Barrett’s Esophagus

Contents

Foreword: Barrett’s Esophagus xiii

Gary W. Falk

Preface: Barrett’s Esophagus: New Insights and Progress xv

Prasad G. Iyer and Navtej S. Buttar

Epidemiology of Barrett’s Esophagus and Esophageal Adenocarcinoma 203

Thomas M. Runge, Julian A. Abrams, and Nicholas J. Shaheen
Barrett’s esophagus (BE) is the precursor to esophageal adenocarcinoma
(EAC), a disease with increasing burden in the Western world, especially in
white men. Risk factors for BE include obesity, tobacco smoking, and
gastroesophageal reflux disease (GERD). EAC is the most common form
of esophageal cancer in the United States. Risk factors include GERD, to-
bacco smoking, and obesity, whereas nonsteroidal antiinflammatory
drugs and statins may be protective. Factors predicting progression
from nondysplastic BE to EAC include dysplastic changes on esophageal
histology and length of the involved BE segment. Biomarkers have shown
promise, but none are approved for clinical use.

Molecular Pathogenesis of Barrett Esophagus: Current Evidence 233

Kausilia K. Krishnadath and Kenneth K. Wang
This article focuses on recent findings on the molecular mechanisms
involved in esophageal columnar metaplasia. Signaling pathways and their
downstream targets activate specific transcription factors leading to the
expression of columnar and the more specific intestinal-type of genes,
which gives rise to Barrett metaplasia. Several animal models have been
generated to validate and study these distinct molecular pathways but
also to identify the Barrett progenitor cell. Currently, the many aspects
involved in the development of esophageal metaplasia that have been
elucidated can serve to develop novel molecular therapies to improve
treatment or prevent metaplasia. Nevertheless, several key events are still
poorly understood and require further investigation.

Role of Obesity in the Pathogenesis and Progression of Barrett’s Esophagus 249

Apoorva Krishna Chandar and Prasad G. Iyer
Central obesity is involved in the pathogenesis and progression of Barrett’s
esophagus to esophageal adenocarcinoma. Involved are likely both me-
chanical and nonmechanical effects. Mechanical effects of increased
abdominal fat cause disruption of the gastroesophageal reflux barrier lead-
ing to increased reflux events. Nonmechanical effects may be mediated by
inflammation, via classically activated macrophages, pro-inflammatory cy-
tokines, and adipokines such as Leptin, all of which likely potentiate reflux-
mediated inflammation. Insulin resistance, associated with central obesity,
viii Contents

is also associated with both Barrett’s pathogenesis and progression to

adenocarcinoma. Molecular pathways activated in obesity, inflammation
and insulin resistance overlap with those involved in Barrett’s pathogenesis
and progression.

Screening for Barrett’s Esophagus 265

Milli Gupta and Prasad G. Iyer
There is substantial interest in identifying patients with premalignant con-
ditions such as Barrett’s esophagus (BE), to improve outcomes of subjects
with esophageal adenocarcinoma. However, there is limited consensus on
the rationale for screening, the appropriate target population, and optimal
screening modality. Recent progress in the development and validation of
minimally invasive tools for BE screening has reinvigorated interest in BE
screening. BE risk scores combining clinical, anthropometric, and labora-
tory variables are being developed that may allow more precise targeting
of screening to high-risk individuals. This article reviews and summarizes
data on recent progress and challenges in screening for BE.

Surveillance in Barrett’s Esophagus: Utility and Current Recommendations 285

Joel H. Rubenstein
Surveillance of Barrett’s esophagus for preventing death from esophageal
adenocarcinoma is attractive and widely practiced. However, empirical
evidence supporting its effectiveness is weak. Longer intervals between
surveillance examinations are being recommended, supported by com-
puter simulation analyses. If surveillance is performed, an adequate num-
ber of biopsies should be performed or the effect of surveillance would be
squandered.

Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett’s

Esophagus 299
Matthew J. Whitson and Gary W. Falk
The prevalence of esophageal adenocarcinoma is increasing dramatically.
Barrett’s esophagus remains the most well-established risk factor for the
development of esophageal adenocarcinoma. There are multiple clinical,
endoscopic, and pathologic factors that increase the risk of neoplastic
progression to high-grade dysplasia or esophageal adenocarcinoma in
Barrett’s esophagus. This article reviews both risk and protective factors
for neoplastic progression in patients with Barrett’s esophagus.

Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection for

Endoscopic Therapy of Barrett’s Esophagus-related Neoplasia 317
Shivangi Kothari and Vivek Kaul
A major paradigm shift has occurred in the management of dysplastic Bar-
rett’s esophagus (BE) and early esophageal carcinoma. Endoscopic ther-
apy has now emerged as the standard of care for this disease entity.
Endoscopic resection techniques like endoscopic mucosal resection
and endoscopic submucosal dissection combined with ablation tech-
niques help achieve long-term curative success comparable with surgical
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outcomes, in this subgroup of patients. This article is an in-depth review of

these endoscopic resection techniques, highlighting their role and value in
the overall management of BE-related dysplasia and neoplasia.

Ablative Endoscopic Therapies for Barrett’s-Esophagus-Related Neoplasia 337

Shajan Peter and Klaus Mönkemüller
Barrett’s esophagus (BE) is more common in developed countries. Endo-
scopic therapy is an effective treatment method in management of
dysplastic BE. Ablation by thermal energy, freezing, or photochemical
injury completely eradicates dysplasia and specialized intestinal meta-
plasia resulting in neosquamation of esophagus. Among the ablative mo-
dalities, radiofrequency ablation (RFA) is the most studied with safe,
effective, and durable long-term outcomes. Cryotherapy, argon plasma
coagulation, and photodynamic therapy can be offered in select patients
when RFA is unavailable, has failed, or is contraindicated. Future research
on natural disease progression, biomarkers, advanced imaging, and appli-
cation of endoscopic techniques will lead to better clinical outcomes for
BE-associated neoplasia.

Challenges with Endoscopic Therapy for Barrett’s Esophagus 355

Sachin Wani and Prateek Sharma
Barrett’s esophagus is the only identifiable premalignant condition for
esophageal adenocarcinoma. Endoscopic eradication therapy (EET) has
revolutionized the management of Barrett’s-related dysplasia and intra-
mucosal cancer. The primary goal of EET is to prevent progression to inva-
sive esophageal adenocarcinoma and ultimately improve survival rates.
There are several challenges with EET that can be encountered before,
during, or after the procedure that are important to understand to optimize
the effectiveness and safety of EET and ultimately improve patient out-
comes. This article focuses on the challenges with EET and discusses
them under the categories of preprocedural, intraprocedural, and postpro-
cedural challenges.

Biomarkers in Barrett’s Esophagus: Role in Diagnosis, Risk Stratification, and

Prediction of Response to Therapy 373
Ajay Bansal and Rebecca C. Fitzgerald
Esophageal adenocarcinoma (EAC) has increased dramatically in the
past 3 decades, making its precursor lesion Barrett’s esophagus (BE) an
important clinical problem. Effective interventions are available, but overall
outcomes remain unchanged. Most of the BE population remains undiag-
nosed; most EACs are diagnosed late, and most BE patients will never
progress to cancer. These epidemiologic factors make upper endoscopy
an inefficient and ineffective strategy for BE diagnosis and risk stratifica-
tion. In the current review, biomarkers for diagnosis, risk stratification,
and predictors of response to therapy in BE are discussed.

Chemoprevention in Barrett’s Esophagus: Current Status 391

Muhammad H. Zeb, Anushka Baruah, Sarah K. Kossak, and Navtej S. Buttar
Chemoprevention in Barrett’s esophagus is currently applied only in
research settings. Identifying pathways that can be targeted by safe,
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pharmaceutical or natural compounds is key to expanding the scope of

chemoprevention. Defining meaningful surrogate markers of cancer pro-
gression is critical to test the efficacy of chemopreventive approaches.
Combinatorial chemoprevention that targets multiple components of the
same pathway or parallel pathways could reduce the risk and improve
the efficacy of chemoprevention. Here we discuss the role of chemopre-
vention as an independent or an adjuvant management option in BE-
associated esophageal adenocarcinoma.

The Effect of Proton Pump Inhibitors on Barrett’s Esophagus 415

Kerry B. Dunbar, Rhonda F. Souza, and Stuart J. Spechler
Proton pump inhibitors (PPIs) may protect against carcinogenesis in Bar-
rett’s esophagus because they eliminate the chronic esophageal inflam-
mation of reflux esophagitis, and because they decrease esophageal
exposure to acid, which can cause cancer-promoting DNA damage and
increase proliferation in Barrett’s metaplasia. Most clinical studies of
PPIs and cancer development in Barrett’s esophagus have found a
cancer-protective effect for these drugs, although there are some contra-
dictory data. Chemoprevention of dysplasia and cancer in Barrett’s esoph-
agus with PPIs appears to be cost-effective, and the indirect evidence
supporting a cancer-protective role for PPIs is strong enough to warrant
PPI treatment of virtually all patients with Barrett’s esophagus.

Cost-Analyses Studies in Barrett’s Esophagus: What Is Their Utility? 425

Lauren B. Gerson
Approximately 10% to 15% of the chronic gastroesophageal reflux dis-
ease population is at risk for the development of Barrett’s esophagus,
particularly in the setting of other risk factors, including male gender,
Caucasian race, age more than 50, and central obesity. The risk of cancer
progression for patients with nondysplastic BE has been estimated to be
approximately 0.2% to 0.5% per year. Given these low progression rates
and the high cost of endoscopic surveillance, cost-effectiveness analyses
in this area are useful to determine appropriate resource allocation.

Advanced Imaging in Barrett’s Esophagus 439

V. Raman Muthusamy, Stephen Kim, and Michael B. Wallace
Barrett’s esophagus (BE) is present in up to 5.6% of the US population and
is the precursor lesion for esophageal adenocarcinoma. Surveillance
endoscopy is the primary management approach for BE. However, stan-
dard protocol biopsies have been associated with significant miss rates
of dysplastic lesions in patients with BE. Thus, a variety of methods to opti-
mize the imaging of BE have been developed to improve the efficiency and
diagnostic yield of surveillance endoscopy in detecting early neoplasia.
These techniques use changes that occur at macroscopic, microscopic,
and subcellular levels in early neoplasia and are the focus of this article.

Surgical Management of Barrett’s Esophagus 459

Christian G. Peyre and Thomas J. Watson
Patients with gastroesophageal reflux disease and Barrett’s esophagus
can be a management challenge for the treating physician or surgeon.
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The goals of therapy include relief of reflux symptoms, induction of histo-

logic regression, and prevention of progression of intestinal metaplasia to
dysplasia or invasive carcinoma. Antireflux surgery is effective at achieving
these end points, although ongoing follow-up and endoscopic surveillance
are essential. In cases of dysplasia or early esophageal neoplasia associ-
ated with Barrett’s esophagus, endoscopic resection and ablation have
supplanted esophagectomy as the standard of care in most cases. Esoph-
ageal resection continues to have a role, however, in a minority of appro-
priately selected candidates.

Genetic and Epigenetic Alterations in Barrett’s Esophagus and Esophageal

Adenocarcinoma 473
Andrew M. Kaz, William M. Grady, Matthew D. Stachler, and Adam J. Bass
Esophageal adenocarcinoma (EAC) develops from Barrett’s esophagus
(BE), wherein normal squamous epithelia is replaced by specialized intes-
tinal metaplasia in response to chronic gastroesophageal acid reflux. BE
can progress to low- and high-grade dysplasia, intramucosal, and invasive
carcinoma. Both BE and EAC are characterized by loss of heterozygosity,
aneuploidy, specific genetic mutations, and clonal diversity. Given the lim-
itations of histopathology, genomic and epigenomic analyses may
improve the precision of risk stratification. Assays to detect molecular al-
terations associated with neoplastic progression could be used to improve
the pathologic assessment of BE/EAC and to select high-risk patients for
more intensive surveillance.

Index 491