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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

n Associated with food allergies and atopic symptoms

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Lichen planus is a chronic progressive disease that can

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Esophagitis Dissecans Superficialis or Sloughing

Esophagitis—Pathologic Features
Gross (Endoscopic) Findings

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

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

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

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

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

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

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

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

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

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

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

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

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

There is a mighty man, which wonnes here by[325]
That with most fell despight and deadly hate,
Seekes to subuert her Crowne and dignity,
And all his powre doth thereunto apply:
And her good Knights, of which so braue a band
Serues her, as any Princesse vnder sky,
He either spoiles, if they against him stand,
Or to his part allures, and bribeth vnder hand.
Ne him sufficeth all the wrong and ill, xix

Which he vnto her people does each day,
But that he seekes by traytrous traines to spill
Her person, and her sacred selfe to slay:
That O ye heauens defend, and turne away
From her, vnto the miscreant him selfe,
That neither hath religion nor fay,
But makes his God of his vngodly pelfe,
And Idols serues; so let his Idols serue the Elfe.
To all which cruell tyranny they say, xx

He is prouokt, and stird vp day and night
By his bad wife, that hight Adicia,
Who counsels him through confidence of might,
To breake all bonds of law, and rules of right.
For she her selfe professeth mortall foe
To Iustice, and against her still doth fight,
Working to all, that loue her, deadly woe,
And making all her Knights and people to doe so.
Which my liege Lady seeing, thought it best, xxi

With that his wife in friendly wise to deale,
For stint of strife, and stablishment of rest
Both to her selfe, and to her common weale,
And all forepast displeasures to repeale.
So me in message vnto her she sent,
To treat with her by way of enterdeale,
Of finall peace and faire attonement,
Which might concluded be by mutuall consent.
All times haue wont safe passage to afford xxii

To messengers, that come for causes iust:
But this proude Dame disdayning all accord,
Not onely into bitter termes forth brust,
Reuiling me, and rayling as she lust,
But lastly to make proofe of vtmost shame,
Me like a dog she out of dores did thrust,
Miscalling me by many a bitter name,
That neuer did her ill, ne once deserued blame.
And lastly, that no shame might wanting be, xxiii

When I was gone, soone after me she sent
These two false Knights, whom there ye lying see,
To be by them dishonoured and shent:
But thankt be God, and your good hardiment,
They haue the price of their owne folly payd.
So said this Damzell, that hight Samient,
And to those knights, for their so noble ayd,
Her selfe most gratefull shew’d, and heaped thanks repayd.
But they now hauing throughly heard, and seene xxiv

Al those great wrongs, the which that mayd complained[326]
To haue bene done against her Lady Queene,
By that proud dame, which her so much disdained,
Were moued much thereat, and twixt them fained,
With all their force to worke auengement strong
Vppon the Souldan selfe, which it mayntained,
And on his Lady, th’author of that wrong,
And vppon all those Knights, that did to her belong.
But thinking best by counterfet disguise xxv

To their deseigne to make the easier way,
They did this complot twixt them selues deuise,
First, that sir Artegall should him array,
Like one of those two Knights, which dead there lay.
And then that Damzell, the sad Samient,
Should as his purchast prize with him conuay
Vnto the Souldans court, her to present
Vnto his scornefull Lady, that for her had sent.
So as they had deuiz’d, sir Artegall xxvi

Him clad in th’armour of a Pagan knight,
And taking with him, as his vanquisht thrall,
That Damzell, led her to the Souldans right.
Where soone as his proud wife of her had sight,
Forth of her window as she looking lay,
She weened streight, it was her Paynim Knight,
Which brought that Damzell, as his purchast pray;
And sent to him a Page, that mote direct his way.
Who bringing them to their appointed place, xxvii

Offred his seruice to disarme the Knight;
But he refusing him to let vnlace,
For doubt to be discouered by his sight,
Kept himselfe still in his straunge armour dight.
Soone after whom the Prince arriued there,
And sending to the Souldan in despight
A bold defyance, did of him requere
That Damzell, whom he held as wrongfull prisonere.
Wherewith the Souldan all with furie fraught, xxviii

Swearing, and banning most blasphemously,
Commaunded straight his armour to be brought,
And mounting straight vpon a charret hye,
With yron wheeles and hookes arm’d dreadfully,
And drawne of cruell steedes, which he had fed
With flesh of men, whom through fell tyranny
He slaughtred had, and ere they were halfe ded,
Their bodies to his beasts for prouender did spred.
So forth he came all in a cote of plate, xxix

Burnisht with bloudie rust, whiles on the greene
The Briton Prince him readie did awayte,
In glistering armes right goodly well beseene,
That shone as bright, as doth the heauen sheene;
And by his stirrup Talus did attend,
Playing his pages part, as he had beene
Before directed by his Lord; to th’end
He should his flale to finall execution bend.
Thus goe they both together to their geare, xxx

With like fierce minds, but meanings different:
For the proud Souldan with presumpteous[327] cheare,
And countenance sublime and insolent,
Sought onely slaughter and auengement:
But the braue Prince for honour and for right,
Gainst tortious powre and lawlesse regiment,
In the behalfe of wronged weake did fight:
More in his causes truth he trusted then in might.
Like to the Thracian Tyrant, who they say xxxi

Vnto his horses gaue his guests for meat,
Till he himselfe was made their greedie pray,
And torne in peeces by Alcides great.
So thought the Souldan in his follies threat,
Either the Prince in peeces to haue torne
With his sharpe wheeles, in his first rages heat,
Or vnder his fierce horses feet haue borne
And trampled downe in dust his thoughts disdained scorne.
But the bold child that perill well espying, xxxii

If he too rashly to his charet drew,
Gaue way vnto his horses speedie flying,
And their resistlesse rigour did eschew.
Yet as he passed by, the Pagan threw
A shiuering dart with so impetuous force,
That had he not it shun’d with heedfull vew,
It had himselfe transfixed, or his horse,
Or made them both one masse withouten more remorse.
Oft drew the Prince vnto his charret nigh, xxxiii

In hope some stroke to fasten on him neare;
But he was mounted in his seat so high,
And his wingfooted coursers him did beare
So fast away, that ere his readie speare
He could aduance, he farre was gone and past.
Yet still he him did follow euery where,
And followed was of him likewise full fast;
So long as in his steedes the flaming breath did last.
Againe the Pagan threw another dart, xxxiv

Of which he had with him abundant store,
On euery side of his embatteld cart,
And of all other weapons lesse or more,
Which warlike vses had deuiz’d of yore.
The wicked shaft guyded through th’ayrie wyde,
By some bad spirit, that it to mischiefe bore,
Stayd not, till through his curat it did glyde,
And made a griesly wound in his enriuen side.
Much was he grieued with that haplesse throe, xxxv

That opened had the welspring of his blood;
But much the more that to his hatefull foe
He mote not come, to wreake his wrathfull mood.
That made him raue, like to a Lyon wood,
Which being wounded of the huntsmans hand
Can not come neare him in the couert wood,
Where he with boughes hath built his shady stand,
And fenst himselfe about with many a flaming brand.
Still when he sought t’approch vnto him ny, xxxvi

His charret wheeles about him whirled round,
And made him backe againe as fast to fly;
And eke his steedes like to an hungry hound,
That hunting after game hath carrion found,
So cruelly did him pursew and chace,
That his good steed, all were he much renound
For noble courage, and for hardie race,
Durst not endure their sight, but fled from place to place.
Thus long they trast, and trauerst to and fro, xxxvii

Seeking by euery way to make some breach,
Yet could the Prince not nigh vnto him goe,
That one sure stroke he might vnto him reach,
Whereby his strengthes assay he might him teach.
At last from his victorious shield he drew
The vaile, which did his powrefull light empeach;
And comming full before his horses vew,
As they vpon him prest, it plaine to them did shew.
Like lightening flash, that hath the gazer burned, xxxviii

So did the sight thereof their sense dismay,
That backe againe vpon themselues they turned,
And with their ryder ranne perforce away:
Ne could the Souldan them from flying stay,
With raynes, or wonted rule, as well he knew.
Nought feared they, what he could do, or say,
But th’onely feare, that was before their vew;
From which like mazed deare, dismayfully they flew.
Fast did they fly, as them their feete could beare, xxxix
High ouer hilles, and lowly ouer dales,
As they were follow’d of their former feare.
In vaine the Pagan bannes, and sweares, and rayles,
And backe with both his hands vnto him hayles
The resty raynes, regarded now no more:
He to them calles and speakes, yet nought auayles;
They heare him not, they haue forgot his lore,
But go, which way they list, their guide they haue forlore.
As when the firie-mouthed steeds, which drew xl

The Sunnes bright wayne to Phaetons decay,
Soone as they did the monstrous Scorpion vew,
With vgly craples crawling in their way,
The dreadfull sight did them so sore affray,
That their well knowen[328] courses they forwent,
And leading th’euer-burning lampe astray,
This lower world nigh all to ashes brent,
And left their scorched path yet in the firmament.
Such was the furie of these head-strong steeds, xli

Soone as the infants sunlike shield they saw,
That all obedience both to words and deeds
They quite forgot, and scornd all former law;
Through woods, and rocks, and mountaines they did draw
The yron charet, and the wheeles did teare,
And tost the Paynim, without feare or awe;
From side to side they tost him here and there,
Crying to them in vaine, that nould his crying heare.
Yet still the Prince pursew’d him close behind, xlii

Oft making offer him to smite, but found
No easie meanes according to his mind.
At last they haue all ouerthrowne to ground
Quite topside turuey, and the pagan hound
Amongst the yron hookes and graples keene,
Torne all to rags, and rent with many a wound,
That no whole peece of him was to be seene,
But scattred all about, and strow’d vpon the greene.
Like as the cursed sonne of Theseus, xliii

That following his chace in dewy morne,
To fly his stepdames loues outrageous,
Of his owne steedes was all to peeces torne,
And his faire limbs left in the woods forlorne;
That for his sake Diana did lament,
And all the wooddy Nymphes did wayle and mourne.
So was this Souldan rapt and all to rent,
That of his shape appear’d no litle moniment.
Onely his shield and armour, which there lay, xliv

Though nothing whole, but all to brusd and broken,
He vp did take, and with him brought away,
That mote remaine for an eternall token
To all, mongst whom this storie should be spoken,
How worthily, by heauens high decree,
Iustice that day of wrong her selfe had wroken,
That all men which that spectacle did see,
By like ensample mote for euer warned bee.
So on a tree, before the Tyrants dore, xlv

He caused them be hung in all mens sight,
To be a moniment for euermore.
Which when his Ladie from the castles hight
Beheld, it much appald her troubled spright:
Yet not, as women wont in dolefull fit,
She was dismayd, or faynted through affright,
But gathered vnto her her troubled wit,
And gan eftsoones deuize to be aueng’d for it.
Streight downe she ranne, like an enraged cow, xlvi

That is berobbed of her youngling dere,
With knife in hand, and fatally did vow,
To wreake her on that mayden messengere,
Whom she had causd be kept as prisonere,
By Artegall, misween’d for her owne Knight,
That brought her backe. And comming present there,
She at her ran with all her force and might,
All flaming with reuenge and furious despight.
Like raging Ino, when with knife in hand xlvii

She threw her husbands murdred infant out,
Or fell Medea, when on Colchicke strand
Her brothers bones she scattered all about;
Or as that madding mother, mongst the rout
Of Bacchus Priests her owne deare flesh did teare.
Yet neither Ino, nor Medea stout,
Nor all the Mœnades so furious were,
As this bold woman, when she saw that Damzell there.
But Artegall being thereof aware, xlviii

Did stay her cruell hand, ere she her raught,
And as she did her selfe to strike prepare,
Out of her fist the wicked weapon caught:
With that like one enfelon’d or distraught,
She forth did rome, whether[329] her rage her bore,
With franticke passion, and with furie fraught;
And breaking forth out at a posterne dore,
Vnto the wyld wood ranne, her dolours to deplore.
As a mad[330] bytch, when as the franticke fit xlix

Her burning tongue with rage inflamed hath,
Doth runne at randon, and with furious bit
Snatching at euery thing, doth wreake her wrath
On man and beast, that commeth in her path.
There they doe say, that she transformed was
Into a Tygre, and that Tygres scath
In crueltie and outrage she did pas,
To proue her surname true, that she imposed has.
Then Artegall himselfe discouering plaine, l

Did issue forth gainst all that warlike rout
Of knights and armed men, which did maintaine
That Ladies part, and to the Souldan lout:
All which he did assault with courage stout,
All were they nigh an hundred knights of name,
And like wyld Goates them chaced all about,
Flying from place to place with cowheard[331] shame,
So that with finall force them all he ouercame.
Then caused he the gates be opened wyde, li

And there the Prince, as victour of that day,
With tryumph entertayn’d and glorifyde,
Presenting him with all the rich array,
And roiall pompe, which there long hidden lay,
Purchast through lawlesse powre and tortious wrong
Of that proud Souldan, whom he earst did slay.
So both for rest there hauing stayd not long,
Marcht with that mayd, fit matter for another song.
FOOTNOTES:
[320] viii 1 hm 1596
[321] 7 despiteous 1609
[322] xiii 1 sir 1596, 1609
[323] xiv 3 Since] Sith 1609
[324] xvi 1 them] then 1596
[325] xviii 2 hereby 1609
[326] xxiv 2 complained. 1596
[327] xxx 3 presumptuous 1609
[328] xl 6 knowne 1596
[329] xlviii 6 whither 1609
[330] xlix 1 mad] bad 1609
[331] 1 8 coward 1609 passim
Cant. IX.
Arthur and Artegall catch Guyle

whom Talus doth dismay,
They to Mercillaes pallace come,
and see her rich array.
What Tygre, or what other salvage wight i

Is so exceeding furious and fell,
As wrong, when it hath arm’d it selfe with might?
Not fit mongst men, that doe with reason mell,
But mongst wyld beasts and saluage woods to dwell;
Where still the stronger doth the weake deuoure,
And they that most in boldnesse doe excell,
Are dreadded most, and feared for their powre:
Fit for Adicia, there to build her wicked bowre.
There let her wonne farre from resort of men, ii

Where righteous Artegall her late exyled;
There let her euer keepe her damned den,
Where none may be with her lewd parts defyled,
Nor none but beasts may be of her despoyled:
And turne we to the noble Prince, where late
We did him leaue, after that he had foyled
The cruell Souldan, and with dreadfull fate
Had vtterly subuerted his vnrighteous state.
Where hauing with Sir Artegall a space iii

Well solast in that Souldans late delight,
They both resoluing now to leaue the place,
Both it and all the wealth therein behight
Vnto that Damzell in her Ladies right,
And so would haue departed on their way.
But she them woo’d by all the meanes she might,
And earnestly besought, to wend that day
With her, to see her Ladie thence not farre away.
By whose entreatie both they ouercommen, iv

Agree to goe with her, and by the way,
(As often falles) of sundry things did commen.
Mongst which that Damzell did to them bewray
A straunge aduenture, which not farre thence lay;
To weet a wicked villaine, bold and stout,
Which wonned in a rocke not farre away,
That robbed all the countrie there about,
And brought the pillage home, whence none could get it out.
Thereto both his owne wylie wit, (she sayd) v

And eke the fastnesse of his dwelling place,
Both vnassaylable, gaue him great ayde:
For he so crafty was to forge and face,
So light of hand, and nymble of his pace,
So smooth of tongue, and subtile in his tale,
That could deceiue one looking in his face;
Therefore by name Malengin they him call,
Well knowen by his feates, and famous ouer all.
Through these his slights he many doth confound, vi

And eke the rocke, in which he wonts to dwell,
Is wondrous strong, and hewen farre vnder ground
A dreadfull depth, how deepe no man can tell;
But some doe say, it goeth downe to hell.
And all within, it full of wyndings is,
And hidden wayes, that scarse an hound by smell
Can follow out those false footsteps of his,
Ne none can backe returne, that once are gone amis.
Which when those knights had heard, their harts gan earne[332], vii
To vnderstand that villeins dwelling place,
And greatly it desir’d of her to learne,
And by which way they towards it should trace.
Were not (sayd she) that it should let your pace
Towards my Ladies presence by you ment,
I would you guyde directly to the place.
Then let not that (said they) stay your intent;
For neither will one foot, till we that carle haue hent.
So forth they past, till they approched ny viii

Vnto the rocke, where was the villains won,
Which when the Damzell neare at hand did spy,
She warn’d the knights thereof: who thereupon
Gan to aduize, what best were to be done.
So both agreed, to send that mayd afore,
Where she might sit nigh to the den alone,
Wayling, and raysing pittifull vprore,
As if she did some great calamitie deplore.
With noyse whereof when as the caytiue carle ix

Should issue forth, in hope to find some spoyle,
They in awayt would closely him ensnarle,
Ere to his den he backward could recoyle,
And so would hope him easily to foyle.
The Damzell straight went, as she was directed,
Vnto the rocke, and there vpon the soyle
Hauing her selfe in wretched wize abiected,
Gan weepe and wayle, as if great griefe had her affected.
The cry whereof entring the hollow caue, x

Eftsoones brought forth the villaine, as they ment,
With hope of her some wishfull boot to haue.
Full dreadfull wight he was, as euer went
Vpon the earth, with hollow eyes deepe pent,
And long curld locks, that downe his shoulders shagged,
And on his backe an vncouth vestiment
Made of straunge[333] stuffe, but all to worne and ragged,
And vnderneath his breech was all to torne and iagged.
And in his hand an huge long staffe he held, xi

Whose top was arm’d with many an yron hooke,
Fit to catch hold of all that he could weld,
Or in the compasse of his clouches tooke;
And euer round about he cast his looke.
Als at his backe a great wyde net he bore,
With which he seldome fished at the brooke,
But vsd to fish for fooles on the dry shore,
Of which he in faire weather wont to take great store.
Him when the damzell saw fast by her side, xii

So vgly creature, she was nigh dismayd,
And now for helpe aloud in earnest cride.
But when the villaine saw her so affrayd,
He gan with guilefull words her to perswade,
To banish feare, and with Sardonian smyle
Laughing on her, his false intent to shade,
Gan forth to lay his bayte her to beguyle,
That from her self vnwares he might her steale the whyle.
Like as the fouler on his guilefull pype xiii

Charmes to the birds full many a pleasant lay,
That they the whiles may take lesse heedie keepe,
How he his nets doth for their ruine lay:
So did the villaine to her prate and play,
And many pleasant trickes before her show,
To turne her eyes from his intent away:
For he in slights and iugling feates did flow,
And of legierdemayne the mysteries did know.
To which whilest she lent her intentiue mind, xiv
He suddenly his net vpon her threw,
That ouersprad her like a puffe of wind;
And snatching her soone vp, ere well she knew,
Ran with her fast away vnto his mew,
Crying for helpe aloud. But when as ny
He came vnto his caue, and there did vew
The armed knights stopping his passage by,
He threw his burden downe, and fast away did fly.
But Artegall him after did pursew, xv

The whiles the Prince there kept the entrance still:
Vp to the rocke he ran, and thereon flew
Like a wyld Gote, leaping from hill to hill,
And dauncing on the craggy cliffes at will;
That deadly daunger seem’d in all mens sight,
To tempt such steps, where footing was so ill:
Ne ought auayled for the armed knight,
To thinke to follow him, that was so swift and light.
Which when he saw, his yron man he sent, xvi

To follow him; for he was swift in chace.
He him pursewd, where euer that he went,
Both ouer rockes, and hilles, and euery place,
Where so he fled, he followd him apace:
So that he shortly forst him to forsake
The hight, and downe descend vnto the base.
There he him courst a fresh, and soone did make
To leaue his proper forme, and other shape to take.
Into a Foxe himselfe he first did tourne; xvii

But he him hunted like a Foxe full fast:
Then to a bush himselfe he did transforme,
But he the bush did beat, till that at last
Into a bird it chaung’d, and from him past,
Flying from tree to tree, from wand to wand:
But he then stones at it so long did cast,
That like a stone it fell vpon the land,
But he then tooke it vp, and held fast in his hand.
So he it brought with him vnto the knights, xviii

And to his Lord Sir Artegall it lent,
Warning him hold it fast, for feare of slights.
Who whilest in hand it gryping hard[334] he hent,
Into a Hedgehogge all vnwares it went,
And prickt him so, that he away it threw.
Then gan it runne away incontinent,
Being returned to his former hew:
But Talus soone him ouertooke, and backward drew.
But when as he would to a snake againe xix

Haue turn’d himselfe, he with his yron flayle
Gan driue at him, with so huge might and maine,
That all his bones, as small as sandy grayle
He broke, and did his bowels disentrayle;
Crying in vaine for helpe, when helpe was past.
So did deceipt the selfe deceiuer fayle,
There they him left a carrion outcast;
For beasts and foules to feede vpon for their repast.
Thence forth they passed with that gentle Mayd, xx

To see her Ladie, as they did agree.
To which when she approched, thus she sayd;
Loe now, right noble knights, arriu’d ye bee
Nigh to the place, which ye desir’d to see:
There shall ye see my souerayne Lady Queene
Most sacred wight, most debonayre and free,
That euer yet vpon this earth was seene,
Or that with Diademe hath euer crowned beene.
The gentle knights reioyced much to heare xxi

The prayses of that Prince so manifold,
And passing litle further, commen were,
Where they a stately pallace did behold,
Of pompous show, much more then she had told;
With many towres, and tarras mounted hye,
And all their tops bright glistering with gold,
That seemed to outshine the dimmed skye,
And with their brightnesse daz’d the straunge beholders eye.
There they alighting, by that Damzell were xxii

Directed in, and shewed all the sight:
Whose porch, that most magnificke did appeare,
Stood open wyde to all men day and night;
Yet warded well by one of mickle might,
That sate thereby, with gyantlike resemblance,
To keepe out guyle, and malice, and despight,
That vnder shew oftimes[335] of fayned semblance,
Are wont in Princes courts to worke great scath and hindrance.
His name was Awe; by whom they passing in xxiii

Went vp the hall, that was a large wyde roome,
All full of people making troublous din,
And wondrous noyse, as if that there were some,
Which vnto them was dealing righteous doome.
By whom they passing, through the thickest preasse,
The marshall of the hall to them did come;
His name hight Order, who commaunding peace,
Them guyded through the throng, that did their clamors ceasse.
They ceast their clamors vpon them to gaze; xxiv

Whom seeing all in armour bright as day,
Straunge there to see, it did them much amaze,
And with vnwonted terror halfe affray.
For neuer saw they there the like array,
Ne euer was the name of warre there spoken,
But ioyous peace and quietnesse alway,
Dealing iust iudgements, that mote not be broken
For any brybes, or threates of any to be wroken.
There as they entred at the Scriene, they saw xxv

Some one, whose tongue was for his trespasse vyle
Nayld to a post, adiudged so by law:
For that therewith he falsely did reuyle,
And foule blaspheme that Queene for forged guyle,
Both with bold speaches, which he blazed had,
And with lewd poems, which he did compyle;
For the bold title of a Poet bad
He on himselfe had ta’en, and rayling rymes had sprad.
Thus there he stood, whylest high ouer his head, xxvi

There written was the purport of his sin,
In cyphers strange, that few could rightly read,
BON FONT[336]: but bon that once had written bin,
Was raced out, and Mal was now put in.
So now Malfont was plainely to be red;
Eyther for th’euill, which he did therein,
Or that he likened was to a welhed
Of euill words, and wicked sclaunders[337] by him shed.
They passing by, were guyded by degree xxvii

Vnto the presence of that gratious Queene:
Who sate on high, that she might all men see,
And might of all men royally be seene,
Vpon a throne of gold full bright and sheene,
Adorned all with gemmes of endlesse price,
As either might for wealth haue gotten bene,
Or could be fram’d by workmans rare deuice;
And all embost with Lyons and with Flourdelice.
All ouer her a cloth of state was spred, xxviii

Not of rich tissew, nor of cloth of gold,
Nor of ought else, that may be richest red,
But like a cloud, as likest may be told,
That her brode spreading wings did wyde vnfold;
Whose skirts were bordred with bright sunny beams,
Glistring like gold, amongst the plights enrold,
And here and there shooting forth siluer streames,
Mongst which crept litle Angels through the glittering gleames.
Seemed those litle Angels did vphold xxix

The cloth of state, and on their purpled wings
Did beare the pendants, through their nimblesse bold:
Besides a thousand more of such, as sings
Hymnes to high God, and carols heauenly things,
Encompassed the throne, on which she sate:
She Angel-like, the heyre of ancient kings
And mightie Conquerors, in royall state,
Whylest kings and kesars at her feet did them prostrate.
Thus she did sit in souerayne Maiestie, xxx

Holding a Scepter in her royall hand,
The sacred pledge of peace and clemencie,
With which high God had blest her happie land,
Maugre so many foes, which did withstand.
But at her feet her sword was likewise layde,
Whose long rest rusted the bright steely brand;
Yet when as foes enforst, or friends sought ayde,
She could it sternely draw, that all the world dismayde.
And round about, before her feet there sate xxxi

A beuie of faire Virgins clad in white,
That goodly seem’d t’adorne her royall state,
All louely daughters of high Ioue, that hight[338]
Litæ,[339] by him begot in loues delight,
Vpon the righteous Themis: those they say
Vpon Ioues iudgement seat wayt day and night,
And when in wrath he threats the worlds decay,
They doe his anger calme, and cruell vengeance stay.
They also doe by his diuine permission xxxii

Vpon the thrones of mortall Princes tend,
And often treat for pardon and remission
To suppliants, through frayltie which offend.
Those did vpon Mercillaes throne attend:
Iust Dice, wise Eunomie, myld Eirene,
And them amongst, her glorie to commend,
Sate goodly Temperance in garments clene,
And sacred Reuerence, yborne of heauenly strene.
Thus did she sit in royall rich estate, xxxiii

Admyr’d of many, honoured of all,
Whylest vnderneath her feete, there as she sate,
An huge great Lyon lay, that mote appall
An hardie courage, like captiued thrall,
With a strong yron chaine and coller bound,
That once he could not moue, nor quich at all;
Yet did he murmure with rebellious[340] sound,
And softly royne, when saluage choler gan redound.
So sitting high in dreaded souerayntie, xxxiv

Those two strange knights were to her presence brought;
Who bowing low before her Maiestie,
Did to her myld obeysance, as they ought,
And meekest boone, that they imagine mought.
To whom she eke inclyning her withall,
As a faire stoupe of her high soaring thought,
A chearefull countenance on them let fall,
Yet tempred with some maiestie imperiall.
As the bright sunne, what time his fierie teme xxxv

Towards the westerne brim begins to draw,
Gins to abate the brightnesse of his beme,
And feruour of his flames somewhat adaw:
So did this mightie Ladie, when she saw
Those two strange knights such homage to her make,
Bate somewhat of that Maiestie and awe,
That whylome wont to doe so many quake,
And with more myld aspect those two to entertake.
Now at that instant, as occasion fell, xxxvi

When these two stranger knights arriv’d in place,

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1​ Non-Neoplastic Disorders of the 12​ Epithelial Neoplasms of the

2​ Tumors of the Esophagus 29 13​ Molecular Testing of Gastrointestinal

6​ Neoplasms of the Small Intestine 151 17​ Non-Neoplastic Disorders of the

9​ Infectious Diseases of the 20​ Pathology of Liver, Small Bowel, and

10​ Non-Neoplastic Disorders of the Index 691

11​ Gastrointestinal Polyposis

The esophagus is designed to simply serve as a conduit ■ ESOPHAGITIS

proximal segment of esophagus. The typical histo-

FIGURE 1.1 FIGURE 1.4

Definition Clinical Features

caused by acid reflux from the stomach

and surgical procedures (Nissen fundoplication) in severe cases

n Deep ulcers are followed by strictures in severe disease

papillae, and spongiosis

and/or neutrophils EOSINOPHILIC ESOPHAGITIS—FACT SHEET

n Balloon cell change, hyperkeratosis, and increased total epithelial Definition

n Can present alone or as part of eosinophilic gastroenteritis

dyspepsia, and solid food impaction

and abdominal pain

Prognosis and Therapy

n May lead to severe esophageal strictures if untreated

n Elimination of food allergens and topical corticosteroids are the

Classic endoscopic findings include mucosal rings, fur-

Biopsies show increased intraepithelial eosinophils

be generated by examining the fragments at low magni-

be seen in patients with reflux esophagitis. Distal esopha­

the papillae, spongiosis, and fibrosis of the lamina propria and

Lymphocytic esophagitis is a poorly defined clinico-

FIGURE 1.9 Symptoms include dysphagia, chest pain, heartburn,

Pathologic Features neutrophils and eosinophils. Esophageal Crohn’s disease

The esophageal biopsy shows increased intraepithelial

n Can be seen anywhere along the esophagus

Gender and Age Distribution

to sixth decade of life

disease, inflammatory bowel disease, or allergy

Prognosis and Therapy

n Gastrointestinal symptoms and histologic findings persist in some

FIGURE 1.10 patients

Daniela S. Allende, MD, MBA

Copyright © 2024 by Elsevier Inc. All rights reserved.

Previous editions copyrighted 2012 and 2005.

Executive Content Strategist: Michael Houston

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Daniela S.Allende, MD, MBA Ilyssa O.Gordon, MD, PhD

Mari Mino-Kenudson, MD Safia NawazishSalaria, MD, MMHC

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

2 Tumors of the Esophagus 29 13 Molecular Testing of Gastrointestinal

6 Neoplasms of the Small Intestine 151 17 Non-Neoplastic Disorders of the

9 Infectious Diseases of the 20 Pathology of Liver, Small Bowel, and

10 Non-Neoplastic Disorders of the Index 691

11 Gastrointestinal Polyposis

be seen in patients with reflux esophagitis. Distal esopha