). Note the collapse of the hyalinized lamina propria in this area, causing a
condensation of these crypts. Look at the left portion of this image for contrast to relatively
normal crypts and lamina propria.

Mucosal ischemia causes a highly characteristic pattern of injury,

including features of surface injury, loss of mucin, lamina propria
hemorrhage and hyalinization, withered crypts, atrophic microcrypts,
and lamina propria collapse (Fig. 4.50). The architectural pattern of
withered crypts and microcrypts is distinctive at low magnification, and
one might even refer to this pattern of injury as the “microcrypt pattern”
(Fig. 4.51). Although ischemic injury is top among the differential
diagnoses, other considerations include vascular injury (such as that seen
in radiation colitis, amyloidosis, or vasculitis), infection (particularly
Escherichia coli 0157:H7 and Clostridium difficile), and medications
(NSAIDs, Kayexalate, and sevelamer).

CHECKLIST: Etiologic Considerations for the Ischemic

Colitis Pattern
Ischemia
Infection (E. coli, C difficile)
Medication (NSAIDs, Kayexalate, sevelamer, ipilimumab, others)

ISCHEMIA
Decreased blood flow and lack of oxygen to the GI tract result in necrosis
or tissue damage, causing ischemia. There are several weak points in the
colonic blood supply, known as watershed areas, which result from
incomplete anastomosis of the marginal arteries and lack of sufficient
collateral circulation. These watershed areas are more vulnerable to
ischemic injury than other parts of the colon and include the splenic
flexure (or Griffith’s point), the rectosigmoid region at Sudeck’s point,
and the ileocecal region. Among the older population, ischemic disease
is typically attributable to atherosclerotic mesenteric vascular disease,
but the causes of colonic ischemia are many (Table 4.2). The histologic
findings are dependent on the timing of the ischemic event (Figs.
4.52–4.63). Early and minimal injury, for example, occurs first as
degeneration and sloughing of superficial epithelial cells, edema, and
vascular congestion. Later, the epithelial cells become markedly
attenuated and the crypts appear compressed and atrophic
(“microcrypts”) as the lamina propria swells and hemorrhages. Within 5
hours of total acute vascular occlusion, almost the entire intestinal wall
appears necrotic. These changes are devoid of acute inflammation until
reperfusion occurs. Paradoxically, reperfusion further injures the tissues
by introducing oxygen free radical formation,16 the severity of which is
dependent on the duration of the preceding hypoxia.

TABLE 4.2: Causes of Colonic Ischemia

Figure 4.52 Ischemic colitis pattern, early. Early ischemic changes may show only lamina propria
hemorrhage and edema with early sloughing of the superficial epithelium.
 Figure 4.53 Ischemic colitis pattern, early. Lamina propria hemorrhage (arrowheads) is present.

Figure 4.54 Ischemic colitis pattern, withered crypts. Crypt epithelium becomes damaged and
sloughs, giving a “withered” appearance to the crypts (arrowheads). Compare these withered
crypts to the right side of the photo, which are better preserved.

Figure 4.55 Ischemic colitis pattern. This low magnification image emphasizes the microcrypt
pattern. Small, withered crypts are present (arrow) along with lamina propria hyalinization. Note
the homogenous pink appearance of the lamina propria in the area of the arrow. By comparison,
 the lamina propria at the base of the field is still preserved.

Figure 4.56 Ischemic colitis pattern. Note the microcrypt pattern of injury at scanning
magnification. There is a gradient of crypt withering and dissolution that worsens as the surface
epithelium is approached. Also, note the relatively homogeneous pink appearance of the
hyalinized lamina propria.

Figure 4.57 Ischemic colitis pattern, microcrypts. Microcrypts with residual withered epithelium
can be seen at the left (arrows), while crypts that have completely lost their epithelium are seen
on the right (arrowheads). Again, note the quality of the lamina propria, which appears densely
pink, rather than the typical colorless (or white) appearance.
 Figure 4.58 Ischemic colitis pattern, early withering crypts. The surface epithelium in this
example shows early sloughing. The crypt epithelium shows loss of cytoplasmic mucin.

Figure 4.59 Ischemic colitis pattern, early withering crypts. The surface epithelium shows
attenuated epithelial cells with loss of cytoplasmic mucin. The crypt epithelium shows an early
“withered’ appearance with undulation of the crypt luminal surface (arrow).
 Figure 4.60 Ischemic colitis pattern, early lamina propria hyalinization. This early ischemic
injury shows background lamina propria hemorrhage and minimal crypt damage; however, note
the presence of lamina propria hyalinization surrounding the top right crypt (arrowheads). This
homogenous pink material eventually replaces the lamina propria.

Figure 4.61 Ischemic colitis pattern, early lamina propria hyalinization. Similar to the previous
example, these crypts show only early signs of cytoplasmic mucin loss; however, note the focal
hyaline deposits (arrowheads) in the lamina propria.

Figure 4.62 Ischemic colitis pattern, early reperfusion injury. Notable in the Figures 4.52–4.61 is
the near-complete absence of acute inflammation. Neutrophils are drawn to the site of injury
only after reperfusion occurs, and therefore are not seen in early or acute ischemia. This example
shows early reperfusion injury with an early neutrophilic infiltrate (arrowhead).
 Figure 4.63 Ischemic colitis pattern, early reperfusion injury. Higher magnification of the
previous figure shows crypt destruction due to a neutrophilic infiltrate.

KEY FEATURES of Ischemia:

• Ischemia can be caused by vascular occlusion, low flow states, or
mechanical obstruction.
• The most common cause of ischemia among the elderly is
atherosclerosis of the mesenteric arteries.
• Watershed areas prone to ischemia due to lack of sufficient
collateral circulation:
• The splenic flexure (or Griffith’s point)
• The rectosigmoid region (Sudeck’s point)
• The ileocecal region
• Early histologic findings include sloughing of superficial epithelial
cells, edema, and vascular congestion.
• Later stages include lamina propria hemorrhage, hyalinization, and
microcrypt formation, followed by coagulative necrosis
• Acute inflammation is absent unless reperfusion occurs.
• Underlying vasculitis and radiation injury can cause ischemic mucosal
changes (Figs. 4.64–4.66).
• Beware not to overcall crush artifact from biopsy forceps as ischemic
change.
• Pseudomembranes may be seen.
Figure 4.64 Ischemic colitis pattern, radiation injury. Withered microcrypts (arrowheads) can be
seen in radiation injury. This patient had radiation proctitis secondary to radiation treatment for
bladder cancer.

Figure 4.65 Ischemic colitis pattern, radiation injury. Higher magnification of the previous image
reveals the presence of abundant apoptoses (arrowheads), a red flag to radiation-induced injury.
 Figure 4.66 Cellular atypia of radiation injury. Large, atypical cells (arrow) are seen following
radiation injury. Their presence can raise concern for recurrent malignancy, but note the
abundant cytoplasm, which conserves the nuclear-to-cytoplasmic (N:C) ratio. Another clue is the
prominent vesicular appearance of these atypical cells.

PEARLS & PITFALLS

Crush Artifact from Biopsy Forceps Can Mimic Ischemic Injury
Cautery effect and crush injury due to biopsy forceps (“squeeze
artifact”) may strip epithelial cells from the surface and crush glands
that can be mistaken for atrophic microcrypts (Fig. 4.67–4.68). To
contrast, true ischemic injury will show lamina propria hemorrhage
and degenerative cellular changes, such as loss of the apical brush
border and ghostlike nuclei. There is no tissue response to biopsy
forceps squeeze artifact.
 Figure 4.67 Crush (“squeeze”) artifact mimicking ischemic colitis pattern. Crush artifact from
biopsy forceps can dislodge crypt epithelium, leaving behind an empty space that mimics the
microcrypts of ischemia. Avoid this pitfall by noting the absence of other ischemic features, such
as lamina propria hemorrhage, loss of cytoplasmic mucin, and lamina propria hyalinization.

Figure 4.68 Cautery artifact mimicking ischemic colitis pattern. Cautery causes thermal injury
and distorts the colonic crypts. In this example, one might consider the possibility of ischemic
injury, due to the loss of surface epithelium and presence of smaller crypts (arrows). Note,
however, the absence of lamina propria hemorrhage or hyalinization.

PEARLS & PITFALLS

Evaluation for Underlying Vasculitis Can be Tricky in Biopsy
Material
Which came first, the chicken or the egg? Although underlying
vasculitis can certainly cause mucosal ischemia, vascular thrombi and
inflammatory changes can be secondary to ischemic-reperfusion
injury. As a result, primary vascular injury should be evaluated in
areas not directly subjacent to ischemia or ulceration, and close
clinical, radiologic, and serologic correlation should be performed in
cases suspected of primary vasculitis (Fig. 4.69–4.72).

Figure 4.69 Ischemic colitis pattern, venulitis in Behçet disease. One should always consider
vasculitis as a cause of ischemia or ulceration, but take care to look in areas away from ulcers.
This example shows a striking lymphocytic venulitis (arrow) that has obliterated the small vein.
It is easier to search for small muscular arteries (pictured top right) and then look in the
proximity for the paired vein.
Figure 4.70 Ischemic colitis pattern, venulitis in Behçet disease. Note how the markedly damaged
and inflamed vein (arrow) blends into the background. By contrast, the pristine and unaffected
artery is easily identified.

Figure 4.71 Ischemic colitis pattern, systemic lupus erythematosus (SLE). This segment of colon
was resected for ischemia. Note the extensive surface ulceration. An underlying vessel shows a
large fibrin thrombus (arrow). However, due to the proximity to the ulcer, it is unclear whether
the vascular change is causative or the result of the ulcer. One must search for vascular changes
away from the ulcer bed.

Figure 4.72 Ischemic colitis pattern, leukocytoclastic vasculitis in systemic lupus erythematosus
(SLE). Sure enough, further examination in the previous case revealed karyorrhectic debris
(arrowheads) of small vessel necrotizing vasculitis, consistent with the patient’s history of SLE.

INFECTION (Escherichia coli 0157:H7 and Clostridium

difficile)
Certain infectious agents also produce an ischemic pattern of injury,
namely enterohemorrhagic E. coli (E. coli 0157:H7) and C. difficile (Fig.
4.73–4.75). The histologic distinction between ischemia and infection
can be nearly impossible, but observers cite the presence of lamina
propria hyalinization as a feature of ischemia that is absent in infectious
colitis (Fig. 4.76).17 Another clue is the distribution of disease, as
infection diffusely involves the colon, whereas ischemia preferentially
involves the watershed areas. Undoubtedly, stool studies remain the gold
standard for diagnosis.

KEY FEATURES of Infection:

• Infection by E. coli 0157:H7 or C. difficile can be histologically
identical to ischemia.
• Hyalinized lamina propria and withered crypts are not typical of
C. difficile colitis.
• C. difficile colitis is more diffusely distributed in the colon compared
to ischemic colitis.
• Fibrin thrombi are seen in association with E. coli 0157:H7
infection, but are not specific.
• Pseudomembranes are a feature of infectious colitis, but can also be
seen in ischemic colitis.

Figure 4.73 Ischemic colitis pattern, Escherichia coli infection. Infection can cause ischemic-like
features. This example of E. coli infection shows withered and atrophic crypts with partial surface
denudation and loss of cytoplasmic mucin. The findings are nearly indistinguishable from those
of true ischemic injury.

Figure 4.74 Ischemic colitis pattern, enterohemorrhagic Escherichia coli infection. A clue to
enterohemorrhagic E. coli infection (strain O157:H7) is the presence of fibrin thrombi
(arrowheads) within small capillary vessels. Focal residual crypt bases remain (arrows).

Figure 4.75 Ischemic colitis pattern, Clostridium difficile infection. The archetypal feature of C.
difficile colitis is the presence of pseudomembranes; however, early C. difficile colitis shows
ischemic pattern features, such as the microcrypt pattern seen here. An early pseudomembrane is
pictured, but these are not always present.
 Figure 4.76 Ischemic colitis pattern, lamina propria hyaline. Although significant histologic
overlap exists between infectious and ischemic etiologies, the presence of lamina propria
hyalinization is cited as a distinctive feature of ischemia. A homogenous pink hyaline material
replaces the lamina propria and its cellular constituents.

TABLE 4.3: Mechanism of Medications Causing Ischemic Colitis

MEDICATION INJURY
A number of medications cause ischemic injury by a variety of
mechanisms (Table 4.3). Also known as polystyrene sulfonate,
Kayexalate is a cation exchange resin used to treat hyperkalemia and is
commonly found among the medication regimens of renal failure
patients. The resin can be found anywhere along the GI tract, as it is
administered via nasogastric tube, orally, or via rectal enema.
Kayexalate was introduced in 1958 with the notable absence of any
randomized clinical trial regarding its efficacy and safety. In the early
use of Kayexalate, complications included bowel concretions and
medication bezoars within the bowel. As a result, the original water-
based suspension was replaced by a sorbitol suspension that caused an
intentional osmotic diarrhea, thereby reducing bowel impactions.
However, not long after, reports of colonic necrosis and resulting death
surfaced, with evidence that sorbitol was the responsible agent.18 In a
more recent systematic review of 58 cases, Kayexalate (with and without
sorbitol) was linked to ischemic colitis, colonic necrosis, perforation and
bleeding, with a notable mortality rate of 33% among patients
manifesting GI injury.19 See also Resins, Pigments, Esophagus Chapter.

Key Characteristic Morphologic Features of Kayexalate:

• Purple on H&E.
• Hot pink on PAS/AB.
• Narrow, rectangular “fish-scales” or a “mosaic” appearance due to
cracking lines at regular intervals. These “fish-scales” are seen in
both small and large crystal fragments (Figs. 4.77 and 4.78).
• Can be differentiated from sevelamer crystals (a phosphate lowering
agent with possible injurious potential), which show broad, curved,
irregularly spaced “fish-scales” with a variably eosinophilic to rusty
brown color on H&E stain, and a violet color on PAS/D.20

Figure 4.77 Ischemic colitis pattern, Kayexalate (sodium polystyrene sulfonate). This segment of
colon was almost entirely necrotic. Embedded in the luminal debris were numerous purple resin
 crystals.

Figure 4.78 Ischemic colitis pattern, Kayexalate. Higher magnification of the previous case shows
a “fish-scale” or mosaic pattern of cracking lines within the irregular resin crystals. The ischemic
colitis pattern and significant morbidity are associated with this finding.

PEARLS & PITFALLS

Always Check the Luminal Contents
In the setting of colonic ischemia, ulceration, and necrosis, take a
moment to check the luminal contents for particulate matter or
embedded crystalline material that might indicate pill fragments.
Correlation with the patient’s medication history (and history of
hyperkalemia or renal failure) may also be helpful. Given the high
mortality rate associated with Kayexalate-induced GI injury, a
pathologist should advise the clinical team to discontinue the
medication and keep the patient under close observation.

PSEUDOMEMBRANOUS PATTERN
Figure 4.79 Pseudomembranous pattern. This fibrin cap along the surface of the colonic mucosa
is the hallmark of pseudomembranous pattern.

A pseudomembrane is yellow-white exudate on the colonic mucosa that

histologically corresponds to a superficial fibroinflammatory exudate
(Fig. 4.79). The pseudomembrane is composed of fibrin, mucin, and
neutrophils, and may have a laminated or layered appearance. Some
regard “pseudomembranous colitis” as synonymous with C. difficile
colitis, but this is not accurate. In practice, pseudomembranes are also
found in ischemia and with other enterotoxic infections (Shigella,
Salmonella, and enterohemorrhagic E. coli), and histologic distinction
between these entities is not possible. Some observers cite the presence
of lamina propria hyalinization as a feature favoring ischemia.17 Another
indicator is the distribution of disease as infection diffusely involves the
colon, whereas ischemia preferentially involves the watershed areas (Fig.
4.80). Undoubtedly, stool studies remain the gold standard for diagnosis.

CHECKLIST: Etiologic Considerations for

Pseudomembranous Pattern
Ischemia
Clostridium difficile Colitis
Salmonella
Shigella
Enterohemorrhagic Escherichia coli
 Figure 4.80 Pseudomembranous pattern, C. difficile. Histologically, distinguishing ischemic
pseudomembranes from C. difficile pseudomembranes can be impossible. However, the gross
distribution of disease in C. difficile colitis is diffuse (pictured here), whereas ischemic colitis is
typically segmental.

KEY FEATURES of Clostridium difficile Colitis:

• Some physicians use “pseudomembranous colitis” synonymously with
C. difficile colitis, but pseudomembranes are not specific for this
infection.
• Potent toxins are produced by the bacteria (Toxin A and toxin B).
• Oral antibiotic use causes a shift in the normal protective gut
flora, resulting in C. difficile infection.
• Clostridium difficile is the most common nosocomial GI pathogen.
• Patients present with watery to bloody diarrhea, fever,
leukocytosis, and abdominal pain.
• Complications include toxic megacolon, perforation, and reactive
polyarthritis.
• Treatment is supportive care and antibiotics, but fulminant cases may
require surgery.
• Histologic features are primarily an acute colitis with pseudomembrane
formation. Ballooned and exploding crypts with volcanic exudate
may be seen (Figs. 4.81–4.87)
• Severe disease may feature full-thickness mucosal necrosis.
• The differential diagnosis includes ischemia, Salmonella, Shigella,
and enterohemorrhagic E. coli.

Figure 4.81 Pseudomembranous pattern, early. At scanning magnification, the early

pseudomembranes (arrows) are visible as eruptive fibroinflammatory debris along the colonic
surface.

Figure 4.82 Pseudomembranous pattern, early. Higher magnification of the previous case shows
the fibrin (arrowhead) erupting from the colonic surface amidst numerous neutrophils.
 Figure 4.83 Pseudomembranous pattern, early. The eruptive pseudomembrane is hard to miss,
even at low magnification. Interestingly, the background mucosa sometimes shows little to no
change, as seen here.

Figure 4.84 Pseudomembranous pattern, marked. Severe cases of pseudomembranous colitis may
require colectomy, as in this case. There is extensive tissue necrosis and only rare residual crypts
(arrowheads) remain.
Figure 4.85 Pseudomembranous pattern. The crypt epithelium begins to slough and the lamina
propria is edematous. The surface shows abundant fibrin and acute inflammatory cells.

Figure 4.86 Pseudomembranous pattern. The pseudomembrane is composed of fibrin, acute

inflammatory cells, and other cellular debris.
 Figure 4.87 Pseudomembranous pattern. A dramatic (and beautiful) example of an eruptive
pseudomembrane. The extensive fibroinflammatory debris appears to erupt from a single crypt
(arrowhead).

CHRONIC COLITIS PATTERN

Figure 4.88 Chronic colitis pattern. This rectal biopsy represents marked active chronic colitis.
The active injury is imparted by cryptitis and crypt abscesses (best seen at higher power) and the
chronic component refers to increased lamina propria chronic inflammation, Paneth cell
metaplasia, and architectural distortion [a villonodular surface, abnormal crypt configuration,
crypt dropout, crypt shortfall, and basal lymphoplasmacytosis (brackets)]. This nonspecific
pattern simply indicates active chronic mucosal injury. This identical pattern can be caused by
IBD, infection, medication injury, among others. Ascribing this injury pattern to a specific
 etiology requires careful clinicopathologic correlation.

The term “chronic colitis” encompasses a wide spectrum of morphology

and invokes a wide range of etiologic considerations (Fig. 4.88). IBD is
only one of many potential causes of the chronic colitis pattern. Nearly
identical histology can be seen in the setting of diverticular disease,
ipilimumab colitis, syphilitic proctocolitis, chronic infections, medication
injury, or radiation injury, among others; therefore, the chronic colitis
pattern is pathognomic for neither IBD nor any other specific etiologic
agent. Accordingly, ascribing this nonspecific injury pattern to a specific
etiology can be challenging and always requires clinicopathologic
correlation. Accurate diagnosis is absolutely essential to ensure
appropriate clinical management: IBD is managed with
immunosuppression and life-long surveillance, ipilimumab colitis is
cured with drug cessation, and syphilitic proctocolitis is cured with
antibiotics. This section will cover the major etiologic considerations of
the chronic colitis pattern with emphasis on clinicopathologic “red flags”
and clues to the underlying etiology.

CHECKLIST: Etiologic Considerations for the Chronic

Colitis Pattern
Inflammatory Bowel Disease
Diverticular Disease
Diversion-Associated Colitis
Syphilitic and Lymphogranuloma Venereum Proctocolitis
Cord Colitis Syndrome
Ipilimumab Colitis
Resins
 Figure 4.89 A pattern-based approach to colitis. Navigating the chronic colitis pattern can be
treacherous since there are so many varied etiologic possibilities. We recommend a systematic,
three-step pattern-based approach to colitis. This simple approach can provide a helpful
framework for all colitis cases, regardless of the inherent complexities: Step 1: Classify the injury
pattern as acute colitis vs. active chronic colitis vs inactive chronic colitis; step 2: Grade the
colitis as mild, moderate, or marked; step 3: clinicopathologic correlation, “See note.”

A THREE-STEP APPROACH TO THE CHRONIC COLITIS

PATTERN
Undoubtedly, navigating the chronic colitis pattern can be treacherous
because there are so many varied etiologic possibilities. Adoption of a
simplified, three-step pattern-based approach to colitis can provide a
helpful framework for all colitis cases, despite their inherent
complexities (Fig. 4.89).

STEP 1: CLASSIFY THE INJURY PATTERN AS ACUTE

COLITIS VS. ACTIVE CHRONIC COLITIS VS INACTIVE
CHRONIC COLITIS
Acute colitis
As discussed earlier, the acute colitis pattern lacks any features of
chronic mucosal injury, by definition. Features of the acute colitis
pattern can include cryptitis (acute inflammation in the crypt
epithelium), crypt abscesses (acute inflammation in the lumen of the
crypt), erosions, and ulcerations. Not all features are required
simultaneously for the diagnosis of “acute colitis pattern”; one feature
alone satisfies the diagnostic criteria. See also Acute Colitis, this chapter.
Chronic colitis
The “chronic colitis pattern” is a broad term that encompasses a laundry
list of descriptors, provided later. Similar to the diagnosis of “acute
colitis pattern,” not all features need be present at once to satisfy the
diagnostic criteria of the “chronic colitis pattern.”
• Pyloric gland metaplasia
• Pyloric glands are always abnormal in the colon.
• Pyloric gland metaplasia is indistinguishable from pyloric glands at
any other site (Figs. 4.90 and 4.91).

Figure 4.90 Chronic colitis pattern, pyloric gland metaplasia. Pyloric-type glands are normally
found in the stomach and proximal duodenum. Their presence in the colon indicates chronic
mucosal injury.
Figure 4.91 Chronic colitis pattern, pyloric gland metaplasia. These pyloric glands have abundant
foamy-to-clear cytoplasm and small, round or ovoid nuclei that may be flattened against the
basement membrane.

Figure 4.92 Chronic colitis pattern, Paneth cell metaplasia. Paneth cells are normally found in the
small bowel, right colon, and transverse colon. Paneth cells in the descending colon, sigmoid,
and rectum are abnormal and indicate chronic mucosal injury. To the junior trainee, Paneth cells
can sometimes be confused with endocrine cells and eosinophils. Important points of distinction
include that the granules of Paneth cells (arrows) are more lightly eosinophilic, large and coarse,
and aggregate near the colonic lumen. In contrast, the granules of endocrine cells (arrowheads)
are more deeply eosinophilic, finely granular, and aggregate toward the basement membrane.
Eosinophils (circle) have brightly orange, coarse granules, which are usually easy to identify,
especially accompanied by characteristic bilobed nuclei.
 Figure 4.93 Chronic colitis pattern, Paneth cell metaplasia (arrows) versus endocrine cells
(arrowheads). Endocrine cells are normally seen throughout the bowel; their presence does not
signify chronic mucosal injury.

• Paneth cell metaplasia

• Although Paneth cells are normal constituents of the small bowel,
right colon, and transverse colon, their presence in the descending
colon, sigmoid, and rectum is always abnormal (Figs. 4.92–4.94).
• Increased lamina propria chronic inflammation
• Architectural distortion (Figs. 4.95–4.98), compare to normal colon
architecture (Figs. 4.2, 4.3, 4.6, and 4.7)
• Villonodular surface
• Abnormal crypt configuration (Figs. 4.99–4.102)
 Figure 4.94 Chronic colitis pattern, Paneth cell metaplasia (arrow) versus endocrine cells
(arrowheads) versus degranulating eosinophil (circle).

Figure 4.95 Chronic colitis pattern, marked active chronic colitis, ulcerative colitis. This biopsy
originates from a patient with long-standing ulcerative colitis. While the acute component is best
seen at higher power, features of chronicity are easily seen at this magnification: villonodular
surface, abnormal crypt configuration, crypt shortfall, and basal lymphoplasmacytosis (brackets).
Note the varying sizes of the crypts ranging from slightly enlarged (asterisk) to large, complex,
branching structures (arrowheads). Architectural distortion can be assessed on either
longitudinally orientated specimens, as in this example, or tangentially embedded sections, as
seen in Figure 4.96. Compare to a longitudinal profile of normal colon architecture (Figs. 4.2 and
4.3).
 Figure 4.96 Chronic colitis pattern, marked active chronic colitis, diversion colitis. This biopsy
originates from a patient with active chronic mucosal injury secondary to diversion colitis. Note
that the architectural changes can be easily assessed on tangentially embedded tissue sections, as
in this case. The nonuniform size and distribution of the crypts are features of architectural
distortion. Asterisks highlight microcrypts and arrowheads highlight large, complex, branching
crypts. Normally, crypts are uniformly distributed with uniform amounts of intervening lamina
propria. This case features crypt dropout with large zones of increased acute and chronic
inflammatory cells in the lamina propria and no intervening crypts (circles). Compare to
tangential profiles of normal colon architecture (Figs. 4.6 and 4.7).

Figure 4.97 Chronic colitis pattern, marked active chronic colitis, sigmoid colon. Crypt abscesses
are easily seen, as are features of chronic mucosal injury, such as a mildly villonodular surface,
increased chronic inflammation in the lamina propria, and abnormal crypt configurations and
 distributions.

Figure 4.98 Chronic colitis pattern, marked active chronic colitis, left colon. Features of
chronicity include a villonodular surface, increased lamina propria chronic inflammation,
abnormal crypt configurations and distributions, and crypt dropout (asterisks).

Figure 4.99 Chronic colitis pattern, abnormal crypt configuration. Normally, crypts are uniform
U-or tube-shaped structures when viewed in profile and uniform circular structures when viewed
tangentially, similar to test tubes in a rack or a bed of flowers (Figs. 4.2, 4.3, 4.6 and 4.7). When
the crypts depart from this normal expected configuration, architectural distortion is present.
This central crypt resembles abstract art, perhaps a Picasso muse, a map of a winding river, or an
ungraceful backbend. If similar wild imagery accurately describes the crypt configuration, then
architectural distortion is present.
Figure 4.100 Chronic colitis pattern, abnormal crypt configuration, sigmoid, diverticular disease.
The appearance of this sigmoid biopsy exemplifies chronic mucosal injury in the setting of
diverticular disease. This image features bifid and branching crypts (asterisks) that are no longer
superimposable because of varying sizes and distributions. Other features of chronicity include a
villonodular surface, increased chronic inflammation in the lamina propria, and Paneth cell
metaplasia (circles).

• Crypt dropout
• Crypt shortfall
• The basal crypts do not sit directly on the muscularis mucosae
(Figs. 4.103 and 4.104).
• Crypt shortfall can occur in the presence or absence of basal
lymphoplasmacytosis.
• Basal lymphoplasmacytosis
• A basal layer of lymphoplasmacytic inflammation prevents the
basal crypts from sitting directly on the muscularis mucosae (Figs.
4.105–4.109).
Figure 4.101 Chronic colitis pattern, abnormal crypt configuration. Bifid crypts refer to two fused
crypts and are a sign of chronic mucosal injury.

Figure 4.102 Chronic colitis pattern, abnormal crypt configuration. This striking example of
abnormal crypt configuration resembles two people dancing. If crypts can invoke vivid imagery,
then abnormal crypt configuration is present and chronic mucosal injury has occurred.
 Figure 4.103 Chronic colitis pattern, crypt dropout and crypt shortfall. Crypt dropout: at low
power, the expected uniform distribution of crypts is absent; some crypts appear “missing”
(asterisks). Crypt shortfall: in addition, some crypts are floating in the lamina propria; these
crypts are not anchored to the muscularis mucosae but, instead, “fall short” of the muscularis
mucosae (brackets). Although both the crypt dropout and shortfall are focal and mild, they
signify chronic mucosal injury.

Figure 4.104 Chronic colitis pattern, crypt shortfall. At higher power, we see the crypts “fall
short” of the muscularis mucosae based on a sprinkling of lamina propria constituents. This
example illustrates that not all cases of crypt shortfall are due to basal lymphoplasmacytosis.
Sometimes, crypt shortfall is due to crypts simply floating above the muscularis mucosae.

Figure 4.105 Chronic colitis pattern, basal lymphoplasmacytosis and crypt shortfall. This case
features a conspicuous example of basal lymphoplasmacytosis. Note the basal band of intense
lymphoplasmacytic inflammation (brackets) that prevents the basal crypts from directing sitting
on the muscularis mucosae (asterisks). This finding is always abnormal and is a feature of chronic
mucosal injury.
Figure 4.106 Chronic colitis pattern, basal lymphoplasmacytosis. On higher power, the band of
inflammatory cells consists predominantly of plasma cells, lymphocytes, eosinophils, and
scattered histiocytes.

Figure 4.107 Chronic colitis pattern, basal lymphoplasmacytosis and crypt shortfall, Crohn
disease. This biopsy is from a patient with Crohn disease. In addition to basal
lymphoplasmacytosis and crypt shortfall (brackets) also note the bifid crypts (arrowheads).
 Figure 4.108 Chronic colitis pattern, basal lymphoplasmacytosis. Basal lymphoplasmacytosis is
often best appreciated on low power. An asterisk highlights the muscularis mucosae and brackets
highlight the basal lymphoplasmacytosis and crypt shortfall.

Figure 4.109 Chronic colitis pattern, basal lymphoplasmacytosis and crypt shortfall (brackets).
Asterisks highlight the muscularis mucosae.

Of all the histologic features of chronicity, the assessment of

architectural distortion is perhaps the most subjective. Recall, the
normal colon has a flat surface with uniform-sized crypts separated by
uniform amounts of lamina propria, which rest directly on the
muscularis mucosae (Figs. 4.2, 4.3, 4.6 and 4.7). Normal colon
architecture is analogous to “test tubes in a rack” with each crypt (or test
tube) nearly identical to and superimposable on its neighbor because of
similar size, shape, and distribution. In contrast, architectural distortion
may feature a villonodular surface with crypts of various widths,
heights, and distribution. These haphazard crypt configurations are no
longer superimposable because of dissimilar size, shape, and distribution
(Figs. 4.99–4.102). The variable lamina propria can result in “crypt
dropout,” or dissolution of the expected uniform crypt distribution.
Although normal basal crypts have an orderly and neat arrangement
directly above the muscularis mucosae, architectural distortion often
features crypts that fall short of the muscularis mucosae (“crypt
shortfall’) (Figs. 4.103 and 4.104). Crypt shortfall can occur in the
presence or absence of basal lymphoplasmacytosis (a variably thickened
band of lymphoplasmacytic inflammation that prohibits the basal crypts
from having an orderly arrangement with the muscularis mucosae) (Figs.
4.105–4.109).

Figure 4.110 Chronic colitis pattern, mild active chronic colitis. Mild active chronic changes are
subtle and often not unequivocally apparent at low power, as in this case. This rectal biopsy has
acute injury in the form of focal cryptitis (not shown) and chronic injury (mildly increased
lamina propria chronic inflammation and focal Paneth cell metaplasia, not shown).
 Figure 4.111 Chronic colitis pattern, marked active chronic colitis. Marked changes would be
universally recognized by most pathologists because the findings are prominently displayed. This
rectal biopsy shows marked changes with a villonodular surface, chronic inflammation in the
lamina propria, wildly abnormal crypt configurations, crypt dropout, crypt shortfall, and basal
lymphoplasmacytosis.

Chronic colitis can be further classified as either active or inactive

depending on the presence or absence of a concomitant acute
component. Active chronic colitis includes histologic features of
chronicity AND a concomitant acute component (ulceration, erosion,
cryptitis, and or crypt abscess), whereas inactive chronic colitis refers to
any of the histologic features of chronicity in the absence of an acute
colitis component.

STEP 2: GRADE THE COLITIS AS MILD, MODERATE, OR

MARKED
“Colitis” is a broad term that describes a spectrum of mucosal injury. It
describes histologic features of injury whether seen in isolation or
combination, and regardless of the prominence or extent of disease; for
example, the term “chronic colitis” appropriately describes a sigmoid
biopsy with five isolated Paneth cells as well as a sigmoid biopsy
showing marked architectural distortion, crypt shortfall, basal
lymphoplasmacytosis, and 55 Paneth cells.** As a result, additional
descriptors allow for a more precise description of the pathology and can
be helpful in monitoring the evolution of disease course and therapy
response. Colitis can be qualified as mild, moderate, or marked
depending on the overall intensity of the mucosal injury. Mild changes
are quite subtle to the extent that not all pathologists would agree on
officially recognizing, or findings that are not readily apparent at low
power (Fig. 4.110). Marked changes encompass all features described
above and in prominent proportions; these changes would be universally
agreed on by most, if not all pathologists (Fig. 4.111). Moderate
changes, literally, fall in between those of the mild and marked
categories (Fig. 4.112).

STEP 3: CLINICOPATHOLOGIC CORRELATION, “SEE NOTE”

Steps 1 and 2 can be performed in a vacuum because pure morphology
dictates colitis classification and grading. The far more interesting aspect
of this three-step pattern-based approach is the final step. In step 3, the
histologic findings are situated in the specific clinical setting. The entire
clinicopathologic context is integrated to share the pathologist’s
particular perspective on this particular mucosal injury pattern. This
note cannot be “quick-texted” or “macro-ed” for mass reproduction
because it is based on the unique clinicopathologic features of the
unique case in question. The succeeding section will introduce and
emphasize clinicopathologic “red flags” to quickly home in on the
underlying etiology and to guide direct etiologic specific therapy.
Sample notes are included to illustrate the utility of the three-step
pattern-based approach to colitis.

Figure 4.112 Chronic colitis pattern, moderate active chronic colitis. Moderate changes are more
 conspicuous than those of the mild category and are identifiable at low power, as in this case.
This rectal biopsy shows a villonodular surface, increased chronic inflammation in the lamina
propria, abnormal crypt configurations with bifid and quadrafid glands, and crypt dropout.

FAQ: What time frame is required for the development of features

of chronic mucosal injury?
Answer: Surprisingly, histologic features of chronic mucosal injury can
be seen with as few as 72 hours of injury, any sort. This includes at
least 3 days of diarrhea due to self-limited infections, medications,
emerging IBD, among many others. As a result, features of chronicity
merely confirm at least 72 hours of mucosal injury; they are
pathognomic for no specific etiology. Adoption of the three-step
pattern-based approach to colitis serves as simple, comprehensive
guide to navigating this nonspecific injury pattern.

INFLAMMATORY BOWEL DISEASE

IBD is a chronic systemic inflammatory disease whose major disease
manifestations impact the gastrointestinal tract (GIT). IBD can be further
subclassified as Crohn disease, ulcerative colitis, and type-indeterminate.
The type-indeterminate category is a provisional category reserved for
those 5% to 10% of cases that cannot be definitively delineated into the
Crohn or ulcerative colitis category because of conflicting or insufficient
clinicopathologic evidence. Eighty percent of the type-indeterminates are
eventually classified as either ulcerative colitis or Crohn disease within
the subsequent 8 years based on evolving clinical, radiographic, and
histologic evidence.21
Ulcerative colitis and Crohn disease constitute the majority of IBD and
are seen in 4 to 20 per 100,000 persons in the United States. All
subtypes are enriched in Caucasians and Ashkenazi Jews, with males
more commonly affected in ulcerative colitis and a female bias seen in
Crohn disease.22 In general, IBD displays a bimodal distribution of age at
time of first presentation. The first wave of patients present between 15
and 30 years of age and the second peak occurs between 60 and 70
years. Most patients present with a history of bloody diarrhea and
weight loss and the disease course is characterized by alternating periods
of disease flares and remissions. Endoscopically, both ulcerative colitis
and Crohn disease display variable loss of vascular pattern, erythema,
friability, erosions, and ulcerations. Histologically, both are
characterized by active chronic inflammatory injury. Although IBD
primarily affects the intestinal tract, 10% to 15% of patients have
extraintestinal manifestations, including ankylosing spondylitis,
seronegative arthritis, primary sclerosing cholangitis, conjunctivitis,
iritis, episcleritis, uveitis, anemia, pyoderma gangrenosum, and
erythema nodosum. Patients with ulcerative colitis and HLA-B27 carry a
particularly strong risk of ankylosing spondylitis and uveitis. Stomatitis
and oral aphthous lesions/ulcerations are more common in Crohn
disease. All IBD patients will eventually enter a surveillance program
based on an increased risk of neoplasia. Surgical candidates include
patients who develop neoplasia and those whose symptoms fail medical
treatment.

FAQ: If the clinicopathologic diagnosis is IBD, why should we

bother with further subclassification as ulcerative colitis or
Crohn disease? Why does subclassification matter?
Answer: Correct IBD subclassification is critical to ensure appropriate
surgical management. Ulcerative colitis may be managed with removal
of the entire colorectum because the entire colorectum is at risk for
the inflammatory disease–dysplasia–carcinoma sequence. In contrast,
the standard of care in Crohn disease is conservative segmental
resection to preserve as much of the bowel length (and quality of life)
as possible because of the increased risk of subsequent GIT injuries
and bowel-shortening surgeries. Another important surgical
management consideration centers on the option of the ileal-pouch
anal anastomosis (IPAA). IPAA is the preferred surgical option
following a total proctocolectomy because it allows for GIT continuity
and preservation of the anal sphincter (Figs. 4.113 and 4.114).
Patients with ulcerative colitis are eligible for an IPAA but those with
Crohn disease are not, in general, based on the increased risk of
disease flares and pouch complications. Instead, Crohn disease
patients are offered a permanent ostomy: the bowel is attached to the
anterior abdominal wall and opens into an ostomy bag through which
the fecal stream exits, necessitating additional hygiene and
maintenance issues (Figs. 4.115–4.116). Correct IBD subclassification
is critical to ensure optimal surgical management and requires
awareness of the IBD “rules” (classic IBD presentations), the IBD
“realities” (nonclassical IBD presentations), and IBD mimics, discussed
subsequently.

Figure 4.113 Normal bowel anatomy features the colon draped over and framing the small
bowel.
 Figure 4.114 Ileal-pouch anal anastomosis (IPAA). Closure of a total proctocolectomy requires
either an ostomy/stoma site or an IPAA (in this illustration the colon is “grayed out” to represent
removal). IPAA is the preferred surgical approach because it maintains GIT continuity and avoids
the need for a permanent ostomy bag (see Fig. 4.115). IPAA involves anastomosis of the ileum to
the anus. A reservoir is created by stitching two loops of ileum together and removing the
internal walls. The resulting reservoir is in the shape of a “J” and often termed a “J-pouch.” IPAA
is the standard of care forulcerative colitis patients but is generally contraindicated in Crohn
cases because of increased risks of disease flares. Instead, Crohn disease patients are offered a
permanent ostomy (either an ileostomy or colostomy).
 Figure 4.115 Ileostomy. In this illustration, the background colorectum is shaded gray to
represent a prior total proctocolectomy. An ileostomy involves bringing the small bowel through
the anterior abdominal wall to form a stoma site. The bowel is then attached to an ostomy bag
through which the fecal stream exits.

Figure 4.116 Colostomy (with Hartmann pouch). A colostomy involves bringing the colon
through the anterior abdominal wall to form the stoma site. The ostomy bag is then attached to
 the stoma, through which the fecal stream exits. An additional Hartmann pouch procedure is
sometimes performed under emergent conditions or when there is insufficient healthy bowel for
primary anastomosis. The Hartmann procedure involves sewing over the proximal rectum so that
the rectum remains in situ as a blind pouch (Hartmann pouch). This pouch is excluded from the
fecal stream and susceptible to diversion colitis.

Inflammatory Bowel Disease “Rules”: Classic Presentations

The IBD “rules” are among the first concepts introduced in medical
school, emphasizing their fundamental clinical importance. The rules
enumerate the discriminating features of ulcerative colitis and Crohn
disease, allowing their reliable distinction. The rules summarize
ulcerative colitis as a mucosa restricted process that starts at the rectum
and progresses in a diffuse manner toward the proximal colon (Figs.
4.117–4.119). According to the rules, these changes are limited to the
colorectum and pseudopolyps are restricted to ulcerative colitis. In
contrast, the rules dictate that Crohn disease is a transmural disease with
possible upper GIT involvement, rectal sparing, and a patchy progression
pattern, resulting in “skip lesions.” As a result of transmural
involvement, predictable transmural pathology is to be expected,
including a stiff or “pipe”-like bowel wall, creeping fat, fissures, fistulas,
strictures, sinus tracts, and transmural lymphoid aggregates and fibrosis
(Figs. 4.120–4.124). In addition, according to the rules, mucosal
“cobblestoning” is unique to Crohn disease and describes alternating
linear ulcerations with edematous mucosa (Figs. 4.125–4.126). Of all of
the rules, those that most consistently point to Crohn disease include
epithelioid granulomata and transmural inflammation and lymphoid
aggregates away from injured mucosa. Classic IBD presentations abide by
the aforementioned rules and allow reliable subclassification as
ulcerative colitis or Crohn disease (Fig. 4.127, Table 4.4).
 Figure 4.117 IBD “rules,” ulcerative colitis, gross examination. Gross examination can reveal
helpful diagnostic clues to the diagnosis of ulcerative colitis versus Crohn disease. First, note that
this specimen is a total proctocolectomy, the standard of care for ulcerative colitis patients.
Additional clues to the diagnosis of ulcerative colitis include rectal-based disease that progresses
in a diffuse manner. Lastly, the wall is of average thickness and would feel floppy upon
examination; both features suggest mucosa-restricted disease.

Figure 4.118 IBD “rules,” ulcerative colitis, gross examination. This specimen shows similar
features ascribed to classic ulcerative colitis, including diffuse disease progression and a thin
bowel wall secondary to mucosa-restricted disease.
 Figure 4.119 Chronic colitis pattern, IBD “rules,” ulcerative colitis. This image represents
histologic features ascribed to classic ulcerative colitis. The mucosa is almost entirely ulcerated,
and increased mucosal acute and chronic inflammation are seen. Also note that the bowel wall is
of average thickness secondary to mucosa-restricted disease.

Figure 4.120 IBD “rules,” Crohn disease, gross examination. The first gross clue to the diagnosis
of Crohn disease is the segmental nature of the specimen. Segmental resections are the standard
of care for Crohn disease patients based on the patchy disease distribution and propensity for
future bowel shortening operations. Transmural disease manifests with transmural pathology: 1.
An obstructing stricture was the indication for this resection (arrow); 2. The bowel wall is thick,
fibrotic, and would feel “pipe-like” or heavy and inflexible on gross examination (arrowheads); 3.
The edge of the specimen demonstrates “creeping fat” or irregular and scarred serosal fat from
repeated bouts of transmural disease (bracket).
 Figure 4.121 IBD “rules,” Crohn disease, gross examination. This case also features classic
stigmata associated with typical Crohn disease, including patchy transmural disease: note the
segmental nature of the resection), thick bowel wall, and fistula (forceps). An arc highlights
pseudopolyps, a feature traditionally described in ulcerative colitis, according to the IBD “rules.”

Figure 4.122 IBD “rules,” Crohn disease, gross examination. This segmental resection displays
numerous strictures (highlighted by toothpicks) in a patient with a long-standing history of
Crohn disease. Each bowel resection leaves the patient with progressively less bowel and may
result in increased diarrhea and further complications. As a result, segmental resections are the
standard of care for patients with Crohn disease in an effort to preserve bowel length and quality
of life.
 Figure 4.123 Chronic colitis pattern, IBD “rules,” Crohn disease. This resection specimen
demonstrates classic features typically ascribed to Crohn disease, including transmural lymphoid
aggregates, granulomata, and fibrosis. The overlying mucosa shows active chronic injury as well,
features best seen at higher power.

Figure 4.124 Chronic colitis pattern, IBD “rules,” Crohn disease. Higher power illustrates a
number of large granulomata.
 Figure 4.125 IBD “rules,” Crohn disease, gross examination. This image illustrates mucosal
cobblestoning, a feature most commonly associated with Crohn disease. This pattern is a result of
linear ulcerations and intervening mucosal edema and resembles cobblestoned streets.

Figure 4.126 IBD “rules,” Crohn disease, gross examination, mucosal cobblestoning.
Figure 4.127 Chronic colitis pattern, IBD “rules,” “macroscopic” examination. Helpful diagnostic
clues to the diagnosis of ulcerative colitis versus Crohn disease can also be gathered by looking at
the glass slides from across the room, without even using the microscope! Illustrated above are
two unique total proctocolectomy resection specimens arranged in six parallel slides (from top to
bottom: appendix, cecum, ascending colon, transverse colon, left colon, and, finally, rectum). The
case on the left shows mucosal restricted disease that diffusely involve all slides, perhaps most
severe in the rectum where the mucosa is entirely sheared off. The case on the right displays
transmural disease, note the thick bowel wall. Also note the patchy disease distribution with
diseased sections interrupted by uninvolved segments. Rectal sparring is present. Without using
the microscope, we have gathered helpful clues that favor classic ulcerative colitis in the case on
the left and classic Crohn disease in the case on the right.
SAMPLE NOTE: CLINICAL HISTORY OF A LONG-
ESTABLISHED ULCERATIVE COLITIS HISTORY
Rectum, Biopsy:
• Marked active chronic proctitis.
Note: The history of ulcerative colitis is noted. The biopsy shows marked
active chronic proctitis with cryptitis, crypt abscesses, architectural
distortion, and increased chronic inflammation. These findings support
the established history of ulcerative colitis. Negative for dysplasia,
granulomata, and viral cytopathic effect.

TABLE 4.4: Inflammatory Bowel Disease “Rules”

SAMPLE NOTE: NO CLINICAL HISTORY PROVIDED; THIS

SAMPLE NOTE IS REFERRED TO AS “GENERAL CHRONIC
COLITIS” IN SUBSEQUENT SUBSECTIONS
Note: The earlier findings are etiologically nonspecific and can be seen in
the following settings: diverticular disease, diversion-associated colitis,
syphilitic and lymphogranuloma venereum proctocolitis,** chronic
nonspecific infection, chronic medication injury, and inflammatory
bowel disease, among others. Clinical correlation is required.

Reference:
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.

FAQ: Is it reasonable to top-line a diagnosis as ulcerative colitis

or Crohn disease and eliminate the note?
Answer: Top-lining a diagnosis of IBD would be discouraged based on
the inherent complexities of the chronic colitis pattern. Recall, the
chronic colitis pattern is etiologically nonspecific. There are no
pathognomic features of IBD; there are no histologic features that can
reliably distinguish IBD from diverticular disease, diversion-associated
colitis, syphilitic or LGV proctocolitis, cord colitis syndrome,
ipilimumab colitis, vasculitis, radiation injury, autoimmune diseases,
among others; therefore, the three-step approach to colitis is suggested
in all cases: classification (step 1), grade (step 2), and
clinicopathologic correlation/ “see note” (step 3) (Fig. 4.89). This
systematic approach can be universally applied to all cases of chronic
colitis, regardless of the complexity. In this manner, the three-step
approach allows for a detailed morphologic description and
consideration of the relevant differential etiologies in the specific
clinicopathologic setting.

Inflammatory Bowel Disease “Reality”: Nonclassic IBD

Presentations
Table 4.4 captures the “rules” of IBD, whereas this section briefly
discusses the “reality” of IBD, otherwise known as the nonclassic IBD
presentations. The essential message is that every “rule of IBD” has a
known exception. Awareness of the spectrum of nonclassical
presentations allows for an appreciation of both the breadth and depth
of IBD and is critical for accurate diagnosis and appropriate clinical
management. The discussion below pairs the select “IBD rule” with its
corresponding “reality” to emphasize the challenges of navigating the
chronic colitis pattern. These inherent complexities further emphasize
the utility of the descriptive three-step pattern-based approach to colitis.

Depth of Involvement “Rule”: Ulcerative colitis is mucosa restricted and

Crohn disease is transmural.
Depth of Involvement “Reality”: Ulcerative colitis can be transmural and
Crohn disease can be mucosal restricted.
In reality, Crohn disease is occasionally superficial or limited to the
mucosa. These cases are referred to as “ulcerative colitis-like” Crohn
disease or “superficial Crohn disease” in the literature.23 Likewise, severe
ulcerative colitis disease flares can present with transmural disease, such
as in the rare case of toxic megacolon (Fig. 4.128). Toxic megacolon is a
life-threatening condition associated with a 16% mortality rate and seen
in up to 10% of hospital admissions for ulcerative colitis.24,25 Criteria
include colonic dilatation greater than 6 cm and systemic toxicity.
Although 46% are associated with ulcerative colitis, toxic megacolon can
also be seen in Crohn disease (2.3%), Behçet disease, infections
(particularly C. difficile), ischemia, collagenous colitis, lymphoma, and
medication injury.24–26 The pathogenesis may relate to a combination of
acute and extensive transmural inflammatory damage, ischemia, and
local increased nitric oxide levels leading to smooth muscle relaxation
and dilatation.26 Emergent proctocolectomy is common and often
accompanied by high-dose intravenous steroids (assuming infections
have been excluded) and correction of underlying and associated
abnormalities such as dehydration, electrolyte disturbances, and anemia.

Disease Progression “Rule”: Ulcerative colitis is rectal based and progresses in

a diffuse manner, and Crohn disease spares the rectum and progresses in a
patchy manner.
Disease Progression “Reality”: Ulcerative colitis can spare the rectum and
show patchy disease distribution, and Crohn disease can involve the rectum
and progress in a diffuse manner.
 Figure 4.128 IBD “reality,” defying the depth of involvement “rule.” The depth of involvement
rule is that ulcerative colitis is mucosal restricted and Crohn disease is transmural, but the
reverse can be the reality. This image represents an emergent colectomy for toxic megacolon in a
patient with severe ulcerative colitis. Note the diffusely edematous and bloody specimen. The
corresponding histologic sections showed transmural active chronic colitis (not shown),
emphasizing that ulcerative colitis can defy the “depth of involvement rule” in severe and acute
cases.

Figure 4.129 IBD “reality,” defying the disease progression “rule.” The disease progression rule is
that ulcerative colitis is rectal based and progresses in a diffuse manner and Crohn disease spares
the rectum and progresses in a patchy manner. The reality is that ulcerative colitis can show
rectal sparing and (therefore) show patchy disease distribution and Crohn disease can be mucosal
restricted and diffusely involve the colorectum. This total proctocolectomy specimen originates
from a patient with ulcerative colitis who developed flat, multifocal dysplasia, requiring
definitive surgical management. Note the relative rectal-sparing (bracket). Rectal sparing in
ulcerative colitis is most common in the setting of treatment effect, particularly in patients using
rectal steroid enemas, and in the pediatric setting. Rectal sparing should not detract from the
established diagnosis of ulcerative colitis.

Figure 4.130 IBD “reality,” defying the disease progression “rule.” The cecal red
patch/periappendicial disease is another very important IBD exception seen in up to 86% of
ulcerative colitis patients. This total proctocolectomy specimen originates from a patient with
ulcerative colitis refractory to medical management. Note the diffuse disease process from the
rectum (asterisk) through the transverse colon, a bit of right colon mucosal clearing (bracket), and
a blush of erythema surrounding the appendiceal orifice (arc). The biopsy showed marked active
chronic colitis similar to that seen in the rectum (not shown). Those not aware of this important
IBD “reality” may misinterpret these findings as representing patchy disease and (erroneously)
raise concerns for Crohn disease. Misclassification as Crohn disease would result in surgical
mismanagement with a permanent ostomy performed for Crohn disease instead of the preferred
IPAA performed for ulcerative colitis. The cecal red patch/periappendiceal disease is entirely
consistent with this patient’s established history of ulcerative colitis.

The reality is treated or severe Crohn disease can exhibit rectal-based

or confluent disease, manifesting as diffuse disease progression.
Similarly, ulcerative colitis can defy the disease progression rule by
showing patchy disease progression, findings most commonly seen in the
setting of treatment effect or in children.27,28 Notorious diagnostic
pitfalls in ulcerative colitis include rectal sparing, which occurs in up to
64% of ulcerative colitis patients at some point, and can be enhanced by
medical therapy (Fig. 4.129).27,29 The cecal red patch, also known as
periappendicial disease, is another important, under-recognized
diagnostic pitfall in ulcerative colitis (Fig. 4.130). Briefly, this finding is
typically seen with left-sided disease, a spared transverse colon, and a
patch of active chronic disease around the appendiceal orifice. This
finding is seen in up to 86% of ulcerative colitis cases and, consequently,
is a notorious rule-breaker that can erroneously raise concerns for Crohn
disease to those unfamiliar with this IBD “reality.”30–33 Awareness of this
important exception is critical to avoid misclassifying a case of rectal
involved Crohn disease as ulcerative colitis, resulting in the
inappropriate surgical management (segmental resection with
permanent ostomy for Crohn disease versus total proctocolectomy with
IPAA in ulcerative colitis).

Upper-Tract Involvement “Rule”: Ulcerative colitis is colorectum restricted

and Crohn disease can involve the entire GIT.
Upper-Tract Involvement “Reality”: Ulcerative colitis can involve the upper-
tract and Crohn disease can be colorectum restricted.
The reality is that ulcerative colitis can extend beyond the colorectum
in a variety of settings. Up to 17% of ulcerative colitis cases display
“backwash ileitis.”34 This process most commonly occurs in the setting
of severe pancolitis whereby the inflammatory milieu refluxes into the
contiguous small bowel, resulting in local inflammatory and reactive
changes in the adjoining 1 to 3 cm of the terminal ileum. The
inflammatory changes in the small bowel are usually of the same
severity as, if not less than, that of the contiguous colon and there is no
association with IPAA pouch complications.34 A study of upper tract
biopsies in patients with ulcerative colitis found 10% were associated
with diffuse chronic duodenitis described as intense plasmacytosis,
patchy cryptitis, variable villous blunting, and reactive changes.35 Forty
per cent of these patients had pouch complications, raising the
possibility that diffuse chronic duodenitis may serve as a surrogate
marker for potential pouch complications. Crohn disease can also break
the upper-tract involvement rule: the reality is that up to 20% of Crohn
disease cases are restricted to the colorectum.36 Awareness of this upper
tract involvement rule/reality is critical for proper IBD subclassification
and surgical management.

Fissures and Transmural Lymphoid Aggregates and Inflammation” Rule”:

 These findings are unique to Crohn disease.
Fissures and Transmural Lymphoid Aggregates and Inflammation “Reality”:
These findings can be seen in either ulcerative colitis or Crohn disease.
The reality is that up to 27% of ulcerative colitis resection cases show
fissuring ulcers37 and these cases are more likely to have fulminant
disease with transmural lymphoid aggregates and inflammation. Beware;
fissures and transmural disease do not always signify Crohn disease, just
as mucosa-restricted disease does not always signify ulcerative colitis.
See also Depth of Involvement “Rule”/“Reality,” this chapter.

Pseudopolyps and Granulomata “Rule”: Pseudopolyps are unique to

ulcerative colitis, and granulomata are unique to Crohn disease.
Pseudopolyps and Granulomata “Reality”: Pseudopolyps and granulomata
can be seen in either ulcerative colitis or Crohn disease.
The reality is that neither pseudopolyps nor granulomata are
pathognomonic for ulcerative colitis or Crohn disease. Granulomata and
pseudopolyps can be seen in either setting (Figs. 4.131 and 4.132).
Although, ulcerative colitis granulomata are most commonly associated
with damaged crypts, Crohn disease granulomata are characteristically
poorly-formed and unassociated with damaged crypts (Figs. 4.133 and
4.134).

Figure 4.131 IBD “reality,” defying the pseudopolyps “rule.” The IBD rules teach that
pseudopolyps are unique to ulcerative colitis, but the reality is that they can be seen in either
ulcerative colitis or Crohn disease. This segmental resection specimen is from a patient with long-
 standing Crohn disease and shows numerous pseudopolyps (arcs).

Figure 4.132 IBD “reality,” defying the pseudopolyps “rule.” The corresponding histologic section
shows that the pseudopolyp is not a true polyp but, instead, consists of an island of semi-intact
bowel flanked by severe ulcerations (asterisks), resulting in a polypoid appearance.

Figure 4.133 IBD “reality,” defying the granuloma “rule.” Although the IBD rules state that
granulomata are unique to Crohn disease, the reality is they can be seen in either ulcerative
colitis or Crohn disease. This example illustrates a crypt rupture granuloma, commonly seen in
the setting of ulcerative colitis. Note that the macrophage collections are intimately associated
with the damaged crypt.
 Figure 4.134 Granuloma in Crohn disease. In contrast to the crypt rupture granulomata of
ulcerative colitis, the granulomata seen in Crohn disease are often easy to miss, as in this
example. An arc highlights this macrophage collection.

SAMPLE NOTE***: ESTABLISHED HISTORY OF LEFT-SIDED

ULCERATIVE COLITIS AND NEW, FOCAL
PERIAPPENDICEAL DISEASE
Rectum, biopsy:
• Marked active chronic proctitis.

Transverse, biopsy:
• Colonic mucosa with nondiagnostic findings.

Cecum, biopsy:
• Marked active chronic colitis.
Note: The history of ulcerative colitis is noted. The rectal and cecal
biopsies show marked active chronic colitis with cryptitis, crypt
abscesses, architectural distortion, and increased chronic inflammation.
The transverse colon is unremarkable. The “cecal red
patch”/periappendiceal involvement is seen in up to 86% of ulcerative
colitis cases and is compatible with the established history. Negative for
dysplasia, granulomata, and viral cytopathic effect.
References:
Mutinga ML, Odze RD, Wang HH, et al. The clinical significance of right-
sided colonic inflammation in patients with left-sided chronic
ulcerative colitis. Inflamm Bowel Dis. 2004;10(3):215–219.
D’Haens G, Geboes K, Peeters M, et al. Patchy cecal inflammation
associated with distal ulcerative colitis: A prospective endoscopic
study. Am J Gastroenterol. 1997;92(8):1275–1279.
Yang SK, Jung HY, Kang GH, et al. Appendiceal orifice inflammation as a
skip lesion in ulcerative colitis: An analysis in relation to medical
therapy and disease extent. Gastrointest Endosc. 1999;49(6):743–747.
Groisman GM, George J, Harpaz N. Ulcerative appendicitis in universal
and nonuniversal ulcerative colitis. Mod Pathol. 1994;7(3):322–325.

CURABLE INFLAMMATORY BOWEL DISEASE MIMICS

As stated earlier, the chronic colitis pattern is challenging because nearly
identical histology can be caused by diverse etiologies with differing
management strategies. All IBD mimics discussed subsequently are 100%
curable, assuming the etiology can be identified. Sorting through the
differential diagnostic possibilities and arriving at the correct etiology
requires thorough clinicopathologic correlation. This section will focus
on common and emerging IBD mimics with emphasis on the
clinicopathologic “red flags” to quickly uncover the causative etiology
and the corresponding cure. Owing to the inherent challenges of the
chronic colitis pattern, this subsection will illustrate the utility of the
three-step pattern-based approach to colitis. Although this approach
requires a bit of chart review, it is essential to ensure appropriate clinical
management and to avoid the diagnostic pitfall of IBD. Remember, not
all chronic colitis is caused by IBD.

CHECKLIST: Curable Inflammatory Bowel Disease Mimics

Diverticular Disease
Diversion-Associated Colitis
Syphilitic and Lymphogranuloma Venereum Proctocolitis
 Cord Colitis Syndrome
Ipilimumab Colitis
Resins

DIVERTICULAR DISEASE
In the United States, diverticular disease is extraordinarily common, seen
in at least 70% of Westernized patients over 80 years of age and
accounting for 23% of all patients who present with acute lower
gastrointestinal bleeding.38 The formation of colon diverticula is
predominantly blamed on the “Western diet” and its low-fiber content.
Low-fiber diets result in low-bulk feces with increased transit time,
increased muscle bulk due to expanded elastin and collagen
deposition,39–41 tenia shortening, luminal narrowing, and increased
intraluminal pressures. As the tenia shorten, the mucosa becomes
increasingly redundant and subject to prolapse, mechanical, and
ischemic damage. Rising intraluminal pressures culminate in herniation
of the delicate mucosa and submucosa through weaknesses in the bowel
wall, resulting in diverticular formation (Figs. 4.135–4.140).
Histologically, the active chronic colitis of diverticular disease is
indistinguishable from IBD and any other cause of chronic colitis, further
emphasizing the utility of the three-step pattern-based approach to
colitis (Figs. 4.141–4.144). While a variety of mechanistic theories exist,
some propose an immune component because some patients respond to
immunosuppression and a small portion eventually progress to IBD
(most commonly ulcerative colitis).42–44 It is unclear if the diverticular
disease-IBD connection is merely coincidental or if diverticular disease
can trigger IBD in genetically susceptible individuals. Important red flags
to the diagnosis of diverticular disease include a history constipation,
gross impression of diverticula, or tissue origin designated as sigmoid
colon in an adult or elderly patient. The nomenclature surrounding colon
diverticular disease can be a point of confusion. “Diverticular disease” is
the broadest term that encompasses “diverticulosis,” “diverticulitis,” and
“segmental colitis associated with diverticulosis” (SCAD syndrome) or
“diverticular-associated segmental colitis” (DAC).
• “Diverticulosis” refers to diverticula lacking inflammation.
 • Colon diverticula are most commonly false diverticula (acquired via
increased intraluminal pressures and involve only the mucosa and
submucosa).
• “Diverticulitis” refers to an epicenter of inflammatory damage within
the diverticula with extension into the adjacent bowel wall.
• Diverticulitis is caused by impacted fecaliths.

Figure 4.135 Diverticular disease, endoscopic image. Diverticular orifices are readily apparent
during endoscopic examination. They appear as variably sized mucosal outpouchings, as seen
here.

Figure 4.136 Diverticular disease, resection specimen. This sigmoidectomy resection shows
numerous mucosal outpouchings (arcs) or diverticula. The patient presented with the classic triad
of diverticulitis: fever, abdominal pain, and leukocytosis. Imaging studies revealed a perforation
(instrument), requiring emergent resection. Although uncomplicated cases can be treated with
 antibiotics, bowel rest, and pain control, complicated cases may require surgical resection.
Common complications include stricture, abscess, fistula, obstruction, clinically significant
bleeding, or perforation.

Figure 4.137 Diverticular disease, resection specimen. Longitudinal sections show the profiles of
numerous diverticula (asterisks). Diverticula are most likely to occur at the weakest points of the
bowel wall, between the taeniae and along the vasa recta penetration points. Based on this
intimate association of the diverticula and vessels, diverticular related inflammatory damage can
result in damage to the adjacent vessels and, consequently, gastrointestinal bleeding.

Figure 4.138 Diverticular disease, resection specimen. This example shows a diverticulum in
association with an (evacuated) hemorrhagic abscess cavity (instrument). This image emphasizes
that diverticular related inflammatory damage can erode into adjacent vessels, culminating in
clinically significant bleeding. Also, note the thick bowel wall (bracket) from repeated bouts of
transmural disease.
• SCAD syndrome or DAC refers to luminal inflammatory damage.
• In this pattern, the inflammatory changes are generally restricted to
the luminal segment of colon involved by diverticular disease.
• SCAD syndrome has no requirement for overt features of
“diverticulitis” or diverticula centered inflammatory damage; SCAD
is not equivalent to “diverticulitis.”
• Some theorize SCAD syndrome stems from progressed
diverticulitis.45

Figure 4.139 Chronic colitis pattern, diverticular disease. Diverticula are classified as true or false
depending on the involved wall layers. “True diverticula” are congenital and involve all layers of
the wall, including the mucosa, submucosa, muscularis propria, serosa, and adventitia. Meckel
diverticulum is the most common type of true diverticulum seen in the tubular GIT. See also
Metaplasia and Heterotopia, Small Bowel Chapter. “False diverticula” are acquired outpouchings
and involve only the mucosa and submucosa, as seen in this example. Colon diverticula are by
far the most common examples of false diverticula. Note that the diverticulum extends deeply
through the bowel wall.
 Figure 4.140 Chronic colitis pattern, diverticular disease. At low power, note the close
association between the diverticulum and the nearby vessel (arrow). When diverticular disease–
related inflammatory damage spills over into adjacent vessels, clinically significant bleeding can
occur.

Figure 4.141 Chronic colitis pattern, diverticular disease. At this power, features of chronicity are
easily seen: there is far too much lamina propria chronic inflammation for the sigmoid colon;
variable amounts of lamina propria are seen splaying the crypts (mild architectural distortion).
Cryptitis and Paneth cell metaplasia were also identified (not apparent at this power). It is
critical to avoid a top line diagnosis of similar histology as IBD based on this nonspecific
histology.
 Figure 4.142 Chronic colitis pattern, diverticular disease. On lower power of the previous case,
we see that the active chronic changes are confined within this tangential section of a
diverticulum. The uninvolved colonic mucosa was unremarkable. Thus, the active chronic colitis
is due to diverticular disease. Remember chronic colitis is not always IBD. Also note the close
proximity of the diverticulum to nearby vessels (arcs).

Figure 4.143 Chronic colitis pattern, diverticular disease. This intermediate power emphasizes a
similar lesson. This left colon section shows active chronic colitis with cryptitis, crypt abscesses, a
villiform mucosal surface, increased lamina propria chronic inflammation, and Paneth cell
metaplasia.
 Figure 4.144 Chronic colitis pattern, diverticular disease. Low power shows that the active
chronic changes are confined within a diverticulum. The background colonic mucosa was
unremarkable; therefore, the active chronic injury was ascribed to diverticular disease. Although
this diagnostic pitfall is easy to avoid on resection specimens when the diverticula are impossible
to ignore, biopsies of diverticular orifices are notoriously treacherous, particularly when
unlabelled, because the findings can be indistinguishable from those of IBD. Helpful red flags to
the diagnosis of diverticular disease include a history of diverticulosis or tissue origin as sigmoid
colon in an adult or elderly patient.

KEY FEATURES of Diverticular Disease:

• Diverticular disease is an extremely common IBD mimic.
• Cause: primarily the “Western” diet.
• Cure: sigmoidectomy and high-fiber diet.
• Red flags: history or gross impression of diverticular disease, tissue
designated as sigmoid colon, and adult or elderly patient.
• Diverticular disease is a clinicopathologic diagnosis requiring
both correlation with the appropriate clinical impression of
diverticula and the histologic impression of active chronic colitis.

PEARLS & PITFALLS

Patients with diverticulitis can have striking clinical overlap with
those with IBD. Extraintestinal manifestations such as arthropathies,
ankylosing spondylitis, pyoderma gangrenosum, and erythema
nodosum have been described in both settings.46

PEARLS & PITFALLS

The history or gross impression of diverticular disease and the
designation of the tissue site as “sigmoid colon” are very important
red flags. Remember, diverticular-associated colitis is far more
common than IBD and its management is completely distinct. Always
consider diverticular disease before IBD in biopsies of the left colon
showing active chronic colitis.

PEARLS & PITFALLS

“Diverticulum” refers to a single mucosal outpouching and
“diverticula” refers to more than one. When in doubt or pressed for
time, use “diverticular disease” because this term covers both the
singular and plural forms.

FAQ: What are the Hinchey criteria?

Answer: The Hinchey criteria were adapted by surgeons to describe
the clinical extent of diverticulitis. They predict risk of adverse
outcomes following a surgical procedure.47 Although pathologists do
not include the Hinchey stage into formal reports, it is helpful to be
aware of this terminology to appreciate the surgeon’s clinical
impressions.
Stage I: Pericolic abscess or phlegmon; risk of death less than 5%
Stage II: Pelvic abscess; risk of death less than 10%
Stage III: Generalized purulent peritonitis: risk of death 5%
Stage IV: Generalized fecal peritonitis; risk of death 57%
 FAQ: Where are colon diverticula most likely identified?
Answer: Diverticula are most likely to occur at the weakest point of
the bowel wall, between the coalesced, linear muscle bundles
(taeniae) and the vasa recti penetration points.

SAMPLE NOTE***: HISTORY OF DIVERTICULAR DISEASE

PROVIDED
Diverticular Orifice, Biopsy:
• Marked active chronic colitis.
Note: The history of diverticular disease is noted. The aforementioned
findings would support the clinicopathologic diagnosis of diverticular
disease-associated colitis.

DIVERSION-ASSOCIATED COLITIS
Diversion-associated colitis is an important, curable IBD mimic and it is
seen in patients with complicated surgical histories. It is an iatrogenic
consequence of surgical detour of the fecal stream away from a segment
of colorectum and deprivation of essential luminal elements in the
excluded bowel segment. Surgical diversion of the bowel is performed
when a diseased bowel segment is removed and the remaining bowel is
not sufficiently long to reestablish continuity, the anal sphincter is
removed, or the remaining bowel segment has excessive inflammation
that precludes immediate anastomosis. Red flags in the chart may
include a history of colonic resection for, as an example, diverticular
disease, neoplasms, necrotizing enterocolitis, intra-abdominal trauma,
IBD, and Hirschsprung disease (Fig. 4.145). At least 70% of diverted
patients report classic stigmata of diversion-associated colitis, such as
abdominal pain, tenesmus, rectal bleeding, and prominent rectal
discharge.48,49 Endoscopic and intraoperative findings include mild to
marked mucosal friability, erosions, ulcerations, aphthous lesions or
ulcerations, and a nodular mucosa secondary to prominent lymphoid
aggregates, restricted to the excluded bowel segment (Fig. 4.146).49
Corresponding histologic features include a mild to marked patchy or
diffuse active chronic colitis with florid lymphoid aggregates,
conspicuous germinal centers, and aphthoid lesions or ulcerations (Figs.
4.147–4.152). Diversion-associated colitis can occur as few as 3 months
following ostomy formation, and its features can persist through the
duration of the diversion (Figs. 4.153 and 4.154).50 Ostomy reversal is
curative with resolution of symptoms seen as early as 2 months
following reestablishment of continuity.51

Figure 4.145 Gunshot wound to the abdomen, radiograph. This radiograph is of a trauma patient
who presented with a gunshot wound to the abdomen (an arrow highlights the main bullet
fragment). His colon was perforated and required emergent resection. The patient was too
unstable for immediate anastomosis and, consequently, the proximal colon was diverted through
the anterior bowel wall to form a temporary colostomy site and the rectum was left as a blind
pouch (Hartmann pouch). Any history of bowel resection is a red flag for consideration of
diversion-associated colitis. See also Figure 4.116.
 Figure 4.146 Diversion-associated colitis, resection specimen. Once the patient recovered 3
months later, he returned to the operating room to reestablish GIT continuity through colostomy
reversal and anastomosis of the diverted colon to the rectum. The surgeons noted the rectal
mucosa appeared nodular (arrows) and submitted a segment for histologic evaluation.

Figure 4.147 Chronic colitis pattern, diversion colitis. Corresponding whole mount sections of the
rectum show florid lymphoid aggregates, conspicuous germinal centers, and aphthoid lesions
(not seen at this power).
 Figure 4.148 Chronic colitis pattern, diversion colitis. Higher power of previous case.

KEY FEATURES of Diversion-Associated Colitis:

• Diversion-associated colitis is an important IBD mimic.
• Cause: surgical detour of the fecal stream leads to a short chain fatty
acid deficiency in the excluded bowel segment.
• Cure: reestablishment of bowel continuity.
• Red flags: prior bowel resection.
• Diversion-associated colitis is a clinicopathologic diagnosis
requiring both correlation with the appropriate clinical history of
diversion and the histologic impression of active chronic colitis
with florid lymphoid aggregates and prominent germinal centers
and aphthoid lesions/ulcerations.

Figure 4.149 Chronic colitis pattern, diversion colitis. This image shows marked active chronic
colitis with cryptitis, crypt abscesses, increased chronic inflammation in the lamina propria, and
architectural distortion. It would be crucial to avoid the diagnostic pitfall of IBD based on these
nonspecific histologic findings. This example of active chronic colitis was due to diversion-
associated colitis based on the detailed clinical history. The patient had an uneventful recovery
following colostomy reversal. Subsequent rectal biopsies 1 year later were unremarkable.
 Figure 4.150 Chronic colitis pattern, diversion colitis. This case of diversion-associated colitis
features crypt rupture granulomata in a background of active chronic colitis. These findings
supported the clinicopathologic diagnosis of diversion-associated colitis based on the history of
diversion and the histologic findings of active chronic colitis.

Figure 4.151 Chronic colitis pattern, diversion colitis. This case of diversion-associated colitis
shows less striking features. While there are no prominent lymphoid aggregates in this
photomicrograph, the patient was 4 months status post diversion related to a large obstructing
sigmoid tumor. This rectal biopsy shows the nonspecific pattern of moderate active chronic
colitis: cryptitis, crypt abscess, a slightly villonodular surface, increased lamina propria chronic
inflammation, and Paneth cell metaplasia (not shown).
 Figure 4.152 Chronic colitis pattern, diversion colitis. Higher power shows cryptitis and crypt
abscess with macrophage collections aggregating around the damaged crypts (arc). Diversion-
associated colitis is due to a deficiency of short-chain fatty acids in the excluded bowel segment.

Figure 4.153 Chronic colitis pattern, diversion colitis. This resection specimen originated from a
patient with a 20-year history of diversion. No residual colonic epithelium is present in this field.
Note the transmural lymphoid aggregates and disorganized mesenchymal tissue.
 Figure 4.154 Chronic colitis pattern, diversion colitis. Higher power of previous image.

FAQ: How does an absence of the fecal stream result in diversion-

associated colitis?
Answer: Short-chain fatty acids are the primary energy resource of
colonic enterocytes and originate from bacterial fermentation.
Diversion deprives the excluded bowel segment from the fecal stream,
bacteria, bacteria fermentation products, and important energy
resources, resulting in this peculiar pattern of chronic colitis. In
support of this theory, enemas rich in short-chain fatty acids
(particularly butyrate and glutamine) can ameliorate or reverse
diversion–associated colitis.52–57

SAMPLE NOTE***: HISTORY OF DIVERSION PROVIDED

Nodularity, Diverted Bowel Segment, Biopsy:
• Colonic mucosa with mild chronic active colitis, prominent lymphoid
aggregates with conspicuous germinal centers, and aphthoid
lesions/ulcerations.
Note: The aforementioned findings would support the clinicopathologic
diagnosis of diversion-associated colitis.
SYPHILITIC AND LYMPHOGRANULOMA VENEREUM
PROCTOCOLITIS
Syphilitic and lymphogranuloma venereum (LGV) proctocolitis are both
important emerging IBD mimics. A recent report details clinical red flags
such as HIV-positive men who have sex with men (MSM) who usually
present with rectal bleeding, anal pain, and tenesmus.58 Ulcerations are
the most common endoscopic abnormality, but nodules, polyps, and
mass lesions up to 4 cm have also been reported (Fig. 4.155).
Overlapping histologic features with IBD included active chronic colitis,
skip lesions, aphthoid lesions, granulomata, foreign body giant cells,
fibrosis, Paneth cell metaplasia, and lymphoid aggregates. Based on the
presentation of mass lesions and the striking histologic overlap with IBD,
malignancy and IBD are common diagnostic pitfalls. Our experience
shows features favoring infection include the presence of an intense
infiltrate of submucosal plasma cells and a lack of the following features:
architectural distortion, acute crypt centric damage, and eosinophilia
(Figs. 4.156–4.168). Before diagnosing IBD, always consider the
possibility of a curable infection, especially in the HIV setting. To
underscore this crucial point, the previously referenced study showed all
cases were clinically confirmed to have syphilitic and or LGV infections
and all patients completely responded to antibiotics, even those with
mass lesions and those scheduled for “IBD” segmental resections.58

Figure 4.155 Syphilitic proctocolitis, endoscopic image. This endoscopic image shows bleeding
 rectal ulcerations, the most common presentation of syphilitic and LGV proctocolitis. Other
common endoscopic findings include nodules, polyps, and mass lesions. Red flags to this
diagnosis include a history of HIV+ MSM behaviors, but such a history is rarely provided,
underscoring the utility of the three-step pattern-based approach to chronic colitis.

Figure 4.156 Chronic colitis pattern, syphilitic proctocolitis. The active chronic colitis of syphilis
(and or LGV) can be strikingly similar to that seen with IBD: overlapping histologic features
include skip lesions, aphthoid lesions, granulomata, foreign body giant cells, fibrosis, Paneth cell
metaplasia, and lymphoid aggregates. Note the intensity and vague nodularity of the deep
mononuclear inflammation of this rectal biopsy. The architectural distortion and rare cryptitis is
subtle.

Figure 4.157 Chronic colitis pattern, syphilitic proctocolitis. Higher power shows copious plasma
cells in the deeper aspects of this biopsy. Eosinophils are not prominent. Intense plasma cells and
a lack of eosinophilia are findings more suggestive of infection and less commonly seen in IBD.
 This patient was clinically diagnosed with syphilis and LGV studies were negative. The rectal
bleeding and ulceration were cured by antibiotics. A CMV immunostain was negative.

Figure 4.158 Chronic colitis pattern, LGV proctocolitis. The active chronic colitis of LGV is
indistinguishable from syphilis. This endoscopic mucosal resection of a rectal mass shows
ulceration (left) with intense, deep mononuclear inflammation. The adjoining rectal mucosa is
relatively well-preserved (right).

Figure 4.159 Chronic colitis pattern, LGV proctocolitis. Higher power shows copious plasma cells
deep in the submucosa. This patient was clinically diagnosed with LGV based on positive nucleic
acid amplification studies from a rectal swab, fever, and inguinal lymphadenopathy. The rectal
pain and mass lesion were cured with antibiotics. Remember, the morphology of syphilitic and
LGV proctocolitis is identical and patients can be co-infected. It is, therefore, imperative that
clinicians consider the possibility of both infections when this morphology is seen in patients
with a history of HIV+ MSM behaviors. A CMV immunostain was negative.
Figure 4.160 Chronic colitis pattern, syphilitic and LGV proctocolitis. This rectal biopsy was from
a young man clinically thought to have rectal cancer based on his overall ill-appearance and the
presence of a rectal mass. Biopsy of the rectal mass shows intense monocular inflammation and
granulomata. No intact epithelium is seen. AFB and GMS special stains for microorganisms were
negative. A CMV immunostain was negative.

Figure 4.161 Chronic colitis pattern, syphilitic and LGV proctocolitis. Higher power shows
copious plasma cells deep in the submucosa. After suggesting the possibility of syphilis and or
LGV, the patient was asked detailed questions about his sexual behavior. He revealed high-risk
behaviors and subsequently tested positive for syphilis, LGV, and HIV. His clinical symptoms and
mass lesions resolved with antibiotics and HAART therapy. Although the morphology and GIT
findings can be cured by appropriate recognition of this IBD mimic, many of these patients have
unrecognized HIV.
Figure 4.162 Chronic colitis pattern, syphilitic proctitis. Similar findings can be seen in syphilitic
and or LGV involving anal mucosa. Note the intense mononuclear inflammation with a bandlike
distribution at the interface between the squamous epithelium and lamina propria. This patient
was clinically confirmed to have syphilis (LGV studies were negative) and the rectal mass was
cured with antibiotics. A CMV immunostain was negative.

KEY FEATURES of Syphilitic or LGV Proctocolitis Pattern:

• Both are curable IBD mimics.
• Cause: Syphilitic and or LGV infections.
• Cure: Antibiotics.
• Red flags: HIV+ MSM.
• Syphilitic and LGV proctocolitis are a clinicopathologic diagnosis
requiring both correlation with the appropriate clinical history
and histologic findings.
 Figure 4.163 Chronic colitis pattern, syphilitic proctitis. Higher power of the previous image
shows copious plasma cells. This patient was ultimately determined to have HIV.

Figure 4.164 Chronic colitis pattern, syphilitic proctitis. This patient was scheduled for a
proctectomy for presumed Crohn disease based on a history of bloody diarrhea and weight loss.
The biopsy shows an intense bandlike pattern of chronic inflammation.

Figure 4.165 Chronic colitis pattern, syphilitic proctitis. An alternative field shows an ulcer on
the left. The intense bandlike pattern of chronic inflammation is easy to appreciate at low power.

Figure 4.166 Chronic colitis pattern, syphilitic proctitis (Treponemal immunostain). The red
chromogen distinguishes the treponemal organisms from the background melanocytes (arc).
Unfortunately, this immunohistochemical stain is far too insensitive to be clinically useful.
Correlation with pertinent clinical studies remains the most effective way to establish the
diagnosis of syphilitic and or LGV proctocolitis.

Figure 4.167 Chronic colitis pattern, syphilitic proctitis. Under highest power, syphilitic and LGV
proctocolitis show pools of plasma cells, particularly in the deeper aspects of the biopsy.
Figure 4.168 Chronic colitis pattern, IBD. In contrast to syphilitic and LGV proctocolitis, IBD
more commonly shows a predominance of eosinophils, lymphocytes, and macrophages in the
deeper aspects of the biopsy, as seen here.

FAQ: Are there any ancillary studies to confirm syphilitic and

LGV infections?
Answer: With preapproval, the Centers for Disease Control and
Prevention provides free syphilis and LGV immunostains and PCR-
based testing on paraffin embedded tissues. (For more information, see
the Specimen Submission Guidelines of the CDC’s Infectious Diseases
Pathology Branch.) Silver stains and Treponemal immunostains are far
too insensitive to confirm or exclude syphilitic infections, and there
are no routine commercially available LGV studies available for the
pathologist.58 Until sensitive diagnostic tools are routinely available to
the pathologist, clinical serologies provide the best means to establish
this diagnosis (detailed earlier). A CMV immunostain is recommended
in all cases due to overlapping morphology.

FAQ: Would you consider syphilitic and LGV proctocolitis if the

patient were presumed HIV negative? Or female?
Answer: Yes.
Presumed HIV negativity is sometimes equivalent to unrecognized
HIV. Indeed, several of the study patients in the above referenced
series were presumed HIV negative.58 After the diagnosis of syphilitic
 and LGV proctocolitis was suggested, a thorough sexual behavior
history was elicited, high-risk sexual behaviors were revealed, and an
HIV test was performed and determined to be positive. Recognition of
this pattern of injury is critical to ensure proper clinical management,
determine HIV status, resolve symptoms, and to prevent onward
transmission of HIV, syphilis, and LGV. Although a suspicion for
syphilitic and LGV proctocolitis is strengthened by a history of HIV
positivity in man with anal receptive sexual contact, do not let a lack
of stated history dissuade you.

SAMPLE NOTE***: SYPHILITIC OR LGV PROCTOCOLITIS

(HIV+ MSM HISTORY PROVIDED)
Rectum, Biopsy:
• Rectal mucosa with marked active chronic proctitis with intense
lymphohistiocytic infiltrate and copious submucosal plasma cells.
Note: The history of HIV and rectal ulceration is noted. The
corresponding histologic sections show an intense lymphohistiocytic
infiltrate and copious submucosa plasma cells. No significant
architectural distortion, acute crypt centric damage, and eosinophilia are
seen. These findings were recently reported in association with syphilitic
and or LGV infections. Clinical serologies provide the best means to
establish this diagnosis (syphilis: serum RPR, RPR titer, and a
treponemal specific serology such as fluorescent treponemal antibody;
Lymphogranuloma venereum: rectal swab collected in the absence of
lubricant for Chlamydia trachomatis nucleic acid probe test or culture and
LGV PCR). A CMV immunostain is nonreactive.

Reference:
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.

CORD COLITIS SYNDROME

Cord Colitis Syndrome (CCS) is an emerging IBD mimic. Red flags
include culture-negative, antibiotic-responsive watery diarrhea in
patients with a history of umbilical cord transplantation. CCS is a
diagnosis of exclusion, and should be considered after GVHD, viral or
bacterial infection, and medication injury have been excluded. In the
largest series, its incidence was 10.6% and the median time of diarrhea
onset was 131 days from transplantation.59 Most patients were febrile,
required hospitalization, and all responded to a 10 to 14 days of
antibiotics, even those with recurrent diarrhea. Endoscopic and
histologic features can be indistinguishable from IBD. Endoscopic images
show edema, erythema, or ulcerations. Histologically, active chronic
colitis is seen, which can be accompanied by granulomata, architectural
distortion, and Paneth cell and pyloric metaplasia (Fig. 4.169). Apoptotic
bodies are not prominent, a feature which helps distinguish CCS from
GVHD. See also GVHD, Lymphocytic Pattern, Esophagus Chapter. More
recently, Bradyrhizobium enterica was identified in biopsies from patients
with CCS and organism levels declined with antibiotic therapy.60 CCS
was not identified in 1,261 patients who underwent non–cord-blood
transplantations, suggesting that the cord colitis syndrome represents a
distinct clinicopathologic entity.59

KEY FEATURES of the Cord Colitis Syndrome:

• CCS represents another curable IBD mimic.
• Cause: Bradyrhizobium enterica.
• Cure: Antibiotics.
• Red flags: Umbilical cord transplantation.
• The cord colitis syndrome is a clinicopathologic diagnosis
requiring both correlation with the appropriate clinical history
(history of umbilical cord transplantation) and histologic findings
(active chronic colitis).

PEARLS & PITFALLS

Although CCS findings are most commonly reported in the colon,
beware additional potential sites of involvement include the stomach,
 duodenum, and liver.61

Figure 4.169 Chronic colitis pattern, cord colitis syndrome. This image shows active chronic
colitis with a poorly formed granulomata (center, base). This histologic pattern is entirely
etiologically nonspecific and can be indistinguishable from Crohn disease, or any other cause of
active chronic colitis, emphasizing the importance of clinicopathologic correlation. Source:
Photomicrograph courtesy of Dr. Andrew M. Bellizzi, University of Iowa Hospital & Clinics, Iowa
City, Iowa.

SAMPLE NOTE***: HISTORY OF UMBILICAL CORD

TRANSPLANTATION AND DIARRHEA
Colon (biopsy):
• Mild active chronic colitis with scattered granulomata and Paneth cell
metaplasia.
Note: The history of umbilical cord transplantation, antibiotic responsive
watery diarrhea, and negative infectious work-up is noted. The biopsy
shows mild active chronic colitis with scattered granulomata and Paneth
cell metaplasia. Such findings can be seen in the setting of CCS and these
patients often respond to a 10 to 14 day course of metronidazole ±
fluoroquinolone. Apoptotic bodies are not prominent. There are no
histologic features of GVHD. A CMV immunostain and AFB/GMS special
stains are negative.
References:
Gupta NK, Masia R. Cord colitis syndrome: A cause of granulomatous
inflammation in the upper and lower gastrointestinal tract. Am J Surg
Pathol. 2013;37(7):1109–1113.
Herrera AF, Soriano G, Bellizzi AM, et al. Cord colitis syndrome in cord-
bloodstem-cell transplantation. N Engl J Med. 2011;365(9):815–824.

IPILIMUMAB COLITIS
Ipilimumab is one of an emerging field of chemotherapeutic agents
whose mechanism is based on enhancing immune-mediated destruction
of tumors.62 Specifically, ipilimumab targets the cytotoxic T-lymphocyte-
associated antigen 4 (CTLA4) found on cytotoxic T-lymphocytes and
regulatory T cells.63 CTLA4 normally functions to suppress T-cell
activation. Consequently, ipilimumab binding of CTLA4 removes
CTLA4’s suppressive effects and, instead, promotes cytoxic T-cell
activation and cytotoxic T-cell mediated destruction of the neoplastic
cells. As an unintended consequence of stimulating the immune system,
up to 60% of patients report immune related adverse effects within 11 to
14 days from the first dose.62–64 The most common site of involvement is
the GIT (stomach, small bowel, and colon), followed by the skin.65 The
diarrhea is described as watery and culture-negative. Common
endoscopic findings range from normal to marked ulcerations (Fig.
4.170). Histologic sections show active chronic injury with increased
apoptotic bodies, granulomata, and eosinophilia (Figs. 4.171–4.176).
Small bowel biopsies can also show villous blunting and prominent
intraepithelial lymphocytosis, mimicking celiac disease. This IBD mimic
is cured with drug cessation. Death and perforation attributed to
immune-related adverse events are rare (1%) but are associated with
delayed recognition, underscoring the importance of recognizing
ipilimumab-associated injury.62,65 We have never encountered a case
submitted with “ipilimumab” listed on the requisition. The most frequent
red flag to this diagnosis is a history of melanoma.
Figure 4.170 Ipilimumab colitis, endoscopic image. The red flag to ipilimumab colitis is a history
of melanoma. This novel drug works by stimulating the immune mediated destruction of the
neoplasm, and GIT complaints are common. This endoscopic image shows a prominent rectal
ulceration.

Figure 4.171 Chronic colitis pattern, ipilimumab colitis. Corresponding histologic sections show
moderate active chronic colitis with cryptitis, crypt abscesses, increased chronic inflammation in
the lamina propria, crypt dropout, crypt shortfall, and basal lymphoplasmacytosis. In the absence
of a clinical history, ipilimumab colitis can be endoscopically and histologically indistinguishable
from IBD, or any other cause of active chronic colitis.
 Figure 4.172 Chronic colitis pattern, ipilimumab colitis. An alternative field shows similar
features. Although this case was submitted in consultation to us as Crohn disease, this curable
IBD mimic emphasizes that not all examples of active chronic colitis are due to IBD.

Figure 4.173 Chronic colitis pattern, ipilimumab colitis. Higher power of previous case. We noted
“rule-out melanoma” on the requisition and confirmed ipilimumab therapy after examining the
medication list.
Figure 4.174 Chronic colitis pattern, ipilimumab colitis. Ulcer debris, crypt abscesses, cryptitis,
and increased chronic inflammation are shown.

Figure 4.175 Chronic colitis pattern, ipilimumab colitis. Higher power shows basal
lymphoplasmacytosis and crypt shortfall (bracket): the basal layer of lymphocytes and plasma
cells prevents the crypts from directly contacting the muscularis mucosae (asterisks).
 Figure 4.176 Chronic colitis pattern, ipilimumab colitis. This case shows a mildly villonodular
surface, increased lamina propria chronic inflammation, and scattered Paneth cell metaplasia.
The patient’s symptoms and rectal pathology reversed with drug cessation.

KEY FEATURES of Ipilimumab-Associated Colitis:

• Ipilimumab colitis is an emerging IBD mimic.
• Cause: ipilimumab targets and inhibits CTLA4’s suppressive effects,
resulting in enhanced cytotoxic T mediated destruction of the
neoplasm.
• Cure: Drug cessation and or concomitant high-dose
immunosuppressive therapy.
• Red flag: history of melanoma.
• Mortality is low but linked to delayed recognition.
• Ipilimumab-associated colitis is a clinicopathologic diagnosis
requiring both correlation with the appropriate clinical history
(ipilimumab administration) and histologic findings (active
chronic colitis).

PEARLS & PITFALLS

Ipilimumab is undoubtedly a promising new chemotherapeutic agent
for melanoma. It is also under active study for its potential role in
treating other malignancies, such as prostate cancer, lung cancer,
 metastatic renal cancer, lymphoma, and pancreatic cancer. As a result,
consider a chart review for ipilimumab therapy when a history of the
above malignancies is encountered.

SAMPLE NOTE***: CLINICAL HISTORY OF A METASTATIC

MELANOMA AND IPILIMUMAB THERAPY
Rectum, Biopsy:
• Marked active chronic proctitis.
Note: The history of metastatic melanoma and ipilimumab therapy is
noted. Active chronic proctitis is a known side-effect of ipilimumab
therapy. In such cases, symptomatology and histology normalize with
ipilimumab cessation or high-dose immunosuppression. Correlation with
microbiologic and infectious studies recommended. Negative for
malignancy. A CMV immunostain is negative.

RESINS
Any chronic medication injury can result in histologically identical
findings to those seen in IBD. Pay particular attention for medication
resins, identification of which can provide etiologic specific clues to the
background injury pattern. Medication resins can be easy to overlook in
the histologically “busy” morphology of active chronic colitis but their
recognition can save a patient’s life, as in the case of Kayexalate
mediated injury (Fig. 4.177).
Figure 4.177 Chronic colitis pattern, Kayexalate. Kayexalate resin displays narrow, regular “fish-
scales” and appears purple on H&E. Kayexalate is notorious for causing ulcerations and ischemia,
features historically attributed to the hyperosmotic effects of its sorbitol diluent. GIT injury can
be fatal and, therefore, it is important to alert the clinicians to this finding so that the medication
list can be safely adjusted.
LYMPHOCYTIC PATTERN

Figure 4.178 Lymphocytic pattern, lymphocytic colitis. Numerous intraepithelial lymphocytes

(arrowheads) are identifiable at high magnification.

The lymphocytic colitis pattern is characterized as the presence of

normal crypt architecture with increased surface intraepithelial
lymphocytes (IELs), which is further defined as >15 to 20 IELs per 100
surface epithelial cells (normal range is <5 to 10 IELs/100 epithelial
cells) (Fig. 4.178). As with all numerically defined inflammatory
disorders of the GI tract, the threshold for disease is widely ranging (in
this case, 10 to 60 IELs, with a median of 20 to 39).66–69 The main
differential diagnosis includes microscopic colitis, an entity that
encompasses both lymphocytic colitis and collagenous colitis. Injury
from medications and viral infection are also considerations in the
differential diagnosis.

CHECKLIST: Etiologic Considerations for the Lymphocytic

Pattern
Lymphocytic Colitis
Collagenous Colitis
Medications
Viral Infection
LYMPHOCYTIC COLITIS
KEY FEATURES of Lymphocytic Colitis:
• This is a form of microscopic colitis having the following triad:
1. Chronic nonbloody diarrhea
2. Normal endoscopy findings
3. Colonic epithelial lymphocytosis without a thickened
subepithelial collagen table.
• Increased IELs is generally defined as: >15 to 20 IELs per 100 surface
epithelial cells.70
• This is a disease of middle-aged to elderly women (mean age 59 to
67 years), but can occur at any age70 and in men.
• Patients present with nonbloody watery diarrhea.
• Although numerous studies have described lymphocytic colitis causing
a chronic diarrhea, more recent studies suggest that patients may have
a single attack in 60% of cases.66
• Most cases are idiopathic, but infectious triggers have been
implicated, including C. jejuni and E. coli.66,67
• Ten percent of patients have a positive family history of
inflammatory intestinal disease, including ulcerative colitis, Crohn
disease, collagenous colitis, and celiac disease.66,67
• Treatment includes removal of any known offending agents (see
medications below) and medical therapy (loperamide, bismuth
subsalicylate, mesalamine, budesonide).
• In addition to IELs, there is increased lamina propria cellularity,
mostly lymphocytes and plasma cells, and also eosinophils (Figs.
4.179–4.183)
• Changes are greater in the right colon than the left.
 Figure 4.179 Lymphocytic pattern, lymphocytic colitis. At scanning magnification, the biopsy
appears “busy.” There is increased mononuclear density of the lamina propria, but preserved
crypt architecture.

Figure 4.180 Lymphocytic pattern, lymphocytic colitis. Higher magnification of the previous case
shows increased cellularity of the intraepithelial lymphocytic component in addition to the
lamina propria lymphocytosis.
 Figure 4.181 Lymphocytic pattern, lymphocytic colitis. The crypts remain evenly spaced and
oriented perpendicular to the colonic surface. The lamina propria shows an increased density of
mononuclear cells, while the crypt and surface epithelium contains increased intraepithelial
lymphocytes.

Figure 4.182 Lymphocytic pattern, lymphocytic colitis. Higher magnification of the previous case
shows the presence of intraepithelial lymphocytes along the colonic surface epithelium. Also,
note the attenuated appearance of the epithelial cells.
 Figure 4.183 Lymphocytic pattern, lymphocytic colitis. Many observers specifically cite the
presence of increased intraepithelial lymphocytes (IELs) along the surface epithelium. Although
IELs are also present in the crypt epithelium (arrows), contrast the density of IELs that are present
along the surface epithelium (arrowheads).

PEARLS & PITFALLS

When available, check the upper GI biopsies for IELs.
The presence of coexisting upper and lower GIT intraepithelial
lymphocytosis (such as the finding of sprue-like changes in the small
bowel AND lymphocytic colitis) could indicate a systemic process. Few
data are available regarding this entity, although associations with
autoimmune enteropathy and medication injury (i.e.,
olmesartan/Benicar) exist. This is best reported as “lymphocytic
enterocolitis” and discussed in a note or directly with the clinician.71

FAQ: Do IELs overlying a lymphoid aggregate indicate

lymphocytic colitis?
Answer: No.
Recall: In the epithelium overlying lymphoid aggregates, IELs are
frequent and they represent messengers of the immunologic crosstalk
between the luminal antigens and the lymphoid follicles. Discount
areas of increased IELs that directly overlie lymphoid aggregates (Figs.
4.184 and 4.185).
 Figure 4.184 Lymphocytic pattern mimic, intraepithelial lymphocytes overlying a lymphoid
aggregate. Under normal conditions, the epithelium overlying a lymphoid aggregate contains
numerous IELs (arrowheads). This area should be discounted when evaluating for IELs.

Figure 4.185 Lymphocytic pattern mimic, intraepithelial lymphocytes overlying a lymphoid

aggregate. The epithelium overlying a lymphoid aggregate always shows IELs (arrowheads) as
part of the normal immunologic crosstalk between the lymphoid organ and the luminal antigens.

COLLAGENOUS COLITIS
KEY FEATURES of Collagenous Colitis:
• This is a form of microscopic colitis having preserved crypt
architecture, abnormal subepithelial collagen deposition, increased
 IELs, and a normal colonoscopic appearance.72,73
• This is a disease of middle-aged to elderly women (mean age 57 to
66 years), but can occur at any age. The female preponderance is
striking compared to that for lymphocytic colitis.
• Patients present with nonbloody watery diarrhea, which may be
nocturnal.
• Most cases are idiopathic, but infection has been implicated,
including C. difficile and Yersinia.
• Proposed mechanisms of disease include abnormal immunologic
response to environmental exposures and abnormal collagen
metabolism.74
• Treatment includes removal of any known offending agents (see
medications below) and medical therapy is generally effective
(loperamide, bismuth subsalicylate, mesalamine, budesonide).75
• Histologic features include increased intraepithelial lymphocytosis with
an abnormal subepithelial collagen table (Figs. 4.186–4.196). This
is defined as thickening and irregularity of the basement membrane
profile; from the lower border of the collagen table, strands of
collagen extend into the lamina propria entrapping fibroblasts and
small capillaries.76,77

FAQ: Do treatment protocols for lymphocytic and collagenous

colitis differ?
Answer: No.
Lymphocytic and collagenous colitis respond to similar treatment
protocols,78 and most centers treat both entities under a “microscopic
colitis” umbrella protocol. Therefore, when struggling to determine
whether a case is better classified as lymphocytic colitis versus
collagenous colitis, rest reassured that the patient receives appropriate
management regardless of this distinction. We handle equivocal cases
by first reporting the presence of lymphocytic colitis, and then suggest
that an early or evolving collagenous colitis cannot be entirely
excluded based on the histologic findings.
Figure 4.186 Lymphocytic pattern, collagenous colitis. Scanning magnification shows colonic
mucosa with normal crypt architecture, but an abnormally thick basement membrane (arrow)
and a subepithelial split (arrowhead).

Figure 4.187 Lymphocytic pattern, collagenous colitis (trichrome stain). A trichrome stain
highlights the abnormal collagen table in blue (arrowheads). Not only is the collagen table
thickened, but it displays an irregular contour and contains entrapped small vessels (arrow).
Figure 4.188 Normal subepithelial collagen table (trichrome stain). By comparison, the collagen
table (arrowhead) of the normal colon is thin. More importantly, however, the contour of the
collagen table is smooth and not ragged.

Figure 4.189 Normal subepithelial collagen table. On routine H&E, the normal collagen table
(arrowheads) may be prominent, but it retains a smooth, linear profile and does not contain
entrapped cells or vessels.
 Figure 4.190 Lymphocytic pattern, collagenous colitis. Surface epithelium detaching from the
irregular collagen table is a common feature of collagenous colitis. Although intraepithelial
lymphocytes are standard, collagenous colitis may also show occasional neutrophils (arrowheads),
a finding that does not necessarily signify infection.

Figure 4.191 Lymphocytic pattern, collagenous colitis (trichrome stain). A trichrome stain
highlights the abnormally irregular subepithelial collagen table blue. Note the entrapped small
vessels (arrowheads) and other nuclei.
 Figure 4.192 Lymphocytic pattern, collagenous colitis. On routine H&E stain, this subepithelial
collagen is extending downward into the lamina propria. This trickling down between the
inflammatory cells (arrowhead) has been likened to “candle wax drippings” by some observers.

Figure 4.193 Lymphocytic pattern, collagenous colitis (trichrome stain). The thickened collagen
table (arrowheads) is evident by trichrome stain, which also highlights the irregular lower border
of the collagen layer. Note how the collagen entraps cells and also trickles downward between
the inflammatory cells of the lamina propria.
Figure 4.194 Lymphocytic pattern, collagenous colitis. By definition, collagenous colitis contains
numerous intraepithelial lymphocytes (arrowheads).

Figure 4.195 Lymphocytic pattern, collagenous colitis. At scanning magnification, this example
shows a prominent subepithelial collagen table (arrowheads).
Figure 4.196 Lymphocytic pattern, collagenous colitis. Higher magnification of the previous case
shows an irregular lower border of the collagen table (arrowheads), and collagen extending down
into the lamina propria like “candle wax drippings” (arrow).

Figure 4.197 Lymphocytic pattern, collagenous colitis. Intraepithelial lymphocytes (arrowheads)

are a normal component of collagenous colitis.

FAQ: Does collagenous colitis exist in the absence of IELs?

Answer: No.
The presence of an abnormal collagen table is sometimes found in
isolation, and one might wonder if this represents collagenous colitis.
As a technical definition, collagenous colitis is both “collagenous” and
a “colitis,” meaning that an inflammatory component must be present
(Fig. 4.197). Cases that show abnormal collagen in the absence of a
colitis are best handled descriptively, as other differential diagnoses
(healed erosion, solitary rectal ulcer syndrome, medication reaction,
etc.) are possible.

MEDICATION
An expanding list of medications is implicated in lymphocytic pattern, as
noted below. By far, NSAIDs are the most common culprit and may
result in FAC in addition to increased IELs. Ischemic-like changes and
lamina propria hyalinization may also be seen, particularly in areas
containing erosions. While the pathologist may suggest the possibility of
medication injury, this is confirmed only when the offending agent is
discontinued and this action results in resolution of clinical symptoms.
Medications Implicated in the Lymphocytic Pattern
• NSAIDs
• Ticlopidine
• Flutamine
• Carbamazepine
• Cimetidine
• Ranitidine
• Iansoprazole
• Gold Salts
• Paroxetine
• Sertraline
• Olmesartan

EOSINOPHILIA PATTERN

Figure 4.198 Intraepithelial eosinophils. Scattered eosinophils may be present within the normal
colonic epithelium, but they are typically solitary. Aggregates of intraepithelial eosinophils
(arrowheads), such as seen here, are abnormal.

In the colon, eosinophils and other constituent inflammatory cells follow

a decreasing gradient along the length of the colon, from proximal to
distal (Fig. 4.198).79,80 As a result of this gradient, the interpretation of
eosinophilic density must be performed in the context of anatomic site.
Normal eosinophil counts range from 10 to 70 eosinophils per high-
power field (HPF) in the cecum to 1 to 30 in the rectum, but no
universally accepted normal range has been established.81–83 Moreover,
geographic and seasonal differences, and participation of eosinophils in
various nonspecific inflammatory responses further contribute to
eosinophil count variability.84–86 Although mild increases in lamina
propria eosinophil counts are difficult to delineate, definitive abnormal
features include increased intraepithelial eosinophils with eosinophil
crypt abscesses, extensive degranulation, epithelial regenerative changes,
and minimal active and chronic inflammation.87 The differential
diagnosis is broad, and includes idiopathic eosinophilic colitis,
inflammatory bowel disease, allergy, medication reaction, parasitic
infections, collagen vascular disorders such as scleroderma, and
vasculitides such as Churg–Strauss syndrome.

CHECKLIST: Etiologic Considerations for the Colonic

Eosinophilia Pattern
Idiopathic Eosinophilic Colitis
Inflammatory Bowel Disease
Allergy
Medications
Infection
Parasite
Collagen Vascular Disorder and Vasculitis

IDIOPATHIC EOSINOPHILIC COLITIS

Primary eosinophilic gastrointestinal disorders represent a spectrum of
inflammatory gastrointestinal disorders in which eosinophils infiltrate
the gut in the absence of known causes, and can only be diagnosed
following exclusion of all other known causes of eosinophilia (Figs.
4.199–4.201).88

Figure 4.199 Colonic eosinophilia pattern, idiopathic eosinophilic colitis. At scanning

magnification, the crypt architecture is essentially preserved; however, the increase in
eosinophils within the mucosa and submucosa is striking.

Figure 4.200 Colonic eosinophilia pattern, idiopathic eosinophilic colitis. Higher magnification of
the previous case shows a condensation of eosinophils around a single crypt. The etiology of this
eosinophilic infiltrate is not apparent in the biopsy.
 Figure 4.201 Colonic eosinophilia pattern, idiopathic eosinophilic colitis. Another high
magnification area from the previous case shows abundant eosinophils traversing the muscularis
propria (arrowheads).

INFLAMMATORY BOWEL DISEASE

Eosinophils comprise a conspicuous component in the inflammatory
infiltrate of both active and inactive IBD, including both ulcerative
colitis and Crohn disease.89,90 Sheets of eosinophils and significant
intraepithelial infiltration, however, are absent in IBD, and when found
in cases of established IBD, should prompt further investigation. In
comparison, among patients without an established diagnosis of IBD, the
finding of an eosinophil-rich infiltrate in the lamina propria is
nonspecific, particularly in the absence of features of chronicity. As such,
one might suggest the possibility of an emerging or early IBD among a
list of differential diagnoses.

ALLERGY
Allergic colitis results in an extensive eosinophilic infiltration of the
mucosa (Figs. 4.202– 4.204). The most common antigens are found in
cow milk and soy formulas, and allergic eosinophilic gastrointestinal
disorders are among the most common causes of diarrhea and rectal
bleeding in infants less than 1 year of age. Other causative agents
include wheat, eggs, corn, fish, seafood, and nuts, which may cause
failure to thrive or food refusal in infants and toddlers. Adults may
demonstrate a hypersensitivity reaction to medications such as 5-amino-
salicilates, NSAIDs, and antiepileptic drugs (see medications later).
Eosinophilia involves any of the gastric layers, including the muscularis
propria and serosa. Mucosal involvement is the most common, reported
to occur in 25% to 100% of cases, and patients typically present with
nausea, vomiting, diarrhea, and abdominal pain.84 Some patients show
occult blood loss, anemia, and protein-losing enterocolopathy. Peripheral
eosinophilia occurs in 50% to 60% of cases and the sedimentation rate is
elevated in approximately 25% of cases, both of which return to normal
following effective diet modification.84 Other medical treatments include
montelukast (a leukotriene receptor antagonist), cromolyn sodium (a
mast cell stabilizer), and oral steroids such as budesonide.91

Figure 4.202 Colonic eosinophilia pattern, allergic colitis. This intense focus of lamina propria
eosinophilia is accompanied by intraepithelial eosinophils (arrowheads). The increased colonic
eosinophilia in this case was attributed to that patient’s known clinical history of food allergies.
 Figure 4.203 Colonic eosinophilia pattern, allergic colitis. This biopsy comes from another
patient with eosinophilia due to known allergic colitis. Note the prominence of intraepithelial
eosinophils (arrowheads).

Figure 4.204 Colonic eosinophilia pattern, allergic colitis. Another field from the previous figure
with prominent intraepithelial eosinophils (arrowheads).

MEDICATIONS
A laundry list of medications is associated with medication-induced
mucosal eosinophilia (Figs. 4.205–4.208), including aspirin, clozapine,
carbamazepine, diclofenac, enalapril, gemfibrozil, ibuprofen, nimesulide,
rifampicin, tacrolimus, ticlopidine, therapeutic gold compounds.92–100
Note that a number of these are NSAIDs, a commonly implicated class of
drugs in various mucosal injuries of the GIT. Practically speaking, an
effort to review the patient’s drug list for known offenders and other
pertinent clinical findings (such as concurrent dermatitis that might
suggest drug reaction) may be helpful to include in the note.

Figure 4.205 Colonic eosinophilia pattern, chemotherapy medication reaction. This colonic
biopsy shows an increased density of lamina propria inflammatory cells, but is otherwise not
remarkable. It was taken from a patient with chronic diarrhea following chemotherapy for a
gynecologic malignancy.

Figure 4.206 Colonic eosinophilia pattern, chemotherapy medication reaction. Higher

magnification of the previous case. Eosinophils comprise a significant proportion of the lamina
propria inflammatory cells. A concurrent skin biopsy showed findings compatible with
medication reaction.
Figure 4.207 Colonic eosinophilia pattern, mycophenolate medication reaction. This colon biopsy
shows a single focus of crypt destruction (arrow) surrounded by an inflammatory infiltrate. This
biopsy is from a kidney transplant patient taking mycophenolate mofetil (an
immunosuppressant).

Figure 4.208 Colonic eosinophilia pattern, mycophenolate medication reaction. Higher

magnification of the previous case shows prominent eosinophilia with an eosinophilic crypt
abscess (arrow).

INFECTION
Tissue invading helminths elicit significant eosinophilic responses in the
colonic mucosa. Thus, the detection of a focal but dense eosinophilic
infiltrate should prompt a search for helminthic larvae (Strongyloides
stercoralis, Schistosoma spp. ova, or fragments of Trichuris trichiura) (Fig.
4.209–4.211). Some lumen dwelling helminthes do not elicit an
eosinophilic response, including: tapeworms, Enterobius vermicularis,
Angiostrongylus costaricensis, Gnathostoma spp, Ascaris lumbricoides,
hookworms, and nonhuman parasites such as Ancylostoma caninum or A.
sum.87 Although initial tissue sections do not always contain the
organism, obtaining deeper levels and suggesting serologic and stool
evaluation may be appropriate in these cases.

Figure 4.209 Colonic eosinophilia pattern, Schistosoma ova. An eosinophilic infiltrate should
prompt examination for parasitic infections in the colon. Schistosoma ova can be mistaken for
small calcified concretions or psammoma bodies. Higher magnification reveals the calcified shell.
The presence and location of a spine (not pictured) can help speciate the organism.

Figure 4.210 Colonic eosinophilia pattern, Strongyloides larvae. This colon biopsy shows
Strongyloides larvae associated with background acute and chronic inflammation.
 Figure 4.211 Colonic eosinophilia pattern, adult female Strongyloides. Cut in cross section, the
adult female Strongyloides is larger than the larvae seen in the previous figure. The cross section
also reveals the reproductive organs of the adult organism.

COLLAGEN VASCULAR DISORDER AND VASCULITIS

The presence of increased eosinophils in the colon should raise the
differential diagnosis of connective tissue disorders such as systemic
lupus erythematosus, scleroderma, dermatomyositis, and polymyositis.
The gastrointestinal findings in connective tissue disorders are
nonspecific but may prompt a note suggesting ancillary studies for serum
autoantibodies. By comparison, specific histologic features of vasculitis
may be found in the submucosa, which contains abundant blood vessels
and lymphatics; for example, Churg–Strauss syndrome shows systemic
necrotizing vasculitis, and the GI tract is affected in 30% of patients (Fig.
4.212).101 Eosinophil-rich granulomas with necrosis involving medium-
to small-sized vessels are characteristic findings.102 Another systemic
necrotizing inflammatory disease of small-and medium-sized arteries is
polyarteritis nodosa, and it affects the GIT in up to 25% of cases.103
These lesions often involve bifurcations of arteries that lead to
aneurysm, thrombosis or rupture of vessels&emdash;vessels that are
often unavailable for review due to the superficial nature of endoscopic
biopsies. The presence of an eosinophil-rich mucosal infiltrate and
correlation with serologic or radiographic findings, however, can prompt
steroid treatment.
Figure 4.212 Colonic eosinophilia pattern, Churg–Strauss syndrome. A small submucosa vessel in
a patient with known Churg-Strauss syndrome is ringed by eosinophils (arrowheads).

PEARLS & PITFALLS

Eosinophils may be the first clue to a neoplastic process.
Systemic mastocytosis and Langerhans cell histiocytosis are often
accompanied by a background infiltrate of benign eosinophils, likely
drawn in by chemokines. In the setting of increased mucosal
eosinophilia, take a moment to examine the surrounding area for
subtle neoplastic processes (Figs. 4.213–4.218).

Figure 4.213 Colonic eosinophilia pattern, systemic mastocytosis. At low magnification, this
colonic biopsy shows intact crypt architecture. The lamina propria appears abnormal with a
 mixture of pallor and eosinophilia.

Figure 4.214 Colonic eosinophilia pattern, systemic mastocytosis. Higher magnification of the
previous case shows an intense eosinophilia in the lamina propria. Recall that eosinophils can be
bystanders of neoplastic processes.

Figure 4.215 Colonic eosinophilia pattern, systemic mastocytosis. Higher magnification of the
previous Figure shows an abundance of mast cells in the background lamina propria. These cells
have a “fried egg” appearance, with basophilic granular cytoplasm and a peripheral halo.
Figure 4.216 Colonic eosinophilia pattern, systemic mastocytosis (CD117 immunostain). CD117
is a normal marker for mast cells. The mast cells are densely packed in sheets.

Figure 4.217 Colonic eosinophilia pattern, systemic mastocytosis (tryptase immunostain).

Tryptase is also a normal marker for mast cells. Again, note the abnormal density of mast cells.

Figure 4.218 Colonic eosinophilia pattern, systemic mastocytosis (CD25 immunostain). CD25 is a
cytoplasmic stain that highlights an aberrant marker in systemic mastocytosis.
GRANULOMATOUS PATTERN

Figure 4.219 Granulomatous pattern, Histoplasmosis. Granulomata can be associated with a

varied list of differential diagnostic considerations, including infection, medication injury, IBD,
and diverticular disease, among many others. This case originated from a patient with an
unremarkable history who presented for screening colonoscopy. A small nodule was noted, which
histologically consisted of a granuloma with foreign body giant cells.

Figure 4.220 Granulomatous pattern, Histoplasmosis. Higher power of the previous image. The
patient originated from Ohio where the thermally dimorphic fungus is seen with regularity. The
characteristic yeast forms displayed a uniform 2 to 3 μm size on GMS or PAS/D (not shown). An
AFB special study was negative.

Common etiologic considerations of the granulomatous pattern are listed

subsequently (Figs. 4.219 and 4.220).

CHECKLIST: Etiologic Considerations for the

Granulomatous Pattern
 Inflammatory Bowel Disease
Nonspecific Mucosal Injury
Diverticular Disease
Infections
Medications
Sarcoidosis
Vascular Injury
Pneumatosis Cystoides Intestinalis
Autoimmune Diseases (including common variable immunodeficiencies
and chronic granulomatous disease)
Cord Colitis Syndrome
Lymphoproliferative Disorders

Granulomata in the colon usually inspire a fair amount of clinical

interest, particularly regarding potential underlying diseases. Cases
without careful notes will invariably result in at least one of the
following clinical inquiries: “Could this finding represent Crohn
disease?” “Sarcoidosis?” “Mycobacterium or fungal infection?”
Unfortunately, granulomata are entirely nonspecific. The key to
navigating the laundry list of considerations is to carefully scrutinize the
background mucosa in search of other diagnostic clues, in addition to a
thorough clinical chart review; for example, if the background shows
active chronic colitis, the differential diagnostic considerations narrow to
those agents associated with both granulomata and active chronic
mucosal injury, such as IBD, diverticular disease, diversion, infections,
medication (such as ipilimumab), or cord colitis syndrome, as detailed in
the chronic colitis pattern discussion, this chapter. While granulomata
can be seen in either ulcerative colitis or Crohn cases, their morphology
and distribution can serve as useful diagnostic clues. Granulomata in
ulcerative colitis are more commonly well-delineated structures seen in
association with damaged crypts and extruded mucin, whereas
granulomata in Crohn disease are more commonly poorly formed
collections of epithelioid macrophages. Those cases accompanied by the
additional red flags of upper-tract injury, transmural disease, and a
patchy progression would favor a diagnosis of classic Crohn disease, and
those with red flags of rectal-based, mucosa-restricted, diffuse disease
progression would favor classic ulcerative colitis (Figs. 4.221–4.225).
Granulomata are seen in up to 26% of diverticular disease-associated
colitis cases, the leading etiology in patients with changes restricted to
the segment of colon involved by diverticular disease.104 Syphilitic and
or LGV infections would be favored if chart review uncovered the red
flags of HIV seropositivity in MSM and the histology showed an intense
mononuclear infiltrate with copious plasma cells (Fig. 4.226). More
common infectious considerations include mycobacterial and fungal
infections. Both are assessed with AFB and GMS special stains, or
separate submission of tissue for cultures. Microbiologic cultures are
preferred, when possible, because of improved sensitivities and the
advantages of speciation and determination of drug susceptibility and
resistance patterns. Diversion-associated colitis would be a consideration
if the granulomata were seen along with florid lymphoid aggregates in
the excluded bowel segment of a patient with a history of diversion (Fig.
4.227). Sarcoidosis involving the GIT is seen in less than 1% of
sarcoidosis patients and most commonly involves the stomach, followed
by the colon.105 The sarcoid granulomata are not uncommonly
multifocal and striking, and their polyp or mass like appearance can
raise clinical concerns for malignancy.106 Correlation with the clinical
history of sarcoidosis or pertinent clinical red flags such as a history of
bilateral hilar lymphadenopathy, elevated serum angiotensin converting
enzyme levels, and joint, skin, eye, or lung dysfunction can help build a
case for sarcoidosis (Figs. 4.228 and 4.229). If the background mucosa
shows an ischemic pattern of injury and the granulomata are centered on
damaged vessels, a granulomatous vasculitis enters the differential
diagnosis; similar findings can be seen in Crohn disease. Granulomata
may also serve as clues to an underlying autoimmune disease. If the
background mucosa is devoid of plasma cells, consider common variable
immunodeficiency (CVID), which is accompanied by granulomata in up
to 19% of colonic specimens.107 In the pediatric setting, the
granulomatous pattern of injury must invoke the possibility of chronic
granulomatous disease (CGD). In a recent study of 87 patients and 15
autopsy cases with established CGD, 65% of colon specimens had
pigmented macrophages and 46% had granulomata.108 Granulomata can
also be a clue to a hematopoietic malignancy. If atypical lymphoid cells
are seen, maintain a low threshold for seeking a formal
hematopathology consultation.109 In summary, scrutiny of the
background histology and careful chart review can prove exceptionally
helpful in ascribing clinical significance to the nonspecific finding of
granulomata.

Figure 4.221 Granulomatous pattern, Crohn disease. This high-power view of florid granulomata
gives few clues to an etiologically specific diagnosis.

Figure 4.222 Granulomatous pattern, Crohn disease; however, on low power we see the
granulomata are transmural and accompanied by transmural chronic inflammation and fibrosis.
Moreover, active chronic inflammatory injury was seen in the stomach, terminal ileum, and in a
patchy distribution throughout the colon, supporting a clinicopathologic diagnosis of Crohn
disease. GMS and AFB special stains were negative and infection and medication injury had been
 clinically excluded.

Figure 4.223 Granulomatous pattern, Crohn disease. More commonly, granulomata in Crohn
disease are poorly formed or difficult to spot at low power, as in this case.

Figure 4.224 Granulomatous pattern, Crohn disease. Higher power of previous image. This
collection of macrophages blends almost imperceptibly with the neighboring lymphocytes. AFB
and GMS stains were noncontributory (the granuloma was exhausted on deeper sections).
 Figure 4.225 Granulomatous pattern, ulcerative colitis. Granulomata in ulcerative colitis are
usually in association with damaged crypts and extruded mucin, as seen in this case.

Figure 4.226 Granulomatous pattern, syphilitic and or LGV infections. Granulomata can also be
seen in the setting of peculiar infections. This rectal biopsy was from a patient clinically
confirmed to be co-infected with syphilis and LGV. The background mucosa showed copious
plasma cells and a lack of architectural distortion, acute crypt centric damage, and eosinophilia
(not shown). Since granulomata are nonspecific findings, careful scrutiny of the background
mucosa is essential to uncovering the hidden etiologic agent to ensure proper treatment. AFB and
GMS special stains were negative.
Figure 4.227 Granulomatous pattern, diversion-associated colitis. These loose foreign body giant
cells and macrophage collections are seen in association with damaged crypts. The patient had
an established history of diversion.

Figure 4.228 Granulomatous pattern, sarcoid. This well-formed granuloma with foreign body
giant cells originated from a patient with a longstanding history of sarcoidosis. The background
mucosa was unremarkable and AFB and GMS special stains were negative for microorganisms.
This case was signed out as “colonic mucosa with scattered granulomata, otherwise
nondiagnostic findings, compatible with the history of sarcoidosis.”

PEARLS & PITFALLS

Pneumatosis Cystoides Intestinalis
Pneumatosis cystoides intestinalis (PCI) is another diagnostic
consideration when macrophage collections are seen. Although PCI
does not feature granulomas per se, biopsy or crush artifact can closely
resemble granulomata. Deeper sections and correlation with the
endoscopic impression can often clarify such suboptimal specimens.
Caution must be exercised to avoid misinterpreting the foreign body
giant cell collections of PCI as an evidence of Crohn disease.110 See
also Pneumatosis Cystoides Intestinalis, Pigments and Extras, this
chapter.

Figure 4.229 Granulomatous pattern, sarcoid. Higher power of previous case.

FAQ: What should I do with an isolated granuloma in an

otherwise unremarkable biopsy in an otherwise unremarkable
patient?
Answer: Despite the aforementioned exhaustive discussion, not
uncommonly, a rogue granuloma in the colon simply signifies a rogue
granuloma in the colon. Subsequent AFB and GMS special stains along
with a careful chart review are obligatory in an effort to uncover
additional diagnostic clues. If these searches prove unrevealing, a
careful note often helps the clinician understand the limitations of
understanding an isolated granuloma.
SAMPLE NOTE: AN ISOLATED GRANULOMA IN THE COLON
OF AN OTHERWISE HEALTHY INDIVIDUAL
Colon, Random (biopsy):
• Colonic mucosa with an isolated granuloma, otherwise nondiagnostic
findings.
Note: The biopsy shows a single granuloma in otherwise unremarkable
colonic mucosa. This injury pattern is etiologically nonspecific and most
likely represents an incidental finding given the unremarkable clinical
history (favor nonspecific, remote mucosal injury). Negative for
histologic features of active or chronic inflammatory disease. AFB and
GMS special stains are negative.

SAMPLE NOTE: AN ISOLATED GRANULOMA,

BACKGROUND MODERATE ACTIVE CHRONIC MUCOSAL
INJURY, AND NO HISTORY PROVIDED
Note: The biopsy shows a single granuloma in a background of moderate
active chronic colitis. This injury pattern is etiologically nonspecific and
can be seen in the setting of infection (including STI proctocolitis),
medication injury, IBD, diverticular disease, sarcoidosis, vasculitides,
autoimmune diseases, among others. Clinical correlation required. AFB
and GMS special stains are negative.

PIGMENTS AND EXTRAS

 Figure 4.230 Melanosis coli. A variety of colorful entities can be seen in the colon. This is a
striking example of melanosis coli, a finding linked to chronic laxative usage.

CHECKLIST: Etiologic Considerations for Pigments and

Extras (Fig. 4.230)
Melanosis Coli
Tattoo Pigment
Air Artifact
Pneumatosis Cystoides Intestinalis
Muciphages
Resins

MELANOSIS COLI (ALSO REFERRED TO AS

PSEUDOMELANOSIS COLI)
Melanosis coli refers to coarse, brown-black pigment in the cytoplasm of
the colon’s resident macrophages. Despite the name, ultrastructural
studies demonstrated the pigment is lipofuscin, not melanin (this
particular factoid is a favorite among those who write test questions!).111
The pigment is derived from stimulant laxatives containing senna, aloe-
emodin, chrysophanol, cascara, frangula, and rhein.112 The purgative
effects of such preparations stem from their ability to increase colonic
motility and decrease colonic absorption, resulting in decreased transit
time and softer stools. The endoscopic images in patients with melanosis
coli can be impressive (Fig. 4.231). Any region of the colon can be
affected with no consistent regional pattern of involvement: some claim
the distal colon is most affected, while others found the changes most
pronounced proximally.113,114 Melanosis coli is seen in up to 73% of
patients with chronic laxative usage and in up to 6% of biopsy and
autopsy cases.115,116 Such findings have been documented within 4
months of regular laxative usage and the findings reverse 6 to 11 months
following cessation (Figs. 4.232–4.238).117,118 Early literature suggested
anthracoid laxatives were a risk factor for colonic neoplasia based on
provocative animal and human studies showing an increased association
of melanosis coli in patients with adenomas and carcinomas.119,120
Today, this theory has been abandoned.121,122

Figure 4.231 Melanosis coli, endoscopic image. This endoscopic image shows striking mucosal
pigment deposition. This patient had a 10-year history of senna intake for chronic constipation.
Figure 4.232 Melanosis coli. The characteristic brown-black pigment is within the cytoplasm of
macrophages. The pigment is lipofuscin, not melanin.

Figure 4.233 Melanosis coli. Under oil immersion, note the bland cytologic features of the
macrophages with perfectly round nuclei, delicate nucleoli, and abundant cytoplasm. The
background shows scattered neutrophils secondary to an unrelated self-limited infection.
 Figure 4.234 Melanosis coli. An alternate field shows coarse clumps of cytoplasmic pigment.

Figure 4.235 Melanosis coli. This example features a more typical (less subtle) case of melanosis
coli.
 Figure 4.236 Melanosis coli. Higher power of previous case.

Figure 4.237 Melanosis coli. This is another subtle case that would be easy to miss on scanning
magnification.
Figure 4.238 Melanosis coli. The lipofuscin is highlighted by a Fontana Masson special stain (this
stain also highlights melanin pigment).

TATTOO PIGMENT
Since tattoo pigment is applied to localize clinically suspicious lesions,
its identification should prompt careful scrutiny for sneaky neoplasms
(Figs. 4.239–4.243). See also, Tattoo Pigment, Pigments and Extras,
Small Bowel Chapter.

AIR ARTIFACT
Endoscopy relies on air insufflation to expand the bowel for proper
visualization. Through this process, increased intraluminal pressure can
force air into the bowel wall. Cases without a concomitant foreign body
tissue response are classified as air artifacts. Air artifacts are so
extraordinarily common that our eyes often glide right over this finding.
When the foci are small and the tissue is of nonpolypoid or flat mucosa,
it is easy to dismiss these peculiar foci as air artifacts. Difficulties arise in
the case of subtle polyps for which the diagnostic dilemma is air artifact
versus lipoma. Deeper sections and endoscopic correlation can often
clarify the issue. Lipomas display a characteristic “pillow” sign when
compressed (Figs. 4.244 and 4.245). Histologic clues can be a bit
subjective and frustrating. In contrast to a lipoma, air artifact gently
pushes apart the neighboring cellular constituents so that inflammatory
and stromal cells as well as vascular and neural structures are seen
coursing between the empty spaces. Additional helpful clues include a
lack of nuclei within the empty spaces (in contrast to an adipocyte with
a bona fide nucleus) and that the sizes and shapes of the empty spaces
can be unnaturally large and bizarre (Figs. 4.246–4.252). In contrast,
lipomas have minimal intervening cellular components, clearly
discernible nuclei, and the cytoplasm is more predictably uniform in size
and shape (Figs. 4.253 and 4.254). Note, well-differentiated
liposarcomas violate these general tips, but they would present as large
mass lesions for which air artifact would not enter in the differential
diagnosis. In challenging cases, well-differentiated liposarcomas display
MDM2 and CDK4 immunoreactivity (Fig. 4.255). Some cases of
entrapped air form cyst-like spaces and illicit a tissue response. These
findings are classified as pneumatosis cystoides intestinalis, see next
subsection.

Figure 4.239 Tattoo. Preoperative application of tattoo pigment helps to endoscopically monitor
suspicious lesions, locate the lesion at time of surgery, and is associated with improved local
lymph node dissections. Tattoo pigment, unlike melanosis coli, is dramatic since its sole purpose
is for gross visibility with the naked eye.
Figure 4.240 Tattoo. India ink remains the most widely employed tattoo agent. Note the black,
coarse cytoplasmic globules within the macrophages. This exuberant case has elicited a foreign
body giant cell reaction (arrowheads).

Figure 4.241 Tattoo. Under oil immersion, the coarse, globular nature of the black tattoo
pigment is apparent. Note the bland nuclear features of the host macrophages that display
perfectly round nuclei and delicate nucleoli.
 Figure 4.242 Tattoo. This case features tattoo pigment free-floating in the submucosa. The
segmental resection occurred a few hours after the tattoo was applied (before a tissue response
could be mounted).

Figure 4.243 Tattoo. This case is a more typical (subtle) example. Tattoo application was applied
2 weeks before this segmental resection. Unlike the skin counterpart, tattooing of the colon is not
performed for cosmetic or artistic expression. Colon tattoos are to localize clinically suspicious
lesions, and identification of the pigment should always prompt a thorough evaluation for sneaky
malignancies.
 Figure 4.244 Lipoma, endoscopic image. This endoscopic appearance of a lipoma is fairly
unrevealing.

Figure 4.245 Lipoma, endoscopic image. However, upon compression, the “pillow sign” is seen.
In this analogy, the instrument is a head and the polyp is its pillow. Note, how the “head”
indents or displaces portions of the “pillow.” This endoscopic finding is highly suggestive of a
lipoma.

Figure 4.246 Air artifact. This resection case originated from a patient with bowel perforation.
Note the large, billowing, cloudlike air pockets coursing through the submucosa. Although subtle
cases of air artifact often raise the possibility of a lipoma, these particular air pockets are far too
large, bizarre, and convoluted to be anything other than entrapped air.

Figure 4.247 Air artifact. Higher power shows the air pockets are pushing apart the normal
cellular constituents (note the lymphoid aggregate in the upper left, vessels in the middle, and
ganglion cells in the upper right). In addition, the air pockets have no endothelial lining (to
suggest a lymphovascular space) or nuclei (to suggest an adipocyte), both helpful clues to the
diagnosis of air artifact. Also, note there is no tissue response (there are no foreign body giant
cells reacting to the displaced gas). This emergent bowel resection occurred almost immediately
after the perforation, before the tissue had sufficient time to react to the infiltrating gas.

Figure 4.248 Air artifact. An alternative field shows large, bizarre air pockets (asterisks), which
dissect the resident tissue. Lipomas do not tend to percolate around native structures such as
ganglion cell clusters, nerves, fibrous tissue, and blood vessels, as seen in this example of an air
artifact. Also, there is no epithelial lining and no nuclei to suggest a lymphovascular space or
adipocytic lesion, respectively.
 Figure 4.249 Air artifact. Air artifacts often inspire the most consideration around lymphoid
aggregates in tissue submitted as a polyp: could the polyp represent a lymphoid aggregate with
nearby air artifact or is the polyp a small lipoma?

Figure 4.250 Air artifact. On higher power, large, irregular air pockets seem to dissect the tissue
(asterisks). Air artifacts are most problematic around lymphoid aggregates, where the air spaces
can compress neighboring lymphoid cells and appear as if the air spaces have nuclei (arcs). In
these scenarios, look carefully for definitive air pockets (asterisks). If definitive air pockets and
adjoining lymphoid aggregates are seen, the indicated focus is most likely an air artifact. Deeper
sections can be reassuring in ambiguous cases.
 Figure 4.251 Air artifact. The assigned resident interpreted this polyp as a lipoma (brackets).

Figure 4.252 Air artifact. Higher magnification shows that the empty spaces lack the diagnostic
features of a lipoma: there are no nuclei lining these spaces. Instead, this focus represents air
artifact. Note the irregular, gaping nature of the empty space. Deeper sections revealed a tubular
adenoma, accounting for the clinical impression of the polyp.

Figure 4.253 Lipoma. In contrast to air artifacts, lipomas show cohesion of the lesional cells.
There are few intervening stromal cells or inflammatory cells present, helpful distinguishing
 features of a lipoma.

Figure 4.254 Lipoma. High power shows that each lipocyte has its own small, peripheral nucleus.
Also the (benign) neoplastic cells have a uniform architecture with few intervening nonlipocytic
elements. These key features of a lipoma contrast with findings in air artifacts.

Figure 4.255 Well-differentiated liposarcoma involving the colonic serosa. In contrast to a benign
lipoma, this adipocytic lesion shows high-grade nuclear features. Note the hyperchromatic,
pleomorphic nuclei of the adipocytes. This patient had a 50 cm retroperitoneal well-
differentiated liposarcoma that focally involved the colon. MDM2 and CDK4 were diffusely
positive in the lesional cells.

PNEUMATOSIS CYSTOIDES INTESTINALIS

Pneumatosis cystoides intestinalis (PCI) refers to cyst-like structures
impregnated with gas and lined by macrophages and foreign body giant
cells. These structures are within the bowel wall and can be visualized
endoscopically and radiographically (Figs. 4.256–4.262). Up to 85% of
PCI cases are secondary to an iatrogenic procedure, mechanical,
bacterial, metabolic, or pulmonary dysfunction.123 An association with
collagen tissue disorders, AIDS, and glucorticoids has also been reported.
While numerous theories of origin exist, the prevailing view is that
increased intraluminal pressures force gas through damaged mucosa,
and a subsequent tissue response manifests as a foreign body giant cell
reaction. PCI can be seen anywhere along the tubular GIT, but most
cases involve the bowel (colon = 78%, small bowel = 57%).123 Patients
are usually asymptomatic. When pneumatosis is identified, it is
important to assure that there is not other pathology in the resection
that may have initiated the rather eye-catching pneumatosis&emdash;a
classic example is scleroderma (which results in sclerosis of the
muscularis propria and obstruction). CMV infection is also detected in
some cases. Complications include obstruction, volvulus, intussception,
ischemia, and perforation. Treatment is aimed at correcting the
underlying disease or conservative medical therapy, where possible. See
also, Pearls & Pitfalls, Granulomatous Pattern, this chapter.

Figure 4.256 Pneumatosis cystoides intestinalis (PCI). This patient had a longstanding history of
chronic obstructive pulmonary disease (COPD) and presented with abdominal pain. The imaging
study shows numerous air pockets within the bowel wall. The bowel wall has a spongelike or
swiss-cheese-like foamy appearance on imaging (bracket). COPD causes PCI secondary to
increased intraabdominal pressure, which forces gas into the bowel wall.
Figure 4.257 PCI, endoscopic image. Corresponding endoscopic images of the bowel wall show
numerous convoluted mucosal folds that appear almost cerebriform.

Figure 4.258 PCI, endoscopic image. An alternate view of the same case shows similar features.
The bowel wall is distended with large air pockets.
Figure 4.259 PCI. Histologic sections show multiple cyst-like spaces in the muscularis propria.

Figure 4.260 PCI. Alternate image, same patient.

 Figure 4.261 PCI. Higher power shows that the cyst-like spaces are lined by histiocytes and
foreign body giant cells.

Figure 4.262 PCI. Highest power shows the bland features of the foreign body giant cells lining
the empty spaces.

MUCIPHAGES
Azzopardi described muciphages as mucoprotein-containing
macrophages in the rectum in 1966.124 The incidence was as high as
50% of rectal biopsies and no correlation with sex, age, or underlying
disease was found. Academic interest in muciphages was likely borne out
of the 1960s burgeoning understanding of Whipple disease, and a
concern that muciphages represented Whipple disease involving the
rectum. Today we know muciphages are extraordinarily common with
essentially no relation to Whipple disease. A more recent study describes
the muciphages as superficially located in the lamina propria and found
that up to 19% present as nodules or polyps.2 These experts found a
backdrop of increased chronic inflammation and mild fibrosis and
suggest muciphages represent nonspecific, resolving injury. Their mucin
presumably originates from “clean up” of epithelial damage or turnover
(Figs. 4.263–4.269). Detailed studies show the mucin contains neutral,
weakly acidic, or strongly acidic mucin with predominantly sialomucin
but also a smaller component of sulfated mucin.2 The clinical
importance of muciphages is simply to be aware of their benign and
nonspecific nature. AFB and GMS special stains are not required upon
identification because muciphages are not granulomata and have no
association with infections.

Figure 4.263 Muciphages. Muciphages are benign oddities, most commonly seen in the rectum.
They can be spotted at low power, as in this case.
Figure 4.264 Muciphages are mucoprotein-containing macrophages that accumulate secondary to
prior rectal injury.

Figure 4.265 Muciphages. Under oil magnification, the bland nuclear features are seen. Dislodged
muciphages can occasionally raise concerns for signet ring cell carcinoma. Helpful clues to the
diagnosis of benign muciphages include the bland cytology and lack of background dysplasia and
desmoplasia. In difficult cases, CD68 will confirm their histiocytic origin. Muciphages are
cytokeratin nonreactive.
 Figure 4.266 Muciphages. This low-power image shows the characteristic distribution of
muciphages as they decorate the superficial lamina propria.

PEARLS & PITFALLS

To those unfamiliar with muciphages, they can appear alarming at
first. An interesting consultation case featured a prostate biopsy
accompanied by bystander rectal tissue with prominent muciphages.
The muciphages had become dislodged and “squished” and raised
concerns for signet ring cell carcinoma. Helpful diagnostic clues
include that the muciphages display bland cytologic features,
immunolabel with the histiocytic marker CD68, and are cytokeratin
nonreactive.
Figure 4.267 Muciphages. Higher power of previous image. Muciphages are histologically
identical to foamy macrophages of any other site.

Figure 4.268 Muciphages.

Figure 4.269 Muciphages. Higher power of previous case shows the muciphages streaming
 through the superficial lamina propria.

MEDICATION RESINS
Medication crystals can be seen anywhere along the tubular GIT, but are
particularly common in the colon (Fig. 4.270). See also Resins, Pigments,
Esophagus Chapter.

Figure 4.270 Medication resin, sevelamer. Sevelamer resins show broad, irregular “fish-scales”
with curvilinear points of intersection and a two-tone coloration on H&E, as in this example.

NEAR MISSES
ENDOMETRIOSIS
Figure 4.271 Endometriosis. This consultation case originated from a 25-year-old woman with a
bleeding rectal mass. It was clinically ominous appearing, leading the surgeon to inform the
patient that the lesion was most likely malignant. Based on the patient’s young age, the family
asked for the case to be externally reviewed.

Figure 4.272 Endometriosis. Higher power shows convoluted glands surrounded by a cuff of
stroma cells and intermixed lymphoid cells.

Figure 4.273 Endometriosis. Higher power of previous image. Cilia are not definitively identified
in this suboptimal specimen. Biopsies of the lesion had raised concerns for an infiltrating
adenocarcinoma because the glandular elements were not recognized as endometrial, the
overlying reactive changes were interpreted as dysplasia, and numerous mitotic figures were
seen.

Endometriosis is the presence of at least two of the three following

features outside of the uterus: endometrial glands, stroma, and
hemorrhage (Figs. 4.271–4.273). Up to 37% of women with
endometriosis have intestinal involvement, and any layer of the bowel
can be involved. The clinicopathologic presentation is diverse and
presentations can overlap with appendicitis, IBD, diverticular disease,
infectious colitis, a surgical acute abdomen, malignancy.125–128
Endometriosis involving the rectum commonly presents as bloody
diarrhea. Associated pathologic findings can include strictures,
ulceration, fissures, ischemia, and intussusception.125 The lesions can
appear as polyps or bleeding mass lesions, raising clinical concerns for
malignancy. The overlying colonic epithelium can be markedly reactive
and mimic dysplasia, leading to the misdiagnosis of colonic
adenocarcinoma. Occasionally, only the stromal component is seen and a
diagnosis of sarcoma is entertained. In these cases, usually the
endometrial glands can be identified on deeper sections. Confirmatory
immunohistochemical stains include ER and PR to highlight the
glandular components and CD10 to highlight the endometrial stroma.

Figure 4.274 Endometriosis (ER immunostain). An ER immunostain shows diffuse nuclear

reactivity in the indicated cells and a CD10 highlighted the stromal component (not shown),
supporting the revised diagnosis of endometriosis. We have seen similar cases raise concerns for
spindle cell sarcomas when the glandular elements were not present. Deeper sections and
ancillary ER, PR, and CD10 are helpful diagnostic tools in challenging cases. Always consider
endometriosis in a reproductive aged woman with a rectal mass.
PEARLS & PITFALLS
Always consider endometriosis (a benign etiology) before malignancy
in a reproductive aged woman with a rectal mass (Fig. 4.274).

BENIGN SIGNET RING CELL CHANGE

Figure 4.275 Signet ring cell change. This consultation case was received with a concern for
infiltrating signet ring cell carcinoma in a background of C. difficile pseudomembranous colitis.
This focus shows ulcer debris surrounding islands of detached colonic epithelium.

Figure 4.276 Signet ring cell change. Higher power shows the detached colonic epithelium
 display a signet ringlike morphology with a crescentic, peripheral nucleus compressed by
abundant cytoplasmic mucin. Great caution must be exercised when evaluating ulcer debris
because degenerating and dislodged normal epithelium can appear markedly atypical.

Figure 4.277 Signet ring cell change. Under oil immersion the degenerating and dislodged goblet
cells show signet ringlike morphology. These changes were interpreted as benign and reactive
because the atypia was in proportion to the background ulcerative and inflammatory changes,
and the adjoining intact mucosa was negative for dysplasia and malignancy.

Figure 4.278 Signet ring cell change. Note the poor preservation of the material and the
background degenerative changes in the neutrophils. Based on the background, the central signet
ringlike cell was interpreted as a benign, degenerating and dislodged goblet cell. While no
additional special stains or immunohistochemical stains were performed in this case, in difficult
cases additional studies can be of use. Benign signet ring cell change displays intact E-cadherin, a
 low Ki-67 proliferation index, and p53 is nonreactive. If the clinical concern for malignancy
remains, repeat biopsy with generous sampling of the interface of the ulcer and adjacent intact
mucosa may be worthwhile.

Signet ring cell change is a benign finding that can mimic signet ring cell
carcinoma (Fig. 4.275–4.278). The indicated cells have a crescentic,
peripheral nucleus and contain abundant cytoplasmic mucin. This
peculiar pattern has been reported in the stomach, colon, gallbladder, a
Peutz–Jeghers polyp, and is particularly common in the setting of
pseudomembranous colitis pattern.129–133 Although signet ring cell
change can be seen anywhere along the GIT, the background mucosal is
often markedly injured, suggesting this change is reparative in nature or
due to mechanical or ischemic insult. Cytologic diagnostic clues include
a lack of nuclear hyperchromasia, atypia, and prominent nucleoli.
Architecturally, benign signet ring cell change lacks an infiltrative
growth pattern and desmoplasia. In challenging cases, a reticulin or
laminin special stain can be useful by demonstrating the signet ringlike
cells are completely confined within the basement membranes. The
indicated cells display intact E-cadherin, a low Ki-67 proliferation index,
and are p53 nonreactive.133 Of note, the mitotic activity can be elevated
in signet ring cell change, particularly if the background mucosa shows
an increased mitotic rate. Atypical mitoses are not seen.

PULSE GRANULOMATA

Figure 4.279 Pulse granuloma. This specimen was designated mesenteric mass and was clinically
 concerning for malignancy. Note the nodular architecture. Eosinophilic ribbons and foreign
material are easily seen at this power. Although the case was submitted in consultation as
sclerosing mesenteritis, the eosinophilic ribbons are characteristic of pulse granulomata. Pulse
granuloma are benign lesions that result from entrapped “pulse” or food forced into privileged
sites (i.e., bowel wall or mesentery) via significant trauma or mucosal injury.

Figure 4.280 Pulse granuloma. Higher power of the previous image shows the characteristic
features of pulse granulomata: eosinophilic ribbons of hyaline material intermixed with abundant
histiocytes, foreign body giant cells, and interspersed foreign material. Although the eosinophilic
material looks like amyloid, Congo red special stains for amyloid are always negative. This
patient had a history of perforated diverticular disease, which likely introduced food and fecal
material into the abdominal cavity, providing a nidus for the pulse granulomata.

Pulse granulomata are curious, benign lesions best characterized in the

oral pathology literature in association with dental caries and dentures
(Figs. 4.279 and 4.280).134 These are also common findings in the
tubular GIT, particularly in the background of bowel injury such as
diverticular disease, IBD, neoplasia, perforation, fistula, or prior
surgery.135–138 The prevailing theory of origin is entrapped, impacted
“pulse” or food introduced through mucosal trauma (Figs. 4.281 and
4.282). An alternative theory suggests the eosinophilic ribbons (or
“hyaline rings”) represent vascular damage.139 The nodules can range up
to 10 cm, raising clinical concerns for malignancy; thorough sampling of
the tissue and familiarity with the morphology can be reassuring. The
histologic features include nodular collections of eosinophilic ribbons of
hyaline material intermixed with abundant histiocytes, circumferential
stellate fibrosis in larger lesions, foreign material, and variable amounts
of granulation tissue with microabscesses (Figs. 4.283–4.285). Most
cases are nodular and multifocal. The hyaline ribbons often raise
concerns for amyloid, but the material is presumed food degradation
material and is consistently Congo red negative. The most common
mimic is sclerosing mesenteritis, particularly in mass lesions involving
the mesentery. Helpful clues to the diagnosis of pulse granulomata,
however, include a history of bowel injury and the core histologic
features of eosinophilic ribbons of hyaline material intermixed with
abundant histiocytes, circumferential stellate fibrosis in larger lesions,
foreign material, and variable amounts of granulation tissue with
microabscesses. Photomicrographs courtesy of Dr. Nicholas Nowacki,
The Ohio State University Wexner Medical Center.

Figure 4.281 Pulse granuloma, abdominal computed tomography. This patient had a long-history
of swallowing foreign bodies and self-inflicted stab wounds through the abdomen. The patient
presented with abdominal pain; the abdominal study shows metallic objects (arcs).
 Figure 4.282 Pulse granuloma, endoscopic image. This endoscopic image shows numerous
swallowed metal hooks and pens in the stomach.

Figure 4.283 Pulse granuloma. As a result of numerous self-inflicted abdomen wounds, this
patient eventually developed an enterocutaneous fistula. A representative section shows classic
features of pulse granulomata. At low power, a nodular architecture and circumferential stellate
fibrosis are seen.
 Figure 4.284 Pulse granuloma. Higher power shows the characteristic features of pulse
granulomata with eosinophilic ribbons of hyaline material intermixed with abundant histiocytes,
foreign body giant cells, and interspersed foreign material (arcs). Pulse granulomata are benign
lesions that result from entrapped “pulse” or food introduced through mucosal trauma. They can
sometimes present as mass lesions and, therefore, they can be clinically concerning for
malignancy.

Figure 4.285 Pulse granuloma. Higher power of previous case. Pulse granulomata are most
commonly seen involving the external surface of the bowel wall in patients with a history of
bowel related trauma.

APOPTOTIC COLOPATHY
 Figure 4.286 Apoptotic colopathy, mycophenolate mofetil (MMF). This rectal biopsy originates
from a patient with a history of renal transplant who presented with watery diarrhea. Low power
shows increased lamina propria chronic inflammation, including increased eosinophils.

Figure 4.287 Apoptotic colopathy, MMF. Higher power shows increased lamina propria
eosinophils and a crypt abscess with focally attenuated epithelium and increased eosinophils.
 Figure 4.288 Apoptotic colopathy, MMF. Apoptotic bodies appear as fragmented, irregular
cellular “bits” or debris. The onset of diarrhea coincided with a recent increase in MMF dose, all
pertinent stool cultures were negative, a CMV immunostain was nonreactive, and no other
medication changes were noted. All symptoms and histologic abnormalities resolved with MMF
cessation. The diarrhea was attributed to MMF.

Apoptotic bodies are easy to overlook because they often require high
power and a bit of time to identify (Figs. 4.286–4.288). To the trainee,
apoptotic bodies can be easily confused with IELs. Apoptotic bodies,
however, appear as variably sized bits of cellular debris or degenerating
dust, while lymphocytes show a uniform size and are more clearly
recognized as intact cells. As a general rule, finding greater than one to
two apoptotic bodies per tissue fragment qualifies as abnormally
increased. Increased apoptotic bodies can be helpful clues to the
underlying diagnosis with differential considerations including the
following:
• Infection (i.e., CMV)
• Medication (i.e., Mycophenolate Mofetil [MMF]/CellCept)
• Graft versus Host Disease (GVHD)
• Autoimmune diseases/immunodeficiencies (i.e., CVID)
The featured case is an example of mycophenolate mofetil
(MMF/CellCept)-associated colitis in a patient with a history of renal
transplantation. MMF is an immunosuppressive medication whose
mechanism of action is inhibition of an enzyme in the de novo pathway
of purine synthesis. Since lymphocytes are exquisitely dependent on this
pathway, they are inhibited. However, GIT epithelium is also dependent
on the de novo pathway (albeit to a lesser extent than lymphocytes) and
thus this medication damages GIT epithelium.140 Mycophenolate is used
most commonly to prevent acute cellular rejection of transplanted solid
organs but is also used in the treatment of autoimmune and
inflammatory diseases, such as psoriasis, lupus nephritis, myasthenia
gravis, among others. Common symptoms include watery diarrhea,
nausea, vomiting, and abdominal pain. Its administration is associated
with increased apoptotic bodies throughout the GIT and drug cessation
reverses the pathology and symptoms. Clinicians are sufficiently familiar
with the association of MMF and GIT side-effects that they often
empirically lower or stop MMF without an endoscopic biopsy.
Importantly, MMF is also used in the setting of stem cell transplant to
treat GVHD. Based on considerable clinicopathologic overlap,
distinguishing MMF injury from GVHD can be challenging. Appropriate
diagnosis is critical since MMF is treated with drug cessation and GVHD
is treated with immunosuppression. Recent case control studies report
that features favoring MMF include a triad of eosinophils >15 per 10
HPF, an absence of endocrine cell aggregates, and an absence of
apoptotic microabscesses (degenerating crypts with luminal necrotic and
apoptotic debris).141 Features favoring GVHD including apoptotic
microabscesses, endocrine cell aggregates, hypereosinophilic
degenerating crypts, architectural distortion, and a lack of eosinophilia.
Others have reported similar findings.142,143 Clinical correlation is
essential with particular attention to history and date of transplantation:
GVHD is not a diagnostic consideration in the absence of a transplant
history, for example. Type of transplantation is also important to
discern: GVHD is infinitely more common with stem cell transplant than
solid organ transplant. Correlation with the physical examination and
laboratory studies is usually of use. Patients with apoptotic colopathy
and concomitant cutaneous and or liver GVHD would be at considerable
risk for GIT-GVHD and would benefit from increased
immunosuppression. Lastly, reconciliation with the medication list is
necessary since MMF is not a consideration if the patient lacks a history
of MMF. In summary, red flags for the pathologist to consider MMF
colitis include a history of transplant or autoimmune diseases, culture
negative watery diarrhea, and increased apoptotic bodies. CMV
immunostains are recommended in all cases of apoptotic prominence.
See also, GVHD, Lymphocytic Pattern, Esophagus Chapter.

SPIROCHETOSIS

Figure 4.289 Intestinal spirochetosis in a tubular adenoma. An abrupt transition (arrowhead) to

nuclear crowding and stratification identified this colonic polyp as a tubular adenoma. At low
magnification, it would be easy to move on to the next case and miss the second diagnosis in this
biopsy.

KEY FEATURES of Intestinal Spirochetosis:

• Intestinal spirochetosis is caused by an infection by spirochetes
Brachyspira aalborgi and B. pilosicoli
• The bacteria attach to the apical cell membrane of colonic
epithelial cells.144
• The prevalence in Western nations is 2% to 16%, and there is a
common association with homosexual men and HIV/AIDS,
although the clinical significance remains strongly debated.
• The infection is also found in otherwise healthy children, and other
associations include diverticular disease, chronic idiopathic
inflammatory bowel disease, hyperplastic polyps, and adenomas
(Figs. 4.290 and 4.291).145
• Fecal-oral route is the proposed mechanism of transmission.146
• Most cases are asymptomatic and found incidentally.147 Other
 patients experience chronic watery diarrhea, abdominal pain, and
anal discharge.
• Symptomatic patients may benefit from antimicrobial and antidiarrheal
therapy.

Figure 4.290 Higher magnification of the previous case. A fine “fuzzy” blue border (arrowhead) is
present on the surface of the epithelial cells, indicating that intestinal spirochetosis is involving
this tubular adenoma.

Figure 4.291 Intestinal spirochetosis. With an oil immersion objective, one can one appreciate
the filamentous appearance of the spirochetes (arrowheads) attached to colonic epithelial cells.
 Figure 4.292 Intestinal spirochetosis. Easily missed at low magnification, a mid-to hipower
review of colonic biopsies is required to note the presence of this “fuzzy” blue border.

Figure 4.293 Intestinal spirochetosis. This diagnosis is challenging due to its subtle findings and
patchy nature. In this example, note how challenging it is to find the spirochetosis on the surface
epithelium. Careful examination along the crypt epithelium reveals a more obvious fuzzy blue
border.
 Figure 4.294 Intestinal spirochetosis. The spirochetes (arrowhead) attach to the surface
epithelium, rarely invading the mucosa.

Figure 4.295 Intestinal spirochetosis.

• Histologic findings may be patchy or involve multiple colonic

segments.
• The spirochetes appear as a characteristic “fuzzy” basophilic border
along the luminal surface of the colonic epithelium (Figs.
4.292–4.295)
• No inflammation or crypt architectural changes are present, making
this an easily missed diagnosis unless one actively looks for it.
• The organisms stain with silver impregnation stains (Warthin-Starry,
Dieterle, Steiner) (Figs. 4.296–4.298). Tissue Gram stain will not stain
the organisms.

FAQ: Does intestinal spirochetosis in an otherwise healthy child

imply sexual abuse?
Answer: NO!
Otherwise healthy children may have incidental colonization with
these organisms, and the finding does not imply sexual abuse. Sexual
transmission was initially proposed as a method of transmission due to
the higher prevalence in homosexual men, but this remains unproven.
Fecal oral transmission via contaminated water sources and colonized
feces is far more likely.

Figure 4.296 Intestinal spirochetosis (Warthin–Starry silver stain). A silver stain, such as the
Warthin–Starry pictured here, highlights the fuzzy blue border as a thick black line.
 Figure 4.297 Intestinal spirochetosis (Warthin–Starry silver stain). Higher magnification of the
previous case shows the filamentous spirochetes.

Figure 4.298 Intestinal spirochetosis (Warthin–Starry silver stain). The spirochetes create a black
border with silver impregnation stain. Individual spirochetes are visible using the oil immersion
objective.

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**Thankfully, it is not necessary to count pyloric and Paneth cells for

the diagnosis of pyloric gland metaplasia or Paneth cell metaplasia,
respectively.
**If sexually transmitted infectious proctocolitis is a clinical
consideration, clinical studies provide the best means to establish this
diagnosis (syphilis: serum RPR, RPR titer, and a treponemal specific
serology such as fluorescent treponemal antibody; lymphogranuloma
venereum (LGV): rectal swab collected in the absence of lubricant for
Chlamydia trachomatis nucleic acid probe test or culture and LGV
PCR).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
***If no history is provided, see general chronic colitis sample note (IBD
subsection, this chapter).
 Index

Note: Page number followed by f and t indicate figure and table

respectively.

A
Adenovirus infection, 198, 199f
Adventitia, esophagus, 2, 3f
AIE. See Autoimmune enteropathy (AIE) Air artifact, 391–392, 393f–
394f
Alcian blue, pH 2.5, 4
Allergic colitis, 379–380, 380f
Allograft rejection, small bowel, 222–225
apoptotic bodies for diagnosis of, 225
crypt architectural disturbance, 223f–224f features of, 225
grading schema for, 223t
AMAG. See Autoimmune metaplastic atrophic gastritis (AMAG)
Amyloidosis
esophagus, 29, 29f–30f, 67f, 68
hemorrhagic gastritis pattern, 156, 156f Antienterocyte antibodies
(AEA), 258
Antral mucosa, 80f, 82, 82f–83f
G cells, 82f
normal, 82f
pyloric glands, 82f
Apoptotic bodies
for diagnosis of GVHD, 220, 220f
in esophagus, 18, 56, 56f, 57, 57f, 71f–72f, 72
with CMV infection, 72f
in MMF colitis, 404–405, 404f
in stomach, 167–168, 167f, 168f
Apoptotic cells, 220
Autoimmune atrophic gastritis. See Autoimmune metaplastic atrophic
gastritis (AMAG) Autoimmune enteropathy (AIE), 256–258, 257f–
258f Autoimmune gastritis (AIG). See Autoimmune metaplastic
atrophic gastritis (AMAG) Autoimmune metaplastic atrophic
gastritis (AMAG), 106–109, 106f–108f. See also Stomach antral
histology of, 107f
body/fundus histology of, 108f
and environmental metaplastic atrophic gastritis (EMAG)
comparison by compartment and potential neoplasia, 119t by
patterns of injury, 119t
features of, 120
G cell location comparison, 108f
linear ECL cell hyperplasia, 108f
morphologic features, 106, 107f–108f neuroendocrine tumors and,
107f
nodular ECL cell hyperplasia, 108f
normal gastric cell populations and, 107f physiology of, 106, 106f

B
Backwash ileitis, 202, 202f, 352
Basal lymphoplasmacytosis, chronic colitis, 342f Bezoar, 173, 173f
Bifid crypts, chronic colitis, 341f
Bile acid breath test, 243
Bile acid sequestrants, 26–27, 26f–27f Bisphosphonates, and acute
esophagitis, 28, 28f

C
Calcinosis, 162–164, 163f
Campylobacter infection, 323, 324f Candida esophagitis, 10–11, 11f–12f
pseudohyphae in, 12, 12f
scattered yellow plaques, 11f
Candidiasis, parakeratosis, 41, 42f–43f, 44
Cardiac mucosa, at gastroesophageal junction, 2, 3f CCS. See Cord colitis
syndrome (CCS) Cecal red patch, 352, 352f
Celiac disease, 243–244, 243t, 244f–248f, 247–257, 247t, 249t, 250f–
251f 2013 American College of Gastroenterology Recommendations,
 247t CD3 and CDX2 immunohistochemical stain for, 251, 251f
confounding features in, 246f
counting IELs in villous tips, 250, 250f endoscopic image, 244f
enteropathy-associated T-cell lymphoma (EATCL), 248, 248f
features of, 248–249
genetic testing, 244
gluten challenge, 252
gluten-free diet (GFD) in, 248, 252
histologic classification and grading systems for, 249t IELs in, 249,
250f
lymphocytic colitis in, 247f
modified Marsh 1, 244f, 245f
modified Marsh 3a, 245f
modified Marsh 3b, 245f, 246f
modified Marsh 3c, 246f, 247f
neutrophils in biopsies for, 250, 251f nonresponsive, 248
refractory celiac disease (RCD), 248
serologic testing, 243–244
treatment for, 248
Cholestyramine, 26, 26f–27f, 164f. See also Bile acid sequestrants Churg–
Strauss syndrome, 382, 383f
Civatte bodies, 51, 51f, 52f
Clostridium difficile
colitis, 217, 217f
infection, 331, 331f
CMV. See Cytomegalovirus (CMV) Colchicine toxicity, 73
Colesevelam, 26. See also Bile acid sequestrants Colestipol, 26. See also
Bile acid sequestrants Colitis, pattern-based approach to, 337, 337f
classification in, 337
active chronic colitis, 343
acute colitis, 337
chronic colitis, 336f–343f, 338–343
inactive chronic colitis, 343
clinicopathologic correlation, 343–344
mild, moderate, marked, 343, 343f, 344f Collagenous colitis, 374,
375f–377f, 377
Collagenous enteritis, 258–261, 259f–261f, 297
 in celiac disease, 297
with collagenous colitis, 298f
Collagenous gastritis, 126–127, 126f–128f Collagenous sprue. See
Collagenous enteritis Colon, 310
acute colitis pattern, 317–318, 317f, 318f Campylobacter infection,
323, 324f crypt abscess, 318f
cryptitis, 318f
cytomegalovirus, 318, 319f–320f
Salmonella infection, 320–321, 321f–322f Shigella infection,
322, 323f chronic colitis pattern, 336, 336f
cord colitis syndrome, 367–368, 367f diversion-associated
colitis, 359–360, 360f–362f diverticular disease, 355–359,
356f–358f inflammatory bowel disease, 344–355
ipilimumab colitis, 368–370, 368f–370f pattern-based approach
to, 337–344, 337f resins, 371, 371f
syphilitic and lymphogranuloma venereum proctocolitis, 362–
366, 363f–365f eosinophilia pattern, 378
allergy, 379–380, 380f
causes, 378
collagen vascular disorder and vasculitis, 382, 383f idiopathic
eosinophilic colitis, 378, 379f infection and, 381, 382f
inflammatory bowel disease, 379
medications and, 380–381, 381f
systemic mastocytosis, 383, 383f–384f focal active colitis
pattern, 314–316, 314f–316f acute self-limited colitis, 317
causes, 316
granulomatous pattern, 384–388
Colon (continued)
ischemic colitis pattern, 324f, 325, 325f infection and, 331, 331f
ischemia and, 325, 326f–330f, 326t, 328
medication injury, 332–333, 332f
lymphocytic pattern, 371–372, 371f
collagenous colitis, 374, 375f–377f, 377
lymphocytic colitis, 372–373, 372f–374f medications in, 377
near misses
apoptotic colopathy, 404–405, 404f
benign signet ring cell change, 400f–401f, 401
 endometriosis, 399–400, 399f, 400f
pulse granulomata, 402–403, 402f–403f spirochetosis, 405f–
408f, 406–407
normal, 310–313, 310f–313f
colonic crypts, 310f–311f
layers of, 310f
left colon, 312f
muciphages in rectum, 313f
near-normal rectum, 313f
normal rectum, 313f
Paneth cells and endocrine cells, 311f, 312f right colon, 312f
serosa, 313
pigments and extras, 389f
air artifact, 391–392, 393f–394f
medication resins, 398, 398f
melanosis coli, 389, 390f–391f
muciphages, 396–397, 397f–398f
pneumatosis cystoides intestinalis (PCI), 395–396, 395f–396f
tattoo pigment, 391, 391f–392f
pseudomembraous pattern, 333, 333f
causes, 333
Clostridium difficile colitis and, 334, 334f early, 334f, 335f
eruptive pseudomembrane, 335f
ischemia and, 333
marked, 335f
Colon diverticula, occurence of, 359
Colostomy (with Hartmann pouch), 346f Common variable
immunodeficiency (CVID) lymphocytic esophagitis pattern, 55, 55f
malabsorption pattern, 255–256, 255f, 256f small bowel, 296, 296f
Cord colitis syndrome (CCS), 367–368, 367f Cowden/PTEN hamartoma
tumor syndrome, 139t Creeping fat, 209
Crohn disease. See also Colon; Inflammatory bowel disease (IBD) crypt
architectural disturbance, 208–211, 209f, 210f granulomatous
pattern, 385, 386f
lymphocytic esophagitis pattern, 50, 50f pouchitis and, 231, 231f–
232f
Cronkhite-Canada syndrome, 139t, 144f–145f, 145
Crypt abscesses, 340f
Crypt dropout, chronic colitis, 341f, 342
Cryptosporidiosis, 293f–294f
Crypt shortfall, chronic colitis, 341f, 342
Crypt-to-villous ratio, 235, 236f
Cuffitis, 227, 228f, 229. See also Pouchitis CVID. See Common variable
immunodeficiency (CVID) 14C-xylose breath test, 243
Cytomegalovirus (CMV)
acute duodenitis pattern, 198, 199f
colitis, 318, 319f–320f
esophagitis, 7f, 12, 13f
immunostain, 103

D
Dart game analogy, 190f
Diaphragm disease, 201, 202, 211–212
crypt architectural disturbance, 211f–212f endoscopic view, 211f
Diffuse corporal atrophic gastritis (DCAG). See Autoimmune metaplastic
atrophic gastritis (AMAG) Diversion-associated colitis, 359–360,
360f–362f Diversion colitis, 339f
Diverticular-associated segmental colitis (DAC), 356. See also
Diverticular disease Diverticular disease, 355–359, 356f–358f
Diverticulitis, 355. See also Diverticular disease Diverticulosis, 355.
See also Diverticular disease Doxycycline, and acute gastritis, 91
Drug reactions, and eosinophilic pattern, 38, 38f Duodenal eosinophilia,
with eosinophilic esophagitis, 234f Dystrophic calcification, 162

E
EMAG. See Environmental metaplastic atrophic gastritis (EMAG)
Endometriosis, 399–400, 399f, 400f
Enterochromaffin-like (ECL) cell hyperplasia, 106, 108, 108f, 109
Enteropathy-associated T-cell lymphoma (EATCL), 248, 248f
Environmental metaplastic atrophic gastritis (EMAG), 109, 119, 120
EoE. See Eosinophilic esophagitis (EoE) Eosinophil degranulation, 130
Eosinophilic esophagitis (EoE), 10, 33, 34f–36f, 36–38, 36t basal cell
hyperplasia in, 34f
endoscopic esophageal furrows in, 34f endoscopic esophageal rings
 in, 34f
endoscopic esophageal trachealization in, 34f eosinophil
degranulation in, 35f
eosinophilic microabscess in, 35f
eosinophilic pattern, 34f, 35f
feline esophagus, 34f
food impaction in, 35f, 36f
and gastroesophageal reflux disease, 36t lamina propria sclerosis in,
36f
Eosinophilic gastritis. See Gastric eosinophilia Eosinophilic pattern of
injury, in esophagus, 30–31
drug reactions and, 38, 38f
eosinophilic esophagitis and, 33, 34f–36f, 36–38, 36t food allergies
and, 38, 39f
gastroesophageal reflux disease and, 31–33, 32f–33f photodynamic
therapy and, 38–39, 39f scleroderma and, 40, 40f
Eosinophils, 31
Eosinophil’s cytoplasmic granules, 31
Erosion, 8, 8f
versus ulceration, 8, 8f
Escherichia coli 0157:H7 infection, 331, 331f Esophageal ducts, 5, 5f–6f
Esophageal eosinophilia, 30f
Esophageal glands, 7f
Esophageal leukoplakia/epidermoid metaplasia, 44–46, 44f–45f
Esophagitis, acute, 7, 7f
amyloidosis and, 29, 29f–30f
causes, 7
CMV esophagitis, 7f
erosions and ulcerations, 7, 8f
gastroesophageal reflux disease and, 8–10, 8f–10f infections and
candida esophagitis, 10–11, 11f–12f
cytomegalovirus (CMV), 12, 13f
Helicobacter, 16, 17f
herpes simplex virus (HSV), 14, 14f–16f malignancy and, 29,
29f
medication injury, 18–28
bile acid sequestrants, 26–27, 26f–27f bisphosphonates, 28, 28f
 iron, 18–19, 18f–19f, 58
Kayexalate, 19–20, 20f–22f, 22
resins, 19–28, 58
sevelamer, 23, 23f–25f, 25
Esophagitis dissecans superficialis, 46–48, 46f–48f Esophagus
acute esophagitis pattern, 7, 7f
amyloidosis and, 29, 29f–30f
gastroesophageal reflux disease and, 8–10, 8f–10f infections
and, 10–17
malignancy and, 29, 29f
medication injury, 18–28
amyloid deposition, 67f, 68
anatomic esophageal constriction points, 2f apoptotic body
prominence, 71f–72f, 72
with artifactual split, 48f
cardiac mucosa at gastroesophageal junction, 2, 3f endoscopic
appearance of, 2, 2f
eosinophilic pattern of injury in, 30–31
drug reactions and, 38, 38f
eosinophilic esophagitis and, 33, 34f–36f, 36–38, 36t food
allergies and, 38, 39f
gastroesophageal reflux disease and, 31–33, 32f–33f
photodynamic therapy and, 38–39, 39f scleroderma and, 40,
40f
gastric inlet patches, 58f, 59
glycogenic acanthosis, 61f–64f, 62, 64
granular cell tumors, 68, 68f–70f, 70
granulomata, 70, 70f–71f
layers of, 2, 3f
lymphocytic esophagitis pattern, 49, 49f common variable
immunodeficiency, 55, 55f contact mucositis, 50
Crohn disease, 50, 50f
gastroesophageal reflux disease, 49–50, 49f graft versus host
disease, 55–58, 56f–57f, 56t, 57t infection
lichen planus/lichenoid pattern, 51, 51f–53f, 54
metastatic lobular breast carcinoma, 73, 73f mucosal surface, pink-
tinged, 2, 2f
 multilayered epithelium, 67, 67f
pancreatic heterotopia/metaplasia, 59–60, 59f–61f parakeratotic
pattern, 40–41, 40f
candida, 41, 42f–43f, 44
esophagitis dissecans superficialis, 46–48, 46f–48f
gastroesophageal reflux disease, 41, 41f–42f leukoplakia
pattern/epidermoid metaplasia, 44–46, 44f–45f ring mitoses,
72–73, 72f
squamous mucosa, 2, 3f
squamous papillomas, 64, 64f–66f, 66
tissue site as, histologic clues for, 5, 5f–7f

F
FAC. See Focal active colitis (FAC) Familial adenomatous polyposis,
137t, 138t Feline esophagus, 34f
Focal active colitis (FAC), 314–316, 314f–316f Focally enhanced gastritis
(FEG), 103–105, 104f in pediatric setting, 104, 105
Fontana–Masson special stain, 288
Food allergy, eosinophilic pattern, 38, 39f Formalin pigment, 286–287,
286f–287f Foveolar hyperplasia, 141–147, 142f–146f Cowden
syndrome, 145f
Cronkhite–Canada syndrome, 144f–145f features of, 146
gastric hyperplastic polyps, 141, 142f juvenile polyposis syndrome,
143f–144f Ménétrier disease, 146, 146f, 147
Peutz–Jeghers polyps, 144f
sporadic gastric hyperplastic polyp, 142, 142f–143f Fundic gland
polyps, 135, 136f, 140

G
Gastric antral vascular ectasia (GAVE), 87, 89f, 153, 154f–155f features
of, 154
intravascular thrombi, 155f
versus portal hypertensive gastropathy, 154t stripped watermelon-
like appearance, 154f Gastric body, 80f, 81, 81f. See also Oxyntic
mucosa; Stomach gastric antrum mislabeled as, 83f
with total oxyntic gland atrophy, 83f Gastric cardia, 84, 84f
Helicobacter pylori carditis, 84, 85f minimal, 84, 85f
Gastric eosinophilia, 128f, 129–130, 129f allergic, 132–133
connective tissue disorder and vasculitis and, 133–134
eosinophilic esophagitis, 129f
features of, 134
idiopathic eosinophilic gastritis and gastroenteritis, 130–131
inflammatory bowel disease and, 133
medications and, 131–132, 131f–132f
neoplasia and, 134
parasitic infection and, 133, 133f
peripheral eosinophilia, 129f
Gastric foveolar metaplasia, acute duodenitis pattern, 198f Gastric
heterotopia, 276–277, 276f, 277f malabsorption pattern, 239f
Gastric inlet patches, in esophageal mucosa, 58f, 59
Gastric lamina propria, 80
Gastric pseudomelanosis, 161, 162f
Gastroesophageal reflux disease (GERD), 8–10, 8f–10f, 31
balloon cells, 8, 9f
eosinophilic esophagitis and, 36t
eosinophilic pattern, 31, 32f–33f, 33
features of, 8
lymphocytic esophagitis pattern, 49–50, 49f marked, 8, 10f
mild, 8, 9f
moderate, 8, 9f, 10f
parakeratosis, 41, 41f–42f
Gastrointestinal tract and oral bacteria, location of, 93, 94f G cells, 82,
82f, 83
GERD. See Gastroesophageal reflux disease (GERD) Giardiasis, 294, 294f,
295f, 296
Gluten sensitive enteropathy. See Celiac disease Glycogenic acanthosis,
of esophagus, 61f–64f, 62, 64
with ballooned squamous cells, 64f
Barrett esophagus and, 62f
cells of, 63f
diffuse, 63f
endoscopic view of, 62f
focal, 63f
PAS/D stain, 62f
 raised nodule of, 63f
Graft versus host disease (GVHD) acute and chronic, 58
apoptosis and diagnosis of, 220
apoptotic bodies for, 220, 220f
crypt architectural disturbance pattern, 218–220, 218f–220f features
of, 218
grading of, 218
histologic grading, 56t
lymphocytic esophagitis pattern, 55–58, 56f–57f, 56t, 57t National
Institutes of Health (NIH) reporting of, 56, 57t Granular cell
tumors, in esophagus, 68, 68f–70f, 70
with pseudoepitheliomatous hyperplasia, 69f, 70f Granulomata, in
esophagus, 70, 70f–71f Granulomatous gastritis, 147–150, 147f,
148f causes, 147
Crohn disease and, 148f, 149f
foreign body reaction, 148f
isolated foreign body giant cell, 150, 150f sarcoidosis and, 148f
Grocott methenamine-silver stain (GMS), 11, 12f GVHD. See Graft versus
host disease (GVHD)

H
Helicobacter heilmannii, 17f acute gastritis pattern, 97–98, 98f–100f, 100
Helicobacter pylori, 17f
acute duodenitis pattern, 197, 197f, 198f carditis, 84, 85f
Diff-Quik stain, 17f
gastritis, 92–93, 96–97
acute gastritis pattern, 92–97, 92f–95f chronic gastritis pattern,
112f
lymphocytic gastritis pattern, 93f, 96
immunostain, 95, 95f, 96
Warthin–Starry stain, 17f
Herpes simplex virus (HSV) esophagitis, 14, 14f–16f Heterotopic gastric
mucosa (HGM), 58f, 59
Hinchey criteria, 359
Histoplasmosis, granulomatous pattern, 384f HSV immunostains, 16
HSV2 infection, 16
I
IBD. See Inflammatory bowel disease (IBD) Ileal-pouch anal anastomosis
(IPAA), 226–227, 226f, 229, 345–346, 345f Ileostomy, 346f
Inflammatory bowel disease (IBD). See also Colon; Crohn disease;
Ulcerative colitis acute ileitis pattern and, 202, 202f–205f, 336
chronic colitis pattern, 344–355
crypt architectural disturbance pattern, 208–211, 209f, 210f
eosinophils in, 379
granulomata in, 385
reality of, 351–354, 351f–354f
rules, 346–350, 347f–349f, 350t
syphilitic proctocolitis and, 362–363, 363f Intestinal ischemia, 212–
217, 214f–217f causes of, 213
earliest signs, 214f
end stage ischemic bowel with necrosis, 214f
eosinophilic/hyalinized lamina propria, 215f features of, 215
and infectious enteritides, 217
ischemic enteritis mimic, crush artifact, 216, 216f mesenteric
venous thrombosis and, 213
mirocrypt formation, 214f
nonocclusive ischemia and, 213–214
pseudomembrane formation, 217f
superior mesenteric artery (SMA) embolism and, 213
superior mesenteric artery thrombosis and, 213
vasculitis, evaluation for, 216, 217f Intestinal metaplasia (IM), 115,
115f, 116–117
Intestinal spirochetosis, 405f–408f, 406–407
Intraepithelial lymphocytes (IELs), 120f–122f, 121, 371–373, 377
Intraepithelial lymphocytosis, 235, 236f Ipilimumab colitis, 368–370,
368f–370f Iron deposition, gastric, 158, 159f–161f, 160–161
features of, 161
pattern A/“nonspecific gastric siderosis,” 159f pattern B/“iron pill
gastritis,” 159f pattern C/“gastric glandular siderosis,” 160f, 161f
Iron encrustation, ulcerative esophagitis, 18f Iron pill esophagitis,
18–19, 18f–19f with Kayexalate, 21f
Isospora belli, 292
Isosporiasis, 292, 292f–293f

J
J-pouch. See Ileal-pouch anal anastomosis (IPAA) Juvenile polyposis,
139t, 143f, 144f

K
Kayexalate, 19–20, 20f–22f, 22, 164f, 332, 332f, 371, 371f

L
Lamina propria granulomata, 70, 70f–71f Large bowel, regions of, 314t
Lichen planus/lichenoid pattern, of lymphocytic esophagitis, 51, 51f–
53f, 54
Lipomas, 392, 393f, 394f
Lymphangiectasia
and lymphangioma, 273
primary, 270, 272
secondary, 270, 271f, 272
Lymphocytic colitis, 372–373, 372f–374f Lymphocytic gastritis, 120–
121, 120f–124f, 125–126
causes, 120
celiac disease and, 123f, 126
features of, 125
and H. pylori infection, 122f–123f, 125
intraepithelial lymphocytes (IELs) in, 120f–122f, 121
medications and, 124f, 125
mucosa associated lymphoid tissue (MALT) lymphoma and, 124f
Lymphogranuloma venereum (LGV) proctocolitis, 362–366, 363f–
365f

M
Masson trichrome, 259, 259f
Mast cell disease, 174f, 175, 175f
Meckel diverticulum, 280, 281f
Medication crystals. See Resins Medication-induced mucosal
eosinophilia, 380–381, 381f Medication related gastritis, 90–92, 91f
 Melanoma, 287–288, 287f–288f
Melanosis coli, 389, 390f–391f
Metaplasia, in stomach, 115–117, 115f, 116f intestinal metaplasia (IM),
115, 115f, 116–117
pancreatic metaplasia, 116, 116f
pyloric metaplasia, 115–116, 115f
Metastatic lobular breast carcinoma, 168f, 169, 169f Micrococcus, 173
MMF. See Mycophenolate mofetil (MMF) Mott cells, 171
Muciphages, 312, 313f, 396–397, 397f–398f Mucosa, esophagus, 2, 3f
Mucosal calcinosis, 162–164, 163f
Mucosal eosinophilia, 130, 234f
Mucus neck cells, 171f, 172, 172f
Multifocal atrophic gastritis (MAG). See Environmental metaplastic
atrophic gastritis (EMAG) Multilayered epithelium, esophagus, 67,
67f Muscularis propria (MP), esophagus, 2, 3f Mushroom, ingested,
174f
Mycobacterium avium-intracellulare (MAI), 262, 263f, 264
Mycophenolate mofetil (MMF)
colitis, 404f, 405
colonic eosinophilia pattern, 381f
damage from, 221, 221f–222f
Mycophenolic acid, damage from, 221, 221f–222f

N
Neuroendocrine tumors
and autoimmune metaplastic atrophic gastritis, 107f, 109
small bowel biopsy, 298f–299f, 299
Nongluten protein sensitivity, 252, 253f Nonsteroidal antiinflammatory
drugs (NSAIDs) and acute gastritis, 91
and acute ileitis pattern, 201, 201f diaphragm disease and, 211, 212
small bowel injury and, 237, 237f
NSAIDs. See Nonsteroidal antiinflammatory drugs (NSAIDs)

O
Olmesartan, 237
collagenous gastritis pattern, 126f, 127f lymphocytic gastritis, 124f,
125
Omphalomesenteric duct, 280
“Owls’ eye” appearance, CMV gastritis, 101, 101f Oxyntic gland
hyperplasia, 135–141, 136f–137f, 140f, 141f features of, 140
fundic gland polyps, 135, 136f, 140
nonpolypoid mucosa biopsy and oxyntic gland dilatation, 141, 141f
syndromic polyposis, 135, 137, 138t–139t, 140
Oxyntic glands, 81
neck of, 81f
Oxyntic mucosa, 60, 80f, 81, 81f
neck of oxyntic glands, 81f
normal, 81f
parietal cell, physiology of, 81f
pits and glands in, 81f

P
Pancreatic heterotopia, 59–60, 59f–61f, 278–279, 278f Pancreatic
metaplasia, 59–60, 59f–61f, 116, 116f Paneth cell metaplasia, 338f–
339f, 339
Parakeratosis, 40–41, 40f
candida, 41, 42f–43f, 44
esophagitis dissecans superficialis, 46–48, 46f–48f gastroesophageal
reflux disease, 41, 41f–42f leukoplakia pattern/epidermoid
metaplasia, 44–46, 44f–45f Parietal cell, physiology of, 81f, 106f
PCI. See Pneumatosis cystoides intestinalis (PCI) Peptic injury,
196–197, 197f
Peptic ulcer disease (PUD), 196, 239
Periappendicial disease, 352, 352f
Periodic acid Schiff/alcian blue stain (PAS/AB), 4, 5
Peutz–Jeghers syndrome, 138t, 144f, 147
Peyer patches, 190f, 191
Peyer patch pigment. See Titanium pigment PHG. See Portal
hypertensive gastropathy (PHG) Photodynamic therapy (PDT), 38–
39
eosinophilic pattern, 39f
Pill esophagitis, 18, 18f
eosinophilic pattern, 38f
Pill fragments, nonspecific, 91f
Plasma cells, absence of, in CVID, 255, 256, 256f Pneumatosis cystoides
intestinalis (PCI), 387, 395–396, 395f–396f Portal hypertensive
gastropathy (PHG), 151–153, 152f–153f congested vessels, 152,
152f
features of, 153
gastric antral vascular ectasia versus, 154t snake skin, mosaic-like
pattern, 152f Pouchitis, 226–232
clinical manifestations of, 227, 227f–228f and Crohn disease, 231,
231f–232f
crypt architectural disturbance, 227f–230f features of, 229
ileal-pouch anal anastomosis and, 227
prepouch ileitis, 230
pyloric gland metaplasia in, 230, 230f risk factors for, 227
Pseudogoblet cells, 3, 3f, 4f
and true goblet cells, 3, 4f
Pseudohyphae, 12, 12f
Pseudomelanosis coli. See Melanosis coli Pseudomelanosis duodeni, 281f,
284, 285f, 286
Pseudomembrane, 333. See also Colon, pseudomembraous pattern Pulse
granulomata, 402–403, 402f–403f Pyloric gland metaplasia, 338,
338f
Pyloric metaplasia, 115–116, 115f, 279–280, 279f–281f in chronic
pouch, 230, 230f

R
Radiation enteritis, and crypt architectural disturbance, 225, 225f–226f
Radiation gastritis, 156–157, 157f
Reactive duodenopathy
malabsorption pattern, 238–240, 238f–239f in small bowel mucosal
biopsies, 274–276, 275f–276f Reactive gastritis/gastropathy, 85–
87, 85f, 86f active chronic, 89, 89f
causes, 85, 87
and erosion, 88f
features of, 87
gastric antral vascular ectasia, 89f iron deposition, 88f
portal hypertensive gastropathy, 89f and ulceration, 88f
Renagel, 23. See also Sevelamer Renvela, 23. See also Sevelamer Resins,
 19, 164, 164f
bile acid sequestrants, 26–27, 26f–27f Kayexalate, 19–20, 20f–22f,
22
sevelamer, 23, 23f–25f, 25
Ring mitoses, 72–73, 72f
Russell body gastritis, 170–171, 170f, 171f

S
Salmonella infection, 320–321, 321f–322f Sarcoidosis, granulomatous
pattern, 387f, 388f Schistosoma ova, 382f
Scleroderma, eosinophilic pattern, 40, 40f Segmental colitis associated
with diverticulosis (SCAD) syndrome, 356. See also Diverticular
disease Sevelamer, 23, 23f–25f, 25, 333, 398
Shigella infection, 322, 323f SIBO. See Small intestinal bacterial
overgrowth (SIBO) Signet ring cell change, 400f–401f, 401
Sloughing esophagitis, 46–48, 46f–48f Small bowel, 186
acute duodenitis pattern, 195, 195f, 196
causes, 196
features of, 199
infection, 197–199, 197f–199f
marked, 196
mild, 196
moderate, 196
peptic injury, 196–197, 197f
acute ileitis pattern, 200, 200f–201f aphthoid lesion, 200f
causes, 201
and Crohn disease, 202, 203f–205
features of, 202
inflammatory bowel disease and, 202, 202f–205f luminal
neutrophils with inflammation in epithelium, 201f
medications and, 201, 201f
chronic inflammation pattern, 206–207, 206f, 207f crypt
architectural disturbance pattern, 208, 208f causes, 208
diaphragm disease and, 211–212, 211f–212f features of, 212
graft versus host disease, 218–220, 218f–220f inflammatory
bowel disease and, 208–211, 209f, 210f ischemia and, 212–
217, 214f–217f (see also Intestinal ischemia) medications and,
 221, 221f–222f
pouchitis and pouch-related changes, 226–232
radiation enteritis and, 225, 225f–226f small bowel allograft
rejection and, 222–225, 223f–224f, 223t dilated lacteal
pattern, 269f, 270
causes, 270
clinically small bowel obstruction, 273f Crohn disease, 273f
metastatic alveolar rhabdomyosarcoma, 272f metastatic
melanoma, 273f
not further specified, 273f
primary lymphangiectasia and, 270
radiation therapy, 273f
secondary lymphangiectasia and, 270, 271f, 272
eosinophilia pattern, 233–234, 233f–234f foamy macrophage
pattern, 261f, 262, 262f mycobacterium avium-intracellulare (MAI),
262, 263f, 264
nonspecific scattered macrophages, 269
Whipple disease, 261f, 262f, 264, 265f–267f, 268–269
malabsorption pattern, 235–236
autoimmune enteropathy and, 256–258, 257f–258f celiac
disease, 243–244, 243t, 244f–248f, 247–257, 247t, 249t,
250f–251f collagenous enteritis and, 258–261, 259f–261f
common variable immunodeficiency and, 255–256, 255f,
256f crypt hyperplasia in, 235, 236f
intraepithelial lymphocytosis in, 235, 236f medication and,
237, 237f
nongluten protein sensitivity and, 252, 253f reactive
duodenopathy and, 238–240, 238f–239f small intestinal
bacterial overgrowth and, 240–243, 240t, 241f–242f tropical
sprue, 253–255, 253f–254f
villous blunting in, 235, 236f
metaplasia and heterotopia, 274f
gastric heterotopia, 276–277, 276f, 277f pancreatic heterotopia,
278–279, 278f pyloric metaplasia, 279–280, 279f–281f
reactive duodenopathy and, 274–276, 275f–276f near misses
collagenous enteritis, 297, 297f–298f common variable
immunodeficiency, 296, 296f giardiasis, 294, 294f, 295f, 296
 isosporiasis, 292, 292f–294f
sneaky adenocarcinoma, 291, 291f
sneaky neuroendocrine tumor, 298f–299f, 299
normal
Brunner glands, 188, 189f
crushed Brunner glands, 189f
crypt base, 188f
crypt to villous ratio, 187f
endoscopic findings in duodenum, 186f lacteals, 187f
layers of small intestine, 186, 186f lipid “hang-up,” 187f
lymphoid aggregates, 190–191, 190f, 192f–195f proximal
duodenum with Brunner glands, 189f smooth muscle within
villous core, 188f terminal ileum, 190f, 192f–195f
variant morphology, 188f
villous projection, 186, 187f
villous tip, 187f
pigments and extras, 281, 281f
features, 290
fig pigment composition, 290f
formalin pigment, 286–287, 286f–287f melanoma, 287–288,
287f–288f
pseudomelanosis duodeni, 284, 285f, 286
tattoo pigment, 283–284, 284f
titanium, 282, 282f, 283f
90yttrium-labeled microspheres, 288, 289f Small intestinal
bacterial overgrowth (SIBO), 240–243, 240t, 241f–242f
Sodium polystyrene sulfonate. See Kayexalate Spirochetosis,
405f–408f, 406–407
Squamous papillomas, of esophagus, 64, 64f–66f, 66
Stomach, 80, 80f
acute gastritis pattern, 90–105, 90f cytomegalovirus, 100–101,
100f–103f, 103
focally enhanced gastritis, 103–105, 104f Helicobacter
heilmannii, 97–98, 98f–100f, 100
Helicobacter pylori, 92–97, 92f–95f medications, 90–92, 91f
anatomic compartments of, 80f
chronic gastritis pattern, 105, 105f atrophic subpattern, 113, 113f,
 114f, 115
autoimmune metaplastic atrophic gastritis, 106–109, 106f–
108f, 119t, 120
basal lymphocytic infiltrate subpattern, 112, 113f
compartments for injury patterns, 110, 110f environmental
metaplastic atrophic gastritis, 109, 119t, 120
lymphoid aggregates subpattern, 117, 117f, 118f metaplastic
subpattern, 115–117, 115f, 116f superficial plasmacytic
infiltrate subpattern, 111–112, 111f, 112f collagenous
gastritis pattern, 126–127, 126f–128f gastric eosinophilia
pattern, 128f, 129–130, 129f allergic, 132–133
connective tissue disorder and vasculitis and, 133–134
features of, 134
idiopathic eosinophilic gastritis and gastroenteritis, 130–131
inflammatory bowel disease and, 133
Stomach (continued)
medications and, 131–132, 131f–132f
neoplasia and, 134
parasitic infection and, 133, 133f
granulomatous gastritis pattern, 147–150, 147f, 148f causes, 147
Crohn disease and, 148f, 149f
foreign body reaction, 148f
isolated foreign body giant cell, 150, 150f sarcoidosis and, 148f
histology and function
antrum and pylorus, 80f, 82, 82f–83f body and fundus, 80f, 81,
81f, 83
gastric cardia, 84, 84f, 85f
transitional mucosa, 84, 84f
hyperplastic pattern, 134–135, 134f
causes, 135
foveolar hyperplasia, 141–147, 142f–146f Ménétrier disease,
134f
oxyntic gland hyperplasia, 135–141, 136f–137f, 140f, 141f
layers of, 80, 80f
lymphocytic gastritis pattern, 120–121, 120f–124f, 125–126
causes, 120
celiac disease and, 123f, 126
 features of, 125
and H. pylori infection, 122f–123f, 125
intraepithelial lymphocytes (IELs) in, 120f–122f, 121
medications and, 124f, 125
mucosa associated lymphoid tissue (MALT) lymphoma and,
124f near misses
amyloidosis, 166f, 167, 167f
apoptotic body prominence, 167–168, 167f, 168f bezoar and
other foreign material, 173, 173f, 174f mast cell disease,
174f, 175, 175f
mucus neck cells, 171f, 172, 172f
poorly differentiated adenocarcinoma with signet ring cell
features, 168f, 169, 169f Russell body gastritis, 170–171,
170f, 171f Sarcina, 172f, 173
pigments and extras, 158
calcinosis, 162–164, 163f
gastric pseudomelanosis, 161, 162f
iron, 158, 159f–161f, 160–161
resins, 164, 164f
90yttrium-labeled microspheres, 164–166, 165f reactive
gastritis/gastropathy pattern, 85–89, 85f, 86f, 88f, 89f (See
also Reactive gastritis/gastropathy) vascular/hemorrhagic
pattern, 151, 151f amyloidosis, 156, 156f
causes, 151
gastric antral vascular ectasia, 153, 154f–155f, 154t portal
hypertensive gastropathy and, 151–153, 152f–153f radiation
gastritis pattern, 156–157, 157f Strongyloides larvae, 382f
Submucosa, esophagus, 2, 3f
Sydney System protocol, gastric mucosa biopsy, 110, 111f Syphilitic
proctocolitis, 362–366, 363f–365f Systemic collagen vascular
disorders, eosinophilic pattern, 40, 40f Systemic mastocytosis, 383,
383f–384f

T
Tattoo pigment, 283–284, 284f, 391, 391f–392f Taxane effect, 72–73,
72f
Ticlopidine, and lymphocytic gastritis, 125
Titanium pigment, 282, 282f, 283f
Toxic-ischemic pattern (TIP), 91
Transitional mucosa, 84, 84f
Tropical sprue, 253–255, 253f–254f
True goblet cells, 3, 4f
Type A gastritis. See Autoimmune metaplastic atrophic gastritis (AMAG)
Type B gastritis. See Environmental metaplastic atrophic gastritis
(EMAG)

U
Ulcer-associated cell lineage (UACL), 280
Ulcerative colitis, 339f, 345. See also Inflammatory bowel disease (IBD)
granulomatous pattern, 385, 387f

V
Varicella-zoster virus (VZV), 16

W
Waldmann disease, 270
Whipple disease, 261f, 262f, 264, 265f–267f, 268–269
features of, 268
histologic treatment effect, 268, 269
Mycobacterium intracellulare (MAI) versus, 268
Whipple immunostain, 265f

Y
90Yttrium-labeled microspheres, 164–166, 165f, 288, 289f

Z
Zollinger–Ellison syndrome, 137, 140, 140f, 196–197
 ESOPHAGUS 1

EQUESTIONS
E-QUIZ QUESTION 1 (e-FIG. 1.1)

e-Figure 1.1

Which of the following is the best diagnosis for this esophageal biopsy
submitted as “rule-out eosinophilic esophagitis”?

A. Amyloidosis underlying squamous mucosa

B. Squamous mucosa with mild graft versus host disease (GVHD) C.
Unremarkable squamous mucosa
D. Granular cell tumor undermining squamous mucosa Answer:
Amyloidosis underlying squamous mucosa (A).
Amyloidosis is an easily overlooked diagnosis owing to the pale and
sometimes focal nature of the findings. Amyloid appears as amorphous,
acellular eosinophilic material on H&E. Congo red staining can be
utilized to confirm the diagnosis with amyloid-appearing bright orange
under direct light, and apple-green when polarized. There are no
apoptotic bodies, dyskeratotic keratinocytes, or prominent intraepithelial
lymphocytes to suggest GVHD (B). Moreover, GVHD is a
clinicopathologic diagnosis requiring the appropriate setting of bone
marrow transplantation and typically a rash and GI symptoms, pertinent
features lacking in this case. Granular cell tumors can have a low-power
appearance similar to that of amyloid, but the eosinophilic material
characteristic of granular cell tumor is more coarse (“granular”),
confined within the cytoplasm, and S100 reactive (D). In contrast,
amyloid deposition is extracellular, smooth and homogenous, and S100
nonreactive.

E-QUIZ QUESTION 2 (e-FIG. 1.2)

e-Figure 1.2

Which of the following is the best diagnosis for this biopsy labeled
“distal esophagus” from a 13-year-old male with abdominal pain and an
unremarkable endoscopic examination?

A. Cardiac mucosa with nondiagnostic findings

B. Barrett mucosa, negative for dysplasia
C. Low-grade dysplasia in Barrett mucosa
D. Eosinophilic esophagitis
E. Small bowel mucosa with nondiagnostic findings (“carry-over”)
Answer: Small bowel mucosa with nondiagnostic findings (“carry-
over”) (E).
 This case had been previously diagnosed as Barrett mucosa but was
submitted to us for consultation based on the patient’s young age and
the important clinical implications. While Barrett mucosa can (rarely)
develop in children, not every goblet cell in an esophageal biopsy
signifies Barrett mucosa. The diagnosis of Barrett mucosa requires both
an abnormal endoscopic impression as well as goblet cells in the
esophagus.1,2 Since this patient had an unremarkable clinical
examination, the diagnosis of Barrett mucosa was not entertained.
Moreover, there are several clues pointing to a small bowel “carry-over”
artifact. First, the villiform architecture and the finding of Paneth cells in
virtually each crypt are more in keeping with small bowel mucosa
whereas Barrett mucosa usually has incomplete metaplasia and lacks
Paneth cells and a brush border. In addition, the depicted duodenal
mucosa is at the edge of the tissue block, suggesting it may represent a
tissue “carry-over” artifact (e-FIG. 1.3). Such artifacts typically occur via
contamination of the endoscopic or grossing instruments.

e-Figure 1.3

E-QUIZ QUESTION 3 (e-FIG. 1.4)

e-Figure 1.4

Which of the following is the best diagnosis for this esophageal biopsy
from a 43-year-old man with a history of bone marrow transplantation,
GI symptoms, and a skin rash?

A. Unremarkable squamous mucosa

B. Squamous mucosa with mild graft versus host disease (GVHD),
grade I C. Squamous mucosa with moderate GVHD, grade II
D. Squamous mucosa with severe GVHD, grade III

Answer: Squamous mucosa with moderate graft versus host disease

(GVHD) (C).
General features of GVHD of the esophagus include intraepithelial
lymphocytes, apoptotic bodies, dyskeratotic keratinocytes, and necrosis.
The overall abundance of the changes are utilized to grade the GVHD as
either mild (grade I), moderate (grade II), or severe (III). In this
example, dyskeratotic keratinocytes and apoptotic bodies are easily
identified such that they reach the threshold for moderate GVHD. Mild
GVHD would have only occasional findings (not quite as conspicuous as
moderate GVHD), and severe GVHD would have mucosal necrosis. In
addition, medication injury and infectious etiologies can have similar
histologic findings and consideration of these possibilities is worthwhile.
Toward this end, a careful medication review and a low threshold to
order CMV and HSV immunohistochemical stains on cases of possible
GVHD is prudent.

E-QUIZ QUESTION 4 (e-FIG. 1.5)

e-Figure 1.5

Which of the following is the best diagnosis given this low-power H&E
impression?

A. Unremarkable squamous mucosa

B. Candidiasis
 C. Eosinophilic esophagitis
D. Esophagitis dissecans superficialis

Answer: Candidiasis (B).

The image shows patchy parakeratosis, which should prompt a careful
examination for candidiasis. Note the high-power view, which shows the
diagnostic pseudohyphae embedded within the parakeratotic debris
(circle, e-Fig. 1.6). Intraepithelial eosinophils and basal hyperplasia are
absent, precluding consideration of eosinophilic esophagitis (C).
Esophagitis dissecans superficialis is characterized by an often
fragmented specimen with a “mummified” or “ghost” superficial
squamous layer (D). Recall the following endoscopic “buzzwords” or
characteristic endoscopic appearances for choices B–D.
• Candidiasis&emdash;white plaques
• Eosinophilic esophagitis&emdash;furrowing or felinization • Esophagitis
dissecans superficialis&emdash;a sloughing appearance with white
sheets of tissue that appear to easily dislodge during the endoscopic
examination

e-Figure 1.6

E-QUIZ QUESTION 5 (e-FIG. 1.7)

 e-Figure 1.7

Which of the following is the best diagnosis for this esophageal biopsy
from a 55-year-old man with a history of reflux and an irregular Z-
line?

A. Cardiac mucosa with multilayered epithelium, negative for Barrett

mucosa B. Barrett mucosa, negative for dysplasia
C. Low-grade dysplasia in Barrett mucosa
D. Dysplasia in Barrett, basal crypt pattern
E. Pancreatic acinar metaplasia

Answer: Cardiac mucosa with multilayered epithelium (A), negative for

Barrett mucosa.
This consultation case was submitted along with a preliminary
diagnosis of intramucosal carcinoma in Barrett mucosa. However, the
histologic features are those of multilayered mucosa, a common mimic
of true goblet cells of the distinctive type. Multilayered mucosa bears
resemblance to both squamous and glandular mucosa with pseudogoblet
cells. The appearance is reminiscent of that of immature squamous
metaplasia of the uterine cervix. A PAS/AB highlights the tinctorial
appearance of the mucin in multilayered mucosa as a two-tone purple-
blue color that is a cross between the character of true-goblet cells
(deeply basophilic) and foveolar mucosa (magenta) (not shown). Some
authors regard multilayered mucosa as the precursor to Barrett
mucosa,3,4 but as of this writing here are no official recommendations on
the diagnosis and management of multilayered epithelium.

E-QUIZ QUESTION 6 (e-FIG. 1.8)

e-Figure 1.8

Which of the following is the best diagnosis of this esophageal biopsy

from an 30-year old with an esophageal nodule?

A. Invasive squamous cell carcinoma

B. Granular cell tumor
C. Granulomatous esophagitis
D. Amyloidosis

Answer: Granular cell tumor (B).

This case was sent to us in consultation as “invasive squamous cell
carcinoma.” The family requested a second opinion before treatment.
Recognition of the underlying granular cell tumor and awareness that
these lesions are often accompanied by tremendous reactive epithelial
changes (pseudoepitheliomatous hyperplasia) are the key to the correct
diagnosis (B) and to avoiding overdiagnosing the reactive epithelial
changes as invasive squamous cell carcinoma (A). These neoplastic cells
have abundant granular cytoplasm owing to an accumulation of
lysosomes; the latter accounting for CD68 reactivity. Although H&E
impressions are generally sufficient for the diagnosis, the lesional cells
are S100 reactive. Neither amyloid nor granulomata are seen (C and D).

E-QUIZ QUESTION 7 (e-FIG. 1.9)

 e-Figure 1.9

Which of the following is the best clinical impression for this endoscopic
image?

A. Barrett mucosa
B. Esophagitis dissecans superficialis
C. Eosinophilic esophagitis (EoE)
D. Normal

Answer: Eosinophilic esophagitis (EoE) (C).

This image shows furrowing or felinization of the esophagus, features
that are suggestive but not diagnostic of EoE (C). Without endoscopic
appearance, clinical history, and biopsy site location, the following
entities can have nearly identical histologic features: EoE, GERD, food
allergy, or photodynamic therapy. As a result, it is imperative to
correlate the endoscopic impression with the clinical history and biopsy
findings of both the distal and the mid- (or proximal-)esophagus.

E-QUIZ QUESTION 8 (e-FIG. 1.10)

 e-Figure 1.10

Which of the following is true about this esophageal biopsy from a 34-
year-old female with an esophageal polyp?

A. It is not typically associated with human papilloma virus B. It is

associated with low-risk human papilloma virus C. It is associated
with high-risk human papilloma virus D. It is often multifocal

Answer: This lesion is not typically associated with human papilloma

virus (A).
In the United States, squamous papillomas are typically incidentally
detected as a solitary nodule in the distal esophagus. There is a slight
female predominance and most are unassociated with human papilloma
virus. These lesions seldom progress to dysplasia or carcinoma, and do
not tend to recur.

E-QUIZ QUESTION 9 (e-FIG. 1.11)

 e-Figure 1.11

Which of the following is the best impression for this endoscopic image?

A. Candidiasis
B. Viral esophagitis
C. Eosinophilic esophagitis
D. Barrett mucosa

Answer: Candidiasis (A).

The endoscopic image shows white plaques suspicious for candidiasis
(B). A similar plaque-like lesion can be seen with glycogenic acanthosis,
lichen planus, and leukoplakia; biopsy is crucial to arrive at the correct
diagnosis. Ulcerations are the typical endoscopic appearance of viral
esophagitis (B). Furrowing or felinization is the characteristic
appearance of eosinophilic esophagitis (C). Salmon-colored mucosal
tongues are the typical description of Barrett mucosa (D).

E-QUIZ QUESTION 10 (e-FIG. 1.12)

 e-Figure 1.12

This low-power view of a distal esophagus biopsy shows basal cell

hyperplasia, elongation of the vascular papillae, and prominent
intraepithelial eosinophils (up to 42 eosinophils in one high power
field). Which of the following is the best diagnosis for this scenario?

A. Eosinophilic esophagitis (EoE)

B. Gastroesophageal reflux disease (GERD)
C. Parasitic infection
D. Correlation with clinical information is necessary Answer:
Correlation with clinical information is necessary (D).
The presence of eosinophils in the esophagus represents only a pattern
of injury, not a specific diagnosis. Answers A and B are wrong because of
the nonspecific nature of eosinophils in the esophagus. Although the
number of eosinophils exceeds 15 (a minimum suggested threshold for
EoE), the number of eosinophils cannot alone distinguish EoE from
GERD or other etiologies, such as photodynamic therapy (PDT) changes
or food allergy. Diagnosis of EoE should be left to the clinician who is
able to correlate all the necessary clinical information. Parasitic infection
[C] is incorrect because parasites essentially never affect the esophagus.

E-QUIZ QUESTION 11 (e-FIGS. 1.13 AND 1.14)

 e-Figure 1.14

e-Figure 1.13

These are two biopsies from the esophagus. Which of the following is
correct about each picture?

A. Figure A shows glycogenic acanthosis; figure B shows ballooned

keratinocytes B. Figure A shows ballooned keratinocytes; figure B
shows glycogenic acanthosis C. Figure A and B both show
glycogenic acanthosis
D. Figure A and B both show ballooned keratinocytes as a result of
GERD

Answer: Figure A is ballooned keratinocytes; figure B is glycogenic

acanthosis (B).
 Although both figures show squamous cells with abundant pale
cytoplasm, figure A shows angulated cells with white/clear cytoplasm
with hard and dense cytoplasmic borders that have a basket weave
appearance, features characteristic of ballooned keratinocytes. The
squamous cells in figure B have abundant pale pink cytoplasm with a
frosted-glass–like texture, features characteristic of glycogenic
acanthosis. The cells have delicate cytoplasmic borders which are
rounded from distention with glycogen.

E-QUIZ QUESTION 12 (e-FIG. 1.15)

e-Figure 1.15

This midesophageal biopsy with prominent intraepithelial eosinophils

comes with a requisition that states “follow-up of Barrett’s.” Which of
the following statements is true?

A. The mucosal eosinophilia could be a result of prior endoscopic

mucosal resection (EMR) for dysplasia in Barrett esophagus B. The
mucosal eosinophilia could be a result of prior photodynamic
therapy (PDT) for dysplasia in Barrett esophagus C. The mucosal
eosinophilia could be a result of prior radiofrequency ablation
(RFA) for dysplasia in Barrett esophagus D. This patient has
eosinophilic esophagitis (EoE) based on the histologic findings
Answer: The mucosal eosinophilia could be a result of prior
photodynamic therapy (PDT) for dysplasia in Barrett esophagus (B).
 A small subset of patients who undergo photodynamic therapy (3% to
4%) for Barrett esophagus demonstrates eosinophilic infiltrates that
histologically resemble the change seen in eosinophilic esophagitis
(EoE). To date, this has not been reported in patients who have received
radiofrequency ablation (C) or endoscopic mucosal resection (A). The
histologic findings of eosinophilic esophagitis are nonspecific and a
diagnosis cannot be made in the absence of the appropriate clinical
context (D).

E-QUIZ QUESTION 13

Which are the most likely causes of infectious, ulcerative esophagitis?

More than one answer may apply.

A. CMV
B. HSV
C. Candida
D. Adenovirus
E. Human papilloma virus

Answer: CMV (A), HSV (B), Candida (C).

E-QUIZ QUESTION 14

Coarse brown pigment is seen entrapped within ulcer debris. The patient
is an 85-year-old woman with a history of iron deficiency anemia. No
history of calcium supplementation is documented. What is the most
likely culprit?

A. Calcium
B. Iron
C. Lipofuscin
D. Melanin

Answer: Iron (B).

E-QUIZ QUESTION 15
Which of the following special stains highlights iron?

A. Fontana Masson
B. Prussian blue
C. Trichrome
D. Congo Red

Answer: Prussian blue (B).

Fontana Masson stains melanin and lipofuscin (A) (B). Trichrome
stains collagen (C). Congo Red stains amyloid (D).

E-QUIZ QUESTION 16 (e-FIG. 1.16)

e-Figure 1.16

Identify the following resin:

A. Kayexalate
B. Sevelamer
C. Cholestyramine
D. Renvela

Answer: Cholestyramine (C).

On PAS/D, cholestyramine is variable gray or hot pink (C), Kayexalate
is hot pink (A), and sevelamer (also known as Renagel or Renvela) is
lavender (B) (D).
E-QUIZ QUESTION 17 (e-FIG. 1.17)

e-Figure 1.17

Identify the following resin:

A. Kayexalate
B. Sevelamer
C. Cholestyramine
D. Renvela

Answer: Kayexalate (A).

On H&E, Kayexalate is purple with a narrow, regular “fish-scales” (A);
sevelamer (B) (or Renvela [D]) is two-toned color (bright pink linear
accentuations and a rusty yellow background) with broad, curved, and
irregularly spaced “fish-scales”; cholestyramine is bright orange and
lacks “fish-scales” (C).

E-QUIZ QUESTION 18 (e-FIG. 1.18)

 e-Figure 1.18

Identify the following resin?

A. Kayexalate
B. Sevelamer
C. Cholestyramine
D. Renvela

Answer: Sevelamer (B) or Renvela (D).

On H&E, Kayexalate is purple with a narrow, regular “fish-scales” (A);
sevelamer (B) (or Renvela [D]) is two-toned color (bright pink linear
accentuations and a rusty yellow background) with broad, curved, and
irregularly spaced “fish-scales”; cholestyramine is bright orange and
lacks “fish-scales” (C).

E-QUIZ QUESTION 19

Which of the following resins are associated with mucosal injury: A.

Kayexalate
B. Sevelamer
C. Cholestyramine
D. Renvela

Answer: Kayexalate (A), Sevelamer (B), and Renvela (D).

Of the above resins, the bile acid sequestrants are the only
medications not associated with mucosa injury (C). Sevelamer is also
known by its trademark names Renvela and Renagel.

E-QUIZ QUESTION 20 (e-FIG. 1.19)

e-Figure 1.19

The following resin is identified in a large esophageal ulcer. The

clinician calls to ask if the associated medication should be discontinued.
Select the appropriate recommendation.

A. Yes, this medication is linked to lethal bezoars; it should be stopped

B. While this medication is linked to lethality, close monitoring in
the hospital is adequate, the medication can be continued C. This
medication has no relation to the mucosal injury, continue the
medication, if clinically indicated D. This is food, not a medication
resin

Answer: This medication has no relation to the mucosal injury, continue

the medication, if clinically indicated (C).
This resin is cholestyramine, which has no relation to mucosal injury
(C). The medication is not the cause of this injury and it can be
continued. Kayexalate and sevelamer are associated with mucosal injury,
and this information should be communicated to the clinician when
these resins are identified.
E-QUIZ QUESTION 21

Match the trademark names to the generic names:

A. Kayexalate
B. Renvela
C. Renagel
D. Questran
E. Welchol
__________ Bile acid sequestrants
__________ Sevelamer
__________ Sodium polystyrene sulfonate

Answer: (D), (E): Bile acid sequestrants; (B), (C): Sevelamer; (A):
Sodium polystyrene sulfonate
E-QUIZ QUESTION 22
Match the select medication resin to its target ion: A. Kayexalate
B. Sevelamer
C. Cholestyramine
D. Renvela
E. Renagel
F. Questran
G. Welchol
__________ Phosphate
__________ Bile acids
__________ Potassium

Answer: (B), (D), (E): Phosphate; (C), (F), (G): Bile acids; (A): Potassium
E-QUIZ QUESTION 23
T/F: The histologic features of GVHD are pathognomonic for GVHD.
Answer: False. The histologic features of GVHD are etiologically
nonspecific and must be correlated with the clinical history.

E-QUIZ QUESTION 24

T/F: CMV immunostains are worthwhile if the only histologic finding is

increased apoptotic bodies.
Answer: True. Increased apoptotic bodies are etiologically nonspecific,
but can be a red flag to a sneaky CMV infection. A low threshold to
order a CMV immunostain is recommended.

E-QUIZ QUESTION 25

T/F: Two apoptotic bodies in one tissue fragment are considered

abnormal.
Answer: True. More than one apoptotic body per biopsy fragment is
abnormal.

References
Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological
Association medical position statement on the management of
Barrett’s esophagus. Gastroenterology. 2011;140:1084–1091.
Wang KK, Sampliner RE, Gastroenterology PPCotACo. Updated
guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s
esophagus. Am J Gastroenterol. 2008;103:788–797.
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;25:569–578.
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;33:818–825.
 STOMACH 2

EQUESTIONS
E-QUIZ QUESTION 1 (e-FIG. 2.1)

e-Figure 2.1

Which of the following is the best diagnosis for this stomach biopsy
submitted as “rule-out carcinoma?”

A. Schistosomiasis
B. 90Yttrium-labeled microspheres
C. Somatostatinoma with psammoma bodies
D. Dystrophic calcifications

Answer: 90Yttrium-labeled microspheres (B).

90Yttrium-labeled microspheres are used in the selective treatment of
unresectable primary and metastatic hepatic malignancies. They can
cause unintended mucosal injury to nontargeted organs, such as
90Yttrium-labeled microsphere related esophagitis, gastritis, duodenititis,
pancreatitis, and cholecystitis (1–4). In ideal specimens, the
characteristic microspheres are adjacent to a radiation gastritis pattern
of injury with lamina propria hyalinization, atypical stromal,
endothelial, and epithelial cells, and prominence of ectatic, damaged
vessels. Unfortunately, as in this case, some cases feature such prominent
ulceration and or acute and chronic inflammation that the background
radiation injury pattern is obscured. Since CMV viral cytopathic effect
can also be obscured by this injury pattern, it is always a good idea to
perform a CMV IHC (which was negative in this case). See also
90Yttrium-labeled microspheres, Stomach Chapter.
Anecdotally, 90Yttrium-labeled microspheres can raise concerns for
Schistosomiasis (A), somatostatinoma with psammoma bodies (C), and
dystrophic calcifications (D). Schistosomiasis would be neither solid in
structure nor uniform in size, and would be associated with eosinophilic
rich inflammation (A). Psammoma bodies are often seen in
somatostatinomas, but there is no neuroendocrine neoplasm to suggest
this diagnosis. In addition, psammoma bodies have a laminated
appearance, or inner mineralized material arranged in concentric rings
(C). Dystrophic calcifications appear more irregular and haphazard than
these uniform and perfectly spherical structures (D). A von Kossa stain
can be helpful in challenging cases (90yttrium-labeled microspheres are
nonreactive and calcifications are positive).

E-QUIZ QUESTION 2 (e-FIG. 2.2)

 e-Figure 2.2

Which of the following is the best diagnosis for this antral biopsy
originating from a 16-year-old boy with bloody diarrhea?

A. Sarcoidosis
B. Upper-tract Crohn disease
C. Granular cell tumor
D. Antral mucosa with lamina propria granuloma, see note.

Answer: Antral mucosa with lamina propria granuloma, see note (D).
This case features a single lamina propria granuloma in a background
of acute and chronic gastritis. Recall, granulomata are collections of
epithelioid histiocytes surrounded by a cuff of lymphocytes and plasma
cells. This finding can be seen in a variety of settings, including infection
(Helicobacter, mycobacterial, fungal), medication, foreign body reaction,
sarcoidosis, upper-tract Crohn disease, vasculitis, common variable
immunodeficiency, and near a neoplasm, among others. Therefore, the
diagnosis cannot be too dogmatic unless the clinical history is very
straightforward. In general, such cases are best signed out descriptively
(D), and follow with a note that places the findings in the most likely
clinicopathologic context. For example, this finding represents upper
tract Crohn disease if the patient had a well-established history of Crohn
disease and medication injury and self-limited infections had been
excluded) (B). Similarly, identical findings can be seen with sarcoidosis
if the patient had an established history of sarcoidosis, although the
background acute and chronic inflammation is not typical of sarcoidal
granulomatous gastritis (A). Ill-formed granulomata can raise concerns
for a granular cell tumor at low-power because of the abundant pink
cytoplasm, but at high-power the requisite granular cytoplasm
characteristic of granular cell tumor is not seen (C). In challenging cases,
an S100 protein stain can be helpful (granular cell tumors show strong
S100 protein nuclear and cytoplasmic reactivity and granulomata are
S100 protein nonreactive). Of note, a Helicobacter immunostain was
negative, as were special stains for fungal elements (PAS) and
mycobacterium (AFB). See also Granulomatous Gastritis, Stomach
Chapter.

E-QUIZ QUESTION 3 (e-FIG. 2.3)

e-Figure 2.3

Which of the following is the best diagnosis for this structure (Diff–Quik,
100×)?

A. Helicobacter heilmannii
B. Helicobacter pylori
C. Food debris
D. Candida

Answer: Helicobacter heilmannii (A).

 The indicated area shows Helicobacter heilmannii as evidenced by the
elongated, spiraled, slender forms that are not adherent to the foveolar
epithelium (A). In contrast, Helicobacter pylori organisms are shorter,
chubbier, with a slightly narrowed midpoint (B). In addition,
Helicobacter pylori organisms are typically more numerous, adherent to
the foveolar epithelium, and seen in a more prominent background of
acute and chronic inflammation (not shown). These structures are too
small and regular to be food debris (C). Also, food debris would not be
highlighted by this bacterial special stains. See also Helicobacter gastritis,
Stomach Chapter.
On morphologic grounds alone we can exclude Candida because the
indicated structure lacks the characteristic large pseudophae forms of
Candida, which should be readily appreciated on 40× (the depicted
image is under oil immersion, 100×) (D). See also Candida Esophagitis,
Esophagus Chapter.

E-QUIZ QUESTION 4 (e-FIG. 2.4)

e-Figure 2.4

Which of the following is the best diagnosis for this stomach biopsy?

A. Unremarkable gastric mucosa

B. Iron pill gastritis
C. Kayexalate
 D. Mucosal calcinosis

Answer: Mucosal calcinosis (D).

This image features mucosal calcinosis (D). These firm calcifications
are roughly the consistency of bone and, consequently, are difficult to
cut, resulting in “tissue holes” as the calcifications are lost during
processing. These “tissue holes” can be important red flags to the
diagnosis, though, and should be examined carefully. Calcinosis can be
highlighted by the von Kossa special stain (calcium is black). The
superficial calcifications eliminate choice A (unremarkable gastric
mucosa). Iron pill gastritis is a terrific mimic and, indeed, a few of these
cases turn out to be a conglomerate of calcium and iron, making routine
ordering of both the von Kossa and Prussian blue special stains
worthwhile (calcium is black with von Kossa and iron is blue with
Prussian blue). Iron pill gastritis, Kayexalate-associated injury, and
mucosal calcinosis are all common in renal failure patients. Although
calcium and Kayexalate both appear purple, Kayexalate crystals are
characterized by a “fish-scale” or “mosaic” appearance and commonly
seen in a background of ulceration and ischemic injury due to the
osmotic effects of the diluent sorbitol solution (C). See also Resins, Acute
Esophagitis, Esophagus Chapter. Mucosal calcinosis is most often seen in
the setting of renal failure, but can also be seen with parathyroid
disorders, tumor lysis syndrome, atrophic gastritis, hypervitaminosis A,
organ transplantation, gastric neoplasia, uremia with
eucalcemia/euphosphatemia, and with the use of aluminum-containing
antacids, citrate-containing blood products, isotretinoin, and sucralfate
(5, 6). If there is no clear cause to the finding of mucosal calcinosis, it is
worthwhile to contact the clinician and suggest a careful clinical workup
to search for causes of calcium dysregulation and potential cardiac
involvement, which can be fatal. See also Calcinosis, Stomach Chapter.

E-QUIZ QUESTION 5 (e-FIGS. 2.5 and 2.6)

 e-Figure 2.5

e-Figure 2.6

Which of the following is the best diagnosis for this gastric biopsy in a
patient with a history of mixed connective tissue disease and whose
upper endoscopy featured a striped appearance to the gastric mucosa?

A. Reactive gastritis/gastropathy
B. Portal Hypertensive Gastropathy (PHG)
C. Gastric Antral Vascular Ectasia (GAVE)
D. Amyloidosis

Answer: Gastric Antral Vascular Ectasia (GAVE) (C).

At low power, the image depicts a prominent reactive
gastritis/gastropathy pattern with foveolar mucin cell depletion, a
corkscrew-like appearance of the foveolar epithelium, lamina propria
edema, smooth muscle bundles splaying foveolar epithelium, and
minimal inflammation (A) (e-FIG. 2.5). Nevertheless, reactive
gastritis/gastropathy is not a good enough diagnosis because there is
more to the story. Recall, the history of a striped watermelon-like
appearance on endoscopic evaluation, suggestive of GAVE (C).
Moreover, mucosal thrombi are identified on higher power (e-FIG. 2.6).
Together, these clinicopathologic features support a diagnosis of GAVE.
As in this case, GAVE is often seen in the setting of mixed connective
tissue diseases or other autoimmune diseases. Choice B is incorrect
because mucosal thrombi are not characteristic of portal hypertensive
gastropathy and a history of portal hypertension was not provided.
Choice D is incorrect because amyloid deposits were not seen (the high-
power image features fibrin thrombi, which are hyperpink and confined
to the luminal space, as opposed to amyloid, which appears faintly pink
and diffusely infiltrates the lamina propria and vascular walls). See also
GAVE, Stomach Chapter.

E-QUIZ QUESTION 6 (e-FIG. 2.7)

e-Figure 2.7

Which of the following is the best diagnosis for this gastric biopsy from
an 88-year-old woman with a history of lobular carcinoma of the left
breast?

A. Mucus neck cells

B. Russell body gastritis
C. Poorly differentiated adenocarcinoma with signet rings
D. Metastatic lobular carcinoma

Answer: Russell body gastritis (B)

This case illustrates Russell body gastritis (B). Recall, the indicated
cells in Russell body gastritis are plasma cells, or Mott cells, which are
engorged with polytypic kappa and lambda light chains. Importantly,
there is no cytologic atypia to suggest malignancy (C)(D). Although
testing is not necessary, these cells would be cytokeratin nonreactive and
CD138 reactive, in contrast to infiltrating carcinoma, which would be
both cytokeratin and CD138 reactive (CD138 frequently labels epithelial
cells). This finding is associated with chronic inflammation of any sort,
but is most commonly associated with Helicobacter infections when seen
in the stomach. Indeed, H. pylori organisms were identified on higher-
power (not shown). Mucus neck cells (A) are another common benign
entity that can raise concerns for poorly differentiated adenocarcinoma,
particularly when the mucus neck cells are dislodged or crushed;
however, mucus neck cells lack the brightly eosinophilic cytoplasm
characteristic of Russell body gastritis (e-Fig. 2.7 vs. e-Fig. 2.8). Instead,
mucus neck cells have large, pale cytoplasmic vacuoles that displace the
nuclei eccentrically (e-FIG. 2.8). Mucus neck cells are reactive for both
cytokeratin and PAS (and mucicarmine), so require careful attention to
their bland nuclear cytology is critical to avoid misdiagnosis of a signet
ring cell carcinoma.
 e-Figure 2.8

E-QUIZ QUESTION 7 (e-FIG. 2.9)

e-Figure 2.9

This antral biopsy shows prominent intraepithelial lymphocytosis. Which

of the following entities does NOT have a reported association with the
lymphocytic gastritis pattern of injury?

A. Helicobacter pylori infection

B. Gluten-sensitive enteropathy (celiac disease)
C. Inflammatory bowel disease
D. Bile reflux
 E. Common variable immunodeficiency (CVID)

Answer: Bile reflux (D).

Increased intraepithelial lymphocytes in the stomach can be seen with
all but bile reflux (D).
Bile reflux (D) characteristically has a reactive gastritis/gastropathy
pattern, including features such as foveolar hyperplasia, tortuosity of the
gastric pits, loss of apical mucin, streaming of smooth muscle in the
lamina propria, and scant inflammatory infiltrate of the lamina propria.
Intraepithelial lymphocytes is not a characteristic features of bile reflux.
The most common associations with a lymphocytic gastritis pattern of
injury include Helicobacter (A) and celiac disease (B), but can also be
seen with Crohn disease (C) and CVID (E).

E-QUIZ QUESTION 8 (e-FIG. 2.10)

e-Figure 2.10

This gastric antral biopsy has sheets of eosinophils expanding the lamina
propria. Which of the following conditions is NOT associated with
gastric eosinophilia?

A. Helicobacter pylori infection

B. Helicobacter pylori eradication
C. Connective tissue disorders, such as scleroderma
 D. Gastroesophageal reflux disease

Answer: Gastroesophageal reflux disease (D).

Gastroesophageal reflux disease (GERD) (D) can cause esophageal
eosinophilia, and may be difficult to differentiate with idiopathic
eosinophilic esophagitis (EoE); however, associated gastric eosinophilia
has been reported in EoE, but there is no such finding in GERD.
Helicobacter pylori infection (A) and treatment (B), as well as scleroderma
are associated with eosinophils in the gastric mucosa.

E-QUIZ QUESTION 9 (e-FIG. 2.11)

e-Figure 2.11

This biopsy of gastric oxyntic mucosa shows a band-like infiltrate of

inflammatory cells at scanning magnification. Even though the picture is
not in perfect focus, the diagnosis is in reach. What is the most likely
etiologic association with superficial plasmacytic infiltrates?

A. Autoimmune metaplastic atrophic gastritis (AMAG)

B. Drug induced injury
C. Food allergy or sensitivity
D. Helicobacter infection

Answer: Helicobacter infection (D).

The superficial plasmacytic infiltrate is so highly characteristic of
Helicobacter infection (D) that the absence of demonstrable organisms on
tissue sections should prompt further clinical workup, such as urease
breath test, serum antibody testing, or stool antigen testing. By
comparison, AMAG (A) characteristically has a body-predominant
basally located lymphocytic infiltrate in combination with oxyntic gland
atrophy, intestinal and pyloric metaplasia, lymphoid aggregate
formation and ECL cell hyperplasia. Drug induced injury (B) and food
allergy or sensitivity (C) may show various patterns of injury, for
example, lymphocytic gastritis or gastric mucosal eosinophilia.

E-QUIZ QUESTION 10 (e-FIG. 2.12)

e-Figure 2.12

Which of the following statements is correct?

A. If this biopsy is from the gastric body, the findings most likely
represent autoimmune metaplastic atrophic gastritis (AMAG).
B. If this biopsy is from the gastric body, the findings most likely
represent early Helicobacter infection or environmental metaplastic
atrophic gastritis (EMAG).
C. If this biopsy is from the gastric antrum, the findings most likely
represent autoimmune metaplastic atrophic gastritis (AMAG).
D. If this biopsy is from the gastric antrum, the findings most likely
represent Crohn disease.

Answer: If this biopsy is from the gastric body, the findings most likely
represent autoimmune metaplastic atrophic gastritis (AMAG) (A).
AMAG shows a characteristic combination of findings limited the
gastric body (A), which include intestinal metaplasia (arrow) and pyloric
metaplasia (arrowhead) in a background of oxyntic gland atrophy (note
the complete absence of oxyntic glands in this body biopsy) with a low-
lying lymphocytic infiltrate, lymphoid aggregate formation, and ECL cell
hyperplasia. By comparison, the findings in the antrum (C) are usually
minimal and may include reactive gastritis/gastropathy pattern. Early
EMAG or Helicobacter pylori infection (B) is limited to the antrum and
intestinal metaplasia and atrophy of the oxyntic mucosa does not occur
until late in the disease. Crohn disease involving the stomach (D) is
usually seen as a pattern of focally enhanced gastritis.

E-QUIZ QUESTION 11 (e-FIGS. 2.13 and 2.14)

e-Figure 2.13
 e-Figure 2.14

The biopsy jar states that this tissue is from the gastric body. Which of
the following statements is true?

A. This pattern of injury in the body is so highly characteristic of

Helicobacter infection that in the absence of demonstrable
organisms, further clinical workup should be suggested.
B. This pattern of injury is entirely nonspecific and a differential
diagnosis of medication-associated injury, food allergy, and
infection should be given for clinical correlation.
C. This pattern of injury in the body is highly characteristic of
autoimmune metaplastic atrophic gastritis (AMAG) and should be
confirmed with gastrin and chromogranin immunohistochemical
stains.
D. This pattern of injury is concerning for malignancy and further
hematologic workup should be suggested.

Answer: This pattern of injury in the body is highly characteristic of

autoimmune metaplastic atrophic gastritis (AMAG) and should be
confirmed with gastrin and chromogranin immunohistochemical stains
(C).
The biopsy fragments are said to originate from the gastric body, but
no oxyntic glands are present. This indicates that there is total atrophy
of the oxyntic glands. In addition, there is intestinal metaplasia and
pyloric metaplasia with lymphoid aggregate formation. A gastrin
immunohistochemical stain can be performed to confirm that absence of
G cells, thereby verifying that the tissue is from the gastric body. In
addition, a chromogranin immunohistochemical stain can be performed
to evaluate for linear and/or nodular ECL cell hyperplasia (C).
Helicobacter infection (A) is typically antral predominant and has active
chronic inflammation with a superficial plasmacytic infiltrate. Rather
than being a nonspecific pattern of injury (B), the pattern of injury seen
here in the gastric body is highly characteristic of AMAG. Although there
is a prominent lymphoid aggregate present, it is well demarcated, there
are no lymphoepithelial lesions or gland destructive features, and there
is no aggressive infiltration into the muscularis mucosae to suggest a
lymphoid malignancy (D).

E-QUIZ QUESTION 12

T/F: The gastric cardia is histologically distinguishable from the gastric

antrum.

Answer: False.
The gastric cardia and antrum (and pylorus) are histologically
indistinguishable on H&E.

E-QUIZ QUESTION 13

Which of the following immunohistochemical or histochemical stains

can identify the gastric antrum?

A. Gastrin
B. Insulin
C. PAS/D
D. Congo Red

Answer: Gastrin (A).

Gastrin-producing G cells are exclusively found in the gastric antrum,
and they can be highlighted as a uniform band with a gastrin
immunohistochemical stain (A).
E-QUIZ QUESTION 14

Which compartment of the stomach has the deepest gastric pits?

A. Cardia
B. Body
C. Fundus
D. Antrum

Answer: Antrum (D).

The deepest pits are found in the antrum, where they can be greater
than 50% of the mucosa thickness (D).

E-QUIZ QUESTION 15

Which of the following compartments comprises 90% of the stomach?

A. Cardia
B. Body/Fundus
C. Antrum
D. Pylorus

Answer: Body/Fundus (B).

E-QUIZ QUESTION 16

Select the correct pairing of similar physiologic stomach compartments:

A. Cardia/Fundus
B. Antrum/Body
C. Pylorus/Body
D. Body/Fundus

Answer: Body/Fundus (D).

E-QUIZ QUESTION 17

Which of the following is NOT an indication for ordering a Helicobacter

immunostain, according to the 2013 Rodger C. Haggitt Gastrointestinal
Pathology Society Recommendations for the Appropriate use of Special
Stains for Helicobacter Detection (7): A. Mild chronic gastritis in a
cardiac biopsy
B. Marked active chronic gastritis, organisms apparent on H&E
C. Mild chronic gastritis with gastroduodenal ulcers
D. Lymphocytic gastritis pattern

Answer: Marked active chronic gastritis, organisms apparent on H&E

(B).
All other answers are an appropriate indication of ordering a
Helicobacter immunostain. See also Pearls & Pitfalls: Highlights from the
2013 Rodger C. Haggitt Gastrointestinal Pathology Society
Recommendations for the Appropriate use of Special Stains for
Helicobacter Detection, Helicobacter pylori subsection, Acute Gastritis,
Stomach Chapter.

E-QUIZ QUESTION 18

Which of the following is the recommended stain for Helicobacter

detection, according to the 2013 Rodger C. Haggitt Gastrointestinal
Pathology Society Recommendations for the Appropriate use of Special
Stains for Helicobacter Detection (7): A. Helicobacter pylori immunostain
B. Diff–Quick special stain
C. Warthin–Starry
D. Giemsa

Answer: Helicobacter pylori immunostain (A).

The Helicobacter immunostain is the recommended stain of choice
based on its superior sensitivity in comparison to histologic stains, and
its enhanced ability to detect Helicobacter with treatment effect (coccoid
forms) and rare organisms present deep in the glands or intracellular
locations.

E-QUIZ QUESTION 19

T/F: According to the 2013 Rodger C. Haggitt Gastrointestinal Pathology

Society Recommendations for the Appropriate use of Special Stains for
Helicobacter Detection (7), up front staining for Helicobacter is
economically advantageous.

Answer: False.
The society argues against “up-front” Helicobacter immunostains on
all esophageal, gastric, and small bowel biopsies, citing insufficient
evidence for reduced turnaround time.

E-QUIZ QUESTION 20

According to the 2013 Rodger C. Haggitt Gastrointestinal Pathology

Society Recommendations for the Appropriate use of Special Stains for
Helicobacter Detection (7), which of the following is a contraindication to
Helicobacter immunostains?

A. Gastric MALT-type lymphoma

B. Duodenal lymphocytosis
C. Uninflammed gastric polyps
D. Prior Helicobacter infection
E. High-risk demographics

Answer: Uninflammed gastric polyps (C).

The Helicobacter immunostain is recommended in all other choices,
assuming the organisms are not seen on H&E. (A, B, D, E).

E-QUIZ QUESTION 21

According to the 2013 Rodger C. Haggitt Gastrointestinal Pathology

Society Recommendations for the Appropriate use of Special Stains for
Helicobacter Detection (7), which of the following is an indication to
order an Helicobacter immunostain?

A. Cases with Helicobacter organisms present on H&E

B. Background normal mucosa
C. Reactive gastritis/gastropathy pattern with active chronic
inflammation D. A clinical request to “rule-out” Helicobacter

Answer: Reactive gastritis/gastropathy pattern with active chronic

inflammation (C).
All other answers are contraindications for ordering a Helicobacter
immunostain (A, B, D). Reactive gastritis/gastropathy pattern without
concomitant inflammation is contraindicated as well.

E-QUIZ QUESTION 22

Coccoid forms are identified which are Helicobacter pylori immunostain

reactive. These forms likely represent which of the following?

A. Oral contamination of yeast buds

B. Partially treated Helicobacter
C. An emerging, novel Helicobacter strain
D. Normal, enteric flora

Answer: Partially-treated Helicobacter (B).

Choices A and D would be nonreactive with a Helicobacter
immunostain. Choice C is a distractor.

E-QUIZ QUESTION 23

Which Helicobacter subtype is most commonly associated with animal

contact in children?

A. Helicobacter heilmannii
B. Helicobacter pylori

Answer: Helicobacter heilmannii (A).

E-QUIZ QUESTION 24

Select the incorrect statement:

A. Helicobacter heilmannii infections are more common than

Helicobacter pylori B. Helicobacter heilmannii infections are less
common than Helicobacter pylori C. Helicobacter heilmannii
infections are associated with fewer organisms and milder
inflammation than Helicobacter pylori D. Helicobacter heilmannii
 infections organisms are spiraled, thin, and more elongated than
Helicobacter pylori Answer: Helicobacter heilmannii infections are
more common than Helicobacter pylori (A).
The remaining statements are correct.

E-QUIZ QUESTION 25

Select the incorrect statement regarding focally enhanced gastritis (FEG):

A. FEG is most associated with UC in the adult setting
B. FEG is most commonly associated with CD in the pediatric setting
C. FEG can be seen with NSAIDS, particularly in adults
D. FEG correlates with active ileitis and granulomata in the pediatric
setting Answer: FEG is most associated with UC in the adult setting
(A).
The remaining answers are correct (B–D) (8–12).

References
1. Crowder CD, Grabowski C, Inampudi S, et al. Selective internal
radiation therapy-induced extrahepatic injury: An emerging cause of
iatrogenic organ damage. Am J Surg Pathol. 2009;33(7):963–975.
2. Kennedy AS, Nutting C, Coldwell D, et al. Pathologic response and
microdosimetry of (90)Y microspheres in man: Review of four
explanted whole livers. Int J Radiat Oncol Biol Phys.
2004;60(5):1552–1563.
3. Neff R, Abdel-Misih R, Khatri J, et al. The toxicity of liver directed
yttrium-90 microspheres in primary and metastatic liver tumors.
Cancer Invest. 2008;26(2):173–177.
4. Ogawa F, Mino-Kenudson M, Shimizu M, et al. Gastroduodenitis
associated with yttrium 90-microsphere selective internal radiation:
An iatrogenic complication in need of recognition. Arch Pathol Lab
Med. 2008;132(11):1734–1738.
5. Gorospe M, Fadare O. Gastric mucosal calcinosis: clinicopathologic
considerations. Adv Anat Pathol. 2007;14(3):224–228.
6. Avci Z, Alioglu B, Canan O, et al. Calcification of the gastric mucosa
associated with tumor lysis syndrome in a child with non-Hodgkin
lymphoma. J Pediatr Hematol Oncol. 2006;28(5):307–310.
7. Batts KP, Ketover S, Kakar S, et al. Appropriate use of special stains
for identifying Helicobacter pylori: Recommendations from the
Rodger C. Haggitt Gastrointestinal Pathology Society. Am J Surg
Pathol. 2013;37(11):e12–e22.
8. McHugh JB, Gopal P, Greenson JK. The clinical significance of
focally enhanced gastritis in children. Am J Surg Pathol.
2013;37(2):295–299.
9. Oberhuber G, Puspok A, Oesterreicher C, et al. Focally enhanced
gastritis: A frequent type of gastritis in patients with Crohn’s
disease. Gastroenterology. 1997;112(3):698–706.
10. Sharif F, McDermott M, Dillon M, et al. Focally enhanced gastritis in
children with Crohn’s disease and ulcerative colitis. Am J
Gastroenterol. 2002;97(6):1415–1420.
11. Ushiku T, Moran CJ, Lauwers GY. Focally enhanced gastritis in
newly diagnosed pediatric inflammatory bowel disease. Am J Surg
Pathol. 2013;37(12):1882–1888.
12. Xin W, Greenson JK. The clinical significance of focally enhanced
gastritis. Am J Surg Pathol. 2004;28(10):1347–1351.
 SMALL BOWEL 3

E-QUESTIONS
E-QUIZ QUESTION 1
Acute ileitis is most commonly ascribed to which etiology?

A. Crohn disease
B. Ulcerative colitis
C. Medication injury
D. Nonspecific infection

Answer: Medication injury (C).

Acute ileitis refers to acute inflammation in the epithelium of the
ileum. This injury pattern is most commonly caused by medication
injury (i.e., NSAIDS) (C), but can also be caused by a myriad of other
unrelated etiologies such as infection (D), IBD (B and C), amyloidosis,
infiltrating malignancy, radiation injury, ischemia, and vasculitis, among
many others. Correlation with background histologic clues and pertinent
aspects of the clinical chart are often necessary to assign a biologically
meaningful etiology to this nonspecific injury pattern.

E-QUIZ QUESTION 2 (e-FIG. 3.1)

 e-Figure 3.1

This biopsy was taken from the duodenum. The structure pictured is:

A. A small neuroma, a diagnosis that can be confirmed with a positive

S100 protein immunostain.
B. A small neuroma, a diagnosis that can be confirmed with an
eosinophilic staining on a PAS stain.
C. A crushed Brunner gland, a diagnosis that can be confirmed with
basophilic staining on an Alcian Blue stain.
D. A crushed Brunner gland, a diagnosis that can be confirmed with
eosinophilic staining on a PAS stain.
E. A Peyer patch, a diagnosis that can be confirmed with a positive
LCA immunostain.

Answer: A crushed Brunner gland, a diagnosis that can be confirmed

with eosinophilic staining on a PAS stain (D).
Brunner glands are found the proximal duodenum and stain intensely
eosinophilic on PAS stain, but not with Alcian Blue (C). Crush artifact
may cause them to be mistaken for neural tumors (A and B), but PAS
stain will confirm their phenotype. Peyer patches are lymphoid
aggregates found in the terminal ileum (E).

E-QUIZ QUESTION 3 (e-FIG. 3.2)

 e-Figure 3.2

This patient presented with clinically significant diarrhea, nonresponsive

to diet modification. The clinical evaluation for celiac disease and
pertinent microbiologic studies were negative. Select the best diagnosis
for this duodenal biopsy: A. Autoimmune enteropathy (AIE)
B. Giardiasis
C. Celiac disease
D. Whipple disease with classic histologic features

Answer: Autoimmune enteropathy (AIE) (A).

The biopsy shows a complete lack of goblet cells (Paneth cells were
also absent), raising concerns for AIE (A). Antienterocyte and antigoblet
cell antibodies were identified and the patient responded to steroid-
based therapies, supporting a clinicopathologic diagnosis of AIE.
Luminal Giardia forms would be easy to see at low power but are not
identified (in addition, the question stem details that microbiologic
studies were negative, making Giardia clinically unlikely) (B). The
villous architecture is intact and pertinent clinical studies for celiac
disease were negative, making Celiac disease unlikely (C). Whipple
disease with classic histologic features disease is characterized by villous
blunting, lamina propria expansion by numerous foamy macrophages,
scattered dilated lacteals, and fat droplets, features that are not present
on this biopsy (D).

E-QUIZ QUESTION 4 (e-FIG. 3.3)

 e-Figure 3.3

This biopsy was labeled as “pouch” from a patient with an ileal anal-
pouch for ulcerative colitis. Which statement best characterizes the
findings?

A. This biopsy was taken from the rectal cuff due to the presence of
anal squamous mucosa.
B. This biopsy was taken from the rectal cuff due to the presence of
squamous metaplasia.
C. This biopsy shows chronic pouchitis due to the presence of
squamous metaplasia.
D. This biopsy shows Crohn disease due to the presence acute
inflammation adjacent to anal squamous mucosa.
E. This biopsy shows Crohn disease due to the presence of squamous
metaplasia.

Answer: This biopsy was taken from the rectal cuff due to the presence
of anal squamous mucosa (A).
The presence of squamous mucosa (arrowhead) identifies this tissue
fragment as adjacent to the anal canal and originating from the rectal
cuff. Squamous metaplasia has not been described as a feature of rectal
cuffs (B), chronic pouchitis (C), or Crohn disease (E). Although perianal
Crohn disease may involve the anal canal and cause acute inflammation
in the distal rectum, this diagnosis cannot be established based on the
figure presented (D).
E-QUIZ QUESTION 5 (e-FIGS. 3.4 and 3.5)

e-Figure 3.4

e-Figure 3.5

Which of the following entities have been associated with the above
finding?

A. Celiac disease
B. Collagenous colitis
C. Lymphocytic gastritis
D. Medication injury
E. All of the above

Answer: All of the above (E).

 The histologic features shown here include a stripped or detached
surface epithelium without crypt architectural changes. The second
figure shows a markedly abnormal subepithelial collagen layer.
Collagenous enteritis (pictured) has been associated with collagenous
gastritis, collagenous colitis, lymphocytic colitis, lymphocytic gastritis,
ulcerative jejunitis, and medication injury due to olmesartan.

E-QUIZ QUESTION 6 (e-FIG. 3.6)

e-Figure 3.6

Select the best answer for the above small bowel biopsy:

A. Unremarkable small bowel mucosa

B. Celiac disease
C. Giardiasis
D. Amyloidosis

Answer: Giardiasis (C).

While the low power view of the duodenal mucosa is fairly
unremarkable (A), numerous Giardia organisms are seen swirling in the
luminal spaces between the villi (C). Giardiasis is one of a host of
diagnoses that are difficult to make unless searched for in every case; the
background mucosa is essentially unremarkable and offers no clues to
the diagnosis. Although this patient was asymptomatic, treatment was
required to eradicate the infection and prevent onward transmission. The
intact villous architecture and lack of intraepithelial lymphocytosis
argue against celiac disease (C). Amyloid deposition is not identified (see
the lamina propria vessels on the far left, which have crisp and delicate
borders, making a Congo red special stain for amyloid unnecessary).

E-QUIZ QUESTION 7 (e-FIGS. 3.7 and 3.8)

e-Figure 3.7

e-Figure 3.8

The first figure shows a small arterial wall directly subjacent to the area
shown in the second figure. Which of the following is a true statement?

A. The first figure shows leukocytoclastic vasculitis and is likely the

cause of the ischemia seen in the second figure.
B. The first figure shows angioinvasive fungal organisms and is likely
 the cause of the ischemia seen in the second figure.
C. The first figure shows karyorrhectic debris, but it is not clear
whether this represents vasculitis, since it was found directly
adjacent to ischemic enteritis.
D. The first figure shows a fibrin thrombus that caused the ischemia
shown in the second figure.
E. The first figure shows E. coli 0157:H7 that caused the hemorrhagic
colitis seen in the second figure.

Answer: The first figure shows karyorrhectic debris, but it is not clear
whether this represents vasculitis, since it was found directly adjacent to
ischemic enteritis (C).
Although inspection for vasculitis in cases of ischemia may yield a
diagnostic focus, one must be wary not to overinterpret vascular changes
that are directly adjacent to areas of ischemia or ulceration. Given the
proximity of the vessel to the ischemic area, it is not possible to
confidently diagnose this as leukocytoclastic vasculitis (A). Invasive
fungal organisms should appear filamentous and their presence can be
confirmed with a GMS stain (B). Fibrin thrombi should be within the
lumen of the vessel and not in the wall (D). Enterotoxic microorganisms
are not typically visible on biopsy and require microbiologic
confirmation (E).

E-QUIZ QUESTION 8 (e-FIG. 3.9)

e-Figure 3.9
This duodenal biopsy was taken from a 54-year-old female with
abdominal pain, bloating, and diarrhea. Prior to endoscopy, she
demonstrated a negative antitissue transglutaminase antibody (TTG). In
addition, she was negative for HLA-DQ2 and DQ8. At the time of biopsy,
a duodenal aspirate was obtained for cultures, which subsequently grew
>100,000 CFU/mL. After reviewing her biopsy, which of the following
statements is most accurate?

A. This woman has celiac disease.

B. This woman has SIBO, and she does not have celiac disease.
C. This woman has SIBO and celiac disease cannot be excluded.
D. This woman has both SIBO and celiac disease.
E. This woman does not have small intestinal bacterial over growth or
celiac disease.

Answer: This woman has SIBO, and she does not have celiac disease (B).
The finding of negative HLA-DQ2 or DQ8 haplotypes in this patient
essentially excludes celiac disease in this patient (A, C and D). The
negative TTG also supports this interpretation. The finding of >100,000
CFU/mL growing from her duodenal aspirate is diagnostic of SIBO SIBO
(E). The histologic findings of SIBO include a malabsorption pattern of
injury that can mimic celiac disease. The presence of crypt hyperplasia,
villous blunting, and intraepithelial lymphocytosis should always be
correlated with clinical information.

E-QUIZ QUESTION 9
Titanium pigment is unique to the terminal ileum and is thought to
derive from which of the following: A. Ingested whitening agents in
toothpaste
B. Topical titanium–containing sunblock solutions
C. Swallowed gum
D. Chewing pencils

Answer: Ingested whitening agents in toothpaste (A).

Titanium is a finely granular dark-brown to black pigment confined
within the cytoplasm of macrophages. It is historically thought to
represent a combination of titanium, aluminum, and silicon from
ingested whitening agents in toothpaste (A). The other answer choices
are distractors (B–D).

E-QUIZ QUESTION 10 (e-FIGS. 3.10 and 3.11)

e-Figure 3.10

e-Figure 3.11

This biopsy was taken from the terminal ileum. Higher magnification of
a metaplastic condition is featured in the second figure. What is the
significance of the pictured finding in figure 2?

A. This finding is pyloric metaplasia and is diagnostic for Crohn

disease when found in the terminal ileum.
B. This finding is pyloric metaplasia and is diagnostic for backwash
 ileitis from ulcerative colitis when found in the terminal ileum.
C. This finding is pyloric metaplasia and is diagnostic for NSAID-
related injury when found in the terminal ileum.
D. This finding is pyloric metaplasia and indicates chronic injury, but
is nonspecific for an etiology.
E. This finding is Paneth cell metaplasia and indicates chronic injury,
but is nonspecific for an etiology.

Answer: This finding is pyloric metaplasia and indicates chronic injury,

but is nonspecific for an etiology (D).
Pyloric metaplasia is a nonspecific finding that indicates chronicity
when found in the terminal ileum. The finding may be seen in
association with Crohn disease, NSAID-related diaphragm disease, or
other chronic inflammatory processes, but is not specific (A, C).
Backwash ileitis is frequently a mild acute pattern of injury, and
typically lacks features of chronic injury (B). Paneth cells are a normal
epithelial constituent of the small bowel, and contain abundant
eosinophilic granules (E). Paneth cells are a feature of chronic injury
when present in the descending and sigmoid colon and rectum.

E-QUIZ QUESTION 11 (e-FIGS. 3.12 and 3.13)

e-Figure 3.12
 e-Figure 3.13

This duodenal mucosal biopsy was submitted as a “polyp.” Which is the

best approach?

A. Lipoma with associated reactive epithelial change. Next case.

B. Sclerosing liposarcoma with associated reactive changes. Order
confirmatory MDM2 FISH amplification studies.
C. Inflamed spindle cell lipoma. Order a confirmatory CD34
immunohistochemical stain.
D. Lipoma with acute inflammation. Order a confirmatory CMV
immunohistochemical stain.

Answer: Lipoma with acute inflammation. Order a confirmatory CMV

immunostain. (D) At scanning magnification, the fatty neoplasm is the
obvious diagnosis for this small, well-circumscribed polyp (e-FIG. 3.12).
On higher power, neither adipocyte atypia nor lipoblasts were shown.
Moreover, liposarcomas and spindle cell lipomas would be exceedingly
uncommon at this site (B and C). It would be easy to grab the diagnosis
of lipoma with reactive epithelial change and move on to the next case,
since the fatty component is apparent at scanning magnification (A);
however every case deserves at least a few “closer looks” at higher
power. In this case, the reactive epithelium and “business” of the pockets
of mixed inflammation are subtle clues to the diagnosis of CMV enteritis
(e-Fig. 3.13, arrowhead). Close inspection of the Brunner glands revealed
classic CMV viral cytopathic effect (e-Fig. 3.13–3.14, arrowhead). In the
stomach and small bowel, epithelial CMV viral cytopathic effect is often
more conspicuous than stromal/endothelial viral cytopathic effect. This
case also underscores that many, if not most cases of CMV infections are
unaccompanied by clinically relevant hints, such as fever, diarrhea, or
immunosuppression.

e-Figure 3.14

E-QUIZ QUESTION 12 (e-FIGS. 3.15 and 3.16)

e-Figure 3.15
 e-Figure 3.16

Select the best diagnosis for the above duodenal biopsy:

A. Gastric metaplasia
B. Gastric heterotopia
C. Brunner gland polyp
D. Unremarkable small bowel mucosa

Answer: Gastric heterotopia (B).

This biopsy is not unremarkable (D). It features both gastric foveolar
epithelium and underlying oxyntic glands, features in keeping with
gastric heterotopia (B). On the PAS/AB special stain, the neutral mucin
of the gastric foveolar epithelium is eosinophilic. In contrast, the acidic
mucin of the goblet cells is basophilic on PAS/AB.

E-QUIZ QUESTION 13 (e-FIGS. 3.17 and 3.18)

 e-Figure 3.17

e-Figure 3.18

This biopsy from the prepouch small bowel in a patient with an ileo-anal
pouch shows marked acute inflammation and crypt architectural
disturbances. Which of the following statements is true?

A. The finding of active and chronic injury in a prepouch biopsy

definitively indicates the presence of Crohn disease.
B. The finding of active and chronic injury in a prepouch biopsy may
indicate the presence of Crohn disease, but only in the proper
clinical context.
C. The finding of active and chronic injury in a prepouch biopsy is
always secondary to infection.
 D. The finding could represent residual or recurrent ulcerative colitis.

Answer: The finding of active and chronic injury in a prepouch biopsy

may indicate the presence of Crohn disease, but only in the proper
clinical context (B).
Prepouch biopsies are not helpful in the diagnosis of Crohn disease
unless mucosal granulomata and clinical features of Crohn disease are
present (A). Although infection should be considered, and exclusion of
cytomegalovirus (CMV) is prudent, the finding of active and/or chronic
injury is not necessarily due to infection (C). It is unlikely that this
finding is related to residual or recurrent ulcerative colitis, since
ulcerative colitis is typically limited to the colorectum (D).

E-QUIZ QUESTION 14 (e-FIGS. 3.19 and 3.20)

e-Figure 3.19
 e-Figure 3.20

This small bowel biopsy originated from a 71-year-old farmer with a

recent history of severe weight loss and diarrhea. What is the most likely
diagnosis?

A. Mycobacterium avium-intracellulare infection

B. Whipple disease with partial histologic treatment effect
C. Whipple disease with complete histologic treatment effect
D. Whipple disease with classic histologic features

Answer: Whipple disease with classic histologic features (D).

The above biopsy features all of the classic findings of Whipple
disease: villous blunting, lamina propria expansion by numerous foamy
macrophages, scattered dilated lacteals, and fat droplets. In addition, the
clinical scenario describes the most common clinical setting of Whipple
disease: the patient is an elderly white male with weight loss and
diarrhea. In summary, the clinicopathologic features of this case are
most in keeping with Whipple disease. MAI, in contrast, most commonly
afflicts patients with HIV and is associated with neither dilated lacteals
nor fat droplets (A). Nevertheless, it is always a good idea (and
extremely satisfying) to perform confirmatory a PAS/D special stain (e-
FIG. 3.21) and a Whipple immunostain (e-FIG. 3.22) (AFB special stains
are negative in Whipple disease, not shown).
As a reminder, Whipple disease with partial histologic treatment effect
refers to cases with attenuated features of classic Whipple disease (B). In
partial treatment effect, subtle changes are seen on H&E and cytoplasmic
inclusions are highlighted by both a PAS/D and Whipple
immunohistochemical stain. This scenario is most often seen in patients
early in their antibiotic course for Whipple disease. In contrast, Whipple
disease with complete histologic treatment effect refers to cases with an
essentially normal H&E and PAS/D special stain (C). In such cases, the
only sign of Whipple disease is a focally positive Whipple
immunohistochemical stain, which usually shows staining restricted to
scattered macrophages deep in the mucosa or even in the superficial
submucosa. Patients with this morphology have often been on Whipple
disease antibiotic therapy for an extended period of time or have a
remote history of Whipple disease.

e-Figure 3.21
 e-Figure 3.22

E-QUIZ QUESTION 15 (e-FIGS. 3.23 and 3.24)

e-Figure 3.23

e-Figure 3.24

Select the best diagnosis for the above duodenal biopsy:

A. Favor malignant melanoma. Order a confirmatory S100 protein

immunostain.
B. Favor pseudomelanosis duodeni. Order a confirmatory CD68.
C. Favor metastatic breast carcinoma. Order confirmatory ER, PR, and
BRST2.
D. Favor Whipple disease. Order confirmatory PAS/D and a Whipple
 immunostain.
E. Favor MAI. Order confirmatory PAS/D and AFB.

Answer: Favor malignant melanoma (A).

Even though a pertinent history was not provided, the diagnosis of
malignant melanoma can be reached by appreciation of the cytoplasmic
pigmentation in association with overtly cytologically malignant cells
(prominent nucleoli, large cell size, and mitotic figures). An S100 protein
immunostain confirmed the diagnosis (not shown) (A). Pseudomelanosis
duodeni can be excluded based on the cytologically malignant cells seen
on H&E; a CD68 immunohistochemical stain is not necessary (B). Breast
carcinoma can be excluded based on the presence of the pigmentation;
additional breast markers are not necessary. Whipple disease and MAI
can result in a similar low power appearance with villous blunting and
an expanded lamina propria, but Whipple disease and MAI are never
seen with pigmentation and in cytologically malignant cells (D and E).

E-QUIZ QUESTION 16 (e-FIG. 3.25)

e-Figure 3.25

These duodenal villi show marked intraepithelial lymphocytosis. Note

how “top-heavy” the lymphocytosis is when the tips of the villi are
compared to the relatively unaffected villous bases. This crescendo
toward the tips is a feature of which of the following differential
diagnoses: A. Small intestinal bacterial overgrowth
 B. Peptic injury
C. Giardia infection
D. Gluten-sensitive enteropathy (celiac disease)
E. Sensitivity to nongluten proteins

Answer: Gluten-sensitive enteropathy (celiac disease) (D).

A crescendo pattern of intraepithelial lymphocytosis is seen more
frequently in celiac disease (D), yielding a top-heavy appearance to the
duodenal villi. Although intraepithelial lymphocytosis is also seen in
SIBO (A), peptic injury (B), Giardia infection (C), and sensitivity to
nongluten proteins (E), a crescendo pattern of intraepithelial
lymphocytosis is not common.

E-QUIZ QUESTION 17
Which of the following statements about small bowel allograft rejection
is TRUE?

A. To ensure proper sampling, biopsies should be taken near the stoma

site.
B. Immediate and aggressive immunosuppressive therapy is required
for small bowel allograft rejection to prevent graft loss and
mortality.
C. Histologic features of small bowel allograft rejection are distinct
from those of graft versus host disease (GVHD).
D. Opportunistic infections are not a concern due to altered
immunologic processes in the allograft.

Answer: Immediate and aggressive immunosuppressive therapy is

required for small bowel allograft rejection to prevent graft loss and
mortality (B).
Progression of allograft rejection can advance to graft loss or
mortality, and requires immediate immunosuppressive therapy (B).
Biopsies should be taken away from the stoma to avoid misleading
chronic and regenerative changes (A). The histologic features of allograft
rejection are similar to those of GVHD, and diagnosis of rejection
requires clinicopathologic correlation (C). Patients with small bowel
allografts are immunosuppressed and are at risk for opportunistic
infections (D).

E-QUIZ QUESTION 18
You receive biopsies labeled as “ileal pouch” in a patient with a history
of ulcerative colitis. Which of the following statements is FALSE?

A. Biopsies of the pouch are sent to exclude infection and confirm

“pouchitis”
B. Crohn disease should only be suggested if strong clinical correlation
is available, such as antibiotic-refractory pouchitis and
extraintestinal manifestations of Crohn disease.
C. The pouch is undoubtedly affected by Crohn disease if features of
chronic injury (crypt branching, crypt shortfall, pyloric metaplasia)
are present.
D. Ileal pouch anal anastomosis is a procedure that can benefit either
ulcerative colitis or Crohn disease patients.

Answer: The pouch is undoubtedly affected by Crohn disease if features

of chronic injury (crypt branching, crypt shortfall, pyloric metaplasia)
are present (C).
Features of chronic injury can be found in pouch biopsies as a result of
diversion of fecal flow, “cuffitis,” or involvement by Crohn disease, but
histologic features must be correlated with clinical information (C).
Biopsies of the pouch are sent to confirm the presence of “pouchitis” and
exclude infection, such that antibiotic therapy may begin (A). Pouch
involvement by Crohn disease should only be suggested if strong clinical
correlation is available (B). Traditionally, the diagnosis of Crohn disease
was an absolute contraindication for an IPAA because of high rates of
pouch complications and failure; however recent studies have
demonstrated good functional outcomes in the majority of Crohn disease
patients, and suggest that trial IPAA may be offered to highly motivated
patients wishing to avoid a permanent stoma (D).

E-QUIZ QUESTION 19
Which of the following statements is TRUE regarding nongluten protein
sensitivity: A. Infants present with anaphylactic reactions and failure to
thrive.
B. Histologic features can be distinguished from celiac disease with
confidence.
C. The most common offending agents are tree nuts.
D. Mucosal eosinophilia is more common in nongluten protein
sensitivity than celiac disease.

Answer: Mucosal eosinophilia is more common in nongluten protein

sensitivity than celiac disease (D).
Mucosal eosinophilia is not seen in all cases of nongluten protein
sensitivity, but is more frequently seen in this condition than in celiac
disease (D). Infants present with vomiting, diarrhea, dehydration, and
failure to thrive (A). Histologic features include a patchy malabsorption
pattern, similar to that of celiac disease (B). The most common agents
include cow’s milk, soy, egg, and wheat proteins. (C)

E-QUIZ QUESTION 20
Which of the following statements regarding tropical sprue is TRUE:

A. Patients describe an insidious and prolonged onset of symptoms,

often linked to fish consumption.
B. Tropical sprue has been linked to autoimmune disorders.
C. Biopsies of the small bowel show a malabsorptive pattern that
cannot be distinguished from that of celiac disease.
D. The duodenum shows villous blunting and intraepithelial
lymphocytosis, but the small bowel findings disappear more
distally.
E. Exclusion of infections etiologies and response to treatment are
required for diagnosis.

Answer: Exclusion of infections etiologies and response to treatment are

required for diagnosis (E).
Diagnostic possibilities in patients with diarrhea acquired in the
tropics are quite extensive, and exclusion of infectious etiologies by stool
and serologic testing is necessary; diagnosis is ultimately confirmed by a
response to treatment (E). Patients report abrupt onset of a diarrheal
illness associated with travel to the tropics (A). The pathogenesis of
tropical sprue is unknown, but patients typically respond to antibiotics
but no specific infectious agent is identified, making an autoimmune
etiology unlikely (B). Biopsies of the small bowel show a malabsorptive
pattern of injury that involves the length of the small bowel, from the
duodenum to the terminal ileum (D), thus allowing distinction from
celiac disease (C).

E-QUIZ QUESTION 21
Which of the following statements regarding CVID is TRUE:

A. CVID is the result of a total absence of immunoglobulins.

B. CVID can always be diagnosed on small bowel biopsies because
patients lack plasma cells.
C. The presence of plasma cells excludes CVID.
D. Patients often present with recurrent infections.

Answer: Patients often present with recurrent infections (D).

Because of their immunocompromised state, patients often present
with recurrent infections, such as Giardia (D). CVID is the result of
ineffective immunoglobulin production, not the total absence (A).
Although most small bowel biopsies from patients with CVID may lack
plasma cells, up to one-third of patients have plasma cells (B). Thus, the
presence of plasma cells does not exclude the possibility of CVID (C),
which can be further evaluated with serum protein electrophoresis.

E-QUIZ QUESTION 22
Which of the following statements regarding collagenous duodenitis
(collagenous sprue) is TRUE: A. An altered or thickened collagen table
can occur as a healing mechanism following erosion or ulceration.
B. The histologic finding of subepithelial collagen deposition is always
accompanied by a malabsorption pattern of injury.
C. Special staining, such as with a PAS, is the preferred method for
highlighting the collagen layer.
D. Strips of epithelial cells detached from the basement membrane are
a pathognomonic feature of collagenous duodenitis.
Answer: An altered or thickened collagen table can occur as a healing
mechanism following erosion or ulceration (A).
Basement membrane thickening is commonly observed in areas of
erosion or ulceration (A). Histologic findings of subepithelial collagen
deposition can be accompanied by a malabsorption pattern, but is not
required (B). In fact, some cases of collagenous duodenitis show intact
villous architecture, making this an easily missed diagnosis. Masson
trichrome stain can help highlight the basement membrane layer (C).
Strips of epithelial cells can detach from the basement membrane, and
are a helpful histologic finding, but by no means pathognomonic;
iatrogenic injury can cause similar findings (D).

E-QUIZ QUESTION 23
Which of the following statements is TRUE regarding pigments found in
the small bowel: A. Formalin pigment is an unavoidable tissue artifact
resulting from routine processing of tissues.
B. Titanium deposition is the result of ingested toothpaste and is found
in the proximal duodenum.
C. Pseudomelanosis duodeni should prompt an investigation for occult
malignancy.
D. Tattoo pigment indicates prior instrumentation within the area
observed.
E. Pigment found in large, atypical cells indicates a benign process, so
long as the cells are S100 protein reactive.

Answer: Tattoo pigment indicates prior instrumentation within the area

observed (D).
Tattoo pigment (usually India ink) is applied endoscopically for lesion
localization in future procedures, for such purposes as targeted
surveillance of endoscopically monitored lesions, localizing lesions at
time of surgery, and improved local lymph node dissections (D).
Formalin pigment is also known as acid formaldehyde hematin and is
derived from hemoglobin reacting with formalin at a low pH. This
bothersome tissue artifact can be easily rectified by using 10% neutral
buffered formalin to a pH of 7; changing the neutral buffered formalin
every 6 months is also an effective measure (A). Pseudomelanosis
duodeni is associated with hypertension, gastrointestinal bleeding, renal
failure, diabetes, and particular medications, but is not a sign of occult
malignancy (C). Pigment found in large atypical cells that are reactive
for S100 protein is highly suggestive of melanoma pigment, not a benign
process (E).

E-QUIZ QUESTION 24
Which of the following statements is TRUE regarding the normal small
bowel anatomy and histology: A. Brunner glands are found throughout
the small bowel, only in the submucosa.
B. Smooth muscle fibers extend from the muscularis mucosae and into
the villi.
C. Broad, leaflike villi and branching villi indicate chronic damage.
D. Submucosal adipose tissue is never present in the small bowel.
E. Due to the predilection for lymphoid malignancies in the terminal
ileum, the finding of abundant lymphoid aggregates in this location
should always be evaluated with at least CD3 and CD20
immunostains.

Answer: Smooth muscle fibers extend from the muscularis mucosae and
into the villi (B).
Tufts of smooth muscle radiate from the muscularis mucosae into the
lamina propria and extend into the villi (B), and should not be mistaken
for histiocytes or parasites. Brunner glands are situated in the submucosa
of the duodenum, and are denser proximally (A). There is a wide
variation of the shape of normal villi, including branching villi, bridging
villi, and broad, leaflike villi (C), which may result from dietary
variations. Submucosal adipose tissue can be found in the ileum,
particularly near the ileocecal valve (D). An abundance of normal
lymphoid aggregates exists at the terminal ileum due to the normal
presence of Peyer patches. Further workup is not required unless the
architecture and cytology are atypical (E).

E-QUIZ QUESTION 25
Which of the following statements regarding acute ileitis is TRUE:
 A. The most common etiologies include Helicobacter infection and
cigarette smoking.
B. The most common etiology is ulcerative colitis (“backwash ileitis”)
and Crohn disease.
C. The most common etiology is medication injury (e.g., nonsteroidal
anti-inflammatory drugs).
D. Longstanding cycles of ulceration and healing can result in
diaphragm disease, most commonly caused by parasitic infection.

Answer: The most common etiology is medication injury (e.g.,

nonsteroidal anti-inflammatory drugs) (C).
While Helicobacter infection and cigarette smoking (A) are associated
with peptic injury, medication-related injury constitutes the most
common etiology for acute ileitis (C). Backwash ileitis and Crohn disease
are other considerations in the differential diagnosis of acute ileitis (B).
Diaphragm disease occurs as the result of repeat cycles of ulceration and
healing due to nonsteroidal anti-inflammatory drugs (D).
 COLON 4

E-QUESTIONS
E-Quiz Question 1 (e-FIG. 4.1)

e-Figure 4.1

This colonic biopsy was taken from a 15-year-old female with abdominal
pain and diarrhea. What stain would you perform to further evaluate
this biopsy?

A. Acetylcholinesterase for the evaluation of Hirschsprung disease.

B. Congo red for the evaluation of amyloidosis.
C. Periodic acid–Schiff (PAS) for the evaluation of Whipple disease.
D. Silver impregnation stain, such as Warthin–Starry, for the
evaluation of intestinal spirochetosis.
E. Tryptase or CD117 immunostain for the evaluation of mast cells.

Answer: Silver impregnation stain, such as Warthin–Starry, for the

evaluation of intestinal spirochetosis (D).
This high magnification image shows a prominent “fuzzy” border
along the surface epithelial cells, indicating the presence of intestinal
spirochetosis. These organisms stain with silver impregnation stains (D).
Acetylcholinesterase is a stain performed on fresh frozen tissue for the
evaluation of Hirschsprung disease, which is typically diagnosed during
infancy (A). It is true that Congo red (B), PAS (C), and tryptase/CD117
(D) may be helpful in other easily missed diagnoses such as amyloidosis,
Whipple disease, and mastocytosis, respectively. However, there is no
evidence of amyloid deposition, abundant foamy histiocytes, or mast
cells in this high magnification image.

E-QUIZ QUESTION 2 (e-FIG. 4.2)

e-Figure 4.2

Following your observations from Question 1, you order a Warthin–

Starry stain (shown), which confirms the presence of intestinal
spirochetosis. Your clinician asks you whether there is concern for sexual
abuse in this 15-year-old female. You answer: A. Intestinal spirochetosis
is sexually transmitted, but not reportable.
B. Intestinal spirochetosis is sexually transmitted, and the finding in a
pediatric patient warrants further investigation into sexual abuse.
C. Intestinal spirochetosis is sexually transmitted, but only colonizes
immunocompromised patients and the patient should be evaluated
for both sexual abuse and HIV/AIDs.
 D. Intestinal spirochetosis is transmitted by fecal-oral route, and the
finding in pediatric patients is not uncommon; the finding does not
implicate sexual abuse.

Answer: Intestinal spirochetosis is transmitted by fecal–oral route, and

the finding in pediatric patients is not uncommon; the finding does not
implicate sexual abuse (D).
Otherwise healthy children may have incidental colonization with
these organisms, and the finding does not imply sexual abuse (D). Sexual
transmission was initially proposed as a method of transmission due to
the higher prevalence in homosexual men, but this remains unproven (A,
B, C). Fecal oral transmission via contaminated water sources and
colonized feces is far more likely.

E-QUIZ QUESTION 3 (e-FIG. 4.3)

e-Figure 4.3

This colon biopsy is showing what feature?

A. Crypt distortion
B. Crypt branching
C. An innominate groove
D. Mucosal prolapse
E. Paneth cell metaplasia

Answer: An innominate groove (C).

 The image depicts a normal finding in the colonic mucosa called an
innominate groove (C) which should not be mistaken for crypt distortion
(A) or crypt branching (B), such as seen in inflammatory bowel disease.
The smooth muscle streaming seen in mucosal prolapse (D) is absent,
and the crypt bases lack pink Paneth cells (E).

E-QUIZ QUESTION 4 (e-FIG. 4.4)

e-Figure 4.4

Which of the following statements is TRUE regarding the

pseudomembranous colitis photomicrograph above?

A. If pseudomembranes are found diffusely throughout the colon,

infection (such as C. difficile) is more likely than ischemia.
B. If pseudomembranes are found diffusely throughout the colon,
ischemia is the most likely cause.
C. Colectomy for pseudomembranous colitis is inappropriate treatment
for an infectious colitis and will likely result in a malpractice
lawsuit.
D. Histologic distinction between infection and ischemic causes of
pseudomembrane formation is always accurate.
E. Pseudomembranes found limited to watershed areas (such as the
splenic flexure) always indicate infection.

Answer: If pseudomembranes are found diffusely throughout the colon,

infection (such as C. difficile) is more likely than ischemia (A).
 Knowledge of the distribution of pseudomembranes can help
differentiate ischemic colitis from infectious pseudomembranous colitis;
for example, when pseudomembranes are diffusely distributed, the cause
is much more likely infectious (A), compared to ischemia, which is often
segmental and found in watershed areas (B and E). Histologic distinction
is rarely possible (D), and stool testing (culture or toxin test) remains the
gold standard. Patients with severe or refractory infectious
pseudomembranous colitis may warrant colectomy (C).

E-QUIZ QUESTION 5 (e-FIG. 4.5)

e-Figure 4.5

Careful examination of this colon biopsy reveals significant surface and

crypt intraepithelial lymphocytosis. Which of the following statements is
true?

A. Lymphocytic colitis qualifies as a “chronic colitis” because of the

significant amount of chronic inflammation.
B. Lymphocytic colitis should never have neutrophils or cryptitis.
C. Lymphocytic colitis is always caused by an infectious etiology.
D. The distinction between lymphocytic and collagenous colitis is
critical, as the treatment protocols differ widely.
E. Lymphocytic colitis is the presence of increased intraepithelial
lymphocytes in the absence of histologic features of chronic injury
(chronicity).
Answer: Lymphocytic colitis is the presence of increased intraepithelial
lymphocytes in the absence of chronicity (E).
Lymphocytic colitis is the presence of increased intraepithelial
lymphocytes (IELs) in the absence of chronicity (E). The IELs are not
considered a feature of chronicity, and lymphocytic colitis is not a
chronic colitis (A). Neutrophils may be seen in lymphocytic colitis,
though sparsely (B). Medication reaction has been implicated in
lymphocytic colitis, though the etiology is not always known (C).
Lymphocytic and collagenous colitis share some overlapping features,
and distinction between the two may not always be possible.
Fortunately, the treatment protocols for both are similar (D).

E-QUIZ QUESTION 6 (e-FIG. 4.6)

e-Figure 4.6

The above colonic biopsy depicts:

A. Collagenous colitis
B. Bullous disease of the colon
C. Pseudomembrane formation
D. Acute ulceration
E. Viral infection

Answer: Collagenous colitis (A).

The colonic biopsy shows a thickened subepithelial collagen table with
marked irregularity of its contour and entrapped small vessels. There is
also a subepithelial cleft with the surface epithelium splitting away from
the abnormal collagen table. The findings are those of collagenous colitis
(A). Bullous diseases of the colon have not been described (B).
Pseudomembranes are composed of fibrin and inflammatory debris, not
pictured here (C). Although acute inflammation can be seen here, there
is no evidence of ulcer formation (D), which should extend to the
submucosa, by definition. No viral cytopathic effect is identified in this
image (E).

E-QUIZ QUESTION 7 (e-FIG. 4.7)

e-Figure 4.7

After reviewing the H&E stained slide, you are concerned for collagenous
colitis and order a trichrome stain to help you evaluate the subepithelial
collagen (pictured). You correctly conclude: A. This is collagenous colitis
because the collagen is markedly thickened.
B. This is collagenous colitis because the collagen is extending
downward as though it were “dripping candle wax.”
C. This is collagenous colitis because the collagen table has entrapped
small blood vessels and fibroblast nuclei.
D. This is collagenous colitis because the abnormal collagen table has
caused the surface epithelium to shear off.
E. This is not collagenous colitis; this is a normal collagen table.

Answer: This is not collagenous colitis; this is a normal collagen table

(E).
Depicted is a normal subepithelial collagen table (E) that appears thin
(A), smooth (B), without entrapped structures (C), and with an intact
overlying epithelium (D).

E-QUIZ QUESTION 8 (e-FIG. 4.8)

e-Figure 4.8

This colon biopsy depicts:

A. Microcrypts of ischemic colitis

B. Amyloid deposition
C. Hyalinized lamina propria of ischemic colitis
D. Biopsy artifact with loss of crypt epithelium
E. Evidence of parasitic infection

Answer: Biopsy artifact with loss of crypt epithelium (D).

The biopsy depicts loss of colonic crypt epithelium (arrows) in an
otherwise normal biopsy, most likely an artifact due to biopsy forceps
(D). This can mimic the microcrypts of ischemic colitis (A), but note the
lack of other ischemic features, such as loss of cytoplasmic mucin,
withering crypts, and lamina propria hyalinization (C). The structures
left behind may look like small vessels, but there is no evidence of
amyloid deposition (B), and no inflammatory response or other evidence
of parasitic infection is present (E).
E-QUIZ QUESTION 9 (e-FIG. 4.9)

e-Figure 4.9

The above colon biopsy shows features of withered microcrypts, and

lamina propria hyalinization in the absence of acute inflammation or
other significant architectural distortion. Which of the following
statements is FALSE?

A. The withered microcrypts indicate infection.

B. The presence of lamina propria hyalinization favors ischemic colitis.
C. The lack of acute inflammation suggests reperfusion injury has not
occurred.
D. If vasculitis is a clinical consideration, careful examination of
vascular structures should be performed in areas away from
ulceration.

Answer: The withered microcrypts indicate infection (A).

The withered microcrypts are a feature of ischemic pattern colitis, the
etiology of which includes both ischemia and infection (A). The
remaining answer choices are true.

E-QUIZ QUESTION 10 (e-FIGS. 4.10 and 4.11)

 e-Figure 4.10

e-Figure 4.11

This colon biopsy comes from a 70-year-old woman with a history of

radiation treatment for bladder cancer. The colonic mucosa is ulcerated,
and you find markedly atypical cells (arrowheads) in the bed of the
ulcer. What do you correctly conclude?

A. The patient has recurrent bladder cancer that has eroded into her
colon.
B. The findings are benign changes of radiation colitis.
C. The patient has cytomegalovirus infection.
D. The patient has herpes simplex virus infection.
E. The patient has adenovirus infection.
Answer: The findings are benign changes of radiation colitis (B).
The atypical cells depicted here show abundant cytoplasm,
maintaining a low nuclear to cytoplasmic (N:C) ratio, and it is correct to
conclude they are cells affected by radiation atypia. There are no
malignant cells (A), which would show a much higher nuclear to
cytoplasmic ratio. In addition, there is no evidence of viral cytopathic
effect, such as nuclear or cytoplasmic inclusions (C, D, E).

E-QUIZ QUESTION 11 (e-FIG. 4.12)

e-Figure 4.12

Which of the following statements is true regarding the above colon

biopsy?

A. This is a normal colon biopsy; intraepithelial eosinophils are a

normal finding in the colon.
B. This represents allergic colitis.
C. Intraepithelial eosinophilia is specific for medication reaction.
D. This finding represents an eosinophilic abscess.
E. The finding of prominent eosinophilia, particularly numerous
intraepithelial eosinophils is abnormal, but nonspecific.

Answer: The finding of prominent eosinophilia, particularly numerous

intraepithelial eosinophils is abnormal, but nonspecific (E).
The finding of prominent eosinophilia, particularly numerous
intraepithelial eosinophils, is abnormal (A) but nonspecific (E). The
differential diagnosis includes allergic colitis (B), medication reaction
(C), parasitic infection, collagen vascular disorders, and idiopathic
eosinophilic enteritis, among others. An eosinophilic abscess is defined
as 4 or more eosinophils clustered together (D). These eosinophils are
present singly within the colonic epithelium.

E-QUIZ QUESTION 12 (e-FIG. 4.13)

e-Figure 4.13

Which of the following statements is true regarding the above colon

biopsy?

A. The structures represent calcification of ingested psyllium, the seed

of the Plantago plant, a common herbal supplement used for its
fiber and mucilage content.
B. The structures represent psammoma bodies and raise the possibility
of a nearby gynecologic malignancy.
C. The structures represent calcified Schistosoma ova.
D. The structures represent dystrophic calcification due to prior
colonic rupture.

Answer: The structures represent calcified Schistosoma ova (C).

The structures are relatively uniform in size and shape, and show an
obvious shell surrounding the calcified material. These are calcified
Schistosoma ova (C). Calcification of psyllium has not been reported, and
like most other ingested material would most likely cause a
granulomatous reaction. Psammoma bodies are lamellated and round
(B). Dystrophic calcification would not appear uniformly ovoid (D).

E-QUIZ QUESTION 13 (e-FIG. 4.14)

e-Figure 4.14

The above cells were identified in a colon biopsy. Which of the following
statements is true?

A. The cells are infected by cytomegalovirus.

B. The cells are infected by herpes simplex virus.
C. The cells are the result of radiation.
D. The cells are most commonly found at the edge of an ulcer, rather
than the base.
E. The cells are most commonly found in the epithelium, rather than
the stroma.

Answer: The cells are infected by cytomegalovirus (A).

These cells show viral cytopathic effect characteristic of
cytomegalovirus (A). They contain nuclear “owl’s eye” inclusions
(arrowheads) and basophilic cytoplasmic inclusions (arrow). There is no
nuclear molding or chromatin margination, as would be expected in
herpes simplex virus (B). The presence of nuclear inclusions excludes
radiation atypia (C). Cytomegalovirus preferentially infects endothelial
cells, fibroblasts and macrophages (E), and is therefore more commonly
found at the base of an ulcer rather than the edge (D).
E-QUIZ QUESTION 14 (e-FIG. 4.15)

e-Figure 4.15

This biopsy of normal colonic tissue most likely represents which

segment of the colon?

A. The cecum, due to the abundant back-to-back Paneth cells.

B. The right colon, due to the scattered Paneth cells.
C. The transverse colon, due to the single Paneth cell.
D. The left colon, due to the lack of Paneth cells.
E. The rectum, due to the mild crypt distortion and lamina propria
muciphages.

Answer: The left colon, due to the lack of Paneth cells. (D).
Taking an educated guess, this colon biopsy is most likely from the left
colon (D), due to the total lack of Paneth cells (A, B, C) and intact crypt
architecture without significant numbers of muciphages (E).

E-QUIZ QUESTION 15
The most common cause of FAC is:

A. Acute self-limited colitis

B. Bowel preparation effect
C. Emerging inflammatory bowel disease
D. Nonsteroidal anti-inflammatory drugs
 E. Ischemic colitis

Answer: Acute self-limited colitis (A).

The most common cause of FAC is acute self-limited colitis (A), a
diarrheal illness lasting less than 4 weeks in duration that is most
commonly attributed to infection, despite negative stool cultures in half
of cases. Bowel preparation effect (B), emerging inflammatory bowel
disease (C), nonsteroidal anti-inflammatory drugs (D), and ischemic
colitis (E) are also associated with a pattern of FAC.

E-QUIZ QUESTION 16
Ischemic colitis and infectious colitis show histologic overlap. Which of
the following features differentiates ischemic colitis from infection?

A. Pseudomembranes
B. Fibrin thrombi
C. Lamina propria hyalinization
D. Microcrypts
E. Lamina propria hemorrhage

Answer: Lamina propria hyalinization (C).

Lamina propria hyalinization is seen more frequently in ischemic
colitis, and can help differentiate the injury pattern from infection.
Pseudomembranes (A), fibrin thrombi (B), microcrypts (D), and lamina
propria hemorrhage (E) are commonly seen in both ischemic and
infectious colitis.

E-QUIZ QUESTION 17 (e-FIG. 4.16)

 e-Figure 4.16

This rectal biopsy is from an elderly man with diarrhea. What is the
diagnosis?

A. Muciphages
B. Signet ring cell carcinoma
C. Metastatic renal cell carcinoma
D. Whipple disease
E. Lipoma

Answer: Muciphages (A).

Muciphages are benign, mucoprotein-containing macrophages seen in
rectal biopsies (A), even those from children. They represent nonspecific,
resolving injury and they usually localize in the superficial mucosa. A
CD68 immunostain can confirm their histiocytic origin. Their cytologic
features are bland and they are cytokeratin nonreactive (B and C). They
have no association with infections (D). While they can occasionally
present as a polyp or nodule, they contain mucin (not lipid, E).

E-QUIZ QUESTION 18 (e-FIG. 4.17)

 e-Figure 4.17

What is the most likely diagnosis for this rectal biopsy? No history is
provided.

A. Crohn disease
B. Ulcerative colitis
C. Diversion colitis
D. Moderate active chronic colitis, see note.

Answer: Moderate active chronic colitis, see note (D).

The chronic colitis pattern is etiologically nonspecific. Nearly identical
histology can be seen in various settings, including diverticular disease,
ipilimumab colitis, syphilitic proctocolitis, chronic infections or
medication injury, radiation injury, among others. As a result, adopting
a three-step pattern-based approach to these cases allows room for the
breadth and depth of the chronic colitis injury pattern (step 1 = classify,
step 2 = grade, step 3 = clinicopathologic correlation). In this case, no
history was provided, so a note detailing the differential possibilities was
most appropriate (D): Note: The above findings are etiologically
nonspecific and can be seen in the following settings: diverticular
disease, diversion-associated colitis, syphilitic and lymphogranuloma
venereum proctocolitis**, chronic nonspecific infection, chronic
medication injury, and IBD, among others. Clinical correlation is
required.
Reference
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.

E-QUIZ QUESTION 19 (e-FIG. 4.18)

e-Figure 4.18

This patient has a 6-month history of diversion related to ischemic

colitis. The excluded bowel segment appeared nodular and a biopsy was
obtained. What is the most likely diagnosis for this rectal biopsy?

A. Crohn disease
B. Ulcerative colitis
C. Diverticular disease
D. Moderate active chronic colitis, see note.

Answer: Moderate active chronic colitis, see note (D).

Since the chronic colitis pattern is etiologically nonspecific, a three-
step pattern-based approach to these cases can be useful. In this case,
careful clinicopathologic correlation resulted in satisfaction of both the
clinical (history of diversion) and histologic (prominent lymphoid
aggregates in a background of active chronic colitis) criteria of
diversion-associated colitis, detailed in the note (D): Note: The history of
diversion is noted. The above findings support the clinicopathologic
diagnosis of diversion-associated colitis.

E-QUIZ QUESTION 20
What is the underlying mechanism of diversion-associated colitis?

A. Deficiency of short-chain fatty acids in the diverted bowel segment

B. Deficiency of short-chain fatty acids in the excluded bowel
segment C. Deficiency of medium-chain fatty acids in the diverted
bowel segment D. Deficiency of medium-chain fatty acids in the
excluded bowel segment Answer: Deficiency of short-chain fatty
acids in the excluded bowel segment (B).
Diversion-associated colitis is an iatrogenic consequence of surgical
detour of the fecal stream away from a segment of colorectum. As a
result, the excluded bowel segment (not the segment of bowel diverted
through the anterior abdominal wall) is deprived of short chain fatty
acids and is vulnerable to this peculiar pattern of chronic colitis (B).
Ostomy reversal is curative, underscoring the importance of recognizing
this curable IBD mimic.

E-QUIZ QUESTION 21
T/F: Diverticula is plural and diverticulum is singular.

Answer: True.
Also, remember, diverticular disease aptly describes both the singular
and plural forms.

E-QUIZ QUESTION 22
Which of the following is not a feature of chronic colitis?

A. Villonodular surface
B. Pyloric gland metaplasia
C. Architectural distortion
D. Cryptitis

Answer: Cryptitis (D).

 Acute colitis refers to ulceration, erosion, cryptitis, and or crypt
abscess.
Chronic colitis refers to any of the following features: • Pyloric gland
metaplasia
• Paneth cell metaplasia
• Increased lamina propria chronic inflammation
• Architectural distortion
• Villonodular surface
• Abnormal crypt configuration
• Crypt dropout
• Crypt shortfall
• Basal lymphoplasmacytosis
Chronic colitis can be further classified as either active or inactive
depending on the presence or absence of a concomitant acute
component. Active chronic colitis includes histologic features of chronicity
AND a concomitant acute component, whereas inactive chronic colitis
refers to any of the histologic features of chronicity in the absence of an
acute colitis component.

E-QUIZ QUESTION 23
Which of the following classic “IBD rules” is commonly broken?

A. Ulcerative colitis is mucosa restricted and Crohn disease is

transmural.
B. Ulcerative colitis is rectal based and progresses in a diffuse manner
and Crohn disease spares the rectum and progresses in a patchy
manner.
C. Ulcerative colitis is colorectum restricted and Crohn disease can
involve the entire GIT.
D. Fissures and transmural lymphoid aggregates and inflammation are
unique to Crohn disease.
E. Pseudopolyps are unique to ulcerative colitis and granulomata are
unique to Crohn disease.
F. All of the above.
Answer: All of the above (F).
As discussed in the “IBD Realities” subsection, every “rule of IBD” has
a known exception. Awareness of the spectrum of the classic,
nonclassical, and IBD mimics is crucial for accurate diagnosis and
appropriate clinical management. These inherent complexities further
emphasize the utility of the descriptive three-step pattern-based
approach to colitis: step 1 = classify; step 2 = grade, step 3 =
clinicopathologic correlation.

E-QUIZ QUESTION 24
What of the following is the best means to establish a diagnosis of LGV
proctitis?

A. Rectal swab for LGV PCR

B. LGV immunohistochemical stain
C. Awareness of the pathognomonic histomorphology
D. LGV rapid serum test

Answer: Rectal swab for LGV PCR (A).

There is no commercially available LGV immunohistochemical stain
(B) or rapid LGV serum test (D) at the time of writing. There are no
pathognomonic morphologic features of LGV proctitis (C); it is
indistinguishable from syphilitic infections. Until sensitive diagnostic
tools are routinely available to the pathologist, clinical laboratory testing
provides the best means to establish this diagnosis (rectal swab collected
in the absence of lubricant for Chlamydia trachomatis nucleic acid probe
test or culture and LGV PCR). It is important for the clinician to also test
for syphilis since either infection in isolation or combination can lead to
the identical morphology (syphilis: serum RPR, RPR titer, and a
treponemal specific serology such as fluorescent treponemal antibody).

E-QUIZ QUESTION 25
Match the following “red flags” to the characteristic etiology: Red flags:
______ Melanoma
______ Long-standing history of constipation
______ Umbilical cord transplantation
______ HIV+ MSM behaviors
______ Traumatic bowel injury, requiring emergent colonic resection
Etiologies:

A. Diverticular Disease
B. Diversion-Associated Colitis
C. Syphilitic and or Lymphogranuloma Venereum Proctocolitis D. Cord
Colitis Syndrome
E. Ipilimumab Colitis

Answer:
E: Melanoma
A: Long-standing history of constipation
D: Umbilical cord transplantation
C: HIV+ MSM behaviors
B. Traumatic bowel injury, requiring emergent colonic resection
**If STI proctocolitis is a clinical consideration, clinical studies provide
the best means to establish this diagnosis (syphilis: serum RPR, RPR
titer, and a treponemal specific serology such as fluorescent
treponemal antibody; Lymphogranuloma venereum: rectal swab
collected in the absence of lubricant for Chlamydia trachomatis
nucleic acid probe test or culture and LGV PCR).