Diagnosis and

Treatment of
Gastrointestinal
Cancers
Editors

RAQUEL E. DAVILA
MARTA L. DAVILA

GASTROENTEROLOGY
CLINICS OF NORTH AMERICA
www.gastro.theclinics.com

Consulting Editor
ALAN L. BUCHMAN

September 2022  Volume 51  Number 3

 Diagnosis and Treatment of Gastrointestinal Cancers

Contributors

CONSULTING EDITOR

ALAN L. BUCHMAN, MD, MSPH, FACP, FACN, FACG, AGAF

Professor of Clinical Surgery, Medical Director, Intestinal Rehabilitation and Transplant
Center, The University of Illinois at Chicago/UI Health, Chicago, Illinois, USA

EDITORS

RAQUEL E. DAVILA, MD, FACP, AGAF, FACG, FASGE

Associate Professor, The University of Texas at Dallas, Dallas, Texas, USA

MARTA L. DAVILA, MD, AGAF, FACG, FASGE

Professor, Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal
Medicine, Department of Clinical Cancer Prevention, Division of Cancer Prevention and
Population Sciences, The University of Texas MD Anderson Cancer Center, Houston,
Texas, USA

AUTHORS

JORDAN E. AXELRAD, MD, MPH

Director of Clinical and Translational Research, Inflammatory Bowel Disease Center at
NYU Langone Health, Assistant Professor, Division of Gastroenterology, Department of
Medicine, NYU Grossman School of Medicine, New York, New York, USA

VEROUSHKA BALLESTER, MD, MSc

University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico, USA;
Assistant Professor, Department of Medicine, Biochemistry and Surgery, University of
Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA

OMER BASAR, MD
Gastroenterology Fellow, The University of Missouri, Department of Gastroenterology,
Columbia, Missouri, USA

ROBERT S. BRESALIER, MD
Department of Gastroenterology, Hepatology and Nutrition, Professor of Medicine,
Distinguished Professor in Gastrointestinal Oncology, The University of Texas MD
Anderson Cancer Center, Houston, Texas, USA

WILLIAM R. BRUGGE, MD
Professor in Medicine, Harvard Medical School, Chief, Mount Auburn Hospital,
Department of Gastroenterology, Cambridge, Massachusetts, USA

SAHIN COBAN, MD
Research Coordinator, Mount Auburn Hospital, Department of Gastroenterology,
Cambridge, Massachusetts, USA
iv Contributors

D. CHAMIL CODIPILLY, MD
Fellow Physician, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester,
Minnesota, USA
CARY C. COTTON, MD, MPH
Department of Medicine, Division of Gastroenterology and Hepatology, Center for
Esophageal Diseases and Swallowing, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, USA
MARCIA CRUZ-CORREA, MD, PhD
University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, Puerto Rico, USA;
Professor, Department of Medicine, Biochemistry and Surgery, University of Puerto Rico
Medical Sciences Campus, San Juan, Puerto Rico, USA

ROHIT DAS, MD
Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania, USA
RAQUEL E. DAVILA, MD, FACP, AGAF, FACG, FASGE
Associate Professor, The University of Texas at Dallas, Dallas, Texas, USA

RICARDO L. DOMINGUEZ, MD
Western Honduras Gastric Cancer Prevention Initiative, Copan Region Ministry of Health,
Honduras

JENNIFER R. EADS, MD
Division of Hematology/Oncology, Department of Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

SWATHI ELURI, MD, MPH

Department of Medicine, Division of Gastroenterology and Hepatology, Center for
Esophageal Diseases and Swallowing, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, USA

ADAM S. FAYE, MD, MS

Assistant Professor, Division of Gastroenterology, Department of Medicine, NYU
Grossman School of Medicine, Inflammatory Bowel Disease Center at NYU Langone
Health, New York, New York, USA

CONRAD J. FERNANDES, MD
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia,
Pennsylvania, USA

MICHAEL GOGGINS, MD
Departments of Pathology, Medicine, and Oncology, Bloomberg School of Public Health,
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical
Institutions, Baltimore, Maryland, USA

ARIELA K. HOLMER, MD
Assistant Professor, Division of Gastroenterology, Department of Medicine, NYU
Grossman School of Medicine, Inflammatory Bowel Disease Center at NYU Langone
Health, New York, New York, USA

BRYSON W. KATONA, MD, PhD

Division of Gastroenterology and Hepatology, Department of Medicine, Perelman Center
for Advanced Medicine, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania, USA
 Contributors v

GALEN LEUNG, MD
Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School
of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

ELEAZAR MONTALVAN SANCHEZ, MD

Western Honduras Gastric Cancer Prevention Initiative, Copan Region Ministry of Health,
Honduras; Department of Medicine, Indiana University School of Medicine, Indianapolis,
Indiana, USA

DOUGLAS R. MORGAN, MD, MPH

UAB Department of Medicine, The University of Alabama at Birmingham, Birmingham,
Alabama, USA

DALTON A. NORWOOD, MD
UAB Department of Medicine, The University of Alabama at Birmingham, Birmingham,
Alabama, USA; Western Honduras Gastric Cancer Prevention Initiative, Copan Region
Ministry of Health, Honduras

HELENA SABA, MD
Post-Doctoral Fellow Michael Goggins, Professor of Pathology, Medicine, and Oncology,
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

NICHOLAS J. SHAHEEN, MD, MPH

Department of Medicine, Division of Gastroenterology and Hepatology, Center for
Esophageal Diseases and Swallowing, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, USA

AATUR D. SINGHI, MD, PhD

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania, USA

ADAM SLIVKA, MD, PhD

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania, USA

KENNETH K. WANG, MD
Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic,
Rochester, Minnesota, USA

JENNIFER A. WARGO, MD, MMSc

Professor, Departments of Genomic Medicine and Surgical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, Texas, USA

MICHAEL G. WHITE, MD, MSc

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, Texas, USA
 Diagnosis and Treatment of Gastrointestinal Cancers

Contents

Preface: Recent Advancements in the Diagnosis and Treatment of Gastrointestinal

Cancers xiii
Raquel E. Davila and Marta L. Davila

Squamous Cell Carcinoma of the Esophagus 457

D. Chamil Codipilly and Kenneth K. Wang
Esophageal squamous cell carcinoma (ESCC) is common in the devel-
oping world with decreasing incidence in developed countries and carries
significant morbidity and mortality. Major risk factors for ESCC develop-
ment include significant use of alcohol and tobacco. Screening for
ESCC can be recommended in high-risk populations living in highly
endemic regions. The treatment of ESCC ranges from endoscopic resec-
tion therapy or surgery in localized disease to chemoradiotherapy in met-
astatic disease, and prognosis is directly related to the stage at diagnosis.
New immunotherapies and molecular targeted therapies may improve the
dismal survival outcomes in patients with metastatic ESCC.

Management of Dysplastic Barrett’s Esophagus and Early Esophageal

Adenocarcinoma 485
Cary C. Cotton, Swathi Eluri, and Nicholas J. Shaheen
While patients with Barrett’s esophagus without dysplasia may benefit
from endoscopic surveillance, those with low-grade dysplasia may be
managed with either endoscopic surveillance or endoscopic eradication.
Patients with Barrett’s esophagus with high-grade dysplasia and/or intra-
mucosal adenocarcinoma will generally require endoscopic eradication
therapy. The management of Barrett’s esophagus with dysplasia and early
esophageal adenocarcinoma is predominantly endoscopic, with multiple
effective methods available for the resection of raised neoplasia and abla-
tion of flat neoplasia. High-dose proton-pump inhibitor therapy is advised
during the treatment of Barrett’s esophagus with dysplasia and early
esophageal adenocarcinoma. After the endoscopic eradication of Bar-
rett’s esophagus and associated neoplasia, surveillance is required for
the diagnosis and retreatment of recurrence or progression.

Gastric Cancer: Emerging Trends in Prevention, Diagnosis, and Treatment 501

Dalton A. Norwood, Eleazar Montalvan Sanchez, Ricardo L. Dominguez, and
Douglas R. Morgan
Gastric adenocarcinoma (GC) is the fourth leading cause of global cancer
mortality, and the leading infection-associated cancer. Helicobacter pylori
is the dominant risk factor for GC and classified as an IARC class I carcin-
ogen. Surveillance of gastric premalignant conditions is now indicated in
high-risk patients. Upper endoscopy is the gold standard for GC diag-
nosis, and image-enhanced endoscopy increases the detection of gastric
premalignant conditions and early gastric cancer (EGC). Clinical staging is
crucial for treatment approach, defining early gastric cancer, operable
viii Contents

locoregional disease, and advanced GC. Endoscopic submucosal dissec-

tion is the treatment of choice for most EGC. Targeted therapies are rapidly
evolving, based on biomarkers including MSI/dMMR, HER2, and PD-L1.
These advancements in surveillance, diagnostic and therapeutic strate-
gies are expected to improve GC survival rates in the near term.

Endoscopic Evaluation and Management of Cholangiocarcinoma 519

Rohit Das, Aatur D. Singhi, and Adam Slivka
Cholangiocarcinoma is a rare malignancy of the biliary tract with a rela-
tively poor prognosis. As a gastroenterologist, our main role is to differen-
tiate between benign and malignant biliary disease, help achieve a
diagnosis, and palliate jaundice related to biliary obstruction. This article
focuses on summarizing the various tools currently available for endo-
scopic evaluation and management of cholangiocarcinoma.

Pancreatic Cystic Neoplasms 537

Sahin Coban, Omer Basar, and William R. Brugge
Early detection of high-risk pancreatic cystic lesions enables potentially
curative surgical resection, and early detection of lesions without worri-
some features may lead to appropriate surveillance. Regrettably, differen-
tiating premalignant and malignant cysts from nonmalignant ones remains
challenging. However, emerging additional diagnostic tools, including the
needle biopsy with microforceps and needle-based confocal laser endo-
microscopy, are of exciting potential along with cyst fluid analysis.

Familial Pancreatic Cancer 561

Helena Saba and Michael Goggins
Individuals at increased risk of developing pancreatic cancer, including
those with a significant family history of the disease and those with pancre-
atic cancer susceptibility gene variants, can benefit from pancreas surveil-
lance. Most pancreatic cancers diagnosed during surveillance are early-
stage and such patients can achieve long-term survival. Determining who
should undergo pancreas surveillance is still a work-in-progress, but the
main tools clinicians use to estimate an individual’s risk of pancreatic cancer
are patient’s age, the extent of their family history of pancreatic cancer, and
whether or not they have a pancreatic cancer susceptibility gene mutation.

Colorectal Cancer Screening in a Changing World 577

Robert S. Bresalier
Early detection of colorectal neoplasia significantly reduces mortality from
colorectal cancer (CRC), and numerous screening options exist. Guidelines
for CRC screening from US and international professional societies provide
menus of options based on strength of evidence. Despite availability of
screening and its proven impact, 40% of guideline-eligible patients are not
screened as recommended in the United States. Adherence to or uptake of
CRC screening is especially poor among underserved populations, including
those with low income and African American and Hispanic populations.
Consideration of screening options must not only take into account test per-
formance, but issues of resources and individual versus population benefits.
 Contents ix

Approach to Familial Predisposition to Colorectal Cancer 593

Veroushka Ballester and Marcia Cruz-Correa
The traditional approach of one-size-fits-all for colorectal cancer has been
replaced by personalized interventions to an individual’s unique genetic,
molecular, and environmental profile, seeking to identify high-risk individ-
uals who would benefit from individualized screening and surveillance.
This change in approach is due, in part, to emerging technologies, such
as next-generation DNA sequencing.

A Gastroenterologist’s Approach to the Diagnosis and Management of

Gastrointestinal Stromal Tumors 609
Raquel E. Davila
Gastrointestinal stromal tumors (GISTs) are the most common mesen-
chymal tumors of the gastrointestinal (GI) tract. These tumors have been
shown to harbor oncogenic mutations of the c-kit tyrosine kinase receptor
or platelet-derived growth factor receptor alpha (PDGFRA). Immunohisto-
chemical analysis of GISTs allows for the differentiation of these tumors
from other mesenchymal tumors of the GI tract such as leiomyomas and
leiomyosarcomas. All GISTs have the potential to behave in a malignant
fashion. Tumor location, size, and mitotic index are factors used to predict
the risk of malignant behavior. Endoscopy and endoscopic ultrasound play
a critical role in the diagnosis of GISTs and can yield important information
to further risk-stratify tumors and determine management. This article pro-
vides a gastroenterologist’s perspective on the diagnosis and manage-
ment of GISTs.

Gastroenteropancreatic Neuroendocrine Tumors 625

Conrad J. Fernandes, Galen Leung, Jennifer R. Eads, and Bryson W. Katona
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most
common type of neuroendocrine tumors and are being increasingly iden-
tified in clinical practice. The diagnosis, staging, management, and surveil-
lance of GEP-NETs rely heavily on endoscopy, and consequently, it is
important for gastroenterologists to have a solid understanding of these
tumors. This article reviews the presentation, diagnosis, and management
of both localized and advanced GEP-NETs, with increased emphasis on
the role of endoscopy, to enable gastroenterologists and other practi-
tioners to have the necessary tools for the care of patients with these
tumors.

Cancer in Inflammatory Bowel Disease 649

Adam S. Faye, Ariela K. Holmer, and Jordan E. Axelrad
Inflammatory bowel diseases (IBD), including Crohn disease and ulcerative
colitis, are chronic inflammatory conditions of the gastrointestinal tract. In-
dividuals with IBD are at increased risk for several malignancies originating
in the intestine, such as colorectal cancer, small bowel adenocarcinoma,
intestinal lymphoma, and anal cancer. There are also several extraintesti-
nal malignancies associated with IBD and IBD therapies, including cholan-
giocarcinoma, skin cancer, hematologic malignancies, genitourinary
cancer, cervical cancer, and prostate cancer. The authors summarize
x Contents

the risk of cancer in patients with IBD, diagnosis and management of colo-
rectal neoplasia in IBD, and management of patients with IBD and active or
recent cancer.

The Microbiome in Gastrointestinal Cancers 667

Michael G. White and Jennifer A. Wargo
The human microbiome has been recognized as increasingly important to
health and disease. This is especially prescient in the development of
various cancers, their progression, and the microbiome’s modulation of
various anticancer therapeutics. Mechanisms behind these interactions
have been increasingly well described through modulation of the host im-
mune system as well as induction of genetic changes and local inactivation
of cancer therapeutics. Here, we review these associations for a variety of
gastrointestinal malignancies as well as contemporary strategies pro-
posed to leverage these associations to improve cancer treatment
outcomes.
 Diagnosis and Treatment of Gastrointestinal Cancers xi

GASTROENTEROLOGY
CLINICS OF NORTH AMERICA

FORTHCOMING ISSUES RECENT ISSUES

December 2022 June 2022
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Laurie Keefer, Editor Crohn’s Disease
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Mitchell S. Cappell, Editor Pelvic Floor Disorder
Darren M. Brenner, Editor
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 Diagnosis and Treatment of Gastrointestinal Cancers

Preface
Recent Advancements in the
D i a g n o s i s a n d Tr e a t m e n t o f
Gastrointestinal Cancers

Raquel E. Davila, MD, FACP, AGAF, FACG, FASGE Marta L. Davila, MD, AGAF, FACG, FASGE
Editors

Approximately 19.3 million new cases of cancer were diagnosed worldwide in 2020, of
which 5 million were cancers of the gastrointestinal (GI) tract. Furthermore, GI cancers
were the cause of more than one-third of all cancer-related deaths.1 In 2022, the esti-
mated incidence of cancers of the digestive system (343,040) in the United States will
surpass the incidence of breast cancers (290,560) and cancers of the respiratory sys-
tem (254,850).2 Although recent trends in incidence and mortality rates have been
encouraging for cancers of the colorectum and stomach, no improvements have
been observed in cancers of the esophagus, liver and intrahepatic bile ducts, and
pancreas. Subsequently, the early detection, diagnosis, and accurate staging of GI
cancers have become essential to gastroenterologists in the care of these patients.
Newer strategies for screening and surveillance have led to the detection of GI cancers
at an earlier stage and in a younger patient population. The availability of enhanced
endoscopic imaging techniques, endoscopic tissue acquisition, endoscopic resection,
and new ablative therapies has completely revolutionized our approach to GI cancer
patients in the past two decades while avoiding the morbidity and mortality associated
with surgery. A greater understanding of GI tumors at the molecular level has ultimately
led to the development of new treatment modalities including tyrosine kinase inhibi-
tors, immune checkpoint inhibitors, and anti-angiogenesis therapies that target key as-
pects of carcinogenesis.
In this issue of Gastroenterology Clinics of North America, you will find an exhaustive
review of the latest topics in GI cancer by distinguished authors recognized internation-
ally as leading authorities in the field. We want to express our deepest gratitude to the
authors, who dedicated their valuable time and efforts to this important endeavor. We

Gastroenterol Clin N Am 51 (2022) xiii–xiv

https://doi.org/10.1016/j.gtc.2022.07.009 gastro.theclinics.com
0889-8553/22/ª 2022 Published by Elsevier Inc.
xiv Preface

hope this issue serves as an essential resource and guidance to practicing gastroen-
terologists worldwide.

Raquel E. Davila, MD, FACP, AGAF, FACG, FASGE

The University of Texas at Dallas
4500 S. Lancaster Road
Dallas, TX 75216-7167, USA
Marta L. Davila, MD, AGAF, FACG, FASGE
Department of Gastroenterology
Hepatology and Nutrition
Division of Internal Medicine
Department of Clinical Cancer Prevention
Division of Cancer Prevention and Population Sciences
The University of Texas MD Anderson Cancer Center
1515 Holcombe Boulevard, Unit 1466
Houston, TX, 77030, USA
E-mail addresses:
[email protected] (R.E. Davila)
[email protected] (M.L. Davila)

REFERENCES

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN es-
timates of incidence and mortality worldwide for 36 cancers in 185 countries. CA
Cancer J Clin 2021;71:209–49.
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin
2022;72:7–33.
S q u a m o u s C e l l C a rci n o m a o f
t h e Es o p h a g u s
D. Chamil Codipilly, MD, Kenneth K. Wang, MD*

KEYWORDS
 Esophageal squamous cell carcinoma  Epidemiology  Prognosis
 Endoscopic eradication therapy  Neoadjuvant chemoradiotherapy

KEY POINTS
 Risk factors for esophageal squamous cell carcinoma (ESCC) include alcohol and to-
bacco use.
 Screening for ESCC may be warranted in endemic regions in high-risk populations.
 Therapy for ESCC may include endoscopic resection, surgery, and chemoradiotherapy.
 Immunomodulatory and molecular targeted therapies may herald a new paradigm in the
treatment of ESCC.

EPIDEMIOLOGY

Esophageal cancer is the 9th most common incident cancer worldwide and contrib-
utes to the 6th highest number of deaths.1 In the United States, esophageal cancer
is the 6th most commonly diagnosed gastrointestinal malignancy but contributes
the 4th highest number of deaths.2 Well over three-quarters of this morbidity and mor-
tality affect men. Esophageal cancer has 2 major histologic subtypes: esophageal
adenocarcinoma, which is prevalent in developed Western nations, and esophageal
squamous cell carcinoma (ESCC), which is prevalent in developing nations.3 Well
more than 80% to 90% of esophageal cancer diagnosed globally is ESCC.3 Despite
the elevated prevalence in developing countries, in developed nations ESCC is seen
disproportionately in minority racial subgroups including Africans, Hispanics, and
Native Americans.
The burden of ESCC disproportionately affects nations and regions along 2 “ESCC
belts”; one which stretches from Eastern Asia through Central Asia to the Caspian
Sea, and the other extending south into sub-Saharan Africa along the eastern coast
of the African continent (Fig. 1).1,4 Within these areas, certain regions, such as the
North Central Taigun Mountain Range of China, have incidence rates of ESCC

Division of Gastroenterology and Hepatology, Mayo Clinic, SMH Campus, 6 Alfred GI Unit, 200
1st Street South West, Rochester MN 55905, USA
* Corresponding author.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 457–484

https://doi.org/10.1016/j.gtc.2022.06.005 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
458 Codipilly & Wang

Fig. 1. Incidence of esophageal squamous cell carcinoma. (WHO 2019. All rights reserved.)

exceeding 125/100,000.5 For perspective, from 2014 to 2018, the incidence of esoph-
ageal adenocarcinoma in the United States was 4.2/100,000.2 In these high incidence
areas, the epidemiology of the disease also changes becoming more evenly divided
between genders and less related to environmental exposures such alcohol or to-
bacco use.
Mortality outcomes for ESCC are quite bleak, with 5-year mortality rates well less
than 20% (and likely significantly lower in developing nations whereby the burden of
ESCC is disproportionately high).6 Five-year survival rates exceed 50% in early-
stage disease, but unfortunately, more than 75% of ESCC is diagnosed at either stage
III or IV.7
Risk factors for ESCC are distinct from those for adenocarcinoma (Table 1). Tradi-
tional risk factors include tobacco use and alcohol, though in several regions whereby
the ESCC incidence is high, these substances are rarely used due to cultural and
 Esophageal Squamous Cell Carcinoma 459

Table 1
Risk factor for esophageal squamous cell carcinoma

Increase in Risk
(Compared with General
Risk Factor Population)
Alcohol 2-9x
Tobacco 2-4x
Consumption of Hot Beverages 1.5–2.5x
Low Fruit Intake 2x
High Pickled Vegetable Intake 2x
Low Socioeconomic Status 2-4x
Esophageal Lichen Planus Up to 6.1% of all affected
Tylosis Up to 80% of all affected

religious beliefs. Regardless, the development of squamous cell carcinoma precursor

lesions has been associated with a smoking history of greater than 20 years (odds ra-
tio: 1.48), alcohol use of more than 30 years (odds ratio: 1.40), and daily alcohol intake
of greater than 100 cc (odds ratio: 1.44).8 Former and current smoking tobacco use is
associated with a 2- to 4-fold increased risk of ESCC compared with never smokers,9
while alcohol use results in a 2- to 9-fold increased risk of ESCC compared with
nondrinkers.10,11
The intake of scalding hot beverages has been postulated to induce inflammatory
processes in the esophagus stimulating the endogenous formation of reactive nitro-
gen species, causing specific TP53 mutations that have been found in patients with
ESCC.12,13 Furthermore, thermal injury may result in loss of the esophageal barrier
function permitting increased exposure of carcinogenic substances.14 Consequently,
population-based studies have demonstrated increased ESCC risk in patients who
consume hot tea, coffee, and mate.12 The effects of multiple risk factors are likely syn-
ergistic. A prospective cohort study based on 10 geographic regions in China demon-
strated that patients with greater than 15 g of alcohol intake and daily “burning” hot tea
had 5 times the odds of ESCC development compared with those without increased
alcohol or hot tea intake.15 Mate is composed of a significant amount of polycyclic ar-
omatic hydrocarbons which may also increase the risk of ESCC.16,17
The association of nitrosamines to the development of ESCC has also been found in
populations with endemic pickled vegetable intake. Due to fermentation, a relatively
high percentage of nitrosamines are formed during the pickling process. A meta-
analysis of 34 studies incorporating data from more than 225,000 patients demon-
strated an odds ratio of 2.08 for those with excess pickled vegetable intake compared
with those with lower intake.18 Low fruit intake may also be associated with ESCC.19,20
Oxidative stress mediated via iron overload, also known as African iron overload, or
Bantu siderosis may play a role in carcinogenesis as this condition has been associ-
ated with ESCC in sub-Saharan Africa.21
Unskilled laborers were found to have a 2.1-fold increased risk of ESCC compared
with skilled professionals in a Swedish population-based database, highlighting the
increased risk of ESCC in those from lower socioeconomic backgrounds.22 Further-
more, those without a life partner were found to have doubled the risk of ESCC in
this same cohort.22 Less well-established risk factors for the development of ESCC
include radiation and agrochemical exposure, excess fried food intake, sedentary life-
style, and low fiber intake.23
460 Codipilly & Wang

Other medical conditions may increase the risk of ESCC, likely through chronic in-
flammatory pathways. Esophageal lichen planus is associated with the development
of ESCC in up to 6.1% of patients.24 Tylosis or hyperkeratosis palmaris et plantaris is a
rare but autosomal dominant genetic disease marked by aberrations of the RHBDF2
gene resulting in a significant risk of ESCC of at least 80% in a small kindred.25,26 Hu-
man papillomavirus has also been associated with the development of ESCC.27

PATHOGENESIS

The dysplasia-carcinoma sequence is believed to mediate the transition from normal

esophageal squamous epithelium to ESCC. Squamous dysplasia is associated with
nuclear atypia, loss of normal cell polarity, and abnormal tissue maturation without in-
vasion through the basement membrane.28 Although early retrospective studies sug-
gested that esophagitis was a risk factor for ESCC, subsequent studies determined
that esophageal squamous cell dysplasia was the only histopathologic factor associ-
ated with a high risk of ESCC.29 Prospective studies further demonstrated that the risk
of ESCC increased with higher grades of dysplasia (Table 2), and confirmed that
dysplasia is the only known precursor lesion of ESCC.30,31
The stepwise progression from normal squamous epithelium to ESCC can be fol-
lowed histologically from basal cell hyperplasia (BCH), to mild dysplasia, moderate
dysplasia, severe dysplasia, carcinoma in situ (CIS), and invasive carcinoma. This
scheme has subsequently been revised by the World Health Organization (WHO)
with mild to moderate dysplasia classified as low-grade intraepithelial neoplasia
(LGIEN), and severe dysplasia or CIS classified as high-grade intraepithelial neoplasia
(HGIEN).32
A significant number of genetic markers have been identified that underlie the
dysplasia-carcinoma sequence. High-level amplification of several oncogenes,
including CCND1, FGF3/4/19, SOX2, and EGFR have been associated with malignant
transformation, as well as homozygous deletions of tumor suppressor genes such as
CDKN2A and CDKN2B.33 Furthermore, sequence analysis of ESCC tumors have iden-
tified several significantly mutated genes that drive carcinogenesis, including the tu-
mor suppressor genes TP53 and NOTCH1, as well as the oncogene NFE2L2.34–37
Indeed, mutations in TP53 may be found in up to 80% of all ESCC.38 Several genetic
mutations may impart prognostic information, as alterations of FAM135 B and TET2
are associated with poor survival.34,39
Epigenetic factors have also been extensively studied in the pathogenesis of ESCC.
Several of the previously mentioned genes, including CDKN2A and TFF1 may be
hypermethylated in ESCC and may indicate early-stage disease. Epigenetic factors

Table 2
Risk of ESCC transformation based on the degree of dysplasia

WHO 2010 OR (95% CI) of

Dysplasia Grade Classification ESCC
Basal Cell Hyperplasia IEN 2.1 (0.4–9.8)
Mild Dysplasia LGIEN 2.2 (0.7–7.5)
Moderate Dysplasia 15.8 (5.9–42.2)
Severe Dysplasia HGIEN 72.6 (29.8–176.9)

IEN: intraepithelial neoplasia; low-grade intraepithelial neoplasia; high-grade intraepithelial

neoplasia (also includes carcinoma in situ).
 Esophageal Squamous Cell Carcinoma 461

may also impart prognostication, as inactivation and methylation of the CDKN2 tumor
suppressor gene are associated with advanced-stage disease.40,41
The transformation of dysplasia to ESCC is likely mediated by a step-wise approach
involving many of the above genetic and epigenetic aberrations (Fig. 2). Mutations in
TP53, NOTCH1, CDKN2A, EP300, and MLL2 are likely early mediators of the dysplasia
sequence given their presence in basal cell hyperplasia and persistence in higher
grades of dysplasia and cancer.42 However, the true cascade of events (and exact
pathogenesis) of ESCC development remains under intense study.
Risk factors for ESCC are likely implicated in the rapid development of genetic ab-
errations that can lead to malignancy. Alcohol is directly toxic to the epithelium which
may allow for further direct toxic damage from persistent alcohol use, and exposure to
other carcinogenic environmental factors.43 Byproducts of alcohol metabolism,
namely acetaldehyde, may further contribute to genetic abnormalities through DNA
adduct formation, resulting in aberrant gene methylation.44 Alcohol-associated
methylation and inhibition of several key pathways, including NOTCH, PI3K/AKT,
and WNT signaling pathways may then drive the pathogenesis of ESCC.45 Variant
copies of ALDH2, which are present in most East Asian populations, result in
decreased metabolism of acetaldehyde and may partly explain the increased risk of
ESCC noted in this region.46
Tobacco is associated with an increased risk of ESCC as previously mentioned and
smoked tobacco is associated with at least 60 carcinogenic compounds.47 The spe-
cific pathogenesis involved is likely multifactorial. Research has demonstrated that to-
bacco smoke increases the levels of acetaldehyde in saliva, and as previously

Fig. 2. Molecular progression of esophageal squamous precancerous lesions to ESCC. BCH,

basal cell hyperplasia; HGIEN, high-grade intraepithelial neoplasia; LGIEN, low-grade intra-
epithelial neoplasia. (From Lin DC, Wang MR, Koeffler HP. Genomic and Epigenomic Aber-
rations in Esophageal Squamous Cell Carcinoma and Implications for Patients.
Gastroenterology. 2018;154(2):374–389. https://doi.org/10.1053/j.gastro.2017.06.066; with
permission)
462 Codipilly & Wang

demonstrated, this could result in downregulation of important cell signaling pathways

that can lead to ESCC.48 Tobacco smoke (particularly nicotine) may activate the EGFR
tyrosine kinase in esophageal tissue resulting in diminished apoptosis, promotion of
angiogenesis, and enhanced invasion capabilities.49 DNA adduct formation can also
occur with tobacco smoking resulting in the inactivation of the tumor suppressor
FHIT gene, further promoting carcinogenesis.50

DIAGNOSIS

Patients may not have any symptoms when presenting with ESCC and may be diag-
nosed incidentally through testing conducted for other indications, or through
screening programs in high-risk regions. However, patients with locally advanced dis-
ease may have dysphagia, initially with solid foods and progressing to liquids as tumor
growth obliterates the esophageal lumen. Indeed, prediagnosis dysphagia is a reliable
predictor of at least T3/T4 advanced disease.51 Some patients may report heartburn,
dyspepsia, or cough, though these symptoms are nonspecific. Hematemesis is an un-
common initial presenting sign of ESCC but may occur, and in some patients, occult or
overt lower GI bleeding may be present. In rare cases, tumor ingrowth can lead to the
formation of a tracheobronchial fistula.52 Patients with metastatic disease may also
exhibit significant weight loss, fatigue, low-grade fevers, and failure to thrive.
Barium esophagography may demonstrate an esophageal mass causing luminal
obstruction or stricture. Computed tomography may show the presence of esopha-
geal wall thickening or mass, and may provide staging information assessing for
regional lymphadenopathy, as well as liver or lung metastases.
The gold standard for diagnosis of ESCC involves histopathologic confirmation of
malignant tissue obtained typically during esophagogastroduodenoscopy (EGD).
The endoscopic appearance of ESCC can vary markedly, from subtle nodularity
that can easily be missed to large, friable, fungating masses completely obstructing
the esophageal lumen. ESCC classically is found in the upper or mid-esophagus, in
comparison to adenocarcinoma, which is typically found in the distal third. Bronchos-
copy may be required for proximal tumors above the carina especially if there is sus-
picion of a tracheoesophageal fistula. Endoscopic ultrasound (EUS) can be used to
assess for regional lymphadenopathy, and the use of a linear echoendoscope allows
for tissue sampling of any suspicious lymph nodes.
Several techniques can be used to enhance the visual detection of abnormalities
that are found in ESCC and squamous dysplasia. Narrow-band imaging (NBI) is an op-
tical technique in which 3 specific wavelengths (under the blue light spectrum) are
used to observe in detail the capillary system of tissues.53 When coupled with magni-
fication, irregularities in the intrapapillary capillary loop (IPCL) structure can highlight
suspicious areas. Superficial carcinoma may demonstrate the dilation and elongation
of IPCLs, and invasive disease has been associated with ectatic, irregularly branched
IPCLs. These visual criteria on NBI are widely used in Japan in the initial staging of
ESCC.54 Studies have demonstrated sensitivity and specificity rates ranging from
75% to 100% in the identification of ESCC when using NBI.55,56
Lugol’s solution composed of iodine and potassium iodide preferentially binds to
glycogen in nonkeratinized tissue. Normal squamous epithelium of the esophagus ab-
sorbs the solution resulting in a dark-brown or black discoloration of the mucosa.
Dysplastic or malignant cells have low levels of glycogen and will not have significant
uptake of this solution. Use of Lugol’s solution during endoscopy can help detect and
demarcate areas of dysplasia and early ESCC allowing for targeted biopsies or endo-
scopic resection (Fig. 3).57
 Esophageal Squamous Cell Carcinoma 463

Fig. 3. Endoscopic images of Lugol’s staining. (A) Lugol’s solution was applied to the lower
third of the esophagus highlighting uniform uptake. (B) An area of poor uptake, due to
decreased glycogen in dysplastic cells, is identified. Biopsies from this region showed low-
grade squamous dysplasia.

The sensitivity and specificity of chromoendoscopy with Lugol’s is comparable to

NBI and superior to high definition white light endoscopy (HD-WLE).55 Importantly,
false-positive Lugol’s unstained lesions may be found in regenerative squamous tis-
sue (for instance, tissue that may have previously undergone ablation) or in tissue
with significant inflammation.58
Invasive ESCC is marked by tumor invasion into the lamina propria and deeper
layers. Pathology hallmarks of ESCC include keratinization, and “tumor budding.” Tu-
mors can range from well to poorly differentiated histopathology based on nuclear aty-
pia and basal cell layer abnormalities.59 Characteristics of well-differentiated tumors
include keratin pearls, individual cell keratinization, and intercellular bridges which
are absent on poorly differentiated specimens.60 Squamous dysplasia and/or carci-
noma in situ may be found at the periphery of resected tumor specimens. Immunohis-
tochemical staining for P63, cytokeratin 5/6, MUC5AC, and AGH2 distinguish ESCC
from esophageal adenocarcinoma.61 A spindle-cell subtype of ESCC has been iden-
tified that is associated with grossly polypoid tissue, and has a slightly improved sur-
vival compared with traditional ESCC.62 Other morphologic subtypes of ESCC
include: basaloid ESCC (predominant basal cell layer changes including oval, hyper-
chromatic nuclei, scant cytoplasm, and solid nests with peripheral palisading); verru-
cous carcinoma (papillary tumor with mild cellular atypia in the basal cell layers, and
may have a broad pushing front without significant metastatic potential); and carcino-
sarcoma (features of malignant spindle and epithelial cells with possible mesenchymal
differentiation).60
Screening for ESCC has been suggested in high-risk regions and populations. This
is discussed in the “Controversies” section of this article.

PROGNOSIS

Staging of ESCC is the most significant predictor of disease prognosis. Formal con-
ventions following American Joint Committee on Cancer guidelines are typically
used for staging (Tables 3 and 4) based on tumor invasion (T), lymph node involve-
ment (N), and metastatic spread (M).63 Staging may involve computed tomography,
which is most helpful for identifying liver or lung metastases, but typically is completed
with positron emission tomography (PET) to assess the distal spread of tumor. EUS
464 Codipilly & Wang

Table 3
Cancer staging categories for cancer of the esophagus and esophagogastric junction

Category Criteria
T catorgory
TX Tumor cannot be assessed
T0 No evidence of primary tumor
Tis High-grade dysplasia, defined as malignant cells confined by the basement
membrane
T1 Tumor invades the lamina propria, muscularis mucosae, or submucosa
T1aa Tumor invades the lamina propria or muscularis mucosae
T1ba Tumor invades the submucosa
T2 Tumor invades the muscularis propria
T3 Tumor invades adventitia
T4 Tumor invades adjacent structures
T4aa Tumor invades the pleura, pericardium, azygos vein, diaphragm, or
peritoneum
T4ba Tumor invades other adjacent structures, such as aorta, vertebral body, or
trachea
N category
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–2 regional lymph nodes
N2 Metastasis in 3–6 regional lymph nodes
N3 Metastasis in 7 or more regional lymph nodes
M category
M0 No distant metastasis
M1 Distant metastasis
Adenocarcinoma G Category
GX Differentiation cannot be assessed
G1 Well-differentiated.> 95% of tumor is composed of well-formed glands
G2 Moderately differentiated. 50% to 95% of tumor shows gland formation
G3b Poorly differentiated. Tumors composed of nest and sheets of cells with
<50% of tumor demonstrating glandular formation
Squamous cell carcinoma G category
GX Differentiation cannot be assessed
G1 Well-differentiated. Prominent keratinization with pearl formation and a
minor component of nonkeratinizing basal-like cells. Tumor cells are
arranged in sheets, and mitotic counts are low
G2 Moderately differentiated. Variable histologic features, ranging from
parakeratotic to poorly keratinizing lesions. Generally, pearl formation is
absent
G3c Poorly differentiated. Consists predominantly of basal-like cells forming
large and small nests with frequent central necrosis. The nests consist of
sheets or pavement-like arrangements of tumor cells, and occasionally are
punctuated by small numbers of parakeratotic or keratinizing cells
Squamous cell carcinoma L categoryd
LX Location unknown

(continued on next page)

 Esophageal Squamous Cell Carcinoma 465

Table 3
(continued )
Category Criteria
Upper Cervical esophagus to lower border of azygos vein
Middle Lower border of azygos vein to lower border of inferior pulmonary vein
Lower Lower border of inferior pulmonary vein to stomach, including
esophagogastric junction
a
Subcategories.
b
If further testing of “undifferentiated” cancers reveals a glandular component, categorize it as
adenocarcinoma G3.
c
If further testing of “undifferentiated” cancers reveals a squamous cell component, or if after
further testing they remain undifferentiated, categorize as squamous cell carcinoma G3.
d
Location is defined by the epicenter of esophageal tumor.
ª Annals of Cardiothoracic Surgery. All rights reserved. www.annalscts.com; Ann Cardiothorac
Surg 2017;6(2):119-130

can determine the depth of tumor invasion and may assess regional lymphadenopathy
if the distant spread is not apparent. Survival by stage of diagnosis is shown in
Table 5. Five-year survival for patients with advanced-stage disease (stages III/IV) is
less than 15%.2,7 Risk factors associated with poor survival regardless of stage at

Table 4
AJCC clinical staging groups, 8th edition

cStage
Froup cT cN cM
Squamous cell carcinoma
0 Tis N0 M0
I T1 N0-1 M0
II T2 N0-1 M0
T3 N0 M0
III T3 N1 M0
T1-3 N2 M0
IVA T4 N0-2 M0
T1-4 N3 M0
IVB T1-4 N0-3 M1
Adenocarcinoma
0 Tis N0 M0
I T1 N0 M0
IIA T1 N1 M0
IIB T2 N0 M0
III T2 N1 M0
T3-4a N0-1 M0
IVA T1-4a N2 M0
T4b N0-2 M0
T1-4 N3 M0
IVB T1-4 N0-3 M1

From Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus
and esophagogastric junction: application to clinical practice. Ann Cardiothorac Surg.
2017;6(2):119–130. https://doi.org/10.21037/acs.2017.03.14; with permission.
466 Codipilly & Wang

diagnosis include male gender, age more than 65 at diagnosis, and family history of
esophageal cancer.7,64 A significant difference between ESCC and esophageal
adenocarcinoma is the finding that ESCC may skip adjacent lymph nodes and metas-
tasize to more distant lymph nodes (nodal skip metastasis).65

CLINICAL MANAGEMENT
Early disease
Carcinoma in situ and T1a/T1b lesions without regional lymphadenopathy may be
definitively treated via endoscopic techniques such as endoscopic mucosal resection
(Fig. 4) or endoscopic submucosal dissection (Fig. 5). However, the role of endo-
scopic resection in the management of healthy patients with T1b lesions is somewhat
controversial and will be discussed in greater detail in the “Controversies” section of
this article. Patients undergoing endoscopic resection should be healthy enough to
undergo general anesthesia. A staging endoscopic ultrasound is typically conducted
to determine tumor depth of invasion and exclude deep involvement which would pre-
clude endoscopic resection. Marking of the lesion of interest is conducted typically
with argon plasma coagulation or a resection knife. This step assists the proceduralist
in identifying the lesion during resection when viewing planes may be inhibited by
bleeding and/or smoke, and to ensure clear margins. Typically, a solution of methylene
blue or indigo carmine, combined with a viscous lifting agent is injected into the sub-
mucosa to assess whether the lesion “lifts,” that is, separates the esophageal mucosa
and submucosa from deeper layers. Evidence of poor lifting indicates a degree of in-
vasion into the deeper layers of the esophageal wall and may preclude endoscopic
resection. Poor lifting may also indicate fibrosis from prior extensive biopsies or resec-
tion, or history of previous radiation, which can result in a technically more difficult pro-
cedure with increased risk of bleeding and perforation.
Cap-assisted endoscopic mucosal resection (cEMR) uses a hard cap with a single-
use snare seated on an inner ring on the distal aspect of the cap or a hard cap with a
modified banding kit allowing for the multiband resection of larger lesions.
After the adequate lift, the lesion is suctioned into the hard cap, and in the single-use
device the snare is closed. When using a multiband device, a band is deployed to cap-
ture the lesion, and the snare is usually closed below the band to allow a wider resec-
tion area. Electrosurgical current is then applied to resect the lesion. The resection bed
is examined carefully, and removal of any residual tissue can then be performed.
Endoscopic submucosal dissection (ESD) is an alternative technique that allows for
en bloc resection of lesions. ESD requires adequate lifting of the lesion of interest.
Various electrosurgical knives may be used to dissect the submucosa and proceed

Table 5
5-year overall survival by stage of diagnosis

Stage 0 52.7%
Stage 1 44.2%
Stage 2 27.5%
Stage 3 15.6%
Stage 4 3.4%

Adapted from Cheng YF, Chen HS, Wu SC, et al. Esophageal squa-
mous cell carcinoma and prognosis in Taiwan. Cancer Med.
2018;7(9):4193–4201. https://doi.org/10.1002/cam4.1499; with
permission.
 Esophageal Squamous Cell Carcinoma 467

Fig. 4. Cap-assisted endoscopic mucosal resection. (A). An area of tissue suspicious for
esophageal squamous cell cancer is identified on narrow-band imaging. (B). The area is
marked with cautery. (C). Using a stained lifting agent, the mucosa is separated from the
submucosa to prepare for resection. (D). The Duette Multiband Mucosectomy Device
(Cook Medical, Bloomington, IN) is attached to the endoscope and resection proceeds
with the removal of the entire suspicious area. Tissue is suctioned into the cap and a
band is released, capturing the involved tissue, followed by the utilization of a snare with
electrosurgical current to cut the banded tissue. (E). Resection bed following complete
removal of lesion. Pathology demonstrated carcinoma-in-situ.

Fig. 5. Endoscopic Submucosal Dissection. (A). A suspicious area of nodularity concerning

squamous cell carcinoma is identified. (B). The area is marked with cautery. (C). Using a
stained lifting agent, the mucosa is separated from the submucosa to prepare for resection.
(D). Dissection of the lesion proceeds using several electrosurgical knives. (E). The resection
bed after complete removal of the lesion. (F) Final pinned specimen after removal of the
lesion. Pathology revealed squamous cell carcinoma in situ.
468 Codipilly & Wang

with careful dissection of the mucosal and submucosal layers from the muscularis
propria (see Fig. 5). Once the entire lesion has been removed, the resection bed is
inspected, and hemostasis can be achieved via coagulation, clipping, or suturing.
Both cEMR and ESD may result in R0, curative resection of early-stage disease, and
save patients from undergoing esophagectomy which carries its own morbidities and
adverse outcomes. However, there are specific differences between these 2 tech-
niques that must be carefully discussed between the proceduralist and patient. Of
note, no head-to-head trials involving these techniques have been completed for
the management of early-stage ESCC, but meta-analyses provide some indication
of the efficacy and differences between these 2 techniques.
ESD is a technically challenging procedure and requires more extensive training
compared with cEMR. Estimates of the number of procedures needed to achieve pro-
ficiency may be as high as 250 for ESD compared with 25 for cEMR.66,67 The optimal
paradigm for ESD training may include: practice in ex vivo porcine models, observer-
ships in high volume ESD centers, experience in third space endoscopy and other
advanced endoscopic techniques, and finally, hands-on training in human subjects.68
In comparison, cEMR training is more widely available and may be accomplished dur-
ing gastroenterology fellowship training.
ESD is associated with significantly longer procedure times compared with cEMR,
with a weighted mean difference of approximately 45 minutes.69 Overall rates of com-
plications of both ESD and cEMR are rare, and occur in less than 5% of cases.69,70
Rates of perforation appear to be approximately 2 times higher in ESD compared
with cEMR. Rates of bleeding and stricture formation do not seem to differ between
these techniques. Variations of ESD that use submucosal tunneling followed by
circumferential dissection have been shown to decrease procedural time without
increasing complications.
Overall, en bloc resection and R0 resection can be achieved at a significantly higher
rate in ESD compared with cEMR.69 This is likely due to the ability to resect broader
and larger areas via ESD. Subsequently, lower rates of recurrence are observed in
ESD compared with cEMR.69 What is unclear at this time, however, is whether the dif-
ferences in these outcomes result in improved cancer-free survival or morbidity.
It is important to note that, in a retrospective study of 171 cases of ESCC treated by
cEMR or ESD, the rate of en bloc resection and local recurrence were equivalent for
lesions measuring < 1.5 cm. cEMR, therefore, may be a reasonable alternative to
ESD for the management of small lesions measuring < 1.5 cm.71 ESD is recommended
for larger lesions as it allows for en bloc resection and accurate histopathologic stag-
ing with the assessment of both lateral and deep margins, which improves the prog-
nostication of cancer and may influence further management.

Locoregional disease
If the involvement of ESCC is beyond the submucosa, but without direct extension into
the heart, great vessels, trachea, lungs, (T1b–T4a lesions) or evidence of metastatic
disease, esophagectomy may be the procedure of choice for definitive management.
Bulky lymphadenopathy may also preclude surgical management. Staging laparos-
copy with peritoneal washings is typically recommended in patients with T3 or N1 dis-
ease as the presence of positive peritoneal cytology would confirm metastatic disease
and preclude surgery. In patients who may require enteral feedings, surgical place-
ment of a percutaneous jejunal feeding tube is recommended over endoscopic place-
ment to prevent tumor seeding. Percutaneous gastric tube placement is not
recommended as this may compromise the ability of the stomach to act as a conduit
if surgical intervention is eventually pursued. Oftentimes, a multidisciplinary approach
 Esophageal Squamous Cell Carcinoma 469

with input from medical oncology, surgery, gastroenterology, nutrition, and radiation
oncology is recommended before finalizing a definitive management plan.

Surgery
There are a number of approaches for the surgical resection of ESCC and the particular
method used will depend in part on surgeon experience, patient preference, and loca-
tion of the tumor. In all patients without preoperative chemoradiotherapy, lymph node
excision is performed with the removal of at least 20 nodes in 2 or 3 fields (mediastinal,
upper abdominal, cervical) to evaluate for nodal metastases. An increase in excised
nodes is associated with improved disease-specific survival.72 Conduits (that is, tissue
to connect the uninvolved proximal esophagus to the digestive tract after removal of the
malignant portion) can be accomplished with the stomach, colon, or small bowel.
Ivor-Lewis esophagogastrectomy is a two-stage procedure in which a midline laparot-
omy is utilized to prepare the (typically gastric) conduit followed by right thoracotomy to
mobilize and resect the esophagus and proceed with lymphadenectomy. Minimally inva-
sive approaches can also be utilized. This procedure is best for tumors in the mid-lower
third of the esophagus as proximal anastomoses are difficult to create via laparotomy.
McKeown (tri-incisional) esophagogastrectomy is similar to the Ivor-Lewis surgery
but a third step involving a cervical incision is added to create the esophago-
conduit anastomosis in the proximal esophagus. A minimally invasive approach
may also be used. The McKeown Esophagogastrectomy is used in proximal tumors
whereby an anastomosis cannot be created via thoracotomy or laparotomy. Given
the cervical anastomosis, there is a greater risk of damage to the recurrent laryngeal
nerve in addition to a higher risk of pulmonary complications.73
A transhiatal approach with a cervical incision for the creation of the anastomosis
can be used but is limited by poor access to lymph nodes. The addition of thoraco-
scopy and other maneuvers can result in successful lymph node dissection. The tran-
shiatal approach may be an option for patients with early-stage disease or those with
disease amenable to endoscopic therapy but who prefer surgical management. For
distal esophageal tumors, a single left thoracoabdominal approach can be used but
requires a large incision (modified Ivor Lewis esophagectomy). This approach is asso-
ciated with increased reflux due to the intraabdominal position of the anastomosis.
It is important to emphasize that not all surgical options are appropriate for all pa-
tients, and patient preference, surgeon/center experience, and tumor characteristics
all impact the ultimate therapeutic option pursued. To that end, regardless of
approach, negative circumferential margins are associated with improved overall sur-
vival, and those with positive margins have a 2 to 4 times higher odds of death within
5 years of surgery compared with those with negative margins.74
A cervical anastomosis may be associated with a higher rate of leaks and trauma to
the recurrent laryngeal nerve compared with thoracic anastomosis, but outcomes
regarding recurrence, perioperative morbidity, stricture formation, and pulmonary
complications seem to be equal.75
Pyloromyotomy during surgery has been advocated to reduce the risk of postopera-
tive gastric outlet obstruction (GOO), but results have been mixed. A nonrandomized
large prospective study of 242 patients demonstrated no difference in GOO between
patients with pyloromyotomy compared with those without. A meta-analysis of 4 studies
with 533 patients demonstrated no difference in GOO rates between groups.76,77

Neoadjuvant therapy
Patients with good performance status and resectable disease may benefit from pre-
operative chemoradiotherapy. In a randomized controlled trial, patients treated with a
470 Codipilly & Wang

5-week course of carboplatin/paclitaxel demonstrated superior median survival

compared with those receiving upfront surgery (49.4 months vs 24.0 months).78
This regimen was well tolerated with less than 10% experiencing any significant
side effects. Fluorouracil with oxaliplatin, irinotecan with cisplatin, and paclitaxel
with fluoropyrimidine are other combinations that can be used as alternative neoadju-
vant therapies. Please see the “Controversies” section within this article for greater
detail regarding neoadjuvant therapies.

Metastatic and unresectable disease

The chemotherapeutic management of ESCC is complex and is reviewed in the guide-
lines published by the National Comprehensive Cancer Network (NCCN).79 Preferred
regimens for patients requiring definitive chemotherapy for the management of ESCC
include paclitaxel with carboplatin, fluorouracil with oxaliplatin, or fluorouracil with
cisplatin, combined with or without radiation therapy. All of these regimens are asso-
ciated with improved survival compared with placebo.78,80,81 A three-drug cytotoxic
drug regimen (docetaxel, cisplatin, and fluorouracil) was compared with a two-drug
regimen (cisplatin and fluorouracil) in a randomized study of 445 patients. The
three-drug group had a significant increase in overall and 2 -year survival.82 However,
this same group also had a significantly higher rate of grade 3/4 toxicities (40%–90%)
compared with the two-drug group (10%–20%). Therefore, a two-drug regimen is usu-
ally preferred, but a three-drug regimen may be considered in patients with excellent
health and high-performance status. Irinotecan-based therapies, typically coadminis-
tered with cisplatin or docetaxel, have also shown modest efficacy (comparable to
cisplatin and fluorouracil), with manageable side effects.83,84 Capecitabine and oxali-
platin, which may have a favorable side effect profiles when compared with cisplatin-
based therapies, have also demonstrated efficacy in the management of metastatic
disease with noninferior 1-year survival.85

Molecule targeting agents and immunotherapies

The understanding of carcinogenesis pathways has led to the identification of specific
molecular targets for the management of a variety of cancers, including ESCC.
Epidermal growth factor receptor (EGFR) overexpression has been identified in up
to 33% of all ESCC and thus targeted therapies have been studied extensively in
ESCC. One of the first studied drugs, Gefitinib, an EGFR inhibitor, showed no signif-
icant improvement in survival when compared with placebo in patients undergoing
salvage therapy.86 Several other EGFR inhibitors (cetuximab, panitumumab, and
nimotuzumab), have shown efficacy with 3 to 4 months improved survival compared
with cisplatin-based therapies.87–89 HER2 status has also been evaluated as a poten-
tial therapeutic target given overexpression in ESCC. Trastuzumab, a HER2 inhibitor,
has an acceptable safety profile when used in combination with traditional chemo-
therapy regimens.90,91
More recent developments in cancer therapeutics include immunotherapies to
target the dysregulation of immune checkpoint inhibitors resulting in carcinogenesis.
Nivolumab, a programmed cell death 1 (PD-L1) inhibitor, demonstrated prolonged
survival and therapeutic efficacy in an open-label trial of 65 patients who failed first-
line therapy.92 This drug may be used after surgery with R0 margins, resulting in
improved survival compared with those who received placebo.93 Pembrolizumab, a
similar PD-L1 inhibitor, has also demonstrated considerable efficacy in patients who
failed first-line therapy.94 Other immune checkpoint inhibitors that have shown prom-
ise in phase I/II trials include camrelizumab and tislelizumab.95,96
 Esophageal Squamous Cell Carcinoma 471

The Combined Positive Score (CPS) was developed to assess the prognostication
of therapy success for PD-L1 inhibitors. This score is a percent of PD-L1 cells divided
by viable tumor cells seen on histopathology. Pembrolizumab, as second-line therapy
in patients with CPS scores greater than 10, was associated with significantly longer
overall survival compared with traditional chemotherapy.97 However, the CPS may not
be a reliable predictor of response to therapy as the recent Checkmate-577 study
showed no difference in survival based on PD-L1 expression whereby nivolumab
was studied for use as adjuvant therapy in resected disease.93
Other targets of immune checkpoint inhibitors include cytotoxic T lymphocyte-
associated protein 4 (CTLA-4), which is involved in the regulatory functioning of
T-cells. Appropriate manipulation of this target by drugs such as ipilimumab may
mediate T-cell destruction of tumor cells, and studies show promising results
regarding overall survival but not progression-free, survival.98

Radiotherapy
Radiotherapy of ESCC seems efficacious when used as an adjunct to chemotherapy-
based regimens. Treatment is usually given in a fractionated dose of 40 to 50 gray to
encompass all known diseases and one nodal field beyond. Studies have demon-
strated that refinements in radiation delivery, such as intensity-modulated radio-
therapy, result in prolonged survival, fewer cancer-related deaths, and fewer side
effects compared with traditional delivery methods.99 Proton-beam therapy has
further improved overall outcomes and safety profiles by allowing a highly targeted ra-
diation dose with minimal effects on surrounding tissues when compared with
intensity-modulated radiotherapy.100
For further detail on the role of radiotherapy in neoadjuvant therapy, please see the
corresponding section in the “Controversies” section.

DISEASE COMPLICATIONS
Pretreatment complications
As previously discussed, patients may present with dysphagia indicating an obstructing
lesion. This can result in significant malnutrition and weight loss, which can be severe
enough to require enteral feedings, either in the form of nasogastric or percutaneous
feeding tube placement, to optimize patient status before more definitive therapy.
Sinusitis has been reported in up to 16% of patients with nasogastric tubes in an inten-
sive care unit setting although it may be less common in other settings.,101 Percuta-
neous feeding tubes may result in other complications including buried bumper
syndrome, malpositioning, soft tissue infections, and tube leakage. Despite these com-
plications, enteral feeding is generally well tolerated with serious adverse events occur-
ring in less than 5% to 10% of patients on long-term therapy.102 Rare cases of tumor
ingrowth into surrounding tissues include the formation of esophagotracheal or esoph-
agobronchial fistula which can result in infectious pulmonary complications.
Posttreatment complications
Endoscopic therapy for early disease (CIS, T1 tumors) is well tolerated, though signif-
icant adverse events such as strictures, bleeding, and perforation can occur. Of these,
clinically significant strictures resulting in dysphagia can occur in 5% to 15% of
cases.103,104 Risk factors for stricture formation include the resection of lesions occu-
pying greater than 75% of the esophageal circumference, longer than 3 cm, and with
deep submucosal invasion.104,105 Steroid injection at the time of resection as well as
short courses of oral steroids postprocedure have been shown to reduce stricture for-
mation.106,107 Clinically significant bleeding requiring blood transfusion or hospital
472 Codipilly & Wang

admission, and perforation occur less frequently in approximately 1% to 2% of all

endoscopic resection procedures.108,109 Although there is not a statistically significant
difference in the overall complication rates of ESD and cEMR, there is a significantly
higher risk of perforation with ESD.69
Surgical complications more frequently occur in elderly patients, as well as those with
renal, hepatic, or pulmonary disease.110 Anastomotic leaks occur in up to 25% of pro-
cedures and are more commonly seen in cases of cervical anastomoses. Frank dehis-
cence is exceedingly rare.111 Patients with transthoracic/transhiatal anastomoses have
leak rates of approximately 10%.112 Anastomotic strictures can complicate approxi-
mately 30% of all esophagectomy procedures and typically can be managed with
endoscopic balloon dilatation. In cases of anastomotic strictures, it is important to
rule out recurrent cancer with careful inspection and targeted biopsies.113 Aspiration
may occur in 10%–15% of all esophagectomies, with cervical anastomoses further
associated with higher risks of pneumonia and empyema.114 Fistula formation to the air-
ways is rare and may occur in less than 1% of all procedures. This complication seems
to be manageable, with small case reports detailing fistula closure rates of 100% after
1.6 years.115 Dumping syndrome with both early and late manifestations can occur in up
to 20% of surgeries, although widely varying incidence rates have been reported.116
Previous neoadjuvant therapy is believed to play a role in conduit ischemia, but pub-
lished reports have been conflicting.117–119 Conduit ischemia is believed to impact the
rate of anastomotic stricture development, which can occur in up to 40% of cases.
Most of these cases can be managed with endoscopic dilation. Creation of the anas-
tomosis with a modified Collard or hybrid staple technique is associated with lower
rates of stricturing.120,121
Chyle leaks from traumatic injury to the thoracic duct occur in less than 10% of sur-
geries and are associated with significant morbidity and mortality.122 These are typi-
cally identified by the presence of milky white drainage from chest tubes placed at
the time of surgery. The management includes nil per os status, parenteral nutrition,
and octreotide, but may require surgical intervention if no improvement occurs after
several days.
In an analysis of nearly 12,000 patients from the Society for Thoracic Surgery data-
base, overall morbidity occurred in approximately 50% of patients within 30 days of
surgery, including 10% requiring reoperation, of which a quarter of these was for
conduit necrosis. Other complications included sepsis (24%), myocardial infarction
(33%), and acute respiratory distress syndrome (37%). Thirty-day mortality in this se-
ries was 3.3%.123 As mentioned previously, the McKeown (tri-incisional) esophagec-
tomy has been associated with higher morbidity and mortality, possibly mediated by
the addition of cervical dissection.73 Perioperative mortality is typically less than 10%
to 15%, with likely improved outcomes in selected patients undergoing minimally inva-
sive, robotic procedures.73,124–126
Chemoradiotherapy-induced strictures requiring endoscopic intervention can occur in
up to 75% of all patients. In a series of patients receiving definitive management of ESCC,
strictures occurred in 52% of patients receiving chemoradiotherapy, and in 76%
receiving radiotherapy alone.127 Cervical location of the primary esophageal tumor is
an independent risk factor for severe stricture formation after chemoradiotherapy.128

CONTROVERSIES
Screening
Given the considerable morbidity and mortality associated with late-stage ESCC,
which accounts for most newly diagnosed disease, screening for early-stage
 Esophageal Squamous Cell Carcinoma 473

ESCC or squamous dysplasia may identify candidates for minimally invasive thera-
pies affording a chance for cure. However, given the lack of noninvasive, cost-
effective screening methods, robust consensus guidelines regarding this topic are
sparse.129
Screening high-risk populations may be warranted in endemic regions whereby
the prevalence of ESCC is particularly high. In a population study from China,
4,116 volunteers from 24 villages underwent endoscopic screening examination
with Lugol’s solution and treatment as needed (14 communities) versus clinical
follow-up by questionnaire and no endoscopic screening (10 communities). Patients
in the endoscopic intervention group had a significantly lower cumulative incidence
of ESCC and a significant reduction in cumulative mortality compared with the con-
trol group.130 Other retrospective studies have demonstrated a significant cancer-
survival benefit in patients living in high-risk regions undergoing endoscopic
screening compared with controls, with Markov modeling suggesting this approach
is cost-effective.131–133
Other high-risk populations that may benefit from ESCC screening include those
with a history of head and neck cancer, tylosis, and history of caustic esophageal
injury.134–136 General population screening in the United States is not recommended,
nor is screening for ESCC in patients with achalasia.137
Upper (usually sedated) endoscopy is typically used for screening but is associated
with increased cost and the need for time away from work for the patient. These bar-
riers and the need for specialized proceduralists may preclude the widespread imple-
mentation of ESCC screening. Transnasal endoscopy (TNE) uses an ultrathin
endoscope inserted through the nasal cavity to allow for the visual inspection of the
esophageal mucosa. This examination can be followed by a traditional upper endos-
copy if suspicious lesions are found. TNE requires no sedation, is well tolerated, is not
time-consuming, has good sensitivity and specificity, and can be performed at the
point of care by primary care physicians.138,139 However, TNE is not widely available
limiting its applicability in the screening setting. Other potential endoscopic screening
tests include high-resolution microendoscopy and endocytoscopy. However, these
are not widely used, have not been studied in large or high-risk screening populations,
and require a significant amount of training.
Nonendoscopic screening methods for ESCC have been advocated with the poten-
tial to increase patient uptake (given the noninvasive manner of testing), as well as
reducing cost. This can be advantageous in resource-scarce regions whereby wide-
spread endoscopic screening is not feasible but ESCC is prevalent. There is broad in-
terest in a variety of direct sampling cell collection devices that have demonstrated
efficacy in ruling out ESCC or squamous dysplasia with specificities exceeding 80%
(Fig. 6).140–144 Other noninvasive screening tests include analysis of exhaled volatile
organic compounds,145 as well as serum tests assessing autoantibodies,146,147
miRNA,148 and circulating tumor cells149 which have all demonstrated good specificity
(>90%) in preliminary trials.

Endoscopic therapy for T1b disease with deep submucosal invasion

Endoscopic management of T1a lesions and T1b lesions with invasion only into the
upper half of the submucosa affords sustained long-term cancer-free survival with
minimal adverse events compared with esophagectomy.103,150 However, surgery
has traditionally been recommended for patients with deep T1b disease
(invasion >500 mm of submucosa) due to the increased risk of lymph node metas-
tasis.151,152 Some studies indicate that patients with deep T1b invasion may have
reasonable survival with endoscopic therapy, which may be further improved with
474 Codipilly & Wang

Fig. 6. Nonendoscopic esophageal cell collection devices. (1) Cytosponge: intact (left) and
expanded (right; Medtronic, Minneapolis, MN). (2) EsophaCap: intact (left) and expanded
(right; Capnostics, Concord, NC). (A) 1 (B) EsoCheck device: the device is swallowed with
sips of water, inflated with 5 cm3 of air (C), pulled 5 cm proximal to the GEJ and then
deflated into a cap (D) before withdrawal to avoid contamination by the squamous epithe-
lium. (Lucid Diagnostics, New York, NY). (From Codipilly DC, Iyer PG. Novel Screening Tests
for Barrett’s Esophagus. Curr Gastroenterol Rep. 2019 Jul 25;21(9):42. https://doi.org/10.
1007/s11894-019-0710-9. PMID: 31346777; with permission.)

the addition of chemoradiotherapy.103 For this reason, patients with otherwise low-risk
disease (lack of moderate or poor differentiation, lack of lymphovascular invasion) or
poor surgical candidates who have deep submucosal T1b disease may be treated
with endoscopic therapy in lieu of surgery.

Neoadjuvant therapy in resectable tumors

Early trials did not demonstrate considerable improvement in cancer-related out-
comes for patients receiving neoadjuvant chemotherapy followed by esophagectomy
compared with those undergoing surgery alone. An initial large-scale trial with 443 pa-
tients assessing outcomes in patients receiving neoadjuvant chemotherapy with
cisplatin/fluorouracil did not show cancer-related mortality benefit in the neoadjuvant
group compared with the group undergoing surgery alone.153 However, a subsequent
study with 802 patients showed significant improvements in cancer-related mortality
and 5-year disease-free survival in the neoadjuvant group, indicating that earlier
studies may have been underpowered to detect this mortality benefit.154 Adverse
events did not differ significantly between groups in these studies.
Neoadjuvant chemoradiotherapy for resectable tumors has also been studied
extensively with conflicting results regarding survival benefits y,155,156 or rate of peri-
operative complications compared with surgery alone.78 However, head-to-head
comparisons of long-term outcomes between neoadjuvant chemotherapy versus neo-
adjuvant chemoradiotherapy show no statistically significant differences in mortality.
The addition of radiotherapy to neoadjuvant treatment seems to be associated with
more perioperative complications.157 As such, neoadjuvant therapy is typically recom-
mended for resectable patients, with no strong recommendation for or against the
addition of radiotherapy to the regimen.
 Esophageal Squamous Cell Carcinoma 475

CLINICS CARE POINTS

 Screening for esophageal squamous carcinoma is recommended for at risk populations

including those with chronic tobacco and alcohol usage, esophageal lichen planus, and
tylosis.
 Screening and diagnosis should be performed with endoscopy and enhancement of the
mucosa through magnification and electronic chromoendoscopy or the use of iodine to
stain the mucosa.
 Treatment involves endoscopic resection of dysplastic tissue or surgical resection in
combination with chemoradiotherapy for more advanced disease.
 Current chemoradiotherapy has been augmented by the use of immune checkpoint
inhibitors to enhance response.
 Survivors of Stage II or greater esophageal squamous cancer should be followed for potential
recurrence and also for potential complications of treatment including stricture formation,
aspiration, fistula, and dumping syndrome.

FUNDING

None.

CONTRIBUTIONS

D C. Codipilly developed the initial draft of the article and subsequent revisions. K K.
Wang provided essential review and feedback on the article drafts.

DISCLOSURE

D C. Codipilly: None. K K. Wang: Research funding from PCI, Interscope, Erbe, Pentax
Medical Consulting: Ironwood Pharma, GIE Medical

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Management of Dysplastic
B a r re t t ’s Es o p h a g u s a n d
E a r ly Es op h ag eal A d eno ca rci n om a
Cary C. Cotton, MD, MPHa, Swathi Eluri, MD, MPH
b
,
Nicholas J. Shaheen, MD, MPHc,*

KEYWORDS
 Endoscopic eradication therapy  Barrett’s esophagus  Dysplasia
 Adenocarcinoma  Radiofrequency ablation  Cryotherapy
 Endoscopic mucosal resection

KEY POINTS
 Barrett’s esophagus with low-grade dysplasia, high-grade dysplasia, or early esophageal
adenocarcinoma may be treated safely and effectively with endoscopic eradication
therapy.
 Endoscopic eradication therapy combines the resection of any raised neoplasia or
mucosal irregularity with an ablative therapy for flat Barrett’s esophagus.
 Endoscopic eradication therapy requires long-term endoscopic surveillance after suc-
cessful treatment.

INTRODUCTION

Barrett’s esophagus (BE) is a common premalignant condition of the esophagus asso-

ciated with esophageal adenocarcinoma (EAC). BE is diagnosed by the finding of
salmon-colored mucosa in the esophagus extending one or more centimeters prox-
imal to the gastroesophageal junction (GEJ), with histologic confirmation of intestinal
metaplasia.1 While BE without dysplasia may benefit from endoscopic surveillance,
therapy for the eradication of BE is appropriate in the presence of confirmed dysplasia

a
Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esopha-
geal Diseases and Swallowing, University of North Carolina at Chapel Hill, CB#7080, 130 Mason
Farm Road, Suite 4153, Chapel Hill, NC 27599-7080, USA; b Department of Medicine, Division of
Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University
of North Carolina at Chapel Hill, CB#7080, 130 Mason Farm Road, Suite 4142, Chapel Hill, NC
27599-7080, USA; c Department of Medicine, Division of Gastroenterology and Hepatology,
Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill,
CB#7080, 130 Mason Farm Road, Suite 4150, Chapel Hill, NC 27599-7080, USA
* Corresponding author.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 485–500

https://doi.org/10.1016/j.gtc.2022.06.004 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
486 Cotton et al

or early EAC. Management of dysplastic BE and early EAC most commonly involves
endoscopic eradication therapy (EET), which combines the resection of raised
neoplasia2 with the ablative treatment of the residual flat BE.3,4 Radiofrequency abla-
tion (RFA) is the most commonly available ablative therapy for BE,3,4 while cryotherapy
and argon plasma coagulation (APC) are also safe and effective primary treatment mo-
dalities.5,6 Cryotherapy has been demonstrated to be effective in a meta-analysis for
BE refractory to RFA.7 Endoscopic submucosal dissection (ESD) is emerging as an
endoscopic option for the treatment of patients with T1b tumors.8 Following EET,
endoscopic surveillance is recommended and is associated with a low rate of progres-
sion.9 A growing evidence base supports decreasing the frequency of endoscopic
surveillance, especially in patients with low-grade dysplasia (LGD), but as the cohort
of patients who complete endoscopic eradication therapy ages, a key question re-
mains as to when to stop surveillance.

PATIENT EVALUATION OVERVIEW

The evaluation of patients with BE requires an analysis of the clinical history, as well as
the endoscopic and histologic data. A general understanding of the patient’s past
medical history is required, and particular attention should be paid to the presence
of cardiopulmonary diseases and anticoagulation use, given the risks of endoscopy.
Competing risks to the patient’s mortality must be considered: the benefits of endo-
scopic treatment of BE and associated neoplasia is conditional on the patient surviv-
ing long enough to have developed a clinically significant cancer in the absence of
endoscopic treatment. Additionally, in patients with BE with LGD, endoscopic eradi-
cation therapy is illogical in those with a short life expectancy, given that they are un-
likely to benefit from a further decrease in the already-low risk of progression to EAC.
As EET requires periodic endoscopic follow-up, barriers to adherence must be under-
stood and addressed.
EET requires a diagnosis of BE with dysplasia. BE is defined by the presence of one
or more centimeters of salmon-colored mucosa extending proximal to the GEJ, which
is defined as the top of the gastric folds. The location of the GEJ, the length of any hi-
atus hernia, the maximum contiguous length of the BE segment (the Prague M length),
the maximum circumferential length of the BE segment (the Prague C length), and the
location of any mucosal irregularities, raised lesions, or islands of salmon-colored mu-
cosa above the maximal contiguous length should be documented (Fig. 1). Current
guidelines require the confirmation of any dysplasia in the BE by a second pathologist
expert in gastrointestinal conditions.1 This is especially important in the case of BE
with LGD, whereby considerable inter-observer variability exists.10 This begs the
question of what qualifies a pathologist as “expert.” Recent work suggests that
greater than 5 years working as a subspecialty GI pathologist was protective against
diagnostic errors, while working in a community-based hospital was a risk factor.
Sadly, self-identification as an expert was not protective.11
The risk of progression to adenocarcinoma is less than 0.5% per year among pa-
tients with nondysplastic BE, and endoscopic eradication therapy is not recommen-
ded. The rationale being that the risks and costs of therapy do not justify the
possible clinical benefit.12 While associated dysplasia or neoplasia is a prerequisite
to endoscopic eradication therapy, differentiation between BE with LGD, high-grade
dysplasia (HGD), or intramucosal adenocarcinoma is essential to ensure appropriate
triage and posttreatment surveillance intervals. To maximize accuracy for the histolog-
ic grade, the entire BE segment should be closely examined, and any mucosal irreg-
ularities should be biopsied. Random 4 quadrant biopsies should be performed within
 Management of Dysplastic Barrett’s Esophagus 487

Fig. 1. Key endoscopic landmarks in the endoscopic evaluation of Barrett’s esophagus.

the BE segment every 1 cm13 Sampling any islands is indicated because it can often
increase the maximum detected histologic grade.14

PHARMACOLOGIC TREATMENT OPTIONS

No medical therapy reliably induces reversion of BE to squamous epithelium.15 While

the management of BE with dysplasia or early EAC is predominantly endoscopic, phar-
macologic treatment with high dose proton-pump inhibitors (PPIs) is used during EET to
promote growth of squamous epithelium (Table 1).16 The AspECT trial found a benefit of
high-dose rather than low-dose PPI therapy in preventing progression of nondysplastic
BE,17 but no studies have identified an antineoplastic effect of PPIs in BE with dysplasia
or early EAC. Observational studies have found protective effects of aspirin, nonste-
roidal antiinflammatory drugs, and statins in BE.15 These studies are subject to a high
risk of bias due to confounding and outcome misclassification. There are no studies
of these agents in populations with BE with dysplasia or early EAC.

Table 1
Standard and high-dose proton-pump inhibitor regimens

Standard-Dose Regimen High-Dose Regimen

Omeprazole 20 mg once daily 30 min before a 40 mg twice daily 30 min before
meal meals
Pantoprazole 40 mg once daily 30 min before a 40 mg twice daily 30 min before
meal meals
Lansoprazole 15 mg once daily 30 min before a 30 mg twice daily 30 min before
meal meals
Esomeprazole 20 mg once daily 30 min before a 40 mg twice daily 30 min before
meal meals
Rabeprazole 20 mg once daily 30 min before a 40 mg twice daily 30 min before
meal meals
Dexlansoprazole 30 mg once daily 30 min before a 60 mg once daily 30 min before a
meal meal
488 Cotton et al

ENDOSCOPIC TREATMENT OPTIONS

Endoscopic treatments for BE with dysplasia or early EAC can be divided into ablative
methods used to eradicate flat BE and methods for the endoscopic resection of raised
lesions or mucosal irregularities. RFA is the most widely available ablative therapy, but
cryotherapy methods, electrocoagulation, argon plasma coagulation, and wide endo-
scopic resection have been described. Endoscopic resection methods include endo-
scopic mucosal resection (EMR), which may be categorized into band-assisted and
cap-assisted approaches, and endoscopic submucosal dissection.

Endoscopic Resection Methods

Before any ablative therapy, resection should be performed on any raised lesions or
visible mucosal irregularities.18 The shallow depth of the treatment of ablative modal-
ities would only treat the surface of raised lesions and may potentially obscure deeper
residual neoplasia in such lesions, making the resection of such lesions imperative
before embarking on any mucosal ablation.19 Mucosal irregularities have higher rates
of neoplasia than flat areas within a Barrett’s segment, and EMR before the ablation of
BE increases remission of dysplasia and decreases recurrence.20 With their low rate of
lymph node metastasis, T1a intramucosal adenocarcinoma is amenable to EMR, with
a meta-analysis of 70 studies reporting a 1.9% rate of lymph node metastases in BE
with T1a EAC.21
EMR uses a hard plastic cap to capture an area of mucosa for resection with an
electrosurgical snare. In the cap-assisted method, saline with or without epinephrine,
or another lifting agent is injected into the submucosa. The mucosa is suctioned into
the cap, the snare is deployed and constrained around the mucosa, and the lesion is
resected. In band-assisted EMR, a lifting agent is not required. The mucosa is suc-
tioned into the cap, a band is deployed, and then an electrosurgical snare is used
to resect the banded mucosa (Fig. 2).While both cap-assisted and band ligation
EMR are highly effective and resect similar-sized pieces of mucosa, band ligation
EMR is significantly faster, and is, therefore, used more commonly in most centers.22
Endoscopic submucosal dissection (ESD) uses a lifting/dying agent along with an
endoscopic electrosurgical knife to dissect the submucosa beneath a lesion. ESD al-
lows for the resection of large lesions en bloc (Fig. 3). Whereas foci of dysplasia or T1a
EAC with low-risk histologic characteristics may be resected with EMR, ESD may pro-
vide more complete resection of both T1a and T1b EAC. A retrospective cohort study
of ESD in BE with early neoplasia found a rate of en bloc and R0 resection of 87% for
HGD and T1a EAC and 49% for T1b EAC.23 Another retrospective cohort found a 98%
en bloc resection rate and a 58% R0 resection rate for a mix of T1a and T1b lesions.24
A retrospective comparison found ESD had a higher rate of en bloc and complete
resection compared with EMR, and a lower rate of recurrence.25,26 Because ESD is
more technically challenging than EMR and only necessary in highly selected lesions,
expertise should be concentrated in high volume centers.

Endoscopic Ablative Methods

After the resection of any raised lesions or irregularities, the goal of endoscopic abla-
tive therapies is the complete eradication of intestinal metaplasia (CEIM), which is
defined as the absence of any visible BE with biopsies negative for intestinal meta-
plasia in the tubular esophagus and negative for dysplasia in the gastric cardia. RFA
therapy applies radiofrequency energy by an electrode in contact with the BE segment
to cause full thickness epithelial ablation while minimizing injury to the submucosa.27
Circumferential treatment is performed using catheter-based electrodes on an
 Management of Dysplastic Barrett’s Esophagus 489

Fig. 2. In band-assisted endoscopic mucosal resection (A) a nodular lesion is carefully examined
under white light and narrow-band imaging at the 11 o’clock position, (B) the perimeter is
marked with a snare tip, the lesion is pulled into the endoscope cap using suction and (C) a
band is deployed, the lesion is ensnared under the band, and (D) the lesion is resected en bloc
by snare electrocautery. The arrows indicate the margins of a raised, dysplastic lesions before
treatment. ([A,B] ª2022 Medtronic. All rights reserved. Used with the permission of Medtronic.)

inflatable balloon, while focal treatment is applied by an electrode either affixed to the
end of the endoscope of via the working channel of the endoscope (Fig. 4).
Before any ablative treatment, careful inspection of the Barrett’s segment is
required to exclude even very slightly raised lesions, which should be first treated
by a resection method. A mucolytic agent such as 1% N-acetylcysteine or saline spray
is applied to the esophagus by a spray catheter advanced through the working chan-
nel of a standard gastroscope.28 Before using a balloon catheter ablation device, a stiff
guidewire is placed transorally into the stomach. While previous technology
demanded that the esophageal luminal diameter be measured with sizing balloons,
newer catheters (Barrx 360 Express RFA balloon catheter, Medtronic, Minneapolis,
MN) are self-sizing.26 The balloon catheter is advanced over the guidewire under
endoscopic visualization and inflated. High radiofrequency energy at 10 J/centimeter2
is applied in sequential 3-cm segments (or 4-cm segments when using the Barrx 360
Express) of the diseased esophagus with minimal overlap. The resulting coagulum is
then cleaned by scraping with an endoscopy cap and spraying water in the treated
segment. Then a second ablative treatment is applied in the same manner as the initial
treatment.29 Focal ablation is delivered via one of the several focal RFA devices avail-
able, which is placed in apposition to any residual islands or tongues following circum-
ferential ablation. The focal ablation devices can also be used as primary therapy in
490 Cotton et al

Fig. 3. In endoscopic submucosal dissection (A) a nodular lesion is carefully examined under
white light and narrow-band imaging, (B) the perimeter is marked with a snare tip, the
lesion is lifted by the injection of methylene blue, (C) the lesion is excised en bloc by submu-
cosal dissection, and (D) the lesion is pinned to Styrofoam marked to indicate the spatial
orientation of the specimen. The arrows indicate the margins of a raised, dysplastic lesions
before treatment. (From Codipilly DC, Dhaliwal L, Oberoi M, et al. Comparative Outcomes of
Cap Assisted Endoscopic Resection and Endoscopic Submucosal Dissection in Dysplastic Bar-
rett’s Esophagus. Clin Gastroenterol Hepatol. 2022;20(1):65-73.e1; with permission.)

cases of short-segment disease. Focal ablation is performed with 2 sequential appli-

cations of 12 J/centimeter.2 In addition to residual islands or tongues, the GEJ is also
circumferentially treated with the focal ablation catheter. Coagulum is cleaned by
scraping with the distal edge of the focal catheter between treatments.
RFA results in a high rate of CEIM in LGD. In the treatment arm of the SURF Trial for
BE with confirmed LGD, 88.2% achieved CEIM and 92.6% achieved eradication of
dysplasia.3 Among control patients in SURF, 26.5% progressed to HGD or EAC, while
only 1.5% in the treatment arm progressed.3 While the SURF trial was performed in a
highly centralized and expert center, outcomes may vary by case volume. In the AIM-
Dysplasia Trial, a smaller effect was observed on LGD, whereby 4.8% progressed in
the treatment arm compared with 13.6% of the control arm.4 Though EET is recom-
mended as an option and is often used for LGD, uncertainty remains about its effec-
tiveness in the North American context due to the reported lower risks of progression.
A randomized controlled trial in the United States is planned. The AIM-Dysplasia Trial
clearly demonstrated a benefit of RFA in BE with HGD.4 While 19.0% in the control arm
progressed to adenocarcinoma only 2.4% in the treatment arm progressed.4
Several modalities of cryotherapy have also been developed in the last 2 decades,30
and are similarly safe and effective, but less widely available. Cryotherapy uses liquid
 Management of Dysplastic Barrett’s Esophagus 491

Fig. 4. Mucosal ablation devices commonly used in the management of flat Barrett’s esoph-
agus include (A) Barrx 360 Express, (B) Barrx 90, (C) C2 cryoballoon, and (D) Trufreeze liquid
nitrogen spray. (Courtesy of (A and B) Medtronic, Minneapolis, MN; (C) Pentax, Tokyo,
Japan; (D) Steris, Mentor, OH; with permission.)

nitrogen or nitrous oxide, and can be applied by spray or balloon-delivered methods.

In observational studies, rates of CEIM with a variety of cryotherapy approaches range
broadly from 23% to 91%, but are generally more than 60%.31,32 Meta-analyses have
been limited by high residual heterogeneity, with mean rates of CEIM ranging from
64% to 86%.32,33 There are no comparative trials between cryotherapy and RFA,
nor any comparative trials between the different cryotherapy methods. Observational
comparisons between treatments are fraught, because the spectrum of disease and
other confounding factors may differ between participants in treatment trials. An
observational comparison using propensity-score matching to mitigate these issues
found that nitrous oxide balloon cryotherapy achieved CEIM at a numerically but
not statistically significant higher rate compared with RFA.34 A cryotherapy balloon
is under study that allows 3 cm hemi-circumferential treatment per application.35
Argon plasma coagulation (APC) uses ionized argon gas to conduct electrical cur-
rent for noncontact tissue coagulation. Clinical trials of APC for the treatment of
dysplastic BE have reported widely variable (57%–99%) rates of CEIM,6,36–38 and rela-
tively poor long-term durability (19%–38%).37,39 Hybrid APC, an ablative method that
combines a mucosal lift before APC with a single catheter, has demonstrated prom-
ising early results.40 In 2 prospective studies, the cumulative incidence of CEIM
(88%) was comparable to RFA and cryotherapy, but durability was marginally worse
492 Cotton et al

than RFA, at 66% at 2 years.41 Chest pain and odynophagia were common after
hybrid APC treatment, requiring pain medications in 21% of patients.41 Fever was re-
ported in 7%, bleeding in 4%, stricture in 4%, and there was a single esophageal
perforation in a study of 154 patients.41

SURGICAL TREATMENT OPTIONS

Over recent decades, esophagectomy has been largely supplanted by endoscopic

therapy for BE with dysplasia and superficial EAC. The American College of Gastroen-
terology recommends that endoscopic therapy be preferred over esophagectomy for
BE with dysplasia or T1a EAC for patients with low risk features.42 Even in high-volume
centers, operative mortality of 2.5%–2.6% has been reported in esophagectomy for
BE with HGD, T1a, or T1b EAC.42,43 Serious adverse effects such as anastomotic
leak, wound infection, aspiration and respiratory failure, and vocal cord paralysis
are common.42,43 In surgical series, lymph node metastasis is reported in 20%–
23% in T1b lesions, although this number may be elevated due to mis-staging of T2
lesions as T1b.44–46 A predictive model built in the National Cancer Database had
moderate (C statistical 0.7)47 discrimination between patients with and without nodal
metastasis (Tables 2 and 3). Given the higher risk of nodal metastasis, esophagec-
tomy with lymph node dissection may be the optimal approach to T1b lesions in
good surgical candidates, especially those with poor differentiation, lymphovascular
invasion, or involvement of the deep submucosa. In patients at higher risk of adverse
effects from surgery, ESD offers an endoscopic alternative for the treatment of T1b le-
sions. Further work is ongoing to describe patients with T1b EAC who may be
amenable to endoscopic management. T1b tumors of smaller size, well-
differentiated histology, invasion to the superficial submucosa, and no evidence of
angiolymphatic invasion may be good candidates for endoscopic management,
based on low risk of lymph node involvement.

TREATMENT RESISTANCE AND COMPLICATIONS

All ablative methods have failures, and the need for second line treatment is common.
Adequate control of reflux is critical to the success of any ablative method and some
patients may require a surgical antireflux procedure to achieve this. The best-
described salvage therapy after RFA is cryotherapy. In a meta-analysis of 8 studies,
cryotherapy as salvage therapy for failed RFA showed a high rate of complete eradi-
cation of dysplasia (76%) and a smaller proportion of CEIM (46%).7 The meta-analysis
did not distinguish between balloon or spray-delivered cryotherapies, but it was

Table 2
Points for tumor characteristics among T1a and T1b lesions in the Weksler et al. scoring system

Tumor Characteristic Points

Well differentiated 0
Moderately differentiated 2
Poorly differentiated 3
Size < 15 mm 0
Size 15–25 mm 1
Size >25 mm 2
No angiolymphatic invasion Angiolymphatic invasion 0
2
 Management of Dysplastic Barrett’s Esophagus 493

Table 3
The proportion with lymph node metastasis among T1a and T1b lesions in the Weksler et al.
scoring system

Proportion with Lymph Proportion with Lymph

Total Points Node Metastasis Among T1a Node Metastasis Among T1b
0 0 4.3
1 0 0
2 1.9 5.7
3 2.6 13.8
4 6.5 22.0
5 16.1 32.4

Adapted from Weksler B, Kennedy KF, Sullivan JL. Using the National Cancer Database to create a
scoring system that identifies patients with early-stage esophageal cancer at risk for nodal metas-
tases. J Thorac Cardiovasc Surg. 2017;154(5):1787-1793; with permission.

dominated by spray-delivered methods. A subsequently published prospective study

of salvage nitrous oxide balloon cryotherapy after RFA reported a similar 76% rate of
complete eradication of dysplasia and a higher 72% rate of CEIM.5
RFA is overall safe and well tolerated. A meta-analysis of RFA with and without EMR
found a rate of stricture of 5.6% (95% confidence interval [CI], 4.2%–7.4%), a rate of
pain requiring medication or medical attention of 3.8% (95% CI: 1.9%–7.8%), and a
rate of bleeding of 1% (95% CI: 0.8%–1.3%).48 Two perforations occurred in
5521 United States RFA registry participants (0.04%), which is comparable to the
background rate in diagnostic upper endoscopy.49,50
The safety of cryotherapy has been evaluated in multiple studies. A comparative
study found a statistically significantly 6% increased cumulative stricture risk for cryo-
therapy compared with RFA (4 vs 10%).34 Stricture rates with various cryotherapy
methods have been reported from 3% to 13%, with a meta-analysis dominated by
liquid nitrogen spray cryotherapy reporting a pooled rate of strictures of
7%.5,31,32,34,51 Bleeding was not reported in most studies, but one case of delayed
bleeding not requiring transfusion was reported in one study.5 Chest pain requiring
pain medication was found in 1% of treatments and chest pain was reported in 3%
to 4% of patients in meta-analyses, which is less than with RFA.31,32,48
APC has been associated with a 3%–5% stricture rate.6,37,38 In one study, 47% had
sore throat after the procedure, 11% had difficulty swallowing, and 5% reported fever
after treatment.37 One study of 71 patients reported one perforation (1.4%) requiring
esophagectomy,6 but this was not reported in other studies of traditional APC.36–38
In the case of hybrid APC, a prospective trial reported a 2% rate of stricture for
APC following EMR, a 12% rate of chest pain, and a 4% rate of odynophagia.52
The rate of stricture requiring dilation was reported as 3.9% in a cohort whereby
most patients also underwent EMR.41 The rate of stricture with or without dilation
requirement was reported at 9.1% in a prospective study without EMR.40
In a pooled analysis of 15 studies, EMR of a focal lesion had an overall 0.7% stricture
rate, a 1.2% rate of delayed bleeding, and a 1.2% rate of perforation.53 In a meta-
analysis of 8 studies evaluating EMR as monotherapy for the complete resection of
the entire Barrett’s segment, the rate of stricture formation was high at 37%, as was
the rate of bleeding (8%), and perforation (2%).54 A single-center prospective study
contends that stepwise EMR, performing no more than 2 EMRs per session, reduced
the stricture rates to 1%. ESD had an 11.6% rate of stricture, 1.8% rate of bleeding,
and 1.5% rate of perforation in a 2018 meta-analysis of 11 studies.55
494 Cotton et al

LONG-TERM RECOMMENDATIONS

Following endoscopic eradication of BE with dysplasia or early EAC, endoscopic sur-

veillance is indicated to reduce the risk of recurrence and progression.56 Recommen-
ded surveillance intervals after CEIM have been recently updated (Table 4).42 Studies
have found that recurrence is higher the first year after CEIM,57 then decreases to a
constant rate in the long term.58,59 As such, the termination of surveillance should
be determined by balancing the risks and benefits of surveillance endoscopy in indi-
vidual patients and considering competing risks of mortality rather than at a set point
in time after CEIM. Since even very late recurrence of disease has been reported, pa-
tients are never “safe” from recurrence after successful endoscopic intervention.

RECENT DEVELOPMENTS

A report from a large Dutch registry was the first to describe poor healing and poor
squamous regeneration after RFA as an outcome.60 It found that half of patients
with poor healing or poor squamous regeneration at follow-up for RFA could success-
fully achieve CEIM with the intensification of acid suppression or longer time between
treatment visits as the most successful strategies.60
A second multicenter randomized trial of RFA for LGD was recently reported,61 the
first reported trial to replicate the findings of the SURF trial.3 The surveillance arm was
notable for similar rates of neoplastic progression (26%) to those observed for
confirmed LGD in the SURF Trial.3 However, a high rate of regression of LGD (31%)
was observed in the surveillance arm, whereas the rates of CEIM and complete remis-
sion of dysplasia were lower.61
An early series of 123 patients treated with the Barrx 360 Express RFA self-sizing
catheter found good efficacy and safety, with lower stricture rate at a 10 J/cm2 setting,
and this has been adopted as the default energy setting for this device.26
A multicenter randomized clinical trial examined a nitrous oxide cryoballoon focal
ablation system for the treatment of BE with dysplasia or intramucosal EAC. This study
reported comparable outcomes to RFA with lower postprocedure pain.5

FUTURE DIRECTIONS

A fundamental challenge in the management of BE with dysplasia and early neoplasia

is right-sizing the population treated by endoscopic eradication therapy in proportion
to the risk of its disease. Trials demonstrating a benefit for ablative treatment of LGD
included only patients with confirmed LGD, whereby the pathology was over-read by a
central expert subspecialty pathologist and showed much higher rates of progression
than in most community series. Future criteria for the treatment of LGD may require
confirmation by 2 expert pathologists using more specific criteria such as,62 persistent

Table 4
Recommended surveillance intervals of the 2020 American Gastroenterological Association
Clinical Practice Update on Endoscopic Treatment of Barrett’s Esophagus with Dysplasia and/
or Early Cancer

Histologic Grade Surveillance Timing

Intramucosal adenocarcinoma At 3, 6, and 12 mo and annually thereafter.
High-grade dysplasia At 3, 6, and 12 mo and annually thereafter.
Low-grade dysplasia At 1 and 3 y.
 Management of Dysplastic Barrett’s Esophagus 495

LGD across examinations,63–65 or other risk factors to identify the patients with LGD
who would most benefit from endoscopic eradication.
While the literature on the endoscopic management of BE with dysplasia or early
EAC has benefited from a series of randomized clinical trials,3,4,6,22,36,37,39,56,61 none
of these compare contemporary ablative therapies head-to-head. Comparing the
currently available trials (featuring different patients and different methods) is fraught,
and head-to-head comparative studies are needed.
Essentially no studies describe the combination of radiation or chemotherapy with
endoscopic resection and mucosal ablation for early stage cancers. Neoadjuvant
chemotherapy or radiation therapy could potentially down-stage lesions to an endo-
scopically curable stage and neoadjuvant or adjuvant therapies might mitigate the
risk of concurrent lymph node metastasis. Such approaches may be particularly but
not exclusively appealing for poor surgical candidates.
A core unanswered clinical question in the management of BE with dysplasia or
early EAC is when to stop surveillance after successful endoscopic eradication ther-
apy. It is not surprising, given that these patients had previously developed neoplastic
BE, that they would be at risk of recurrent or progressive BE even after it is treated, and
studies suggest a low but persistent rate of recurrence after 5 years. At what point
does the risk of performing a surveillance endoscopy outweigh the benefits? This
varies both depending on the patient’s risk characteristics for undergoing an endos-
copy and their risk characteristics for developing recurrent and progressive disease.

SUMMARY

In summary, endoscopic surveillance or endoscopic eradication therapy is indicated

for BE with LGD, and endoscopic eradication therapy is indicated for BE with HGD
or T1a EAC with low-risk histologic features. Some patients with T1b EAC may simi-
larly benefit from endoscopic therapy. Esophagectomy with lymph node dissection is
indicated for most T1b EAC and T1a EAC with high-risk histologic features. RFA and
EMR remain the most widely available techniques for endoscopic eradication therapy,
but the landscape of endoscopic therapies continues to evolve. Surveillance intervals
after treatment are well-defined, but when to stop surveillance considering ongoing
recurrence risk, decreasing life expectance, and increased adverse effect risk from
endoscopy, remains an area of inquiry.

CLINICS CARE POINTS

 There is no proven benefit in the endoscopic eradication of BE without dysplasia, and

endoscopic surveillance is the standard of care for these patients.
 Evaluation of a patient with BE should begin with a comprehensive clinical evaluation to
judge the safety of endoscopy and competing risks to the patient, as well as the
endoscopic and histologic characteristics of their disease.
 A diagnosis of BE requires at least 1 cm of salmon-colored mucosa proximal to the top of
gastric folds with biopsies confirming the presence of intestinal metaplasia.
 A high-dose proton-pump inhibitor is the standard of care in the management of BE with
dysplasia and early neoplasia, but other chemopreventative agents remain investigational.
 Endoscopic eradication therapy combines endoscopic resection of any raised or irregular
regions, with ablative therapy for any remaining flat BE.
 Band-assisted EMR is similarly safe and effective to cap-assisted EMR but less time consuming.
496 Cotton et al

 Endoscopic submucosal dissection may allow for the resection of large T1a lesions and T1b
lesions in some cases, but is associated with a higher stricture and perforation rate than EMR.
 RFA is the most widely available ablative therapy. RFA is safe and effective, and is associated
with self-limited postprocedure chest pain in most patients and stricture formation in about
5%.
 Hybrid APC and cryotherapy seem to offer similar effectiveness to RFA as ablative therapies.
APC may have a higher rate of recurrence and cryotherapy a higher rate of stricture
compared with RFA. However, cryotherapy has less postprocedure pain than RFA and APC is
less costly. Head-to-head data are lacking.
 Esophagectomy is appropriate for most good surgical candidates with T1b EAC. It may also
be considered in patients with T1a EAC and high risk features of poor differentiation or
lymphovascular invasion, due to a higher risk of nodal metastasis.
 For patients who are refractory to RFA, cryotherapy can be used as salvage therapy with a
76% rate of complete eradication of dysplasia.
 Regular surveillance is required following the endoscopic eradication of BE with dysplasia or
early EAC and should continue until an individual’s risks from surveillance endoscopy
outweigh the risk of recurrence and progression.

DISCLOSURE

C.C. Cotton has no conflicts of interest. S. Eluri has no conflicts of interest. N.J. Sha-
heen has received research funding from Medtronic, Pentax, Steris, CDx Medical,
Lucid, and Interpace Diagnostics and has worked as a consultant for Boston Scienti-
fic, Cernostics, Cook Medical, Aqua, Exact Sciences, and Phathom.

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Gastric Cancer
Emerging Trends in Prevention, Diagnosis, and
Treatment

Dalton A. Norwood, MDa,b,1, Eleazar Montalvan Sanchez, MDb,c,

Ricardo L. Dominguez, MDb, Douglas R. Morgan, MD, MPHa,*

KEYWORDS
 Gastric cancer  Prevention  Diagnosis  Treatment

KEY POINTS: IMPORTANT TRENDS IN GASTRIC CANCER

 Recent guidelines for surveillance of gastric premalignant conditions (GPMCs)

 Major paradigm shift in gastric cancer prevention
 Surveillance endoscopy at 3 years is recommended for high-risk patients
 Advances in diagnostic technology and approaches
 Image-enhanced endoscopy and artificial intelligence
 Dissemination of expertise in the endoscopic management of early gastric cancer
 Endoscopic submucosal dissection is now available in US centers of excellence
 Expansion of gastric cancer targeted treatment options based on genetic biomarkers
 Outgrowth from the National Institute of Health The Cancer Genome Atlas program
 Leverage of technology advancements

INTRODUCTION

Gastric adenocarcinoma (GC) is the third leading cause of global cancer mortality, and
the leading infection-associated cancer with more than 1 million incident cases annu-
ally and nearly 800,000 deaths in 2020 (Box 1).1–4. GC was highlighted as a cancer sur-
vival “disparity” because of the breadth of 5-year survival (10%–69%), ranging from

a
UAB Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL
35294, USA; b Western Honduras Gastric Cancer Prevention Initiative, Copan Region Ministry of
Health, Sala de Endoscopia, Calle 1 S, Hospital Regional de Occidente, Santa Rosa de Copán
41101, Honduras; c Department of Medicine, Indiana University School of Medicine, Indian-
apolis, IN 46202, USA
1
Present address: 1720 2nd Avenue South BDB373, Birmingham, AL 35294, USA.
* Corresponding author. UAB Gastroenterology and Hepatology, The University of Alabama at
Birmingham, BDB 373, 1808 7th Avenue South, Birmingham, AL 35233, USA
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 501–518

https://doi.org/10.1016/j.gtc.2022.05.001 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
502 Norwood et al

Box 1
Gastric cancer core epidemiology

Gastric cancer is an important global cancer

 Fourth leading cause of global cancer mortality
 Fifth leading cause of cancer incidence, approaching 1 million
 Incidence is expected to rise due to the growing and aging populations in the high incidence
regions
Marked 5-year survival cancer disparity, range 10% to 70%
 US 5-year survival is w30%, compared with East Asia nearly 70%, and low and low-middle
income countries 10%–15%
Lead infection-associated cancer
 Helicobacter pylori is a WHO class I carcinogen
 The H pylori attributable risk is 75%–88%
 EBV coinfection drives 10% of gastric cancers
Gastric cancer represents a marked cancer disparity in the United States
 Incidence rates are nearly double in all minorities compared with Whites
 Although incidence is decreasing since WWII, it is more common than esophageal cancer
Consistent 2:1 male to female ratio in the world
 Estrogen may play a protective role by unknown mechanisms
Gastric cancer has striking geographic variability
 The high-incidence regions: Latin America, Eastern Asia, Eastern Europe
 Immigrants from high-incidence regions maintain the risk of their country of origin

Abbreviations: EBV, Epstein-Barr virus; LMICs, low and low-middle income countries; WHO,
World Health Organization.

nearly 70% in eastern Asia to 10% to 15% in India and Latin America. In the United
States, 5-year survival is 33%.5 The principal histologic subtypes are intestinal and
diffuse GC. This review focuses on distal (noncardia) gastric cancer.
Gastric cancer has remarkable geographic variability, regionally and within coun-
tries, which offers the opportunity for focused prevention programs and scientific dis-
covery. The high-incidence regions include eastern Asia, mountainous Latin America,
and areas in Eastern Europe and Russia.2 Immigrants from high-incidence regions
maintain the risk of their nation of origin.6 Large foreign-born immigrant populations
in the United States from high-incidence regions include: Mesoamerica (Southern
Mexico, Central America), South America, East Asia, Eastern Europe, and Russia.
The Central America four region (Honduras, El Salvador, Guatemala, Nicaragua) is
the principal low and low-middle income countries region in the western
hemisphere.6–11
In the United States, GC represents a marked cancer disparity, with nearly double
the incidence rates in all non-White minorities.12–22 Although Helicobacter pylori prev-
alence is increased in minorities, other risk factors play an important role. Additional
key features of GC epidemiology in the United States include the decrease in overall
incidence since World War II, and the recent increase in gastric cancer in young indi-
viduals, including young White females, which may be related to environmental factors
or changes in the western microbiome.23
General Risk Factors
H pylori infection is the dominant risk factor for GC with an attributable risk of 75%
to 88%.24,25 H pylori is classified by the World Health Organization (WHO) as a
 Emerging Trends in Gastric Cancer 503

class I carcinogen. H pylori has important virulence and oncogenic genotypes, such
as CagA (cytotoxin-associated gene A) and VacA (vacuolating cytotoxin A). Addi-
tional risk factors include male sex, older age, family history of cancer, low socio-
economic status, cigarette smoking, alcohol consumption, dietary and
environmental factors (eg, salt, lack of fruits and vegetables), previous gastric sur-
gery, and pernicious anemia.4,26–29

BIOLOGY AND CLASSIFICATION

Gastric Carcinogenesis Pathway (Correa Cascade)
Gastric cancer is a multifactorial process, with progression through a series of histo-
pathology stages: normal mucosa, chronic gastritis, multifocal atrophic gastritis,
gastrointestinal metaplasia (GIM), dysplasia (indeterminant, low-grade, high-grade),
and adenocarcinoma (Fig. 1).30–39 This model fits optimally within the setting of
chronic H pylori infection and the intestinal type GC. Progression is driven by H pylori
virulence factors and cumulative duration of infection, host genetics and responses,
and dietary and environmental factors. Atrophy, GIM, and dysplasia are considered
gastric premalignant conditions (GPMCs). The accruing literature suggests that
incomplete GIM (colon-like phenotype with mucin drops) has a higher risk of progres-
sion than complete GIM (small intestine–like phenotype with a brush border). Exten-
sive GIM, involving the corpus and antrum, is also considered higher risk for
progression. Although atrophy may be reversible with H pylori eradication, GIM and
dysplasia are considered beyond the point of no return, wherein surveillance and/or
endoscopic treatment is indicated in addition to H pylori eradication. Spasmolytic
polypeptide-expressing metaplasia is a specialized form of metaplasia observed in
the setting of repair, regeneration, and progression to GIM, yet its precise role in
gastric carcinogenesis in humans is unclear.
Host Genetic Factors and Hereditary Gastric Cancer
Familial clustering occurs in 5% to 10% of cases and germline mutations are found in
a subset of these individuals.40–43 A proportion of the clustering is caused by H pylori

Fig. 1. Gastric cancer risk factors and pathogenesis. EBV, Epstein-Barr virus.
504 Norwood et al

prevalence within families. Hereditary diffuse gastric cancer, with autosomal-

dominant inheritance and CDH1 gene mutations, represents the principal germline ge-
netic syndrome. Surveillance and prophylactic total gastrectomy are considered for
individuals with confirmed CDH1 mutations.44,45 Putative germline mutations (eg, in
PALB2, FBXO24, BRCA1) in diffuse and intestinal cancers underscore ongoing inves-
tigations in the field.44 Lastly, gastric cancer occurs more frequently in a variety of pol-
yposis and hereditary syndromes (eg, familial adenomatous polyposis, Cowden
syndrome, juvenile polyposis syndrome, Li-Fraumeni syndrome, Lynch syndrome,
and Peutz-Jeghers syndrome).40

Histologic Classification of Gastric Cancer

Gastric cancers demonstrate significant heterogeneity in morphology and histology
(discussed later). The Lauren Classification of gastric cancer histology continues to
be the most commonly used system in the United States and most of the world.46
The Lauren classification characterizes the intestinal type, diffuse type, mixed and
indeterminate, or unclassifiable subtypes. Alternate classifications systems include
Nakamura47 and the WHO48 classification. The Nakamura classification is commonly
used in East Asia and is important in the setting of screening and surveillance pro-
grams for early gastric cancer (EGC). The Nakamura system discriminates between
the differentiated and undifferentiated subtypes.47,49 The WHO classification is com-
plex, with more than 10 different subtypes, limiting its use in clinical practice. The
severity of gastric atrophy and metaplasia is quantified by the Operative Link on
Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia
(OLGIM) systems, and the Correa Histopathology Score. These scoring systems are
primarily used in research, although OLGA and OLGIM are used clinically in some
European and South American settings.

Molecular Classification of Gastric Cancer

The molecular characterization of gastric cancer has been one of the central suc-
cesses of The Cancer Genome Atlas National Institutes of Health program.50
Four distinct molecular subtypes were categorized: chromosomal unstable (CIN),
genomically stable (GS), Epstein-Barr virus–positive (EBV1), and microsatellite un-
stable (MSI). Supporting the Lauren classification, the CIN and GS subtypes
strongly correlate with the intestinal and diffuse subtypes, respectively. The EBV
and MSI subtypes each account for about 10% of cases. Limited percentages of
EBV and MSI were noted in the intestinal and diffuse Lauren subtypes, and CIN
and GS among the diffuse and intestinal subtypes, respectively. For cancer biology,
the The Cancer Genome Atlas results are instructive (eg, defining EBV-associated
GC as a distinct entity). Clinical utility in precision medicine is emerging for prog-
nosis and targeted therapies, with HER2 and immune checkpoint inhibitors as
examples.

GASTRIC CANCER PREVENTION

General measures to reduce the risk of GC follow recommendations to reduce cancer

risk in general. These measures include tobacco cessation, limited alcohol use, and
dietary advice (eg, salt restriction, increased fruits and vegetables). Cumulative data
from a range of studies suggest that H pylori eradication reduces the risk of gastric
cancer, particularly in subjects with chronic gastritis and without premalignant le-
sions.51,52 Population-based treatment in healthy individuals with antibiotic regimens
for H pylori is impractical and may have adverse effects related to antibiotic resistance
 Emerging Trends in Gastric Cancer 505

and the microbiome. H pylori treatment as a prevention measure should be individu-

alized, with the example of patients with a family history of GC.53

Management of Gastric Premalignant Conditions

Recent international guidelines recommend surveillance with upper endoscopy in pa-
tients with GPMCs that are at higher risk for progression based on demographic fac-
tors and histologic diagnosis (Table 1).54–56 This represents a major paradigm shift in
patient management and aligns surveillance with standards for premalignant lesions
of the esophagus and colon. The overall goal is to reduce the burden of gastric cancer
and improve survival in regions without screening programs, such as North America
and Europe. The current evidence for surveillance is modest and based on the global
GC literature, and the recent recommendations are expected to generate important
evidence in the coming decade. In patients with GIM, surveillance is recommended
for high-risk groups (GC family history, non-White racial and ethnic groups, immi-
grants from high-incidence regions, autoimmune gastritis) and for those with high-
risk histology (incomplete GIM, extensive GIM, severe extensive atrophy [OLGA 3–
4]). For GIM or severe atrophy, the recommended interval is 3 years, but may be indi-
vidualized based on the presence of other risk factors. Surveillance in 12 months is
indicated for patients with low-grade dysplasia with no visible lesion. Definitive treat-
ment (eg, endoscopic submucosal dissection [ESD]) is indicated when there is a
visible lesion or high-grade dysplasia.54–56
Screening for GPMCs, such as intestinal metaplasia, in the general population is not
recommended. Focused screening may be indicated in higher risk patients according
to demographic and health factors, which include a GC family history, non-White racial
and ethnic groups, immigrants from high-incidence areas, and autoimmune gastritis.
The chemoprevention of gastric cancer for patients with GPCs is not recommended,
because agents and data are lacking. Observational studies suggest that regular
aspirin use may reduce GC risk. Regular aspirin was associated with a significant
reduction of risk of GC in women in the US Nurses Health Study.57 Other studies in
Asia and Latin America have reported the role of aspirin as protective for noncardiac
GC.58,59 There are ongoing clinical trials in high-risk populations with various agents,
such as eflornithine, curcumin, and cyclooxygenase-2 inhibitors.

Table 1
Recommendations for screening and surveillance of gastric premalignant conditions

Characteristic Recommendation
Screening
Average risk Average risk Screening not indicated
High risk High-risk groupsa Individualize screening
Surveillance
GPMC (eg, GIM) High-risk groupsa or histologyb Surveillance indicated
Low-grade dysplasia No visible lesion Surveillance in 6–12 mo
Visible lesion Definitive treatment
High-grade dysplasia All patients Definitive treatment

Notes: Surveillance endoscopy at 3 years should be considered for high-risk GPMCs.

a
High-risk groups: Family history of gastric cancer, non-White racial and ethnic groups, immi-
grants from high-incidence regions, autoimmune gastritis.
b
High-risk histology: Incomplete-type GIM, extensive GIM, and severe extensive atrophy (OLGA
3–4).
506 Norwood et al

Helicobacter pylori Eradication

The eradication of H pylori is recommended for patients with GPMCs or gastric can-
cer, particularly EGC, to prevent progression to GC and recurrence, respectively. A
recent meta-analysis of 19 studies in Japanese populations that included healthy in-
dividuals and patients with EGC showed that eradication was associated with a signif-
icant decrease in GC.51,60 Studies are emerging for eradication in patients with
GPMCs. In a recent follow-up of a 20-year Hispanic cohort high-risk population, expo-
sure to H pylori therapy and H pylori–negative status reduced progression, as
measured by the Correa score.61 International guidelines are consistent with the
recommendation for H pylori eradication in patients with GPMCs, including guidelines
from the America Gastroenterological Association.62

DIAGNOSIS
Clinical Presentation
Gastric cancer is generally classified as EGC, operable GC, and advanced GC with
respect to diagnosis and treatment. EGC is an invasive gastric cancer that involves
the mucosa and submucosa, irrespective of the lymph node metastasis. Endoscopic
resection is the treatment of choice for EGC, with a 5-year survival of greater than
90%. Operable GC is defined as resectable, locally advanced (T2 N1) tumor.
Advanced gastric cancer is inoperable locally advanced or metastatic disease.
The clinical presentation varies between individuals and may be nonspecific,
ranging from mild dyspepsia to significant obstructive symptoms signaling advanced
disease. The most common symptoms and signs are dyspepsia, anorexia, early
satiety, weight loss, abdominal pain, and anemia. Proximal GC may present with
dysphagia or regurgitation.

Endoscopic Evaluation
Esophagogastroduodenoscopy with histologic confirmation is the gold standard for
gastric cancer diagnosis. The examination should include localization of any abnor-
mality, extension and macroscopic delineation, and targeted biopsies of suspected le-
sions. Systematic nontargeted biopsies of the antrum, incisura, and corpus may be
indicated in patients at risk for GPMCs and to define the background mucosa in those
with suspected GC. Studies underscore the importance of careful inspection, which
includes adequate mucosal cleansing and insufflation, systematic visual inspection,
and adequate examination time. An examination time of 7 to 9 minutes has been
shown to increase the detection of GMPCs and EGC, analogous to colonoscopy with-
drawal time.63–65 Visual inspection consists of at least 20 to 22 “stations,” with photo-
documentation of select landmarks.66–68
The macroscopic classification of EGC is described as type I (protruded), type II (su-
perficial), and type III (excavated) according to the Paris Classification.69,70 Non-EGC
is classified according to the Borrmann system into four main types: type I (polypoid
without ulceration and a broad base), type II (ulcerated with elevated borders and
sharp margins), type III (ulcerated with diffuse infiltration at base), and type IV (diffusely
infiltrative thickening of the wall) (Fig. 2).71 The Borrmann type has been shown to be
an independent prognostic factor.72

Image-Enhanced Endoscopy
Image-enhanced endoscopy, when available, in conjunction with white-light endos-
copy (WLE), is indicated for EGC and operable GC, and for patients at risk for GPMCs.
Gastric cancer screening programs in Eastern Asia have driven the development of
 Emerging Trends in Gastric Cancer 507

Fig. 2. (A, B) Macroscopic classification of gastric cancer.

novel endoscopic imaging technologies and endoscopic resection techniques, with

applications throughout the gastrointestinal tract. Image-enhanced endoscopy in-
cludes magnification (near-focus imaging and optical/digital zoom), optical technol-
ogy (narrow-band imaging [NBI], autofluorescence), and chromoendoscopy (indigo
carmine). In the near term, the technologies that are readily available in the United
States are NBI and near-focus imaging.
NBI has demonstrated greater diagnostic accuracy over conventional WLE in
several studies with sensitivity and specificity of 60% and 89%, respectively.73–80 A
substantial increase in sensitivity and specificity (95.0% and 96.8%, respectively)
has been noted for the detection of small depressed gastric cancer lesions when
NBI is combined with conventional WLE.81 The criteria for a suspicious lesion are:
disappearance of fine mucosal structure, microvascular dilation, and the heteroge-
nous shape of vessels.82 NBI findings that are specific for GIM include marginal turbid
band, light blue crest, and white opaque substance. Magnification endoscopy with the
vascular surface classification system is commonly used in Eastern Asia. The vascular
surface system characterizes the microvascular and microsurface patterns
independently.83,84

Clinical Staging
Gastric cancer should be staged in accordance with standards from the American
Joint Committee on Cancer, and the National Comprehensive Cancer Network. Re-
view by a multidisciplinary tumor board is recommended to determine the treatment
plan.85,86 The staging evaluation may include: chest/abdominal/pelvic computed to-
mography (CT), endoscopic ultrasound, fluorodeoxyglucose-PET-CT, and laparos-
copy with cytology.
Biomarkers for targeted therapies are evolving rapidly, and include MSI or dMMR
in all patients, and HER2 and PD-L1 in M1 disease. High tumor mutational burden,
NTRK gene fusions, and EBV status are examples of additional biomarkers that
may emerge in the near term. Next-generation sequencing, when available, is
appropriate for multiple determinations rather than individual assays. Lastly, circu-
lating tumor DNA offers diagnostic and surveillance information for patient
management.
508 Norwood et al

Diagnosis and Staging Clinical Care Points

 Upper gastrointestinal endoscopy is the diagnostic procedure of choice. This includes six to
eight biopsies of the lesion and nontargeted biopsies from the neighboring mucosa,
antrum, and corpus.
 All patients with newly diagnosed gastric cancer should have a history and physical, detailed
family history, complete blood count, and comprehensive metabolic panel.
 Chest/abdominal/pelvic CT for staging for all patients.
 For patients without evident metastatic disease fluorodeoxyglucose-PET-CT and laparoscopy
with cytology may be considered.
 Endoscopic ultrasound should be performed for EGC and to differentiate early stage and
locally advanced disease.
 Endoscopic resection is appropriate for EGC with the intent of curative resection, and also for
staging in some cases.
 Genetic testing includes MSI (all patients), and HER2 and PD-L1 (M1 disease). Biomarkers for
targeted therapies will continue to evolve rapidly.
 The staging work-up differentiates the three clinical stages: EGC, locoregional disease, and
advanced cancer.

TREATMENT

Guidelines recommend a multidisciplinary team approach to therapeutic decisions for

patients with gastric cancer.87 GC treatment should be individualized and dependent
on the consensus of the endoscopic findings, histology, and staging evaluation. We
provide a brief overview of treatment approaches for EGC, locoregional operable dis-
ease, and advanced gastric cancer (Fig. 3). A detailed listing of targeted therapy and
chemotherapeutic regimens is beyond the scope of this review.

Fig. 3. Gastric cancer treatment algorithm. * Individualized per patient. ** Endoscopy,

Endoscopic ultrasound, abdominal/chest CT. *** See table 3.
Abbreviations: ESD, endoscopic submucosal dissection; EMR, endoscopic mucosal resection.
 Emerging Trends in Gastric Cancer 509

Helicobacter pylori Treatment

Various studies, including meta-analyses, suggest that H pylori eradication could
reduce the development of metachronous gastric carcinoma following endoscopic
resection of EGC.88–92 Several studies have not shown a decrease in incidence of
metachronous GC.93,94 Although H pylori eradication is generally recommended for
patients with resected EGC, the decision on treatment should be individualized and
discussed with the patient.

Early Gastric Cancer

EGC involves the mucosa and submucosa, irrespective of the lymph node status
(T1Nx), with 5-year survival rates greater than 90%. Endoscopic resection is the treat-
ment of choice in patients with a criteria-based low probability of lymph node involve-
ment. These criteria include a mucosal tumor without ulceration, size less than 20 mm
in diameter, differentiated histology, and without known lymphovascular inva-
sion.15,95,96 Endoscopic ultrasound and CT are usually performed in the staging eval-
uation. Gastrectomy and adjuvant therapy are reserved for cases with a high
probability of nodal involvement or a noncurative resection.
Originally developed in East Asia, there is now ample ESD experience in the United
States, Europe, and Latin America in centers of excellence.97–99 The data comparing
outcomes of ESD versus endoscopic mucosal resection suggest higher rates of com-
plete en bloc and histologic resection, curative resection, and lower risk of local recur-
rence with ESD. However, ESD does require more procedure time and clinical
expertise.15,95 Resections of lesions less than 1 cm may be appropriate for endo-
scopic mucosal resection. Some experts recommend ESD en bloc resection of
high-grade dysplasia and low-grade dysplasia with mucosal irregularities to rule out
an underlying EGC.55

Operable Gastric Cancer

For clinically staged T1 N1 and T2–T4a Nx M0 tumors, the principal treatment is sur-
gical resection with D2 lymphadenectomy, combined with perioperative/neoadjuvant
or adjuvant chemotherapy.100,101 Notably, targeted therapies are developing rapidly
and based on ongoing trials, may transition to first-line therapy (MSI/dMMR, HER2,
and PD-L1 status). Curative surgery is divided into standard gastrectomy and
nonstandard gastrectomy. The standard gastrectomy includes the resection of two-
thirds of the stomach with D2 lymphadenectomy. Nonstandard gastrectomy includes
other types of gastric resection and depends on the stage.98 Several meta-analyses
suggest equivalent or improved postoperative and long-term outcomes with laparo-
scopic gastrectomy versus open gastrectomy.102

Neoadjuvant/Perioperative Chemotherapy
Perioperative chemotherapy has become the cornerstone in the treatment of locally
advanced GC. Examples of regimens include FLOT (5-fluorouracil, folinic acid, oxali-
platin, docetaxel) and ECF (epirubicin, cisplatin and infused fluorouracil). An improve-
ment in survival from 23% to 36% is observed with the use of perioperative
chemotherapy with ECF for 2 to 3 months.103,104 The FLOT regimen demonstrated
better pathologic response, higher R0 resection rates, and better survival when
compared with ECF, and is the recommended standard of care for patients with locally
advanced gastric cancer who can tolerate a perioperative three-drug combination
regimen.86,105,106 Chemoradiation regimens are less common in the United States,
with ongoing studies.107,108
510 Norwood et al

Advanced Gastric Cancer

Chemotherapy and targeted therapies (discussed previously) represent the stan-
dard of care in patients with metastasis or locally advanced unresectable
GC.96,109 Palliative resection or bypass surgery are commonly indicated in specific
situations, such as refractory bleeding or obstruction. The only published random-
ized controlled trial of chemotherapy versus surgery plus chemotherapy failed to
show any survival benefit.110 The current three lines of treatment, based on
response and biologic markers with their corresponding evidence, are summarized
in the National Comprehensive Cancer Network Guidelines and the litera-
ture.86,111–120

Treatment Clinical Care Points

 Endoscopic resection is appropriate for EGC with the intent of curative resection. ESD is
generally recommended. Endoscopic mucosal resection may be considered for lesions less
than 1 cm.
 If the histopathology features of the EGC resection are high-risk for locoregional disease
(poorly differentiated, invasion of deep submucosa, positive lateral or deep margins,
lymphovascular invasion), then gastrectomy with lymphadenectomy should be considered.
 H pylori eradication is indicated, particularly in EGC patients.
 Operable gastric cancer eligible for gastrectomy with D2 lymphadenectomy includes patients
with T1b-T3 Nx tumors who are medically fit.
 For operable gastric cancer T2-T3 Nx or higher, perioperative or adjuvant chemotherapy is
recommended.
 For advanced gastric cancer, consideration of systemic chemotherapy and supportive care is
recommended, with individualized care plans.
 Targeted therapy based on genetic markers (MSI/dMMR, HER2, PD-L1) is evolving rapidly for
patients with operable and advanced disease.

GASTRIC CANCER: FUTURE TRENDS AND NEEDED RESEARCH

The gastric cancer research agenda includes a wide range of initiatives in epidemiology,
prevention, diagnosis, and treatment. Gastric cancer represents an important US can-
cer disparity. Further research in risk factors that are specific to at-risk populations is
needed, including H pylori, germline mutations, and dietary and environmental factors.
The recent US and global guidelines for GPMC surveillance represents a paradigm shift
and will generate important data for the first time, aligning with surveillance recommen-
dations in the esophagus and colon. Promotion of the guidelines is important, since
adoption in clinical practice is usually a lengthy process. Endoscopic technologies
are changing to support new diagnostic and therapeutic approaches. Targeted thera-
pies will continue to evolve, providing important options for patients with operable and
advanced gastric cancer. Lastly, “liquid biopsy” trials are underway, and may change
screening, surveillance, prognosis, and treatment monitoring paradigms in the near
term.

Future Trends and the Research Agenda

 Gastric cancer represents a major US cancer disparity.
 Intentional programs for racial and ethnic minorities are indicated.
 Research in potential prevalent germline mutations is needed.
 Implementation of surveillance guidelines for high-risk gastric GPMCs.
 Outcomes research with US data on GPMC surveillance programs.
 Development of novel biomarkers for gastric cancer to better define GMPC and GC risk.
 Improved biomarkers for the risk of progression of GPMCs.
 Emerging Trends in Gastric Cancer 511

 Research in novel H pylori treatments beyond antibiotics.

 Precision treatment approaches may be envisioned: who to test/treat versus not treat.
 Research in technology and quality diagnostics for GPMCs and EGC is needed.
 Image-enhanced endoscopy, artificial intelligence (AI), and cytoendoscopy.
 Research in quality endoscopy metrics and enhancement of training programs.
 Management of EGC will evolve in parallel with GPMC surveillance programs.
 Outcomes data are needed for endoscopic resection (ESD) in the United States.
 Expansion of gastric cancer targeted treatment options.
 Research in “liquid biopsy” technologies have the potential to foster new paradigms.
 Screening and GPMC surveillance, prognosis, and treatment monitoring.

FUNDING

This work was funded in part by the U.S. National Cancer Institute (NCI):
P01CA028842 (DRM), R01CA190612 (DRM), PAR-15-155 (DRM), NCI CGH
HSN261200800001E (DRM), P30CA068485 (DRM), K07 CA125588 (DRM).

DISCLOSURE

Cancer Prevention Pharmaceuticals and Thorne Research (NCI funded studies, with
company donation of study medications) (DRM). CDx Diagnostics (Investigator initi-
ated study, with company donation of disposables) (DRM). Freenome Inc. (Trial partic-
ipation by the University) (DRM).

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E n d o s c o p i c E v a l u a t i o n an d
Management of
C h o l a n g i o c a rc i n o m a
Rohit Das, MDa, Aatur D. Singhi, MD, PhDb, Adam Slivka, MD, PhDa,*

KEYWORDS
 Cholangiocarcinoma  ERCP  Next-generation sequencing

KEY POINTS
 Diagnosis of cholangiocarcinoma can be challenging due to the poor sensitivity of stan-
dard endoscopic retrograde cholangiopancreatography sampling techniques.
 Next-generation sequencing is a novel diagnostic tool that greatly improves on the accu-
racy of standard biliary sampling.
 Metal stents may improve the durability of biliary decompression as compared with plastic
stents but add expense and do not affect prognosis.

INTRODUCTION

Cholangiocarcinoma (CCA), or cancer of the biliary tract, arises from the epithelial cells
of the extrahepatic and intrahepatic bile ducts. CCA is a relatively rare condition, ac-
counting for approximately 3% of gastrointestinal malignancies overall. In a study
examining the incidence of CCA in the United States from 2001 to 2015 using the
US Cancer Registry database, the calculated incidence of CCA was 1.26 cases per
100,000 people per year.1 Although this reflects a relatively low burden of disease in
high-income countries, CCA is a much more significant problem in particular parts
of the world, especially in China and Thailand, where the incidence is 30- to 40-fold
higher.2 For localized disease that is amenable to resection, the 5-year survival for
CCA varies between 10% and 40%, and depends on several factors, including site
of disease, histologic margin status, and extent of lymph node involvement.3 For
advanced disease that is not resectable, the prognosis of CCA is poor, with a median
survival of 5 to 6 months.4

The authors have no financial or commercial conflicts of interest to disclose.

a
Division of Gastroenterology, Hepatology and Nutrition, UPMC Presbyterian, 200 Lothrop
Street, Pittsburgh, PA 15213, USA; b UPMC Presbyterian, Department of Pathology, 200 Lothrop
Street, Pittsburgh, PA 15213, USA
* Corresponding author. UPMC Presbyterian, 200 Lothrop Street, Mezzanine Level, C-2 Wing,
Pittsburgh, PA 15213.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 519–535

https://doi.org/10.1016/j.gtc.2022.06.003 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
520 Das et al

Several risk factors for the development of CCA have been identified with strong
causal association, which include primary sclerosing cholangitis (PSC),5 cystic dis-
eases of the liver and biliary tract such as Caroli disease and choledochal cysts,6
chronic intrahepatic stone disease,7 parasitic infections of the biliary tree with liver
flukes,8 certain genetic disorders including cystic fibrosis,9 and chronic hepatitis C
infection.10 Some of these risk factors, specifically primary intrahepatic stone disease
and chronic liver fluke infection, are more prevalent in Southeast Asia, accounting for
the higher incidence of CCA in this region of the world.
CCA can present anywhere in the biliary tree, and a given patient’s presentation de-
pends on the site of disease. In a prospective study of 564 patients, 50% of the pa-
tients had perihilar disease, 42% had disease distal to the biliary bifurcation, and
8% had disease isolated to the intrahepatic ducts.11 Patients with distal and perihilar
disease most commonly present with painless jaundice, in the context of cross-
sectional imaging evident for signs of biliary obstruction. Patients with isolated intra-
hepatic disease can present differently, often without jaundice, and rather with
nonspecific systemic symptoms and/or cholestatic liver test abnormalities. Not un-
commonly, isolated intrahepatic disease can present incidentally, diagnosed on imag-
ing done for alternative indications.
The role of a gastroenterologist in the evaluation and management of CCA is 2-fold.
Firstly, to aid in obtaining a definitive tissue diagnosis of malignancy and secondly, to
palliate jaundice in patients with biliary obstruction amenable to endoscopic interven-
tion. The former objective is especially important in patients who may have biliary stric-
turing disease related to benign causes, such has immunoglobulin G4–related
cholangiopathy or primary sclerosing cholangitis. The latter objective is used to
decrease the incidence of postprocedure infectious complications, palliate symptom-
atic cholestasis, and allow for the administration of full-dose systemic chemotherapy
in select patients. Endoscopic retrograde cholangiopancreatography (ERCP) is the
primary endoscopic procedure to achieve these goals. This article focuses on the
role of ERCP in the diagnosis and management of CCA and the relative efficacy of
the various endoscopic tools and techniques that have emerged over time to help
us manage this disease.

THE ROLE OF IMAGING AND ENDOSCOPIC ULTRASOUND IN THE EVALUATION OF

CHOLANGIOCARCINOMA
The Role of Imaging in the Evaluation of Cholangiocarcinoma
As part of the initial evaluation of CCA, cross-sectional imaging in the form of
computed tomography (CT) and MRI offers valuable information that helps direct sub-
sequent testing and management. In the absence of suspected metastatic disease,
focal malignant-appearing mass lesions in the liver may represent either intrahepatic
CCA or hepatocellular carcinoma (HCC). This distinction is important to make, as man-
agement differs for these 2 diseases. Typically, on CT, mass-forming intrahepatic CCA
appears as a hypoattenuating lesion with associated biliary dilatation and occasionally
retraction of the liver capsule. On triphasic contrast imaging, there is predominantly
peripheral enhancement on both arterial and portal venous phases, in contrast to
HCC that demonstrates washout of contrast on portal venous phase.12 Importantly,
a histologic subtype of intrahepatic CCA, known as combined hepatocellular-
cholangiocarcinoma (HCC-CCA), may exhibit contrast enhancement patterns that
overlap with HCC, making radiologic evaluation less helpful.13
On MRI, CCA is typically hypointense on T1-weighted images and hyperintense on
T2-weighted images. On dynamic gadolinium contrast MRI, CCA usually shows
 Management of Cholangiocarcinoma 521

peripheral enhancement on early images, with central contrast enhancement on more

delayed imaging, eliciting a so-called target sign. This radiologic appearance seems to
allow for better delineation between CCA and combined HCC-CCA as compared with
CT scan.14,15 MRI also offers the advantage of concurrently performing magnetic
resonance cholangiopancreatography (MRCP), which can provide accurate recon-
struction of the biliary tree that helps guide biliary intervention and potential operative
resection (Fig. 1).
For extrahepatic CCA in the absence of mass-forming disease, the main role of
cross-sectional imaging is to identify the site of biliary obstruction, help evaluate for
other malignant processes that lead to distal biliary obstruction, and provide vascular
staging for potential resectability. Although there are some data to suggest that certain
MRI and CT features can help identify malignant changes of the biliary tree,16,17 these
findings are not as reliable as compared with those described for mass-forming intra-
hepatic CCA.

The Role of Endoscopic Ultrasound in the Evaluation of Cholangiocarcinoma

Endoscopic ultrasound (EUS) has emerged as an important tool in the diagnosis and
staging of extrahepatic cholangiocarcinoma, particularly distal disease. The distal
biliary tree can be very well visualized with the echoendoscope positioned in the
duodenal bulb in the long position or in the second part of the duodenum with the
echoendoscope usually in the short position. On EUS, extrahepatic cholangiocarci-
noma typically appears as a hypoechoic lesion adjacent to or involving the biliary
tree. Fine-needle aspiration (FNA) can be performed intraprocedurally to help obtain
a diagnosis of malignancy. In addition, prior studies have demonstrated the utility of
EUS for visualization and FNA of regional (hilar, cystic duct, common bile duct, hepatic

Fig. 1. Reconstructed MRCP imaging in a patient presenting with painless jaundice. Imaging
is evident for marked bilateral intrahepatic biliary dilatation with a normal caliber extrahe-
patic duct, suspicious for proximal CCA.
522 Das et al

artery, posterior pancreatoduodenal, and portal vein) lymphadenopathy in CCA.18,19 In

a small study of 47 patients with hilar CCA undergoing EUS evaluation, echo features
and morphology of regional lymph nodes did not correlate with malignancy, with
benign-appearing lymph nodes demonstrated to be malignant on EUS-FNA.18 Subse-
quently, EUS characteristics of lymph nodes should not guide decisions during the
procedure on what nodes to target with FNA. EUS can also provide accurate assess-
ment of extent of portal vein involvement. Both findings of regional lymphadenopathy
and portal vein involvement can help determine a given patient’s eligibility for resec-
tion in distal extrahepatic disease. There are also data on EUS-FNA of regional lymph
nodes in the setting of proximal extrahepatic/hilar CCA and intrahepatic CCA, sug-
gesting a potential role of EUS in the evaluation of these patients.19 The finding of ma-
lignant regional lymph nodes in these cases may preclude patients from further
therapy and liver transplantation. Further studies are needed in this area.
In a study of 81 prospectively enrolled patients with extrahepatic CCA, EUS was
found to have a sensitivity of 73% in the diagnosis of CCA. In patients with preproce-
dural imaging, the sensitivity of EUS was significantly superior to both dynamic
contrast CT and MRI (94% vs 30% and 94% vs 42%, respectively) in the detection
of tumor.20 The sensitivity for EUS-guided diagnosis was higher for distal than prox-
imal tumors, and this is not surprising given less accurate EUS evaluation of the prox-
imal bile duct due to its increased distance from the duodenal lumen. EUS was also
accurate in determining resectability, correctly predicting resectable tumors in 38 of
39 patients.
Importantly, there are data to indicate that FNA of proximal extrahepatic/hilar CCA,
either percutaneously or via EUS, increases the risk of tumor seeding and the devel-
opment of metastatic peritoneal disease.21 For this reason, it is recommended to
avoid EUS-guided FNA of hilar CCA, as the increased risk of tumor seeding could pre-
clude curative resection or liver transplantations in select centers. For distal disease,
transduodenal FNA is within the field of resection, and so EUS-guided sampling
should be considered part of the standard diagnostic approach.
Intraductal ultrasound (IUS) has also been used as an adjunct diagnostic tool for the
evaluation of extrahepatic CCA. These catheters are small caliber (2–3 mm), operate at
a frequency of 20 MHz, and can be advanced over a guidewire through a standard
duodenoscope into the biliary tree, usually via a preexisting biliary sphincterotomy.
IUS findings that suggest malignancy include disruption of the normal wall layers of
the bile duct, identification of a hypoechoic mass, heterogeneous/irregular wall bor-
ders, and identification of malignant-appearing peribiliary lymphadenopathy. In one
study, the addition of IUS to standard ERCP diagnostic techniques increased the
sensitivity diagnosing CCA from 48% to 90%.22 Given that IUS is not widely available,
unable to provide a tissue diagnosis, and associated with high interobserver vari-
ability, it is not commonly used.

Our Practice
We always obtain some form of cross-sectional imaging before endoscopic evalua-
tion, and especially for hilar CCA, dynamic MRI with MRCP is our preferred imaging
modality. For distal extrahepatic CCA, we perform EUS initially and concurrently
with ERCP, to help obtain a tissue diagnosis and exclude pancreatic or ampullary neo-
plasms. For proximal extrahepatic CCA, we rarely consider pursuing an EUS initially
even if there is a focal mass evident amenable to EUS-guided FNA. Many of our pa-
tients are considered for surgical resection, and live-donor liver transplantation is a
part of our institution’s management algorithm for proximal CCA.23
 Management of Cholangiocarcinoma 523

Endoscopic Retrograde Cholangiopancreatography and Diagnosis of Extrahepatic

Cholangiocarcinoma
ERCP is the preferred modality for obtaining a tissue diagnosis of CCA. Standard
ERCP allows for accurate delineation of extent and site of extrahepatic disease and
fluoroscopically directed sampling of the biliary tree. In addition, treatment of biliary
obstruction with placement of plastic or metal biliary prostheses can be performed
during the same session. This section focuses on the various tools at our disposal dur-
ing ERCP when evaluating suspected CCA.

Endoscopic Retrograde Cholangiopancreatography with Brushings for Cytologic

Analysis
Bile duct brushings for cytologic analysis is a time-tested diagnostic tool that is
commonly used for evaluation of suspected CCA during ERCP. It is technically easy
to perform, carries minimal to no added risk, inexpensive, and widely available. Since
the early 1990s, several studies have examined the diagnostic accuracy of bile duct
brushings for diagnosis of biliary malignancy. The diagnostic accuracy has been rela-
tively similar across multiple studies, with a sensitivity ranging between 40% and 56%
and a specificity between 90% and 97%.24–26 In the presence of concomitant inflam-
matory cholangiopathies, this sensitivity decreases significantly.27 Most recently, a
meta-analysis of 1123 patients with CCA was conducted examining the pooled sensi-
tivity for various methods of endoscopic diagnosis of CCA. Among 719 patients for
whom bile duct brushings were performed, the pooled sensitivity for cytologic analysis
was 56%.28 Therefore, although positive cytologic analysis accurately confirms a
diagnosis of malignancy, negative cytologic analysis is fraught with a high false-
negative rate, leading to repeat procedures if there remains a strong concern for
malignancy.

ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY WITH BIOPSIES AND

SINGLE-OPERATOR USE CHOLANGIOSCOPY

Histologic analysis via intraductal biopsies is another diagnostic tool commonly used
during ERCP for evaluation of CCA. Although bile duct biopsies are relatively more tech-
nically challenging as compared with bile duct brushings, especially for more proximal
disease, it is similarly safe, inexpensive, and widely available. Therefore, bile duct bi-
opsies are often performed concurrently with bile duct brushings in an effort to maximize
the diagnostic yield of ERCP. However, the addition of histologic analysis with bile duct
biopsies unfortunately leads to only minimal improvement of diagnostic sensitivity as
compared with cytologic analysis with bile duct brushings alone.25,26,28
Cholangioscopy has been developed over time as a means to directly visualize the
bile duct for various reasons, including lithotripsy of large choledocholiths, helping to
obtain guidewire access when standard fluoroscopic techniques fail, and in the case
of CCA, allow for direct biliary visualization and performance of visually directed intra-
ductal biopsies of biliary mucosal abnormalities. Single-operator use cholangioscopy
(SOC) is a catheter-based system that is most commonly used and allows for a single
endoscopist to control both the duodenoscope and a through-the-scope cholangio-
scope simultaneously. Most recent SOC platforms afford high-definition imaging that
maximize detection of biliary mucosal abnormalities. The findings on cholangioscopy
that suggest biliary malignancy include raised intraductal lesions, tortuous and dilated
blood vessels (“tumor” vessels), mucosal friability, irregular nodularity, and mucosal ul-
ceration (Figs. 2 and 3). The recently described Mendoza criteria minimizes the interob-
server variability of these findings.29 The addition of narrow-band imaging (NBI) to SOC
524 Das et al

Fig. 2. Cholangioscopic image showing a papillary mass with “tumor vessels” in the left
main hepatic duct. Cholangioscopy-directed biopsies confirmed an adenocarcinoma, with
KRAS and TP53 mutations on next-generation sequencing.

may complement current cholangioscopy technology,30 but more data are required,
and NBI is not available on the most commonly used SOC platforms.
Since the mid-2000s when SOC first became introduced, several studies have been
done examining the performance characteristics of SOC in the diagnosis of CCA. A
meta-analysis was performed in 2015 summarizing the results of these studies.
Across 8 different studies and 337 patients, the sensitivity for SOC visual impression

Fig. 3. Cholangioscopic image showing a friable, polypoid mass in the common hepatic
duct. Cholangioscopy-directed biopsies showed intraductal papillary neoplasm of the bile
duct, a diagnosis that carries a high risk for the development of CCA. The patient underwent
definitive resection.
 Management of Cholangiocarcinoma 525

and SOC guided biopsies were 90% and 69%, respectively, whereas the opposite
was the case in regard to specificity (87% and 98%, respectively).31 These results
could have several explanations, including interobserver variability of cholangioscopic
findings, technique, and volume of biliary sampling. Overall, although SOC visual
scoring systems are improving, the false-negative rate of SOC-guided sampling is still
significant, and negative results must be interpreted with caution.

In-vivo Microscopy of Biliary Strictures

Confocal laser endomicroscopy (CLE) is a modality that has been used to obtain high-
resolution imaging of gastrointestinal mucosa for various premalignant and malignant
conditions, including Barrett’s esophagus, colon polyps, pancreatic cysts, and so
forth. CLE relies on laser technology to illuminate fluorescently highlighted tissue (us-
ing intravenous fluorescein), and subsequently capturing images reflected from the
tissue that is targeted. Probe-based CLE (pCLE) has been developed to make CLE
more convenient during endoscopy, as such probes can be easily passed through
the working channel of endoscopes; this has allowed pCLE to have a role in evaluating
CCA during ERCP.
A few studies have been performed evaluating the diagnostic utility of pCLE in CCA.
Initially, the Miami classification was developed to differentiate between malignant and
benign biliary strictures32; this was later revised to the Paris classification to include
criteria for inflammatory strictures, such as those seen in PSC, and improve the spec-
ificity of pCLE.33 In a prospective, multicenter international study, the utility of pCLE
was examined in 112 patients undergoing ERCP for evaluation of biliary strictures.
The combination of cholangiogram impression without pCLE and with tissue sampling
yielded a sensitivity and specificity of 85% and 69%, with a diagnostic accuracy of 79%.
The addition of pCLE yielded a similar sensitivity but increased specificity to 88%, and
overall accuracy to 88%. This increase in accuracy was not statistically significant.
Overall, pCLE may be a promising adjunct tool when evaluating biliary strictures
during ERCP. However, it is relatively expensive, and its true cost-effectiveness
should be better determined. Furthermore, as with all forms of endoscopic imaging,
there is a learning curve for interpretation of pCLE imaging, and consequent interob-
server variability may affect its diagnostic utility.

The Role of DNA Analysis as an Adjunct to Biliary Biopsies and Brushings

As a consequence of the significant false-negative rate with standard endoscopic
retrograde cholangiography (ERC) sampling, and even SOC-guided sampling, several
adjunct tools focusing on detecting abnormalities associated with biliary malignancy
at the molecular level have been studied in an effort to maximize the diagnostic yield
of biliary biopsies and brushings; these have included looking at chromosomal struc-
tural abnormalities with various techniques, most commonly with fluorescence in situ
hybridization (FISH), as well as genetic mutational analysis with next-generation
sequencing (NGS).
FISH is a process by which fluorescently labeled oligonucleotide probes are used to
detect chromosomal aberrations, particularly changes in chromosomal number, at
loci associated with biliary malignancy. Several studies have been conducted looking
at the performance characteristics of FISH in the diagnosis of CCA and how much it
adds to standard sampling during ERCP. In perhaps the largest study to date, among
233 prospectively enrolled patients undergoing ERCP for evaluation of biliary stric-
tures, an FISH probe targeting regions of chromosomes 3, 7, 9, and 17 was used.
The most common abnormality found among positive diagnoses was polysomy and
trisomy of chromosome 3 or 7. The sensitivity for standard cytologic analysis with
526 Das et al

bile duct brushings was approximately 20% (less than expected based on other insti-
tutions published experience, as stated earlier), and the addition of FISH increased
sensitivity to approximately 60% without significantly compromising specificity.34
Other similar studies, including one that used a different set of FISH probes optimized
toward biliary malignancy, have shown similar findings.35–37 Thus, FISH, which is
expensive and operator dependent, falls short for optimizing tissue sampling of inde-
terminate biliary strictures.
Over the past several years, significant effort has been made to better understand
the genetic landscape of biliary malignancy, from both a diagnostic and therapeutic
perspective. Early studies identified alterations in several key genes that affect the
pathogenesis of biliary malignancy, including KRAS, TP53, CDKN2A, and SMAD4 to
name a few, as well as genetic alterations that are potentially targetable for anticancer
therapies.38 As knowledge of this genetic landscape has expanded, and technology
for molecular testing become more refined, the ability to perform multigene testing
with NGS has transformed the evaluation and management of CCA.
Singhi and colleagues performed the largest study to date evaluating the diagnostic
performance of NGS among patients with biliary strictures. This study used a targeted
NGS assay, termed “BiliSeq,” looking at 28 genes associated with biliary malig-
nancy.39 Among 220 patients (including both training and validation cohorts) with
greater than 1 year of follow-up, and either pathologically proven malignancy
(n 5 145) or benign biliary disease as defined by clinical criteria (n 5 75), the sensitivity
and specificity of BiliSeq combined with pathologic evaluation of biliary brushings/bi-
opsies was 83% and 100%, as compared with 48% and 98% with pathologic evalu-
ation alone and 73% and 100% with BiliSeq alone. In a subset of patients with PSC
(n 5 37), combined BiliSeq and pathologic evaluation had nearly identical perfor-
mance characteristics. Therefore, the performance of BiliSeq did not degrade in the
presence of inflammatory cholangiopathies the same way standard cytology does.
Finally, in 13% of cases, an actionable mutation was found that affected anticancer
therapy, most commonly alterations in genes involved in the mitogen-activated pro-
tein pathway, particularly ERBB2.
Similar findings were reported by Dudley and colleagues who also compared the
performance of NGS with FISH of bile duct brushing specimens.40 Using a panel of
39 genes, the investigators found NGS had a sensitivity and specificity for malignancy
of 74% and 98%, whereas cytopathologic evaluation had a 67% sensitivity and 98%
specificity, and FISH was associated with a 55% sensitivity and 94% specificity. More
importantly, the combination of cytopathologic evaluation and NGS yielded an 85%
sensitivity and 96% specificity, whereas the cytopathologic evaluation plus FISH anal-
ysis achieved a 76% sensitivity and 92% specificity.
Although additional studies are needed to fully understand the utility of NGS in eval-
uation of CCA, based on the aforementioned data, NGS seems to confer significantly
increased diagnostic accuracy as compared with other diagnostic tools and adds no
technical challenge to standard ERC sampling techniques. The ability to identify
actionable mutations for anticancer therapy clearly distinguishes NGS as a tool to
not only aid in diagnosis but also potentially greatly improve prognosis, even among
patients who are not candidates for resection. NGS assays to this point are not widely
available but given the aforementioned, should be adopted as standard of care when
evaluating CCA endoscopically.

Our Practice
When evaluating possible extrahepatic CCA via ERC, our standard approach is to
send histologic and/or cytologic samples along with NGS on all samples, based on
 Management of Cholangiocarcinoma 527

the strong diagnostic performance characteristics of this combined approach in our

institution’s experience, as detailed earlier. In patients who have negative results
from this combined evaluation, we generally perform repeat sampling before consid-
ering a diagnosis and potential treatment of benign cholangiopathies. We consider
performing SOC in select cases, especially in the setting of more proximal disease
where standard biliary brushings and fluoroscopic biopsies can technically be more
challenging. Other diagnostic tools described earlier, such as FISH and pCLE, are
not part of our standard clinical practice.

Management of Cholangiocarcinoma During Endoscopic Retrograde

Cholangiopancreatography
The main role of ERCP in management of CCA is to relieve biliary obstruction in pa-
tients with unresectable disease, for relief of related signs and symptoms, including
jaundice and pruritis, as well as for medical optimization before systemic anticancer
therapy. In patients who are candidates for definitive surgical resection, the clinical
utility of preoperative biliary decompression is not completely clear. If surgery is to
be delayed, preoperative biliary decompression is usually pursued to palliate symp-
toms and prevent chronic liver injury related to ongoing biliary obstruction. Otherwise,
there are significant data to suggest that preoperative biliary decompression is not
necessarily of clinical benefit and may even increase the risk of postoperative
complications.41,42

Endoscopic Management of Distal Biliary Obstruction in Cholangiocarcinoma

In patients with extrahepatic CCA that is at least 1 to 2 cm distal to the biliary bifurca-
tion, ERCP can usually palliate biliary obstruction effectively with a single biliary pros-
thesis. The question as to whether to place a plastic stent versus metal stent has been
addressed in several studies, which have all looked at distal malignant biliary obstruc-
tion of various causes. In a meta-analysis of these studies from 2015, including 19
studies and nearly 2000 patients, the investigators examined plastic versus metal
stents in both distal and proximal malignant biliary obstruction and subdivided their
analysis based on site of disease.43 Among patients with distal biliary obstruction,
as compared with plastic stents, metal stents had significantly decreased rates of oc-
clusion and need for reintervention, but no significant difference in short-term mortality
or incidence of cholangitis. A more recent meta-analysis looking only at distal biliary
obstruction showed similar findings but also suggested increased survival and
decreased cholangitis with metal stents.44 Given these data, metal stents should be
favored over plastic stents in most patients with unresectable distal CCA, although
plastic stents can be considered in patients with a very poor short-term prognosis
to minimize expense.
When a metal stent is placed, the choice as to whether place an uncovered versus
covered prosthesis is controversial. Uncovered stents are less expensive, but theoret-
ically carry an increased risk of occlusion due to potential for in-stent tissue/tumor
ingrowth. Covered stents can counteract this risk but have a higher risk of migration
and theoretically an increased risk of cholecystitis if the cystic duct orifice lies within
the path of the stent. A meta-analysis by Sawas and colleagues examining this ques-
tion was conducted in 2018 using 11 randomized controlled trials, totaling 1272 pa-
tients.45 Although there was an increased rate of stent ingrowth in uncovered metal
stents, covered stents had a higher rate of migration, sludge/stone formation, and tu-
mor overgrowth. Overall, there was no statistically significant difference in mortality
rate or stent failure between the 2 groups. Furthermore, there was no difference in
rates of adverse events, including cholangitis and cholecystitis.
528 Das et al

Endoscopic Management of Biliary Obstruction in Proximal/Hilar

Cholangiocarcinoma
Endoscopic management of biliary obstruction in patients with proximal CCA can be
much more technically challenging as compared with patients with distal obstruction.
On occasion, especially for angulated, severe hilar stenoses, retrograde access into
obstructed biliary systems is not achievable, and percutaneous transhepatic biliary
decompression may be necessary to best palliate jaundice in these patients. For
this reason, ERCP for proximal CCA should be performed at centers of expertise for
both advanced endoscopy and interventional radiology and decisions made in a multi-
disciplinary fashion.
Similar to distal obstruction, several studies have examined the comparative effi-
cacy of plastic versus metal stents in the management of proximal, unresectable
CCA. The largest randomized trial to help answer this question was published in
2012 and included 108 patients with unresectable hilar CCA. These patients already
had a diagnosis, no prior biliary intervention, and received either a unilateral plastic
(7-French [Fr] or 10-Fr) or an uncovered metal stent. In their intention-to-treat analysis,
patients who received metal stents had a higher rate of achieving successful biliary
decompression (defined as 50% decrease in total bilirubin at 4 weeks) and increased
survival.46 In the same meta-analysis by Sawas and colleagues discussed previously,
in patients with proximal CCA, metal stents led to lower occlusion rates and incidence
of cholangitis, and higher rates of successful drainage, but did not affect 30-day mor-
tality or reintervention rates.43 These data suggest that metal stents may be more
beneficial than plastic stents in proximal CCA for some important clinical outcomes
but not necessarily long-term survival. Importantly, uncovered stents are usually
preferred in this setting, as covered stents can obstruct the contralateral tributaries
of intrahepatic ducts, which can significantly increase the risk of cholangitis.
A second question to ask in the setting of proximal CCA is whether bilateral drainage
offers more benefit than unilateral drainage. Several things need to be considered
when approaching this issue as an endoscopist. Firstly, studies using liver volumetrics
have shown that drainage of greater than 50% of the liver is required to achieve effec-
tive biliary decompression47; this takes into account the “quality” of the liver drained,
as drainage of sectors of the liver that are atrophied, infiltrated by tumor, or affected by
portal vein thrombosis does not lead to clinical benefit and likely increases the risk of
infectious complications (Fig. 4). These factors should all be considered when
deciding between unilateral versus bilateral decompression, and high-quality prepro-
cedural imaging is paramount in guiding this decision.
Studies looking at unilateral versus bilateral stenting, either with plastic or metal
stents, have been equivocal. A randomized trial in 2013 comparing plastic and metal
stents in proximal CCA, with a nearly equal number of patients who underwent unilat-
eral versus bilateral stenting, showed no difference in stent occlusion rates.48 In their
meta-analysis, Sawas and colleagues also showed no difference in clinical outcomes
between unilateral versus bilateral stenting.43 A more recent randomized trial looking
at unilateral versus bilateral metal stents did show better stent patency and less need
for reintervention in the bilateral stent group but no difference in survival.49
In some patients, ERCP fails to address biliary obstruction; this could be due to a
wide variety of reasons, including failed biliary cannulation, surgically altered anatomy,
or inability to access desired obstructed segments retrograde. Percutaneous transhe-
patic biliary drain placement is the most commonly used management alternative in
this setting. However, EUS-guided biliary drainage (EUS-BD) is an emerging endo-
scopic alternative whereby decompression can be achieved in a transduodenal (for
 Management of Cholangiocarcinoma 529

Fig. 4. Contrast-enhanced CT imaging in a patient with hilar CCA. The patient has left-sided
biliary dilatation, but the left lobe is atrophic. In such a scenario, left-sided biliary interven-
tion may not be of clinical benefit.

distal obstruction) or transgastric (for proximal obstruction, targeting left intrahepatic

ducts) fashion. EUS-BD has been shown to be effective, but associated with signifi-
cant morbidity, and should only be performed at centers of expertise.50
Novel intraductal ablative techniques have also been studied in the setting of unre-
sectable proximal CCA. Photodynamic therapy (PDT) is an ablative technique that de-
stroys tumor tissue through the interaction of locally applied light and an intravenously
administered photosensitizing agent that is preferentially absorbed by neoplastic tis-
sue. Modalities to apply PDT within the biliary tree have been developed, and its utility
in management of CCA has been examined in several studies. A meta-analysis of
these studies does suggest that the addition of PDT to standard endoscopic manage-
ment improves survival.51 The largest randomized trial (39 patients) actually prema-
turely halted their study due to the increased benefit of PDT immediately seen in
their population, with a median survival of 493 days in the PDT group versus
98 days in the group receiving standard of care.52 PDT is expensive, often not covered
by insurance, and requires patients to avoid sunlight for prolonged periods of time.
Radiofrequency ablation (RFA) is another ablative technique that is becoming a
more popular alternative to PDT, which uses heat energy to induce tissue necrosis.
RFA probes that can be advanced through the working channel of a duodenoscope
have been developed, and consequently, the utility of RFA in management of unre-
sectable extrahepatic CCA has been examined. The largest randomized trial con-
sisted of 96 patients and compared 8.5-Fr stent placement with and without RFA.
The study did show significantly improved stent patency and overall mean survival
in the RFA group, without an increase in adverse events.53 Importantly, patients
with more complex stenoses (Bismuth III or IV) were excluded from this study, ques-
tioning whether RFA would have shown any benefit if a metal stent was used. Overall,
for both PDT and RFA, more data are needed to determine their true cost-
effectiveness, as they are relatively expensive technologies and not widely available.

Our Practice
For patients presenting with suspected biliary obstruction from distal CCA, we usually
place a covered metal or plastic stent at initial ERCP while awaiting the results of
530 Das et al

Fig. 5. Cholangiogram image of a patient with hilar CCA, showing bilateral biliary dilata-
tion. A guidewire and balloon are in place in the left intrahepatic duct. Access into the
dilated right intrahepatic system is later achieved.

sampling and plan of management. Once a diagnosis of CCA has been confirmed and
a patient is deemed unresectable, in patients who started with a plastic stent, we place
uncovered stents due to the added expense of covered metal stents and lack of data
supporting their use over their uncovered counterparts.
In the case of more proximal disease, we use MRCP and dynamic cross-sectional
imaging to help determine which liver sectors are worth draining and the utility of uni-
lateral versus bilateral decompression. As in distal disease, we place plastics stents at
index ERCP while awaiting the results of biliary sampling and plan of management
(Figs. 5 and 6). We generally exchange to plastic stents during subsequent ERCPs

Fig. 6. Cholangiogram image of the same patient from Fig. 5, after bilateral 10-Fr plastic
stent placement into the systems that were accessed and opacified.
 Management of Cholangiocarcinoma 531

Fig. 7. Cholangiogram image of a patient with hilar CCA, showing bilateral biliary dilata-
tion and access into both opacified systems. This patient had recurrent cholangitis with
bilateral plastic stents, and this procedure was performed with the intent of exchanging
to bilateral uncovered metal stents.

mainly because of their reduced expense and longer survival in these patients as
compared with patients with pancreatic cancer with obstructive jaundice. Subsequent
uncovered metal stent-–related complications can be challenging to manage endo-
scopically and is another important consideration.
The use of uncovered metal versus plastic stents in patients in whom bilateral stent-
ing is being contemplated is determined on a case-by-case basis, considering access
to anatomic segments and prognosis. Guidewire access without contrast injection,
and subsequent anterograde contrast injection, is useful to fulfill the “drain what you
fill” axiom and minimize infectious complications (Figs. 7 and 8). Preprocedural and
postprocedural antibiotics are used for all cases of proximal CCA. Adjunct endoscopic
modalities, such as RFA and PDT, are not part of our standard practice, but we have
been using RFA in selected patients with increasing frequency.

Fig. 8. Cholangiogram image of the same patient from Fig. 7, after successful placement of
bilateral uncovered metal stents.
532 Das et al

SUMMARY

Among gastrointestinal malignancies, CCA is a relatively rare condition, which, in the

absence of resection, has a poor prognosis. Obtaining a tissue diagnosis of malig-
nancy can be challenging in CCA due to the poor sensitivity of standard ERCP sam-
pling techniques. More novel diagnostic tools, particularly DNA analysis of biliary
tissue with NGS, has greatly improved our ability to diagnose CCA and differentiate
between benign and malignant biliary disease. ERCP with placement of plastic or
metal biliary stents remains the mainstay of managing biliary obstruction related to
CCA, although evolving intra-ductal ablative platforms may significantly improve the
capability of ERCP to palliate this disease.

CLINICS CARE POINTS

 CCA is a rare malignancy with a poor prognosis in patients who are not candidates for
definitive resection. Strong risk factors for CCA include primary sclerosing cholangitis,
cystic diseases of the biliary tree, and chronic intrahepatic stone disease, among others.
 Dynamic contrasted cross-sectional imaging is a key part of the evaluation in CCA, especially
in patients with intrahepatic disease, where differentiation from other hepatic lesions/
malignancies is imperative.
 For extrahepatic CCA, standard sampling techniques have a high specificity but are fraught
by poor sensitivity that often leads to repeat procedural evaluation. DNA analysis of biliary
tissue with NGS significantly improves on the sensitivity of ERCP sampling, without sacrificing
specificity nor adding technical complexity to ERCP.
 In endoscopic management of CCA, metal stents may offer more durability and less need for
reintervention as compared with plastic stents in both distal and proximal extrahepatic CCA
but do not necessarily affect long-term outcome. Whether to pursue unilateral or bilateral
drainage should be determined on a case-by-case basis, using preprocedural imaging as a
guide.

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P a n c re a t i c C y s t i c N e o p l a s m s
a, b c
Sahin Coban, MD *, Omer Basar, MD , William R. Brugge, MD

KEYWORDS
 Pancreatic cysts  Neoplasms  Diagnostic modalities  Treatment

KEY POINTS
 Pancreatic cystic neoplasms continue to be a diagnostic and management dilemma to cli-
nicians and may require a multidisciplinary approach.
 Differentiating premalignant and malignant cysts from nonmalignant ones remains
challenging.
 Emerging diagnostic tools, including the needle biopsy with microforceps and needle-
based confocal laser endomicroscopy, are of exciting potential along with cyst fluid
analysis.
 Minimally invasive surgical approaches and newly developed endoscopic ultrasound-
guided ablation techniques are promising as treatment options.

INTRODUCTION

A cystic lesion of the pancreas can be caused by various conditions, including cystic
neoplasm, a non-neoplastic cyst, or a solid tumor with cystic degeneration. Histolog-
ically, non-neoplastic pancreatic cysts are mainly categorized as nonepithelial and
epithelial cysts. Nonepithelial cysts include pancreatic pseudocysts (the most com-
mon) and infection-related cysts. Epithelial cysts include retention cysts (the most
common), mucinous nonneoplastic cysts, squamoid cysts, lymphoepithelial cysts,
enterogenous cysts, endometrial cysts, and para-ampullary duodenal wall cysts.1,2
Pancreatic cystic neoplasms (PCN), they are a heterogeneous group of pancreatic
cysts mainly categorized as mucinous cystic lesions and nonmucinous cystic lesions,
according to the epithelial lining of the cyst. Mucinous cystic lesions include intraduc-
tal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs).
Both these lesions produce mucin. Therefore, they are called either mucinous neo-
plasms or mucin-producing neoplasms and have similar cyst fluid features that can
transform into pancreatic adenocarcinoma. Nonmucinous neoplastic cystic lesions
consist of serous cystic neoplasms (SCNs) and other rare cystic lesions, including

a
Department of Gastroenterology, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge,
MA 02138, USA; b Department of Gastroenterology, The University of Missouri, Columbia, MO
65211, USA; c Department of Gastroenterology, Harvard Medical School, Mount Auburn Hos-
pital, 330 Mt Auburn St, Cambridge, MA 02138, USA
* Corresponding author. 330 Mt Auburn St, Cambridge, MA 02138, USA
E-mail addresses: [email protected]; [email protected]

Gastroenterol Clin N Am 51 (2022) 537–559

https://doi.org/10.1016/j.gtc.2022.06.008 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
538 Coban et al

solid pseudopapillary neoplasms (SPNs) and cystic pancreatic neuroendocrine tu-

mors (cPNETs).3 These cystic neoplasms have various clinical, pathological, and
radiological features and are mainly detected incidentally (Table 1).
Increasing awareness and widespread use of high-quality cross-sectional imaging
and the trend for healthy individuals to undergo preventive health check-ups (including
imaging) have increased PCN detection. PCN prevalence varies among studies,
depending on the type of imaging used. Whereas abdominal ultrasonography only
detected PCN in 0.21% of participants,4 they are identified in up to 20% of MRI5
and 3% of computed tomography (CT) scans. Indeed, MRI with cholangiopancreatog-
raphy (MRCP) revealed PCN in up to 49.1% of scanned individuals.6 Similarly, in au-
topsy studies, PCNs are detected in up to 50% of patients4,7
The presence of PCN strongly correlates with increasing age, but there is no differ-
ence between genders.6 Additionally, diabetes mellitus and chronic pancreatitis are
risk factors associated with the development of IPMNs.8,9
The identification of a pancreatic cyst causes anxiety in both patients and physi-
cians due to its malignant potential. Thus, further medical evaluation usually is needed
for more clarification of the cysts’ nature. The risk of malignancy of incidental pancre-
atic cysts varies among studies. A retrospective study of Veterans Administration pa-
tients with pancreatic cysts reported a hazard ratio of 19.64 for developing pancreatic
cancer.10 A Japanese study demonstrated that patients with pancreatic cysts have an
observed incidence of pancreatic cancer 22.5 times higher than that of the expected
mortality from pancreatic cancer in the general population (95% CI, 11.0–45.3).11
However, another study of incidental pancreatic cysts stated a lower risk of malig-
nancy for pancreatic cancer with a hazard ratio of 3.0.12 The 2015 American Gastro-
enterological Association (AGA) technical review of incidental asymptomatic
neoplastic pancreatic cysts estimated an incident risk of malignancy at 0.24% per
year with a prevalent malignant risk of 0.25% at the time the cyst is detected.13 These
data justify the anxiety of patients and physicians that no matter how asymptomatic a
pancreatic cyst is at initial presentation, either it can be malignant at the time of diag-
nosis or it has the potential of turning into cancer.
More than two-thirds of PCN are diagnosed incidentally and are more frequently
diagnosed at smaller sizes in the last decades. The most common pathological diag-
nosis has been IPMN, which has malignant potential in resected PCN series.14,15
Therefore, differentiation between PCN subtypes is crucial since their malignancy po-
tential varies. Whereas SCNs are mostly benign and do not need surveillance, other
types of cystic lesions such as main duct IPMN (MD-IPMN), side-branch IPMN (SB-
IPMN), MCN, SPN, and cPNET, are considered premalignant and require either a
curable treatment or surveillance.16,17 The risk of advanced neoplasia (high-grade
dysplasia [HGD] or invasive cancer) in IPMN is increased predominantly by main
duct involvement, reported in up to 100%, of resected specimens.8,17–19 Additionally,
individuals with IPMN are at increased risk of developing conventional pancreatic
ductal adenocarcinoma.20 Advanced neoplasia has also been reported in up to
39% of patients in resected MCN,21,22 up to 30% of those in resected side-branch
IPMN specimens,23,24 up to 15% of those with resected SPN,25 and 10% of those
with resected cPNET.26

Clinical Presentation
Most PCNs are detected incidentally during the imaging workup for an unrelated med-
ical situation. Namely, they are mostly asymptomatic in terms of typical pancreatic
symptoms such as jaundice, pancreatitis, or new-onset diabetes mellitus. However,
 Table 1
General features of cystic neoplasms of the pancreas

Features MD/IPMN SB/IPMN MCN SCN SPN cPNET

Median age at 5th to 7th decade 5th to 7th decade 5th to 7th decade 5th to 7th decade 2nd to 3rd decade 5th to 6th decade
diagnosis
Gender M5F M5F F F F M5F
distribution
Localization Head Entire pancreas Body and tail Entire pancreas Body and tail Entire pancreas
Morphology Unilocular, dilated Multilocular, Unilocular Microcystic Mixed solid and Associated mass
MPD septated, normal cystic
MPD
Communication Yes No No No No No
with the MPD
Solitary/ Solitary or Solitary or Solitary Solitary Solitary Solitary
Multifocal multifocal multifocal
Clinical Pancreatitis, Pancreatitis, Abdominal pain, Abdominal pain, Abdominal pain, Abdominal pain,
presentation jaundice, exocrine jaundice, malignancy- mass effect mass effect mass effect
insufficiency, malignancy- related
malignancy- related
related
Typical imaging Dilated MPD or Dilated side Unilocular, Microcystic Solid and cystic Solid and cystic

Pancreatic Cystic Neoplasms

features dilated MPD with branches macrocystic (honeycomb mass mass,
dilated side appearance) hypervascularity
branches
Risk of High High High Low Low Low
malignancy
Fluid analysis High CEA, high High CEA, high High CEA, variable Low CEA, low Low CEA, low Low CEA, low
amylase, high amylase, high amylase, low amylase/lipase, amylase/lipase, amylase/lipase,
viscosity viscosity viscosity low viscosity low viscosity low viscosity
Common KRAS, GNAS KRAS, GNAS KRAS vHL Variable Variable
molecular
markers in
cyst fluid

Abbreviations: MD/IPMN, main duct/intraductal papillary mucinous neoplasm; SB/IPMN, side-branch/intraductal papillary mucinous neoplasm; MCN, mucinous

539
cystic neoplasm; SCN, serous cystic neoplasm; SPN, solid-pseudopapillary neoplasm; cPNET, cystic pancreatic neuroendocrine tumor.
540 Coban et al

MCNs can be symptomatic in up to 10% of cases.27 If they are large, symptoms can
be caused by the mass effect of these neoplasms.
In most cases, patients with IPMN are asymptomatic. Nonetheless, both MD-IPMNs
and SB-IPMNs can cause mild and often recurrent flares of acute pancreatitis due to
transient mucinous ductal obstruction in 7%–34.6% of cases.28,29 Progressive inflam-
matory changes and development of atrophy and fibrosis in the pancreas, secondary
to main pancreatic duct (MPD) obstruction, can also result in permanent structural
damage, leading to endocrine and exocrine pancreatic insufficiency. In addition, if
there is obstructive jaundice in a patient with IPMN, it indicates that the lesion is in
the pancreatic head and may suggest the features of high-risk malignant lesions,
including mass size of >3 cm, enhancing solid component, and MPD size of
10 mm.30
cPNETs are most often detected as an incidental finding on imaging. A vast majority
of cPNETs are nonfunctioning, whereas active neuroendocrine tumors hypersecrete
single or multiple hormones and can present with symptoms such as tachycardia,
flushing, or lightheadedness.31 Patients with ductal adenocarcinoma with a cystic
component—despite its rarity—can present with abdominal pain or discomfort,
weight loss, jaundice, or recurrent pancreatitis.32

Intraductal Papillary Mucinous Neoplasms

IPMNs may occur at any age; however, the mean age at diagnosis is 65 years, and it is
seen equally in both sexes. However, IPMNs can arise from the main duct or side
branches only, or a combination of both, known as mixed IPMN (Fig. 1). They are char-
acteristically lined with intraductal papillary mucin-producing neoplastic epithelium
and have different levels of malignancy potential.
MD-IPMN has the highest malignant potential and is characterized by diffuse or
segmental dilatation of the MPD due to a mucus-producing cystic tumor within the
duct. The most common IPMN is the side-branch IPMN. Most SB-IPMNs do not prog-
ress to pancreatic cancer.33 Multifocal SB-IPMNs can occur in up to 40% of cases but
there is no evidence that the risk of malignant transformation is higher in these cysts.34
SB-IPMNs are classically thin-walled cysts without calcification, and there is usually a
connection between the cyst and the MPD.
Although the localization of cysts is not helpful in the differentiation of PCNs, being
multifocal and communicating with the MPD is suggestive of SB-IPMNs. Alterna-
tively, most MCNs are solitary. Both main-duct and side-branch IPMNs may lead
to acute pancreatitis, caused by occlusion of the pancreatic duct orifice by thick
mucin. In addition, patients may present with abdominal pain, malaise, jaundice,
or weight loss. However, most patients with IPMNs are free of symptoms and diag-
nosed incidentally.
High-risk features of malignant IPMNs include having an enhancing nodule or a solid
component, MPD dilation of >1 cm, jaundice, and cytology with advanced neoplasia
(HGD or cancer), which are associated with a lower 5-year survival rate compared to
those who do not have these high-risk features.35
Histologically, IPMNs are classified into four subtypes: gastric foveolar (predomi-
nant in SB-IPMNs), intestinal (predominant in MD-IPMNs), pancreaticobiliary, and
oncocytic. According to histological studies, this categorization is highly efficient in
predicting the biological behavior of IPMNs. The gastric foveolar subtype is more
commonly found in SB-IPMN and mixed type IPMN, and exhibits the best prognosis.
In contrast, the intestinal subtype tends to occur in MD-IPMNs and exhibits a worse
prognosis.36
 Pancreatic Cystic Neoplasms
Fig. 1. An illustration of PCNs along with various examples of imaging. (A) Axial view of CT scan of a 6 cm multicystic serous cystic adenoma (with cen-
tral (calcification). (B) Axial view of MRI of a 6 cm multicystic serous cystic adenoma (same patient). (C) Endoscopic view of the ampulla of Vater with
leaking mucus indicative of an MD-IPMN (fish-mouth appearance). (D) ERCP view of an MD-IPMN (same patient). (E) Axial view of CT scan of a large
pseudocyst with debris. (F) Axial view of CT scan of an MCN. (G) Axial view of MRI of an MCN (same patient). (H) EUS view of a serous SPN.

541
542 Coban et al

Mucinous Cystic Neoplasms

MCNs occur almost entirely in middle-age women. They are characterized by the
presence of ovarian-like stroma, explaining why they occur predominantly in women.
The term “mother cysts” is generally applied to them. The pathognomonic ovarian-like
stroma, which surrounds the cyst’s inner epithelial layer, helps to differentiate MCNs
from IPMNs.
On imaging, MCNs can be seen as unilocular cysts located in the body or tail of the
pancreas in over 97% of cases (see Fig. 1E, F).37 Unlike SB-IPMNs, there is typically
no communication with the MPD which is of normal caliber.
MCNs have malignant potential; however, the risk is lower when compared to IPMNs.
Risk factors for malignancy include size >6 cm, enhancing nodule, thick irregular wall,
and peripheral calcifications, which are found in approximately 25% of MCNs.13
A review of 90 resected MCNs reported that only 10% of the lesions contained
advanced neoplasia.21 In this study and in a review covering 344 MCNs, there were
no cases of advanced neoplasia in MCNs of <3 cm in diameter.21,38 Therefore, there
is a conflict regarding whether MCNs should be surgically resected or followed by im-
aging. There is an agreement on immediate resection of MCNs, in patients with symp-
toms (such as pancreatitis), and in patients with concerning endoscopic ultrasound
(EUS) features such as solid component or positive cytology for HGD or adenocarci-
noma. However, there is still a conflict between patients without these concerning fea-
tures and MCNs less than 3 cm in diameter.

Serous cystic neoplasms

SCNs are nonmucinous, predominantly benign cystic neoplasms (serous
cystadenomas-SCAs). SCAs occur more commonly in women (75%), who are typi-
cally in their 60s. They are therefore sometimes called “grandmother cysts.”39 Malig-
nant cases (serous cystadenocarcinoma) are extremely rare. A recent multicenter
study of over 2500 SCAs reported that the risk of serous cystadenocarcinoma was
extremely low at 0.1%.40 The vast majority of SCAs are asymptomatic, mostly
detected incidentally. Histologically, the cysts are lined by a single, uniform layer of
glycogen-containing cuboidal epithelial cells with round nuclei and abundant clear
cytoplasm. The more common type is the microcystic variant, in which numerous mul-
tiple cysts are grouped and separated by thin septations. It makes the classic imaging
features of a honeycomb or sponge-like appearance. A central scar is also a charac-
teristic imaging feature caused by calcifications but is present in less than 30% of
SCAs (see Fig. 1A, B). Calcification occurs at the center of SCNs, whereas it is periph-
eral in MCNs. The oligo- or macrocystic variant is the less common type and is difficult
to differentiate from an SB-IPMN or MCN.
SCNs are slow-growing cysts. Although related symptoms are rare, SCAs can
cause symptoms due to their size. The prognosis of SCNs is excellent and given their
benign nature, they should be followed by surveillance imaging; however, most
asymptomatic SCAs do not require surveillance. Surgical resection is not recommen-
ded unless there is uncertainty about malignancy, rapid growth, or significant symp-
toms. The intervals of surveillance imaging remain unclear.

Solid Pseudopapillary Neoplasms

Solid SPNs are rare heterogeneous lesions, predominant in women, with a 10:1 female-
to-male ratio. They are most frequently present in women in their 20s but have a wide
age range with cases described in children and adults over 50. They can occur in any
part of the pancreas and have malignant potential. Histologically, they are characterized
by pseudopapillary and cystic spaces containing hemorrhage and cholesterol clefts in
 Pancreatic Cystic Neoplasms 543

myxoid stroma alternating with solid tissue. Therefore, these lesions appear cystic and
solid (see Fig. 1H). A systematic review of 484 studies including 2744 patients with SPN
showed that the most common presentations were abdominal pain (63%) or asymp-
tomatic incidental finding (38%). Smaller tumors tend to be solid, whereas larger
ones have a mixed solid and cystic appearance. Typically, SPNs are benign or low-
grade malignant tumors. Advanced neoplasia (HGD or invasive carcinoma) is found in
approximately 10% of SPNs. In contrast to pancreatic adenocarcinoma, outcomes of
patients with PCNs are excellent with a 5-year disease-free survival of over 98%.41

Cystic Pancreatic Neuroendocrine Tumors

cPNETs are rare variants of pancreatic neuroendocrine tumors that are usually
nonfunctioning and often diagnosed incidentally. Morphologically, they can be solid,
cystic, or mixed with a variable malignant potential. They can occur sporadically or
in individuals with multiple endocrine neoplasia type 1, Von Hippel Lindau (VHL) syn-
drome, and neurofibromatosis type 1. Sexes are equally affected with peak presenta-
tion in the 60s. Incidence increases with age. Imaging reveals a well-circumscribed
multi- or unilocular cyst surrounded by a thick fibrous capsule. EUS-guided fine needle
aspiration (FNA) is often required to reach an accurate diagnosis. Surgical resection is
the optimal treatment modality for clinically active cPNETs; however, asymptomatic
cPNETs of <1 cm are managed with surveillance. Patients with resected cPNETs
have an excellent prognosis.42,43

Diagnostic Approaches to PCNs

Cystic lesions of the pancreas are more commonly diagnosed because of the wide-
spread use of cross-sectional imaging. Incidentally detected pancreatic cystic lesions
are challenging to physicians, and typically require a multidisciplinary approach. The
most crucial concern is differentiating neoplastic lesions from non-neoplastic ones.
The distinction between the different subtypes is also important since the manage-
ment of PCNs varies according to their subtype.
Assessment of a patient with an incidental pancreatic cyst should begin with a
detailed history including any description of acute or chronic pancreatitis, and a family
history of pancreatic cancer or hereditary cancer syndromes. For newly diagnosed
PCNs, imaging may include a pancreatic protocol CT or gadolinium-enhanced MRI
with MRCP.16,17,44 EUS is kept as a next step if there are suspicious features of
concern for PCNs such as nodules, dilatation of the pancreatic duct, or a thickened
enhancing wall. In addition, EUS can be used to obtain cyst fluid for cytology and
biochemical analysis to get a more precise diagnosis.
MRI with MRCP is usually preferred over CT as a surveillance modality for several
reasons. Firstly, MRI/MRCP is more sensitive than CT in detecting communication be-
tween a lesion and the MPD. In addition, MRI/MRCP is an excellent imaging modality
for outlining the gross appearance of PCNs including the presence of enhancing mural
nodules, any solid component within a cystic lesion, or internal septations.45 Sec-
ondly, MRI does not expose patients to the ionizing radiation of CT scanning with
its increased risk for malignancy.46 If MRI cannot be performed, a pancreatic protocol
CT with contrast-enhanced images should be obtained. The imaging findings will help
define the next steps in management and these may include EUS for further diagnostic
assessment, surgical resection, or the initiation of a surveillance program.47
On imaging, PCNs can be identified by some of their unique features. MD-IPMN can
be recognized by marked dilation of the MPD. In some cases, a bulging ampulla with
leaking thick mucin from the orifice can be observed during endoscopic examination
(fish-mouth appearance), which is practically pathognomonic for MD-IPMN (see
544 Coban et al

Fig. 1C). SB-IPMN can be predicted by the dilation of side branches of the MPD, or a
“grape-shaped” cystic lesion that communicates with the MPD. Mixed-type IPMN
may show features of both types of IPMNs. However, IPMNs appear in the head of
the pancreas in up to 70% of the patients, but 20% occur in the body or tail. Alterna-
tively, 5%–10% of IPMNs are multifocal.
MCNs usually arise from the body or tail of the pancreas, mainly being unilocular or
septated macrocystic lesions.48–50
Morphologically, SCN can appear in microcystic, macrocystic (or oligocystic), or
mixed microcystic and macrocystic. A central calcification or scar can occur in SCN
(see Fig. 1A, B). Macrocystic or oligocystic SCNs are composed of more extensive
and fewer cysts that can be unilocular; however, this variant is not common. Distin-
guishing a macrocystic SCN from an MCN or SB-IPMN can be difficult because of
the similarity in shape. Also, differentiating a solid SCN can be difficult from an SPN
or cPNET, which are most commonly identified as a mixed appearance lesion with
cystic and solid components, but they can also appear as a cystic mass or a calcified
cystic mass in the pancreas.51,52
In recent years, secretin-enhanced MRCP has been developed to improve the visu-
alization of a connection between a pancreatic cyst and the pancreatic duct.53
Secretin is a polypeptide hormone that stimulates the release of pancreatic juice
from acinar cells into the pancreatic ducts, leading to enlargement and visibility of
the MPD.54 Several studies have shown that secretin-enhanced MRCP provides bet-
ter visualization of the MPD than conventional MRCP.53,55,56

Endoscopic Ultrasound
EUS is an important diagnostic modality in the evaluation of pancreatic cystic lesions
as MRI, MRCP, and CT have less than 50% accuracy for differentiating PCNs.47
Following radiologic imaging, a pancreatic cyst should be evaluated by EUS if the
cyst is indeterminate, has high-risk features, or when the results are likely to alter man-
agement. EUS imaging provides visualization of borders, wall thickness, septations,
masses, mural nodules, and papillary projections and demonstrates communication
with the MPD. However, EUS alone also has limitations similar to CT and MRI. Brugge
and colleagues57,58 reported that EUS imaging alone showed only 51% diagnostic ac-
curacy for differentiating mucinous from nonmucinous cysts. However, the addition of
FNA, which allows for cytological, biochemical, and DNA analysis, can further help in
diagnosis and differentiation.57,59
Societal guidelines published in recent years provide guidance as to when EUS
evaluation is indicated in the management of PCNs (Box 1). It is reasonable to perform
EUS-FNA in a PCN with clinical and imaging features that are indeterminate, or in the
setting of worrisome features. However, EUS-FNA may not always be feasible in PCNs
if they are small in size or because of their location. Generally, EUS can be recommen-
ded in patients with worrisome features such as cyst of 30 mm, thickened/enhanced
cyst wall, MPD between 5 mm and 9 mm, nonenhancing mural nodule, and abrupt
change in MPD caliber with atrophy.
Currently, contrast-enhanced EUS seems the most accurate diagnostic modality for
differentiating mural nodules from mucin clots or debris, producing a low false-
negative rate compared to other imaging modalities.60–62 Contrast-enhanced har-
monic EUS is a unique imaging technique in which particular intravenous contrast
agents are used to highlight microvasculature differences between normal and
abnormal tissue. Contrast-enhanced EUS can identify vascularity by detecting signals
from microbubbles in vessels produced by intravenously administered contrast
agents. In addition, contrast-enhanced EUS seems to help diagnose not only mural
 Pancreatic Cystic Neoplasms 545

Box 1
Indications of EUS in diagnosing PCN
2015 AGA guideline44 At least two of the following worrisome features:
 Cyst size s30 mm
 Dilated MPD
 Presence of a solid component (mural nodule)
2017 IAP guideline17 If any of the following present:
 Cyst size 30 mm
 Growth rate 5 mm/2 years
 MPD dilatation between 5 and 9 mm
 Acute pancreatitis due to cyst
 Enhancing mural nodule (<5 mm)
 Increased levels of serum CA19–9
 Abrupt change in caliber of MPD with distal pancreatic
atrophy
 Thickened/enhancing cyst walls
 Lymphadenopathy
2018 ACG guideline47 If any of the following present:
 IPMN or MCN s30 mm
 MPD s5 mm
 Change in MPD caliber with marked atrophy
 Increase in cyst size of s3 mm/year during surveillance
 Jaundice due to cyst
 Acute pancreatitis due to cyst
 Presence of solid component (mural nodule)
2018 European guideline16  Clinical or radiological worrisome features for
malignancy—EUS can be alternated or performed in
conjunction with MRI during surveillance
Abbreviations: ACG, American College of Gastroenterology; AGA, American Gastroenterolog-
ical Association; CA19-9, cancer antigen 19-9; European, European Study Group on Cystic Tu-
mors of the Pancreas; EUS, endoscopic ultrasound; FNA, fine needle aspiration; IAP,
International Association of Pancreatology; IPMN, intraductal papillary mucinous neoplasm;
MPD, main pancreatic duct; PCN, pancreatic cystic neoplasm.

nodules but also differentiate nodules with advanced neoplasia from nodules with low-
grade dysplasia (LGD).63 Recently, Marchegiani and colleagues64 published a meta-
analysis including 70 studies with 2297 resected IPMNs and reported a positive pre-
dictive value of 62% for the presence of advanced neoplasia in the histology of an
enhancing mural nodule on contrast-enhanced EUS.

Cyst Fluid Analysis

Researchers have focused on searching for the ideal cyst fluid markers to distinguish
mucinous from nonmucinous cysts and to predict the malignant progression of cysts.
EUS-FNA provides for cytopathological examination, identification of cyst fluid,
biochemical analyses, and analysis of molecular biomarkers.65 EUS-FNA is a safe pro-
cedure with a low risk of complications estimated to be 2%–3%, including abdominal
pain, infection, intracystic bleeding, and pancreatitis.16,66 In malignant lesions, needle
tract seeding is extremely rare through EUS-FNA; thus, the risk of peritoneal metasta-
ses is not increased, and it can be ignored.67
The cyst fluid is viscous in mucin-producing neoplasms but nonviscous in SCNs.
Macroscopically, the string sign is the most informative indicator in differentiating be-
tween mucinous and nonmucinous PCNs as mucinous PCNs typically contain highly
viscous cyst fluid.68 For the string sign, a drop of aspirated cyst fluid is placed between
546 Coban et al

the thumb and index finger and stretched. A string length measuring at least 3.5–
10 mm indicates a mucinous PCN, with a pooled sensitivity of 58% and specificity
of 95%.69 The string sign has limitations due to the subjective nature of the interpre-
tation of the test.
Cyst fluid obtained during EUS-FNA is often acellular. Therefore, cytopathological
examination typically has a low diagnostic yield with less than 50% sensitivity for
mucinous lesions. However, if positive, it is helpful for a specific diagnosis.44 In a
meta-analysis of cytopathological cyst fluid analyses, Thornton and colleagues70 re-
ported a sensitivity of 54% and specificity of 93% for differentiating between
mucinous and nonmucinous PCNs. Cyst fluid cytology is highly specific for malig-
nancy with at best 60% sensitivity for malignant lesions.44 Further, cyst fluid cytology
appears more useful for the diagnosis of SPEN and cPNETs with 70%–89% and 70%–
81% accuracy, respectively.71,72
For mucinous or malignant cysts, a 29% improvement in diagnostic yield has been
reported with cyst wall cytology using a technique of puncturing the wall of the cyst
and repeatedly passing the needle back and forth through the collapsed cyst wall.73
Phan and colleagues74 looked at 47 patients who underwent EUS-FNB (core biopsy)
of the cyst wall following complete aspiration of the cyst. This study revealed a higher
diagnostic yield with EUS-FNB compared to cyst fluid cytology. Therefore, cyst wall
cytology might be preferred over cyst fluid alone in the diagnosis of PCNs.
Recently, through-the-needle forceps have been introduced for EUS-guided tissue
acquisition. These microforceps have an outer diameter of < 1 mm and can be
advanced through a standard 19-gauge EUS needle to obtain samples of the cyst
wall and/or mural nodules for histological evaluation (Fig. 2). In a multicenter study

Fig. 2. New diagnostic approaches in PCNs. (A) A microbiopsy forceps wide open outside of
a cyst. (B) EUS view showing a microbiopsy forceps used for tissue acquisition. (C) Confocal
endomicroscopy view showing superficial network in an SCA. (D) Confocal endomicroscopy
view showing papillary structures in an IPMN. (E) Confocal endomicroscopy view showing
epithelial borders in an MCN.
 Pancreatic Cystic Neoplasms 547

of 42 patients, Basar and colleagues75 reported that microforceps were significantly

superior to cytology alone for providing a specific cyst diagnosis. Recently, a system-
atic review of 9 studies with 463 patients undergoing EUS with microbiopsy forceps
reported a 68.6% diagnostic accuracy and a 10% complication rate, with intracystic
hemorrhage and mild acute pancreatitis reported more frequently.76 Currently, further
studies are needed to increase the experience with this sampling technique.
The quantification of tumor marker carcinoembryonic antigen (CEA) levels, which is
a glycoprotein found in the embryonic endodermal epithelium, is the most helpful
biomarker for differentiating between mucinous and nonmucinous PCN in biochemical
analyses of pancreatic cystic fluid.65 Whereas mucinous cysts are lined by endoderm-
derived columnar epithelial cells secreting CEA, nonmucinous cysts are lined by sim-
ple cuboidal epithelium, containing little or no CEA. However, CEA levels of >192 ng/
mL in cyst fluid favor a diagnosis of a mucinous cyst rather than that of an SCN. CEA
levels of <5 ng/mL are suggestive of an SCN.16,17,58,65 The presence of mucin on
cytology or a positive string sign with a high cyst fluid CEA level is nearly diagnostic
for a mucin-producing neoplasm.69
Another biomarker used in the evaluation of PCNs is the cyst fluid amylase level,
which is usually high in IPMNs and low in MCNs and SCNs. Although not specific,
high levels of amylase in cyst fluid strongly suggest a connection between the cyst
and the pancreatic ductal system (IPMN and pseudocysts).77,78 Pancreatic cyst fluid
glucose levels have also been studied as a potential biomarker for differentiating
mucinous from nonmucinous PCNs. Two studies have reported that cyst fluid glucose
levels have similar diagnostic accuracy when compared to cyst fluid CEA, amylase,
and cytological tests, with the added advantage that is rapid, inexpensive, and require
minimal cyst fluid.79,80 Again, further confirmatory evidence is needed in large, pro-
spective, multicenter trials.
DNA testing of pancreatic cyst fluid is also helpful to differentiate mucinous cysts
from nonmucinous ones. It also seems to help distinguish between mucinous pancre-
atic lesions sub-types (IPMN vs. MCN) and between premalignant lesions and
advanced neoplasia.81–83 Investigating mutated genes in cyst fluid (released into
pancreatic cyst fluid after cell death), also has a high potential in differentiating
mucinous cyst subtypes. The presence of cystic fluid KRAS and GNAS mutations is
highly sensitive for IPMN and specific for mucinous PCNs.82
KRAS mutations are frequently seen in MCN, and the prevalence of these mutations
is reported to be correlated with the severity of dysplasia. Singhi and colleagues82 re-
ported that KRAS mutations were detected in 13% of patients with LGD MCN and
100% in those with HGD MCN.
However, GNAS mutations are not detected in MCN; however, when present, it could
be useful to differentiate IPMN from MCN. VHL mutations or deletions are associated with
SCN.84,85 SMAD4, CDKN2A, TP53, PIK3CA, and PTEN mutations or deletions are also
related to advanced neoplasia in PCNs.83,86 Singhi and colleagues82 demonstrated in
their prospective study that the combination of KRAS or GNAS mutations and alterations
in TP53, PIK3CA, or PTEN had an 89% sensitivity and 100% specificity for advanced
pancreatic neoplasia. Nonetheless, further studies are still needed to integrate DNA-
based molecular testing in pancreatic cyst fluid into current management guidelines.

Other Diagnostic Modalities

Newly developed tools during EUS that may improve the diagnosis of pancreatic cysts
have been introduced in recent years, including needle-based confocal laser endomi-
croscopy (nCLE) and microforceps.87 Confocal laser endomicroscopy is a novel imag-
ing method providing in vivo histologic imaging. EUS-nCLE using a confocal probe
548 Coban et al

through a 19-gauge FNA needle provides real-time visualization of the microscopic

cellular features of the cyst wall (see Fig. 2). EUS-nCLE imaging is obtained after
the intravenous injection of fluorescein. Visualizing a superficial vascular network
pattern has over 90% sensitivity and 100% specificity for the diagnosis of SCA. Sensi-
tivity for mucinous cysts ranges from 59% to 100%, with finger-like papilla noted in
IPMN and epithelial bands are seen in MCN.88
Both nCLE and microbiopsy forceps are exciting tools capable of improving the
diagnosis of PCNs; however, further studies are necessary to understand their safety
profile and find the optimal place for these tools along with currently available cyst fluid
biomarkers.

Treatment
Surgery
Surgery should be considered when the cyst is malignant, has a high risk for malig-
nancy, or when symptomatic. Surgical resection is recommended for symptomatic
SCAs.16 In contrast, surgical resection should be considered for all MCN patients.
Similarly, surgical resection is suggested for MD-IPMN and mixed-type IPMNs due
to their higher malignant risk.17,89 As per guidelines, surgical resection indications
for MCNs and IPMNs are shown in Table 2. SPNs are considered for surgical resec-
tion due to their malignancy potential, favorable post-resection outcomes, and pres-
ence mainly in young women.16,41
A recent meta-analysis comparing the Fukuoka and AGA guidelines reported that
they both had similarly modest sensitivity (67% and 59%, respectively) and specificity
(64% and 77%, respectively) for identifying HGD and invasive cancer [61].
The AGA technical review covering asymptomatic cysts determined the following as
the most significant risk factors for malignancy in incidental pancreatic cysts: solid
component [odds ratio (OR) 7.7], cyst size of >3 cm (OR 3), and dilated MPD (OR
2.4).13 Studies have reported that the size of MPD correlates with varying malignant
potential. A study of 563 radiologically diagnosed and resected branch duct IPMNs
(BD-IPMNs) revealed that 18% of cysts of >3 cm had advanced neoplasia. In contrast,
no malignancy was detected in cysts of <2 cm, and no HGD was noted in lesions of
<1 cm.90 Larger cysts seem to be associated with the development of high-risk fea-
tures, including nodules and MPD dilation.91

EUS-guided ablation modalities

Current guidelines for managing MCNs and IPMNs recommend either long-term sur-
veillance, which is expensive or nontherapeutic or surgical resection which is associ-
ated with high morbidity. Moreover, surgery may not be an option for patients with
significant comorbidities. Therefore, EUS-guided cyst ablation was developed to
destroy the neoplastic epithelial lining of cysts in patients who decline surgery or
are not operative candidates. Cyst ablation can be performed by injecting ethanol
or antitumor agents such as paclitaxel; or by radiofrequency ablation (RFA). Pancre-
atic cysts can be resolved by EUS-guided ablation in 33% to 79% of cases and
improve quality of life by avoiding surgery.92 A propensity score matching analysis
comparing a EUS-guided ethanol ablation (EUS-EA) group (n 5 118) and a group
without an endoscopic intervention (or natural course of disease group, n 5 428)
revealed that the EUS-EA group had a significantly lower rate of surgical resection
when compared to the control group (4.8% vs. 26.2%) with a mean follow up of
over 6 years.93 Ideal cyst features for EUS-guided ablation include unilocular cysts
or oligolocular cysts with fewer than 3–7 locules (to ensure each locule is injected
properly), cyst size 2–6 cm, and no open communication with the MPD.92
 Pancreatic Cystic Neoplasms 549

Table 2
Indications for surgical resection of PCN by different guidelines

Cytology Imaging
2015 AGA guideline44 Positive for malignancy  Both a solid component and
dilated PD (MPD s5 mm
2017 IAP guideline17 Suspicious or positive  Obstructive jaundice with PCN
for malignancy in head of pancreas
 Enhanced mural nodule s5 mm
 MPD s10 mm
 MD-IPMN
2018 ACG guideline47 Positive for advanced  Mural nodule
neoplasia (HGD or  Concerning features on EUS
malignancy)  All MD-IPMNs
2018 European Suspicious or positive Absolute indications:
guideline16 for advanced neoplasia  Solid component
 Obstructive jaundice in head of
the pancreas (PCN related)
 Enhancing mural nodule >5 mm
 MPD s10 mm
 Symptoms due to PCN
Relative indications:
 PCN growth rate s5 mm/year
 Elevated CA-19–9 level (>37 U/mL)
 MPD 5–9.9 mm
 PCN size s40 mm
 New-onset diabetes mellitus
 Acute pancreatitis (due to IPMN)
 Enhancing mural nodule <5 mm

Abbreviations: ACG, American College of Gastroenterology; AGA, American Gastroenterological

Association; CA19-9, cancer antigen 19-9; European, European Study Group on Cystic Tumors of
the Pancreas; EUS, endoscopic ultrasound; FNA, fine needle aspiration; HGD, high-grade dysplasia;
IAP, International Association of Pancreatology; IPMN, intraductal papillary mucinous neoplasm;
MPD, main pancreatic duct; PCN, pancreatic cystic neoplasm.

Response to ablation is described by volume reduction in the cyst. Complete

response is defined as at least 95% reduction in volume, partial response as 75%
to 95%, and nonresponse as 0% to 74%.94
Paclitaxel, a quite viscous and hydrophobic chemotherapeutic agent, is theoreti-
cally capable of remaining in the cyst for a long time to exert its apoptotic effects along
the epithelial lining. A prospective study of 164 patients investigated the effect of cyst
ablation with alcohol and paclitaxel combined and reported complete resolution, par-
tial resolution, and persistent cyst rates in 72%, 20%, and 8% of patients, respec-
tively. Only 1.7% cyst recurrence was detected during the 6-year follow-up period
in the 114 patients who had complete cyst resolution after this combination therapy.93
Cyst size of <35 mm and absence of septa were predictors of complete response.95,96
Moreover, it has been demonstrated that in 72% of the cysts where the ethanol–
paclitaxel combination was applied, baseline DNA mutations were eliminated in the
post-ablation cyst fluid.97
The ethanol–paclitaxel combination therapy has replaced ethanol alone for cyst
ablation because of increased efficacy and decreased complications such as
pancreatitis, attributed to the ethanol.98 Therefore, other ablation regimens without
ethanol have been investigated. In a randomized trial of paclitaxel and gemcitabine
with and without ethanol, comparable complete ablation rates with no adverse
550 Coban et al

effects were observed in the ethanol-free group.99 Recently, in a long-term analysis

of 36 patients, Lester and colleagues100 showed that complete cyst resolution in
mucinous pancreatic cysts after EUS-guided chemoablation with paclitaxel and
gemcitabine is long-lasting, with 87% of complete responders at 12 months having
maintained resolution at their latest follow up. The application of EUS-guided cyst
ablation will be more common with the development of new delivery agents,
improved techniques, and standardized definitions of clinical success in future
studies.

Radiofrequency ablation
RFA is a safe and effective technique to treat cystic lesions. RFA induces direct cell
death via coagulative necrosis and hyperthermic energy. Currently, only a 19-gauge
EUS-guided RFA needle is available, and only a few studies have investigated the
role of EUS-RFA in treating PCNs.101,102
In a prospective study, Barthet and colleagues101 treated 16 BD-IPMNs and 1 MCN
using EUS-guided RFA. Complete resolution at 6 and 12 months was shown in 47%
and 64.7% of the 17 PCNs, respectively. This delayed response can be due to the
immunostimulatory effects of RFA. At the end of the 42 months of follow up, the au-
thors reported that there was still a significant response in 66.6% of the 15 patients

Fig. 3. Approach to an incidental pancreatic cyst. EUS, Endoscopic ultrasound; MRCP, Mag-
netic resonance cholangiopancreatography.
 Pancreatic Cystic Neoplasms 551

with no mural nodules.102 However, larger- and longer-term studies are required to
assess the efficacy and safety of EUS-RFA in PCNs.

Surveillance
Although newer diagnostic techniques have been developed, the management of
PCNs is still very challenging, and a constant source of debate among experts due
to the malignant potential of these cysts. A practical algorithm can be suggested as
a framework for approaching these lesions (Fig. 3). However, it is vital to decide
whether the patient needs further evaluation before proceeding with this management
algorithm. Is the cyst an asymptomatic or a benign lesion that needs no follow up? Or if
required, is the patient eligible for surgery? Several scoring indexes, including the
Charlson Comorbidity Index and the Adult Comorbidity Evaluation 27, have been
used to help with clinical decisions. High scores on the Charlson Comorbidity Index
(>7) are associated with shorter survival and a higher risk of dying from non-IPMN-
related causes.103,104 In another study that used the Adult Comorbidity Evaluation
27 scoring system, 793 patients with IPMNs were assessed. The study showed that
patients with higher scores were more likely to die from non-IPMN-related causes.105
These scoring systems, therefore, can help clinical decision-making, especially if sig-
nificant comorbidities are present.
The AGA 2015 guideline recommends stopping surveillance after 5 years of stabil-
ity in cysts’ condition; however, long-term studies of pancreatic cysts reveal that this
guideline may place some patients at risk. A retrospective study, in which 108 pa-
tients with SB-IPMN  1.5 cm were followed for more than 5 years, found there
was a low rate of malignant progression of 0.9%.106 Another study following 144
BD-IPMNs without worrisome or high-risk features for a median of 84 months
revealed that in 18%, worrisome or high-risk features developed beyond 5 years
of follow up.107 In line with those, in a cohort of 1036 BD-IPMNs without worrisome
features, after a median of 62 months, worrisome features and pancreatic cancer
were observed in 4% and 1% of cysts, respectively.108 Given these studies, surveil-
lance should not be stopped in all patients after 5 years. Further long-term studies

Table 3
Recommendations of the guidelines based on the PCN size detected incidentally (if no high-
risk or worrisome features)

PCN
Guidelines sizes Recommendations
2015 AGA guideline44 1–4 cm MRI in 1 year
2017 IAP guideline17 1–2 cm MRI or CT in 1 year
2–3 cm EUS in 3–6 months
>3 cm Alternating MRI with EUS in 3–6 months,
strongly consider surgery in young and
fit patients
2018 ACG guideline47 1–2 cm MRI in 1 year
2–3 cm MRI or EUS in 6–12 months
>3 cm MRI or EUS every 6–12 months (and refer to
the multidisciplinary task)
2018 European guideline16 1–4 cm MRI or EUS in 6 months (together with serum
CA-19–9 level and clinical evaluation)

Abbreviations: ACG, American College of Gastroenterology; AGA, American Gastroenterological

Association; CA19-9, cancer antigen 19-9; European, European Study Group on Cystic Tumors of
the Pancreas; EUS, endoscopic ultrasound; IAP, International Association of Pancreatology; PCN,
pancreatic cystic neoplasm.
552 Coban et al

are required to determine a subgroup of patients in whom follow up can be safely

discontinued.

SUMMARY

PCNs continue to be a diagnostic and management challenge to clinicians and may

require a multidisciplinary approach, including gastroenterology, radiology, surgery,
and pathology. Currently, early detection of high-risk lesions enables potentially cura-
tive surgical resection. Furthermore, early detection of lesions without worrisome fea-
tures can lead to appropriate surveillance. However, differentiating premalignant and
malignant cysts from nonmalignant ones remains a difficult task. Emerging diagnostic
tools, such as the needle biopsy with microforceps and nCLE, are of exciting potential
along with cyst fluid analysis. Although there is no single algorithm for PCN manage-
ment because of the lack of high-quality evidence, current guidelines provide recom-
mendations for the management of these lesions based on cumulative data (Table 3).
Ongoing prospective studies with a larger number of patients will be helpful to modify
these recommendations and future guidelines. Clinicians should discuss the manage-
ment of these patients with a multidisciplinary team with expertise in the diagnosis and
surgical treatment of PCNs, especially in the setting of indeterminate cysts or worri-
some high-risk features. Minimally invasive surgical approaches and newly developed
EUS-guided ablation techniques are promising, but their effectiveness needs further
validation in more extensive studies.

CLINICS CARE POINTS

 Endoscopic ultrasound remains the main diagnostic modality for further assessing PCNs since
imaging modalities have less than 50% accuracy for differentiating PCNs. Currently, contrast-
enhanced EUS seems the most accurate diagnostic modality for differentiating mucinous and
nonmucinous PCNs, producing a very low false-negative rate compared to other imaging
modalities.
 EUS-FNA helps differentiate mucinous from nonmucinous cysts when imaging is
indeterminate. However, EUS-FNA may not always be feasible if a pancreatic cyst is small
in size or because of its location.
 The guidelines are helpful on whom to select for EUS and EUS-FNA based on the presence of
specific risk features.
 EUS–FNA provides cyst fluid analysis including cytopathological examination, identification
of cyst fluid, biochemical analyses, and analysis of molecular biomarkers. Cyst fluid analysis
has been the ideal method for distinguishing a mucinous cyst from the nonmucinous one
and predicting the malignant progression of a cyst.
 Emerging additional diagnostic tools, including through the needle biopsy with
microforceps and needle-based confocal laser endomicroscopy, are of exciting potential
along with cyst fluid analysis.
 Minimally invasive surgical approaches and newly developed EUS-guided ablation
techniques are promising in the treatment of PCNs.

DISCLOSURE

The authors have nothing to disclose.

ACKNOWLEDGMENTS

The authors give special thanks to Mehmet Emre Coban for preparing the illustration
and figures.
 Pancreatic Cystic Neoplasms 553

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Fa milia l P an c re at i c C ance r
a a,b,c,d,
Helena Saba, MD , Michael Goggins, MD *

KEYWORDS
 Pancreatic cancer  Familial  Hereditary  Pancreas surveillance  Screening

KEY POINTS
 First-degree relatives of individuals with familial pancreatic cancer and individuals with a
deleterious germline mutation in one of the pancreatic cancer susceptibility genes are at
significantly increased risk of developing pancreatic cancer and can potentially benefit
from surveillance.
 Surveillance focuses on the early detection of pancreatic ductal adenocarcinoma and its
high-grade precursor lesions using endoscopic ultrasound examination and/or magnetic
resonance imaging/magnetic resonance cholangiopancreatography.
 Patients undergoing pancreas surveillance are more likely to be diagnosed with low-stage
resectable pancreatic cancers and to achieve long-term survival.
 Novel strategies are needed to better stratify pancreatic cancer risk. Emerging tests are
currently being evaluated, which could eventually improve the detection of high-grade
precancerous lesions and early-stage invasive pancreatic cancer.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all major cancer types
with most patients having advanced disease at diagnosis. Recent data from the
National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results
(SEER) registry reveal a 5-year survival rate of 3% for patients with metastatic pancre-
atic cancer, increasing to 14.4% for those with regional (node-positive) disease and
41.6% for those with localized disease confined to the pancreas.1 Pancreatic cancer
survival rates have increased significantly in the past decade, and the current 5-year

The authors have no disclosures to report.

a
Departments of Pathology, Johns Hopkins Medical Institutions, CRB2 351, 1550 Orleans
Street, Baltimore, MD 21231, USA; b Departments of Medicine, Johns Hopkins Medical In-
stitutions, CRB2 351, 1550 Orleans Street, Baltimore, MD 21231, USA; c Departments of
Oncology, Johns Hopkins Medical Institutions, CRB2 351, 1550 Orleans Street, Baltimore, MD
21231, USA; d Bloomberg School of Public Health, The Sol Goldman Pancreatic Cancer Research
Center, Johns Hopkins Medical Institutions, CRB2 351, 1550 Orleans Street, Baltimore, MD
21231, USA
* Corresponding author. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins
Medical Institutions, CRB2 351, 1550 Orleans Street, Baltimore, MD 21231.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 561–575

https://doi.org/10.1016/j.gtc.2022.06.006 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
562 Saba & Goggins

survival is 11%. Experts predict that by 2030 PDAC will be the second-leading cause
of cancer death in the United States.2
Progress is needed, not only in the treatment of this disease but also in the diagnosis
and pancreatic risk assessment that would enable more individuals to pursue early
detection. Despite the high mortality associated with pancreatic cancer, screening
the general population for PDAC is not recommended.3 The average lifetime risk of
developing PDAC is low (1.6%, 1 in 64), and more importantly, the age-specific inci-
dence in the general population is low (approximately 1/1000 to 1/10,000, depending
on age). As a result, even the best screening tests would generate hundreds to thou-
sands of false positives for every true positive test.4 However, individuals with an esti-
mated 5% or a higher lifetime risk of developing PDAC are now encouraged to
undergo surveillance, as per the International Cancer of the Pancreas Screening
(CAPS) Consortium recommendations.5 The so-called high-risk individuals (HRIs)
carry either a deleterious germline mutation in one of the pancreatic cancer suscepti-
bility genes and/or have a strong family history of PDAC, with at least one first-degree
and one second-degree relative affected with PDAC.5
In this review, we elaborate on the inherited predisposition to familial pancreatic cancer
(FPC) and focus on the role of surveillance for individuals at high risk of pancreatic cancer.

INHERITED PREDISPOSITION

Pancreatic cancer has a significant inherited predisposition.6–8 It is well-known that

having a family history of PDAC increases the risk of developing the disease. The entity
of FPC refers to kindred with at least a pair of first-degree relatives with pancreatic
cancer, a definition that helps quantify risk. Both the number of family members
affected, and their degree relation to one another can be used to estimate this risk.
For example, Klein and colleagues6 found that having two first-degree relatives with
pancreatic cancer equates to an elevated PDAC risk ratio of 6.4-fold over average
risk, corresponding to a lifetime risk of 8% to 12%. The magnitude of the risk is
also associated with the age-at-PDAC of the relatives, with higher risk observed
among relatives diagnosed at younger than 50 years.9 Further studies are needed
to better define these risk estimates, including how inherited susceptibility gene vari-
ants modify the risk in families. The definition of FPC was created before the availabil-
ity of widespread gene testing. Nowadays, individuals at increased risk are typically
grouped according to whether they have a familial-only risk or if they have a known
pancreatic cancer susceptibility gene variant.3,10
Despite the value of obtaining a detailed cancer family history, relying on a family
history of pancreatic or other cancers to identify potential gene mutation carriers
will miss most mutation carriers, and most affected individuals do not come from
kindred with a recognizable inherited cancer syndrome.8 When multigene panel
testing is applied to unselected patients with PDAC, close to 10% are found to
have a high-penetrance pathogenic variant in one of the known pancreatic cancer
susceptibility genes,11–13 including BRCA2 (breast cancer 2), ATM (ataxia telangiecta-
sia mutated), BRCA1 (breast cancer 1), Lynch syndrome-associated genes, CDKN2A
(cyclin dependent kinase inhibitor 2A) (responsible for Familial Atypical Mole and Mul-
tiple Melanoma)7 or STK11 (serine threonine kinase 11) (responsible for Peutz–Jeghers
syndrome), among others (Table 1).
The significant potential of lowering cancer mortality by identifying close relatives of
PDAC cases who have deleterious susceptibility gene variants has led the National
Comprehensive Cancer Network14,15 and the American Society of Clinical Oncology16
to develop guidelines recommending germline gene testing to all patients diagnosed
 Table 1
Pancreatic cancer susceptibility genes

Increased
Average Relative
Lifetime Risk of
Gene Risk for Developing Mechanism of
Name PDAC PDAC Associated Inherited Syndromes Other Cancers/Clinical Manifestations Action
BRCA2 5–10%13,17 w4–6x13 Hereditary breast and ovarian cancer Breast, ovarian, prostate, gastric cancers17 Homologous repair
3%13,17 w2.5x13 Breast, ovarian, prostate, colorectal,
BRCA1 gallbladder cancers17
ATM 9.5%18 w6x13 Ataxia telangiectasia Breast, prostate cancers DNA repair
CDK2NA 17% 19,20
w12–20x13 Familial atypical mole and multiple Melanoma Cell cycle regulation
melanoma syndrome
MLH1 4%21 w7x13 Lynch syndrome Colorectal, gynecologic, urothelial, brain Mismatch repair
MSH2 w7x13 cancers intestinal, gastric
MSH6 Unknown
PALB2 2–3%22 w6x13 None Breast cancer Homologous repair
TP53 Unknown w7x13 Li–Fraumeni syndrome Most human cancers DNA repair
PRSS1 7–40%23,24 w10x13 Hereditary pancreatitis Recurrent acute pancreatitis Trypsin activation

Familial Pancreatic Cancer

STK11 11–36%25,26 w30x13 Peutz–Jeghers syndrome Breast, GIT, gynecologic, lung cancers AMPK signaling
CPA1 w0.5% w3x Hereditary pancreatitis None Acinar-cell ER stress
CPB1 w9x27 Subclinical pancreatitis

Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; CPA1, carboxypeptidase A1; CPB1, carboxypeptidase B1; ER, endoplasmic reticulum;
GIT, Gastrointestinal tract; MLH1, mutL homolog 1; MSH2, mutS homolog 2; MSH6, mutS homolog 6; PALB2, partner and localizer of BRCA2; PRSS1, serine protease
1; TP53, tumor protein p53.

563
564 Saba & Goggins

with PDAC regardless of their age at diagnosis or family history, and if appropriate,
their first-degree relatives.
For most of these pancreatic cancer susceptibility genes, deleterious variants pre-
dispose to other cancers as well.8 Hereditary recurrent acute pancreatitis, mostly due
to deleterious variants in PRSS1 is a rare but important mechanism of pancreatic can-
cer susceptibility.8
In most populations, deleterious susceptibility gene variants are most commonly
identified in BRCA2 and ATM among unselected PDAC cases, with a prevalence of
approximately 2%.11,13 Founder mutations are an important contributor in certain
populations such as the common BRCA2 founder mutation in individuals of Ashkenazi
Jewish descent28 and the CDK2NA founder mutation in the Dutch.19
The average lifetime risk of PDAC is highest among patients with Peutz–Jeghers
syndrome (11% to 36%25,26) and those who have a germline pathogenic variant in
CDKN2A (17%).19,20 The risk of pancreatic cancer is also high for PRSS1 mutation
carriers with earlier studies estimating a lifetime risk of approximately 40%. However,
a more recent study estimated a much lower risk of about 7%.23,24
The lifetime risk for BRCA2 and ATM mutation carriers is estimated to be approxi-
mately 10%. For ATM mutation carriers, this risk has been estimated to be about 1.0%
by age 50 years, increasing to 6.3% by 70 years of age, and to 9.5% by 80 years.18
Among BRCA2 mutation carriers, estimates of the relative risk17 and the odds ratio
(OR)13 are similar (approximately 6-fold overall in most studies). In contrast, the lifetime
risk among BRCA1 mutations carriers is approximately 3%, below the 5% risk
threshold that risk experts have used as a guideline when considering who should
be screened for pancreatic cancer in the absence of a family history.
The PDAC risk among carriers with Lynch syndrome-associated germline mutations
(in MLH1, MSH2, PMS2, and MSH6) is also estimated to be near the 5% threshold for
surveillance,21 and the PDAC risk among PALB2 germline mutation carriers is thought
to be similar to BRCA2, though limited data are available (see Table 1).
Recent efforts to identify additional FPC susceptibility genes have identified several
genes with variants that are thought to contribute to pancreatic cancer risk by inducing
pancreatic acinar cell endoplasmic reticulum stress, a mechanism known to
contribute to some forms of hereditary pancreatitis.27 The case-control studies27,29
have found evidence that rare variants in CPA1 and CPB1 (functionally classified as
endoplasmic reticulum [ER] stress-inducing variants genes) are more common in pa-
tients with PDAC than in non-cancer controls (OR for CPA1: 3.65 [95% CI, 1.58–8.39]
and OR for CPB1: 9.51 [95% CI, 3.46–26.15]).27 A recent genome-wide association
study identified a common deletion variant in CTRB2 (chymotrypsinogen B2) as ER-
stress inducing (OR for PDAC 1.36).30 Of note, acute pancreatitis is usually not a
feature of PDAC cases associated with ER stress variants.
The aforementioned risk values are subject to variation depending on the germline
variant itself as well as additional inherited and environmental factors.8 For example,
smoking is a major nongenetic factor that independently contributes to the increased
risk of PDAC with OR, 3.7 (95% CI, 1.8–7.6).6,7 Smoking is also associated with a sub-
stantially lower average age-at-diagnosis in familial PDAC kindred. In individuals with
hereditary pancreatitis, smoking lowers the age of onset by approximately 20 years.31
Overall, pathogenic variants in the known germline pancreatic susceptibility genes
known to date explain only a minor portion (less than 20%) of the familial clustering
of pancreatic cancer.8
Polygenic risk scores (the risk of developing a disease based on the total number of
changes related to the disease) are being developed for several cancer types in an
effort to refine risk estimates.32 Although polygenic risk scores can refine risk and
 Familial Pancreatic Cancer 565

have promise for common diseases, their clinical value for less common diseases
such as pancreatic cancer is currently limited, even when combined with other risk
factors (family history, smoking, obesity, and so forth).33 One study has used poly-
genic risk scores to estimate PDAC risk among patients with new-onset diabetes.34

PANCREATIC CANCER SURVEILLANCE

For over two decades, the potential of early detection to reduce pancreatic cancer
mortality has formed the basis of pancreas surveillance studies. In recent years, the
accumulated evidence of these studies finds that pancreatic surveillance of HRIs
can downstage tumors with significantly improved outcomes among those diagnosed
with pancreatic cancer. Candidates for pancreatic surveillance should have a detailed
discussion about the potential benefits and risks of surveillance and the need for long-
term compliance. A patient-tailored approach should consider an individual’s family
history, germline mutation status, most recent imaging findings, and genetic and envi-
ronmental factors.

Goals of Surveillance
In 2020, the International CAPS Consortium issued its modified recommendations
with regard to pancreatic surveillance, updating the CAPS consensus statements
from 2013.35 Consensus regarding the main goal of pancreatic surveillance did not
change: reducing pancreatic cancer-related deaths by the detection and treatment
of Stage I PDAC and precursor lesions with high-grade dysplasia.5,36 The clearest ev-
idence to date that pancreatic surveillance can improve long-term outcomes is re-
ported in a study of 354 HRIs enrolled in the CAPS program, where long-term
survival was common among patients who maintained surveillance compared with
those whose surveillance lapsed.37

Whom to Screen and When

The selection of individuals eligible for pancreatic surveillance currently relies on three
key criteria: family history, germline mutation status, and age (Table 2). These criteria
allow clinicians to best assess pancreatic cancer risk.5
Current recommendations of the International CAPS Consortium regarding family
history (when there is no known susceptibility gene mutation) state that individuals
are eligible for surveillance if they have at least two affected blood relatives with
PDAC on the same side of the family, of whom at least one is an affected first-
degree relative, who in turn has an affected first-degree relative.5 The recommenda-
tions regarding age-to-commence surveillance are based on the age-at-diagnosis
of pancreatic cancer in HRIs. Most pancreatic cancers in individuals with a family his-
tory of PDAC are diagnosed after age 55, and on average have a later age-at-
diagnosis than those with a known pancreatic cancer susceptibility variant.11,37 The
consensus at the last International CAPS Consortium was to initiate surveillance at
age 50 years or later for this group, although 22.1% of the experts considered 55 years
as the adequate age to begin. This was consistent with the latest American Gastroen-
terological Association (AGA) clinical practice update recommendations36 and the
American College of Gastroenterology (ACG) guidelines.38
The recommendations for surveillance of those with susceptibility gene variants are
specific for each gene.5,36,38 Given their high lifetime risk of pancreatic cancer, carriers
of mutations in STK11 (Peutz–Jeghers syndrome) and CDKN2A (Familial Atypical Mul-
tiple Mole Melanoma, only mutations that inactivate p16) are advised to participate in
pancreatic surveillance, regardless of their family history.5 Initiating surveillance for
 566
Saba & Goggins
Table 2
Summary of the pancreatic cancer surveillance recommendations in high-risk individual by organization

AGA36
International CAPS Consortium5 (2020) (2020) ACG38 (2015
 All patients with Peutz–Jeghers syndrome
 All patients with hereditary pancreatitis
 All carriers of a germline CDKN2A mutation
Who?  Carriers of a germline BRCA2, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least one affected FDR or SDR
 Individuals from familial pancreatic cancer kindred, defined as at least two affected FDRs who are an FDR to at least one with pancreatic cancer.
 Carriers of a germline BRCA1 gene mutation with at least one affected FDRa  Carriers of a germline BRCA1 gene mutation with at least one
affected FDR or SDR
 Age to begin surveillance depends on patient’s gene mutation status and family history
 There is no consensus on the age to end surveillance
 Start surveillance at age 40 y for all individuals with Peutz–  Start surveillance at age 35 y for all individuals with Peutz–Jeghers
Jeghers syndrome syndrome
 Start surveillance at age 40 y for all carriers of a germline CDKN2A mutation  Start surveillance at age 50 y, or 10 y younger than the earliest
When? and individuals with hereditary pancreatitis age of PC in the family for all carriers of a germline CDKN2A
mutation
 Start surveillance at age 45 or 50 y or 10 y younger than  Start surveillance at age 50 y, or 10 y younger than the earliest age of PC in
youngest affected blood relative for all carriers of a germline the family for all carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1,
BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 mutation MSH2, or MSH6 mutation and for individuals with FPC kindred (without a
 Start surveillance at age 50 or 55 ya or 10 y younger than known germline mutation)
youngest affected blood relative for FPC kindred (without a
known germline mutation)
How?  MRI/MRCP and EUS at baseline
 Alternate MRI/MRCP and EUS (no consensus if and how to alternate) during follow-up
 Serum CA19–9 and CT only for concerning findings  Not considered
 Surveillance annually if no or only non-concerning abnormalities
 Surveillance every 3 or 6 mo if concerning abnormalities for which
immediate surgery is not indicated
 Surgery if positive FNA and/or high suspicion of malignancy on imaging

FDR, first-degree relative; SDR, second-degree relative; FPC, Familial Pancreatic Cancer; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangio-
pancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; CT, computed tomography; PC, pancreatic cancer.
a
Consensus was not reached.
 Familial Pancreatic Cancer 567

CDKN2A mutation carriers is recommended at age 40 years and at age 30 to 40 years

for patients with Peutz–Jeghers syndrome,5 with the ACG suggesting 35 years as a
suitable age.38 For patients with hereditary pancreatitis, owing to disease-causing var-
iants in PRSS1, CPA1, and CTRC,5 surveillance is recommended after age 40 years,
or 20 years after the first pancreatitis attack, irrespective of gene status.5,31,36,38
Discriminating changes of pancreatitis from the presence of pancreatic neoplasia
using current imaging tests is challenging, and for this reason, pancreas surveillance
of those with a history of recurrent acute pancreatitis should be undertaken at centers
of excellence.36 For ATM, BRCA2, PALB2, and Lynch syndrome mutation carriers,
most guidelines recommend surveillance if individuals have at least one affected
first-degree blood relative with pancreatic cancer.5,36 Consensus as to the pancreatic
cancer family history criteria for BRCA1 mutation carriers (who have a low average life-
time risk of developing PDAC) was not reached among CAPS experts, although most
still encourage surveillance in this group.5
Among mutation carriers, a family history of pancreatic cancer modifies risk, but
the extent to which it does is not well-defined. In the early years of pancreas surveil-
lance, before much evidence and experience had been accumulated, it was consid-
ered important to limit eligibility to the highest risk individuals. In recent years,
groups have begun investigating the yield of surveillance among mutation carriers
without a family history of PDAC. Katona and colleagues39 examined this question
among BRCA1, BRCA2, ATM, and PALB2 mutation carriers. The sample size was
too small to adequately address this question, but two individuals (3%) developed
PDAC, a similar detection rate to that reported in other studies among high-risk
groups with a family history of PDAC (yielding an estimate that 111 to 135 patients
will need to be screened to identify one with a PDAC or a high-grade precursor
lesion).40,41
Some studies have reported a low diagnostic yield among individuals under sur-
veillance with familial-only risk. For example, the Dutch FPC Surveillance Study
Group reported on 366 HRIs (including 201 mutation-negative FPC kindred and
165 PDAC susceptibility gene mutation carriers) and revealed a cumulative PDAC
incidence of 9.3% in the mutation carriers group, as opposed to 0% in the FPC
kindred one (P < 0.001).42 These findings led Overbeek and colleagues42 to question
the value of surveillance in those with meeting only familial risk criteria. However, this
conclusion is likely premature as this has not been the experience in the CAPS pro-
gram, although not all familial risk patients undergo gene testing. Indeed, most of the
risk estimates in FPC kindred were based on genetically untested families.6,43 How-
ever, the low number of PDAC cases and the relatively young age of their cohort
(whose risk of PDAC will increase with time) were limitations of their study. Abe
and colleagues44 demonstrated through a study involving 464 HRIs that the risk of
neoplastic progression is higher among patients with a known deleterious germline
mutation than in those with a familial risk alone [hazard ratio (HR), 2.85; 95% CI, 1.0
to 8.18; P < 0.05]. Abe and colleagues44 showed the risk of developing PDAC among
individuals with familial risk alone is still significant and recommended surveillance in
this group. The latest AGA Clinical Practice Update recommended as their third best
practice advice that genetic testing should be offered to FPC kindred who meet the
criteria for surveillance.36

Pancreas Surveillance Tests

Endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI)/magnetic
retrograde cholangiopancreatography (MRCP) are currently the most widely used
modalities for pancreatic surveillance. Pancreatic protocol computed tomography
568 Saba & Goggins

(CT) has been shown to be useful in characterizing solid lesions after they were found
on surveillance imaging,7 but CT is not generally used as a first-line test because of
the radiation dose and intravenous contrast requirement. Furthermore, EUS and
MRI/MRCP have the advantage of being superior at detecting very small pancreatic
cysts.5,45 Developments in CT, such as the use of artificial intelligence methods to
improve the detection of subtle lesions, could change that recommendation in the
future.46
Several studies have attempted to compare the diagnostic yield of these imaging
technologies. For example, Canto and colleagues 47compared EUS, MRI/MRCP,
and CT and found that the detection of subcentimeter pancreatic cysts was superior
with EUS and MRI/MRCP. Some studies have compared overall diagnostic yield that
includes cysts and solid lesions. A meta-analysis of 2,122 HRIs who underwent imag-
ing found no significant difference between EUS and MRI in their ability to detect high-
grade dysplasia, T1N0M0 PDAC, or cysts.40 This study and prior studies40,48,49 found
that EUS can detect subtle focal parenchymal abnormalities which might result from
pancreatic intraepithelial neoplasia (PanIN), although their clinical significance in the
setting of surveillance has yet to be defined.
The detection of PanIN remains a major challenge of pancreatic surveillance. Most
PDACs are thought to originate from PanIN, whether the individual has a family his-
tory, inherited susceptibility gene mutation, or a sporadic form of cancer. As sub-
centimeter pancreatic cysts with imaging characteristics of intraductal papillary
mucinous neoplasms (IPMNs) are commonly observed in patients undergoing sur-
veillance, it would be easy to conclude (incorrectly) that PDACs that emerge in those
with a familial/inherited risk often go through an IPMN-like pathway. However,
PDACs that do arise in the background of pancreatic cysts, often do so away from
preexisting, non-worrisome pancreatic cysts, and have independent genetics.50
Indeed, even among patients with large sporadic IPMNs, it is common to find that
the pancreatic cancer is genetically distinct from the IPMN and presumed to have
arisen from PanIN.51 Concomitant high-grade PanINs originating in areas of the
pancreas distinct from pancreatic cysts are often found in subjects with resected
sporadic low-grade IPMNs. Among HRIs, the presence of pancreatic cysts is asso-
ciated with a modest increased relative risk of developing PDAC compared with
those without such cysts.37
Developments in imaging may one day allow for the detection of PanIN within the
intact pancreas, but this remains a challenge. Some investigators are looking at
pancreatic juice collected from the duodenum at the time of EUS (pancreatic juice
profiling) using digital next-generation sequencing. Such profiling can reveal the mo-
lecular alterations within the pancreas, but they are not sufficient to localize PanIN.52
Other approaches using molecular imaging such as those targeting the integrin avb6-
binding peptide which has been used to image pancreatic cancer53 could have utility
for detecting large PanIN.
The most important question regarding the diagnostic yield of imaging tests in the
setting of pancreatic surveillance is the accuracy for detecting small (1 cm or less)
pancreatic cancers. Many factors contribute to diagnostic performance including
clinician/radiologist expertise, imaging technique used, and the variable imaging char-
acteristics of small tumors. The low incidence of PDAC even in high-risk cohorts has
made it a difficult question to answer definitively. A multicenter blinded prospective
study by Harinck and colleagues,45 comparing the efficacy of MRI and EUS in HRIs
revealed that EUS was particularly sensitive for the detection of solid lesions less
than 20 mm, with two PDACs (including a Stage I PDAC) detected by EUS but not
by MRI.
 Familial Pancreatic Cancer 569

Outcomes of Surveillance
Few studies of pancreatic surveillance among HRIs have reported sufficient numbers
of patients diagnosed with PDAC to evaluate long-term outcomes. In their long-term
(16-year) CAPS study of 354 HRIs undergoing surveillance, Canto and colleagues37
demonstrated that PDAC and/or high-grade dysplasia developed in 7% of the cohort
(24 patients), with 71% of the PDACs detected at stages I and II. Outside of surveil-
lance, patients with symptomatic PDAC have less than a 20% chance of having
low-stage resectable disease.1 The downstaging observed in the CAPS study was
associated with better overall 3-year survival; 85% for the 10 PDACs detected in
asymptomatic HRIs during surveillance versus 25% for the four symptomatic HRIs
who developed PDAC after dropping out of surveillance (P < 0.0001).37 Similarly, a
prospective study following 178 CKDN2A/p16 Leiden mutation carriers in three expert
European centers demonstrated that 75% of the PDACs detected during surveillance
were resectable,19 and a much higher proportion than the 15% reported for historical
controls.54 Furthermore, the 5-year survival rate was markedly higher (24%) than that
previously described for individuals with symptomatic sporadic PDAC (4% to 7%) in
the Dutch Cancer Registry.55
Early detection could be improved if it was possible to identify features on imaging
or other characteristics to better tailor surveillance interval recommendations. Based
on what has been estimated about the growth rate of pancreatic tumor masses56 and
the experience gained from surveillance of HRIs, most patients are recommended to
undergo annual surveillance. Progression to PDAC occurs most often in those older
than 60 years, those with numerous pancreatic cysts,37 and in mutation carriers,44
but these factors alone are not sufficiently discriminating of future PDAC risk to war-
rant changing surveillance intervals.
When worrisome features are detected on imaging, surveillance intervals should
generally be adjusted.36 The experience of surveillance of sporadic pancreatic cysts
that led to the Sendai and Fukuoka International Consensus Guidelines for manage-
ment of mucinous cysts are helpful: cyst size  3 cm, thickened/enhancing cyst walls,
mural nodule in the cyst or main pancreatic duct (MPD), MPD dilation greater than
5 mm, abrupt change in MPD caliber, suspicious cytology for pancreatic malignancy,
or rapid cyst growth rate greater than 2 mm in 6 months or greater than 4 mm in
1 year.57 The ACG clinical guidelines acknowledge the difficulty in establishing
clear-cut inclusion criteria for surgery and state that the decision should be individu-
alized after multidisciplinary evaluation by experts of the field.38 In fact, Dbouk and col-
leagues58 assessed the diagnostic performance of the Fukuoka and CAPS guidelines
for the management of pancreatic cysts in HRIs and showed that both would have
failed to adequately recommend surgery for PDAC patients. They found that the
Fukuoka criteria had a lower sensitivity (40%) for selection of HRIs for surgery
compared with individuals with sporadic cysts, missing 60% of cysts with invasive
carcinoma or IPMNs with high-grade dysplasia. The CAPS criteria also missed 40%
of resected neoplastic IPMNs. Both consensus criteria might have recommended un-
necessary surgery for 15% of HRIs.58 One reason for the poor ability of imaging char-
acteristics to predict the emergence of PDAC, especially in the familial/inherited risk
setting, is the inability of current imaging tools to detect PanIN with high-grade
dysplasia.
In the early years of pancreatic surveillance, patients were often sent for pancreatic
resection for worrisome features, or other concerning abnormalities. For example, in
their meta-analysis including 1,551 familial HRIs, Paiella and colleagues59 reported
a pooled proportion of overall surgery of 6% (95% CI 4.1–7.9, P < 0.001) and
570 Saba & Goggins

unnecessary surgery of 68.1% (95% CI 59.5–76.7, P < 0.001), with final pathology re-
ports revealing diagnoses incompatible with screening goals in most cases. In addi-
tion, a review of such cases found that up to 15% of solid pancreatic lesions were
benigns.55 Nowadays, clinicians have learned to be more selective.
In summary, pancreatic surveillance of HRIs has been shown to detect PDAC with a
high-resectability rate. Surgical resection in this setting is associated with acceptable
morbidity, minimal mortality, and remarkable long-term survival.60 There is some ev-
idence that participation of HRIs in a screening program did not lead to an increase
in cancer worry, as could have been previously presumed.61 Instead, taking part in
a surveillance plan procured a sense of control and even reduced anxiety in some pa-
tients.62 The evaluation of long-term outcomes of HRIs should continue, but not
without acknowledging that compliance to a surveillance program remains a territory
that requires substantial exploration. Longitudinal studies should aim at identifying
factors associated with poor surveillance compliance in HRIs.63 In the United States,
cost can be a barrier to being able to undertake annual EUS or MRI/MRCP surveil-
lance, as insurance coverage for pancreatic surveillance is variable. Indeed, across
the United States, among individuals diagnosed with PDAC (NCI SEER data-general
population cases), having insurance is associated with a lower stage at diagnosis.64

THE POTENTIAL OF BIOMARKER TESTS TO IMPROVE PANCREAS SURVEILLANCE

Remarkable efforts have been made to identify HRIs who qualify for pancreas surveil-
lance in the hope of optimizing early detection of pancreatic cancer in this unique pop-
ulation. Novel strategies are needed to better stratify PDAC risk in HRIs with the aim of
increasing the number of eligible patients for pancreatic cancer surveillance.65 Likewise,
new tests are being evaluated to improve detection of high-grade precancerous lesions
and early-stage invasive carcinomas not only in HRIs but also in the general population.
Improving the diagnostic accuracy of circulating tumor markers such as CA19-9
would be of great value. As a marker, CA19-9 is significantly influenced by common
variants in the genes responsible for its synthesis (FUT2 and FUT3). Abe and col-
leagues66 found that classifying individuals into CA19-9 reference ranges based on
these FUT2/FUT3 variants significantly improved the accuracy of CA19-9 (and other
tumor markers) for diagnosing pancreatic cancer. They showed that a tumor marker
gene test combined with a CA19-9 test enhanced its diagnostic performance (partic-
ularly in patients with intact FUT3), with 66.4% sensitivity and 99.2% specificity for
subjects with localized PDAC. To have the greatest impact, these tests need to detect
stage I PDAC. A major challenge for the detection of stage I PDACs with a blood-
based test is that smaller cancers generally shed fewer biomarkers into the blood-
stream. Studying biomarkers from patients with stage I PDACs is similarly challenging
because these cases are very rare,66 and many newly diagnosed patients now receive
neoadjuvant chemotherapy, obscuring assessment of their pathologic stage at
presentation.67
Liquid biopsies have been used to evaluate circulating tumor DNA (ctDNA) as a
noninvasive tool to detect early-stage pancreatic cancer. For pancreatic cancer
detection, initial studies relied on mutated KRAS ctDNA. More recent studies have
used pan-cancer ctDNA tests as part of multi-cancer detection approaches.68 Further
evidence is needed before considering its implementation in a clinical setting.

SUMMARY

Studies in recent years have provided a deeper understanding of the inherited predis-
position to PDAC and its relationship to FPC. Experts have identified at present at least
 Familial Pancreatic Cancer 571

a dozen genes known to contribute to the development of PDAC in mutation carriers.

Patients whose PDAC is localized to the pancreas have a better chance of survival
than those with a more advanced form of the disease.64,69 Individuals with familial
and inherited risk of pancreatic cancer who undertake pancreas surveillance and
are diagnosed with early-stage PDAC, especially stage I disease, have an excellent
chance to achieve long-term survival.

CLINICS CARE POINTS

 Pancreatic ductal adenocarcinoma (PDAC) has an overall poor prognosis. Symptoms

associated with PDAC commonly manifest late in the course of disease.
 Eligibility criteria for pancreas surveillance are based on age, germline mutation status, and
family history. High-risk individuals (HRIs) with an estimated 5% or higher lifetime risk of
developing PDAC are advised to undergo surveillance for PDAC.
 The accumulated evidence of pancreas surveillance studies demonstrates that pancreatic
surveillance of HRIs can result in the diagnosis of early-stage PDAC, and this is associated
with improved outcomes.
 Endoscopic ultrasound and/or magnetic resonance imaging/magnetic resonance
cholangiopancreatography are considered the standard imaging modalities for screening
to date. Computed tomography scan has been shown to be useful in characterizing
concerning solid lesions found on surveillance but is not generally used as a first-line test.
 Blood-based biomarkers and circulating tumor DNA tests represent promising noninvasive
tools to detect early-stage pancreatic cancer.

FUNDING

This work was supported by NIH grants U01210170, and R01CA176828). This work
was also supported by a Stand Up To Cancer-Lustgarten Foundation Pancreatic Can-
cer Interception Translational Cancer Research Grant (Grant Number: SU2C-AACR-
DT25-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation.
SU2C research grants are administered by the American Association for Cancer
Research, the scientific partner of SU2C. MG is the Sol Goldman Professor of Pancre-
atic Cancer Research.

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and screening: impact on perceived risk and psychological functioning. Fam
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C o l o re c t a l C a n c e r S c re e n i n g
i n a C h a n g i n g Wo r l d
Robert S. Bresalier, MD

KEYWORDS
 Colorectal cancer screening  Guidelines  Underserved populations
 Early-onset colorectal cancer  Quality colonoscopy  Non-invasive screening tests
 Artificial intelligence

KEY POINTS
 Numerous professional societies have issued serial updates of CRC screening guidelines
that have evolved to provide evidence-based recommendations, which include menus of
options designed to maximize screening compliance.
 The incidence of CRC among adults younger than 50 years in the United States has nearly
doubled since the early 1990s and continues to increase.
 Adherence to or uptake of CRC screening is especially poor among underserved popula-
tions, resulting in increased mortality.
 Quality metrics must be incorporated into CRC screening guidelines and practice.
 Overcoming multiple barriers to screening will require efficient use of multiple screening
modalities, continued development of noninvasive screening tests, improved personal
risk assessment to best risk-stratify patients, and development of organized screening
programs to achieve target screening rates and reductions in CRC morbidity and
mortality.

INTRODUCTION

Colorectal cancer (CRC) is the second leading cause of cancer death in industrial-
ized nations, accounting for 10% of the total cancer burden with an individual lifetime
risk of approximately 6% in western countries.1–13 In 2022 it is estimated that
151,000 Americans will be diagnosed with CRC and 52,580 individuals will die of
this disease.1 Over 20 years of SEER data, US CRC incidence (all races, men,
women) has decreased from 59.5 cases to 39.3 cases per 100,000 (35% reduction)
with a corresponding mortality reduction over the same time period from 24 to 15.1
deaths per 100,000 (37% reduction).2 However, although early detection by
screening significantly reduces mortality and numerous screening options exist,5–8

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD

Anderson Cancer Center, 1515 Holcombe Boulevard Unit 1466, Houston, TX 77030, USA
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 577–591

https://doi.org/10.1016/j.gtc.2022.05.002 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
578 Bresalier

40% of guideline-eligible patients are not screened as recommended in the United

States. Globally, 1.4 million new CRC cases and 700,000 related deaths occur
yearly, and compliance with screening may even be lower. Guidelines for CRC
screening from US and international professional societies most often provide
menus of options based on strength of evidence,5–8 but generally applied screening
methods vary globally and even within the United States depending on access and
resources. Consideration of screening options must take into account not only test
performance but also issues of resources and individual versus population benefits
(Fig. 1).
In the United States, colonoscopy is clearly the dominant method of CRC
screening, but most of the developed countries recommend a 2-step approach
(Fig. 2) and do not universally support first-step endoscopic screening. Universal
implementation of colonoscopy for CRC screening for all persons ages 50 to 74
years would require a capacity to screen 250 million individuals over a 10-year
period in North America and Europe, for example; this will increase substantially
due to revisions in guidelines that recommend initiation of CRC screening at age
45 years.6–8 Adherence to or uptake of CRC screening is especially poor among un-
derserved populations, including those with low income and African American and
Hispanic populations.2,9–14 Novel strategies to improve screening uptake overall
and efforts to deploy best practices to underserved populations is a high priority
for health care and reducing CRC related morbidity and mortality. On the positive
side, increased future adherence to screening guidelines in the United States
may be driven by the profound changes in the organization of medical care
including enhanced access via the Affordable Care Act, rigid guideline enforcement
by payers with physician performance incentives and disincentives, and the rapid
adaptation of electronic medical record systems enabling ease of referrals for
screening, compliance reminders, and management tracking of compliance to
care guidelines.

RESOURCES

Sensitivity Specificity

Individual Versus Population Benefit

Fig. 1. The performance and success of a screening test in reducing colorectal cancer mor-
tality does not simply depend on its test sensitivity and specificity at a single point in
time, but programmatic benefit, including optimal use of available resources. (Adapted
from Bresalier RS, Grady WM, Markowitz SD, et al. Biomarkers for early detection of colo-
rectal cancer: The Early Detection Research Network, a framework for clinical translation.
Cancer Epidemiol Biomarkers Prev 2020; 29:2431-2440; with permission.)
 Colorectal Cancer Screening in a Changing World 579

Engage subject

Start Here?
Screening Test
Positive (FIT, stool DNA,
blood test)
Diagnostic Procedure (colonoscopy)

Start Here?

Treatment

Rescreen/Surveillance
Fig. 2. Although in the United States colonoscopy represents a “first approach” to colo-
rectal cancer screening, many countries that emphasize programmatic screening have taken
a “2-step” approach where a less expensive, noninvasive test is first performed. If positive,
this is then followed-up by colonoscopy.

The strength of evidence for individual CRC screening tests has been extensively
reviewed in updated screening guideline recommendations.5–8 Rather than duplicate
this effort, this article discusses key issues that affect CRC screening in a changing
world, including new test development.

SCREENING AND EARLY DETECTION: CURRENT GUIDELINES AND RECOMMENDED

PRACTICE

Numerous professional societies have issued serial updates of CRC screening guide-
lines that have evolved to provide evidence-based recommendations, which include
menus of options designed to maximize screening compliance.5–8,15–17 Current guide-
lines for CRC screening and surveillance from major US societies are detailed in
Tables 1 and 2, respectively. Although not all options have proved equivalence of ef-
ficacy and have different advantages and limitations, all societies conclude that there
is a high certainty that screening for CRC in average-risk asymptomatic adults is of
substantial net benefit. A broad set of screening choices for different levels of CRC
risk is offered, thereby allowing greater flexibility in achieving screening goals.
The US Multi-Society Task Force on Colorectal Cancer (MSTF) representing the
American College of Gastroenterology (ACG), the American Gastroenterological Asso-
ciation (AGA), and the American Society for Gastrointestinal Endoscopy (ASGE) in
2017 ranked CRC screening tests into 3 tiers based on performance features, cost,
and practical considerations.5 First-tier tests are colonoscopy every 10 years and
annual fecal immunochemical tests (FIT), with colonoscopy offered first. Second-tier
tests include computed tomography (CT) colonography every 5 years, FIT-fecal
DNA every 3 years, and flexible sigmoidoscopy (FS) every 5 to 10 years. Capsule
580 Bresalier

Table 1
Guidelines for screening average-risk persons for colorectal cancer

US Preventive
Services Task American Cancer US Multi-Society Task
Screening Tool Forcea Societyb Forcec
Stool-Based Tests
High-sensitivity Recommended Recommended Not specifically
FOBT (guaiac-based) annually as annually as recommended
an option an option
Fecal immunochemical Recommended Recommended Recommended
test (FIT) annually as annually as annually as an
an option an option option (tier 1
recommendation)
FIT-fecal DNA testing Recommended Recommended Recommended every
every 3 y as every 3 y as 3 y as a tier 2 option
an option an option
Direct Visualization
Colonoscopy Recommended Recommended Recommended every
every 10 y as every 10 y as 10 y as a tier 1 option
an option an option
Flexible Recommended Recommended Not recommended
sigmoidoscopy every 5 y or every 5 y as as an option
every 10 y plus an option
FIT annually
as an option
CT colonography Recommended Recommended Recommended every
every 5 y as every 5 y as 5 y as a tier 2 option
an option an option
Colon capsule Not recommended Not recommended Recommended every
5 y as a tier 3 option
Blood-based Tests
Septin 9 Not recommended Not recommended Not recommended

Abbreviation: FOBT, fecal occult blood test.

a
The US Preventive Services Task Force (USPSTF) recommends screening for adults aged 50 to
75 years (Grade A high certainty recommendation) and aged 45 to 49 years (Grade B moderate cer-
tainty recommendation). The decision to screening adults aged 76 to 85 years should be an individ-
ual one (selective screening), taking into account the patient’s overall health and prior screening
history. Adults in this age group who have never been screened for CRC are more likely to benefit.
These guidelines discuss the strength of evidence for each modality and recommend individualized
decision-making to the specific patient or situation. Cost is not considered by the USPSTF.
b
The American Cancer Society recommends average-risk screening beginning at age 45 years as
a qualified recommendation. Screening adults aged 76 to 85 years should be individualized based
on patient preferences, life expectancy, health status, and prior screening history. Discussion is pre-
sented regarding the 2018 MISCAN modeling analysis with comparison of potential life years
gained (LYG) for each screening scenario. Data from CA Cancer J Clin. 2018; 68:250-281.
c
The US Multi-Society Task Force (MSTF) on Colorectal Cancer representing the American Col-
lege of Gastroenterology (ACG), the American Gastroenterological Association (AGA), and the
American Society for Gastrointestinal Endoscopy (ASGE) recommends average-risk screening
beginning at age 45 years. Discontinuation should be considered when individuals up to date
with screening and who have prior negative screening reach age 75 years or have less than 10 years
life expectancy. For individuals ages 76 to 85 years the decision to start or continue screening
should be individualized based on prior screening history, life expectancy, CRC risk, and personal
preference. Screening is not recommended after age 85 years. The MSTF ranks screening tests by
 Colorectal Cancer Screening in a Changing World 581

recommended tiers. In a separate document the ACG discussed one-step screening (colonoscopy)
versus a 2-step approach and examined the quality of evidence for each test. The recommendation
to begin average-risk screening at age 50 years was considered a strong recommendation based on
moderate-quality evidence, whereas the recommendation to begin screening at age 45 years was
considered to be a conditional recommendation based on very low-quality evidence.
Data from Refs.5–7

colonoscopy every 5 years is a third-tier test. It is suggested that the Septin9 blood
test not be used for screening. Tools for enhancing colonoscopy quality are stressed.
These guidelines were updated in 2022, with a consensus statement focusing on
when to start and when to stop CRC screening.6 The MSTF now recommends that
average-risk screening begin at age 45 years. In a separate document the ACG dis-
cussed 1-step screening (colonoscopy) versus a 2-step approach and examined
the quality of evidence for each test. The recommendation to begin average-risk
screening at age 50 years was considered a strong recommendation based on
moderate-quality evidence, whereas the recommendation to begin screening at age
45 years was considered to be a conditional recommendation based on very low-
quality evidence.17
The American Cancer Society (ACS) updated its guidelines in 2018 and recommen-
ded that average-risk individuals undergo regular screening beginning at age 45 years
with either a high-sensitivity stool-based test (FIT or high-sensitivity guaiac-based
fecal occult blood test annually, multitarget stool DNA test every 3 years) or a struc-
tural examination (colonoscopy every 10 years, CT colonography every 5 years, FS
every 5 years).8 All positive results on noncolonoscopy screening tests should be fol-
lowed by timely colonoscopy.
The US Preventive Services Taskforce (USPSTF) commissioned a systematic re-
view to evaluate the benefits and harms of CRC screening. In an updated recommen-
dation statement in 2021, the USPSTF concluded with “high certainty” that CRC
screening in average-risk asymptomatic adults aged 50 to 75 years has “substantial”
net benefit and concluded with “moderate certainty” that screening in adults aged 45
to 49 years has “moderate net benefit.” The USPSTF indicated that multiple strategies
are available to choose from with different levels of evidence to support their effective-
ness, as well as unique advantages and limitations. Eight screening strategies were
recommended with details of evidence of efficacy and discussion of considerations
including stool-based tests and direct visualization tests. Stool-based tests include
high-sensitivity guaiac-based fecal occult blood testing, FIT, and a multitarget stool
DNA test, which includes an FIT component. Direct visualization tests include colo-
noscopy, CT colonography, flexible sigmoidoscopy, and flexible sigmoidoscopy
with FIT. Numerous international CRC screening programs have been initiated, as ev-
idence grows for an impact of CRC screening on mortality.18

CHANGING DEMOGRAPHICS, UNDERSERVED POPULATIONS, AND THE IMPACT ON

COLORECTAL CANCER SCREENING
Early Onset Colorectal Cancer
Although the incidence of CRC continues to decline in older populations, the incidence
among adults younger than 50 years in the United States has nearly doubled since the
early 1990s and continues to increase. Similar increases in incidence of early onset
CRC (EoCRC) have been observed in Europe, Canada, Australia, as well as in some
countries in Asia. Time trends demonstrate that incidence of young-onset CRC has
continued to increase across successive birth cohorts2,13 of individuals born after
1960, suggesting that exposures accumulated over the life course may increase the
 582
Bresalier
Table 2
Guidelines for surveillance after high-quality colonoscopy

Risk Category Time or Age to Begin Surveillance Recommended Test Comment

Persons with Adenomas at Colonoscopy
Persons with 1 or 2 tubular 7–10 y after initial polypectomy Colonoscopy Precise timing is based on clinical
adenomas <10 mm factors and on patient and
physician preferences
Persons with 3–4 tubular adenomas 3–5 y after initial polypectomy Colonoscopy —
< 10 mm
Persons with 5–10 adenomas or 1 3 y after initial polypectomy Colonoscopy If the follow-up examination is
adenoma 10 mm or any normal or shows 1 or 2 small tubular
adenoma with villous features or adenomas, subsequent
high-grade dysplasia examination at 5 y
Persons with >10 adenomas on a 1 y after initial polypectomy Colonoscopy Consider familial syndrome
single examination
Persons with serrated polyps at colonoscopy
Persons with sessile adenomas or 6 mo after initial colonoscopy Colonoscopy Surveillance individualized based on
sessile serrated polyps 20 mm clinical judgment
that are removed piecemeal
Persons with 1–2 sessile serrated 5–10 y after initial polypectomy Colonoscopy —
polyps/lesions < 10 mm without
dysplasia
Persons with 3–4 sessile serrated 3–5 y after initial polypectomy Colonoscopy —
polyps/lesions < 10 mm without
dysplasia
Persons with 5–10 sessile serrated 3 y after initial polypectomy Colonoscopy —
polyps/lesions, sessile serrated
polyps 10 mm or with dysplasia
or traditional serrated adenoma
Hyperplastic polyp  10 mm 3–5 y after initial polypectomy Colonoscopy —
Persons with CRC
 Persons undergoing curative Preoperatively or 3–6 mo after surgery Colonoscopy Persons with CRC should undergo
resection for CRC in the case of obstructive CRC, then high-quality perioperative clearing
1 y after surgery (or 1 y after the of the colon. For nonobstructing
clearing perioperative colonoscopy) tumors, examination can be done
preoperatively; for obstructing
cancer, CTC can be used to detect
proximal neoplasms
— — If the examination at 1 y is normal,
perform the next examination at 3 y
(ie, 4 y after surgery or
perioperative colonoscopy).
If that examination is normal, then
perform the next examination at 5 y
(ie, 9 y after surgery or
perioperative colonoscopy), and

Colorectal Cancer Screening in a Changing World

then at 5-y intervals.
Periodic examination of the rectum
with FS or EUS (3- to 6-mo intervals
for the first 2–3 y) may be
considered after resection of rectal
cancer in those at high risk for
recurrence (in addition to
colonoscopy surveillance for
metachronous neoplasia)
Persons with a Family History of CRC
CRC or an advanced adenoma in 2 Age 40 y, or 10 y before the youngest Colonoscopy every 5 y For those in whom no significant
first-degree relatives diagnosed case in the immediate family neoplasia appears by age 60 years,
at any age OR colorectal cancer or consider offering an expanded
an advanced adenoma in a single interval between colonoscopies
first-degree relative <60 y

(continued on next page)

583
 584
Bresalier
Table 2
(continued )
Risk Category Time or Age to Begin Surveillance Recommended Test Comment
CRC or an advanced adenoma in a Age 40 y Screening options at intervals Screening should begin at an earlier
single first-degree relative  age recommended for average-risk age, but patients may be screened
60 y persons with any recommended form of
testing
Persons at High Risk
Lynch syndrome Age 20–25 y or 2–5 y before the Colonoscopy every 1–2 y For MSH6 mutation carriers, consider
youngest case in the immediate a later age of onset for colonoscopy
family, whichever comes first
Family colon cancer syndrome X Age 10 y before the age of diagnosis Colonoscopy every 5 y —
of the youngest affected relative
BMMRD syndrome Age 6 y Colonoscopy annually —
IBD (UC and Crohn colitis) 8 y after the onset of pancolitis Colonoscopy (chromoendoscopy) Surveillance interval depends on
with targeted biopsies every 1–3 y clinical history and colonoscopy
findings

Patients with cumulative greater than 20 hyperplastic polyps of any size throughout the colon with at least 5 proximal to the rectum, as well as those with 5
serrated polyps proximal to the rectum greater than 5 mm, with at least two 10 mmm meet criteria for serrated polyposis syndrome and may require specialized
management.
Abbreviations: BMMRD, biallelic mismatch deficiency syndrome; CTC, CT colonography; FS, flexible sigmoidoscopy; IBD, inflammatory bowel disease; UC, ulcer-
ative colitis.
Data from Rex DK, Boland CR, Dominitz JA et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Taskforce
on Colorectal Cancer. Gastroenterology 2017;153:307-323; Gupta S, Lieberman DA, Anderson JC et al, Guidelines for colonoscopy surveillance after screening and
polypectomy: Recommendations for follow-up after colonoscopy and polypectomy: A consensus update by the US Multi-Society Taskforce on Colorectal Cancer.
Gastroenterology 2020; 158:1131-1153; Kahi CJ, Boland CR, Dominitz JA et al. Colonoscopy surveillance after colorectal cancer. Gastroenterology 2016; 150:758-
768.
 Colorectal Cancer Screening in a Changing World 585

risk of CRC. Many have suggested that changes in diet, alterations in gut microbiota,
and increases in obesity may contribute to colorectal carcinogenesis.19,20 Interest-
ingly, the increase in incidence rates of EoCRC has been driven primarily by increases
in rectal (vs colon) cancer. Racial disparities, described in detail later, also exist in
EoCRC, with blacks experiencing higher incidence of CRC and worse CRC survival
when compared with non-Hispanic whites.21,22
Studies have demonstrated that 16% to 20% of individuals diagnosed with EoCRC
carry pathogenic germline variants in genes associated with cancer susceptibility.23
Lynch syndrome and familial adenomatous polyposis are implicated in 3% and 1%
of unselected CRC diagnoses overall, with pathogenic germline variants in other can-
cer susceptibility genes found in an additional 5% to 6%. Importantly, a significant
proportion of patients with CRC who carry pathogenic germline variants associated
with cancer susceptibility do not meet clinical diagnostic criteria for the corresponding
genetic diagnosis, which presents challenges to identifying individuals at increased
risk for early onset colorectal neoplasia.
The approach to CRC screening in asymptomatic individuals ideally takes into ac-
count risk stratification and the likelihood of developing the disease. Compared with
individuals with no family history of CRC, the relative risk of developing CRC when
at least one first-degree relative has CRC is 2.24. Among individuals with more than
1 first-degree relative with CRC diagnosed younger than 50 years, the relative risk
of CRC is 3.55. Current CRC risk assessment algorithms consider patient’s age, family
history, and personal history of CRC. However, more than two-thirds of individuals
diagnosed with EoCRC report no family history of CRC in first-degree relatives. As
noted earlier, the USPSTF, the ACS, and the MSTF have all made qualified recommen-
dations to expansion of CRC screening to individuals aged 45 to 49 years. EoCRCs,
however, are also diagnosed in those older than 45 years (especially rectal cancers),
and a high index of suspicion is warranted in individuals presenting with a family his-
tory of CRC and/or suggestive histories.

Underserved Populations
Adherence to or uptake of CRC screening is especially poor among underserved pop-
ulations, including those with low income and African American and Hispanic popula-
tions.9–12 CRC incidence and mortality rates are also higher in non-Hispanic blacks
compared with non-Hispanic whites, whereas insurance coverage is disproportion-
ately lower. This problem will continue to grow with shifting demographics in the
United States. Texas, for example, is a high population state with substantial racial
and ethnic diversity. It is home to the second largest population of African Americans
in the United States and is projected to be a Hispanic-majority state by 2022. Over the
last 4 decades CRC incidence rates for all ages have dropped 33.9% in US whites but
only 6.6% in African Americans. Novel strategies to improve screening uptake and
deploy best practices to underserved populations is a high priority for health care in
the nation. Black Americans have the highest incidence of CRC (45.7 per 100,000), fol-
lowed by Native Americans (43.3), Whites (38.6), Hispanics (34.1), and Asians (30.0).
Racial/ethnic variation in deaths due to CRC show similar patterns.13 Compared
with whites, incidence rates are 24% higher in African American men and 19% higher
in African American women.24 Stage-adjusted CRC mortality is also disproportion-
ately higher in African Americans, with rates being 47% higher in African American
men and 34% higher in African American women compared with whites.25 The rea-
sons for these differences are not entirely clear but disparities in care, such as lower
rates of screening, diagnostic follow-up, and treatment are postulated. One study es-
timates that 19% of the racial disparity in CRC mortality rates can be attributed to
586 Bresalier

lower screening rates and 36% to lower stage-specific survival among African Amer-
icans.26 Access barriers to screening disproportionality affect racial/ethnic, low socio-
economic status, recent immigrants, and uninsured/Medicaid populations, whom all
have lower colonoscopy rates compared with white, high socioeconomic status,
and private/Medicare groups.13 Screening rates are lowest among individuals with
low education attainment, lack of health insurance, poor access to care, low socio-
economic status, and from racial/ethnicity minority backgrounds. Safety-net popula-
tions, similar to those served in community health centers (CHCs), have among the
lowest rates of CRC screening.27 Although results from modeling studies such as CIS-
NET do not specifically support different screening strategies by race,28,29 the MSTF
beginning in 2017 recommended initiation of screening in Black adults at age 45 years
while starting screening at age 50 years for other races. Current guidelines from the
MSTF, USPSTF, and ACS recommend starting screening for everyone at age 45
years, removing this differentiation. Access to colonoscopy is a major barrier to
CRC screening, particularly in community settings, including federally qualified health
centers and community health centers.30,31 In CHCs, similar to other settings where
screening colonoscopy may not be feasible or easily accessible, stool-based
screening (ie, FIT and s-DNA-FIT) has emerged as a common, noninvasive screening
strategy.32–35

Quality Metrics
As the number of colonoscopies (and endoscopists) have increased, quality-
assurance measures have been adopted and are included in the most recent CRC
screening guidelines.5 Quality metrics and standardization included in the Affordable
Care Act mandate that the Center for Medicare and Medicaid Services change reim-
bursement to a value-based system. Adenoma detection rate (ADR) is defined by the
percentage of screening colonoscopies of average-risk patients with at least one ad-
enoma and is the most commonly used quality measure in practice. Benchmarks for
adequate ADRs set in 2015 by the ASGE suggested ADR requirements of at least 20%
for women and 30% for men (30% overall),36 but progressive technical and quality
improvements in colonoscopy suggest that a higher bar be set with updated bench-
marks. The ADR is considered by the ASGE/ACG Task Force on Quality in Endoscopy
and the MSTF to be the best neoplasia-related indicator of quality performance for
screening colonoscopy. The ADR has been demonstrated to be an independent pre-
dictor of the risk of interval CRC after screening colonoscopy, and increased ADR is
associated with reduced risk of CRC-related mortality.37 The recent qualified recom-
mendations from the USPSTF, ACS, and MSTF to initiate average-risk CRC screening
at age 45 years may require age-adjusted ADRs.38 Increasing knowledge regarding
sessile serrated lesions or sessile serrated polyps has led to the suggestion of inclu-
sion of a separate criteria for recognition of these lesions, but this has not yet been uni-
versally adopted. A measure of adenomas per colonoscopy (APC) has also been
suggested,39 as it measures the quality of colonoscopy over a complete examination.
Performance indicators of other CRC screening modalities such as FIT in organized
screening programs have also been suggested.40 Endoscopist characteristics (vol-
ume, polypectomy and completion rate, specialization, and setting) derived from
administrative data are correlated with the development of postcolonoscopy CRC
and have potential use as quality indicators. Other quality measures include quality
of bowel preparation and completeness of polyp resection. The MSTF recommended
in 2014 that at least 85% of outpatient colonoscopies should have adequate bowel
preparation, but increasing standardization and quantitative clinical grading scales
such as the Boston Bowel Preparation Scale may lead to improvements in practice.
 Colorectal Cancer Screening in a Changing World 587

The incomplete resection rate in the Complete Adenoma Resection study was 10.1%
overall and varied broadly among endoscopists.41 A physician performance measure-
ment set for endoscopy and surveillance has been proposed in a joint document by
the ASGE, the AGA, the Physician Consortium for Performance Improvement, and
the National Committee for Quality Assurance. Quality measures also have been
stressed by European quality control programs.

New Screening Tests and Technology

One-third of guideline eligible individuals in the United States do not access CRC
screening as recommended. In addition, the paradigm for CRC screening world-
wide outside the United States is often a 2-step process whereby an initial positive
screening test then triggers colonoscopy as a diagnostic test (see Fig. 2). Although
this is especially important in resource-limited countries, it is also the model in
many countries with organized CRC screening programs such as the United Kingdom,
Canada, Australia, Denmark, the Netherlands, and many other countries in Europe and
Asia. As a result, development of, and clinical interest in noninvasive screening tests
for CRC using “biomarkers” has been high, including various forms of stool- and
blood-based tests.42 Patient-friendly approaches that improve patient uptake are
needed to achieve the CRC screening goal of high compliance but must also demon-
strate high performance characteristics (sensitivity and specificity) for detection of
early stage cancer and high-risk precursor lesions and must have broad acceptability
to the general population, health care providers, regulatory agencies, and third-party
payers. Consistent with this goal, adoption of cost-effective noninvasive methodolo-
gies designed to improve overall acceptance of the screening process are highly
desirable.
Stool-based tests such as fecal immunochemical tests and the multitarget FIT-DNA
test (commercially Cologuard, Exact Sciences, Madison, WI) are relatively sensitive
and specific for the detection of CRC (up to 90%) but less so for advanced adenomas
(28% for FIT and 40% for FIT-DNA in one pivotal trial).43,44 Successful use of these
tests highly depends on compliance. FIT is the most commonly used noninvasive stool
test world-wide and is often the first step in 2-step population-based screening; this is
to some extent due to its relatively low cost per test. Threshold for test positivity and
test performance over multiple rounds of screening is important in evaluating overall
performance in these population-based screening programs.45 FIT is currently recom-
mended as a first-tier test by the MSTF and is the comparator for many studies aimed
at validating other noninvasive markers. Single-application FIT tests have moderate-
to-high sensitivity for detecting CRC, depending on the threshold for positivity used,
but sensitivity for advanced adenomas is low.
A molecular approach to CRC screening is attractive because it targets biological
changes that are fundamental to the neoplastic process. The feasibility of detecting
altered DNA in stool has been demonstrated using a multitarget assay panel of molec-
ular markers. The multitargeted stool FIT-DNA test (Cologuard, Exact Sciences) is
approved by Food and Drug Administration (FDA) and Centers for Medicare and
Medicaid Services (CMS) as a CRC screening test and is included as part of USMSTF
guidelines (every 3 years; tier 2 recommendation). The false-positive rate for CRC ap-
proaches 14%, however, and a second-generation test is currently under evaluation.
Serum or plasma markers have been considered an important “next step” for the
successful implementation of population-based screening for colorectal neoplasia,42
but blood-based markers have, to date, proved inadequate for this purpose. Although
any screening test must demonstrate high positive and negative predictive values in
clinically relevant settings, blood-based markers are attractive in several ways.
588 Bresalier

Specimens are easy to sample and control for reproducibility, can be combined to
enhance performance, and should lead to high-compliance, cost-effective tests.
Blood-based biomarkers also have good potential for use in low-compliance or under-
served populations and in some cases may lead to easily administered point-of-care
tests. Blood tests are also noninvasive compared with colonoscopy and are likely to
prove more socially acceptable compared with stool-based tests. An integrated signal
in blood should make it possible to detect both proximal (right-sided) and distal le-
sions. Noninvasive tests have proved useful in individuals refusing other forms of
screening and may be valuable as reflex tests following inadequate colonoscopy.
Although existence of an acceptable blood-based biomarker would of course not
result in 100% compliance by screen-eligible individuals, the target of unscreened in-
dividuals is substantial.
A large number of blood-based markers have been proposed for early detection of
colorectal neoplasia, but few have been evaluated in adequately powered prospective
screening trials. An assay for methylated Septin 9 (Epi proColon, Epigenomics AG,
Berlin, Germany) is commercially available and FDA approved for individuals refusing
other screening tests but is not guideline recommended, nor reimbursed by the CMS
due to limited performance in detecting early stage lesions. Several promising blood-
based marker assays are on the horizon, either as CRC limited tests or as multicancer
detection tests. Many are based on measurement of aberrantly methylated circulating
DNA, and the term “liquid biopsy” is often used to describe the use of circulating
cell-free DNA to detect neoplasia. “Multi-omics” tests that include panels of both
circulating DNA and protein markers are also being evaluated. CMS has recently intro-
duced metrics for coverage of blood-based biomarker tests for average-risk individ-
uals, which include FDA marker authorization, proven test performance of sensitivity
for detecting CRC equal to 74% and specificity greater than 90%, and inclusion as
a recommended routine CRC screening test in at least one professional society guide-
line or consensus statement or recommendation by the USPSTF.46
Deep learning systems with real-time computer-aided polyp detection have been
recently introduced as a means of increasing adenoma detection rates. Incorporation
of artificial intelligence during colonoscopy as an aid for detection of neoplastic lesions
resulted in increases in ADR and APC in recent studies,47 especially in the hands of
less experienced examiners.48 Such systems are now commercially available, but at
the moment do not differentiate polyp histology.

Knowledge Gaps and a Roadmap for Future Colorectal Cancer Screening

An expert consensus conference held by the AGA recently suggested that a once-
size-fits-all approach to CRC screening was unlikely to result in increased screening
uptake or desired outcomes and that overcoming the multiple barriers to screening
will require efficient use of multiple screening modalities, continued development of
noninvasive screening tests, and improved personal risk assessment to best risk-
stratify patients. Furthermore, organized screening programs will ultimately be needed
to achieve target screening rates and reductions in CRC morbidity and mortality.49
Knowledge gaps will ultimately need to be provided by research aimed at under-
standing what affects uptake and adherence to individual screening tests, improved
risk-stratification, performance of screening tests not simply at one point in time but
in programmatic screening, factors that affect incidence and mortality in underserved
populations, and screening approaches to young-onset CRC. Acceptable approaches
that allow new screening tests to proceed from discovery to clinical practice at an
accelerated pace will need to be determined, including whether it is necessary to
directly compare the effectiveness of new tests in head-to-head randomized trials.
 Colorectal Cancer Screening in a Changing World 589

CLINICS CARE POINTS

 Colorectal cancer screening reduces cancer-related mortality.

 Quality metrics are key to improving outcomes of colorectal cancer screening and reducing
the occurrence of interval cancers.
 Uptake and adherence to colorectal cancer screening guidelines are key to reducing
colorectal cancer mortality, especially in underserved populations.

FUNDING

The work was supported in part by grants from the National Cancer Institute
(U01CA086400) and the National Institutes of Health (NIH P30DK056338, the Texas
Medical Center Digestive Disease Center).

DISCLOSURE

The author has nothing to disclose.

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Approach to Familial
P re d i s p o s i t i o n to C o l o re c t a l
Cancer
a,b a,b,
Veroushka Ballester, MD, MSc , Marcia Cruz-Correa, MD, PhD *

KEYWORDS

Colorectal cancer
Familial colorectal cancer

Hereditary colorectal cancer syndromes
Polyposis syndromes

Nonpolyposis syndromes
Lynch syndrome
Familial adenomatous polyposis

KEY POINTS

Approximately 20% to 30% of patients with colorectal cancer have a potentially definable
inherited cause.

Our understanding of familial predisposition to colorectal cancer and colorectal cancer
syndromes has significantly increased due to advances in next-generation sequencing
technologies.

A personalized approach to colorectal cancer prevention requires appropriate assess-
ment of familial and genetic risk of colorectal cancer development.

INTRODUCTION

Approximately 20% to 30% of patients with colorectal cancer (CRC) have a potentially
definable inherited cause. Most families with a history of CRC and/or adenomas do not
carry genetic variants associated with cancer syndromes; this is called common famil-
ial CRC. Individuals with a family history of CRC are at increased risk for developing
CRC; the magnitude of risk depends on the number of relatives with CRC, whether
the relatives are first-degree relatives (FDR) versus second-degree relatives, and the
age at which their relatives were diagnosed with CRC. Studies have reported an esti-
mated 2-fold increase in risk of CRC in individuals with 1 or more FDR with CRC
compared with individuals without a family history.1–5 Furthermore, the age of CRC
diagnosis in a relative affects the risk of CRC. A systematic review found that in

a
University of Puerto Rico Comprehensive Cancer Center, PMB 711 89 De Diego, De Diego
Avenue 105, Rio Piedras, PR 00927-6346, USA; b Department of Medicine, Biochemistry and
Surgery, University of Puerto Rico Medical Sciences Campus, PO BOX 365067, San Juan, PR
00936, USA
* Corresponding author. University of Puerto Rico Comprehensive Cancer Center, PMB 711 89
De Diego, De Diego Avenue 105, Rio Piedras, PR 00927-6346.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 593–607

https://doi.org/10.1016/j.gtc.2022.06.001 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
594 Ballester & Cruz-Correa

persons with an FDR who were diagnosed with CRC at an age of 50 years or younger,
the relative risk of CRC was 3.55 (95% confidence interval [CI], 1.84–6.83) compared
with 2.18 (95% CI, 1.56–3.04) for individuals with an FDR who were diagnosed with
CRC at an age older than 50 years.1
Approximately 3% to 5% of CRCs are associated with hereditary cancer syn-
dromes. Our understanding of familial predisposition to CRC and inherited CRC syn-
dromes has significantly improved due to advances in next-generation sequencing
technology, which has led to more effective identification of individuals with germline
pathogenic variants and tailored management for the proband and at-risk family mem-
bers to effectively decrease CRC incidence and mortality. Hereditary CRC syndromes
are a group of conditions that are associated with an increased lifetime risk of colo-
rectal adenocarcinoma and extraintestinal malignancies. There are several hereditary
CRC syndromes, assigned to categories of polyposis or nonpolyposis syndromes.
Criteria to be considered in differentiating the various hereditary cancer syndromes
include polyp distribution throughout the gastrointestinal (GI) tract, polyp number,
the presence of extraintestinal manifestations or malignancy, and family history. Iden-
tification of relevant causative genes has improved our understanding of specific he-
reditary cancer syndromes including phenotypic characteristics and associated
cancer risks.

Nonpolyposis Colorectal Cancer Syndromes

Lynch syndrome
Lynch syndrome is the most common CRC syndrome, accounting for approximately
3% of all newly diagnosed CRC cases.6,7 In addition, it accounts for nearly 10% of
CRC diagnosed at the age of 50 years. Lynch syndrome is an autosomal dominant dis-
order caused by germline pathogenic variants in the mismatch repair (MMR) genes
MLH1, MSH2, MSH6, or PMS2, as well as the EPCAM gene, in which deletions in
EPCAM cause epigenetic silencing of MSH2. Although CRC is the most common can-
cer, Lynch syndrome is also associated with a predisposition for developing extraco-
lonic cancers, including cancers of the endometrium, ovaries, stomach, small
intestine, hepatobiliary system, pancreas, and brain, as well as transitional cell carci-
noma of the ureters and renal pelvis.8 Specific MMR gene alterations are associated
with different phenotypes and cancer risks. The risk of CRC associated with patho-
genic variants in MLH1 and MSH2 ranges from 58% to 82%, with mean age of diag-
nosis ranging from 44 to 61 years.9–14 A weaker phenotype is associated with
pathogenic variants in the more prevalent genes, MSH6 and PMS2, with CRC risks
of 10% to 22% with mean age of 55 to 66 years.9,10,12,14–17 Pathogenic variants in
MSH6 and PMS2 might be more commonly detected in individuals with CRC (regard-
less of age at diagnosis, family history, or results of tumor testing), than MLH1 and
MSH2 variants, which are more commonly identified in individuals at high risk for
CRC. In an international population–based study of 5744 CRC cases, the pathogenic
variant in MLH1 was estimated to occur in 1 in every 1946 persons with CRC, patho-
genic variants in PMS2 were estimated to be 1 in 714, and 1 in 758 for those with path-
ogenic variants in MSH6.18

Diagnosis
The genetics of both the tumor and the germline have an important role in the diag-
nosis of Lynch syndrome. Approximately 90% of colorectal and extraintestinal tumors
from patients with Lynch syndrome exhibit microsatellite instability (MSI). In addition,
most of the Lynch syndrome tumors exhibit a unique histopathology characterized by
the absence of expression of one of the MMR proteins on immunohistochemistry
 Familial Predisposition to Colorectal Cancer 595

(IHC)19–23; therefore, tumor testing is a key component in the diagnosis of Lynch syn-
drome, in addition to family history. Universal tumor testing of all individuals with newly
diagnosed CRCs at the the age of 70 years or younger for MMR deficiency is a recom-
mended strategy to screen for Lynch syndrome, in order to identify those individuals
who will need germline genetic testing. If there is no tissue available for MSI or IHC
testing, it is reasonable to begin with germline genetic testing in a patient with cancer.
Several computer-based clinical prediction models based on personal and family
history have been developed as alternative modalities to provide systematic genetic
risk assessment for Lynch syndrome. These risk models include the prediction of
MMR gene mutations (PREMM),24–26 MMRPredict,27 and MMRpro.28 The PREMM
model has been most extensively validated and has been updated to include all 5
genes associated with Lynch syndrome (PREMM5 model).25

Screening and management

Intensive cancer screening and surveillance strategies, including frequent colonos-
copy and risk-reducing surgeries for the prevention of endometrial and ovarian can-
cer, are mainstays in the clinical management of individuals with Lynch syndrome.
Surveillance of other organs, such as small intestine, pancreatic and biliary systems,
or brain, is not supported by evidence although recommendations by expert
consensus panels may vary.
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a
double-blind, placebo-controlled, randomized trial to determine the role of aspirin in
preventing CRC in patients with Lynch syndrome.29 Results from this study supported
the use of aspirin for prevention of CRC in Lynch syndrome without significant differ-
ences in adverse events between the aspirin and placebo groups. However, experts
believe the evidence is not sufficiently robust to recommend its standard use.14
Results from a recent study support the concept of frameshift peptide neoantigen
vaccination as a promising strategy for the immunoprevention of intestinal mismatch
repair deficiency (MMRD) tumors, particularly for individuals with Lynch syndrome.30
These results were limited to a mouse model, and clinical effectiveness needs to be
demonstrated in clinical trials.

Lynch-like syndrome
Lynch-like syndrome (LLS) relates to MMR-deficient CRC cases that are not caused
by germline MMR mutations (or MLH1 hypermethylation). LLS is observed in 2.5%
to 4% of individuals with CRC.31,32 The incidence of CRC in patients with LLS is
increased (standard incidence ratio, 2.12; 95% CI, 1.16–3.56) compared with patients
with colorectal tumors that have not lost MMR proteins (0.48; 95% CI, 0.27–0.79).31
These individuals have a lower incidence of cancer in their families than patients
with Lynch syndrome and have low rates of synchronous and metachronous CRC.
The implications of this recently identified colorectal tumor phenotype on screening
and surveillance recommendations are unclear. Recommendations for CRC screening
are based on family history of CRC.33

Familial colorectal cancer type X

Familial CRC type X refers to individuals suspected of having Lynch syndrome based
on family history of CRC (Amsterdam criteria: 3 relatives in 2 generations) and young-
onset CRC diagnosed before the age of 50 years but do not carry pathogenic MMR
gene variants and whose colorectal tumors are MMR proficient.34 The risk of CRC
in patients with familial CRC syndrome X is estimated to be twice that of the general
population (standard incidence ratio, 2.3, 95% CI, 1.7–3.0) and modest compared with
Lynch syndrome with defects in MMR (standard incidence ratio, 6.1, 95% CI, 5.7–7.2).
596 Ballester & Cruz-Correa

CRC surveillance recommendations are similar to those with family history of CRC
with colonoscopy every 5 years.
Polymerase proofreading–associated polyposis
Polymerase proofreading–associated polyposis (PPAP) is an autosomal dominant dis-
order associated with pathogenic variants in the DNA polymerase epsilon, catalytic
subunit gene (POLE) and DNA polymerase delta 1, catalytic subunit gene (POLD1)
that cause an oligo-polyposis phenotype, in which polyps are often fewer than those
in patients with familial adenomatous polyposis (FAP).35 PPAP is rare, only 0.12% to
0.25% of patients suspected of having FAP or familial CRC are found to have PPAP.
Although the precise risk and mean age of CRC development are still not clear, a study
found patients with mutations in POLE to have a 28% risk and patients with POLD1
mutations to have an 82% to 90% risk of CRC by age 70 years. The spectrum of can-
cer increases with age and includes, but is not limited to, endometrial, ovarian, small
bowel, and central nervous system.36–38
The AXIN2 gene regulates degradation of beta-catenin in the Wnt pathway. Patho-
genic variants in AXIN2 have been associated with autosomal-dominant colorectal
adenomatous polyposis. The phenotype seems similar to attenuated FAP. Tooth
agenesis is related to pathogenic variants in this gene and possibly breast and liver
cancer.
Polyposis Syndromes
Familial adenomatous polyposis
FAP is one of the most clearly defined polyposis syndromes and is estimated to occur
in one of 10,000 births. FAP is caused by pathogenic variants in the APC gene, on
chromosome 5q21, with nearly complete penetrance.39 Up to 25% to 30% of new
FAP cases are de novo, without any known clinical or genetic evidence of FAP in
the family.40 Individuals with classic FAP develop hundreds to thousands of colonic
adenomatous polyps at young ages, usually in the mid- to late teens and early
20s.41 CRC risk approaches 100% by age 50 years without intervention, which in-
volves prophylactic colectomy in young adulthood or when polyp burden becomes
too high to be managed endoscopically. Without treatment, 7% of patients with
FAP have CRC by age 21 years, 50% by age 39 years, and 90% by age 50 years.
The FAP mutation spectrum has been studied in a limited number of Hispanic coun-
tries. Most mutations identified in Hispanic patients from both Latin America, Portugal,
and Spain have been in exon 15 of the APC gene.42 This exon comprises more than
75% of the coding sequence and is the most commonly mutated region of the APC
gene.43
Clinical manifestations
In addition to a high risk of colon adenomas in patients with FAP, various extracolonic
manifestations have also been described, including upper GI tract adenomas and ad-
enocarcinomas. Fundic gland polyps occur in 50% or more of persons with FAP but
gastric cancer is uncommon, occurring in about 1% of patients. Duodenal adenomas
are found in up to 90% of patients with FAP, and cancer risk increases with age, reach-
ing 10%. In addition, there is a 0.5% to 2.0% risk of cancers of the thyroid, pancreas,
brain, and liver in the first decade of life. Benign growths are also a common feature of
FAP; there is a 20% to 30% incidence of osteoma and epidermoid cysts and a smaller
incidence of pilomatricomas, supernumerary teeth, and odontomas. Congenital hy-
pertrophy of the retinal pigment epithelium is common and relates to the location of
mutation in the APC gene. Desmoid tumors occur in 20% to 30% of patients with
FAP and although benign, are associated with significant morbidity and mortality.
 Familial Predisposition to Colorectal Cancer 597

A low-penetrance APC variant, I1307K is found in approximately 7% of Ashkenazi

Jews and is associated with a 2-fold increase in CRC risk without colonic polypo-
sis.44–46 There is little difference in the clinical presentation of individuals with sporadic
CRC and those with the APC I1307K variant. It is not clear whether risk of CRC is
further affected by family history of CRC in individuals with this mutation. Based on
available data, it is unclear whether the I1307K carrier state should guide decisions
regarding age to initiate screening or the frequency of screening.
Management
Management of FAP involves intensive endoscopic surveillance and appropriately
timed colectomy. Patients with attenuated FAP (AFAP) can delay initiation of endos-
copy for several years, with intensive surveillance intervals based on polyp burden.
Currently, there are no Food and Drug Administration–approved drugs for chemo-
prevention in FAP. Celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, and
sulindac, a nonspecific COX-2 inhibitor, have been associated with a decrease in
polyp size and number in patients with FAP, suggesting a potential role as chemopre-
ventive agents.47,48 However, some issues regarding the use of COX-2 inhibitors for
the treatment of colonic and duodenal polyps in patients with FAP include partial elim-
ination of polyps, complications from COX-2 inhibitors including cardiac-related
events, and loss of effect after the medication is discontinued.49 A study that evalu-
ated the efficacy of the combination of nonprescription supplements curcumin and
quercetin to regress adenomas in patients with FAP found that the combination seems
to reduce the number and size of ileal and rectal adenomas without appreciable
toxicity. Randomized controlled trials are needed to validate these findings.50 Addi-
tional chemoprevention strategies are currently under study.51
Attenuated familial adenomatous polyposis
AFAP is a less severe form of FAP associated with particular APC pathogenic variants,
including pathogenic variants at the 50 end of the APC gene and exon 4 in which pa-
tients can present with 2 to more than 500 adenomas, pathogenic variants at the 30
region in which patients have less than 50 adenomas, and exon 9–associated pheno-
types in which patients may have 1 to 150 adenomas without upper GI manifesta-
tions.52,53 Patients with AFAP have fewer colonic adenomas than those with classic
FAP and are predominantly located in the proximal colon. The emergence of ade-
nomas is believed to occur to patients in their mid- to late 20s.54 The average age
at diagnosis is greater than in classic FAP, at age 56 years.52,55,56 Patients with atten-
uated FAP may present with extracolonic manifestations including gastric and
duodenal adenomas; however, these occur less often than in patients with classic
FAP. AFAP may be challenging to diagnose without genetic testing. APC testing is
pivotal in the evaluation of these patients, as the differential diagnosis is broad and in-
cludes MUTYH, Lynch syndrome, biallelic mismatch repair deficiency, and polymer-
ase proofreading–associated polyposis (POLD1 and POLE).
Autosomal Recessive Polyposis Syndromes
MUTYH-associated polyposis
MUTYH-associated polyposis (MAP) is an autosomal recessive attenuated polyposis
syndrome caused by biallelic germline variants in MUTYH, a gene involved in DNA
oxidative damage repair. The phenotype of MAP is similar to that of AFAP. Individuals
with MAP can develop duodenal adenomas and cancer, as well as sebaceous gland
carcinomas and benign extraintestinal findings similar to patients with FAP. Biallelic
MUTYH pathogenic variants are found in 7% (95% CI, 6%–8%) of patients with 20
to 99 adenomas and 7% (95% CI, 6%–8%) of patients with 100 to 999 adenomas.57
598 Ballester & Cruz-Correa

Although the predominant polyp type is adenoma, serrated adenomas and hyper-
plastic polyps may also be seen in patients with MAP. Full gene sequencing of MUTYH
is recommended in individuals with polyposis without a pathogenic variant in the APC
gene. Specific mutations in the MUTYH gene that give rise to polyposis vary among
individuals from different countries. In Caucasians of northern European descent, 2
variants, Y179C and G396D, account for 70% of biallelic pathogenic variants in pa-
tients with MAP.58 CRC associated with MAP is predominantly right sided, may pre-
sent with synchronous lesions at presentation, and have a better prognosis
compared with sporadic CRC.59 Recommendations for colonic surveillance range be-
tween yearly to every 3 years beginning at age 18 to 30 years.60,61 If polyp burden
cannot be managed endoscopically or if there is evidence of advanced histology, total
colectomy with ileorectal anastomosis or subtotal colectomy should be considered
depending on polyp burden.
Monoallelic pathogenic variants in MUTYH are detected in up to 2% of the general
population. Monoallelic MUTYH pathogenic variants do not have much effect on CRC
risk (odds ratio 1.15;95% CI, 0.98–1.36) in the absence of family history of CRC.62 The
risk of CRC in monoallelic MUTYH carriers with a family history of CRC is approxi-
mately 2-fold compared with the general population.17 Similar to individuals with fam-
ily history of an FDR with CRC diagnosed before the age of 50 years, MUTYH
heterozygotes with an FDR with CRC warrant more intensive surveillance compared
with the general population.17,63
Constitutional mismatch repair deficiency syndrome
Constitutional mismatch repair deficiency syndrome (CMMRDS) is a rare autosomal
recessive polyposis syndrome caused by homozygous pathogenic variants in MMR
genes associated with Lynch syndrome.64 PMS2 gene is markedly overrepresented
in cases of CMMRD. This syndrome is characterized by early childhood onset of ma-
lignancies (hematologic, brain, small bowel, colorectal, ureter, bone/soft tissues) and
features of neurofibromatosis NF1, most notably café-au-lait macules.65 GI manifes-
tations include colonic polyposis, predominantly adenomas, and CRC, which typically
presents before the age of 20 years.64 The likelihood of CMMRD involving homozy-
gous MMR gene pathogenic variants is higher among consanguineous unions. No
consensus has been reached regarding surveillance guidelines for CMMRDS. Annual
colonoscopy, esophagogastroduodenoscopy (EGD), and capsule endoscopy starting
in the first decade of life is recommended by the International Biallelic MMR Deficiency
(BMMRD) Consortium and the European Consortium for the Care of CMMRD.66,67
NTHL1
The NTHL1 gene is associated with an autosomal recessive adenomatous polyposis
phenotype with an increased risk of CRC. Carriers of biallelic germline NTHL1 patho-
genic variants have extracolonic malignancies, including breast and endometrial can-
cer.68 Currently, there is no known risk of cancer for individuals with a single
monoallelic germline pathogenic variant in NTHL1. Cumulative cancer risk is uncer-
tain, and there is minimal data on optimal surveillance approach.
Other Polyposis Syndromes
Hereditary mixed polyposis syndrome
Hereditary mixed polyposis syndrome (HMPS) is a rare syndrome caused by patho-
genic variants in the GREM1 gene, a bone morphogenetic protein antagonist. This
syndrome has been associated with GREM1 pathogenic variants among Ashkenazi
Jews. The phenotype of HMPS is characterized by oligopolyposis, which includes a
variety of histology including adenomas, serrated adenomas, atypical juvenile polyps,
 Familial Predisposition to Colorectal Cancer 599

and hyperplastic polyps. It is also characterized by early onset CRC. There is high de-
gree of variability in polyp number, histology, and age of onset. Extracolonic malig-
nancies have been described in a small number of carriers.
Serrated polyposis syndrome
Serrated polyposis syndrome (SPS), previously referred to as hyperplastic polyposis
syndrome, is characterized by a predisposition to sessile serrated polyps. SPS is diag-
nosed based on clinical criteria, as the genetic cause remains elusive. Rarely, families
with SPS can be identified to harbor a germline pathogenic variant in the RNF43
gene.69,70 The World Health Organization diagnostic criteria for SPS include any
one of the following1: at least 5 serrated polyps proximal to the sigmoid colon with
2 or more of them larger than 10 mm in diameter2; any number of serrated polyps prox-
imal to the sigmoid colon in an individual who has an FDR with SPS; or3 more than 20
serrated polyps of any size distributed throughout the colon. Approximately half of the
SPS cases have a positive family history of CRC.71 The prevalence of CRC in patients
who meet criteria for SPS is 50% or more.71 Very limited data exist as to whether
extracolonic polyps or cancers are associated with SPS. Management includes colo-
noscopy with polypectomy. Removal of all polyps is preferred but not always feasible.
Colonoscopy should be repeated every 1 to 3 years, depending on the number, size,
and histology of polyps. Subtotal colectomy with ileorectal anastomosis should be
considered if polyposis cannot be controlled endoscopically or if there is evidence
of histologically advanced polyps or colon cancer. Data do not support extracolonic
cancer screening at this time. The National Comprehensive Cancer Network recom-
mends that FDR should have colonoscopy at the earliest of the following1: age 40
years2; same age as the youngest SPS diagnosis in the family3; 10 years before
CRC in the family in a patient with SPS.60 Further work is ongoing to better define
the cancer risks in probands and their relatives so that more accurate risk stratification
and screening recommendations can be made.
Hamartomatous Polyposis Syndromes
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited syndrome
caused by pathogenic variants in the STK11/LKB1 gene. Patient’s with this syndrome
develop histologically distinctive hamartomatous polyps of the GI tract and character-
istic melanocytic macules on the lips, perioral region, and buccal region.72,73 A high
risk for GI and non-GI cancers is integral to this condition, including malignancies in
the colon, stomach, pancreas, breast, and ovary. More than half of PJS cases have
colon polyps, and the risk for CRC is 39% at a mean age of 46 years.40 The cumulative
risks for breast cancer is estimated to be 32% to 54% and 21% for ovarian cancer.74
For pancreatic cancer, the risk has been estimated to be more than 100-fold higher
than for the general population.74
Diagnosis
Diagnosis is made based on evaluating for the presence of any one of the following: (1)
2 or more histologically confirmed PJS polyps; (2) any number of PJS polyps detected
in 1 individual who has a family history of PJS in close relatives; (3) characteristic
mucocutaneous pigmentation in an individual who has a family history of PJS in close
relatives; (4) any number of PJS polyps in an individual who also has characteristic
mucocutaneous pigmentation.75 In addition to these criteria, genetic testing is a stan-
dard part of clinical practice. Surveillance guidelines for PJS are empiric and based on
the risk for GI complications and cancer. A consortium review group has recommen-
ded EGD and colonoscopy starting at age 8 years.76
600 Ballester & Cruz-Correa

Management
Treatment involves endoscopic removal of polyps. Colectomy is sometimes neces-
sary if colonic polyp burden cannot be controlled endoscopically or if histology shows
neoplastic changes. Intussusception is the primary complication of small bowel
polyps, starting at a young age, and continuing throughout life. Surveillance and treat-
ment of the small bowel are based on prevention of this complication. Surveillance for
other extraintestinal cancers including breast, pancreas, and ovarian is
recommended.

Juvenile polyposis syndrome

Juvenile polyposis syndrome (JPS) is a rare autosomal dominantly inherited condition
characterized by hamartomatous polyposis throughout the GI tract, predominantly in
the colon with childhood to early adult onset. JPS is caused by germline pathogenic
variants in the SMAD4 gene (also called the MADH4/DPC4), in approximately 15%
to 60% of cases,77 and pathogenic variants in the gene encoding bone morphogenic
protein receptor 1A, BMPR1A in approximately 25% to 40% of cases.78,79 A clinical
diagnosis of JPS is done when individuals fulfill one or more of the following criteria1:
more than 5 juvenile polyps in the colon or rectum2; juvenile polyps in other parts of the
GI tract3; any number of juvenile polyps in a person with a known family history of ju-
venile polyps.80 Colon polyps begin to develop in the first decade of life and if left un-
treated, CRC incidence approaches 68%, with a mean age of occurrence of 34 years.
Colorectal screening consists of colonoscopy starting at age 12 years and is repeated
every 1 to 3 years depending on polyp burden.77 Similarly, upper GI endoscopy should
be done every 1 to 3 years beginning at age 12 years or earlier if symptoms present.
The small bowel should be examined if duodenal polyposis is present.

Phosphatase and Tensin homology hamartoma tumor syndrome

PTEN hamartoma tumor syndrome includes several autosomal dominant disorders
that arise from mutations of the Phosphatase and Tensin homology (PTEN) gene.
The clinical phenotypes overlap considerably, and the conditions seem to be a spec-
trum of a single disease. The disorders include Cowden syndrome, Bannayan-Riley-
Ruvalcaba syndrome (BRRS), and adult-onset dysplastic gangliocytoma of the cere-
bellum (Lhermitte–Duclos disease). Approximately 85% of patients diagnosed with
Cowden syndrome and approximately 60% of patients with BRRS have a pathogenic
variant in the PTEN gene.81 Primary features include multiple hamartomas of the skin,
mucous membranes, GI tract, and other organs, as well as an increased risk of can-
cers of several sites, including CRC risk, which is modestly increased. Polyps of mul-
tiple histologic types, including ganglioneuromas, occur throughout the GI tract.
Screening and surveillance recommendations are based on expert opinion.

Identifying High-Risk Individuals: Who Is a Candidate for Genetic Evaluation and

Testing?
Referral for genetic evaluation for hereditary CRC syndromes is largely underused.
Many questions remain regarding the integration of a multigene panel into a screening
strategy and eligibility criteria to direct testing with multigene panels. Genetic evalua-
tion is an integral part of the risk assessment process, and referral to genetic special-
ists is recommended for high-risk individuals. Genetic specialists help to identify the
appropriate genetic testing options and educate patients on cancer risks attributed
to inherited susceptibility. They also provide tailored screening (Table 1) and surveil-
lance recommendations for the proband and at-risk family members based on the
interpretation of genetic test results.
 Table 1
Recommendations for colorectal cancer screening for individuals with hereditary cancer syndromes

Age to Initiate
Condition Gene Screening Screening Interval Comments
Lynch syndrome MMR genes: MLH1, 20–25 y 1–2 y —
MSH2, MSH6, PMS2
FAP APC 10–15 y 1y —
AFAP APC 25–30 y 1–3 y based on polyp burden —
MAP Biallelic variants in MUTYH 25–30 y 1–3 y based on polyp burden —
Monoallelic variants 40 y 5y Based on presence of CRC in family
in MUTYH
Juvenile polyposis SMAD4 and BMPR1A 15 y 1–3 based on polyp burden —
syndrome
PJS STK11/LKB1 15 y 2–3 y based on polyp burden —
PTEN hamartomatous PTEN 35 y 3–5 y based on polyp burden —

Familial Predisposition to Colorectal Cancer

tumors or Cowden
disease
Polymerase POLE, POLD1 25–30 y 2–3 y; 1–2 y if polyps —
proofreading–associated
polyposis
AXIN2, GREM1, 25–30 y 2–3 y; 1–2 y if polyps —
and biallelic
variants in NTHL1
Familial colorectal Unknown 5–10 y before 5y Defined as 3 relatives with CRC, in 2
cancer type X earliest CRC generations, 1 diagnosis before age 50
diagnosis in family y, with negative results from germline
testing for Lynch syndrome; consider
germline testing, such as multi-gene
panel testing
Family history None 40 y 5y Consider referral for genetic evaluation;
CRC (1 FDR) evaluate if PREMM5 of 2.5% or more

Data from Refs.45,60,85

601
602 Ballester & Cruz-Correa

Box 1
How to identify individuals with a high-risk personal and/or family history of cancer

Colon cancer diagnosed < 50 years of age

Multiple colonic malignancies present either synchronous or metachronous

Multiple primary cancers diagnosed, either colonic or extracolonic

Over a lifetime, 10 adenomas present or 2 histologically characteristic hamartomatous
polyps

Colon cancer in more than one generation of the individual’s family

Clustering of extracolonic cancers in family members

To decrease morbidity and mortality, institutions are adopting universal Lynch syn-
drome colorectal tumor testing, which has been endorsed by the National Compre-
hensive Cancer Network. This strategy has been shown to maximize sensitivity for
identifying individuals with Lynch syndrome compared with selection based on clinical
criteria.10 In addition, to try to systemize the evaluation of inherited CRC, risk assess-
ment tools have been developed, including the PREMM5 model to help identify which
individuals would benefit from germline testing for Lynch syndrome.82 These strate-
gies can be implemented in clinical practice to help recognize individuals at increased
risk based on phenotype and family history who will benefit from referral for genetic
evaluation and genetic testing.
Genetic evaluation of individuals with high colorectal polyp burden is often triggered
by the number of cumulative polyps (10 cumulative adenomas), the presence of mul-
tiple hamartomatous polyps, extracolonic cancers, and other manifestations of polyp-
osis syndromes. Identification of these patients is important because they may require
personalized interventions including frequent surveillance colonoscopies, EGDs, and
risk-reducing surgery such as prophylactic colectomy or colectomy for polyp burden
that cannot be managed endoscopically.
Taking a detailed history is pivotal in identifying patients with high-risk personal and
family history of cancer (Box 1).83,84 Assessing risk of CRC requires evaluation of can-
cer history in multiple generations and extends beyond CRC. Clinicians should obtain
a detailed history of CRC and extracolonic cancers (including, but not limited to uter-
ine, ovarian, gastric, and pancreatic cancers), age at diagnosis of any affected family
member, and personal and family history of colon polyps (in particular the number of
polyps they have had throughout their lifetime), to be able to differentiate polyposis
syndromes from nonpolyposis syndromes.

SUMMARY

To optimize our ability to identify individuals with pathogenic genetic variants before
CRC develops requires effective implementation of strategies for genetic risk assess-
ment and testing, followed by tailored screening and surveillance recommendations.
The introduction into clinical practice of next-generation sequencing technology has
changed the traditional paradigm to hereditary cancer risk assessment, which was
based on phenotype-driven genetic testing. We have now transitioned to multigene
panel testing, which has the advantage of detecting germline mutations that would
not have been discovered based on phenotype and clinical guidelines. This change
in approach has led to more effective management of patients with potentially high-
risk CRC and a decrease in CRC incidence and mortality.
 Familial Predisposition to Colorectal Cancer 603

CLINICS CARE POINTS

Taking a detailed history, including history of CRC and extracolonic cancers, age at diagnosis
of any affected family member, and personal and family history of colon polyps is pivotal in
identifying patients with high-risk personal and family history of cancer.

Universal tumor screening is recommended to identify high-risk individuals by testing all CRC
tumors for molecular features suggestive of Lynch Syndrome.

DISCLOSURE

Dr V. Ballester has nothing to disclose. Dr M. Cruz-Correa—pharmaceutical industry

research support: Merck, Bristol, SeaGen, QED, Abbvie, Janssen, Regeneron, MIR-
ATI, Gilead, and Pfizer. Chief Medical Officer and stock ownership, Pan American
Center for Oncology Trials. Governing board memberships (voluntary): American As-
sociation for Cancer Research, Precision Oncology Alliance, American Association for
Cancer Institutes, and Foundation for Clinical Oncology.

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and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up
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A G a s troen t ero l o g i s t ’s
Approach to the D iagnosis
a n d M ana g emen t o f
G a s t ro i n t e s t i n a l S t ro m a l Tu m o r s
Raquel E. Davila, MD

KEYWORDS
 Gastrointestinal stromal tumors  GIST  GI stromal tumors  Subepithelial lesions
 Endoscopic ultrasound  Endoscopic ultrasound fine-needle aspiration
 Endoscopic ultrasound fine-needle biopsy  Endoscopic biopsy

KEY POINTS
 Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal
(GI) tract, omentum, mesentery, and peritoneum.
 The majority of GISTs harbor gain-of-function mutations of the c-KIT proto-oncogene
which encodes a tyrosine kinase receptor that regulates cell growth.
 Mutations of c-KIT lead to constitutive activation of the tyrosine kinase receptor, which in
turn leads to oncogenic cell transformation.
 Tumor location, size, and mitotic index are factors used to predict the risk of malignant
behavior.
 Endoscopy and endoscopic ultrasound play a critical role in the evaluation and diagnosis
of GISTs, and can significantly impact the management of these tumors.

DEFINITION, PROPOSED PATHOGENESIS, AND IMMUNOHISTOCHEMISTRY OF

GASTROINTESTINAL STROMAL TUMORS

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors
of the gastrointestinal (GI) tract. These tumors were previously misclassified as
smooth muscle tumors of the GI tract, including leiomyomas and leiomyosarcomas,
but are now defined as soft tissue sarcomas of the digestive system.1 Although GISTs
are typically found within the bowel wall, some tumors can also arise in the omentum,
mesentery or peritoneum, and are described as extragastrointestinal stromal tumors.2
GISTs are characterized by almost universal expression of the c-KIT proto-
oncogene protein.3,4 The c-KIT proto-oncogene is located in the long arm of chromo-
some 4, and it encodes a 145 kD transmembrane receptor that has internal tyrosine

University of Texas at Dallas, 4500 S. Lancaster Road, Dallas, TX 75216-7167, USA

E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 609–624

https://doi.org/10.1016/j.gtc.2022.06.009 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
610 Davila

kinase activity known as c-kit (receptor) or CD117. The binding of ligand known as
stem cell factor, causes dimerization and activation of the c-kit receptor. Once the re-
ceptor is activated, a series of intracellular signals are turned on resulting in cell
growth. In a landmark study published in Science in 1998, Hirota and colleagues re-
ported the finding of gain-of-function mutations in the c-KIT proto-oncogene in the
large majority of GISTs.5 These mutations result in the constitutive activation of
the c-kit receptor without ligand binding, leading to uncontrolled cell proliferation, in-
hibition of normal apoptotic cell death, and oncogenic cell transformation.5–7 Subse-
quently, the development of gain-of-function mutations of the c-KIT proto-oncogene
has been proposed as a key step in the pathogenesis of GISTs. A small minority of
GISTs harbor mutations of the platelet-derived growth factor receptor alpha
(PDGFRA), which result in ligand-independent activation of the receptor and similar
intracellular signal transduction.
Immunohistochemical analysis of tissue specimens can help differentiate GISTs
from other mesenchymal tumors of the GI tract. CD117 is an antigen on the extracel-
lular portion of the c-kit tyrosine kinase receptor and has become a term interchange-
able with the c-kit receptor. More than 95% of GISTs stain positive for CD117 on
immunohistochemical analysis.8,9 (Fig. 1) Leiomyomas, leiomyosarcomas, and other
mesenchymal tumors of the GI tract do not express the c-kit protein and are CD117
negative. DOG1 (Discovered On Gastrointestinal Stromal Tumors 1) is another marker
expressed in GISTs and can be found in greater than 95% of cases.10 (Fig. 1) Positive
staining for DOG1 is most helpful in identifying GIST cases where the tumor stains
negative for CD117.11 Approximately 60% to 70% of GISTs are positive for CD34, a

Fig. 1. (A) H & E stain of a GIST specimen showing spindle cell type histology with eosino-
philic cytoplasm and ovoid, elongated nuclei. (B) H & E stain of a GIST specimen showing
epithelioid type histology with round, irregular cells, and uniform, round nuclei. (C) Immu-
nohistochemical staining for CD117 demonstrating diffuse uptake. (D) Immunohistochem-
ical staining for DOG1 demonstrating diffuse uptake.
 Gastrointestinal Stromal Tumors 611

sialylated transmembrane glycoprotein and hematopoietic progenitor cell antigen

found in mesenchymal cells. In a study of 300 GIST cases, 90% of gastric, esopha-
geal, and rectal GISTs were found to stain positive for CD34, whereas only 50% of
small intestinal GISTs were CD34 positive.9 Although a small subset of small intestinal
GISTs can stain positive for smooth muscle actin (SMA), the majority of GISTs are
negative for SMA. GISTs are also typically negative for desmin and S100. Leiomyomas
usually stain positive for SMA and desmin, and are negative for CD117 and CD34.
Similarly, schwannomas, another class of benign mesenchymal tumors of the GI tract,
stain negative for CD117 and CD34, and are positive for S100 protein.
It has been proposed that GISTs arise from the interstitial cells of Cajal (ICCs) which
are a complex network of cells found within the muscle layers of the gastrointestinal
wall. The ICCs serve as a pacemaker system within the GI tract wall that regulates
gut motility.12 The development of ICCs appears to be dependent on normal c-kit ac-
tivity, with animal studies showing the inhibition of the normal development of ICCs
and disruption of gut motility in the setting of genetic mutations of c-KIT.12 Immuno-
histochemical studies of ICCs have shown identical patterns of staining to a range
of antigens compared with GISTs, including strong CD117 staining.13,14 Subse-
quently, it is thought that GISTs may originate from the ICCs or may evolve from a pre-
cursor pluripotential stem cell that differentiates toward a pacemaker cell
phenotype.13,15 Since the ICCs are normally found within the GI tract wall, it has
been suggested that rare ICCs may migrate to other sites during embryologic devel-
opment and can lead to extragastrointestinal stromal tumors.

EPIDEMIOLOGY

In a systematic review of 29 studies of more than 13,550 patients with GIST from 19
countries, the incidence of GISTs was estimated to be 10 to 15 cases per million pop-
ulation year.16 In the same study, the median age at presentation was in the mid 60’s
and there was no gender difference. In an analysis of GIST cases from the United
States Cancer Statistics database from 2001 to 2015, the overall incidence of GISTs
was 0.70 per 100,000 people per year.17 Furthermore, the incidence in blacks
increased with an annual percent change of 6.27 from 2001 to 2015.17 In a study of
the Surveillance, Epidemiology, and End Results (SEER) database for GISTs from
2002 to 2015, the incidence rate of GIST was 0.75 per 100,000 and was found to
be twice as high in African Americans compared to white patients.18 Overall, patients
with GIST tend to be older, and typically present in their 6th decade. In general, GISTs
are rarely seen in patients younger than 40, and are very rare in children. Hereditary
forms of GIST due to genetic alterations and germline mutations can occur in up to
5% of patients including primary familial GIST syndrome; neurofibromatosis type 1;
Carney–Stratakis syndrome; and Carney triad.

CLINICAL PRESENTATION

Up to 30% of GIST may be asymptomatic and can be identified incidentally at the time
of endoscopy, imaging, or surgery for other indications.3,19 The clinical presentation of
patients with symptomatic GIST depends on tumor location. Approximately 60% to
70% of GISTs occur in the stomach, 20% to 30% in the small intestine, 5% in the co-
lon and rectum, and less than 5% can be found in the esophagus and other sites (ap-
pendix, gallbladder, mesentery, omentum, retroperitoneum).4,20 In the stomach,
tumors are more commonly found in the cardia and fundus rather than in the body
and antrum. Small intestinal tumors tend to occur in the jejunum more than in the ileum
and are relatively rare in the duodenum. Rectal tumors are typically more common
612 Davila

than colonic GISTs. The majority of the gastric, small intestinal, and colonic GISTs pre-
sent with gastrointestinal bleeding (occult or overt), anemia, abdominal pain, or a
palpable mass on physical examination. Larger tumors can present with acute gastro-
intestinal bleeding, tumor rupture with ascites, small bowel obstruction, and perfora-
tion. Other presentations of gastrointestinal and extragastrointestinal tumors have
been described elsewhere.21

TUMOR HISTOPATHOLOGY

There are three main types of GISTs on histopathology including spindle cell type
(70%–80% of tumors), epithelioid type (20%–30%), and mixed type (<10%) (Fig. 1).
The spindle cell type consists of uniform eosinophilic cells arranged in short fascicles
or whorls, with pale eosinophilic cytoplasm, and uniform nuclei in an ovoid shape. The
epithelioid type has round or irregular cells with variable eosinophilic to clear cyto-
plasm. These cells have uniform nuclei which can be round or ovoid. The epithelioid
type can sometimes have a carcinoid-like appearance. The mixed type can have his-
tologic features of both the spindle cell and epithelioid types. The addition of immuno-
histochemical staining of tissue specimens with antibodies against CD117, CD34, and
other markers can confirm the diagnosis of GIST and can differentiate GISTs from
other mesenchymal tumors.

TUMOR BEHAVIOR AND PREDICTORS OF MALIGNANCY

Malignancy or malignant behavior is defined by: direct invasion to adjacent organs;

metastasis to extra-intestinal organs or the abdominal wall; omental, mesenteric, or
peritoneal seeding; and tumor recurrence after surgical resection.3,19 The majority
of metastases occur in the liver (50%), followed by the peritoneum, mesentery, and
omentum (<25%), lung (<10%), and bone (<10%). Lymph node metastases are
extremely rare, but have been reported in wild-type GISTs (<10% of all tumors) which
have no detectable c-KIT or PDGFRA mutations. Up to 30% of GISTs are considered
to be clinically malignant,3 although all GISTs have the potential to behave in a malig-
nant fashion. When tumors are intact without evidence of malignancy, the clinical chal-
lenge becomes accurately predicting which tumors are at risk of postoperative
recurrence or metastasis, so that surgical planning can be performed and selected tu-
mors can be targeted with medical therapy using tyrosine kinase inhibitors (see Man-
agement section).
Tumor size and mitotic index, or the number of mitoses seen per 50 high power field
(HPF), are the most widely used pathologic features for the risk stratification of
GISTs.22 In 2001, the NIH GIST Workshop developed a guideline for predicting malig-
nant behavior based on tumor size and mitotic index.23 In general, tumors that are
small (<5 cm) and have a low mitotic index (5 per 50 HPF) have a low risk for malig-
nancy, whereas large tumors (>5 cm) or tumors with high mitotic index (>5 per 50 HPF)
are associated with a high risk. However, the Workshop recommended considering
decreasing the size threshold for small intestinal tumors by 1 cm to 2 cm in each cate-
gory, as these tumors can exhibit more aggressive behavior compared with gastric tu-
mors. In 2006, a new risk stratification scheme was developed based on the Armed
Forces Institute of Pathology data on more than 1600 intestinal GISTs.24 (Table 1)
This scheme takes into account tumor size, mitotic index, and tumor location. Based
on this scheme, small GISTs that are 2 cm in size and have a low mitotic index (5
per 50 HPF) have no risk of malignant behavior, irrespective of tumor location. How-
ever, intestinal and rectal tumors >2 cm in size with a mitotic index of 5 per 50 HPF
have a significantly higher risk of malignancy compared to gastric tumors with the
 Gastrointestinal Stromal Tumors 613

Table 1
Risk stratification of GIST by mitotic index, tumor size, and tumor location based on data from
the Armed Forces Institute of Pathology

Tumor Parameters Risk of Progressive Diseasea (%)

Jejunum/
Mitotic Index Size Stomach Duodenum Ileum Rectum
5 per 50 hpf  2 cm None (0%) None (0%) None (0%) None (0%)
5 per 50 hpf >2  5 cm Very low (1.9%) Low (4.3%) Low (8.3%) Low (8.5%)
5 per 50 hpf >5  10 cm Low (3.6%) Moderate (24%) (Insuff. data) (Insuff. data)
5 per 50 hpf >10 cm Moderate (10%) High (52%) High (34%) High (57%)
>5 per 50 hpf  2 cm Noneb Highb (Insuff. data) High (54%)
>5 per 50 hpf >2  5 cm Moderate (16%) High (73%) High (50%) High (52%)
>5 per 50 hpf >5  10 cm High (55%) High (85%) (Insuff. data) (Insuff. data)
>5 per 50 hpf >10 cm High (86%) High (90%) High (86%) High (71%)

Abbreviations: GIST, gastrointestinal stromal tumor; hpf, high power field; Insuff, Insufficient.
a
Defined as metastases or tumor-related death.
b
Denotes small number of cases.
Adapted from Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis
at different sites. Semin Diagn Pathol. 2006;23(2):70-83; with permission.

same features. A modified scheme taking into account tumor size, mitotic index, tu-
mor location, and tumor rupture has also been proposed for the risk stratification of
patients with GIST.25

GENETIC MUTATIONS

More than 80% of GISTs harbor mutations of the c-KIT proto-oncogene which result in
constitutive activation of the c-kit tyrosine kinase without the binding of ligand.4,7,26,27
Mutations involving exon 11 of c-KIT are the most common, and occur in up to 70% to
85% of GISTs in a variety of locations throughout the GI tract.28–30 These mutations
affect the intracellular portion of the tyrosine kinase receptor in the juxtamembrane
domain. In a study of 124 patients with GIST, patients with exon 11 mutations had a
worse prognosis compared to mutation-negative cases, with a statistically significant
increase in tumor recurrence and decreased 5-year survival.31 Mutations of exon 9 are
found in 5% to 13% of GISTs and affect the extracellular dimerization domain of the
tyrosine kinase, which lead to the dimerization and activation of the receptor indepen-
dent of ligand.30 Exon 9 mutations are predominantly found in small intestinal tumors
and are associated with a more aggressive clinical behavior.32,33 Mutations affecting
exons 13, 14, 17, and 18 have also been described and are rare, occurring in less than
2% of cases. These mutations are seen more often as secondary mutations that
develop after treatment with tyrosine kinase inhibitors. Interestingly, c-KIT mutations
(predominantly exon 11 mutations) have been found in small incidental GISTs
measuring 1 cm.34 This supports the view that c-KIT mutations may be acquired
early in the development of GISTs.
PDGFRA mutations occur in 5% to 10% of GISTS and result in ligand-independent
activation of a tyrosine kinase receptor resulting in an intracellular signal transduction
pathway similar to what is seen with the c-kit receptor.35 c-KIT and PDGFRA muta-
tions are mutually exclusive in GISTs. Exon 18 mutations account for more than
80% of PDGFRA mutations and have 2 forms: D842V and non-D842V. The D842V
exon 18 mutation is more common (>60% of PDGFRA mutations), and has important
614 Davila

implications for tumor response to tyrosine kinase inhibitors (see Management sec-
tion).36 Exon 12 mutations comprise approximately 9% of PDGFRA mutations,
whereas exon 10 and 14 mutations are very rare.
There is a small subset of GISTs (5%) that do not harbor c-KIT or PDGFRA muta-
tions and are referred to as “wild-type.” These tumors may express mutations in the
genes encoding for subunits of the enzymes in the succinate dehydrogenase (SDH)
enzyme family.37 Mutations result in functional loss or deficiency of one of several en-
zymes in the SDH enzyme family. These mutations have been associated with
Carney–Stratakis syndrome (GIST and paragangliomas) and Carney triad (GIST, pul-
monary chondromas, and paragangliomas) in pediatric patients. Other genetic muta-
tions found in wild-type GIST may affect BRAF, NF-1 (neurofibromatosis type 1), and
NTRK (neurotrophic tyrosine kinase receptor).

IMAGING IN THE INITIAL EVALUATION OF GISTs

Radiologic imaging of GISTs can be used to characterize primary tumors, determine

location and size, rule out extension to other organs or adjacent structures, and rule
out metastatic disease. Computer tomography (CT) is the preferred modality for sus-
pected GISTs; however, magnetic resonance imaging (MRI) may be a reasonable
alternative.38–40 (Fig. 2) MRI may be considered in cases of rectal tumors.41 Positron
emission tomography (PET) is typically not used during the initial evaluation of patients
presenting with GIST; however, it may be used to establish a baseline prior to treat-
ment with tyrosine kinase inhibitors.

ENDOSCOPY AND ENDOSCOPIC ULTRASOUND

On endoscopic evaluation, GISTs usually appear as a subepithelial lesion (also known

as “submucosal” lesion) or a smooth bulge in the lumen of the GI tract. Lesions usually
have normal overlying mucosa, although there can be central ulceration or umbilica-
tion (Fig. 3). The differential diagnosis of a suspected GIST or subepithelial lesion
on endoscopy includes leiomyoma, lipoma, duplication cyst, granular cell tumor,
pancreatic rest, neuroendocrine tumor, glomus tumor, schwannoma, inflammatory
fibroid polyp, varices, endometriosis, metastatic cancer, lymphoma, or extrinsic
compression from an adjacent extramural structure.42,43 Probing of a suspected

Fig. 2. (A) Axial CT image of an ileal GIST. (B) Coronal CT image of the same ileal tumor.
 Gastrointestinal Stromal Tumors 615

Fig. 3. Endoscopic image of a gastric GIST appearing as a subepithelial lesion with central
ulceration.

GIST lesion with closed biopsy forceps can be done and may demonstrate a firm con-
sistency.42 Forceps biopsies are usually nondiagnostic as they typically cannot reach
deeper to the mucosa. Use of large capacity jumbo biopsy forceps with a bite-on-bite
or tunnel technique has been shown to have a low diagnostic yield.44,45 When ulcer-
ation is present, forceps biopsies of the ulcerated area should be considered as it may
be diagnostic, although this may not be recommended in the setting of GI bleeding.46
Video capsule endoscopy (VCE) and deep enteroscopy (DE) can be used to eval-
uate small-bowel tumors including GISTs (Fig. 4). In a large European multicenter
study including 5,129 patients undergoing VCE, 124 (2.4%) had small-bowel tumors,
including 112 primary tumors and 12 metastatic tumors.47 Nearly a third of the primary
small-bowel tumors (32%) were found to be GIST. In general, the diagnostic yield of
double-balloon enteroscopy (DBE) for small-bowel tumors is 9% to 14%.48 In a retro-
spective Japanese multicenter study of DBE in 1,035 consecutive cases, 144 small-
bowel tumors were identified, including 27 (18.8%) GISTs.49 In a meta-analysis
comparing VCE to DBE in patients with suspected small-bowel disorders, there was
no difference in the overall diagnostic yield or detection of small-bowel tumors.50
The advantage of deep enteroscopy is that it allows for biopsies of tumors, tattoo
placement for subsequent localization during surgery, and therapeutic interventions.
VCE can miss up to 18.9% of small-bowel tumors,51 and in this setting, DE can suc-
cessfully detect tumors missed by VCE.52,53 However, GIST may be subtle, especially
if exophytic, and can be missed on VCE followed by DE.54
Endoscopic ultrasound (EUS) is critical in the evaluation, characterization, and diag-
nosis of GISTs. Typically on EUS, GISTs appear as a hypoechoic mass lesion arising
from the fourth hypoechoic layer or muscularis propria.55–58 A subset of GIST can arise
within the muscularis mucosa and can be seen within the second wall layer. Some
GISTs can be found in the submucosa (third wall layer), and in these cases, it has
been suggested that these tumors originated from the muscularis propria or muscu-
laris mucosa and grew into the submucosa.59 GISTs are typically ovoid or elliptical
in shape, although they can be pedunculated or multilobular. In a study of CD117
616 Davila

Fig. 4. Video capsule endoscopy image of an ulcerated GIST in the ileum.

positive versus CD117 negative mesenchymal tumors of the upper GI tract, large size
greater than 4 cm, ulceration, cystic spaces, and nonesophageal location were EUS
features associated with a diagnosis of GIST.44 Overall, EUS has a sensitivity of
64.7% to 95% and specificity of 72% to 91.7%.60
EUS features may be helpful in identifying malignant tumors. In a study of 35 GISTs,
tumor size greater than 4 cm, irregular border, echogenic foci, and cystic spaces were
independent risk factors associated with malignancy.61 In cases where 2 out of 3 fea-
tures (irregular borders, echogenic foci, and cystic spaces) were present, the sensi-
tivity of EUS for detecting malignant GISTs was 80% to 100%. In a retrospective
study of 56 GISTs, the presence of cystic spaces and irregular margins were indepen-
dent predictors of malignancy.62 The combined presence of 2 out of 3 EUS features
(cystic spaces, irregular borders, and lymph nodes) had a positive predictive value
of 100% for malignant or borderline stromal cell tumors. Furthermore, size  3 cm, ho-
mogeneous echo pattern, and regular margins were EUS features associated with
benign GISTs. The presence of all 3 features combined had a specificity of 100%
for benign tumors. Additional retrospective studies have suggested that large tumor
size (>3 cm), ulceration, irregular tumor margins, and cystic spaces are associated
with malignant behavior.63–65 However, conflicting results have been reported, with
some studies showing no correlation between EUS features and risk of malig-
nancy.66,67 Further prospective studies are needed to determine the value of EUS fea-
tures in predicting malignancy.
More recently, enhanced EUS imaging with contrast-enhanced EUS (CE-EUS) or
elastography, and artificial intelligence (AI)-based applications have been used to
improve the accuracy of EUS in the diagnosis of GIST, and increase the predictive
value of EUS in determining malignancy. In a study of 157 patients with submucosal
lesions of the upper GI tract evaluated with CE-EUS, 84.5% of GISTs had hyperen-
hancement compared to 26.7% of non-GISTs.68 Furthermore, 36.2% of GISTs
showed inhomogeneous contrast enhancement compared to 13.3% of non-GISTs.
If hyperenhancement was considered to indicate GISTs, the sensitivity, specificity,
and accuracy were 84.5%, 73.3%, and 82.2%, respectively. In a study of 29 resected
GISTs, CE-EUS identified irregular vessels and thereby, predicted malignant GIST
 Gastrointestinal Stromal Tumors 617

with a sensitivity, specificity, and accuracy of 100%, 63%, and 83%, respectively.69
Tsuji and colleagues studied the diagnostic utility of EUS elastography in 25 gastric
submucosal tumors.70 Higher Giovannini elasticity scores (4–5) correlated with a diag-
nosis of GIST, whereas lower scores (2–3) correlated with a diagnosis of leiomyoma. In
a study of 631 subepithelial lesions (SELs) and 16,110 images, an AI-based diagnostic
system had an accuracy of 86.1% for differentiating SELs (GIST, leiomyoma, schwan-
noma, neuroendocrine tumor, and ectopic pancreas).71 The sensitivity, specificity,
and accuracy of the AI system for differentiating GISTs from non-GISTs were
98.8%, 67.6%, and 89.3%, respectively.
In general, EUS-guided fine-needle aspiration (EUS-FNA) is the preferred method
of diagnosis of GISTs. In a systematic review of 46 studies of EUS including 4,534
cases of GISTs, the diagnostic yield of EUS-FNA was 84% (73.8%–100%) compared
to 68.7% (40%–100%) for EUS alone. Some studies have suggested that certain fac-
tors may influence the diagnostic yield of EUS-FNA including lesion location (gastric
location being more favorable); tumor size (>2 cm more favorable); tumor shape (oval
or round more favorable than irregular); wall layer of origin (3rd or 4th layers more
favorable); and the presence of on-site cytopathologist.72,73 Factors such as needle
size and number of needle passes do not appear to influence diagnostic yield.
In addition to cytologic analysis, FNA specimens are normally evaluated with immu-
nohistochemical staining for CD117 and other markers to make the diagnosis of
GIST.74 In general, EUS-FNA alone is not helpful for predicting tumor behavior, as
the mitotic index is inconsistently present on FNA specimens.75 The addition of immu-
nohistochemical staining for Ki-67 (a labeling index that denotes mitotic activity and
cell proliferation) to FNA specimens may be helpful for predicting tumor risk of malig-
nancy. In a study of 23 GISTs, the use of Ki-67 combined with EUS-FNA cytology had
a sensitivity and specificity of 100% for malignant GIST.76
The addition of EUS-guided core biopsy to EUS-FNA is performed to increase
the diagnostic yield, and provide mitotic index, which can be used to risk-stratify
GISTs and potentially guide patient management. Initial studies on the use of
EUS-guided (Trucut core) biopsy, known as EUS-TCB, were performed using a
19 gauge Tru-cut needle which is no longer available on the market. Although initial
studies showed an increase in diagnostic yield with EUS-TCB, other studies
showed that EUS-TCB had either no improvement or only modest improvement
in diagnostic yield compared with EUS-FNA, mainly due to the high rate of failure
of EUS-TCB.77–79 In the past decade, a variety of needles have been introduced
to the market which have been effectively used for EUS fine-needle biopsy (EUS-
FNB) of subepithelial lesions and suspected GISTs. In a study of 229 patients
with subepithelial lesions, the sensitivity and accuracy of EUS-FNB were superior
to EUS-FNA (79.4% vs 51.9%, and 88% vs 77.2%, respectively).80 In a multicenter
study of 147 suspected GISTs, the diagnostic yield of EUS-FNB was 89%
compared to 37% seen with EUS-FNA.81
Several studies have now demonstrated the utility of EUS-FNB for mutational anal-
ysis to detect c-KIT and PDGFRA mutations prior to neoadjuvant treatment with tyro-
sine kinase inhibitors. DNA sequencing of FNB specimens is successful in 95% to
98% of cases.82–84 The detection of c-KIT and PDGFRA mutations allows for individ-
ualized, targeted therapy with tyrosine kinase inhibitors. (See Management section).

MANAGEMENT

A detailed review of the surgical and medical management of GISTs is beyond the
scope of this article and is outlined elsewhere.1
618 Davila

Surgical resection is the primary treatment for patients with localized tumors 2 cm
or potentially resectable lesions without evidence of metastasis.1 The goal is to
achieve complete resection. Segmental or wedge resection is recommended, and
wide margins of resection do not appear to be necessary. Lymphadenectomy does
not need to be performed as lymph node metastases are rare. Resection of patholog-
ically enlarged nodes should be considered in cases of SDH-deficient tumors. Lapa-
roscopic approach is preferred in select cases (tumors in the stomach anterior wall,
jejunum, and ileum), and may be associated with low recurrence, short hospital dura-
tion, and low morbidity.1,85
Imatinib is a selective inhibitor of several tyrosine kinases including c-KIT and
PDGFRA. The FDA approved imatinib in 2002 for the treatment of unresectable and
metastatic GIST. The optimal dose is 400 mg daily. Currently, imatinib is indicated
in the treatment of advanced diseases including tumors that are metastatic, and
locally invasive tumors. Imatinib is also indicated as adjuvant therapy for resected tu-
mors with high-risk features. Neoadjuvant therapy with imatinib is indicated in patients
with potentially resectable tumors with significant perioperative morbidity, locally
advanced unresectable tumors, borderline resectable tumors, and rectal tumors.
The presence and type of c-KIT or PDGFRA mutation have been identified as pre-
dictors of response to imatinib.1,86 Subsequently, genetic analysis for mutations or
genotyping, should be considered in patients undergoing neoadjuvant or adjuvant
therapy. In a study by Blanke and colleagues, response to imatinib was found to be
dependent on c-KIT mutation.87 Exon 11 mutations were associated with better sur-
vival.87 Furthermore, exon 9 mutations were associated with lower survival, and
increasing the dose of imatinib to 800 mg a day resulted in a benefit in progression-
free survival.87 Several randomized trials have shown that the presence of c-KIT
exon 11 mutation is associated with better response rates, progression-free survival,
and overall survival compared to exon 9 mutations or wild-type tumors.1 GISTs with
D842V exon 18 PDGFRA mutation are resistant to imatinib and should be treated
with alternative tyrosine kinase inhibitors. SDH deficient GISTs are poorly responsive
to imatinib and have higher probability of responding to sunitinib, another tyrosine ki-
nase inhibitor. Sunitinib is indicated in patients who are intolerant to imatinib, or who
are shown to have disease progression on imatinib. Other tyrosine kinase inhibitors
can be used in the setting of advanced GISTs with resistance to imatinib and sunitinib,
including regorafenib, sorafenib, nilotinib, dasatinib, and pazopanib.1
The management of small <2 cm, incidentally found, asymptomatic GISTs is contro-
versial. Surveillance with EUS can be considered in stomach GISTs less than 2 cm
with no high-risk EUS features (irregular border, heterogeneous echo pattern, pres-
ence of cystic spaces, and echogenic foci).1,88 The frequency of EUS surveillance is
not known, but every 12 months may be considered.88
Endoscopic resection of GISTs using a variety of endoscopic techniques has been
described.60 It can be performed in small (<2 cm) lesions of the stomach located within
the muscularis mucosa or submucosa. Resection of tumors in the muscularis propria
and tumors >2 cm in size has been reported with variable follow-up and is associated
with expected risk of perforation and bleeding. If performed, this should be done in
expert, high-volume centers. Additional studies are needed to determine the role of
endoscopic resection in the management of GIST.

SUMMARY

GISTs are mesenchymal tumors of the gastrointestinal tract that harbor oncogenic
mutations of c-KIT and PDGFRA. All GISTs have the potential to behave in a malignant
 Gastrointestinal Stromal Tumors 619

fashion. Several models have been proposed to risk stratify tumors based on location,
size, and mitotic index. EUS-FNA is the most reliable method of obtaining tissue diag-
nosis. EUS-guided fine-needle biopsy can be used to obtain core tissue specimens
which can then be analyzed for genetic mutations of c-KIT and PDGFRA. This informa-
tion can help determine neoadjuvant therapy in select patients. Current management
of patients includes surgical resection and tyrosine kinase inhibitors. Gastroenterolo-
gists currently play a critical role in the care of these patients.

CLINICS CARE POINTS

 All GISTs have the potential to behave in a malignant fashion.

 EUS with FNA and FNB are essential in the diagnosis and risk-stratification of GISTs.
 Surgical resection is the mainstay of treatment.
 Tyrosine kinase inhibitors can be used as neoadjuvant therapy in potentially resectable and
locally advanced unresectable GISTs. They are also indicated in the treatment of recurrent or
metastatic disease.

DISCLOSURE

The authors have nothing to disclose.

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G a s t ro e n t e ro p a n c re a t i c
N e u ro e n d o c r i n e Tu m o r s
Conrad J. Fernandes, MDa, Galen Leung, MD
b
, Jennifer R. Eads, MD
c
,
Bryson W. Katona, MD, PhDb,*

KEYWORDS
 Gastroenteropancreatic neuroendocrine tumor  Endoscopy
 Functional neuroendocrine tumor  Carcinoid syndrome

KEY POINTS
 The incidence of neuroendocrine tumors of the gastrointestinal tract and the pancreas
(GEP-NETs) is increasing.
 GEP-NETs are oftentimes discovered incidentally on imaging or during endoscopic eval-
uation for other indications.
 Upon diagnosis, it is critical to classify GEP-NETs based on their location, grade, stage,
and functionality, because these factors are important for prognosis and management.
 Management of GEP-NETs depends on multiple tumor-specific factors and can involve
surveillance alone, endoscopic therapy, surgery, somatostatin analogues, peptide recep-
tor radionuclide therapy (PRRT), liver-directed therapies, and systemic therapy with tar-
geted agents or chemotherapy.
 Gastroenterologists play a major role in the diagnosis, treatment, and surveillance of GEP-
NETs and should therefore be an integral part of all comprehensive GEP-NET manage-
ment teams.

INTRODUCTION

Neuroendocrine tumors (NETs) are an uncommon, heterogeneous group of tumors

arising from cells of neuroendocrine origin, which can be found at multiple sites
throughout the body. Although NETs have classically been considered more indolent

a
Department of Medicine, Hospital of the University of Pennsylvania, 3400 Civic Center
Boulevard, 751 South Pavilion, Philadelphia, PA 19104, USA; b Division of Gastroenterology
and Hepatology, Department of Medicine, Perelman School of Medicine at the University of
Pennsylvania, 3400 Civic Center Boulevard, 751 South Pavilion, Philadelphia, PA 19104, USA;
c
Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at
the University of Pennsylvania, 3400 Civic Center Boulevard, 751 South Pavilion, Philadelphia,
PA 19104, USA
* Corresponding author. Perelman Center for Advanced Medicine, University of Pennsylvania
Perelman School of Medicine, 3400 Civic Center Boulevard 751 South Pavilion, Philadelphia,
PA 19104.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 625–647

https://doi.org/10.1016/j.gtc.2022.06.002 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
626 Fernandes et al

than many other tumor types, there is now growing recognition that some NETs can be
aggressive, leading to substantial morbidity and mortality.1

EPIDEMIOLOGY

The incidence of NETs has increased in the last few decades, with the Surveillance,
Epidemiology, and End Results (SEER) database showing a 6.4-fold increase in the
age-adjusted incidence rate of NETs in the United States from 1973 to 2012, now
totaling 6.98 per 100,000.2 Similar trends are noted in other countries and across
different primary NET sites.3–7 Although some of this increased incidence may be
due to improved detection of earlier-stage asymptomatic lesions and an aging popu-
lation, there are likely other unknown factors contributing as well.2,5,8 The overall sur-
vival of patients with NETs has also improved over the last few decades.2 Although
increased detection of asymptomatic and indolent NETs likely plays a role in this trend,
the observed improved overall survival in metastatic NETs also results from improve-
ments in NET treatment modalities.2
NETs originate from multiple primary sites as illustrated in Fig. 1. Most NETs are
found in the luminal gastrointestinal (GI) tract or pancreas (55%–70%), collectively
known as gastroenteropancreatic NETs (GEP-NETs).9,10 The remainder of this review
focuses primarily on the diagnosis and management of GEP-NETs.

CLASSIFICATION
Location
GEP-NETs themselves are heterogeneous and can be located throughout the GI tract.
These tumors can be subgrouped based on location and classified as gastric, small
bowel (including duodenal/ampullary and jejunal/ileal), pancreatic, and colonic (including
colonic, rectal, and appendiceal) NETs. The relative proportions of these subgroups are
shown in Fig. 1. GEP-NET location is important in diagnosis and management and may
help define prognosis because overall survival varies by location, with pancreatic NETs
having the worst median overall survival and rectal NETs having the best.1,7 GEP-NET
location is also particularly important for management because pancreatic NETs (pNETs)
have some unique treatment options that are not used for luminal NETs.11
Grading
GEP-NET grade is assigned as G1, G2, or G3 as outlined by the most recent World
Health Organization definitions from 2019.12 Grade is based on histologic character-
istics of the tumor including differentiation, mitotic rate, and Ki-67 indices as outlined
in Table 1. Tumor grading should be performed on all newly diagnosed GEP-NETs,
because NET grade is important for management and prognosis.13 While NETs are
by definition well-differentiated tumors, neuroendocrine carcinomas (NECs) are poorly
differentiated tumors with distinct molecular differences from NETs.14 Collectively,
NETs and NECs fall under the umbrella term of neuroendocrine neoplasms (NENs).
GEP-NECs are divided into large-cell type and small-cell type based on histology,
with approximately 60% of GEP-NECs being large-cell type.15 Overall survival of
GEP-NECs is poor, with a median survival ranging from 5 months in metastatic dis-
ease to 38 months in localized disease.16 Given the scope of this article, the remainder
of this review focuses only on GEP-NETs.
Functional Versus Nonfunctional
NETs can also be classified as functional or nonfunctional based on their ability to
secrete hormones. Most GEP-NETs are nonfunctional (approximately 60%), although
 Gastroenteropancreatic Neuroendocrine Tumors 627

Fig. 1. Distribution of NETs. The relative distribution of NETs based on data from the SEER
database. (Data from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid
tumors. Cancer. 2003;97(4):934-959 and Sackstein PE, O’Neil DS, Neugut AI, Chabot J, Fojo
T. Epidemiologic trends in neuroendocrine tumors: an examination of incidence rates and
survival of specific patient subgroups over the past 20 years. Semin Oncol. 2018;45(4):249-
258)

the incidence of functional GEP-NETs may be increasing.17 Functional GEP-NETs can

present with a wide variety of clinical syndromes that depend on the site of origin of the
tumor. Functional pNETs include insulinomas, gastrinomas, VIPomas, glucagonomas,
and somatostatinomas, which are found mainly in the pancreas, and also sometimes
in the duodenum (Table 2). NETs arising in the intestinal tract, especially those of small
bowel origin, are known to cause carcinoid syndrome. Carcinoid syndrome is associ-
ated with secretory diarrhea (58%–100%), skin flushing (45%–96%), wheezing (3%–
18%), pellagra-like skin lesions (1%), and right-sided heart disease (11%–70%),

Table 1
Classification and grading criteria of neuroendocrine neoplasms of the gastrointestinal tract
and pancreas

Mitotic
Rate
(Mitoses/
2 mm2 or
Mitoses/ Ki-67
Classification Differentiation Grade 10HPFs) Index
Grade 1 NET (G1) Well differentiated Low <2 <3%
Grade 2 NET (G2) Well differentiated Intermediate 2–20 3%–20%
Grade 3 NET (G3) Well differentiated High >20 >20%
NEC Poorly differentiated High >20 >20%

Characteristics used to classify NENs, including NETs and NECs.

Abbreviations: HPFs, high-power fields; NEC, neuroendocrine carcinoma; NEN, neuroendocrine
neoplasm.
Adapted from Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumors of
the digestive system. Histopathology. 2020;76(2):182–188; with permission.
 628
Fernandes et al
Table 2
Most common functional pancreatic neuroendocrine tumors

Incidence
per
100,000/ Primary Tumor Secreted
Tumor Type year Location Malignant Hormone Important Clinical Associations Clinical Syndrome
Insulinoma 1–3 Pancreas 5%–15% Insulin Hypoglycemia, neuroglycopenic N/A
symptoms (visual changes,
confusion, seizures), autonomic
symptoms (diaphoresis
palpitations)
Gastrinoma 0.5–1.5 Duodenum 60%–90% Gastrin Peptic ulcer disease, esophagitis, Zollinger-Ellison syndrome
(70%), pancreas diarrhea, abdominal pain
(25%), gastrinoma
triangle
VIPoma 0.05–2 Pancreas 70%–90% VIP Diarrhea, achlorhydria/ Verner-Morrison syndrome,
hypochlorhydria, hypokalemia, WDHA syndrome, pancreatic
dehyration cholera syndrome
Glucagonoma 0.01–0.1 Pancreas 60%–75% Glucagon Diabetes mellitus, necrolytic N/A
migratory erythema (rash),
weight loss
Somatostatinoma <0.1% Pancreas 40%–60% Somatostatin Diabetes mellitus, cholelithiasis, N/A
diarrhea (steatorrhea)

Incidence and clinical characteristics of the more common functional pNETs.

Abbreviations: N/A, not applicable; VIP, vasoactive intestinal peptide; WDHA, watery diarrhea-hypokalemia-achlorhydria.
Adapted from Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin
Gastroenterol. 2012;26(6):737–753; with permission.
 Gastroenteropancreatic Neuroendocrine Tumors 629

also known as cardiac carcinoid. Carcinoid syndrome can be present in up to 20% of

patients with a small bowel NET.18–20 Symptoms of carcinoid syndrome result from
NET secretion of multiple vasoactive products, including serotonin and serotonin me-
tabolites.18 Oftentimes carcinoid syndrome only arises from NETs with substantial
liver metastases, because hepatic metabolism normally neutralizes vasoactive sub-
stances secreted by NETs into the portal circulation before they reach the systemic
circulation. However, carcinoid syndrome can arise in the absence of extensive hepat-
ic disease, particularly in patients with a large tumor burden.18,21–24

PRESENTATION AND DIAGNOSIS OF GASTROENTEROPANCREATIC

NEUROENDOCRINE TUMORS

There are differences in the presentation and diagnosis of GEP-NETs based on pri-
mary tumor site; therefore, each primary tumor site is reviewed separately. Diagnosis
of GEP-NETs often relies on multiple different modalities, including endoscopy, sur-
gery, laboratory tests, and imaging. The widespread use of endoscopy has led to
an increase in the diagnosis of early-stage GEP-NETs.25 In addition, although tradi-
tional cross-sectional imaging modalities such as computed tomography (CT) and
MRI are frequently used in NET diagnosis, there have also been great improvements
in functional somatostatin-receptor-based imaging using 68Ga-DOTATATE, 68Ga-
DOTATOC, and 64Cu-DOTATATE that have substantially improved the ability to image
GEP-NETs.26,27
Gastric
Presentation
Gastric NETs (gNETs) can present with nonspecific symptoms such as abdominal
pain, anemia, or GI bleeding but can also be identified incidentally on endoscopy.
gNETs are divided into 3 subtypes with different characteristics, mechanisms of
tumorigenesis, and metastatic potential as outlined in Table 3.28,29 Type 1 gNETs typi-
cally arise in the setting of chronic atrophic gastritis, resulting from either autoimmune
gastritis or Helicobacter pylori-associated atrophic gastritis, which leads to loss of pa-
rietal cells, an increase in gastrin levels, and resulting hypertrophy of
enterochromaffin-like cells. There is emerging evidence that long-term treatment
with proton pump inhibitors (PPIs) can also lead to elevated gastrin levels, which
can be associated with the development of type 1 gNETs.30,31 Type 2 gNETs are typi-
cally associated with Zollinger-Ellison syndrome, a rare syndrome in which a gastri-
noma leads to elevated gastrin levels, and which can be associated with multiple
endocrine neoplasia type 1 (MEN1) syndrome.32 Although localized gNETs are most
frequently asymptomatic, individuals with Zollinger-Ellison syndrome-associated
type 2 gNETs may have substantial upper GI symptoms resulting from reflux esoph-
agitis and peptic ulcer disease due to acid hypersecretion.28 Type 3 gNETs develop
independently of hypergastrinemia and occur sporadically, yet these gNETs are the
most aggressive and are associated with the worst prognosis.
Diagnosis
gNETs are most frequently identified incidentally on esophagogastroduodenoscopy
(EGD) being performed for other indications, and will most often present as polypoid
lesions predominantly found in the fundus or body of the stomach.28 Type 1 gNETs will
typically be associated with flattened gastric folds and atrophic-appearing gastric mu-
cosa, often coupled with an elevated gastric pH (while off acid suppression ther-
apy).28,33 In contrast, type 2 gNETs are found along with hypertrophied gastric
folds, and can be associated with a low gastric pH (while off acid suppression
630 Fernandes et al

Table 3
Comparison of gastric neuroendocrine tumor subtypes

Type 1 Type 2 Type 3

Proportion of all 70%–80% 5%–10% 15%–20%
gastric NETs
Location Body and fundus Body and fundus Body and fundus
Size Small (<2 cm) Small (<2 cm) Large (>2 cm)
Number of tumors Frequently multiple Frequently multiple Single lesion
Associated Chronic atrophic Gastrinoma None
conditions gastritis, possibly (Zollinger-Ellison
chronic PPI use syndrome), MEN1
syndrome
Fasting serum [ [ Normal
gastrin level
Gastric pH [ Y Normal
Gastric mucosa Atrophic Hypertrophic Normal
appearance
Invasion Rare Intermediate Common
Lymph node 5%–10% 10%–20% 50%–100%
metastases
Prognosis Excellent Very good Similar to gastric
adenocarcinoma

Characteristics, distinguishing features, and prognostic features of the subtypes of gastric NETs.
Abbreviations: [, Increase; Y, decrease; MEN1, multiple endocrine neoplasia type 1; PPI, proton
pump inhibitor.
Adapted from Grozinsky-Glasberg S, Alexandraki KI, Angelousi A, Chatzellis E, Sougioultzis S,
Kaltsas G. Gastric carcinoids. Endocrinol Metab Clin North Am. 2018;47(3):645-660; with
permission.

therapy), especially in the setting of Zollinger-Ellison syndrome.33 Endoscopically,

type 1 and 2 gNETs, which arise from the mucosa or muscularis mucosa and may
invade into the submucosa, generally appear as multiple smooth round subepithelial
or polypoid lesions.34 There may also be a red or yellow mucosal hue with central
depression.34 Type 3 gNETs usually appear as a single lesion with signs of ulceration,
indicating deeper invasion.35 Type 1 and 2 gNETs are also usually smaller in size (<1–
2 cm) compared with type 3 gNETs, which can often be greater than 2 cm.28 Diagnosis
of a gNET is typically made endoscopically via forceps biopsy or after gastric polypec-
tomy. If suspicion for a gNET is high on the index EGD, biopsies should be obtained
from the antrum and body to assess for underlying atrophic gastritis, intestinal meta-
plasia, and H pylori. In addition, a gastric pH and fasting serum gastrin level should be
obtained.28 Gastric pH and fasting gastrin levels can both be altered by chronic PPI
use, therefore, ideally a PPI should be stopped for 1 to 2 weeks before testing if clin-
ically safe to do so.36
Once a histologic diagnosis of a gNET is made, other ancillary data are critical to
determine the type of gNET. Elevated serum gastrin levels can help differentiate be-
tween type 1/2 (elevated gastrin) and type 3 (normal gastrin). Gastric biopsies showing
atrophic gastritis, an elevated gastric pH (off acid suppression therapy), and positive
anti-parietal cell and anti-intrinsic factor antibodies would be consistent with a type 1
gNET in the setting of chronic autoimmune atrophic gastritis, where resulting hyper-
gastrinemia would be considered appropriate. Normal gastric histology, a low gastric
pH, and inappropriately elevated gastrin level would be consistent with a type 2 gNET.
 Gastroenteropancreatic Neuroendocrine Tumors 631

With type 2 gNETs further localization of a causative gastrinoma may be warranted

with cross-sectional and/or functional imaging. Finally, because type 3 gNETs are
not gastrin driven, fasting gastrin levels in these cases are typically normal.
If a type 1 gNET is suspected, endoscopic ultrasonography (EUS) can be consid-
ered to look for depth of invasion and lymph nodes in larger tumors (>1–2 cm), but
is not necessary if less than 1 cm.28 If a type 2 gNET is suspected, the duodenum
should be carefully inspected for a duodenal gastrinoma given the concern for
Zollinger-Ellison syndrome.33 In these cases, EUS as well as cross-sectional/
functional imaging are also performed to look for a gastrinoma in the gastrinoma trian-
gle (duodenal sweep, porta hepatis, and pancreatic head/body). If a type 3 NET is sus-
pected, EUS should be performed to assess for depth of invasion and the presence of
lymph nodes.33 In addition, with type 3 NETs, patients should undergo cross-sectional
and functional imaging.

Duodenal and Ampullary

Presentation
Duodenal and ampullary NETs (dNETs) make up a small minority of NETs originating
from the small intestine with 90% of dNETs being located in the first or second part of
the duodenum.9,10,37 Among dNETs, ampullary lesions have a higher risk of metas-
tasis and worse survival compared with those arising from other areas of the duo-
denum.38 There are 4 distinct types of NETs that can originate in the duodenum
including gastrinoma, somatostatinoma, gangliocytic paragangliomas, and nonfunc-
tioning dNETs.39 Most dNETs are nonfunctional, and therefore these tumors are often
incidentally discovered on EGD being performed for other indications40; however,
dNETs can also present with clinical syndromes. Ampullary dNETs may present
with jaundice if there is biliary obstruction. Gastrinomas are the most frequent func-
tional dNET (27% to 58% of cases) and are associated with Zollinger-Ellison syn-
drome, which can present with abdominal pain and diarrhea, as well as severe
esophagitis and peptic ulcer disease.41 Somatostatinomas can also arise in the duo-
denum, often localizing in the periampullary region, and can present with clinical
symptoms including weight loss and abdominal pain, as well as in some cases dia-
betes mellitus, steatorrhea and diarrhea, and cholelithiasis.42

Diagnosis
dNETs are often diagnosed incidentally on EGD. However, dNETs may be inacces-
sible with a standard upper endoscope, especially if they are located in the third or
fourth portion of the duodenum or in the periampullary region. These tumors usually
appear as small solitary lesions, except in the case of gastrinomas, which may appear
as multiple lesions.35 dNETs have an increased rate of lymph node metastases, even
when small in size, with a 2003 study showing that 11% of dNETs less than or equal to
5 mm in size had lymph node metastases.43 Therefore EUS as well as cross-sectional
and functional imaging are important to properly stage dNETs. If the tumor has not
invaded the muscularis propria, is less than 1 cm in size, and there is no evidence
of lymph node involvement, endoscopic resection may be appropriate (discussed
later).44 If there is suspicion for a gastrinoma or somatostatinoma additional laboratory
workup is also indicated.

Pancreatic
Presentation
pNETs (pNETs) are most commonly identified incidentally on an imaging study as
most pNETs are nonfunctional and asymptomatic. However, some pNETs are
632 Fernandes et al

functional (such as insulinoma and gastrinoma) and can present with a variety of clin-
ical syndromes as noted in Table 1. Additionally a small subset of pNETs arise in the
context of rare genetic syndromes including multiple endocrine neoplasia type 1
(MEN1) syndrome (previously referred to as Wermer syndrome), von Hippel-Lindau
syndrome, neurofibromatosis type 1, and tuberous sclerosis.45 MEN1 syndrome,
which is also associated with parathyroid and pituitary tumors, is the most common
cause of familial pNETs, with 30% to 80% of patients with MEN1 developing a
pNET during their lifetime, with these tumors often being multifocal.45
Diagnosis
pNETs are often detected as an incidental lesion found on CT or MRI; however, histo-
logic confirmation is typically made by EUS-guided fine-needle aspiration (FNA) or
fine-needle biopsy (FNB). EUS can also be used to mark a pNET for easier intraoper-
ative identification.46,47 Although histologic confirmation is not always required for
pNET diagnosis, EUS may be better than CT for detection of small pNETs, and there-
fore, may still have utility in the preoperative setting.48–50 Finally, as part of pNET diag-
nosis, it is important to consider whether germline genetic testing is warranted,
because management of pNETs arising in the setting of a genetic syndrome such
as MEN1 is often different from that of sporadic pNETs.
Jejunal and Ileal
Presentation
The postduodenal small bowel is a common site for GEP-NETs to develop; and of the
small bowel, the ileum is the most common site, especially the distal 100 cm.9,10,51 Je-
junal and ileal NETs often present with advanced disease because they are rarely
found incidentally, unlike other luminal GEP-NETs. The most common method
whereby ileal NETs are incidentally identified is through routine intubation of the termi-
nal ileum during colonoscopy.52 Presenting symptoms of jejunal and ileal NETs (which
are often metastatic at the time of presentation) can include abdominal pain as well as
the symptoms of carcinoid syndrome.18 Postduodenal small bowel NETs are in fact
the most common cause of carcinoid syndrome. In addition, jejunal and ileal NETs
can induce fibrosis in the mesentery, which can lead to small bowel obstruction as
well as intestinal ischemia.53,54
Diagnosis
Endoscopically, jejunal and ileal NETs appear as small, sessile, or polypoid lesions
with a smooth surface and often a normal-appearing mucosal layer. Because jejunal
and ileal NETs often present with metastatic disease, initial diagnosis is often made
with biopsy of a metastatic lesion. Subsequent localization of the primary tumor in
the small intestine can be very challenging. Functional imaging with a 68Ga-DOTA-
TATE PET-CT scan can identify the primary tumor in many cases of jejunal and ileal
NETs, after which patients will often proceed to surgical resection.55 In cases of met-
astatic NET where a primary tumor is not identified on functional imaging, there should
be a high level of suspicion for a jejunal or ileal NET. In this situation, use of video
capsule endoscopy (VCE) or balloon-assisted enteroscopy (BAE) may be helpful for
localizing a postduodenal NET primary before proceeding with more invasive explor-
atory surgery.56 VCE has been shown to successfully detect small bowel tumors,
although the yield is rather low, and the sensitivity and specificity is less than that of
surgery.57–61 One obvious disadvantage to VCE is the inability to obtain histology,
necessitating either surgery or a BAE to histologically diagnose an observed lesion.
BAE can also be used to identify small bowel NETs and has the advantage of allowing
concurrent tissue sampling; however, whether VCE or BAE is superior for detection of
 Gastroenteropancreatic Neuroendocrine Tumors 633

jejunal and ileal NETs remains uncertain with conflicting studies to date.62–64 Jejunal
and ileal NETs may also present with multifocal primary lesions, although interestingly,
as a recent tumor genome sequencing study suggested, these lesions may be clonally
independent.51,65

Colorectal and Appendiceal

Presentation
Among colorectal NETs, rectal NETs are more prevalent and more commonly benign
when compared with NETs arising from the rest of the colon.66,67 Many of these NETs
are actually found incidentally on colonoscopy performed for other indications. Colo-
rectal NETs can present with nonspecific abdominal symptoms such as abdominal
pain, bloating, changes in bowel habits, weakness, and bleeding, but rarely with carci-
noid syndrome. Colonic NETs present symptomatically more often than rectal NETs,
and those presenting symptomatically are metastatic in approximately 40% of
cases.68 Appendiceal NETs are often identified incidentally on imaging or on postop-
erative histologic examination after an appendectomy for appendicitis. Rarely, appen-
diceal NETs can metastasize and lead to systemic symptoms such as abdominal pain,
GI bleeding, or bowel obstruction. Metastasis and systemic symptoms are rarely seen
with appendiceal NETs less than 2 cm.69

Diagnosis
Diagnosis of a colorectal NET is typically made during colonoscopy, although in some
instances, there may be cross-sectional imaging suggesting a colonic mass before-
hand. During colonoscopy, colorectal NETs appear as yellowish smooth, round,
polypoid lesions, most commonly occurring within 5 to 10 cm from the anal verge.67,70
There may also be central mucosal depression or ulceration, which increases risk of
advanced, nonlocalized disease.71 Patients with rectal NETs can undergo EUS to
determine size, depth of invasion, and lymph node involvement, with the accuracy
of EUS in determining these characteristics shown in multiple studies.72,73 The deci-
sion to perform further staging of rectal NETs should depend on EUS findings and his-
tology, and is discussed in the management of localized gastroenteropancreatic
neuroendocrine tumors section - colorectal and appendiceal subsection. Patients
with colonic NETs should undergo imaging if there is any concern for more advanced
disease given the preference for surgical management in these patients.
Appendiceal NETs are typically diagnosed histologically after examination of a
resection specimen, most frequently an appendectomy. A diagnosis of an appendi-
ceal NET less than 1 cm with clean resection margins does not merit further studies.
If an appendiceal NET is 1 to 2 cm with clear margins on resection, one-time imaging
with CT or MRI is recommended to rule out lymph node involvement per the European
Neuroendocrine Tumor Society (ENETS) guidelines, but not per National Comprehen-
sive Cancer Network (NCCN) guidelines.11,74 If margins are not clear with a 1 to 2 cm
appendiceal NET and for all appendiceal NETs greater than > 2 cm, cross-sectional
imaging should be performed with additional consideration of performing functional
imaging.11,74

MANAGEMENT OF LOCALIZED GASTROENTEROPANCREATIC NEUROENDOCRINE

TUMORS
Gastric
Management of gNETs has classically depended on the tumor subtype and depth of
tumor invasion because these features were thought to be determinants of recurrence
634 Fernandes et al

and survival. However, recent data have challenged that notion, showing that tumor
size and grade may also be used in the management independent of gNET subtype.75

Type 1
The NCCN and ENETS guidelines largely agree on the endoscopic management of
type 1 gNETs, where for tumors without invasion of the muscularis propria or metas-
tasis, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection
(ESD) is recommended.11,76,77 Endoscopic resection by ESD is preferable for tumors
with submucosal invasion, which is often the case with type 1 and 2 gNETs, because it
offers higher complete resection rates compared with EMR.78 All type 1 gNETs that
are 1 cm or greater in size should be endoscopically removed; however, there remains
controversy about whether all small (<1 cm) type 1 gNETs should be removed or
instead followed with continued endoscopic surveillance. For tumors greater than
2 cm, ESD offers a higher rate of complete resection.79 In tumors with invasion beyond
the submucosa or with lymph node metastasis, surgical resection is recommended.
Treatment with somatostatin analogues (SSAs) is an option in patients with refractory
disease or in those who are unable or unwilling to be managed endoscopically.80,81 A
newer gastrin/cholecystokinin-2 receptor antagonist, netazepide, is currently in clin-
ical trials for treatment of type 1 gNETs after positive preliminary results.82 Finally, in
patients with refractory disease, surgical antrectomy is also an option to reduce
gastrin, which is responsible for driving tumorigenesis, and subsequently lower recur-
rence risk of gNETs.83 Regardless of the initial treatment strategy, surveillance upper
endoscopy should be performed every 1 to 3 years, with shorter intervals being used
for more extensive disease. Finally, because type 1 gNETs are associated with chronic
autoimmune atrophic gastritis, vitamin B12 levels should be followed because B12 sup-
plementation may be warranted.

Type 2
Management of type 2 gNETs, which are driven by gastrin production from gastrino-
mas, is directed at management of the gastrinomas and the gNETs. Similar to type 1
gNETs, prominent (1 cm or greater) type 2 gNETs can be resected endoscopically by
EMR or ESD, especially when the primary gastrinoma is not resected.11,76,77 Unlike
type 1 gNETs, antrectomy will not be effective in suppressing growth of these
gastrin-driven NETs; however, surgical removal of the causative gastrinoma may be
considered, especially in patients without MEN1 syndrome. For patients with MEN1
syndrome, multifocal gastrinomas may be present and it may not be practical to
remove all lesions. Medical treatment of type 2 gNETs with SSAs has also shown a
benefit when the primary gastrinoma is not removed.84 Furthermore, for patients
without gastrinoma removal, high-dose PPI use will be required. Regardless of the
treatment modality selected, once a diagnosis of a type 2 gNET is established, surveil-
lance upper endoscopy should be performed every year.

Type 3
At present, type 3 gNETs should typically be managed through surgical resection
given their more aggressive nature and higher rates of metastasis. Recent data, how-
ever, have challenged this surgery-first approach with the assertion that small (<1 cm),
superficial, low-grade type 3 gNETs have lower risk, and therefore, endoscopic resec-
tion or limited surgical resection may be considered.75,85 If endoscopic resection is
considered, ESD is preferred over EMR. If a decision is made to manage a type 3
gNET with nonsurgical endoscopic resection, the patient will continue to need ongoing
endoscopic surveillance, likely on at least a yearly basis.
 Gastroenteropancreatic Neuroendocrine Tumors 635

Duodenal and Ampullary

All dNETs should be staged with cross-sectional imaging, and consideration of addi-
tional functional imaging and/or EUS should be individualized. All dNETs should un-
dergo resection. Endoscopic resection with EMR or ESD is appropriate for all
nonampullary dNETs less than 1 cm that are confined to the submucosal layer without
metastatic disease.77 Other endoscopic resection techniques that can be considered
include ligation-assisted EMR as well as full-thickness endoscopic resection. Simpler
polypectomy techniques such as forceps biopsy or cold and hot snare have been
effective for small dNETs in a single-center series.44,86 ESD allows for higher en
bloc and histologic complete resection rates of dNETs compared with EMR or
device-assisted EMR, but has a higher complication rate, including bleeding and
perforation.87 A recent study of endoscopic surveillance versus resection of small
(<1 cm), grade 1, nonfunctioning, nonampullary dNETs did not have any tumor-
related deaths, so it may also be reasonable to offer surveillance in select cases.85
There is less clarity for dNETs that are between 1 and 2 cm, in which case endo-
scopic or surgical resection (pancreaticoduodenectomy or duodenotomy with trans-
duodenal local excision) are both considered feasible options, and this remains an
area where additional study is needed.77 For dNETs greater than 2 cm, if there is no
evidence of distant metastatic disease, surgical resection should be considered.77
These size-based recommendations result from data showing that the risk of lymph
node or distant metastasis and recurrence is low in dNETs less than 1 cm, whereas
there is reduced disease-specific survival in dNETs greater than 2 cm.39,88–90 Although
there are size-based management considerations for nonampullary dNETs, ampullary
dNETs should all be managed surgically, regardless of their size.77 Surgical resection
should also be performed for all sporadic (ie, non-MEN1-associated) gastrinomas
given improved cure rates in this specific population. However, surgery is not always
recommended for gastrinomas arising in the setting of MEN1 syndrome.91,92 For pa-
tients who undergo local resection of a dNET, endoscopic surveillance should be per-
formed, although the interval for this monitoring remains uncertain. Initially after
resection, endoscopic surveillance can be performed every 6 to 12 months, with
consideration of an increased interval if no recurrence is identified.

Pancreatic
Management of pNETs depends on the subtype and functionality of the tumor,
whether the pNET developed in the context of a high-risk genetic syndrome, and
whether there is evidence of metastatic disease. Unlike other GEP-NETs, there is
currently no role for endoscopy in the treatment of pNETs. However, EUS can be use-
ful for staging and tissue acquisition either via FNA or FNB. Per a recent North Amer-
ican Neuroendocrine Tumor Society (NANETS) consensus statement, sporadic
functional pNETs that are both localized and biochemically confirmed should undergo
surgical resection, even when small in size, given the clinical significance of their asso-
ciated syndromes and increased malignant potential.48 Likewise, localized nonfunc-
tional pNETs greater than 2 cm in size should also always undergo surgical
resection per ENETS, NCCN, and NANETS recommendations.11,48,93,94 There is no
consensus on the optimal management approach of nonfunctional pNETs less than
2 cm in size, with disagreement about whether surgical resection or observation is
best. A meta-analysis of 327 patients under surveillance with a pNET (with a range
of different sizes) showed that 14% eventually underwent resection, but there were
no deaths in the surveillance group.95 On the other hand, a study of 300 patients
with pNETs less than 2 cm from the National Cancer Database showed an 82.2%
636 Fernandes et al

5-year survival in patients who underwent resection and a 34.3% in those who did
not.96 Furthermore, a study of 392 patients who had surgical resection for pNETs
less than 2 cm suggested that pNETs between 1.5 cm and 2 cm had a significantly
higher chance of lymph node metastasis, suggesting that the cutoff for surveillance
versus surgery may fall somewhere between 1 and 2 cm.97 For low-grade, nonfunc-
tional pNETs less than 2 cm that are not treated surgically, surveillance imaging every
6 to 12 months should be performed, with consideration of surgery if there is a 5 mm or
greater increase in size during surveillance, or if the pNET surpasses 2 cm in size.98

Jejunal/Ileal
The management of localized NETs of the jejunum and ileum is surgical resection. At
this time, there is no role for endoscopic resection in the treatment of jejunal and ileal
NETs. However, VCE or BAE may be used to locate a NET of the jejunum or ileum, and
BAE may also be used to facilitate a tissue diagnosis. As noted earlier, because NETs
of the jejunum or ileum are often multifocal, manually inspecting the bowel during lap-
arotomy to ensure that all NETs are resected is important. Postoperatively, these pa-
tients receive follow-up imaging to monitor for recurrence, but there is no role for
endoscopy in follow-up.99

Colorectal and Appendiceal

For nonrectal colonic NETs that are greater than or equal to 2 cm in size, there is
consensus that surgical resection is the favored treatment approach.11,100 However,
there remains controversy about how to manage nonrectal colonic NETs less than
2 cm in size. For this subset, ENETS recommends endoscopic resection so long as
margins are clear, there is no invasion of the muscularis propria, and the NET is grade
1 or 2.100 However, NCCN differs, and recommends surgical resection for all nonrectal
colonic NETs.11 Patients undergoing endoscopic resection of a nonrectal colonic NET
will need regular endoscopic surveillance to monitor for recurrence.
Rectal NETs should also be completely resected, which has been proved to be su-
perior to observation.101 Given the more indolent nature of rectal NETs when
compared with colonic NETs, staging imaging is not always required, especially if a
small (<1 cm), low-grade, incidentally discovered rectal NET is completely resected
during colonoscopy. However, there is some evidence that even presumed low-risk
rectal NETs are capable of lymph node metastasis, with a recent study demonstrating
that 25% of rectal NETs less than or equal to 10 mm had nodal involvement, leading to
the investigators’ proposal to stage all rectal NETs greater than 4 mm.102 Staging can
be performed with EUS, after which grade 1/2 rectal NETs less than 1 cm without in-
vasion of the muscularis propria (ie, T1 lesion) can undergo endoscopic resection with
EMR or ESD, which has been demonstrated to be effective when compared with sur-
gical resection.71,103 ESD is preferred over EMR if there is suspicion for submucosal
invasion.79 The data are less clear on whether endoscopic excision or surgical exci-
sion (which can be performed via a transanal approach) is the best management for
localized rectal NETs between 1 and 2 cm. One study of 239 patients in Japan showed
no local recurrence, a complication rate less than 4%, and only a 2.5% metastasis rate
following ESD, suggesting that endoscopic management is a reasonable option.104
For rectal NETs greater than 2 cm, those that have lymph node involvement, and those
with grade 3 histology, radical surgical resection should be performed. However, a
recent retrospective analysis of 178 patients from the National Cancer Database
with rectal NETs greater than 2 cm showed similar survival between patients who un-
derwent local excision and radical surgery. This indicates that there may be a subset
 Gastroenteropancreatic Neuroendocrine Tumors 637

of patients with NETs greater than 2 cm who may be able to be treated with less inva-
sive surgery without compromising survival.105
After resection, grade 1/2 rectal NETs less than 1 cm with clean resection margins
do not need follow-up. If margins are indeterminate, endoscopic evaluation should be
repeated in 6 to 12 months for grade 1 rectal NETs, whereas more definitive resection
should be attempted for grade 2 rectal NETs.11 After local resection of a rectal NET 1
to 2 cm in size, patients should undergo EUS or MRI within 6 to 12 months
postresection.11,100
Management of appendiceal NETs is surgical, and there is no routine role for endos-
copy. Appendiceal NETs greater than 2 cm should typically be treated with a right
hemicolectomy. However, for appendiceal NETs less than 2 cm in size with clear mar-
gins, without deep tissue invasion, and without concerning histologic features, appen-
dectomy alone is sufficient for management.

MANAGEMENT OF ADVANCED GASTROENTEROPANCREATIC NEUROENDOCRINE

TUMORS

Although this review has been primarily devoted to the diagnosis and management of
localized GEP-NETs, the authors briefly discuss some of the other treatments avail-
able for advanced GEP-NETs. There are multiple comprehensive reviews that cover
management of advanced GEP-NETs in more detail.106,107

Somatostatin Analogues
Most GEP-NETs express high levels of somatostatin receptors (SSTRs), and as such,
this unique property has been used in treatment. The first SSA, octreotide, has been in
use since the 1980s initially as a treatment of carcinoid syndrome, with later data
showing improvement in survival in both functional and nonfunctional metastatic
GEP-NETs.108,109 Lanreotide is another SSA that also increases progression-free sur-
vival (PFS) in metastatic low-grade GEP-NETs.110 Both octreotide and lanreotide are
well-tolerated and administered as long-acting injectables, and are generally used as
early-line treatments for metastatic GEP-NETs.

Surgery
Resection of the primary tumor in metastatic GEP-NETs has been an area of ongoing
controversy. However, a recent study showed that primary GEP-NET resection was
associated with prolonged survival.111 Surgical resection can also be used to debulk
metastatic disease, especially with extensive hepatic metastases, which has also
been shown to prolong survival in select cases.112

Liver-Directed Therapies
GEP-NETs typically metastasize to the liver, and patients with extensive hepatic meta-
static disease may benefit from liver-directed therapies including transarterial emboliza-
tion (TAE), transarterial chemoembolization (TACE), or transarterial radioembolization
(TARE). Although one retrospective analysis did show improved long-term survival in
patients undergoing TACE, currently there are no clear data supporting one type of
liver-directed therapy over others. This question is being investigated by the ongoing
Randomized Embolization Trial for Neuroendocrine Tumor Metastases to the Liver
(RETNET) study.113,114 Liver-directed therapies do have risks, including hepatotoxicity,
and there is ongoing work examining combining liver-directed therapy with systemic
therapy.115,116
638 Fernandes et al

Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) exploits the high proportion of SSTRs
on the surface of GEP-NETs for therapeutic benefit. Although PRRT has been used
for years in Europe, it was not until 177Lu-DOTATATE was approved by the US Food
and Drug Administration in 2018 for SSTR-positive GEP-NETs, based on the favorable
results from the Neuroendocrine Tumors Therapy (NETTER-1) trial, that PRRT became
widely available in the United States.117 Real-world data have alluded to small bowel
NETs having better response to PRRT than pNETs; however, it remains to be deter-
mined how to optimally incorporate PRRT among other modalities into the treatment
of NETs.118–120 PRRT is also associated with systemic toxicities that require close
monitoring, including hematologic, renal, and hepatic toxicities.121,122

Targeted Therapies, Chemotherapy, and Immunotherapy

There are several targeted agents used in the treatment of GEP-NETs including mech-
anistic target of rapamycin (mTOR) inhibitors as well as tyrosine kinase inhibitors.
Everolimus, which is an mTOR inhibitor, has been shown to prolong PFS in nonfunc-
tional NETs of the GI tract and lung and has received FDA approval for this indica-
tion.123,124 Sunitinib, a multireceptor tyrosine kinase inhibitor, has shown improved
PFS in pNETs, and has received FDA approval for this indication.125 Multiple other
tyrosine kinase inhibitors are currently being investigated in clinical trials, including
cabozantinib, lenvatinib, surufatinib, pazopanib, and axitinib, with these studies
reviewed in-depth elsewhere.106,107 Cytotoxic chemotherapy can also be considered
in pNETs and in some refractory bowel NETs, the specifics of which are beyond the
scope of this review.11

SPECIAL CONSIDERATIONS FOR MANAGEMENT OF FUNCTIONAL

GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS

In addition to treating disease burden, patients with functional GEP-NETs may also
need additional treatments to aid in control of their symptoms.

Functional Pancreatic Neuroendocrine Tumors

The foundation of controlling hormone production in patients with functional pNETS is
treatment with a SSA. Additional treatments may be indicated, however, depending on
the specific type of tumor and associated hormone that is produced. Patients with a
gastrinoma should be treated with high-dose PPIs to suppress their gastrin-driven hy-
persecretion of acid. Continuation of PPI therapy in these individuals is important un-
der all circumstances, which should be made clear to the patient and all of their
treating providers. Patients with insulinomas who have not undergone curative resec-
tion can be treated with lifestyle modifications such as frequent small feedings, and
when refractory, can be treated with glucose infusions as well as diaxozide.126 Pa-
tients with VIPomas causing symptoms that are difficult to control can be treated
with alpha-interferon, which has demonstrated a significant antisecretory effect in
these patients.126 Patients with ACTHomas can be treated with metyrapone and ke-
toconazole for the hormone excess.126

Carcinoid Syndrome
Carcinoid syndrome commonly manifests with diarrhea and flushing. The diarrhea
from carcinoid syndrome can oftentimes be exceedingly difficult to manage. Dietary
modifications, with frequent small meals and avoidance of aged cheeses and fer-
mented foods with high amine content are generally advised to help with symptoms,
 Gastroenteropancreatic Neuroendocrine Tumors 639

although there is no robust evidence for this practice.127 Use of SSAs such as octreo-
tide or lanreotide can be effective in controlling diarrhea symptoms. In addition, empir-
ical trials of bile acid sequestrants or antidiarrheals such as diphenoxylate and
loperamide can be considered.127 However, if SSA treatment is not effective for con-
trolling carcinoid syndrome-related diarrhea, telotristat ethyl can be used. Telotristat
ethyl is an inhibitor of tryptophan hydroxylase, the rate-limiting step in the synthesis
of serotonin, and multiple clinical trials have shown its effectiveness in reducing diar-
rhea from carcinoid syndrome.128,129 Although telotristat ethyl has been primarily
studied with respect to diarrhea, it may also help with other symptoms of carcinoid
syndrome, with patients on telotristat ethyl showing improved clinical outcomes.130

SUMMARY

GEP-NETs are a heterogeneous group of tumors that can be classified by their loca-
tion, grade, functionality, and stage, with management varying based on these
different elements. Given the increasing incidence of GEP-NETs, it is important for
all medical practitioners to have a basic understanding of the principles of GEP-
NET diagnosis and management, especially gastroenterologists, who will either
encounter these tumors incidentally or will be intimately involved in the diagnosis
and/or management of these patients.

CLINICS CARE POINTS

 The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is increasing,

and these tumors are increasingly being identified incidentally in clinical practice.
 GEP-NETs are typically classified by their location, grade, stage, and functionality. GEP-NET
classification has significant implications for subsequent tumor management.
 Diagnosis and management of GEP-NETs requires a multidisciplinary team of medical
professionals, of which gastroenterologists are an important part.
 Endoscopy is critical in the diagnosis, management, and/or surveillance of GEP-NETs.

DISCLOSURE

C.J. Fernandes, G. Leung, and B.W. Katona: No relevant disclosures. J. R. Eads: Bris-
tol Meyers Squibb (employment, stock—spouse); Janssen (employment—spouse);
Advanced Accelerator Applications (advisory board); Ipsen (advisory board).

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91. Norton JA, Alexander HR, Fraker DL, et al. Does the use of routine duodenotomy
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 Gastroenteropancreatic Neuroendocrine Tumors 645

95. Partelli S, Cirocchi R, Crippa S, et al. Systematic review of active surveillance

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96. Sharpe SM, In H, Winchester DJ, et al. Surgical resection provides an overall
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98. Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for
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99. Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American neuroen-
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agement of midgut neuroendocrine tumors. Pancreas 2017;46(6):707–14.
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agement of patients with digestive neuroendocrine neoplasms: colorectal
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101. Zhao B, Hollandsworth HM, Lopez NE, et al. Outcomes for a large cohort of pa-
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102. O’Neill S, Haji A, Ryan S, et al. Nodal metastases in small rectal neuroendocrine
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103. Kwaan MR, Goldberg JE, Bleday R. Rectal carcinoid tumors: review of results
after endoscopic and surgical therapy. Arch Surg 2008;143(5):471–5.
104. Chen T, Yao LQ, Xu MD, et al. Efficacy and safety of endoscopic submucosal
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575–81.
105. Izquierdo KM, Humphries MD, Farkas LM. Size criteria is not sufficient in select-
ing patients for local excision versus radical excision for rectal neuroendocrine
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108. Kvols LK, Moertel CG, O’Connell MJ, et al. Treatment of the malignant carcinoid
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109. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind,
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110. Caplin ME, Pavel M, Cwik1a JB, et al. Lanreotide in metastatic enteropancreatic
neuroendocrine tumors. N Engl J Med 2014;371(3):224–33.
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9713–9.
Cancer in Inflammatory
Bowel Disease
1 1
Adam S. Faye, MD, MS , Ariela K. Holmer, MD , Jordan E. Axelrad, MD, MPH*

KEYWORDS
 Inflammatory bowel disease  Crohn disease  Ulcerative colitis  Cancer
 Colorectal neoplasia  Dysplasia

KEY POINTS
 Individuals with inflammatory bowel diseases (IBD) are at an increased risk of developing
intestinal neoplasia—particularly colorectal neoplasia, small bowel adenocarcinoma, intes-
tinal lymphoma, and anal cancer—as a consequence of chronic intestinal inflammation.
 Individuals with IBD are also at risk for extraintestinal malignancies, such as cholangiocar-
cinoma, skin cancer, hematologic malignancies, genitourinary cancer, cervical cancer,
and prostate cancer, thought to be a consequence of immunosuppressive therapies
and an underlying inflammatory state.
 Colorectal cancer surveillance with colonoscopy using high-definition white light endos-
copy should commence 8 to 10 years after IBD diagnosis among patients with significant
colonic involvement (beyond the rectum) and continue at an interval of 1 to 3 years based
on patient- and disease-related factors.
 If invisible dysplasia is identified, referral to an expert in IBD surveillance using chromoen-
doscopy is required.

INTRODUCTION

Inflammatory bowel diseases (IBD), comprising Crohn disease (CD) and ulcerative co-
litis (UC), are chronic inflammatory conditions of the gastrointestinal tract driven by
inappropriate immune responses to an altered gut microbiome in genetically suscep-
tible individuals.1 IBD affects at least 0.4% of Europeans and North Americans, with a
rising prevalence worldwide.2–4
Individuals with IBD are at an increased risk of developing intestinal neoplasia—
particularly colorectal neoplasia (CRN), including colorectal dysplasia and colorectal

Grant support: J.E. Axelrad and A.S. Faye receive research support from the Crohn’s and Colitis
Foundation, J.E. Axelrad also receives research support from the Judith & Stewart Colton Cen-
ter for Autoimmunity, the New York Crohn’s and Colitis Organization, and the NIH NIDDK
K23DK124570.
Inflammatory Bowel Disease Center at NYU Langone Health, 305 East 33rd Street, Lower Level,
New York, NY 10016, USA
1
Co-first authors.
* Corresponding author.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 649–666

https://doi.org/10.1016/j.gtc.2022.05.003 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
650 Faye et al

cancer (CRC)—as a consequence of chronic colonic inflammation.5–7 Others include

small bowel adenocarcinoma, intestinal lymphoma, and anal cancer. In addition to
cancers common in the general population, patients with IBD have also been shown
to be at increased risk of developing extraintestinal malignancies, thought to be a
consequence of immunosuppressive therapies and an underlying inflammatory state,
including cholangiocarcinoma, skin cancer, hematologic malignancies, genitourinary
(GU) cancer, cervical cancer, and prostate cancer. The focus of this review is to sum-
marize (1) the risk of cancer in patients with IBD, (2) the diagnosis and management of
CRN in IBD, and (3) the management of patients with IBD and active or recent cancer.

CANCER RISK AMONG PATIENTS WITH INFLAMMATORY BOWEL DISEASES

Colorectal Cancer
One of the most common malignancies in patients with IBD is CRC and is often the
result of ongoing inflammation. Although prior studies have reported a risk of more
than 15% after 30 years of active colonic disease, more recent estimates have shown
a declining risk.8,9 In a recent meta-analysis of population-based cohort studies, pa-
tients with IBD were estimated to have a 1%, 2%, and 5% risk of CRC after 10, 20, and
greater than 20 years from initial IBD diagnosis, respectively.10,11 It should be noted,
however, that despite the decreasing rate of CRC, the incidence rate for early cancers
has been increasing.12 This is likely the result of a shift in the management of colonic
dysplasia, with many being managed endoscopically rather than by colectomy.
This may lead to a higher number of dysplastic areas being incompletely or partially
resected, increasing the risk of progression to early-stage CRC. Despite this,
10-year survival rates remain high at almost 80%, with other studies showing no dif-
ference in outcomes when comparing IBD-associated and sporadic CRCs.12,13
Clinicians should also be aware that active colitis can increase the risk of multifocal
dysplasia. Among a cohort of UC patients diagnosed with CRC, more than one-third
had synchronous CRC or dysplasia at a distant site at time of colectomy.12 This em-
phasizes the importance of close dysplasia surveillance and reinforces the need for
endoscopic healing as outlined in the STRIDE-II guidelines.14
In addition to length of time with IBD, and extent of colonic disease, there are addi-
tional risk factors that increase the risk of CRC among patients with IBD. This includes
(1) cumulative inflammation (calculated by summing the endoscopic disease severity
at each surveillance endoscopy), which increases the likelihood of CRC more than
two-fold for each 10-unit increase in score15,16; (2) the presence of concomitant pri-
mary sclerosing cholangitis (PSC), which on meta-analysis increased the odds of colo-
rectal dysplasia and cancer more than three-fold when compared with patients with
IBD who do not have PSC17; and (3) family history of CRC, which based upon a
population-based cohort study of 19,876 individuals showed that a positive family his-
tory increased the risk of developing CRC more than two-fold among patients with
IBD.18,19 It should also be noted that patients with older-onset IBD are not at higher
risk for developing CRC as compared with patients who have younger-onset IBD.20

Small Bowel Adenocarcinoma

Individuals who have CD with small bowel involvement are also at higher risk for small
bowel adenocarcinoma. Although estimates have suggested an almost 20-fold in-
crease in the likelihood of small bowel adenocarcinoma among patients with CD,
the absolute risk remains very low (3 in 10,000 person-years).21 In a more recent
Denmark population-based study, analogous results were seen, as patients with CD
had a higher likelihood of both small bowel adenocarcinomas (standardized incidence
 Cancer in Inflammatory Bowel Disease 651

ratio [SIR] 14.38) and neuroendocrine tumors (SIR 6.83), but a low overall incidence
(0.15%).22 In a Surveillance, Epidemiology and End Results Medicare database study,
the relative risk (RR) appeared similar in older individuals with CD, as patients aged
67 years and older had a 12-fold increase in risk of small bowel adenocarcinoma as
compared with older adults without CD, although prevalence was reportedly higher
at 1.6%.23
Regarding risk factors, small studies have suggested a higher risk of small bowel
adenocarcinoma among men, tobacco users, those who have long-standing CD,
penetrating CD, or prior small bowel resection, or as a result of therapy for
CD.22,24–26 These findings, however, are limited by small sample size.27 In a recent,
larger, population-based study of 47,370 patients with CD, identifiable risk factors
for small bowel adenocarcinoma included those newly diagnosed, childhood-onset,
ileal, and stricturing CD.28

Intestinal Lymphoma
In a large cross-sectional analysis of individuals living in Switzerland with IBD, intesti-
nal lymphoma occurred at a rate of 48.3 cases per 100,000 patient-years (PY).
Although this represents a two- to three-fold increase as compared with the general
population (18 cases per 100,000 PY), similar to small bowel adenocarcinoma, the ab-
solute risk remains low.29 Furthermore, these intestinal lymphomas are predominantly
B-cell non-Hodgkin lymphoma and are often associated with the presence of Epstein-
Barr virus.7,30 Furthermore, intestinal lymphomas occur more often in men, in patients
with ongoing intestinal inflammation, and in patients who have had CD for more than
8 years.7

Anal Cancer
Similar to small intestinal adenocarcinoma and intestinal lymphoma, the absolute risk
of anal cancer among patients with CD, although higher than the general population,
remains low. One such risk factor for the development of anal squamous cell carci-
noma is the presence of human papillomavirus.31 In a recent study from the CESAME
database, the incidence of anal squamous cell carcinoma was 2.6 per 10,000 PY
among patients with IBD with anal or perianal lesions, as compared with 0.8 per
10,000 PY among patients with IBD without anal or perianal lesions.32 In addition to
human papillomavirus, longstanding perianal fistulizing disease has been shown to in-
crease the risk of both anal squamous cell carcinoma and adenocarcinoma, with an
incidence of 3.8 per 10,000 PY.32

Extraintestinal Malignancies
In addition to intestinal-related malignancies as described above, patients with IBD
are also at risk for extraintestinal malignancies. Cholangiocarcinoma is 4 times more
likely to occur in patients with IBD as compared with patients without IBD. In a Danish
national cohort study assessing this, the incidence of cholangiocarcinoma was found
to be 7.6 per 100,000 PY among patients with IBD as compared with 1.9 per 100,000
PY among controls.33 Although not completely understood, this risk is predominantly
driven by the concomitant presence of PSC, as patients with PSC have more than a
150-fold higher risk for developing cholangiocarcinoma compared with individuals
without PSC.34 This equates to a 5% to 10% lifetime risk of developing cholangiocar-
cinoma and often portends a poor prognosis once diagnosed.7,34,35
Skin cancer, including both nonmelanoma and melanoma skin cancer, is the most
common cancer in the United States, with an estimated 5.4 million individuals
affected.36 This risk is higher among patients with IBD and is thought to be in part
652 Faye et al

from the use of immunosuppressive therapy. Analogous to the increased risk of non-
melanoma skin cancer seen in the transplant population, a similar increased risk is
seen among patients with IBD who are using thiopurines. In a study of 108,579 pa-
tients with IBD, thiopurine use was associated with an almost two-fold increase in
the development of nonmelanoma skin cancer.37 In addition, ongoing thiopurine use
may increase the risk of recurrent nonmelanoma skin cancer. In a recent retrospective
Veterans Health Administration study, patients who had a prior basal cell carcinoma
were more likely to have recurrence of disease in the setting of continued thiopurine
use.38 This increased risk of skin cancer is thought to persist even after discontinua-
tion of thiopurines, emphasizing the importance of annual dermatologic examinations
in patients with IBD, particularly if they are on thiopurines.39
Among patients using anti-tumor necrosis factor (anti-TNF) therapy, the increased
risk of skin cancer seems to be predominantly melanoma in origin. In the above study
looking at 108,579 patients with IBD, exposure to anti-TNF therapy increased the likeli-
hood of developing melanoma by almost two-fold.37 This, however, is in contrast to a
prior nationwide study in Denmark that found no association between anti-TNF therapy
and the development of melanoma.40 In order to further elucidate this issue, a recent
meta-analysis was performed that showed no significant difference in risk of melanoma
among patients treated with biologics as compared with patients treated with nonbio-
logic therapies.41 Regardless of anti-TNF use, however, all patients with IBD should
receive yearly dermatologic examinations, as certain studies have even shown an
increased risk of melanoma among patients with IBD not on biologic therapy.42
Nonintestinal lymphoma is another risk associated with IBD-related therapy, and
more specifically with thiopurine use. In a recent meta-analysis, the SIR of lymphoma
among patients with IBD treated with thiopurines ranged from 2.8 to 9.2.43 The abso-
lute risk was highest among older individuals (1:354 per PY), whereas the highest rela-
tive risk was among individuals under the age of 30 years (SIR 7.0).43 Although most of
these lymphomas are B cell in origin, men under the age of 35 years are also at risk for
hepatosplenic T-cell lymphoma. This often results from long-term use of thiopurines,
is often fatal, and requires close monitoring if used in this setting.44 Although data sur-
rounding the use of ani-TNF and development of lymphoma have been conflicting,
more recent studies have suggested no increased risk associated with anti-TNF
monotherapy.45–48
GU cancer is another malignancy that has been shown to be associated with thio-
purine use among patients with IBD. More specifically, in the CESAME cohort, 16 of
19,486 (0.08%) patients developed kidney and/or bladder cancer, with those using thi-
opurines having a 2.8 times higher risk as compared with individuals not using thiopur-
ines.49 These results are analogous to a population-based study in Denmark, which
showed that use of azathioprine among patients with IBD was associated with a 2.8
times higher rate of developing urinary tract cancer.50 Additional risk factors for the
development of GU cancer among patients with IBD include male sex and older age.49
In addition to GU cancer, there have also been recent data suggesting a link be-
tween IBD and prostate cancer. In a recent retrospective single-center study of
10,000 men, the incidence of prostate cancer was 4.4% among those who had IBD
as compared with 0.65% among those who did not have IBD (hazard ratio [HR],
4.8).51 In a prospective study of UK biobank samples, prostate cancer appeared to
be associated with the presence of UC (HR, 1.47), but not CD.52 Although further
research is needed to make more definitive conclusions, preliminary laboratory-
based work has shown an association between ongoing intestinal inflammation and
the development of protumorigenic states in the prostate, suggesting a biologically
plausible link.53
 Cancer in Inflammatory Bowel Disease 653

In a nationwide cohort study, similar results were seen when assessing rates of cer-
vical cancer in women with and without IBD. Notably, women with UC and CD had a
higher risk for cervical cancer development both before and after diagnosis of their
IBD.54 These results were confirmed in a recent multicenter Dutch prospective cohort
study, where women with IBD were noted to be at a 1.3 times higher risk for devel-
oping high-grade dysplasia (HGD) and/or cervical cancer as compared with female-
matched controls without IBD.55 Additional risk factors included smoking and the
presence of ileocolonic or upper gastrointestinal disease, which also increased the
risk of cervical dysplasia and cancer 1.8 to 3 times, respectively.55

COLORECTAL CANCER SURVEILLANCE AND DYSPLASIA MANAGEMENT

Endoscopic surveillance programs for CRC, which are endorsed by all major gastro-
enterology and oncology societies, are based on indirect evidence of benefit.56–63
Generally, US guidelines recommend that CRN surveillance commence 8 to 10 years
after diagnosis among patients with significant colonic involvement (beyond the rectum)
and continue at an interval of 1 to 3 years based on patient- and disease-related factors.
Among patients with colonic IBD who are diagnosed with PSC, colonoscopy should be
performed at the time of PSC diagnosis with annual surveillance thereafter. Among pa-
tients without concomitant PSC, the interval for surveillance varies by society, with
some recommending specific intervals based on risk stratification according to patient-
and disease-related clinical characteristics.64,65 Among patients with a first-degree
relative with CRC, the initial examination should occur 10 years before age of CRC in
the first-degree relative or after 8 years of IBD, whichever occurs first. Patients with iso-
lated IBD proctitis do not require regular surveillance, unless there is proximal disease
extension. Ileoanal pouch surveillance should be performed at least annually in those at
high risk for developing CRN (PSC or previous CRN), as well as in those with persistent
moderate to severe pouchitis and/or prepouch ileitis. In those patients at lower risk with
a pouch, surveillance intervals should be individualized.
Quality metrics for colonoscopic surveillance in IBD reflect CRC screening and
surveillance recommendations in the general population with some additional consid-
erations, including the use of image-enhancing techniques, such as chromoendo-
scopy (CE).59,60,63–67 It is recommended that surveillance examinations be
performed by an experienced gastroenterologist specialized in IBD when disease is
in remission and with adequate bowel preparation. Even with active disease, the iden-
tification of low-grade dysplasia (LGD), HGD, and CRC is still reliable with interob-
server agreement. In quiescent disease, a large field of pseudopolyps, scars, or
impassable strictures that compromise surveillance should prompt discussion of
colectomy. Despite guidelines and quality metrics, widespread adherence to recom-
mended surveillance techniques remains low.68–71
Based on updated guidance, standard of care for surveillance using high-definition
white light endoscopy (HD-WLE) should include 4 nontargeted random biopsies every
10 cm from flat mucosa in areas previously affected by colitis, and placed in separate
jars with the goal of detecting subtle or “invisible” dysplasia.63 Additional biopsies
should be taken from areas of prior dysplasia or poor mucosal visibility. However,
CE has substantially improved dysplasia detection and brought into question whether
“invisible” dysplasia is a true entity.72,73 Application of dye CE (DCE) during colonos-
copy with indigo carmine or methylene blue improves the visualization of
subtle lesions in areas of adequate bowel preparation, minimal pseudopolyps, and
endoscopically quiescent disease. A meta-analysis of 6 studies including 1358 pa-
tients with IBD undergoing surveillance with DCE (n 5 670) or HD-WLE (n 5 688) found
654 Faye et al

that more dysplasia was identified with DCE compared with HD-WLE (19% vs 9%,
P 5 .08).74 However, a randomized controlled trial comparing HD-WLE with random
biopsies (n 5 102) with DCE with targeted biopsies (n 5 108) showed no difference
in dysplasia detection.75 Virtual chromoendoscopy (VCE), such as narrow-band imag-
ing, is an electronic imaging technology that provides mucosal contrast enhancement
without the use of a dye. Studies evaluating the utility of VCE have not consistently
demonstrated a higher yield of dysplasia detection.66,76–78 A recent randomized
controlled trial comparing VCE, DCE, and HD-WLE found that HD-WLE and VCE
were noninferior to DCE,79 and a follow-up meta-analysis of 11 randomized controlled
trials comprising 1328 patients demonstrated that VCE performed similarly to DCE
and HD-WLE with respect to dysplasia detection on a per-patient basis.80
Although CE is endorsed by multiple consensus recommendations,63,66 the role of
CE and random biopsies with HD-WLE is controversial, as the vast majority of
neoplasia is accepted to be visible and CE adds to procedural time.73,75,81–84 Although
nontargeted biopsies are not required if CE is performed using HD-WLE, it should be
considered for those at high risk of CRC, including patients with PSC, a personal his-
tory of dysplasia, or tubular-appearing colon suggestive of high cumulative inflamma-
tory burden.73 Currently, questions remain regarding which surveillance technique is
superior for the group of patients with IBD and colonic involvement but no other risk
factors for CRC: HD-WLE with random biopsies, HD-WLE with targeted biopsies, or
HD-WLE with CE and targeted biopsies.

Dysplasia Types and Categories

The management of IBD-associated CRN is highly dependent on consistent defini-
tions and characterization of lesions. Imprecise terminologies, such as dysplasia-
associated lesion or mass, adenoma-associated lesion or mass, flat and raised
dysplasia, were replaced by a modified Paris classification85—which has been classi-
cally applied to dysplastic lesions diagnosed in individuals without IBD—in an effort to
more appropriately and consistently describe dysplastic lesions in individuals with
IBD.66 The SCENIC consensus statement recommended broad categorization of
dysplasia as “visible,” defined as a dysplastic lesion seen on endoscopy, and “invis-
ible,” defined as dysplasia diagnosed on histopathology from a nontargeted biopsy in
the absence of a discrete lesion. The modified classification also included polypoid
(2.5 mm) and nonpolypoid (<2.5 mm) lesions under the broader category of “visible”
and further modified to include descriptors for visible dysplasia, including the pres-
ence of ulceration and the distinctness of the borders of the lesion.86
When a lesion concerning for dysplasia is identified on endoscopy, descriptors
should include size, morphology (polypoid vs nonpolypoid), border (distinct vs indis-
tinct), and features suggestive of submucosal invasion and invasiveness, such as
depressed areas, ulceration, or nonlifting with injection.66 A potentially resectable
lesion should have discrete margins that are identifiable and would enable complete
resection endoscopically. Biopsies should be obtained of the tissue surrounding the
polyp to ensure that the surrounding tissue is free of dysplasia.

Dysplasia Management
The management of visible dysplasia in IBD is multidisciplinary. It requires confirmation
by an expert IBD pathologist, therapeutic resection, medical management with risk
factor modification, and surgical consultation with continued surveillance in the
absence of colectomy (Fig. 1). The SCENIC consensus emphasized the importance
of distinguishing polypoid from nonpolypoid (ie, flat) lesions, primarily owing to thera-
peutic and prognostic implications, as well as subsequent surveillance considerations.
 Cancer in Inflammatory Bowel Disease 655

Fig. 1. HD-WLC for CRN screening/surveillance in an at-risk patient with colonic IBD. (Special
considerations: concomitant PSC, history of CRN.)

Nonpolypoid lesions have a higher risk of progression to CRC compared with

polypoid lesions.87,88 In addition, histologic grade and focality impact prognosis and
subsequent surveillance. For patients with en bloc resection of polypoid lesions less
than 1 cm with confirmed negative margins, surveillance colonoscopy is recommen-
ded at 12 months.66 For lesions removed piecemeal or with size greater than 1 cm,
surveillance colonoscopy should be performed within 3 to 6 months, with the shorter
interval favored for HGD.66 Progression to HGD or CRC following complete resection
of unifocal LGD is rare, whereas multifocal LGD carries substantial risk.72,89–91 The
management following complete resection of a visible lesion with HGD is controver-
sial, and the decision of continuing shorter interval surveillance should be made on
a case-by-case basis.66,67,92 Compared with polypoid lesions, the course of nonpoly-
poid lesions following endoscopic resection is not well defined. In patients with
complete endoscopic resection of nonpolypoid dysplasia, ongoing surveillance is
suggested rather than colectomy with intervals similar to those recommended for
polypoid dysplasia and with similar alterations according to histology and other fac-
tors. Surgical referral should still be discussed given the higher risk of incomplete
resection of nonpolypoid lesions with a corresponding higher rate of recurrence and
progression to HGD/CRC compared with polypoid lesions.93
If invisible dysplasia is identified and confirmed by a second pathologist with IBD
expertise, timely referral to an expert in IBD surveillance using CE with HD-WLE is
required. If no lesions are identified, random biopsies should be repeated. If LGD is
detected randomly, surveillance should be performed every 3 to 6 months; however,
surgery should still be discussed with patients given the significant risk of progressing
to HGD/CRC.93 In patients with PSC and LGD, there is a much lower threshold for
colectomy given the significantly higher risk of progression. If HGD is detected on
random biopsies, a repeat examination should be performed by an endoscopist expe-
rienced in IBD dysplasia detection and resection using HD-WLE with CE, and if no
resectable lesions are identified, colectomy is indicated.
The success of endoscopic resection relies on the achievement of en bloc resection
with negative margins. Endoscopic resection techniques include mucosal resection
and submucosal dissection, with the latter having only limited data in the IBD popula-
tion.94–96 If endoscopic resection cannot be reliably achieved, then surgery may be
indicated, with the surgery of choice being colectomy in UC or segmental resection
versus colectomy in Crohn colitis depending on disease involvement. Other indica-
tions for surgery include any dysplasia in a patient with PSC, a personal history of
CRC, severe pseudopolyposis or stricture limiting adequate quality surveillance, or
multifocal dysplasia.97
Finally, optimal disease control with effective medical therapy is critical to mini-
mizing an individual’s lifetime risk of developing CRC.
656 Faye et al

MANAGEMENT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASES WITH

ACTIVE OR RECENT CANCER

With a rapidly growing aging population, the medical management of patients with IBD
and active or recent cancer will become increasingly more important.98 The effect of
cancer treatment on underlying IBD disease activity and the risk of cancer progression
or recurrence with IBD-directed immunosuppressive therapy are unique concerns in
this patient population.

Impact of Cancer Treatment on Inflammatory Bowel Diseases Management

The treatment of extraintestinal cancers can impact the underlying course of IBD, as
immunosuppressive therapy is used in the management of both cancer and IBD. In a
retrospective study of 84 IBD patients diagnosed with cancer, 67% of patients with
active IBD achieved remission during their cancer treatment course.99 Of these,
90% received treatment with cytotoxic chemotherapy, suggesting a protective effect
on intestinal inflammation. Furthermore, 90% of these patients remained in remission
at 5 years, indicating a durable benefit to cytotoxic chemotherapy in patients with
concomitant IBD. Conversely, hormonal therapy alone or in combination with cyto-
toxic chemotherapy was associated with an increased risk of IBD relapse (HR,
11.04; 95% confidence interval [CI], 1.22 to 99.85 and 9.7; 95% CI, 1.16 to 81.08
respectively).
The effect of hormonal deprivation therapy on the disease course of IBD was further
examined in a multicenter study of 447 patients with either breast or prostate cancer
and IBD. Of 400 patients with inactive IBD, 28% experienced disease relapse, and
hormonal therapy alone or in combination with cytotoxic chemotherapy was signifi-
cantly associated with risk of IBD flare (HR, 2.00; 95% CI, 1.21–3.29 and 1.86; CI,
95% CI, 1.01–3.43, respectively).100 Of those in remission, only 42% of patients
receiving hormone compared with 75% receiving cytotoxic chemotherapy remained
in remission on follow-up (250 months). In patients with active IBD, no significant
risk factors for achieving remission were identified.
Consistent hormone replacement therapy in postmenopausal patients with IBD was
found to provide a significant protective effect on IBD disease activity, likely attributed
to the anti-inflammatory properties of estrogen.101 However, in premenopausal
women, others describe an increased risk of developing IBD, specifically CD, with
exposure to oral contraceptives.102 Although further evidence is needed to clarify
the impact of hormonal therapy on the development and disease course of IBD, pa-
tients diagnosed with cancers that are commonly treated with hormone deprivation
therapy may be at increased risk for IBD disease reactivation and should be closely
followed by a gastroenterologist.
In terms of IBD management, oncologists commonly defer to a gastroenterologist
regarding guidance on IBD-directed immunosuppressive therapy. This underscores
the importance of understanding the interplay between IBD disease activity and spe-
cific cancer treatment types, as well as maintaining close communication with the
oncologist throughout the cancer treatment course.

Impact of Inflammatory Bowel Diseases Therapies on Active Cancer

Although there is considerable evidence for the risk of malignancy associated with
immunosuppressive therapy in patients with IBD, less is known regarding the risk in
those with active cancer. Pivotal randomized control trials and long-term safety regis-
tries have few to no data on patients with IBD with active cancer, and smaller obser-
vational studies have commonly excluded patients with active cancer.45,103,104
 Cancer in Inflammatory Bowel Disease 657

Recently, a retrospective, multicenter study evaluating the safety of IBD-directed

immunosuppressive therapy in patients with active and recent prior cancer found
similar rates of cancer progression in patients exposed to TNF-⍺ antagonists versus
non-TNF biologics versus immunomodulator monotherapy.105 Of 107 patients with
active cancer (72% solid tumor, 400 PY follow-up), 19 patients had progression of
cancer and 20 were hospitalized for serious infection. After adjusting for age, type
of active cancer, and immunomodulator status, there was no difference in the risk
of cancer progression (HR, 1.55; 95% CI, 0.48–5.03), mortality (HR, 2.74; 95% CI,
0.25–30.5), and serious infections (HR, 1.90; 95% CI, 0.15–24.0) between TNF-⍺
antagonists versus non-TNF biologics.
Similar to IBD, checkpoint inhibitor colitis is also commonly treated with bio-
logics, such as TNF-⍺ antagonists and anti-integrins. Immune therapies, such as
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death
protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors, have
improved outcomes for patients with non–small cell lung cancer and melanoma,
however are associated with an increased risk of diarrhea and colitis.106,107 In a
meta-analysis of 10 studies evaluating the gastrointestinal toxicities associated
with immune checkpoint inhibitors, the RR of all-grade diarrhea and colitis was
1.64 (95% CI, 1.19–2.26; P 5 .002) and 10.35 (95% CI, 5.78–18.53; P<.00001),
respectively.108 Although there are no prospective clinical trials to guide manage-
ment of checkpoint inhibitor colitis, both infliximab and vedolizumab are used in
patients who are steroid refractory.109 Treatment with infliximab has been associ-
ated with faster symptom improvement and shorter duration of steroid use.110
Compared with infliximab, treatment with vedolizumab has led to shorter duration
of steroid exposure (35 vs 50 days; P<.001), fewer hospitalizations (16% vs 28%;
P 5 .005), and shorter length of hospital stay (median 10.5 vs 13.5 days; P 5 .043);
however, treatment resulted in a longer time to clinical response (17.5 vs 13 days;
P 5 .012).111
In patients with underlying IBD, treatment with immune checkpoint inhibitors can in-
crease the risk of relapse in IBD and need for biologic therapy. In a meta-analysis of 12
studies consisting of 193 patients with IBD, treatment with immune checkpoint inhib-
itors led to IBD relapse in 40% of patients with at least one-third requiring biologics.112
CTLA-4 inhibitors were associated with a higher risk of relapse compared with PD-1
and PD-L1 inhibitors. As a greater proportion of patients with cancer receive immuno-
therapy in the near future, further data on predictive biomarkers, therapeutic drug
monitoring, and long-term safety of biologics are needed to optimize management
in patients with checkpoint inhibitor colitis.

Impact of Inflammatory Bowel Diseases Therapies on Prior Cancer

Patients with IBD with a history of cancer may be at risk for developing a new or
recurrent cancer. Evidence-based recommendations for the management of IBD-
directed immunosuppressive therapy in patients with prior cancer remain limited,
although steadily increasing. Given the known risks of lymphoma and other malig-
nancies associated with immunosuppressants, there may be concern that IBD-
directed therapy increases the risk of cancer recurrence.113 However, recent retro-
spective data have not corroborated this increased risk. In a multicenter study from
the New York Crohn’s and Colitis Organization, the investigators evaluated the risk
of new or recurrent cancer in patients with a prior history of cancer, with exposure to
either TNF-a antagonists, antimetabolites, combination therapy, or no treatment. Of
333 patients, 90 (27%) patients developed an incident cancer. There was no differ-
ence in the risk of incident cancer or time to recurrent cancer between TNF-a
658 Faye et al

antagonists versus antimetabolites versus combination therapy versus no treatment

(incidence rate per 100 PY 5 2.46 vs 5.75 vs 3.63 vs 5.40, respectively).114 Similarly,
in a meta-analysis of 16 retrospective studies, including more than 11,700 patients
with immune-mediated diseases and a prior history of cancer, there was no signifi-
cant difference in the rates of cancer recurrence in patients receiving anti-TNF ther-
apy, immunomodulators, or no immunosuppression (33.8 per 1000 PY vs 36.2 per
1000 PY vs 37.5 per 1000 PY).115
Vedolizumab, a gut-selective a4b7 integrin inhibitor, is considered to be less immu-
nosuppressive with an overall favorable safety profile, and has recently been evalu-
ated in patients with prior malignancy.116 Vedamurthy and colleagues117 compared
the risk of new or recurrent cancers in patients with IBD treated with vedolizumab
(96 patients) compared with TNF-a antagonists (184 patients) compared with no treat-
ment (183 patients) after an index cancer diagnosis. After adjusting for confounders,
there was no increase in the risk of new or recurrent cancer in patients exposed to
vedolizumab versus TNF-a antagonists versus no therapy (HR, 1.38; 95% CI, 0.38–
1.36 vs HR, 1.03; 95% CI, 0.65–1.64, respectively). These data suggest that, overall,
treatment with TNF-a antagonists or vedolizumab is not associated with an increased
risk of cancer recurrence or development of a new incident cancer, and the initiation or
continuation of IBD-directed therapy should be based on disease extent, severity, and
oncologic treatment plan.
Prospective studies on the risks of immunosuppressive therapy will be highly
informative when managing patients with IBD and cancer. The ongoing SAPPHIRE
registry is currently examining the risks of cancer recurrence in patients with IBD
exposed to immunosuppression compared with those not exposed to immunosup-
pression.118 In preliminary data, 231 patients with IBD and an index cancer were
evaluated (48% men, median age 54 years, 47% solid tumor cancers). Of these,
23% of patients was exposed to immunomodulators, 31% was exposed to TNF-a
antagonists, 28% was exposed to vedolizumab, 14% was exposed to ustekinumab,
and 39% was exposed to no immunosuppression. On follow-up, exposure to bio-
logics or immunomodulators was not associated with an increased risk of new or
recurrent cancer when compared with no therapy (6.2 per 100 PY; RR, 4.6; 95%
CI, 0.84–25; 5.9 per 100 PY; RR, 3.3, 95% CI, 0.94–11.58; 3.0 per 100 PY, respec-
tively). Exposure to combination therapy with a biologic plus immunomodulator
was however associated with an increased risk of new or recurrent cancer (14.4
per 100 PY; RR, 6.1; 95% CI, 1.7–22).

SUMMARY AND FUTURE DIRECTIONS

Patients with IBD are at an increased risk of cancer secondary to long-standing intes-
tinal inflammation and secondary to immunosuppressive therapies. As the population
of patients with IBD ages, there is an increasing risk of cancer development. Many of
these patients will require cancer treatment, and many will require further treatment for
their IBD. Much remains unknown regarding the interaction between IBD, medications
for IBD, and cancer treatment, as well as the risk of cancer recurrence in patients with
IBD and a history of cancer.
Overall, data are lacking regarding specific cancers, treatments, and risk of recur-
rence under varying medications for IBD. More data from prospective registries,
such as SAPPHIRE,118 will permit the development of evidence-based, quantitative
risk-benefit models, including cancer and IBD-related variables to assist clinicians in
managing this complex patient population.
 Cancer in Inflammatory Bowel Disease 659

CLINICS CARE POINTS

 In addition to cancers common in the general population, patients with IBD have also been
shown to be at increased risk of developing intestinal and extraintestinal malignancies.
 The identification of cancer in a patient with IBD requires close collaboration with the
treating gastroenterologist and oncologist.

DISCLOSURE

J.E. Axelrad reports receiving research grants from BioFire Diagnostics; consultancy
fees or honorarium from BioFire Diagnostics, Janssen, Pfizer, Abbvie, and BMS; and
holds US Patent 2012/0052124A1 and no other conflicts of interest. A.K. Holmer re-
ports consultancy fees or honorarium from Pfizer.

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T h e Mi c ro b i o m e i n
G a s t ro i n t e s t i n a l C a n c e r s
a a,b,
Michael G. White, MD, MSc , Jennifer A. Wargo, MD, MMSc *

KEYWORDS
 Microbiome  Tumor microenvironment  Colorectal adenocarcinoma
 Gastric adenocarcinoma  Pancreatic ductal adenocarcinoma

KEY POINTS
 The gut microbiome and host immune system are in a dynamic homeostasis whose alter-
ations have been associated with the development and progression of a variety of
malignancies.
 The tumoral microbiome plays a role in the tumor microenvironment modulating immune
responses to tumors and has the potential to affect the pharmacodynamics of some cyto-
toxic therapies.
 Further work is needed to delineate mechanisms behind these observations and translate
them to clinical benefit for patients.

INTRODUCTION

Not long after the introduction of the germ theory of disease by Louis Pasteur and
Robert Koch, Izmar Isidor Boas and Bruno Oppler began to describe bacteria within
the luminal contents of the stomach of patients with gastric cancer and specific spe-
cies that were notably absent from the contents of healthy controls. This noted “colo-
nization” of the stomach with bacteria was thought to potentially relate to physiologic
changes within the stomach itself associated with carcinogenesis.1 Given the inherent
limitations of the time, however, these associations could only be made through
microscopic evaluation of stomach or stool contents or by culturing these contents
within various media—leading to notable biases in observations and clouding more
in-depth study. A century later, we are continuing to discover and describe the role
of bacteria in cancer initiation, progression, and evasion of contemporary therapeutics
(cytotoxic chemotherapy, immunotherapy, and radiation therapy). In the last

a
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Boulevard, Unit 1484, Houston, TX 77030, USA; b Department of Genomic Medicine,
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484,
Houston, TX 77030, USA
* Corresponding author. Department of Genomic Medicine, The University of Texas MD Ander-
son Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX 77030.
E-mail address: [email protected]

Gastroenterol Clin N Am 51 (2022) 667–680

https://doi.org/10.1016/j.gtc.2022.06.007 gastro.theclinics.com
0889-8553/22/ª 2022 Elsevier Inc. All rights reserved.
668 White & Wargo

3 decades, with the introduction and popularization of next-generation sequencing

(NGS) technologies, an omics-based approach to the microbiome has led to a vastly
more comprehensive and detailed descriptions of human microbiology and down-
stream insights into their role in gastrointestinal (GI) malignancies outlined here.
Although several hypotheses have been suggested across disease histologies, the
role of bacterial or viral species in the development of GI malignancies continues to be
elucidated. To date, several viruses and bacteria including Helicobacter pylori, hepa-
titis B and C, HIV human papillomavirus, Epstein–Barr virus, human herpesvirus type
8, human T-cell lymphotropic virus type 1, Opisthorchis viverrini, Clonorchis sinensis,
and Schistosoma haematobium have been clearly linked to carcinogenesis.2 These
microbes, and others under active study, are thought to affect cancer outcomes
through alterations of metabolomic pathways, induced changes in the host immune
system, and alterations in the pharmacokinetics of anticancer agents. Beyond the
epidemiologic or culture-based systems of study, the contemporary hypotheses of
the role of microbes in these systems are heavily dependent on accurate descriptions
of the host immune system and the tumor microenvironment.
The introduction of NGS techniques was a disruptor in microbial research. Using
NGS techniques, it is now possible to definitely and precisely describe the microbial
compositions of gut luminal contents, tumors, healthy tissues, and circulating plasma.
One of the earliest of these techniques sequences the RNA from the 16s ribosomal
component of the 30s ribosomal subunit of prokaryotic species. These RNA can be
sequenced using NGS technology to provide the rapid and accurate identification
of bacterial species. In addition, several software packages have recently been devel-
oped to identify bacterial, viral, or fungal sequence reads in transcriptomic, exomic,
and genomic sequencing of human tissue. Classically discarded as a quality control
step in standard human sequencing, these tools leverage discarded raw sequence
reads aligned to microbial sequences or various bacterial taxa or viruses.
Importantly, these observations describe a point in time of a complex system and
are independent of culture growth kinetics or other microbial factors that were inherent
biases in years passed. Simultaneously, recognition of the importance of the immune
system in cancer surveillance and suppression has been increasingly appreciated in
the last decade. This has led to the description of a critical axis that exists between
the host microbiome, immune system, and cancer-specific outcomes. Ultimately, as
the importance of these bacterial and viral species throughout the body is understood,
therapeutics leveraging these observations to improve care is being developed,
providing the opportunity for these advances in knowledge to improve patient
outcomes.
Here, we review work demonstrating a variety of associations between GI malig-
nancies (gastric, pancreatic, and colorectal adenocarcinoma [CRC]) and the gut and
tumoral microbiome. We also review the role these microbes play in evasion of ther-
apeutics targeting these cancers. Last, hypotheses and early data supporting the
mechanistic underpinnings of these associations are described. Understanding of
these factors is critical to leveraging work associating microbial changes with disease
to tailor dietary or novel targeted therapies to improve health across the spectrum of
malignant disease.

THE MICROBIOME AND CARCINOGENESIS

The host microbiome has long been considered a potential contributing factor to the
development of a variety of malignancies. To date, several bacteria and viruses have
been clearly delineated as contributing to carcinogenesis. These contributions occur
 Microbiome in Gastrointestinal Cancers 669

through direct cytotoxic effects disrupting autophagy and apoptosis pathways as well
as modulating oncogenic signaling pathways. Observed effects vary by bacterial taxa
and cancer histology of interest. Moreover, beyond individual taxa associations,
broader microbial community level shifts have the potential to modulate cancer risk
via microbial metabolites and the overall health of the gut-immune axis.

Colon Polyps and the Microbiome

A CRC is classically thought of as the progression of normal colonic epithelium to
polyp formation through progressive cellular changes that eventually lead to an ade-
noma and continued cellular alterations resulting in the CRC. Microbes have been
shown to correlate both with CRC and their precursor polyps. At the polyp stage,
these tissues have been noted to have higher rates of proteobacteria as well as lower
rates of bacteroidetes when compared with healthy colonic tissue.3 In studying the gut
microbiome of patients with colon polyps, a general bacterial dysbiosis as well as
fungal signatures of the ascomycota/basidiomycota ratio was noted along with the
increased proportions of opportunistic fungi Trichosporon and Malassezia.4,5 Although
these correlations are intriguing, a causal role of these gut microbiomes in CRC devel-
opment has, to date, only been suggested in murine models via the administration of
stool from patients with CRC leading to higher rates of high-grade dysplasia and polyp
formation.6 Furthermore, the impact of the gut microbiome on the host immune sys-
tem was reflected in upregulation of inflammatory pathways and intestinal recruitment
of T-helper-1 (Th1) and Th17 cells. Lastly, in animal models with induced colorectal
carcinogenesis, germ-free rats grew fewer and smaller tumors when compared with
rats with conventional gut microbiota suggesting a critical role of the microbiome in
formation of colonic polyps.6

Colorectal Adenocarcinoma and the Gut Microbiome

CRC is the third most commonly diagnosed malignancy worldwide and the third most
common cause of cancer-related mortality. It has been associated with diets high in
red meat, low-fiber diets, alcohol consumption, smoking, and obesity. Importantly,
CRC has been rising in incidence (especially in younger populations) and hypothe-
sized to have a potential link to environmental exposures given this recent and sudden
rise. Moreover, several studies are underway to correlate this increase in incidence
with the gut microbiome given its strong link to environmental exposure and potentially
with CRC development.
The flora of the gut under normal physiologic conditions varies from proximal to
distal and is reflective of one’s exposome—their location, diet, medications, and other
lifestyle factors.7 These changes are reflected in enzymatic activity, pH, and fermen-
tation of luminal contents. The resulting changes are reflected in various genera of
bacteria being abundant within the GI tract and colon. Beyond red meat, epidemio-
logic associations have been made with high-fat diets which have been shown to in-
crease sulfate-reducing bacteria. These bacteria are critical to the transformation of
primary to secondary bile acids shown be potentially related to carcinogenesis.8
Conversely, butyric acid and short-chain fatty acids (generated from fermented fiber)
have been shown to be protective of CRC development.9 The role of metabolites has
also been shown to affect the function of p53, converting it from a tumor suppressor to
oncogene depending on the levels of luminal gallic acid.10 These well-described asso-
ciations between CRC and diet have therefore led to intensive study of the role of the
gut microbiome in the development of CRC.11 Various reports have suggested the
most abundant geni of bacteria to be Bacteroides, Prevotella, and Ruminococcus in
670 White & Wargo

CRC patients.12 Importantly, markers of a “healthy” microbiome remain elusive,

although markers of carcinogenesis and dysregulation are increasingly well described.
As noted in other malignancies, the gut microbiome and metabolome have been
shown to correlate with colorectal cancer in a stage-specific manner.13,14 In the
case of CRC, Fusobacterium nucleatum, and Solobacterium moorei were present in
higher abundance in patients with later-stage CRC. Bacteroides fragilis and
colibactin-producing Escherichia coli have also been associated with CRC and have
been suggested to play a potential causal role in initiation and progression of these
tumors.15–18
It has been demonstrated that B fragilis enterotoxin plays a multifactorial role in
oncogenesis. This enterotoxin’s mechanism is similar to colibactin produced by E
coli19,20 and has the ability to induce direct DNA damage via reactive oxygen species.
This then leads to the Th17 recruitment which produces IL-17 and downstream NF-kB
(Nuclear factor kappa-light-chain-enhancer of activated B cells) signaling as well as
E-cadherin, b-catenin, and STAT3 (Signal transducer and activator of transcription
3).21,22 This induces a pro-inflammatory setting stimulating IL-8, TGFb (Transforming
growth factor beta), C5a (complement component 5a), leukotriene B4, and growth-
related oncogene-⍺, featuring immature myeloid cells that lead to an oncogenic
microenvironment favoring cancer initiation and progression.15,23,24 At the same
time, B fragilis enterotoxin plays a role breaking down mucus overlying the colonic
epithelial cells allowing for the adhesion of B fragilis and other opportunistic species.25
At a more global level, the administration of stool from patients with CRC was able to
induce higher rates of dysplasia and polyp formation suggesting a causal role of the
gut microbiome in colorectal cancer initiation.6 Beyond direct invasion, toxin produc-
tion, and DNA damage, the effect of the immune system is significant with the host im-
mune system recognizing various microbial markers. Recognition of these microbe-
associated molecular patterns (MAMPs) leads to the activation of NOD (nucleotide-
binding oligomerization domain)-like receptors and Toll-like receptors (TLRs) that
lead to the regulation of inflammatory pathways and the proliferation of various im-
mune compartments.26–28 In particular, TLR2 has been suggested to play a role sup-
pressing local immune response and leading to protection of the colonic
epithelium.29–31 The importance of the interface between host systemic immunity
and the gut microbiome in these observed effects was demonstrated in animal models
of CRC carcinogenesis, germ-free rats grew fewer and smaller tumors than those with
a common gut microbiota.32

Gastric Adenocarcinoma and the Gut Microbiome

Gastric cancer is the fourth most common cancer worldwide and the second most
common cause of cancer-related death. Chronic H pylori infection has been associ-
ated with the development of peptic ulcer disease and gastric adenocarcinoma.
Gastric adenocarcinoma development has been correlated with both local gastric
luminal contents33 and the colonic gut microbiome.34 In the case of luminal contents,
the most robustly described is the case of H pylori that has been clearly and mecha-
nistically associated with the development of peptic ulcer disease. Intriguingly, the as-
sociation between H pylori infection and gastric cancer risk was shown to be strongly
associated with patient ancestry in a cohort of Colombian patients.35 Although those
with Amerindian ancestry were at a high risk of gastric cancer in the setting of H pylori
infection, it was relatively benign in a cohort of those with African ancestry suggesting
germline risk is strongly intertwined with this risk profile.
The demonstrated mechanism behind the development of gastric adenocarcinoma
secondary to H pylori infection is the injection of cytotoxin-associated gene A (CagA)
 Microbiome in Gastrointestinal Cancers 671

and vacuolating toxin A (VacA) into gastric epithelial cells. In the case of CagA, this
leads to the loss of cell polarity, induction of inflammation (interferon-g, TNF [Tumor
necrosis factor]-⍺, IL-1, IL-1b, IL-6, IL-7, IL-8, IL-10, and IL-18), disruption of epithelial
junctions, and oncogenic signaling initiation (ERK/MAPK [extracellular signal-regu-
lated kinases/mitogen-activated protein kinase], PI3K/Akt [Phosphoinositide 3-ki-
nase/Protein kinase], NF-jB, Wnt [Wingless-related]/b-catenin, Ras [Rat sarcoma
virus], sonic hedgehog, and STAT3) that induce an oncologic inflammatory milieu.36–38
In addition, VacA induces vacuolation and autophagy of epithelial cells, increased
MAP kinase activity, VEGF (Vascular endothelial growth factor), and Wnt/
b-catenin.39–43
Aside from the specific associations and mechanism behind H pylori carcinogen-
esis, more global dysbiosis has been noted in the gastric luminal contents of these pa-
tients. These changes have been noted to change across stages of development and
progression of gastric adenocarcinoma. This work has identified overall compositional
changes in gastric luminal contents as well as enrichments of P stomatis (Peptostrep-
tococcus stomatis), Dialister pneumosintes, S exigua (Slackia exigua), Parvimonas
micra, and Streptococcus anginosus.33
Beyond these local associations of gastric luminal contents and local effect, the role
of the gut microbiome in gastric cancer carcinogenesis has been elucidated recently.
Specifically, Clostridium and Fusobacterium species have been noted in higher abun-
dance in patients with gastric cancer as compared with the general population.44
These findings were further validated along with a more comprehensive report of dif-
ferential abundance in patients with gastric cancer described by Zhang and col-
leagues.34 In the representative of the translational potential of this work, both
Lactobacillus and Megasphaera were found to be potentially useful as markers for
gastric adenocarcinoma detection. These associations must be taken in light of the
significant work in other disease histologies and associations between colonic gut
flora and disease initiation and progression. Further work will ultimately be needed
to define whether these associations are correlative or causal.

Pancreatic Adenocarcinoma and the Gut Microbiome

Pancreatic cancer is the 12th most common cancer worldwide and the 7th cause of
cancer-related death. It has an almost inherently poor prognosis with a median sur-
vival of 9 months. It is associated with smoking, obesity, alcohol, chronic pancreatitis,
and type 2 diabetes.
Epidemiologic data have intriguingly linked periodontal disease with pancreatic
ductal adenocarcinoma (PDAC) incidence across several cohort studies with a wide
range of reported risks.45–49 Given these associations, directed analyses of the oral
microbiomes of patients with pancreatic cancer and healthy controls demonstrated al-
terations in a variety of bacterial species including Neisseria elongate, Streptococcus
mitis, Fusobacterium, Leptotrichia, Firmicutes, and Porphyromonas. These were
shown to be differentially abundant between groups of cases and controls.50–54
Intriguingly, one of these studies also noted circulating antibodies to these oral bacte-
ria correlated with risk of PDAC.54
Similar to previously described associations in colorectal and gastric cancer, it has
been noted that there are differential abundances of bacteria in fecal samples of pa-
tients with PDAC as compared with healthy controls. This is perhaps not surprising
given the critical role the colonic gut microbiome plays in normal pancreas physi-
ology.55 To date, however, this has only been completed in a single study demon-
strating an increase in proteobacteria in PDAC and a depletion in short-chain fatty
acid synthesis association modules, with an increase in modules associated with
672 White & Wargo

bacterial virulence.56 Ultimately, validation and further study is needed to solidify these
observations and study any potential causal role of the gut microbiome in PDAC.
Although minimal data exist for associations between the colonic microbiome and
PDAC, there are correlative trials associating gastric H pylori infection with PDAC—
although these are significantly confounded by lifestyle factors such as smoking
and obesity.57 The proposed mechanism lies behind the upregulation of KRAS,
mutated in the majority of PDAC, by H pylori.58 In addition, H pylori has the potential
to upregulate Bcl-xL (B-cell lymphoma-extra large), MCL-1 (Induced myeloid leukemia
cell differentiation protein), surviving, c-myc (Myelocytomatosis), and cyclin D1 which
all have the potential to contribute to PDAC carcinogenesis.59–61
As described in CRC, the role of MAMPs in PDAC has been preliminarily studied as
well. The induction of the immune system via MAMPs has been shown to lead to
pancreatitis and potentially progress to pancreatic cancer.62,63 Although F nucleatum,
as in CRC, is also a negative prognostic factor in PDAC.64 Finally, the taste receptor 2
member 38 (T2R38) has been shown to be expressed in PDAC. Moreover, Pseudo-
monas aeruginosa is a T2R38 ligand that has been shown to lead to invasion and
metastasis via ABCB1.65

THE MICROBIOME IN DISEASE PROGRESSION

Beyond cancer initiation and carcinogenesis, bacteria have the potential to induce
metastatic spread. These effects are possible both in the disruption of vascular bar-
riers that may initially confine malignancies and alterations in the immune system
both globally and locally that diminish its routine immune surveillance functions that
act to suppress metastatic spread. For clinicians caring for solid tumors such as the
GI malignancies reviewed here, this is a particularly critical step in disease progression
as this classically represents the point at which patients move from being curable to
incurable. As such, the potential future role of the microbiome in prognosis, surveil-
lance, and therapy is immense.

Colorectal Adenocarcinoma
Beyond gut microbial associations, the specific bacterial taxa previously mentioned (F
nucleatum) is oftentimes found within colorectal cancers themselves. These observa-
tions suggest a potential role in carcinogenesis for a subset of patients with colorectal
cancer.66–71 Beyond associations with colorectal cancer, a specific phenotype seems
to be associated with F nucleatum positive CRC. These tumors are predominantly
right sided and associated with an overall poor prognosis.72–75 In the case of F nucle-
atum positive rectal cancer, clearance of tumoral F nucleatum is associated with
improved recurrence free survival as compared with those that remain positive
post-neoadjuvant chemoradiotherapy, demonstrating tumoral levels to be a modifi-
able risk factor that has the potential to improve cancer-specific outcomes. Although
numerous groups have posited hypotheses as to the mechanisms behind these ob-
servations, the role of F nucleatum in carcinogenesis is likely multifactorial.
Of these hypotheses, the role of Fap2 (fusobacterial Gal-GalNAc-binding lectin), a
virulent epithelial adhesin, is often suggested as a potential mechanism to explain these
observations. Fap2 permits adhesion to a CRC polysaccharide and generates a FadA
(Fusobacterium Adhesions Gene A) adhesion complex capable of stimulating Wnt/
b-catenin, leading to the increased expression of oncogenic and inflammatory re-
sponses.76–78 Treatment of murine models of CRC with F nucleatum was able to mimic
similar transcriptional and inflammatory pathways seen clinically.68,79 Furthermore,
 Microbiome in Gastrointestinal Cancers 673

incubation of CRC cell lines with F nucleatum before injection into mice led to increased
growth rates of incubated cell lines as compared with control.76,80
As detailed above, several bacterial taxa have been implicated in the development
of CRC. Beyond these associations, overlapping and unique species also play a role in
the progression of disease. In the case of F nucleatum, murine models of colorectal
cancer liver metastasis have been shown to show a less virulent phenotype with the
eradication of F nucleatum from the murine gut.81 Interestingly, these tumors that
are F nucleatum positive have F nucleatum present in positive lymph nodes as well
as liver metastases, further strengthening the potential association between its pres-
ence and disease progression and metastasis.81
Similarly, the development of metastasis via disruption of the vascular barrier and
formation or a pre-metastatic niche has been shown to be driven, in murine models
by gut bacteria (potentially E coli C17). Moreover, circulating markers of gut vascular
permeability (plasmalemma vesicle-associated protein-1) were shown to correlate
with outcomes in clinical specimens and again be diminished with eradication of gut
bacteria.82–86

Pancreatic Adenocarcinoma
Apart from limited data describing the role of the gut microbiome in pancreatic cancer,
there has been a significant body of work recently describing the role of the tumoral
microbiome’s role in the microenvironment of PDAC. In the case of PDAC, the tumoral
microbiome seems to play two distinct roles—in the modulation of immune response
as measured by T-cell activation87–89 and in the inactivation of common cytotoxic
agents such as gemcitabine.90 Importantly, these observations are tied to outcomes
of patients with PDAC, as long-term survivorship was associated with a more diverse
tumor microbiome, specific bacterial taxa (Saccharopolyspora, Pseudoxanthomonas,
and Streptomyces), and a more robust microbially driven immune response in the tu-
mor microenvironment.

THE MICROBIOME AND RESPONSE TO THERAPY

Intriguingly, a variety of bacterial species have been shown to alter response to various
therapeutics. In the case of immune checkpoint blockade (ICB), this is somewhat ex-
pected given the known significant impact the gut microbiome has on modulating the
host immune system. A similar effect has been seen locally as well, with the tumor
microbiome modulating response to immunotherapies. Lastly, the degradation of
cytotoxic therapies by tumoral bacterial have been shown to by decrease in the effi-
cacy of cytotoxic chemotherapy. These initial findings lay the groundwork for the po-
tential of microbial modulation to augment other therapies—as has been seen in the
case of fecal transplantation inducing response to ICB in melanoma.91

Colorectal Adenocarcinoma
A subset of colorectal cancers, microsatellite mismatch repair deficient, are known to
be responsive to the ICB.92 Response to ICB, however, is not uniform. Similar to other
histologies, this heterogeneity has been hypothesized to, at least partially, correlate
with specific gut microbial communities and changes.93 Studies quantifying this asso-
ciation and overlap with gut signatures predictive of response in other histologies,
however, are ongoing in the setting of promising preclinical models.94
Although microbial markers of response to checkpoint blockade are actively being
studied, markers of response to cytotoxic therapies are increasingly well described. In
the case of F nucleatum, previously associated with carcinogenesis, it has also been
674 White & Wargo

associated with chemoresistance in CRC.14,74 This induced chemoresistance has

been noted with both oxaliplatin and 5-FU via the activation of autophagy pathways
and innate immune signaling via TLR4 and MyD88.74 These effects were shown to
be abrogated in preclinical models via the modulation of the gut microbiome with anti-
biotic therapy, again suggesting a causal rather than correlative association.95

Pancreatic Adenocarcinoma
As previously noted, bacteria within PDAC tumors have the ability to inactive cytotoxic
agents such as gemcitabine. These initial analyses importantly provide insights in
prognostication while also suggesting potential future novel treatment strategies.
Moreover, unique neoantigen properties of long-term survivors noted by Balachan-
dran and colleagues demonstrate circulating levels of MUC16 (CA125) and T-cell
reactivity are associated with survival and that their loss is associated with relapse.87
Pushalkar and colleagues were able to demonstrate the tumoral microbiome acts to
suppress monocytic cellular differentiation that leads to T-cell anergy.88 These mech-
anistic associations are important keys as the correlative versus causal role of the
microbiome continues to be delineated while also allowing for more directed hypoth-
esis generation in other disease sites.

SUMMARY

As outlined above, the interplay between the gut and tumoral microbiome, host im-
mune responses, carcinogenesis, and evasion of therapeutics is a complex system
with significant cross-talk between these interrelated variables. Although these asso-
ciations begin to be deconvoluted, the perennial question in microbiome research ex-
ists between causation and correlation. Hypotheses exist for several specific bacteria,
and we see overlap between taxa or pathway associations with various disease histol-
ogies—short-chain fatty acids, H pylori, and F nucleatum are clear examples of this.
Moreover, with the initiation of clinical trials modulating the microbiome through fecal
transplantation, prebiotics, or other novel methods, of these associated mechanisms
will be tested with continued rigor and continue to provide further insights.
Microbial modulation via phase I studies of fecal transplantation in melanoma pa-
tients demonstrated the potential efficacy of gut microbial alteration in optimizing re-
sponses to therapy.91,96 This work provided clear insight that fecal transplantation was
able to increase tumor immune infiltrates and induce response in 30% to 40% of
otherwise checkpoint blockade refractory patients. Although these findings were
noted in cutaneous malignancies, these therapies have the potential to improve out-
comes in checkpoint responsive GI malignancies and warrants study in cytotoxic ther-
apies. In the case of fecal transplant technologies, inherent difficulties in scalability are
likely insurmountable on a population level. These studies, however, importantly
inform the development of directed microbial modulation as well as dietary and prebi-
otic modulation of the gut microbiome.
An increasing interest in the use of changes in diet and/or the use prebiotics (non-
digestible agents used to promote beneficial microbes) has driven directed work
studying the potential benefits of these agents in improving response to various ther-
apies. Dietary associations with various malignancies have long been described, such
as associations between red meat intake and colorectal cancer.11 In this case, how-
ever, the use of nutritional supplements such as fiber97 or soluble vitamins such as
magnesium98 has been shown to improve response with these dietary effects seen
during their treatment window. This allows clinicians to make a more targeted and
directed intervention beyond global dietary changes. Intriguingly, probiotics (ingested
 Microbiome in Gastrointestinal Cancers 675

live bacteria) decrease gut microbial diversity and have been associated with worse
outcomes in immunotherapy-treated patients.97
Perhaps the most immediate potential clinical application of the microbiome lies in
the ability of gut, tumoral, or circulating microbes to act as screening or prognostic
tests at population or individual levels. Recent analysis of the cancer genome atlas
has shown histology and stage-specific circulating microbial signatures detectable
across disease sites.99 These microbes exist in tissue and/or blood oftentimes already
collected as part of standard of care and could be queried through scalable targeted
assays or can be sequenced as part of exploratory research protocols. Furthermore,
with continued optimization of gut microbial collection techniques, patients can now
submit stool samples remotely for 16s or whole-genome sequencing. The ability of
these or other markers to augment current standard of care tests, however, remains
unknown and will require independent study for each disease histology.
As the microbiome is increasingly recognized as critical to human health and normal
immune function, its importance to malignant disease development, progression, and
response to therapy is increasingly clear. Moving forward, clinical trials and careful
prospective studies are needed to begin to integrate these findings into clinical prac-
tice. As the early adoption of various treatment modalities is initiated, it will be increas-
ingly important to actively study these patients to further improve and learn from these
early studies. Ultimately, the last decade has shown continued interest and mo-
mentum behind the study and utilization of microbial modulation to improve cancer
care.

CLINICS CARE POINTS

 The gut microbiome is an emerging factor in the development and progression of

gastrointestinal malignancies.
 While emerging therapeutics in benign disease such as refractory clostridium difficile
infection are approaching approval in the United States, therapeutic and diagnostic
strategies are still under development.
 Commercially available fecal profiling offer little insight into one’s overall microbial health
and their results should be interpreted with caution.

FUNDING

M.G.W. is supported by the National Institutes of Health (T32 CA 009599) and the MD
Anderson Cancer Center support grant (P30 CA016672). J.A.W. is supported by the
NIH (1 R01 CA219896-01A1), the Melanoma Research Alliance (4022024), the Amer-
ican Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17)
and the MD Anderson Cancer Center’s Melanoma Moon Shots Program.

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