THEMATIC REVIEW ON GASTROENTEROLOGICAL DISEASES

Barrett Esophagus
Prasad G. Iyer, MD, MSc, and Vivek Kaul, MD

CME Activity

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accredited by the Accreditation Council for rial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D.
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(ACPE), and the American Nurses Credential- Dr Iyer has received research funding from Exact Sciences, C2 Therapeutics,
ing Center (ANCC) to provide continuing ed- and Medtronic. He has received consulting fees from Medtronic and Symple
ucation for the healthcare team. Surgical. Dr Kaul has received research funding from CSA Medical and is a
Credit Statement: Mayo Clinic College of Medicine and Science designates consultant for Medtronic, Olympus, CSA Medical, and Cook-Medical.
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Learning Objectives: On completion of this article, you should be able to Hardware/Software: PC or MAC with Internet access.
(1) obtain state of the art information related to screening and surveillance in Date of Release: 9/1/2019
Barrett esophagus, (2) acquire a good understanding of the various modal- Expiration Date: 8/31/2021 (Credit can no longer be offered after it has
ities of treatment available for dysplastic Barrett esophagus and early esoph- passed the expiration date.)
ageal neoplasia, and (3) identify the key best practices and guideline based Privacy Policy: http://www.mayoclinic.org/global/privacy.html
recommendations for management of Barrett esophagus. Questions? Contact [email protected].

Abstract

Barrett esophagus is a metaplastic change in the lining of the distal esophageal epithelium, characterized by
replacement of the normal squamous epithelium by specialized intestinal metaplasia. The presence of
Barrett esophagus increases the risk of esophageal adenocarcinoma several-fold. Esophageal adenocarci-
noma is a malignancy with rapidly rising incidence and persistently poor outcomes when diagnosed after the
onset of symptoms. Risk factors for Barrett esophagus include chronic gastroesophageal reflux, central
obesity, white race, male gender, older age, smoking, and a family history of Barrett esophagus or esophageal
adenocarcinoma. Screening for Barrett esophagus in those with several risk factors followed by endoscopic
surveillance to detect dysplasia or adenocarcinoma is currently recommended by society guidelines.
Minimally invasive nonendoscopic tools for the early detection of Barrett esophagus are currently being
developed. Multimodality endoscopic therapydusing a combination of endoscopic resection and ablation
techniquesdfor the treatment of dysplasia and early adenocarcinoma is successful in eliminating intestinal
metaplasia and preventing progression to adenocarcinoma, with outcomes comparable to those after
esophagectomy. Risk stratification of those diagnosed with Barrett esophagus is a challenge at present, with
active research focused on identifying clinical and biomarker panels to identify those with low and high risk
of progression. This narrative review highlights some of the challenges and recent progress in this field.
ª 2019 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(9):1888-1901

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BARRETT ESOPHAGUS

B
arrett esophagus (BE) refers to the metaplasia measuring at least 1 cm above
metaplastic transformation of esopha- the gastric folds (the anatomic landmark
geal squamous epithelium to special- for the gastroesophageal junction). The sec-
ized columnar epithelium with intestinal ond component is that of intestinal meta-
metaplasia in the distal esophagus. This is plasia characterized by the presence of
thought to occur as a consequence of goblet cells in biopsies obtained from the
chronic injury, likely mediated by reflux of area of columnar metaplasia at endoscopy
gastric contents.1 The significance of BE (Figure 2).1 Fulfillment of both of these
lies in it being the strongest risk factor for criteria is essential to the diagnosis of BE.
and precursor of most esophageal adenocar- Of note, the second criterion has been
cinomas (EAC). It is presumed that EAC deemed to be optional in some society rec-
arises as the end result of a stepwise transfor- ommendations such as the British Society
mation from metaplasia to dysplasia (low of Gastroenterology. Recent guidelines from
grade and high grade) to carcinoma.2,3The the American College of Gastroenterology8
clinical significance of BE is related to the have, however, retained the requirement
increasing incidence of EAC over the past for intestinal metaplasia to be seen on histol-
few decades, relative to other solid malig- ogy, given that cohort studies have demon-
nancies. This increase has been estimated strated a substantially lower risk of
to be approximately 600% over the past 3 progression to EAC in the absence of intesti-
to 4 decades. This increased incidence has nal metaplasia.9
also been paralleled by an increase in disease Careful examination of the gastroesopha-
related mortality.4 The outcomes of patients geal junction and distal esophagus is critical
with EAC diagnosed after the onset of symp- to making appropriate diagnoses of BE. The
toms remains grim, with a 5-year survival endoscopic criteria for BE was set at 1 cm
not exceeding 20%. This has remained rela- of columnar mucosa in the tubular esoph-
tively unchanged over the past several agus, given previous studies documenting
decades. poor inter-agreement among endoscopists
This situation has led to substantial in- for lengths less than 1 cm.10 In addition,
terest in understanding the risk factors for population-based11 and multicenter cohort
BE and early detection followed by surveil- studies12 have shown that the risk of
lance for the detection of prevalent /incident
dysplasia and adenocarcinoma. Substantially
improved outcomes (5-year survival rates
greater than 80%) in patients diagnosed
with T1 esophageal adenocarcinoma (treated
endoscopically or surgically)5d and ran-
domized trials showing the ability of endo-
scopic ablation techniques to eliminate BE
in up to 80% of patients and reduce the
risk of progression to EAC 6,7dhave added
further interest and momentum to these
efforts.

DIAGNOSIS
Normally, the esophagus is lined by squa-
mous epithelium (which appears pale white
endoscopically). Columnar metaplasia is re-
FIGURE 1. Endoscopic appearance of Barrett
flected by change of this epithelium to pale
esophagus. (A) Squamous epithelium. (B)
pink columnar metaplasia (Figure 1). The Columnar metaplasia suggestive of Barrett
diagnosis of BE requires 2 components. esophagus.
The first component is that of columnar
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 MAYO CLINIC PROCEEDINGS

FIGURE 2. Diagnostic criteria for BE. Endoscopic ( >1 cm of columnar metaplasia in the distal esophagus)
and histological criteria (intestinal metaplasia on histology) need to be met.1

progression to dysplasia or adenocarcinoma EPIDEMIOLOGY AND RISK FACTORS

in patients with less than 1 cm of columnar Several studies have attempted to assess the
mucosa in the distal esophagus is substan- prevalence of BE in different populations.
tially lower than that of patients meeting Large population based studies in Europe
criteria for the diagnosis of BE. Moreover, (Scandinavia16 and Italy17) have screened
studies have shown that a substantial pro- the general population with upper endos-
portion of patients diagnosed with BE in copy and have reported BE prevalence esti-
the community (up to 33%) can have this mates ranging from 1.3 to 1.6%. However,
diagnosis reversed on careful examination a more recent population based screening
by well-trained gastroenterologists.13 study in Olmsted County, Minnesota, re-
This is particularly important, given im- ported that 8.5% of adults above the age of
plications of a Barrett diagnosis in terms of 50 had evidence of BE.18 Other cross-
the need for endoscopic surveillance with sectional studies from tertiary care institu-
associated procedural risks, costs, and tions in the Unites States have also reported
adverse effects on health care-related quality higher rates of BE prevalence from 8 to
of life and, potentially, the ability to obtain 17%.19 These estimates suggest that there
health insurance.14,15 are potentially 3 to 5 million patients with
A reporting system for BE has been devel- BE in the United States.
oped (Prague Classification, Supplemental The incidence of endoscopically detected
Figure 1) and may help in making reporting BE appears to be increasing as well.
BE length and endoscopic appearance more Although studies from the United States
uniform. It was developed using an interna- have revealed that this incidence has
tional consortium of experts.10 The BE increased in parallel with increasing endos-
segment length is expressed as the maximal copy volume,11 other studies have shown
(M) and circumferential (c) components. that the proportion of patients diagnosed

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TABLE 1. Society Recommendations for Screening for Barrett Esophagus

American College of Gastroenterology Screening may be considered in male patients with chronic (
5 years) and/or frequent (>1/week) reflux and
(2016)8 2 or more risk factors (strong recommendation, moderate level of evidence)
d White race

d Central obesity

d Smoking (current or past history)

d Confirmed family history in a first degree relative

Screening is not recommended in female patients (may consider in those with multiple risk factors).
Unsedated transnasal esophagoscopy is an alternative to sedated esophagogastroduodenoscopy (EGD) for
Barrett esophagus screening.
Before screening is performed, overall life expectancy of patient should be considered.

British Society of Gastroenterology Screening can be considered in patients with chronic reflux symptoms and multiple risk factors (at least 3 of
(2013)26 age 50 years or older, white race, male sex, obesity). Decrease by 1 in presence of at least 1 first-degree
relative with Barrett esophagus or esophageal adenocarcinoma
Screening with endoscopy is not feasible or justified for an unselected population with gastroesophageal
reflux symptoms.5
American Gastroenterological In patients with multiple risk factors for esophageal adenocarcinoma, screening is recommended (weak
Association (2011)25 recommendation, moderate quality evidence).
Screening the general population not recommended (strong recommendation, moderate quality evidence).
American Society of Gastrointestinal Consider screening with EGD in select patients with multiple risk factors.
Endoscopy (2012)28 Inform patients there is insufficient evidence that screening prevents cancer or prolongs life.
American College of Physicians (2012)29 Screening with EGD for Barrett esophagus and esophageal adenocarcinoma may be considered in men older
than 50 years of age, with symptoms of chronic gastroesophageal reflux disease (for more than 5 years)
and additional risk factors: nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use,
and intra-abdominal distribution of fat.

with BE, adjusted for endoscopy volume, has for BE. There is significant overlap between
increased.20 However, it remains unclear if these risk factors and those for EAC. Alcohol
this is truly an actual increase in incidence consumption has not been found to be a
or a manifestation of increasing awareness consistent risk factor for BE.22 Indeed, some
among endoscopists and a reflection of studies have shown that wine consumption
detection bias. may be protective against the development of
Despite the increasing detection of BE, BE. A recent study also suggests that Helico-
population studies suggest that only one bacter pylori infection may have a protective ef-
third of patients with prevalent long- fect against development of BE.23
segment BE in the community have been
clinically diagnosed.3 This suggests that SCREENING FOR BE
only a minority of prevalent cases of BE are The rationale for BE screening is based on
receiving clinical attention in terms of sur- the predicate that most EACs arise in a back-
veillance and detection of dysplasia. ground of BE and that if BE is diagnosed
Several risk factors have been identified for early, effective endoscopic surveillance
BE. Endoscopic database studies have reported would detect dysplasia/early EAC, which
that the prevalence of BE sharply increases in can then be treated endoscopically or surgi-
the fourth and fifth decades of life. Male cally. Although there is, at present, no Level
gender, white race, chronic symptomatic 1 evidence demonstrating the effectiveness
reflux (defined the symptoms occurring more of screening, the efficacy of endoscopic ther-
than once a week for more than 5 years), cen- apy in preventing progression to EAC in ran-
tral obesity (measured by waist hip ratio or domized trialsdand consistent evidence
waist circumference),21 current or past history establishing excellent survival of patient’s
of smoking, and a confirmed family history of diagnosed with early stage EAdhave pro-
BE or EAC are other documented risk factors vided support to the strategy of BE screening
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 MAYO CLINIC PROCEEDINGS

followed by surveillance. Several modeling

studies have shown that this approach may
be cost effective, particularly with the recent
availability of minimally invasive tools for
screening.24
Current society guidelines suggest
considering BE screening in patients with
chronic reflux and other risk factors such as
male gender, older age (>50 years), central
obesity, current or past smoking, and family
history of BE or EAC (Table 1).5,8,25-29
Although there are several limitations and
weaknesses in this approach, there has been
recent progress on several fronts. FIGURE 3. Capsule sponge device intact (left)
Sedated endoscopy (at present, the most and expanded to 25 mm (right) with attached
used technique for screening) is an invasive string.
and expensive tool and hence unsuitable
for widespread application. Given evidence validated in multiple cohorts.31 Although
from multiple studies and clinical trials sug- these scores can assist in identifying the at-
gesting excellent sensitivity and specificity risk population, the risk score at which BE
(for the diagnosis of BE), along with excel- screening should be recommended is still
lent safety and tolerability,27 unsedated to be determined. Importantly, life expec-
transnasal endoscopy has been accepted as tancy and performance status need to be
an alternative to sedated endoscopy for BE considered carefully while making a decision
screening. However, its use remains low to screen for BE, given other implications af-
because of perceived physician and patient ter its diagnosis.
barriers.28
More recently, minimally invasive tools
MANAGEMENT OF PATIENTS WITH BE
such as capsule sponges (Figure 3) and swal-
lowed balloons (which are swallowed, Proton Pump Inhibitor Therapy
expand, and then pulled with attached cords, The goal of proton pump inhibitor (PPI)
providing circumferential sampling of the therapy in patients with BE is to control
esophagus) have been developed in conjunc- symptoms of gastroesophageal reflux and
tion with molecular biomarkers (such as heal esophagitis. This is somewhat chal-
epithelial protein markers: trefoil factor 329 lenging, given the known hyposensitivity of
and methylated DNA markers30) to diagnose patients with BE to reflux, which makes
BE in a minimally invasive fashion, with assessment of symptoms unreliable as a mea-
moderate to excellent sensitivity (78% to sure of reflux control. Physiologic studies
100%) and specificity (90% to 100%). These have also demonstrated that patients with
devices are also well tolerated and likely sub- BE have the most severe reflux in the contin-
stantially less expensive than sedated endos- uum of phenotypes from normal to nonero-
copy. Studies performed in screening sive disease, erosive disease, and BE. Current
populations are ongoing and awaited. society guidelines recommend placing pa-
Exhaled volatile organic compounds have tients diagnosed with BE on a dose of PPI
also been used to detect BE in pilot proof- that is adequate to control symptoms and
of-concept studies, with moderate sensitivity heal esophagitis. There is some evidence
and specificity. from nonrandomized observational studies
In addition, Barrett risk assessment that PPIs may reduce the risk of progression
scores, which integrate risk factorsdsuch to esophageal adenocarcinoma.32 Random-
as age, gender, waist hip ratio, and smoking ized controlled trials to test this association
historydhave also been developed and are ongoing, and results are awaited.
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FIGURE 4. (A): White light endoscopy view of Barrett esophagus (BE) segment (B): Narrow band imaging
view of BE segment (illumination with blue and green light, highlighting mucosal and vascular details) (C):
Image of confocal laser endomicroscopy, showing dark, irregular, and distorted glands suggestive of
dysplasia.

Endoscopic Surveillance. The goal of endo- importance of a careful and methodical

scopic surveillance in BE is to detect incident white-light endoscopic examination after
or prevalent dysplasia/adenocarcinoma early, washing and cleaning the mucosa cannot be
enabling treatment and improved outcomes. overemphasized.
Several society guidelines recommend endo- A more recent development in BE
scopic biopsies of the Barrett mucosa in a screening/surveillance has been the use of
4-quadrant fashion every 1 to 2 cm, wide area transepithelial sampling (WATS-
depending on the presence of previously 3D). This adjunctive (to forceps biopsies)
known dysplasia (Seattle protocol), in addi- tissue sampling technique in BE uses a stiff
tion to sampling any visible lesions sepa- endoscopic brush catheter, which increases
rately.8,25 Various imaging modalities have the surface area of the BE epithelium
been investigated to assist in and enhance sampled and provides cellular samples,
the endoscopic detection of dysplasia in BE. which are scanned first by an artificial neural
These include dye-based chromoendoscopy network computerized algorithm before pre-
using methylene blue or acetic acid, which is senting the 200 most abnormal cells for eval-
somewhat cumbersome, given the need for uation by a pathologist. This technique has
dye spraying and suctioning. Electronic been shown to increase the yield of dysplasia
chromoendoscopy using optical imaging and neoplasia in patients with BE in a multi-
technologies such as narrow-band imaging center prospective randomized crossover
(Figure 4B), i scan or blue-laser imaging are trial by Vennalganti.34 Additional data on
also available and more commonly used, validation of these findings in a lower risk
given their convenience (given integration (nondysplastic patients with BE) cohort are
into the endoscope and activation with but- awaited.
tons, without the need for additional dyes Recommended intervals of surveillance
and spray catheters) and ease of use. A of patients with BE vary, depending on the
recent systematic review and meta-analysis grade of dysplasia, given variation in the
reported that use of any of these adjunctive risk of progression to cancer (Table 2). The
imaging modalities increases dysplasia yield estimated annual risk of progression in non-
by 33%.33 In addition, imaging modalities, dysplastic BE is low, at 0.33%,35 whereas
such as confocal laser endomicroscopy that in patients with low-grade dysplasia
(Figure 4C), are also used, which provide (LGD) is higher and more variably estimated
real-time histology at the microscopic level from 0.7% to 1%.36 This risk of progression
and can be used to discriminate between in patients with LGD applies to cases
normal and dysplastic tissue. However, the confirmed by an expert gastrointestinal

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 MAYO CLINIC PROCEEDINGS

TABLE 2. Recommendations for Management of Patients With Barrett Esophagus Stratified by Dysplasia Grade and Risk of Progression
Risk of progression to
high-grade dysplasia/
esophageal
Grade of dysplasia adenocarcinoma Recommendation for management
No dysplasia 0.33% per year Endoscopic surveillance every 3 to 5 years
Low-grade dysplasia 0.7% to 1.0% per year Confirm diagnosis by expert gastrointestinal pathologist
Discuss endoscopic ablation
Endoscopic surveillance every 6 to 12 months
High-grade dysplasia 8% per year Confirm diagnosis by expert gastrointestinal pathologist
Refer for endoscopic therapy to center with expertise for
- Endoscopic resection of visible lesions
- Endoscopic ablation

T1a (mucosal) adenocarcinoma NA Refer for staging (with endoscopic ultrasound and CT/PET) and potentially
endoscopic therapy to center with expertise
T1b (submucosal) adenocarcinoma NA Refer for staging (with endoscopic ultrasound and CT/PET) and evaluation by
multidisciplinary (gastrointestinal, thoracic surgery, and oncology) team
CT ¼ computed tomography; PET ¼ positron emission tomography

pathologists. The annual progression risk in reasonable as per patient preference and in
high-grade dysplasia (HGD) is highest, esti- cases of medical comorbidities limiting life
mated at 7% to 8%.37 expectancy or performance status.39 Typi-
Given the low risk of progression, pa- cally, those patients with BE and LGD who
tients with BE without dysplasia are recom- have long segments with multifocal (at
mended to undergo endoscopic surveillance more than 1 level in the BE segment), persis-
every 3 to 5 years, unless there is a family tent (present at more than 1 endoscopy),
history of BE or EAC, suggestive of a familial and confirmed (by a pathologist with gastro-
syndrome, in which case ablation can be intestinal expertise) LGD would be at high-
considered on a case-by-case basis. Endo- est risk for progression and hence also the
scopic ablation of nondysplastic BE is not best candidates for ablation. Patients with
currently recommended by guidelines and HGD are recommended to undergo endo-
should only be considered on a case-by- scopic therapy and ablation to eliminate BE
case basis, typically at expert centers with a and reduce the risk of progression to
clinical and research interest in BE. Diag- EAC.8 Additional details on BE endoscopic
nosis of dysplasia (low grade or high grade) therapy are provided in subsequent sections.
should be confirmed by expert gastrointes- Despite these theoretical advantages and
tinal pathologists, as most dysplasia rationales, the effectiveness of endoscopic
diagnosed in the community is usually surveillance is limited because of the patchy
downgraded by expert gastrointestinal pa- nature of dysplasia in BE mucosa (making
thologists to nondysplasia with low rates of dysplasia and carcinoma hard to localize),2
progression. lack of compliance with surveillance biopsy
Patients with LGD may undergo endo- recommendations leading to missed
scopic surveillance annually, given the dysplasia,40,41 and the relatively poor inter-
somewhat increased risk of progression to observer agreement even among expert
HGD/EAC. However, evidence from recent gastrointestinal pathologists for the diag-
randomized control trials7 and cohort nosis of dysplasia.42 A recent systematic re-
studies38 has shifted the recommendation view and meta-analysis of more than 20
for the management of patients with LGD studies suggested that although endoscopic
to endoscopic ablation, although close sur- surveillance was associated with detection
veillance (every 6 to 12 months) may be of EAC at earlier stages, there was only a
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modest improvement in EAC-related mortal- a monumental way. The decision whether

ity. Moreover, this modest benefit in esoph- to proceed with endotherapy vs continued
ageal cancer-related mortality was likely endoscopic surveillance in patients with BE
susceptible to underlying biases (such as is primarily based upon the presence and de-
length and lead time), given the retrospec- gree of dysplasia. In nondysplastic BE, the
tive observational nature of most of these risk of progression to neoplasia is very
studies.43 low,35 and therefore it is thought that the
risks and cost of the procedures outweigh
Risk Stratification in BE the benefits.
Histological grade of dysplasia is, at present, There remains some controversy among
the only currently clinically used tool to professional societies regarding treatment
stratify risk of progression in BE. However, of patients with LGD. For LGD that is
several patients with no dysplasia and LGD confirmed by 2 pathologists (including 1
do progress to adenocarcinoma, and several with expertise in gastrointestinal pathology),
patients with HGD do not. Similarly, some the American College of Gastroenterology
patients with LGD may regress to “no and the American Gastroenterological Asso-
dysplasia” on continued surveillance. Hence, ciation recommend consideration of endo-
several studies have attempted to develop therapy, whereas the British Society of
clinical risk scores to predict progression in Gastroenterology advises endoscopic surveil-
BE. Advanced age, male gender, increasing lance.8,24,25 In general, expert opinion favors
segment length, endoscopic presence of nod- proceeding with treatment of persistent,
ularity, and low-grade dysplasia have been confirmed multifocal LGD in a patient with
identified factors as increasing the risk of long-segment BE, especially in younger pa-
progression in BE.44 Indeed, a recent study tients with acceptable overall comorbidities.
has developed a progression in BE (PIB) When repeat endoscopic surveillance re-
score, integrating some of these clinical fac- veals persistent LGD confirmed by an expert
tors into a single score predictive of the pathologist, endoscopic therapy should be
risk of progression.45 considered strongly.
In addition, the use of biomarkers to pre- Best-practice recommendations also
dict the risk of progression has been studied dictate that a thorough discussion should
extensively. However, none of these bio- take place between the physician and the pa-
markers is currently recommended or avail- tient, during which the risks, benefits, and
able for clinical use. Some of these alternatives of surveillance vs treatment are
candidate markers include P53 expres- discussed in detail with patients who have
sion,46,47 copy number changes in chromo- BE with LGD.
somes detected by fluorescent in situ In patients with HGD, the risk of pro-
hybridization (FISH), methylated DNA gression to neoplasia is elevated, and hence
markers, and other panels of molecular treatment is recommended universally as
epithelial and stromal markers.48 The ulti- per current guidelines. Although surgery
mate goal of these clinical and biomarker was previously the standard of care for pa-
panels would be to identify low-risk and tients with BE and HGD, endotherapy is
high-risk groups that could be either dis- now the standard of care, given high degree
charged from surveillance (low-risk group) of success, significantly less morbidity and
or managed with intensive surveillance or mortality, and overall long-term survival
proactive ablation (high-risk group). comparable with esophagectomy.5

Endoscopic Therapy Principles of Endoscopic Therapy. The basic

Patient Selection. The evolution of endo- principles of endoscopic therapy include
scopic resection techniques and the advent identification of focal lesions (which may
of esophageal ablation technology have reflect more advanced neoplasia such as car-
transformed our approach to this disease in cinoma), resection of these visible lesions (to

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lesions. ESD is more time consuming, and

the risk of complications may be higher,
although ESD more frequently achieves en
bloc, R0, and curative resection.52 However,
the decision between continued endoscopic
therapy vs referral for esophagectomy de-
pends on depth of invasion of the tumor;
this information is provided equally well by
both EMR and ESD. Metastatic lymphade-
FIGURE 5. Endoscopic mucosal resection sites (A) using band-ligation de- nopathy is uncommon in T1a EAC (<2%),
vice and (B) using plastic cap and snare. making endoscopic therapy suitable but sub-
stantially higher in T1b EAC (20% to 30%),
making esophagectomy the primary modal-
characterize the histology of these lesions ity of treatment, except in those patients
accurately), followed by endoscopic abla- with life-limiting medical comorbidities and
tion, while ensuring maximal acid-reflux favorable histological features.
control medically, leading to replacement EMR is the most frequently used resec-
of the metaplastic BE epithelium by neo- tion technique, either with a banding device
squamous epithelium. This multistep (band-EMR) or with the use of an endo-
approach has been shown to reduce the risk scopic resection cap (cap-EMR). With
of progression to EAC in randomized band-EMR, the nodular lesion is sucked
controlled trials and leads to comparable into the banding device to create a “pseudo-
survival for early stage (mucosal) adenocar- polyp” and then resected with a snare, using
cinoma vis-à-vis esophagectomy in cohort electrocautery. In the cap-EMR technique,
studies. following the injection of submucosal saline
solution to lift the lesion away from the mus-
Endoscopic Resection. The rationale for cularis propria, a flexible snare is seated on
endoscopic resection (ER) is based on the the inner edge of a dedicated EMR cap, the
need for accurate histological characteriza- lesion is suctioned into the cap, and then
tion of visible lesions (30 % to 40% of which resected using electrocautery. 53
may harbor early-stage adenocarcinoma). ESD, which involves lifting the lesion
The somewhat poor interobserver agreement with submucosal injection, followed by
for the identification of dysplasia in biopsies dissection in the submucosal plane, using
among pathologists is substantially improved specialized endoscopic “knives,” has
with larger endoscopic resection specimens.49 emerged as an option for resecting larger
In addition, accurate T staging (primarily nodular lesions and early neoplasia in BE,
distinguishing between T1a (mucosally although experience in the Western world
confined) and T1b (submucosally invasive is still evolving. Recent studies have shown
EAC) and margin assessment (lateral and ESD to be superior to EMR in achieving
deep) can be performed.50 Importantly, complete en bloc and curative resection.
prognostic information, such as degree of However, it is technically more demanding;
differentiation and lymphovascular invasion, leads to longer procedure times; and carries
can also be provided.51 Finally, if the margins greater risk for bleeding, perforation, and
are negative, and the tumor is confined to the formation of stricture, especially if circum-
mucosa, the resection can be curative. ferential ESD is performed for complete BE
Endoscopic resection can be achieved by eradication. 52
band- (Figure 5A) or cap- (Figure 5B) assis- ER is safe but associated with some com-
ted endoscopic mucosal resection (EMR) plications. These include perforation (<1%
technique or by endoscopic submucosal for EMR, 1% to 3% for ESD), bleeding
dissection (ESD); the latter allows en bloc (5%), and formation of stricture. The risk
resection of larger (>1.5 cm size) visible of formation of stricture is low if the
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BARRETT ESOPHAGUS

resection area is limited to focal lesions and

TABLE 3. Different Modalities for Barrett Ablation
less than 50% of the esophageal circumfer-
ence. Strictures can be successfully treated Thermal Devices
Radiofrequency ablation (RFA)
endoscopically with dilation.54
Circumferential RFA
If the histology from the resected EMR/
Focal RFA (60, 90, Ultra)
ESD specimen reveals LGD, HGD, or EAC Channel RFA catheter
(T1a histology with no lymphovascular inva- Argon plasma coagulation
sion [LVI], and negative deep and lateral Multipolar electrocoagulation
margins), endoluminal ablative therapy is Cryotherapy Devices
recommended for complete eradication of Spray cryotherapy (liquid nitrogen)
any residual intestinal metaplasia (IM). Abla- Balloon cryotherapy (nitrous oxide)
tive therapy may be a consideration in pa- Historical
tients with well-differentiated T1b EAC Photodynamic therapy
with superficial submucosal invasion
(<500 mm, sm1) and without LVI and therapy caused mucosal ablation using
well-to-moderately differentiated, especially photochemical energy but is no longer
for those patients who are poor surgical can- used because of cost, associated morbidity
didates.55 However, this decision should be (photosensitivity and strictures), and lack
made after consultation with a multidisci- of availability.
plinary surgical oncology team.
Radiofrequency Ablation. Radiofrequency
Ablation Modalities ablation is the most commonly used ablation
Following the resection of visible focal le- technique to treat dysplastic BE. In RFA,
sions, elimination of residual BE mucosa is radiofrequency energy is directly applied to
essential to reduce the risk of recurrent the esophageal mucosa, either using a
neoplasia. A variety of techniques are avail- balloon or focal catheter. This technique
able to accomplish this (Table 3). Despite has been well studied and is highly effective
the emergence of several new modalities, at eradicating IM and dysplasia. A multi-
radiofrequency ablation (RFA) remains the center randomized controlled trial in the
most commonly performed endoscopic abla- United States found that 81% of patients
tion procedure for BE, owing to its ease of with HGD and 91% with LGD achieved com-
use and high degree of efficacy. RFA is a plete eradication of dysplasia within 12
thermal technique for mucosal ablation us- months, with a statistically significant
ing bipolar electrodes arranged on circum- decrease in progression to EAC in the abla-
ferential (balloon) or focal ablation devices tion arm.6 The most common adverse
(Figure 6A, B, and C).56 events of RFA include postablation stricture
Liquid nitrogen based endoluminal spray and postprocedure chest pain, especially if a
cryotherapy is another ablation modality long segment of BE has been treated at a
that is highly effective in eradicating BE single session. Bleeding and perforation are
and appears very useful in managing cases extremely uncommon.
refractory to initial RFA treatment.57,58
Balloon-based cryotherapy uses nitrous ox- Cryoablation. Endoscopic cryoablation is
ide and is a relatively newer device that another option for ablative therapy that has
also appears promising in treatment of emerged in the past decade, with recent
BE.59 Argon plasma coagulation and multi- studies suggesting less postprocedural chest
polar electrocautery are used mostly for pain and better patient tolerance compared
treatment of focal areas of IM and are less with RFA.60,61 At least 2 platforms for
often used in the United States and more cryotherapy are now commercially available
popular in Europe and Asia. Photodynamic and in use.

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 MAYO CLINIC PROCEEDINGS

In the case of spray cryotherapy histology. A recent meta-analysis reviewed

(Figure 6D), liquid nitrogen is delivered all modalities of BE endotherapy and showed
at e196 C (e320 F) through a novel spray that the annual incidence of recurrent IM
catheter, which is introduced through the was 7.1%, recurrent dysplastic BE was
working channel of a standard endoscope. 1.3%, and recurrent HGD and/or EAC was
In the newer balloon-based cryotherapy sys- 0.8%. It is reassuring to note that more
tem, nitrous oxide is used to achieve ablation than 95% of all recurrences were endoscopi-
by direct contact with the tissue via an cally treatable.63 Hence, continued endo-
inflated balloon with an internal spray cath- scopic surveillance after successful
eter. Studies have shown eradication of HGD endotherapy is currently recommended to
in 81% to 94% of patients with detect and treat recurrent BE. Recommenda-
cryotherapy.62 tions on intervals of follow-up after success-
Successful endotherapy is defined by ful ablation are expert-opinion based and
both absence of visible IM at endoscopy suggest that those with CR-IM after endo-
and on histology. This milestone is referred therapy for BE-HGD/EAC should be sur-
to as complete remission of intestinal meta- veyed endoscopically every 3 months for
plasia (CR-IM). Despite high rates of suc- the first year, every 6 months for the second
cessful endotherapy in BE, there remains year, and then once a year thereafter. Pa-
significant risk of recurrence of IM and/or tients reaching CR-IM after endotherapy for
dysplasia in certain patients, warranting BE-LGD should be surveyed endoscopically
close postablation surveillance in all patients every 6 months for the first year and then
after treatment has been deemed complete. annually. There is no consensus at this
Those at highest risk for recurrence include time on whether surveillance can be
patients with long-segment BE and those extended or discontinued after a certain in-
with HGD or worse pathology on initial terval following CR-IM.

CHALLENGES IN BE ENDOTHERAPY
Endoluminal therapy is highly effective in
the majority of patients. Treatment failures
are infrequent (10% failure in achieving
CR-D and 20 % failure in achieving CR-
IM) and are defined as those patients who
do not achieve CR-IM or CR-D after
completing 3 to 5 ablation sessions. Manage-
ment options for such patients have included
continued treatment with the same modality,
with documentation of adequate acid reflux
control (by ambulatory pH testing); resect-
ing the residual BE mucosa by endoscopic
resection; reverting to surveillance; or
referral to surgery (especially if persistent
or recurrent HGD or neoplasia is present in
patients who are surgical candidates). More
recently, cryotherapy has emerged as an
effective tool for managing this cohort of
difficult-to-treat patients with BE.57 In a
recently published systematic review and
FIGURE 6. (A) Circumferential balloon radiofrequency ablation (RFA)
meta-analysis, 46% of all patients with RFA
catheter. (B) Focal ablation RFA catheter. (C) Focal ablation catheter being
used to ablate the gastroesophageal junction. (D) Endoscopic liquid nitro-
failure achieved CR-IM, and 76% achieved
gen spray cryotherapy being administered via spray catheter. CR-D with cryotherapy.64 In addition,
although there is concern regarding “buried”
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BARRETT ESOPHAGUS

Barrett mucosa (underneath squamous Abbreviations and Acronyms: BE = Barrett esophagus;

epithelium, persisting after apparent success- CR-IM = complete remission of intestinal metaplasia; EAC =
esophageal adenocarcinomas; EMR = endoscopic mucosal
ful ablation, and rarely progressing to EAC), resection; ESD = endoscopic submucosal dissection; HGD =
the rates of this phenomenon appear to be high-grade dysplasia; IM = intestinal metaplasia; LGD = low-
low (0.9%) within limitations of data as grade dysplasia; PPI = proton pump inhibitor; RFA = radi-
reported.65 ofrequency ablation

Potential Competing Interests: Dr Iyer has received

research funding from Exact Sciences, C2 Therapeutics,
CONCLUSIONS and Medtronic. He has received consulting fees from Med-
BE is an established precursor to EAC, with tronic and Symple Surgical. Dr Kaul has received research
malignant transformation potentially occur- funding from CSA Medical and is a consultant for Medtronic,
Olympus, CSA Medical, and Cook-Medical.
ring in a stepwise fashion from nondysplas-
tic BE to LGD, HGD, and ultimately Correspondence: Address to Prasad G. Iyer, MD, MSc, Bar-
invasive adenocarcinoma. This provides the rett’s Esophagus Unit, Division of Gastroenterology and
Hepatology, Mayo Clinic, 200 First Street SW, Rochester,
window for early detection by screening
MN 55905 ([email protected]).
and surveillance. Substantial recent progress
has been made in the development of mini- The Thematic Reviews on Gastroenterological Diseases
mally invasive nonendoscopic approaches will continue in an upcoming issue.
in the detection of BE and related dysplasia,
along with effective endoscopic therapy of
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