J Gastroenterol

https://doi.org/10.1007/s00535-018-1491-x

REVIEW

Endoscopic diagnosis and treatment of esophageal

adenocarcinoma: introduction of Japan Esophageal Society
classification of Barrett’s esophagus
Ryu Ishihara1 • Kenichi Goda2 • Tsuneo Oyama3

Received: 15 May 2018 / Accepted: 27 June 2018

Ó The Author(s) 2018

Abstract Endoscopic surveillance of Barrett’s esophagus evaluated based on the histology of the resected specimen.
has become a foundation of the management of esophageal European guidelines describe endoscopic resection as
adenocarcinoma (EAC). Surveillance for Barrett’s esoph- curative for well- or moderately differentiated mucosal
agus commonly involves periodic upper endoscopy with cancers without lymphovascular invasion, and these crite-
biopsies of suspicious areas and random four-quadrant ria might be extended to lesions invading the submucosa
biopsies. However, targeted biopsies using narrow-band (B 500 lm), i.e., to low-risk, well- or moderately differ-
imaging can detect more dysplastic areas and thus reduce entiated tumors without lymphovascular involvement,
the number of biopsies required. Several specific mucosal and \ 3 cm. These criteria were confirmed by a recent
and vascular patterns characteristic of Barrett’s esophagus study in Japan.
have been described, but the proposed criteria are complex
and diverse. Simpler classifications have recently been Keywords Endoscopic diagnosis
Endoscopic treatment

developed focusing on the differentiation between dys- Esophageal adenocarcinoma
Barrett’s esophagus
plasia and non-dysplasia. These include the Japan Eso-
phageal Society classification, which defines regular and
irregular patterns in terms of mucosal and vascular shapes. Introduction
Cancer invasion depth is diagnosed by endoscopic ultra-
sonography (EUS); however, a meta-analysis of EUS Esophageal adenocarcinoma (EAC) is an aggressive dis-
staging of superficial EAC showed favorable pooled values ease with an increasing incidence in the Western world
for mucosal cancer staging, but unsatisfactory diagnostic [1–3]. Although no equivalent data are available for East-
results for EAC at the esophagogastric junction. Endo- ern countries, the rate of EAC is expected to increase in
scopic resection has recently been suggested as a more Asia because of the decreasing prevalence of Helicobacter
accurate staging modality for superficial gastrointestinal pylori infection and Westernization of the diet [4, 5].
cancers than EUS. Following endoscopic resection for Survival of patients with EAC correlates with disease
gastrointestinal cancers, the risk of metastasis can be stage, with a 5-year-survival rate of about 20% in patients
with locally advanced disease [6]. The poor survival of
patients with advanced EAC indicates the need for its early
& Ryu Ishihara detection [7, 8]. Endoscopic surveillance of Barrett’s
[email protected] esophagus (BE) has become a foundation of the manage-
1
Department of Gastrointestinal Oncology, Osaka
ment of EAC, especially in Western countries [9–11], and
International Cancer Institute, 1-69 Otemae 3-chome, Chuo- this trend has accelerated in line with recent developments
ku, Osaka 541-8567, Japan in advanced imaging and endoscopic resection
2
Digestive Disease Centre, Showa University, Koto-Toyosu technologies.
Hospital, Tokyo, Japan
3
Department of Endoscopy, Saku Central Hospital Advanced
Care Center, Saku, Japan

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Surveillance and classification of lesions in patients vascular patterns are described as either regular or irregular
with BE (Table 2), based on detailed definitions of regular and
irregular in terms of mucosal and vascular shape or
Surveillance for EAC in patients with BE commonly arrangement (Figs. 1, 2) (Table 3), thus making the find-
involves periodic upper endoscopy, with biopsies of sus- ings easy to interpret. This classification also includes a flat
picious areas and random four-quadrant biopsies [12]. pattern (Fig. 3) as a regular pattern corresponding to non-
However, this biopsy protocol is time consuming, carries a dysplastic histology [30]. A validation study conducted by
risk of sampling error, and is hampered by low patient 10 endoscopic image reviewers using 156 still images
compliance [13]. New endoscopic techniques have, there- showed promising accuracy and inter-observer agreement
fore, been developed to improve the recognition of spe- (Table 1).
cialized intestinal metaplasia (SIM), dysplasia, and cancer,
by enhancing mucosal morphology. The most widely used
such modality is narrow-band imaging (NBI) [14], and Diagnosis of cancer invasion depth
targeted biopsies sampled by this method allowed the
detection of more dysplastic areas, therefore, reducing the Correct preoperative staging is crucial, given that the
number of biopsies required [15]. patient’s treatment strategy is determined largely on the
Several groups have described specific mucosal and basis of cancer invasion depth. Non-magnified endoscopy
vascular patterns characteristic for the diagnosis of lesions is the primary modality for diagnosing gastrointestinal
in BE using NBI [16–22]. These classification systems cancer, and is also helpful for diagnosing cancer invasion
suggested that irregular mucosal pattern and vessels are depth. Correlations between endoscopic macroscopic type
predictive of dysplasia, while a ridged/villous pattern is and invasion depth of superficial EAC have been reported
predictive of SIM; however, despite promising initial [31, 32], and previous studies showed that non-magnified
findings, subsequent validation studies of these classifica- endoscopy could accurately diagnose invasion depth in
tion systems have reported unfavorable results [23–27]. gastrointestinal cancers [33–36]. One study found that the
Furthermore, the proposed criteria were complex and overall correct diagnostic assessment of early esophageal
diverse, thus limiting their use in daily clinical practice, cancers was high using either non-magnified endoscopy or
with the complexity associated with the concept of differ- endoscopic ultrasonography (EUS) with a 20-MHz mini-
entiating between SIM and non-SIM and between dysplasia probe, with no significant differences between the two
and non-dysplasia within the same classification. techniques (Table 4) [37]. Although its relative simplicity
Simpler classifications have recently been developed means that non-magnified endoscopy may be a good
focusing on differentiating between dysplasia and non- modality for diagnosing EAC invasion depth, the diagnosis
dysplasia, with the aim of improving the clinical utility of is subjective, and more objective criteria are, therefore,
the classification [28, 29]. The new classifications classify needed.
most mucosal or vascular descriptors as ‘‘regular’’ for non- EUS can also be used to diagnose cancer invasion depth.
dysplastic and ‘‘irregular’’ for dysplastic BE (Table 1). Conventional EUS (7.5 MHz) can differentiate between
These simple descriptors make the classifications easy to advanced T3/T4 carcinomas and T1/T2 carcinomas in
apply in clinical practice, with acceptable sensitivity, more than 80% of cases; however, accurate differentiation
specificity, and inter-observer agreement for the diagnosis between mucosal and submucosal (SM) invasion is difficult
of dysplasia in BE (Table 1). [38–41]. However, EUS using a mini-probe (20 MHz)
These new classifications include the Japan Esophageal enables the esophageal wall to be imaged in nine layers,
Society classification of BE [29], in which the mucosal and thus permitting the muscularis mucosa to be seen in greater

Table 1 New endoscopic BING classification JES classification for Barrett’s esophagus
classifications for the diagnosis
of lesions in patients with Non-dysplasia Mucosal pattern: regular Mucosal pattern: regular
Barrett’s esophagus
Vascular pattern: regular Vascular pattern: regular flat pattern
Dysplasia Mucosal pattern: absent or irregular Mucosal pattern: irregular
Vascular pattern: irregular Vascular pattern: irregular
Diagnostic accuracy Sensitivity 80% Sensitivity 87%
Specificity 88% Specificity 97%
Reproducibility j = 0.68 j = 0.77
BING Barrett’s International NBI Group, JES Japan Esophageal Society

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Table 2 Japan Esophageal Society classification of Barrett’s distinguish between mucosal and SM cancers, thereby
esophagus improving staging accuracy.
Pattern Visibility Morphologic features Regularity A previous meta-analyses of EUS staging of superficial
esophageal cancers showed favorable pooled values for
Mucosal Visible Pit Regular or irregular
mucosal cancer staging, with a sensitivity of 0.85 [95%
Non-pit confidence interval (CI) 0.82–0.88], specificity of 0.87
Invisiblea (95% CI 0.84–0.90), positive likelihood ratio of 6.62
Vascular Visible Net Regular or irregular (95%CI 3.6–12.12), and negative likelihood ratio of 0.20
Non-netb (95%CI 0.14–0.30). The equivalent values for SM cancer
Invisible staging were 0.86 for sensitivity (95%CI 0.82–0.89), 0.86
a
Including a flat pattern for specificity (95%CI 0.83–0.89), 5.13 for positive like-
b
Including normal-appearing long branching vessels and thick lihood ratio (95%CI 3.36–7.82), and 0.17 for negative
greenish vessels suggestive of a flat pattern likelihood ratio (95%CI 0.09–0.30) [42].
However, when the results were limited to the diagnosis
of EAC, the performance of EUS was not satisfactory
(Table 5) [43–46] compared with its ability to diagnose
esophageal squamous cell carcinoma and gastric cancer.
Meta-analyses of the diagnostic accuracy of EUS for
mucosal or SM micro-invasive esophageal squamous cell
carcinoma showed a sensitivity of 0.87 (95%CI 0.81–0.92),
specificity 0.94 (95%CI 0.88–0.98), positive likelihood
ratio 11.6 (95%CI 5.4–24.7), and negative likelihood ratio
0.15 (95%CI 0.10–0.23) [47], with equivalent results for
mucosal gastric cancer of sensitivity 0.87 (95%CI
0.81–0.92), specificity 0.75 (95%CI 0.62–0.84), positive
likelihood ratio 3.4 (95%CI 2.3–5.0), and negative likeli-
hood ratio 0.17 (95%CI 0.12–0.24) [48].
The poor diagnostic yield was probably caused by dif-
ficulties in diagnosing EAC in the distal part of the
esophagus, given that the diagnostic accuracy for EAC in
the distal part of the esophagus was significantly worse
Fig. 1 Barrett’s esophageal cancer showing irregular vascular pat- than that for EAC in the mid- and proximal parts of the
tern (net type)
esophagus (Table 6) [37, 49]. This emphasizes the fact that
it is particularly difficult to achieve adequate water
preparation in the distal esophagus by instilling fluid
through the endoscopic channel, in addition to substantial
motility that prevents dilatation of the distal esophagus
from being maintained for longer periods.

Endoscopic resection

Endoscopic resection has recently been suggested as a

staging modality for superficial gastrointestinal cancers,
based on the limited accuracies of EUS and non-magnified
endoscopy. Endoscopic resection, in the form of endo-
scopic mucosal resection (EMR) and endoscopic submu-
cosal dissection (ESD), allows for removal of visible
lesions and histologic assessment of the resected tissue,
Fig. 2 Barrett’s esophageal cancer showing irregular mucosal pat-
tern (non-pit type)
thus facilitating accurate diagnostic staging of the disease
(Figs. 4, 5, 6, 7) [50, 51].
detail. Mini-probe EUS can, therefore, be used to The various modalities of EMR include the use of a
transparent cap, two-channel endoscope, and ligation.

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Table 3 Definition of regularity in Japan Esophageal Society classification of Barrett’s esophagus

Pattern Regular Irregular

Mucosal
Form/size Similar Various
Arrangement Regular Irregular
Density Low or same as surrounding area High
White zone Clearly visible and/or with homogeneous width Obscure/invisible or heterogeneous width
Vascular
Form Similar or bending and branching gently or regularly Various or bending and branching steeply
or irregularly
Caliber Gradual Abrupt
change
Location Between or in mucosal patterns Beyond of regardless of mucosal patterns
Flat pattern Completely flat surface without a clear demarcation line. Greenish thick vessels
and/or long branching vessels

fragments, and histologic evaluation of several specimens

does not allow the outer margins of the neoplastic area to
be identified, and complete resection, therefore, cannot be
confirmed. In addition, piecemeal resection of early neo-
plasia in BE is associated with a high local recurrence rate,
probably because of small remnants of neoplastic tissue left
in situ [52–55]. ESD provides larger specimens than EMR,
thus allowing more precise histological analysis and higher
en bloc and curative resection rates, and potentially
reducing the incidence of recurrence. A recent meta-anal-
ysis of non-randomized studies showed that ESD of early
gastrointestinal tumors was superior to EMR in terms of en
bloc and curative resection rates, but was more time con-
suming and associated with higher rates of bleeding and
perforation [56].
Several studies have reported on the use of ESD for
EAC and esophagogastric junction cancer [57–66]. In
Fig. 3 Flat-type mucosa: completely flat surface without a clear general, ESD is associated with favorable outcomes with
demarcation line and greenish thick vessels acceptable en bloc resection and complication rates.
However, the curative resection rate, defined as en bloc
However, these modalities are limited with respect to resection with cancer-free margins and minimal risk of
resection size, and large lesions must be resected in several metastasis, limited to EAC at the esophagogastric junction,
fragments. Histological assessment of cancer invasion was significantly lower than those for cardia and non-
depth can be inaccurate if lesions are resected in small

Table 4 Diagnostic performances of non-magnified endoscopy and endoscopic ultrasonography for superficial esophageal adenocarcinoma
(sensitivity and specificity for mucosal cancer)
Author Country/year/sample size Modality Sensitivity Specificity Accuracy

May A [37] Germany/2004/93 Non-magnified endoscopy 94 56 83

EUS 91 48 79
EUS endoscopic ultrasonography

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Table 5 Diagnostic Author Country/year Sample size Sensitivity Specificity Accuracy

performance of endoscopic
ultrasonography for superficial Thomas T [43] UK/2010 46 94 67 85
esophageal adenocarcinoma
Fernández-Sordo JO [44] USA/2012 109 84 50 83
(sensitivity and specificity for
mucosal cancer) Bergeron EJ [45] USA/2014 107 72 49 64
Dhupar R [46] USA/2015 130 59 69 64

Table 6 Diagnostic performance of endoscopic ultrasonography for superficial esophageal adenocarcinoma (sensitivity and specificity for
mucosal cancer) with regard to imaging modality and lesion location
Author Country/year/sample size Modality Location Sensitivity Specificity Accuracy

May A [37] Germany/2004/93 Non-magnified endoscopy Distal 92 43 78

Mid to proximal 97 91 95
EUS Distal 89 14 69
Mid to proximal 94 91 93
Chemaly M [49] France/2008/91 EUS Distal Not described Not described 48
Mid to proximal Not described Not described 87
EUS endoscopic ultrasonography

Fig. 4 IIa type esophagogastric junctional cancer Fig. 5 IIa type esophagogastric junctional cancer with indigo
carmine staining

cardia gastric cancers (Table 7) [57, 66]. One cause of Risk of metastasis
incomplete resection of esophagogastric junction EAC was
positive lateral margins caused by sub-epithelial progres- The risk of metastasis after endoscopic resection for gas-
sion of the tumor proximally, which were hard to recognize trointestinal cancers is evaluated based on histologic find-
before treatment, while the low accuracy of diagnosing ings of the resected specimen. Studies of esophagectomy
cancer invasion depth before treatment and high lympho- specimens have indicated a low risk of 0.0–1.3% for
vascular involvement, confirmed in resected specimens, mucosal EAC [67–69], thus providing the rationale for
were also contributory factors. endoscopic treatment of mucosal EAC with curative intent.
The frequency of metastasis in EAC is known to
increase with increasing depth of tumor invasion into the
SM [70–72]. SM1 cancer, i.e., cancer invading the shallow

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Fig. 6 Histology of resected

specimen showed deep
muscularis mucosa invasion of
cancer. SMM superficial
muscularis mucosa, LPM
lamina propria, DMM deep
muscularis mucosa

the rate of metastasis is stratified by pathologic findings,

SM1 cancers without risk factors such as lymphovascular
involvement and a poorly differentiated component have
very low rates [76–78]. Some studies [79, 80] have
accordingly suggested that a subgroup of SM cancers could
be adequately treated by endoscopic resection.
European guidelines [80] indicate that endoscopic
resection appears to be curative for well- or moderately
differentiated mucosal cancers without lymphatic or vas-
cular invasion, and that these criteria might be extended to
lesions with invasion into the SM (B 500 lm), namely to
low-risk tumors (well or moderately differentiated, without
lymphovascular involvement, \ 3 cm) (Table 8). A recent
study in Japan [81] validated these criteria, showing no
metastases (0/186 lesions) in patients with mucosal cancer
without lymphovascular involvement and a poorly differ-
Fig. 7 Mapping of the cancer. SMM superficial muscularis mucosa,
LPM lamina propria, DMM deep muscularis mucosa, MM muscularis entiated component, or in patients with SM cancer
mucosa (B 500 lm) without lymphovascular involvement, a
poorly differentiated component, and B 30 mm (0/32
part of the SM, remains the most controversial, with some lesions).
studies reporting a relevant incidence of lymph node
metastasis even in SM1 cancers [73–75]. However, when

Table 7 Outcomes of Author Location Complete resectiona Curative resectionb

endoscopic submucosal
dissection for esophagogastric Osumi H [66] Esophagus 100% (55/55) 62% (34/55)
junctional cancer with regard to
Cardia 100% (87/87) 82% (71/87)
location
Hoteya S [57] Esophagus 64% (16/25) 48% (12/25)
Cardia 96% (99/103) 81% (83/103)
a
Complete resection: en bloc resection with cancer-free margins
b
Curative resection: complete resection with low risk of metastasis

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Table 8 Assessment of metastasis risk based on histology of endoscopically resected specimen

European guideline [80] Curative for Curative criteria might be extended to
Mucosal cancer Submucosal cancer (B 500 lm)
Well or moderately differentiated Well or moderately differentiated
Lymphovascular involvement(-) Lymphovascular involvement(-)
Tumor size \ 3 cm
Report from Japan Ishihara R [81] Very low risk (no metastasis in 186 cancers) Low risk (no metastasis in 32 cancers)
Mucosal cancer Submucosal cancer (B 500 lm)
Poorly differentiated component (-) Poorly differentiated component (-)
Lymphovascular involvement (-) Lymphovascular involvement (-)
Tumor size B 3 cm

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