THEMATIC REVIEW ON GASTROENTEROLOGICAL DISEASES

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

CME Activity

Division of Gastroenterology
and Hepatology (P.G.I.), Mayo
Clinic, Rochester, MN, and
Division of Gastroenterology
and Hepatology (V.K.), Uni-
versity of Rochester Medical
Center, Rochester, NY.
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(1) obtain state of the art information related to screening and surveillance in
Barrett esophagus, (2) acquire a good understanding of the various modal-
ities of treatment available for dysplastic Barrett esophagus and early esoph-
ageal neoplasia, and (3) identify the key best practices and guideline based
recommendations for management of Barrett esophagus.
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Dr Iyer has received research funding from Exact Sciences, C2 Therapeutics,
and Medtronic. He has received consulting fees from Medtronic and Symple
Surgical. Dr Kaul has received research funding from CSA Medical and is a
consultant for Medtronic, Olympus, CSA Medical, and Cook-Medical.
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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

1888 Mayo Clin Proc. n September 2019;94(9):1888-1901 n https://doi.org/10.1016/j.mayocp.2019.01.032

www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research
BARRETT ESOPHAGUS
B
arrett esophagus (BE) refers to the
metaplastic transformation of esopha-
geal squamous epithelium to special-
ized columnar epithelium with intestinal
metaplasia in the distal esophagus. This is
thought to occur as a consequence of
chronic injury, likely mediated by reflux of
gastric contents.1 The significance of BE
lies in it being the strongest risk factor for
and precursor of most esophageal adenocar-
cinomas (EAC). It is presumed that EAC
arises as the end result of a stepwise transfor-
mation from metaplasia to dysplasia (low
grade and high grade) to carcinoma.2,3The
clinical significance of BE is related to the
increasing incidence of EAC over the past
few decades, relative to other solid malig-
nancies. This increase has been estimated
to be approximately 600% over the past 3
to 4 decades. This increased incidence has
also been paralleled by an increase in disease
related mortality.4 The outcomes of patients
with EAC diagnosed after the onset of symp-
toms remains grim, with a 5-year survival
not exceeding 20%. This has remained rela-
tively unchanged over the past several
decades.
This situation has led to substantial in-
terest in understanding the risk factors for
BE and early detection followed by surveil-
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-
flected by change of this epithelium to pale
pink columnar metaplasia (Figure 1). The
diagnosis of BE requires 2 components.
The first component is that of columnar
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metaplasia measuring at least 1 cm above
the gastric folds (the anatomic landmark
for the gastroesophageal junction). The sec-
ond component is that of intestinal meta-
plasia characterized by the presence of
goblet cells in biopsies obtained from the
area of columnar metaplasia at endoscopy
(Figure 2).1 Fulfillment of both of these
criteria is essential to the diagnosis of BE.
Of note, the second criterion has been
deemed to be optional in some society rec-
ommendations such as the British Society
of Gastroenterology. Recent guidelines from
the American College of Gastroenterology8
have, however, retained the requirement
for intestinal metaplasia to be seen on histol-
ogy, given that cohort studies have demon-
strated a substantially lower risk of
progression to EAC in the absence of intesti-
nal metaplasia.9
Careful examination of the gastroesopha-
geal junction and distal esophagus is critical
to making appropriate diagnoses of BE. The
endoscopic criteria for BE was set at 1 cm
of columnar mucosa in the tubular esoph-
agus, given previous studies documenting
poor inter-agreement among endoscopists
for lengths less than 1 cm.10 In addition,
population-based11 and multicenter cohort
studies12 have shown that the risk of
FIGURE 1. Endoscopic appearance of Barrett
esophagus. (A) Squamous epithelium. (B)
Columnar metaplasia suggestive of Barrett
esophagus.
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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
mucosa in the distal esophagus is substan-
tially lower than that of patients meeting
criteria for the diagnosis of BE. Moreover,
studies have shown that a substantial pro-
portion of patients diagnosed with BE in
the community (up to 33%) can have this
diagnosis reversed on careful examination
by well-trained gastroenterologists.13
This is particularly important, given im-
plications of a Barrett diagnosis in terms of
the need for endoscopic surveillance with
associated procedural risks, costs, and
adverse effects on health care-related quality
of life and, potentially, the ability to obtain
health insurance.14,15
A reporting system for BE has been devel-
oped (Prague Classification, Supplemental
Figure 1) and may help in making reporting
BE length and endoscopic appearance more
uniform. It was developed using an interna-
tional consortium of experts.10 The BE
segment length is expressed as the maximal
(M) and circumferential (c) components.
Several studies have attempted to assess the
prevalence of BE in different populations.
Large population based studies in Europe
(Scandinavia16 and Italy17) have screened
the general population with upper endos-
copy and have reported BE prevalence esti-
mates ranging from 1.3 to 1.6%. However,
a more recent population based screening
study in Olmsted County, Minnesota, re-
ported that 8.5% of adults above the age of
50 had evidence of BE.18 Other cross-
sectional studies from tertiary care institu-
tions in the Unites States have also reported
higher rates of BE prevalence from 8 to
17%.19 These estimates suggest that there
are potentially 3 to 5 million patients with
BE in the United States.
The incidence of endoscopically detected
BE appears to be increasing as well.
Although studies from the United States
have revealed that this incidence has
increased in parallel with increasing endos-
copy volume,11 other studies have shown
that the proportion of patients diagnosed

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BARRETT ESOPHAGUS

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
(2013)26
American Gastroenterological
Association (2011)25
American Society of Gastrointestinal
Endoscopy (2012)28
American College of Physicians (2012)29 Screening with EGD for Barrett esophagus and esophageal adenocarcinoma may be considered in men older
Screening can be considered in patients with chronic reflux symptoms and multiple risk factors (at least 3 of
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
In patients with multiple risk factors for esophageal adenocarcinoma, screening is recommended (weak
recommendation, moderate quality evidence).
Screening the general population not recommended (strong recommendation, moderate quality evidence).
Consider screening with EGD in select patients with multiple risk factors.
Inform patients there is insufficient evidence that screening prevents cancer or prolongs life.
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
increased.20 However, it remains unclear if
this is truly an actual increase in incidence
or a manifestation of increasing awareness
among endoscopists and a reflection of
detection bias.
Despite the increasing detection of BE,
population studies suggest that only one
third of patients with prevalent long-
segment BE in the community have been
clinically diagnosed.3 This suggests that
only a minority of prevalent cases of BE are
receiving clinical attention in terms of sur-
veillance and detection of dysplasia.
Several risk factors have been identified for
BE. Endoscopic database studies have reported
that the prevalence of BE sharply increases in
the fourth and fifth decades of life. Male
gender, white race, chronic symptomatic
reflux (defined the symptoms occurring more
than once a week for more than 5 years), cen-
tral obesity (measured by waist hip ratio or
waist circumference),21 current or past history
of smoking, and a confirmed family history of
BE or EAC are other documented risk factors
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for BE. There is significant overlap between
these risk factors and those for EAC. Alcohol
consumption has not been found to be a
consistent risk factor for BE.22 Indeed, some
studies have shown that wine consumption
may be protective against the development of
BE. A recent study also suggests that Helico-
bacter pylori infection may have a protective ef-
fect against development of BE.23
SCREENING FOR BE
The rationale for BE screening is based on
the predicate that most EACs arise in a back-
ground of BE and that if BE is diagnosed
early, effective endoscopic surveillance
would detect dysplasia/early EAC, which
can then be treated endoscopically or surgi-
cally. Although there is, at present, no Level
1 evidence demonstrating the effectiveness
of screening, the efficacy of endoscopic ther-
apy in preventing progression to EAC in ran-
domized trialsdand consistent evidence
establishing excellent survival of patient’s
diagnosed with early stage EAdhave pro-
vided support to the strategy of BE screening
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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.
Sedated endoscopy (at present, the most
used technique for screening) is an invasive
and expensive tool and hence unsuitable
for widespread application. Given evidence
from multiple studies and clinical trials sug-
gesting excellent sensitivity and specificity
(for the diagnosis of BE), along with excel-
lent safety and tolerability,27 unsedated
transnasal endoscopy has been accepted as
an alternative to sedated endoscopy for BE
screening. However, its use remains low
because of perceived physician and patient
barriers.28
More recently, minimally invasive tools
such as capsule sponges (Figure 3) and swal-
lowed balloons (which are swallowed,
expand, and then pulled with attached cords,
providing circumferential sampling of the
esophagus) have been developed in conjunc-
tion with molecular biomarkers (such as
epithelial protein markers: trefoil factor 329
and methylated DNA markers30) to diagnose
BE in a minimally invasive fashion, with
moderate to excellent sensitivity (78% to
100%) and specificity (90% to 100%). These
devices are also well tolerated and likely sub-
stantially less expensive than sedated endos-
copy. Studies performed in screening
populations are ongoing and awaited.
Exhaled volatile organic compounds have
also been used to detect BE in pilot proof-
of-concept studies, with moderate sensitivity
and specificity.
In addition, Barrett risk assessment
scores, which integrate risk factorsdsuch
as age, gender, waist hip ratio, and smoking
historydhave also been developed and
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FIGURE 3. Capsule sponge device intact (left)
and expanded to 25 mm (right) with attached
string.
validated in multiple cohorts.31 Although
these scores can assist in identifying the at-
risk population, the risk score at which BE
screening should be recommended is still
to be determined. Importantly, life expec-
tancy and performance status need to be
considered carefully while making a decision
to screen for BE, given other implications af-
ter its diagnosis.
MANAGEMENT OF PATIENTS WITH BE
Proton Pump Inhibitor Therapy
The goal of proton pump inhibitor (PPI)
therapy in patients with BE is to control
symptoms of gastroesophageal reflux and
heal esophagitis. This is somewhat chal-
lenging, given the known hyposensitivity of
patients with BE to reflux, which makes
assessment of symptoms unreliable as a mea-
sure of reflux control. Physiologic studies
have also demonstrated that patients with
BE have the most severe reflux in the contin-
uum of phenotypes from normal to nonero-
sive disease, erosive disease, and BE. Current
society guidelines recommend placing pa-
tients diagnosed with BE on a dose of PPI
that is adequate to control symptoms and
heal esophagitis. There is some evidence
from nonrandomized observational studies
that PPIs may reduce the risk of progression
to esophageal adenocarcinoma.32 Random-
ized controlled trials to test this association
are ongoing, and results are awaited.
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BARRETT ESOPHAGUS
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-
scopic surveillance in BE is to detect incident
or prevalent dysplasia/adenocarcinoma early,
enabling treatment and improved outcomes.
Several society guidelines recommend endo-
scopic biopsies of the Barrett mucosa in a
4-quadrant fashion every 1 to 2 cm,
depending on the presence of previously
known dysplasia (Seattle protocol), in addi-
tion to sampling any visible lesions sepa-
rately.8,25 Various imaging modalities have
been investigated to assist in and enhance
the endoscopic detection of dysplasia in BE.
These include dye-based chromoendoscopy
using methylene blue or acetic acid, which is
somewhat cumbersome, given the need for
dye spraying and suctioning. Electronic
chromoendoscopy using optical imaging
technologies such as narrow-band imaging
(Figure 4B), i scan or blue-laser imaging are
also available and more commonly used,
given their convenience (given integration
into the endoscope and activation with but-
tons, without the need for additional dyes
and spray catheters) and ease of use. A
recent systematic review and meta-analysis
reported that use of any of these adjunctive
imaging modalities increases dysplasia yield
by 33%.33 In addition, imaging modalities,
such as confocal laser endomicroscopy
(Figure 4C), are also used, which provide
real-time histology at the microscopic level
and can be used to discriminate between
normal and dysplastic tissue. However, the
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importance of a careful and methodical
white-light endoscopic examination after
washing and cleaning the mucosa cannot be
overemphasized.
A more recent development in BE
screening/surveillance has been the use of
wide area transepithelial sampling (WATS-
3D). This adjunctive (to forceps biopsies)
tissue sampling technique in BE uses a stiff
endoscopic brush catheter, which increases
the surface area of the BE epithelium
sampled and provides cellular samples,
which are scanned first by an artificial neural
network computerized algorithm before pre-
senting the 200 most abnormal cells for eval-
uation by a pathologist. This technique has
been shown to increase the yield of dysplasia
and neoplasia in patients with BE in a multi-
center prospective randomized crossover
trial by Vennalganti.34 Additional data on
validation of these findings in a lower risk
(nondysplastic patients with BE) cohort are
awaited.
Recommended intervals of surveillance
of patients with BE vary, depending on the
grade of dysplasia, given variation in the
risk of progression to cancer (Table 2). The
estimated annual risk of progression in non-
dysplastic BE is low, at 0.33%,35 whereas
that in patients with low-grade dysplasia
(LGD) is higher and more variably estimated
from 0.7% to 1%.36 This risk of progression
in patients with LGD applies to cases
confirmed by an expert gastrointestinal
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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
No dysplasia 0.33% per year
Low-grade dysplasia 0.7% to 1.0% per year
High-grade dysplasia 8% per year
Recommendation for management
Endoscopic surveillance every 3 to 5 years
Confirm diagnosis by expert gastrointestinal pathologist
Discuss endoscopic ablation
Endoscopic surveillance every 6 to 12 months
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
high-grade dysplasia (HGD) is highest, esti-
mated at 7% to 8%.37
Given the low risk of progression, pa-
tients with BE without dysplasia are recom-
mended to undergo endoscopic surveillance
every 3 to 5 years, unless there is a family
history of BE or EAC, suggestive of a familial
syndrome, in which case ablation can be
considered on a case-by-case basis. Endo-
scopic ablation of nondysplastic BE is not
currently recommended by guidelines and
should only be considered on a case-by-
case basis, typically at expert centers with a
clinical and research interest in BE. Diag-
nosis of dysplasia (low grade or high grade)
should be confirmed by expert gastrointes-
tinal pathologists, as most dysplasia
diagnosed in the community is usually
downgraded by expert gastrointestinal pa-
thologists to nondysplasia with low rates of
progression.
Patients with LGD may undergo endo-
scopic surveillance annually, given the
somewhat increased risk of progression to
HGD/EAC. However, evidence from recent
randomized control trials7 and cohort
studies38 has shifted the recommendation
for the management of patients with LGD
to endoscopic ablation, although close sur-
veillance (every 6 to 12 months) may be
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1894 Mayo Clin Proc.
reasonable as per patient preference and in
cases of medical comorbidities limiting life
expectancy or performance status.39 Typi-
cally, those patients with BE and LGD who
have long segments with multifocal (at
more than 1 level in the BE segment), persis-
tent (present at more than 1 endoscopy),
and confirmed (by a pathologist with gastro-
intestinal expertise) LGD would be at high-
est risk for progression and hence also the
best candidates for ablation. Patients with
HGD are recommended to undergo endo-
scopic therapy and ablation to eliminate BE
and reduce the risk of progression to
EAC.8 Additional details on BE endoscopic
therapy are provided in subsequent sections.
Despite these theoretical advantages and
rationales, the effectiveness of endoscopic
surveillance is limited because of the patchy
nature of dysplasia in BE mucosa (making
dysplasia and carcinoma hard to localize),2
lack of compliance with surveillance biopsy
recommendations leading to missed
dysplasia,40,41 and the relatively poor inter-
observer agreement even among expert
gastrointestinal pathologists for the diag-
nosis of dysplasia.42 A recent systematic re-
view and meta-analysis of more than 20
studies suggested that although endoscopic
surveillance was associated with detection
of EAC at earlier stages, there was only a
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BARRETT ESOPHAGUS
modest improvement in EAC-related mortal-
ity. Moreover, this modest benefit in esoph-
ageal cancer-related mortality was likely
susceptible to underlying biases (such as
length and lead time), given the retrospec-
tive observational nature of most of these
studies.43
Risk Stratification in BE
Histological grade of dysplasia is, at present,
the only currently clinically used tool to
stratify risk of progression in BE. However,
several patients with no dysplasia and LGD
do progress to adenocarcinoma, and several
patients with HGD do not. Similarly, some
patients with LGD may regress to “no
dysplasia” on continued surveillance. Hence,
several studies have attempted to develop
clinical risk scores to predict progression in
BE. Advanced age, male gender, increasing
segment length, endoscopic presence of nod-
ularity, and low-grade dysplasia have been
identified factors as increasing the risk of
progression in BE.44 Indeed, a recent study
has developed a progression in BE (PIB)
score, integrating some of these clinical fac-
tors into a single score predictive of the
risk of progression.45
In addition, the use of biomarkers to pre-
dict the risk of progression has been studied
extensively. However, none of these bio-
markers is currently recommended or avail-
able for clinical use. Some of these
candidate markers include P53 expres-
sion,46,47 copy number changes in chromo-
somes detected by fluorescent in situ
hybridization (FISH), methylated DNA
markers, and other panels of molecular
epithelial and stromal markers.48 The ulti-
mate goal of these clinical and biomarker
panels would be to identify low-risk and
high-risk groups that could be either dis-
charged from surveillance (low-risk group)
or managed with intensive surveillance or
proactive ablation (high-risk group).
Endoscopic Therapy
Patient Selection. The evolution of endo-
scopic resection techniques and the advent
of esophageal ablation technology have
transformed our approach to this disease in
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a monumental way. The decision whether
to proceed with endotherapy vs continued
endoscopic surveillance in patients with BE
is primarily based upon the presence and de-
gree of dysplasia. In nondysplastic BE, the
risk of progression to neoplasia is very
low,35 and therefore it is thought that the
risks and cost of the procedures outweigh
the benefits.
There remains some controversy among
professional societies regarding treatment
of patients with LGD. For LGD that is
confirmed by 2 pathologists (including 1
with expertise in gastrointestinal pathology),
the American College of Gastroenterology
and the American Gastroenterological Asso-
ciation recommend consideration of endo-
therapy, whereas the British Society of
Gastroenterology advises endoscopic surveil-
lance.8,24,25 In general, expert opinion favors
proceeding with treatment of persistent,
confirmed multifocal LGD in a patient with
long-segment BE, especially in younger pa-
tients with acceptable overall comorbidities.
When repeat endoscopic surveillance re-
veals persistent LGD confirmed by an expert
pathologist, endoscopic therapy should be
considered strongly.
Best-practice recommendations also
dictate that a thorough discussion should
take place between the physician and the pa-
tient, during which the risks, benefits, and
alternatives of surveillance vs treatment are
discussed in detail with patients who have
BE with LGD.
In patients with HGD, the risk of pro-
gression to neoplasia is elevated, and hence
treatment is recommended universally as
per current guidelines. Although surgery
was previously the standard of care for pa-
tients with BE and HGD, endotherapy is
now the standard of care, given high degree
of success, significantly less morbidity and
mortality, and overall long-term survival
comparable with esophagectomy.5
Principles of Endoscopic Therapy. The basic
principles of endoscopic therapy include
identification of focal lesions (which may
reflect more advanced neoplasia such as car-
cinoma), resection of these visible lesions (to
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FIGURE 5. Endoscopic mucosal resection sites (A) using band-ligation de-
vice and (B) using plastic cap and snare.
characterize the histology of these lesions
accurately), followed by endoscopic abla-
tion, while ensuring maximal acid-reflux
control medically, leading to replacement
of the metaplastic BE epithelium by neo-
squamous epithelium. This multistep
approach has been shown to reduce the risk
of progression to EAC in randomized
controlled trials and leads to comparable
survival for early stage (mucosal) adenocar-
cinoma vis-à-vis esophagectomy in cohort
studies.
Endoscopic Resection. The rationale for
endoscopic resection (ER) is based on the
need for accurate histological characteriza-
tion of visible lesions (30 % to 40% of which
may harbor early-stage adenocarcinoma).
The somewhat poor interobserver agreement
for the identification of dysplasia in biopsies
among pathologists is substantially improved
with larger endoscopic resection specimens.49
In addition, accurate T staging (primarily
distinguishing between T1a (mucosally
confined) and T1b (submucosally invasive
EAC) and margin assessment (lateral and
deep) can be performed.50 Importantly,
prognostic information, such as degree of
differentiation and lymphovascular invasion,
can also be provided.51 Finally, if the margins
are negative, and the tumor is confined to the
mucosa, the resection can be curative.
Endoscopic resection can be achieved by
band- (Figure 5A) or cap- (Figure 5B) assis-
ted endoscopic mucosal resection (EMR)
technique or by endoscopic submucosal
dissection (ESD); the latter allows en bloc
resection of larger (>1.5 cm size) visible
n n
1896 Mayo Clin Proc. September 2019;94(9):1888-1901
MAYO CLINIC PROCEEDINGS
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-
nopathy is uncommon in T1a EAC (<2%),
making endoscopic therapy suitable but sub-
stantially higher in T1b EAC (20% to 30%),
making esophagectomy the primary modal-
ity of treatment, except in those patients
with life-limiting medical comorbidities and
favorable histological features.
EMR is the most frequently used resec-
tion technique, either with a banding device
(band-EMR) or with the use of an endo-
scopic resection cap (cap-EMR). With
band-EMR, the nodular lesion is sucked
into the banding device to create a “pseudo-
polyp” and then resected with a snare, using
electrocautery. In the cap-EMR technique,
following the injection of submucosal saline
solution to lift the lesion away from the mus-
cularis propria, a flexible snare is seated on
the inner edge of a dedicated EMR cap, the
lesion is suctioned into the cap, and then
resected using electrocautery. 53
ESD, which involves lifting the lesion
with submucosal injection, followed by
dissection in the submucosal plane, using
specialized endoscopic “knives,” has
emerged as an option for resecting larger
nodular lesions and early neoplasia in BE,
although experience in the Western world
is still evolving. Recent studies have shown
ESD to be superior to EMR in achieving
complete en bloc and curative resection.
However, it is technically more demanding;
leads to longer procedure times; and carries
greater risk for bleeding, perforation, and
formation of stricture, especially if circum-
ferential ESD is performed for complete BE
eradication. 52
ER is safe but associated with some com-
plications. These include perforation (<1%
for EMR, 1% to 3% for ESD), bleeding
(5%), and formation of stricture. The risk
of formation of stricture is low if the
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BARRETT ESOPHAGUS
resection area is limited to focal lesions and
less than 50% of the esophageal circumfer-
ence. Strictures can be successfully treated
endoscopically with dilation.54
If the histology from the resected EMR/
ESD specimen reveals LGD, HGD, or EAC
(T1a histology with no lymphovascular inva-
sion [LVI], and negative deep and lateral
margins), endoluminal ablative therapy is
recommended for complete eradication of
any residual intestinal metaplasia (IM). Abla-
tive therapy may be a consideration in pa-
tients with well-differentiated T1b EAC
with superficial submucosal invasion
(<500 mm, sm1) and without LVI and
well-to-moderately differentiated, especially
for those patients who are poor surgical can-
didates.55 However, this decision should be
made after consultation with a multidisci-
plinary surgical oncology team.
Ablation Modalities
Following the resection of visible focal le-
sions, elimination of residual BE mucosa is
essential to reduce the risk of recurrent
neoplasia. A variety of techniques are avail-
able to accomplish this (Table 3). Despite
the emergence of several new modalities,
radiofrequency ablation (RFA) remains the
most commonly performed endoscopic abla-
tion procedure for BE, owing to its ease of
use and high degree of efficacy. RFA is a
thermal technique for mucosal ablation us-
ing bipolar electrodes arranged on circum-
ferential (balloon) or focal ablation devices
(Figure 6A, B, and C).56
Liquid nitrogen based endoluminal spray
cryotherapy is another ablation modality
that is highly effective in eradicating BE
and appears very useful in managing cases
refractory to initial RFA treatment.57,58
Balloon-based cryotherapy uses nitrous ox-
ide and is a relatively newer device that
also appears promising in treatment of
BE.59 Argon plasma coagulation and multi-
polar electrocautery are used mostly for
treatment of focal areas of IM and are less
often used in the United States and more
popular in Europe and Asia. Photodynamic
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TABLE 3. Different Modalities for Barrett Ablation
Thermal Devices
Radiofrequency ablation (RFA)
Circumferential RFA
Focal RFA (60, 90, Ultra)
Channel RFA catheter
Argon plasma coagulation
Multipolar electrocoagulation
Cryotherapy Devices
Spray cryotherapy (liquid nitrogen)
Balloon cryotherapy (nitrous oxide)
Historical
Photodynamic therapy
therapy caused mucosal ablation using
photochemical energy but is no longer
used because of cost, associated morbidity
(photosensitivity and strictures), and lack
of availability.
Radiofrequency Ablation. Radiofrequency
ablation is the most commonly used ablation
technique to treat dysplastic BE. In RFA,
radiofrequency energy is directly applied to
the esophageal mucosa, either using a
balloon or focal catheter. This technique
has been well studied and is highly effective
at eradicating IM and dysplasia. A multi-
center randomized controlled trial in the
United States found that 81% of patients
with HGD and 91% with LGD achieved com-
plete eradication of dysplasia within 12
months, with a statistically significant
decrease in progression to EAC in the abla-
tion arm.6 The most common adverse
events of RFA include postablation stricture
and postprocedure chest pain, especially if a
long segment of BE has been treated at a
single session. Bleeding and perforation are
extremely uncommon.
Cryoablation. Endoscopic cryoablation is
another option for ablative therapy that has
emerged in the past decade, with recent
studies suggesting less postprocedural chest
pain and better patient tolerance compared
with RFA.60,61 At least 2 platforms for
cryotherapy are now commercially available
and in use.
n https://doi.org/10.1016/j.mayocp.2019.01.032 1897

In the case of spray cryotherapy
(Figure 6D), liquid nitrogen is delivered
at e196 C (e320 F) through a novel spray
catheter, which is introduced through the
working channel of a standard endoscope.
In the newer balloon-based cryotherapy sys-
tem, nitrous oxide is used to achieve ablation
by direct contact with the tissue via an
inflated balloon with an internal spray cath-
eter. Studies have shown eradication of HGD
in 81% to 94% of patients with
cryotherapy.62
Successful endotherapy is defined by
both absence of visible IM at endoscopy
and on histology. This milestone is referred
to as complete remission of intestinal meta-
plasia (CR-IM). Despite high rates of suc-
cessful endotherapy in BE, there remains
significant risk of recurrence of IM and/or
dysplasia in certain patients, warranting
close postablation surveillance in all patients
after treatment has been deemed complete.
Those at highest risk for recurrence include
patients with long-segment BE and those
with HGD or worse pathology on initial
FIGURE 6. (A) Circumferential balloon radiofrequency ablation (RFA)
catheter. (B) Focal ablation RFA catheter. (C) Focal ablation catheter being
used to ablate the gastroesophageal junction. (D) Endoscopic liquid nitro-
gen spray cryotherapy being administered via spray catheter.
n n
1898 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
histology. A recent meta-analysis reviewed
all modalities of BE endotherapy and showed
that the annual incidence of recurrent IM
was 7.1%, recurrent dysplastic BE was
1.3%, and recurrent HGD and/or EAC was
0.8%. It is reassuring to note that more
than 95% of all recurrences were endoscopi-
cally treatable.63 Hence, continued endo-
scopic surveillance after successful
endotherapy is currently recommended to
detect and treat recurrent BE. Recommenda-
tions on intervals of follow-up after success-
ful ablation are expert-opinion based and
suggest that those with CR-IM after endo-
therapy for BE-HGD/EAC should be sur-
veyed endoscopically every 3 months for
the first year, every 6 months for the second
year, and then once a year thereafter. Pa-
tients reaching CR-IM after endotherapy for
BE-LGD should be surveyed endoscopically
every 6 months for the first year and then
annually. There is no consensus at this
time on whether surveillance can be
extended or discontinued after a certain in-
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
meta-analysis, 46% of all patients with RFA
failure achieved CR-IM, and 76% achieved
CR-D with cryotherapy.64 In addition,
although there is concern regarding “buried”
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BARRETT ESOPHAGUS
Barrett mucosa (underneath squamous
epithelium, persisting after apparent success-
ful ablation, and rarely progressing to EAC),
the rates of this phenomenon appear to be
low (0.9%) within limitations of data as
reported.65
CONCLUSIONS
BE is an established precursor to EAC, with
malignant transformation potentially occur-
ring in a stepwise fashion from nondysplas-
tic BE to LGD, HGD, and ultimately
invasive adenocarcinoma. This provides the
window for early detection by screening
and surveillance. Substantial recent progress
has been made in the development of mini-
mally invasive nonendoscopic approaches
in the detection of BE and related dysplasia,
along with effective endoscopic therapy of
dysplasia (reducing risk of progression to
EAC) and early EAC (with excellent survival
rates comparable with esophagectomy). The
most effective treatment regimen can be
multimodal and individualized to the pa-
tient, with endoscopic resection (EMR/
ESD) of nodular/raised lesions, followed by
ablation of residual IM. It is recommended
that BE endotherapy is performed in high-
volume centers of excellence to ensure
optimal outcomes. Ongoing endoscopic sur-
veillance after successful endotherapy is
essential to detect and treat recurrences.
Challenges that likely need to be addressed
in the coming years include making surveil-
lance more efficient and effective (likely us-
ing novel imaging and molecular
strategies), integrating risk stratification,
identification of likely nonresponders to
treatment, and the integration of quality
measures (assessing diagnosis, surveillance
and treatment of dysplastic BE) into clinical
practice.
SUPPLEMENTAL ONLINE MATERIAL
Supplemental material can be found online
at http://www.mayoclinicproceedings.org.
Supplemental material attached to journal
articles has not been edited, and the authors
take responsibility for the accuracy of all
data.
Mayo Clin Proc. n September 2019;94(9):1888-1901
www.mayoclinicproceedings.org
Abbreviations and Acronyms: BE = Barrett esophagus;
CR-IM = complete remission of intestinal metaplasia; EAC =
esophageal adenocarcinomas; EMR = endoscopic mucosal
resection; ESD = endoscopic submucosal dissection; HGD =
high-grade dysplasia; IM = intestinal metaplasia; LGD = low-
grade dysplasia; PPI = proton pump inhibitor; RFA = radi-
ofrequency ablation
Potential Competing Interests: Dr Iyer has received
research funding from Exact Sciences, C2 Therapeutics,
and Medtronic. He has received consulting fees from Med-
tronic and Symple Surgical. Dr Kaul has received research
funding from CSA Medical and is a consultant for Medtronic,
Olympus, CSA Medical, and Cook-Medical.
Correspondence: Address to Prasad G. Iyer, MD, MSc, Bar-
rett’s Esophagus Unit, Division of Gastroenterology and
Hepatology, Mayo Clinic, 200 First Street SW, Rochester,
MN 55905 (iyer.prasad@mayo.edu).
The Thematic Reviews on Gastroenterological Diseases
will continue in an upcoming issue.
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