Ann. N.Y. Acad. Sci.

ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

Special Issue: Global Perspectives on Esophageal Diseases
REVIEW

Recent advances in Barrett’s esophagus

John Inadomi, 1 Hani Alastal,2,3 Luigi Bonavina,4,5 Seth Gross,6 Richard H. Hunt,7
Hiroshi Mashimo,8,9 Massimiliano di Pietro,2 Horace Rhee,10 Marmy Shah,11
Salvatore Tolone,12 David H. Wang,13 and Shao-Hua Xie14
1
Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington. 2 MRC Cancer Unit at the
University of Cambridge, Cambridge, UK. 3 Faculty of Life Sciences and Education, University of South Wales, Newport City,
UK. 4 Department of Biomedical Sciences for Health, University of Milano School of Medicine, Milan, Italy. 5 Division of General
Surgery, IRCCS Policlinico San Donato, Milan, Italy. 6 Division of Gastroenterology, New York University, New York, New York.
7
McMaster University, Hamilton, Ontario, Canada. 8 Division of Gastroenterology, Harvard Medical School, Boston,
Massachusetts. 9 VA Boston Healthcare System, Boston, Massachusetts. 10 Division of Gastroenterology and Hepatology,
Stanford University, Palo Alto, California. 11 Division of Gastroenterology, Loyola University Chicago Stritch School of Medicine,
Chicago, Illinois. 12 Division of General, Mini-Invasive and Bariatric Surgery, University of Campania “Luigi Vanvitelli”, Naples,
Italy. 13 Division of Hematology and Oncology, UT Southwestern Medical Center and VA North Texas Health Care System,
Dallas, Texas. 14 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

Address for correspondence: John Inadomi, M.D., Division of Gastroenterology, University of Washington School of Medicine,
1959 NE Pacific Street, Box 356424, Seattle, WA 98195. [email protected]

Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma, one of the few cancers with
-

increasing incidence in developed countries. The pathogenesis of BE is unclear with regard to either the cellular
origin of this metaplastic epithelium or the manner in which malignant transformation occurs, although recent
C
*
3
data indicate a possible junctional origin of stem cells for BE. Treatment of BE may be achieved using endoscopic
->
eradication therapy; however, there is a lack of discriminatory tools to identify individuals at sufficient risk for
cancer development in whom intervention is warranted.- Reduction in gastroesophageal reflux of gastric contents
including acid is mandatory to achieve remission from BE after endoscopic ablation, and can be achieved using
medical or nonmedical interventions. Research topics of greatest interest include the mechanism of BE development
and transformation to cancer, risk stratification methods to identify individuals who may benefit from ablation
of BE, optimization of eradication therapy, and surveillance methods to ensure that remission is maintained after
eradication is achieved.

Keywords: Barrett’s esophagus; esophageal adenocarcinoma; screening; surveillance; endoscopy; imaging

Background risk for EAC in individuals with BE, and achieving

CBarrett’s esophagus (BE) is defined as the replace- durable eradication of intestinal dysplasia and meta-
plasia. Our review examines emerging data about
ment of the normal squamous lining of the
the pathogenesis, screening and surveillance strate-
esophagus with columnar epithelium (intestinal
gies, and treatment options for individuals with
metaplasia) and is the only known precursor for the
development of esophageal adenocarcinoma (EAC).
-
94. BE.
While the incidence of EAC has increased in west-
Pathogenesis of BE
ern countries over the past several decades, the
vast majority of patients with BE do not develop -
The metaplastic transition from a stratified squa-
EAC. The main barriers to optimal management of mous to glandular columnar epithelium, which
BE include the inability to accurately identify indi- defines BE remains poorly understood, hampered
viduals harboring Barrett’s or correctly stratify the in part by uncertainties regarding the cellular

doi: 10.1111/nyas.13909
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Ann. N.Y. Acad. Sci. xxxx (2018) 1–12 ! 1
 -
q alle from
Repopulation se
Reogr Barrett’s esophagus

submunal
Inadomi et al.

gland ells
sq
-

nature
gatrgentinentin

&

Figure 1. Cellular origins of Barrett’s esophagus. Potential theories that give rise to Barrett’s epithelium include (1) reprogramming
* -
of native squamous stem cells, (2) repopulation from submucosal gland stem cells, and (3) migration of gastric stem cells including
cells at the squamocolumnar junction (see Ref. 1).

origin. Several potential theories have been pro- Amarkers of basal (p63+ KRT5+ KRT7+ ) and lumi-* -

posed including reprogramming of squamous stem nal (p63– KRT7+ ) cells have also been found in the
cells, repopulation from submucosal esophageal human SCJ and organoids derived from these cells
glands, or direct extension of gastric cells adjacent express markers of Barrett’s epithelium when over-
to the esophagus.1 Active investigation is being pur- expressed with CDX2. These results support the
sued for each of these potential cells of origin and hypothesis that- transitional basal cells at the SCJ *
ultimately they could all contribute to the patho- - give origin to the intestinal metaplastic epithelium
genesis of BE (Fig. 1).
-
in BE. Acid reflux certainly plays a role in the patho-
One study used a p63 gene knockout mouse in genesis of BE; however, the main effect may not
which precursor cells of metaplasia were found at be a chemical injury but rather the induction of
the squamocolumnar junction (SCJ).2 Upon dis- inflammation in the distal esophagus. A prospec-
-

tal esophageal injury, these junctional cells rapidly tive study following patients with severe esophagitis
- -
- -

expand and replace squamous mucosa presumably successfully treated with acid suppression, who sub-
-

in the absence of additional mutations. Similarly, sequently discontinued medication, observed that a
-

a rodent model of BE that overexpresses cytokine T-cell lymphocytic infiltration developed in squa-
&
e

IL-1! found progressive inflammation, metaplasia, mous epithelia in the absence of mucosal erosions.5
-

Y -

and even dysplasia localized at the SCJ.3 The devel- The mechanism underlying this observation was
-

opment of these metaplastic glands was potenti- examined by Souza et al. in an animal model of sur-
ated by bile acids and hypersecretion of gastrin.4 gically induced reflux. They reported that cytokines
Recently, Jiang and coworkers identified a multi- originating from squamous cells, including IL-1!,
-

layered transitional zone in the murine SCJ with potentially attract T lymphocytes in response to
~

a basal layer of cells.4 With multiple lineage trac- acid reflux.6 These human and animal observa-
ing strategies, in vitro 2D and organoid cultures, tions support the hypothesis that gastroesophageal
*
the authors showed that these basal cells at the reflux might cause esophagitis through a cytokine-
SCJ act as progenitors to maintain the transitional mediated mechanism rather than caustic acid injury.
columnar epithelium. These cells can transform to BE recurrence post endoscopic ablation could
intestinal-like mucosa with goblet cells after sur- originate from deeper stem cells surviving mucosal
gical redirection of bile acid to the esophagus or ablation.7 Several genetic studies have demon-
ectopic expression of CDX2, an intestinal tran- strated the clonality of Barrett’s glands and the
scription factor expressed in BE. The same murine evolution into adenocarcinoma through progressive

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Inadomi et al. Barrett’s esophagus

mutations.8,9 Using gene expression profiling and ple, the greatest rise in EAC incidence has occurred
exome sequencing, Barrett’s stem cells have been in the Netherlands, yet the rate of obesity has not
found to be distinct from esophageal and gastric increased to the extent seen in the United States
stem cells derived from the same patient. Interest- where the absolute number and rate of increase in
ingly, many metaplastic cells already harbored driver EAC trails the Netherlands.13 Similarly, smoking is
mutations found in EAC, and yet other cells contain associated with EAC but the proportion of smok-
a similar mutational burden as the adjacent nor- ers in the United States, the Netherlands, and Spain
mal gastric stem cells.10 Yamamoto et al. isolated have been decreasing during the period of increase
ground state esophageal, BE, and gastric stem cells in the rate of EAC.13
from matched biopsies derived from patients with National guidelines vary in the recommendations
BE.10 These stem cells possess the ability of long- for screening. The most recent is from the Ameri-
term self-renewal, multipotent differentiation, and can College of Gastroenterology in which the low
absolute commitment to their original lineage. They incidence of cancer among women influenced their
express SOX9 and CDH17 and can generate in the recommendation to screen only men with gastroe-
air–liquid interface 3D cultures with goblet cells and sophageal reflux symptoms with two of the follow-
expression of typical BE markers. The derived stem O
ing additional five factors: age 50 years and older,
Caucasian, central obesity, smoking, or a family
cells showed distinctive mutational spectrum com-
mon to BE and EAC, including homozygous loss of history of BE.14
CDKN2A (gene for p16) and less commonly TP53
Surveillance
and other established oncogenes. Immortalization
and subcutaneous injection in the immunodeficient One of the keys to effective and efficient surveillance
mice generate tumors that recapitulate morpholog- is the identification of patients with BE who are at
ically human adenocarcinomas. high risk of progression to EAC and would bene-
In summary, this evidence supports the hypoth- fit from surveillance and treatment, and those with
esis that BE could originate from transitional basal low risk in whom surveillance could be discontin-
progenitors at the SCJ. More work is required to ued. Parasa et al. recently developed and validated a
establish the similarity between these progenitor scoring system based on four differentially weighted
cells and the stem cells identified within BE. Fur- parameters (two clinical and two endoscopic) that
ther validation of these data is required to confirm accurately stratified patients with BE into three risk
the nature of the Barrett’s stem cells. categories.15 The greatest risk was conferred upon
those with low-grade dysplasia (LGD) (11 points),
Screening
male sex (9 points), cigarette smoking (5 points),
Current strategies to detect BE are inadequate. The and the length of BE (1 point per cm of length).
vast majority of patients who develop EAC are not Patients scoring more than 20 points had an annual
diagnosed with BE prior to their cancer diagnosis; risk of progression to high-grade dysplasia (HGD)
conversely, cancer is a rare outcome among indi- or cancer of 2.1%, while those scoring 10 points or
viduals with BE who are undergoing endoscopic fewer had an annual risk of 0.13%. Patients whose
surveillance to detect dysplasia and cancer.11 It is scores were between 11 and 20 points had an aver-
clear that strategies to detect BE based on the pres- age annual risk of 0.73%. Interestingly, inclusion
ence of symptoms of gastroesophageal reflux disease of other factors including age, race, and obesity, or
(GERD) are ineffective. There are risk factors other body mass index did not improve the model predic-
than reflux symptoms that are associated with BE, tion, which have been reported in prior studies as
such as obesity, age, sex, race, and smoking history. risk factors for EAC.16,17 The Parasa/Sharma scoring
Women, even those with gastroesophageal reflux system does not only highlight patients who most
symptoms, have a risk of EAC that is similar to the benefit from surveillance, but also it is able to iden-
risk of breast cancer among men.12 While obesity, tify patients with BE who possess a low risk of cancer
or more specifically abdominal obesity or waist cir- and may potentially be discharged from a surveil-
cumference or waist-to-hip ratio, is associated with lance program.15
BE and EAC, the time trends of obesity do not match There are emerging biomarkers that may
the time trends of EAC across countries. For exam- assist in stratifying the risk of cancer among

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Barrett’s esophagus Inadomi et al.

individuals with BE and different prediction models persistence of LGD itself increases risk of progres-
have been proposed combining both the epidemio- sion to HGD and EAC. In a retrospective analysis of
logic variables and biomarkers.18 Martinez and col- a randomized controlled study of patients with LGD
laborators analyzed brush cytology specimens from randomized to either surveillance or radiofrequency
195 nondysplastic BE (NDBE) patients in order ablation (RFA) (the SURF trial), three expert pathol-
to identify molecular biomarkers of cancer risk.19 ogists reviewed baseline and follow-up biopsies on
Fourteen patients developed either HGD or ade- patients who either were not enrolled in the trial
nocarcinoma during follow up. The authors used or were randomized to endoscopic surveillance.28
fluorescence in situ hybridization to assess seven When consensus was reached by all three patholo-
markers (CEP7, CEP17, TP53, CDKN2A, ERBB2, gists of a diagnosis of LGD on the baseline biopsy,
20q, and MYC). By comparing the change in the the odds ratio of neoplastic progression was 47 com-
clonal composition between the two-time points, pared to 10 or 27 when LGD was confirmed by only
the authors found an overall dynamic equilibrium one or two pathologists, respectively. In patients
with relatively stable levels of genetic diversity over who had LGD diagnosed on two subsequent biop-
time. However, patients who progressed had higher sies, the odds of neoplastic progression was nine.
levels of clonal diversity at baseline that could be Emerging biomarkers include differential methyla-
predicted using single-probe clonal diversity mea- tion drift that occurs in “clock genes,” which appear
sures of MYC or CEP7. to reflect the age of Barrett’s tissue in relationship to
There is abundant evidence that TP53 muta- the normal squamous tissue; thus, it may be that the
tions, changes in DNA ploidy, and persistence of duration of time an individual has BE will be a better
LGD diagnosed by consensus of expert patholo- indication of the risk of EAC than the individual’s
gists more accurately predict neoplastic progres- chronological age.29
sion in patients with BE. Mutation of the tumor A sampling error is known to occur in endoscopic
suppressor TP53 correlates well with HGD and biopsies using the Seattle protocol of four-quadrant
EAC as shown in 40 patients with NDBE and 39 biopsies every 2 cm (1 cm in patients with dysplasia)
patients with HGD.20 TP53 was mutated in 72% along the length of Barrett’s epithelium. WATS3D
of HGD and 69% of EAC samples and only in (CDx Diagnostics) obtains a full-thickness, transep-
2.5% of NDBE. TP53 immunohistochemistry often ithelial tissue sample using a brush device that is
is used as an alternative to mutational analysis used through the endoscopy biopsy port and aims
with strong and diffuse expression felt to represent to reduce this error (Fig. 2). A neural network ana-
mutated TP53. In multiple studies, TP53 overex- lyzes 100 "m thick tissue samples in 1 "m optical
pression precedes by several years the development slices and synthesizes a single 3D image that pro-
of HGD or EAC.21,22 As a result, the British Soci- vides an en-face view of the epithelium. The studies
ety of Gastroenterology Guidelines on the Diag- have demonstrated significant increase in the detec-
nosis and Management of Barrett’s Oesophagus tion of dysplasia in BE over standard endoscopic
recommends using TP53 immunohistochemistry biopsies alone.30 A recent prospective randomized
(grade B, evidence from clinical studies that are study showed that compared with standard four-
not randomized) as an adjunct to routine diagnosis quadrant biopsies every 2 cm (the Seattle protocol),
of dysplasia in BE.23 The follow-up studies have WATS plus standard biopsies provided an absolute
demonstrated that TP53 immunohistochemistry increase of 14.4% (95% CI 7.9–19.3) in the cases of
decreases “indefinite for dysplasia” diagnoses and HGD/EAC detected, with a number needed to test
increases interobserver diagnostic agreement.24 of seven additional patient tests with WATS in order
Since TP53 acts as a gatekeeper of genomic sta- to detect one additional case of HGD/EAC.31
bility, it is not surprising that aneuploidy detected Advances in endoscopic imaging beyond con-
by flow cytometry also reliably predicts progression ventional white light endoscopy (WLE) may also
to HGD and EAC.25 A landmark study demon- improve the quality of surveillance to detect neo-
strated that in patients with BE diagnosed with neg- plasia in patients with BE undergoing surveil-
ative, indefinite, or LGD, those with neither ane- lance. Besides digital enhancements such as narrow
uploidy nor an increased 4N fraction, had a 0% band imaging (NBI; Olympus), I-Scan (Pentax),
5-year cumulative cancer incidence.26,27 Finally, the and flexible spectral imaging color enhancement

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Inadomi et al. Barrett’s esophagus

by the small coverage area, contrast agents that may

obscure the view with extravasation during ablative
therapies, and inability of pCLE to simultaneously
mark the imaged mucosal surface for guiding biop-
sies, ablations, and resections.
Several histopathology criteria have been estab-
lished to discern regions of nondysplastic and dys-
plastic BE. The Mainz criteria based on mucosal
architecture and vascular patterns demonstrated a
sensitivity and specificity of 93% and 94% for BE-
associated dysplasia, respectively, with a high inter-
observer agreement.37 The use of eCLE was also
demonstrated to reduce the number of biopsies
and increase the sensitivity for detecting dyspla-
sia from 40% to 96% without significant reduction
in specificity, thereby exceeding the Preservation
and Incorporation of Valuable endoscopic Inno-
vation (PIVI) threshold.35 In another multicenter
study, the use of pCLE improved the sensitivity and
Figure 2. WATS: high-grade dysplasia. specificity of detecting dysplasia from 45.0% and
88.2% using WLE with NBI to 75.8% and 84.2%,
respectively.36 In another study, 100 patients at a
(FICE; Fujinon) to allow for improved mucosal tertiary referral center were evaluated by WLE, of
contrast through virtual chromoendoscopy32 and whom 50 also had pCLE imaging, HGD was found
marked improvement in optics to allow for high in three of 100 patients and LGD in 16 of 100
magnification33 and microscopic Endocytoscopy patients. With WLE alone, 10% of patients with
(Olympus),34 two major imaging modalities have no suspicious lesions were found to have dysplasia
emerged toward detection of dysplastic and neoplas- on random biopsies. With the addition of pCLE,
tic lesions: confocal laser endomicroscopy (CLE) suspicious areas for dysplasia were detected in 21
and optical coherence tomography (OCT). of 50 patients and confirmed as dysplasia in 14 of
CLE employs a low-power laser to detect fluo- 50 cases, showing a sensitivity of 100%, specificity
rescent light from tissues at cellular and subcel- of 83%, and positive and negative predictive val-
lular levels of resolution. Two major commercial ues of 67% and 100%, respectively.38 Through a
systems are the Pentax! R
endoscopic CLE (eCLE; consensus of pCLE users, the Miami criteria were
no longer available), which uses a dedicated endo- developed and showed a 88% sensitivity and 96%
scope, and the Cellvizio! R
disposable probe-based specificity for detecting dysplasia/EAC, with kappa
CLE (pCLE; Mauna Kea Technologies), which can agreement of 0.72.39 Another pCLE criteria incor-
be introduced through the accessory channel of porated saw-toothed epithelial surface with pleo-
standard endoscopes thereby allowing the concomi- morphic enlarged cells and glands that are unequal
tant use of virtual chromoendoscopy such as NBI for in shape and size, plus areas depleted of goblet cells.
added diagnostic value.35 The pCLE offers a stan- The overall accuracy in diagnosing dysplasia was
dard miniprobe with a 600 "m field and 70–130 "m 81.5% with good interobserver agreement (kappa
depth of view, and high-definition probe with a of 0.61), no significant difference between experts
more restricted 240 "m field and 50–65 "m depth and nonexperts, and a short learning curve.40 Use
of view. CLE generally uses topical (e.g., fluorescein, of the same criteria was also compared among gas-
acriflavine, tetracycline, or cresyl violet) or intra- trointestinal pathologists and demonstrated similar
venous (e.g., fluorescein) contrast agents to provide accuracy (77.8%), interobserver agreement (kappa
“optical biopsies” and potentially decide on treat- of 0.65) for interpreting the same set of videos
ment without blind biopsies or histopathological as endoscopists.41 More recently, the sensitivity,
interpretation.36 However, CLE is currently limited specificity, and accuracy of pCLE for detecting

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Barrett’s esophagus Inadomi et al.

HGD/EAC in the absence of visible lesions were As a preablative tool, OCT is conceivably opti-
92.9%, 71.4%, and 80%, respectively, compared to mized to identify who, where, and how to ablate. Its
78.6%, 61.9%, and 68.6% for histological biopsy, role to identify who to ablate will be contingent on
respectively, when using the final histological results meeting the PIVI thresholds of the American Soci-
after endoscopic resection.42 Meta-analysis of CLE ety for Gastrointestinal Endoscopy,47 toward which
performance compared to random four-quadrant current OCT work is approaching, with reassuring
biopsies reported a sensitivity for detecting patients agreement among high-volume users.48–51 Where to
with HGD and EAC of 86% and specificity of 83%.43 ablate may be less of an issue, given that the present
Another recent meta-analysis showed that the addi- ablative paradigm is to destroy all metaplastic tissue
tional detection rate of CLE for per-lesion detection once dysplasia is detected; however, this may achieve
of dysplasia in patients with BE was 19.3% com- greater relevance if future studies demonstrate a
pared to NBI with a pooled sensitivity of 72.3% com- need for a focally directed ablation for durable erad-
pared to 62.8% for NBI, but with similar specificity ication of BE. OCT may also help during ablation,
of 83.8% for CLE and 85.3% for NBI.44 However, particularly for assessing the lateral borders of dys-
these studies were performed at tertiary academic plasia during EMR.52 OCT is also poised to address
referral centers and may not be reflective of perfor- choosing how to ablate. The present ablative meth-
mance achievable in a community practice. Enthusi- ods include RFA, cryoablation, EMR or endosur-
asm for CLE is somewhat guarded by another study gical or endoscopic submucosal dissection (ESD),
showing that the combination of pCLE and WLE photodynamic therapy (PDT), and hybrid lift-argon
to assess residual metaplasia after ablation or resec- plasma coagulation (APC). OCT has revealed that
tion did not necessarily improve determination of the depth of BE is quite variable, and several markers
treatment versus continued surveillance when com- are predictive of poor RFA response, including BE
pared to WLE alone.45 Moreover, CLE has not been thickness of >333 "m and the number of residual
shown to be superior to other advanced imaging gland-like structures immediately following RFA.53
modalities.35 OCT has also demonstrated that tissue architec-
OCT is a uniquely suited imaging modality that tural change suggestive of ablative depth is deeper
provides a real-time wide-field near-microscopic for cryoablation compared with RFA.54 Thus, taken
and depth-resolved evaluation of the esophagus. together, OCT may be helpful in identifying patients
Unlike surface endoscopic image enhancements who may be more optimally treated using meth-
such as chromoendoscopy, magnification endo- ods other than RFA. Moreover, OCT detects areas
scopes, NBI, or color digital enhancements, OCT of subsurface fibrosis such as over the regions of
can reveal a subsurface detail down to approxi- prior EMR or PDT, and recent advances in OCT
mately 3 mm depth with approximate 5–7 "m using speckle pattern analysis (similar to Doppler
axial resolution. OCT technology is thus capable ultrasonography) have allowed the identification of
of obtaining deeper images with similar resolu- abnormal microvasculature correlating with areas of
tion compared with currently available confocal dysplasia.55 Such information may help guide areas
endomicroscopy, but without the need for intra- to avoid using EMR/ESD and direct areas for focal
venous contrast agents that may extravasate and ablation.
obscure visualization during biopsies or endoscopic OCT is also likely to play a significant role postab-
mucosal resection (EMR). Moreover, unlike con- lation, particularly since the neosquamous epithe-
focal endomicroscopy, OCT allows visualization of lium may cover over areas of BE, dysplasia, or
a large surface area or even the entire esophagus.46 nascent cancer. OCT is able to show that the major-
This is of particular importance since dysplasia often ity of patients have subsurface gland-like structures
arises as small and scattered lesions within BE and even after RFA,56 which was underappreciated from
current random biopsies using the Seattle protocol random superficial biopsies that sample less than
assess less than 3% of the BE surface. As such, OCT 1/40 of the surface under the current Seattle proto-
is uniquely poised for both pre and postablative col. The significance for neoplastic progression of
assessment in BE. Present commercial endoscopic these buried glands remains unclear, since certain
platforms are the NvisionVLE! R
(NinePoint Medi- marker studies suggest a downregulation of stem
TM
cal) and the LuminScan (Micro-Tech). cell and proliferative properties.57

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Inadomi et al. Barrett’s esophagus

Several upcoming advances in OCT technology light scattering spectroscopy64 or angle-resolved low
are addressing some of the unmet needs in BE coherence interferometry65 to further improve the
imaging. Laser-marking balloon OCT (Nvision- quality of surveillance.
VLE Imaging System! R
, NinePoint) will hopefully
address what specific image features correlate best Treatment
with dysplasia by allowing precise coregistry of Current guidelines suggest that the risk of cancer
images with histological samples. An ongoing multi- progression in patients with NDBE is 0.2–0.5% per
center study may also enable future computer-aided year, with an incidence of 3.3–6.2%/1000 person
diagnosis to help identify regions of dysplasia or per year.14 Thus, the recommendation for NDBE
early cancers. This marking system may also help patients is to undergo endoscopic surveillance every
mark areas for ablation or resection, and the precise 3–5 years, and to be prescribed once-daily protein
energy delivery may also render this a therapeutic pump inhibitor (PPI) therapy, using higher doses
tool for targeted ablation in the future. The teth- only if it is necessary to achieve a better control of
ered capsule OCT58,59 may allow an office-based reflux symptoms. Furthermore, it is suggested that
nonendoscopic screening and possible surveillance endoscopic ablative therapies should not routinely
of at-risk patients and help identify patients at risk performed in NDBE because of its low risk of cancer
for progression to cancer early, when they are yet progression, and that antireflux surgery should not
most likely to benefit from interventions. However, be considered as an antineoplastic procedure.
as with CLE, these modalities have yet to be proven
broadly applicable in community-based practices Endoscopic therapy for BE
where the pretest probability of dysplasia is lower There are several modalities available for the treat-
compared to academic centers. There is presently ment of BE, each having its strengths and deficits.
no single ideal imaging device for BE surveillance EMR is the treatment of choice for nodular disease,
and point-interrogation and higher magnification short segment disease, and focal lesions in long-
reduce the breadth of field and restricted depth. segment BE. Multiple studies have demonstrated
Also, a significant disadvantage of OCT is presently that complete eradication of intestinal metaplasia
the inability to localize fluorescent biomarkers for (CE-IM) is high (80–85%).66–68 However, the long-
molecular imaging. As such, fluorescent molecular term recurrence rate varies from 16% to 39% for
endoscopy (FME) is an exciting field of research CE-IM and 6% for recurrence after achieving com-
as it can potentially allow direct endoscopic imag- plete eradication of neoplasia (CE-N) respectively.
ing of molecular markers related to progression The major complication is stricture formation that
to dysplasia or cancer. FME employs fluorescently occurs in 37% of patients.
labeled probes, administered either topically or RFA is the use of thermal energy to destroy tis-
systemically, and an endoscopic detection system sue and allowing for replacement of the tissue with
to visualize specific fluorescence in a range not neo-squamous epithelium. The AIM dysplasia trial
affected by natural autofluorescence (typically in the illustrated a 98% CE-N and 91% CE-IM.69 A meta-
near-infrared range). Examples of molecular probes analysis by Orman et al. reported that among 3802
used so far for Barrett’s dysplasia include the anti- patients treated with RFA 91% achieved CE-N and
vascular endothelial growth factor A (VEGFA) anti- 78% CE-IM.70 The UK Halo registry reported that
body bevacizumab,60 wheat germ agglutinin, which after a mean of 2.5 RFA procedures (19 months of a
probes cancer-related surface glycoprotein,61 and follow-up), 81% of patients achieved CE-N and 62%
a synthetic polypeptide ASYNYDA, which likely achieved CE-IM. Three percent of patients, however,
binds cyclophilin A.62 These detection modali- developed invasive cancer after 12 months despite
ties have only been validated ex vivo or in very endoscopic therapy.71 Strictures were reported in
small and selected patient cohorts and will require 5.6% of patients.72
further studies to prove their potential in Bar- In complex cases, a combination of multiple
rett’s dysplasia detection. Future imaging will likely modalities may provide the best results. Combi-
incorporate multimodal surveillance allowing nation therapy with EMR followed by RFA was
simultaneous imaging of fluorescence,63 or incor- examined by Phoa et al. who performed a multi-
porate other novel imaging modalities such as center study in 132 patients with BE and HGD or

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Barrett’s esophagus Inadomi et al.

early adenocarcinoma. Over a 5-year follow up, they coexisting hiatal hernia of > 3 cm83 or more severe
reported 92% CE-N and 87% CE-IM after com- reflux exposure.84
bination therapy. The recurrence rate of neoplasia
Medical therapy
after complete eradication was 4% and recurrence
of metaplasia was 8% at a 27-month follow up.73 The primary objective for the management of GERD
EMR had a higher risk for esophageal stricture (OR is to control symptoms, heal esophagitis, and pre-
4.7), perforation (OR 7.0), and bleeding (OR 6.8).74 vent complications such as a peptic stricture.85 The
Sengupta et al. reported the use of cryotherapy in evidence that supports therapeutic acid suppression
a cohort of patients who had failed to achieve erad- for chemoprevention in BE is based on observations
ication of dysplasia despite three RFA sessions.75 Of that the presence of acid increases cell proliferation
121 patients with dysplasia who underwent RFA, and that there is a synergistic effect of acid and bile
30 (25%) failed RFA therapy of whom 16 under- on cell proliferation. However, a target pH has not
went cryotherapy as salvage. CE-N was achieved in been defined and it is not known if this is impor-
12 (5%) and CE-IM was achieved in 5 (31%) of tant and if so, what that target pH might be. There
patients. Stenosis was reported in three (19%) of is also an ongoing question of the potential harms
patients; however, all responded to dilation therapy. that might be a consequence of long-term acid sup-
Larger prospective trials are needed to study the role pression.
of cryotherapy in RFA refractory disease. Indirect evidence from retrospective studies sup-
The APE study evaluated the efficacy of APC ver- ports the use of PPIs as a chemopreventive strat-
sus surveillance for patients who had undergone egy in patients with BE.86 Several studies have
EMR for neoplastic BE. The study showed a decrease examined the practice of monitoring a 24-h
in residual (secondary) lesions with APC (3% ver- ambulatory esophageal pH to titrate the PPI dose
sus 36%) and the need for secondary therapy.68,76 to normalize esophageal acid exposure for patients
The hybrid APC technique (submucosal injection with BE. To date, however, there are insufficient
of saline prior to thermal ablation) also showed data to introduce this approach into clinical prac-
promising results in a study by Manner et al. with tice and to support the practice of prescribing PPIs
78% histologic remission.77 The rate of esophageal at doses higher than those needed to eliminate the
strictures was reported to be 4–9% and 2% in the symptoms and endoscopic signs of GERD. Despite
APC and hybrid APC arms, respectively. Unfortu- the lack of hard evidence, there are several impor-
nately, there is a 30–50% histologic relapse with the tant arguments that support the use of standard
APC techniques. However, there is a paucity of data dose delayed-release PPIs given twice daily. One
for the optimal technique and patient population study showed that in healthy volunteers, the intra-
that this modality may be best offered to. Long-term gastric pH was less than 4 in up to one-third of the
data are currently limited. nighttime period despite taking esomeprazole 40 mg
There is the need to reduce recurrence of BE after twice daily.87 Other studies have shown that between
RFA that may occur in up to 32% of patients.78 A 60% and 80% of patients have persistent intragas-
systematic review and meta-analysis identified PPI tric acidity at night despite taking PPIs twice daily
use associated with a 71% risk reduction of EAC and that about 25% of patients with reflux symp-
and HGD in BE patients, supporting the role of toms fail to respond to twice daily PPI.88,89 In a
acid reduction to reduce cancer risk.79,80 Further- further study in GERD patients who were refrac-
more, it has been recently proposed that an effec- tory to PPI treatment, using the strictest criteria,
tive reflux control is associated with a statistical pH was abnormal in 30% of those patients who
significant reduction in BE recurrence after RFA.81 were taking once-daily PPIs and in 25% of those
Optimizing the PPI dose or receiving fundoplica- taking their PPI twice daily.90 Clinical studies report
tion was correlated with a low rate of BE recurrence that abnormal esophageal acid exposure persists
after RFA. Some studies suggest that fundoplication after esomeprazole 40 mg three times daily in 16–
may result in improved control of gastroesophageal 23% of patients despite a significant reduction in
reflux (acid, weakly acid, and weakly alkaline)82 acidity.91
and is associated with fewer recurrences of intesti- The promise of more effective and predicted
nal metaplasia after RFA in selected patients with a control of acid secretion in patients with GERD

8 C 2018 New York Academy of Sciences.

Ann. N.Y. Acad. Sci. xxxx (2018) 1–12 !
Inadomi et al. Barrett’s esophagus

and particularly BE comes with the new class of the intuitive concept that stopping both acid and
potassium channel acid-blocking drugs.92 These biliary components of reflux could normalize gene
antisecretory drugs, the first of which is vonoprazan, expression.
block the ingress of potassium to the parietal cell
thus preventing the exchange with H+ ion. Mean Conclusions
intragastric pH between 5 and 6 is achieved in BE is an increasingly prevalent condition that can
healthy volunteers depending on the dose93 and lead in the minority of individuals to development
healing of severe esophagitis exceeds 95% even in of EAC. Various strategies are available to detect BE
patients with Los Angeles (LA) grade C and D and further risk-stratify individuals to their cancer
esophagitis.94 risk; however, deficits in our understanding of the
The possibility of reducing cancer risk by combin- pathogenesis limit our ability to accurately predict
ing acid suppression with an additional chemopre- who harbors this cancer precursor and who will
vention drug in patients with BE has been consid- progress to EAC. There are medical, endoscopic,
ered. Most available reports suggest that aspirin and and surgical treatments that may reduce cancer risk,
other nonsteroidal anti-inflammatory drugs pro- but the appropriate use of these interventions will
tect against the development of cancer in patients require additional data about their long-term effec-
with BE, but definitive studies are still lacking. The tiveness, safety, and costs compared with the natural
AspECT study (Clin Trials.gov 2006) is studying the history of BE.
effect of aspirin and PPIs alone and in combination
in patients with BE to prevent dysplasia progres- Competing interests
sion. At this time, we believe that it is appropriate The authors declare no competing interests.
to consider the prescription of low-dose aspirin for
patients with BE who also have risk factors for car-
diovascular disease but the best guidance will come
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