EDITORIAL
Barrett’s esophagus indefinite for dysplasia carries a definite
risk of neoplasia
The risk of progression of Barrett’s esophagus (BE) to
esophageal adenocarcinoma (EAC) is measured by the grade
of histologic dysplasia identified on esophageal biopsy spec-
imens or resection specimens. This risk is better defined in
patients with BE with low-grade dysplasia (LGD) or high-
grade dysplasia (HGD) in comparison with patients who
have a diagnosis of indefinite for dysplasia (BE-IND). BE-
IND refers to the presence of epithelial abnormalities that
are not sufficient to establish a concrete diagnosis of
dysplasia or are of uncertain nature because of inflammation
or technical limitations. In these cases, the histologic appear-
ance contains subtle abnormalities that cannot be classified
as normal but do not meet the diagnostic threshold to be
defined as dysplasia. The clinical impact of a diagnosis of
BE-IND has been difficult to study, in part because there
are no well-defined, specific diagnostic criteria, with consid-
erable disagreement between expert and nonexpert pathol-
ogists; even among expert pathologists, there is only fair
agreement regarding a diagnosis of BE-IND.1
With this background in mind, we read with great plea-
sure the study by Phillips et al2 that aims to fill our gaps in
knowledge regarding the clinical impact of a diagnosis of
BE-IND. This multicenter retrospective cohort study de-
scribes the clinical outcomes of 242 patients with
confirmed BE-IND across 2 academic centers with experi-
ence in the treatment of patients with BE. Endoscopic
follow-up of at least 1 year and no history of BE dysplasia
were required for inclusion. Prevalent and incident
neoplasia, defined as progression within <1 year or 1
year of follow-up occurred in 9.5% and 14.5% of patients,
respectively. In this cohort of patients, the incidence rates
of any neoplasia (LGD, HGD, EAC) and advanced neoplasia
(HGD, EAC) were 3.2 and 0.6 cases per 100 patient-years,
respectively. The authors conclude that BE-IND should be
monitored closely because nearly a quarter of patients
experienced dysplasia during follow-up.
The rate of prevalent neoplasia in patients with BE-IND
reported in the present study is consistent with rates in
previous publications, including a study by Henn et al3
that showed a prevalent neoplasia rate of 9.3%. However,
the reported incidence rate of advanced neoplasia
appears to be somewhat lower than that shown in
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previous studies. In a recent systematic review and meta-
analysis, Krishnamoorthi et al4 identified 8 studies from
North America and Europe that showed an incidence of
advanced neoplasia in patients with BE-IND of 1.5 per
100 person-years. Furthermore, Horvath et al5 reported
higher incidence rates of any neoplasia and advanced
neoplasia with BE-IND, namely, 4.5 and 1.2 cases per 100
patient-years, respectively.
The present study identified BE length as an indepen-
dent risk factor associated with progression in BE-IND;
the authors report an odds ratio of 1.2 for every 1 cm of
The present study certainly highlights that BE-
IND is a condition that warrants close follow-
up and monitoring. This suggests that BE-IND
has a similar risk of progression to EAC as BE-
LGD and that surveillance of these 2 entities
should also be similar.
BE segment. Other studies have found multifocal and
persistent BE-IND to represent risk factors for progres-
sion.5 Younes et al6 showed that BE with multifocal IND
was more likely to progress to advanced neoplasia than
were nondysplastic BE and BE-IND, and multifocal BE-
IND appears to have similar implications as BE-LGD. In
the present study, >30% of patients had evidence of persis-
tent BE-IND; however, the authors did not find this to be a
risk factor for progression on multivariate analysis.
There are limitations to the present study that are worth
reviewing before the generalizability of the results can be
considered. First, the 2 study centers (Cambridge University
and Mayo Clinic) represent large tertiary referral centers
with expertise in the clinical management of BE. By contrast,
the diagnosis and clinical management of BE-IND in com-
munity hospitals that lack this level of expertise remains un-
known. Extrapolating from studies that examined the
interobserver agreement between GI and community pa-
thologists for a diagnosis of BE-LGD suggest that there is a
risk of overcalling a diagnosis of dysplasia in community cen-
ters, perhaps out of a concern for the clinical implications of
a missed diagnosis of dysplasia.7 In addition, adherence to
BE endoscopic surveillance plays a fundamental role in the
Volume 94, No. 2 : 2021 GASTROINTESTINAL ENDOSCOPY 271
Editorial
diagnosis of dysplasia and BE-IND. Factors associated with
better adherence include shorter BE length and surveillance
in dedicated centers of expertise.8 In the present study, the
length of BE was associated with higher prevalent and
incident dysplasia in patients with BE-IND, suggesting that
these patients require careful attentiondeven by experi-
enced BE endoscopists.
The present study certainly highlights that BE-IND is a con-
dition that warrants close follow-up and monitoring. This sug-
gests that BE-IND has a similar risk of progression to EAC as
BE-LGD and that surveillance of these 2 entities should also
be similar.9 These findings are consistent with the current
American and European guidelines for the management of
BE-IND. The American College of Gastroenterology guide-
lines recommend optimizing acid-suppressive medications
and repeating endoscopy in 3 to 6 months for patients with
BE-IND.10 The British Society of Gastroenterology also
recommends maximal acid-suppressive therapy for patients
with BE-IND, followed by repeated endoscopy in 6 months.11
The international Benign Barrett’s and Cancer Taskforce
suggests that patients with BE-IND, confirmed by at least 2
expert GI pathologists, should undergo repeated biopsy
within 1 year to detect prevalent neoplasia and have their
acid suppression increased.12 This taskforce noted that BE-
IND should be considered an interim diagnosis only and
that further endoscopic surveillance is necessary to upgrade
or downgrade this diagnosis.12
The use of biomarkers promises to help identify patients
with BE-IND who are at risk of progression to dysplasia or
cancer. In 2 separate studies, abnormal p53 expression in
BE-IND was significantly associated with the presence of
prevalent advanced neoplasia and increased progression
to advanced neoplasia, with a hazard ratio of 4 to 12.13,14
Mutational load, in a pilot study, has also been shown to
be helpful in predicting the risk of progression in BE-
IND.15 Finally, the clinically available tissue systems
pathology test (TissueCypher Barrett’s esophagus assay)
has been shown to help risk stratify patients with BE-LGD,
and it may be promising in BE-IND as well.16
In our practice, we start by confirming a diagnosis of BE-
IND, providing recommendations for an intensive acid sup-
pression regimen, and performing repeated surveillance
endoscopy in 6 months with detailed examination of the
entire BE segment under high-definition white-light endos-
copy and narrow-band imaging. Patients with certain risk
factors, such as long-segment BE, multifocal BE-IND, and
abnormal p53 expression, may be at elevated risk of pro-
gression to neoplasia and require closer monitoring. This
approach is supported by the present study, which
elegantly highlights that one thing is certain: BE-IND
carries a definite risk of neoplasia that cannot be ignored.
DISCLOSURE
Both authors disclosed no financial relationships.
272 GASTROINTESTINAL ENDOSCOPY Volume 94, No. 2 : 2021
Kamboj & Leggett
Amrit K. Kamboj, MD
Cadman L. Leggett, MD
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, Minnesota, USA
Abbreviations: BE, Barrett’s esophagus; BE-IND, Barrett’s esophagus
indefinite for dysplasia; EAC, esophageal adenocarcinoma; HGD, high-
grade dysplasia; IND, indefinite for dysplasia; LGD, low-grade dysplasia.
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