Expert Review of Gastroenterology & Hepatology

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Risk of lymph node metastasis in submucosal

esophageal cancer: a review of surgically resected
patients

Ines Gockel, George Sgourakis, Orestis Lyros, Ursula Polotzek, Carl Christoph
Schimanski, Hauke Lang, Toshitaka Hoppo & Blair A Jobe

To cite this article: Ines Gockel, George Sgourakis, Orestis Lyros, Ursula Polotzek, Carl
Christoph Schimanski, Hauke Lang, Toshitaka Hoppo & Blair A Jobe (2011) Risk of lymph node
metastasis in submucosal esophageal cancer: a review of surgically resected patients, Expert
Review of Gastroenterology & Hepatology, 5:3, 371-384, DOI: 10.1586/egh.11.33

To link to this article: https://doi.org/10.1586/egh.11.33

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Risk of lymph node metastasis

in submucosal esophageal
cancer: a review of surgically
resected patients
Expert Rev. Gastroenterol. Hepatol. 5(3), 371–384 (2011)

Ines Gockel†1,
George Sgourakis1,2,
Orestis Lyros1,
Ursula Polotzek1,
Carl Christoph
Schimanski1,
Hauke Lang1,
Toshitaka Hoppo3
and Blair A Jobe3
1
Johannes Gutenberg-University of
Mainz, Mainz, Germany
2
Red Cross Hospital, Athens, Greece
3
The Heart, Lung and Esophageal
Surgery Institute, University of
Pittsburgh Medical Center, PA, USA
†
Author for correspondence:
Department of General and
Abdominal Surgery, Johannes
Gutenberg-University,
Langenbeckstr. 1, 55131 Mainz,
Germany
Tel.: +49 613 117 7291
Fax: +49 613 117 6630
gockel@ach.klinik.uni-mainz.de
Objectives: Endoscopic local procedures are increasingly applied in patients with superficial
esophageal cancer as an alternative to radical oncologic resection. The objective of this article
is to determine the risk of nodal metastases in submucosal (sm) esophageal cancer, comparing
the two predominating histologic tumor types, squamous cell cancer (SCC) and adenocarcinoma
(ADC). Methods: A query of PubMed, MEDLINE, Embase and Cochrane Library (1980–2009)
using predetermined search terms revealed 675 abstracts, of which 485 full-text articles were
reviewed. A total of 105 articles met the selection criteria. A review of article references and
consultation with experts revealed additional articles for inclusion. Studies that enrolled patients
with submucosal esophageal cancer and provided adequate extractable data were included.
Results: The pooled outcomes of 7645 patients with esophageal cancer involving the sm level
of infiltration were included in the ana­lysis. Overall, the percentage of lymph node metastasis
in submucosal cancer was 37%. Lymph node (N), lymphatic (L) and vascular (V) invasion in
sm1 esophageal cancers was 27, 46 and 22%, respectively. Within sm2 lesions, N, L and V
invasion were involved in 38, 63 and 38% of patients, respectively. Finally, N, L and V
involvement in patients with sm3 lesions was 54, 69 and 47%, respectively. The rates of lymph
node metastasis for sm1 and sm2 were higher in SCC compared with ADC, whereas the lymph
node metastasis for sm3 was comparable, with >50% involvement in both histologic subtypes.
SCC revealed an overall more aggressive behavior compared with ADC (N+: 45 vs 26%; L+: 57
vs 37%; V+: 40 vs 18%). Discussion: While endoscopic therapy may be adequate in selected
patients with ‘low-risk’ sm1 ADC, submucosal SCC necessitates esophageal resection and
systematic lymphadenectomy because of its aggressive nature and tendency for early metastasis.
Keywords : risk of lymph node metastasis • sm1 • sm2 • sm3 • submucosal depth of tumor infiltration
• submucosal esophageal cancer • surgically resected specimens

Although endoscopic submucosal dissection Endoscopic resection has been demonstrated

(ESD) techniques are increasingly applied in
submucosal esophageal cancer [1–3] , the gold
standard is still esophagectomy. The extent of
lymph node involvement can only be determined
by a histologic examination of the surgical speci-
men following systematic lympha­denectomy.
Although the mortality rate after esophagectomy
has significantly decreased, there remains a con-
siderable morbidity rate associated with this pro-
cedure [4] . The effectiveness of endoscopic resec-
tion of submucosal esophageal cancer in view
of the increasing rate of lymph node involve-
ment after penetration through the muscularis
mucosae has not been determined in prospective
studies with long-term follow-up [5–9] .
to be feasible, yielding favorable results with
minimal associated morbidity and mortality in
cases of Barrett’s carcinoma with ‘low-risk’ sub-
mucosal invasion [10] . In addition, studies from
surgical specimens in adenocarcinoma (ADC)
demonstrated nearly absent nodal involvement
in patients with sm1 level of infiltration [11,12] .
Conversely, studies from specimens of super­ficial
squamous cell cancer (SCC) demonstrated a rela-
tively high rate of lymph node metastasis, even in
mucosa-type m3 depth of infiltration – ranging
from 8 to 23% [13–15] . Although local procedures
for submucosal SCC do not seem to be oncologi-
cally justifiable, pooled analyses of larger series
are not available in the current literature.

www.expert-reviews.com 10.1586/EGH.11.33 © 2011 Expert Reviews Ltd ISSN 1747-4124 371

 Review Gockel, Sgourakis, Lyros et al.
Potentially relevant studies identified and screened
for retrieval (n = 675)
Studies retrieved for more detailed evaluation (n = 485)
Potentially appropriate studies to be included in the
review (n = 351)
Studies included in the review (n = 120)
Studies with usable information, by outcome (n = 105)
Studies only included for descriptive statistics (n = 105)
Studies included for the review process (n = 46)
Figure 1. Progress through the stages of the review process.
Thus, risk assessment of nodal metastases including histologic
criteria may allow for curative treatment strategies with less inva-
sive approaches. The aim of this article is to determine the risk
of lymph node metastases in submucosal esophageal carcinoma
by an extensive review and assimilation of the literature and
­stratifying results for ADC and SCC.
Methods
Literature search
All studies concerning resected superficial esophageal cancer
were identified [5–14,16–120] . In order to select appropriate stud-
ies, the electronic databases, including MEDLINE, Embase,
PubMed and the Cochrane Library, were used to search for arti-
cles from 1980 to 2009 in the English language literature that
included the following terms and/or combinations in their titles,
abstracts or keyword lists: early esophageal cancer, esophageal
dysplasia, high-grade dysplasia, low-grade dysplasia, Barrett’s
esophagus, superficial esophageal cancer, mucosal esophageal
cancer, submucosal esophageal cancer, intramucosal/submucosal
carcinoma of the esophagus, esophageal adenocarcinoma, ADC,
esophageal squamous cell carcinoma, SCC, T1a, T1b, T1m and
T1sm. Where it was applicable, the aforementioned terms were
used in ‘[MESH]’ (PubMed and the Cochrane Library), other-
wise the terms were combined with ‘AND/OR’ and asterisks. In
372
Studies excluded (n = 190)
Non-English literature (n = 156)
Animal studies (n = 34)
Studies excluded (n = 134)
Reviews (n = 58)
Case reports (n = 76)
Studies excluded (n = 231)
Not submucosal cancer, neoadjuvant therapy included,
only lymph node negatives included, submucosal
invasion without lymph node involvement mentioned,
benign submucosal tumors, other therapy, lymph node
prediction not the primary end point
Studies withdrawn (n = 15)
Duplicate publications (n = 15)
Studies withdrawn (n = 59)
Data for prediction variables not
included (n = 59)
addition, the abstracts from national and international confer-
ences were searched using online search engines corresponding
to the particular conference.
After the initial screening of abstracts, additional criteria were
imposed and full-length manuscripts were obtained. The addi-
tional criteria were as follows: information from the pathology
reports after esophagectomy with curative intent; studies admin-
istering neoadjuvant treatment were excluded; studies including
patients with esophagogastric junction (only adenocarcinoma of
the esophagogastric junction [AEG] type Siewert I) carcinoma
were eligible for ana­lysis; studies including patients with distant
metastasis were excluded.
If necessary, the corresponding authors were contacted to obtain
supplementary information. The reference lists of full-length articles
were also reviewed to find additional candidate studies. Experts
were asked to list any additional articles that met the inclusion cri-
teria. If a cohort or case series from a group appeared to be published
more than once with significant temporal overlap, only the report
that included the largest number of patients was used in the ana­lysis.
Data extraction
Two authors (Ines Gockel and George Sgourakis) independently
selected studies for inclusion and exclusion and reached consensus
when they did not agree in the initial assignment. The following
Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)
 Lymph node metastasis in submucosal esophageal cancer Review

variables concerning studies addressing superficial esophageal mentioned, or other reasons (Figure 1) . In order to draw infer-
cancer were recorded: authors, journal and year of publication, ences about tumor biology and metastatic behavior between the
country of origin, trial duration, participant demographics, his- two predominating histologic types of esophageal cancer (SCC
topathological parameters (histological type, tumor diameter, and ADC), 46 [5,11–13,17–20,25,28,32,36,40,44,47,53–55,58,63,65,67,70–
tumor location, pattern of growth, degree of differentiation, depth 74,76,77,80,86,87,91,93,95,98,105,106,110,111,113,118,120] of 105 studies pro-
of tumor invasion, necrosis, ulceration, vascular invasion, neural vided sufficient data and were selected for this portion of the ana­
invasion and lymphatic infiltration) and lymph node status. In lysis. The Maxwell test statistic was not significant (p = 0.852),
the majority of studies, histologic grade was not provided for indicating that the raters did not disagree significantly. The gener-
each separate sm (1–3) category, but instead provided collectively. alized McNemar statistic (p = 0.56) indicated that the agreement
Studies providing data separately for SCC and ADC were ana- was spread evenly.
lyzed as two different data sets.
Determinants of lymph node metastasis
Definitions The overall percentage of lymph node metastasis in submucosal
Submucosal lesions were classified as sm1 for tumors invading the cancer was 37%. Lymph node (N), lymphatic (L) and vascular
superficial layer of the submucosa (corresponding to a third of (V) invasion in sm1 esophageal cancers were 27, 46 and 20%,
its thickness), sm2 for those invading the middle third and sm3 respectively. In patients with sm2 lesions, N+, L+ and V+ rates
for those invading the deeper submucosal layer. The assessment were 38, 63 and 38%, respectively. Finally, when sm3 depth
of depth of infiltration into the submucosal layer was based on lesions were present, N+, L+ and V+ rates were 54, 69 and 47%,
the guidelines for clinical and pathologic studies for carcinomas respectively (Table 1) . The percentage of patients with lymph node
of the esophagus according to the Japanese Society for Esophageal metastasis paralleled an increase in the percentage of lymphatic
Diseases [121] . and vascular invasion, and the depth of submucosal invasion. The
numbers of patients with good, moderate and poor histologic
Data ana­lysis differentiation were 267, 752 and 582, respectively. However,
In order to quantify the level of agreement between reviewers, the aforementioned data were not provided in relation to tumor
the Maxwell test statistic and the generalized McNemar statistic depth of infiltration and lymph node status. Therefore, the his-
were calculated. Pooled data were assimilated in absolute numbers tologic grade could not be evaluated as a possible predictor of
and percentages. lymph node metastasis. Concerning the remaining histologic
In an attempt to determine whether histologic characteris- parameters, such as intramural metastasis, macroscopic tumor
tics of aggressiveness could serve as a predictor of nodal status view and tumor size, the data among studies were sparse and
in the face of submucosal involvement, the incidence of two heterogeneously presented, and thus precluded us from drawing
histologic findings (lymphatic infiltration [L+] and vascular meaningful conclusions.
invasion [V+]), were compared with the
incidence of lymph node positivity (N+) Table 1. Numbers of patients with positive and negative lymph node
in this pooled ana­lysis. The ratios of these status, lymphatic and vascular invasion according to the depth of
findings (L+:N+ and V+:N+) among the tumor invasion based on 105 studies.
three submucosal layers (sm1, sm2 and Node status sm1 (n = 663) sm2 (n = 942) sm3 (n = 1493)
sm3) were examined as a ‘litmus’ of this (n = 7645)
possible relationship. We postulated that N- N+ N- N+ N- N+ N- N+
the prevalence of L+ or V+ would increase
4825 2820 481 148 583 303 692 699
in parallel with nodal positivity, and that
(63%) (37%) (73%) (27%) (62%) (38%) (46%) (54%)
this could potentially be used as a predic-
tor of nodal status when considering an Lymphovascular sm1 (n = 195) sm2 (n = 182) sm3 (n = 275)
endoscopic therapy. invasion (n = 1593)
L- L+ L- L+ L- L+ L- L+
Results 741 852 105 90 68 114 85 190
In total, 105 of 675 screened studies were (47%) (53%) (54%) (46%) (37%) (63%) (31%) (69%)
included [5,7,8,10–14,16–30,32,34–44,46–51,53–
Microvascular sm1 (n = 110) sm2 (n = 204) sm3 (n = 264)
56,58–78,80–89,91–95,97,98,100–112 ,114,118,120] ,
invasion (n = 1580)
representing a total of 7645 cases. The
main reasons for exclusion were: case V- V+ V- V+ V- V+ V- V+
reports, non-English literature, animal 951 629 88 22 126 78 139 125
studies, reviews, duplicate publications, (60%) (40%) (80%) (20%) (62%) (38%) (53%) (47%)
absent submucosal invasion, studies exclu- Submucosal cancers (105 studies and 7645 participants).
The last six columns present the data of studies that provide patients’ histologic information with regard to
sively addressing patients with submucosal the sm level.
invasion without lymph node metastasis L: Lymphatic; N: Lymph node; sm: Submucosal; V: Vascular.

www.expert-reviews.com 373
 Review Gockel, Sgourakis, Lyros et al.

Of the studies that performed multivariate ana­lysis, factors

[13]

[80]
Vascular Ref.

[91]

[5]

[19]

[53]

[105]

[70]

[11]

[85]

[42]

[113]
such as perineural invasion [19] , tumor size [53,91,113] , intra­
mural metastasis [91] , macroscopic tumor view [53,91,105] , extent
invasion

of Barrett’s esophagus (short and long segment) [17] , vascular

0.037
invasion [113] and hyperlipidemia [80] were considered predictors
of lymph node metastasis. In total, 12 of 105 studies analyzed
the potential predictor of lymph node positivity in multivariate
†
0.02
p53

ana­lysis (Table 2) .

Biological markers & lymph node metastasis

lipidemia

The following molecular markers were considered as potential

Hyper-

0.001
predictors of lymph node metastasis: D2–40 immunostain-
ing [18,105,113] ; E-cadherin [27,93] ; monoclonal antibody MIB-1
for the Ki-67 antigen [28] ; flow cytometric DNA ana­lysis [43,76] ;
amplification of int-2 and c-erbB [47] ; p53 status and Ki-67
0.001
ADC
SCC/

labeling index [48] ; signaling molecules, such as VEGF-A and C,

PDGF-A and p53 [49] ; monoclonal anti-epithelial-cell antibody
Table 2. Independent risk factors for lymph node metastasis in patients with submucosal cancer.
Macroscopic

Ber-EP4 [51] and p53 accumulation; cyclin D1 overexpression; and

MIB-1 labeling index [70,93] . All of the these markers except for
p53 status (in one study) were established as significant risk factors
0.001
view

0.06

0.01

for the presence of lymph node metastasis in univariate ana­lysis.

Better defining patients at risk for lymph node

Tumor Intramural
metastasis

metastasis in the face of superficial cancer of

the esophagus
Based on our selection criteria, 46 out of 105 studies represent-
0.02

ing 2831 patients provided detailed information regarding depth

of tumor invasion (sm1, sm2 or sm3), lymphatic invasion, vascu-
0.002

0.002
0.06
size

lar invasion and histologic tumor type (Table 3) . The following is

a synopsis of these findings stratified by histologic tumor type:
Grade

0.05

0.01

Squamous cell cancer

• Cancers with sm3 invasion had a higher rate of lymph node
invasion

metastasis (55%) than cancers with sm1 (27%) and sm2

Depth of tumor Lymphatic Neural

(36%) involvement;
0.03

All p-values are extracted from manuscripts included in the pooled ana­lysis.

• The rate of lymphatic channel invasion increased with increasing

tumor depth (sm 1–3: 52, 65 and 64%, respectively);
invasion

0.009
0.007
0.001

0.001

• The L+:N+ ratio decreased from sm1 to sm3 tumor depths

0.04
0.05
0.03

(sm1: 1.92; sm2: 1.80; sm3: 1.16), suggesting that lymphatic

channel invasion is not a predictor of lymph node metastasis
in SCC;
ADC: Adenocarcinoma; SCC: Squamous cell cancer.

• The V+:N+ ratio remained constant from sm1 to sm3 tumor

invasion

depths (sm1: 0.74; sm2: 1.02; sm3: 0.87), suggesting that

0.002

0.002
0.658

0.001
0.001
0.001
0.05
0.05
Bollschweiler et al. (2006) 0.01

0.01

In endoscopically resected specimens.

vascular invasion may be a predictor of lymph node metastasis

in SCC.
Nakajima et al. (2002)
Shimada et al. (2006)

Adenocarcinoma
Hölscher et al. (1995)
Buskens et al. (2004)
Ancona et al. (2008)

Gockel et al. (2009)

Tomita et al. (2008)
Eguchi et al. (2006)

Sako et al. (2004)

Kim et al. (2008)

Rice et al. (1998)

• ADC patients with sm1 lesions have the lowest incidence of

Study (year)

nodal metastasis;
• As the depth of sm invasion increased, there was an increase
in the rate of nodal metastasis, which was 6% in sm1, 23%
in sm2 and 58% in sm3;
†

374 Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)

 Lymph node metastasis in submucosal esophageal cancer
• The L+:N+ ratio remained constant
Table 3. Numbers of patients with positive lymph nodes, lymphatic
from sm1 to sm3 tumor depths (sm1: 1.5;
and vascular invasion stratified by depth of tumor invasion and
sm2: 1.17; sm3: 1.31), suggesting that
histologic type.
lymphatic channel invasion may be a
predictor of lymph node metastasis sm1
in ADC; SCC ADC
• No vascular invasion was found in sm2 N+
and sm3 patients with ADC. 60/224 4/65
(27%) (6%)
SCC versus ADC L+
• Both histologic entities displayed consid- 58/111 2/23
erable rates of nodal metastasis, espe- (52%) (9%)
cially in the presence of sm2 and sm3 V+
tumor depth; 19/97 1/7
• The rates of nodal metastasis for sm1 and (20%) (14%)
sm2 were higher in SCC compared with ADC: Adenocarcinoma; L: Lymphatic; N: Lymph node; SCC: Squamous cell cancer; sm: Submucosal;
V: Vascular.
ADC, whereas N+ status for sm3 was
similar in both entities (>50%);
• SCC exhibited a higher rate of L+ than ADC in sm1 and sm2,
while the reverse was true for sm3;
• Both histologic types had comparable rates of vascular invasion
in sm1 (20% in SCC and 14% in ADC);
• The percentage of V+ in SCC increased from sm2 to sm3,
whereas no V+ status was observed in sm2 and sm3 in ADC;
• SCC had a more aggressive presentation overall compared with
ADC (N+: 45 vs 26%; L+: 57 vs 37%; V+: 40 vs 18%).
Discussion
Endoscopic therapy has been developed as an esophagus-sparing
method of treatment for patients with high-grade dysplasia and
early esophageal cancer who are felt to be at low risk for lymph
node metastases based on pretreatment staging. The goal of
endoscopic therapy for superficial esophageal cancer is to pro-
vide definitive treatment for patients with low-risk lesions, while
sparing the esophagus and avoiding the morbidity of an esopha-
gectomy. Patients with early esophageal cancer should be coun-
seled that esophagectomy remains the current standard of care
and is the only treatment that definitively removes all neoplastic
esophageal tissue with lymph node basins that can be histologi-
cally assessed. However, for patients with only an early esopha-
geal cancer, endoscopic therapy may be offered as a reasonable
esophagus-sparing treatment in carefully selected, willing patients
or in patients who are poor surgical candidates, although it must
be emphasized that it is not known whether long-term results will
be comparable to surgical outcomes.
To achieve successful endoscopic resection for superficial esoph-
ageal cancer, accurate pretreatment staging is crucial to avoid
endoscopic therapy in patients who have a higher risk of lymph
node involvement. All patients should undergo diagnostic upper
gastrointestinal endoscopy with extensive biopsies. Some authors
advocate the use of enhanced endoscopic imaging, including
www.expert-reviews.com
Review
sm2 sm3
SCC ADC SCC ADC
107/296 10/44 300/544 33/57
(36%) (23%) (55%) (58%)
88/135 4/15 118/184 19/25
(65%) (27%) (64%) (76%)
67/183 0/2 114/239 0/12
(37%) (0%) (48%) (0%)
narrow-band imaging and chromoendoscopy, to adequately detect
all foci of mucosal abnormalities. In addition, several diagnostic
modalities, such as endoscopic ultrasound, staging endoscopic
resection, computed tomography and PET, have been reported,
with variable success for N-status prediction [122–124] . Among
them, a complete staging evaluation should include endoscopic
ultrasound followed by endoscopic resection of visible lesions, with
pathologic ana­lysis guiding the subsequent approach. Therefore,
it is very important to assess the risk of lymph node metastasis
based on the histologic characteristics of resected specimens. In
the context of staging, it is important to remember that endo-
scopic resection specimens tend to have artifactural shrinkage
due to fixation, which may falsify the interpretation [125] . Further
improvements in nodal staging are necessary and may eventually
include sentinel node sampling.
The results of this review highlight several important aspects
of superficial esophageal cancer involving the submucosa: the
rate of lymph node metastasis for sm1 and sm2 were higher in
SCC compared with ADC, but the incidence of lymph node
metastases was comparable in both histologic types in the face
of sm3 involvement; therefore, it will be important to stratify
sm cancer into thirds when considering endoscopic therapy
with esophageal preservation. With respect to endoscopic sub­
mucosal dissection or other local therapies, our findings imply
that positive lymph node rates of 6% (ADC) to 27% (SCC)
can be anticipated in patients with sm1 involvement. This find-
ing stands in contrast to the assumption that sm1 invasion in
the absence of lymphatic/vascular invasion, histological grade
G1/2 and macroscopic type I/II [53,91,105] is ‘low risk’. As nodal
metastasis is the strongest predictor of survival, patients with
sm1 SCC should undergo esophagectomy, if their functional
status is such that they can tolerate the procedure. High percent-
ages of lymph node metastasis were noticed in sm3 invasion in
both entities, thus lending strength to the supposition by some
authors that tumor depth and size >2 cm are the decisive factors
predicting lymph node positivity [53,91,113] . When considering
375
 Review Gockel, Sgourakis, Lyros et al.

Table 4. A total of 46 studies were included in the pooled ana­lysis for the prediction model of lymph
node positivity.
Study (year) SCC/ sm sm1 sm2 sm3 N0 N+ N0 N+ N0 N+ N0 N+ L0 L+ L0
ADC sm sm sm1 sm1 sm2 sm2 sm3 sm3 sm sm sm1
Tomita (2008) SCC 89 11 10 68 38 51 6 5 6 4 26 42 5 32
Kim (2008) SCC 133 36 27 69 94 39 30 6 22 5 41 28 103 30
Amano (2007) SCC 83 10 10 63 36 47 6 4 6 4 24 39 15
Natsugoe SCC 92 21 28 43 50 42 15 6 17 11 18 25 41 51
(2004)
Araki (2002) SCC 58 12 18 28 43 15 11 1 14 4 18 10 46 12 12

Nakajima SCC 84 9 29 46 51 33 9 0 24 5 18 28 24 60
(2002)
Shiozaki SCC 180 21 73 86 88 92 13 8 36 37 39 47 61 119 10
(2002)
Noguchi SCC 38 6 10 22 18 20 5 1 7 3 6 16 9 31 2
(2000)
Chino (1998) SCC 22 5 8 9 11 11 4 1 2 6 5 4 7 17 2
Makuuchi SCC 81 18 25 38 48 33 14 4 14 11 20 18 21 60 5
(1997)
Shima (1994) SCC + 38 6 19 13 25 13 4 2 15 4 6 7
other
Westerterp ADC 66 25 23 18 48 18 25 0 17 6 6 12
(2005)
Buskens ADC 42 16 13 13 30 12 16 0 10 3 4 9 26 16 16
(2004)
Shimada SCC + 123 25 32 66 77 46 17 8 22 10 38 28 32 91 9
(2006) ADC
Bollschweiler SCC 22 3 6 13 11 11 2 1 5 1 4 9
(SCC) (2006)
Bollschweiler ADC 22 9 4 9 13 9 7 2 4 0 2 7
(ADC) (2006)
Ancona (2008) SCC + 71 36 7 28 51 20 33 3 5 2 13 15 28 43 22
ADC
Tachibana SCC + 49 14 16 19 33 16 11 3 12 4 10 9 14 35
(2008) ADC
Higuchi (2007) SCC 15 15 12 3 12 3 1 14 1
Eguchi (2006) SCC 364 32 168 196 15 17 21 11 21
Matsumoto SCC 87 15 26 46 46 41 39 48
(2006)
Kuwano SCC 26 4 3 20 16 10 8 18
(2002)
Watanabe SCC + 78 15 27 36 54 24 61 17
(2000) other
Nakano (1998) SCC + 44 26 18 21 23
other
Nishimaki SCC + 58 34 24
(1993) other
ADC: Adenocarcinoma; L: Lymphatic; N: Lymph node; SCC: Squamous cell cancer; sm: Submucosal; V: Vascular.

376 Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)

 Lymph node metastasis in submucosal esophageal cancer Review

Table 4. A total of 46 studies were included in the pooled ana­lysis for the prediction model of lymph
node positivity (cont.).
L+ L0 L+ L0 L+ V0 V+ V0 V+ V0 V+ V0 V+ Grade I Grade II Grade III Ref.
sm1 sm2 sm2 sm3 sm3 sm sm sm1 sm1 sm2 sm2 sm3 sm3
27 44 18 27 7 [105]

21 94 18 [53]

23 8 10 6 [18]

67 25 19 52 21 [72]

0 14 4 20 8 52 6 12 0 16 2 24 4 [20]

42 42 4 20 9 [70]

11 22 51 29 57 135 45 18 3 55 18 62 24 25 101 54 [93]

4 3 8 4 19 30 10 5 1 10 1 15 8 [74]

5 2 6 3 6 18 6 7 0 6 2 5 4 [28]

13 6 19 10 28 50 31 16 2 16 9 18 20 [65]

14 24 4 2 8 11 2 11 15 8 6 [118]

59 [12]

0 9 4 1 12 1 24 17 [11]

16 10 22 13 53 49 [91]

8 [5]

5 [5]

14 34 [19]

21 28 [98]

14 8 7 8 7 [40]

11 [13]

61 26 [67]

16 10 3 12 6 [58]

71 7 8 45 20 [110]

6 15 6 [71]

26 33 [73]

ADC: Adenocarcinoma; L: Lymphatic; N: Lymph node; SCC: Squamous cell cancer; sm: Submucosal; V: Vascular.

www.expert-reviews.com 377
 Review Gockel, Sgourakis, Lyros et al.

Table 4. A total of 46 studies were included in the pooled ana­lysis for the prediction model of lymph
node positivity (cont.).
Study (year) SCC/ sm sm1 sm2 sm3 N0 N+ N0 N+ N0 N+ N0 N+ L0 L+ L0
ADC sm sm sm1 sm1 sm2 sm2 sm3 sm3 sm sm sm1
Sugimachi SCC + 197 133 64
(1991) other
Goseki (1992) SCC 30 15 15 9 21
Ohno (1991) SCC 16 14 2 10 6
Schmidt SCC 5 3 2 3 3
(1986)
Soga (1982) SCC 4 2 2 1 3
Cen (2008) ADC 51 39 12 31 14
Liu (2005) ADC 37 27 10 22 15
Altorki (2008) SCC + 45 37 8 36 9
ADC
Ikeda (1996) SCC 45 26 19

Tsutsui (1995) SCC 38 30 8

Yoshikane SCC 17 5 12 8 11
(1994)
Scheil-Bertram ADC 21 7 2 12 16 5 6 1 2 0 8 4 12 9 5
(2008)
Kimura (1999) SCC 26 17 9 15 11
Endo (1997) SCC 121 18 48 55 70 51 16 2 33 15 21 34
Ide (1994) SCC 85 59 26 31 54
Paraf (1995) ADC 12 11 1
Kitamura Not 59 46 13
(1993) provided
Rice (1998) ADC 24 19 5
Rice (1998) SCC 3 2 1
Gockel (2009) ADC 15 8 2 5 12 3 7 1 1 1 4 1
Gockel (2009) SCC 15 7 4 4 13 2 6 1 3 1 4 0
ADC: Adenocarcinoma; L: Lymphatic; N: Lymph node; SCC: Squamous cell cancer; sm: Submucosal; V: Vascular.

the completeness and applicability of evidence, only 46 out of
105 of the initially included studies provided satisfactory data
to properly address the issues of lymphatic infiltration, vascular
invasion, tumor grade and histologic type in reference to each
of the three submucosal layers. Making allowances for the qual-
ity of the evidence, the 46 studies included in the ana­lysis had
a total of 2831 patients with good methodological quality. The
level of evidence is ‘4’, and the grade of recommendation is ‘C’
according to the Oxford Centre for Evidence-Based Medicine
levels of evidence [201] .
Expert commentary
The results of our pooled ana­lysis could be employed to assist
decision-making with regard to risk categories of patients
considered to undergo endoscopic submucosal dissection ver-
sus limited surgical procedures (Merendino’s procedure), ver-
sus transhiatal versus transthoracic esophagectomy, and, in
some instances, two-field versus three-field lymphadenectomy.
According to the current evidence, submucosal (T1b) esophageal
cancer should be managed by oncologically adequate surgical
resection and systematic lymphadenectomy. Whereas endoscopic
therapy may be justified for sm1 ADC in selected ‘low-risk’ situ-
ations, submucosal SCC necessitates radical oncologic surgery
based on its more aggressive tendency for metastatic spread.
Owing to large variabilities of the reported mortality following
esophagectomy in the literature, surgery should be performed in
specialized centers after careful evaluation of each individual case
in interdisciplinary expert meetings.

378 Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)

 Lymph node metastasis in submucosal esophageal cancer Review

Table 4. A total of 46 studies were included in the pooled ana­lysis for the prediction model of lymph
node positivity (cont.).
L+ L0 L+ L0 L+ V0 V+ V0 V+ V0 V+ V0 V+ Grade I Grade II Grade III Ref.
sm1 sm2 sm2 sm3 sm3 sm sm sm1 sm1 sm2 sm2 sm3 sm3
83 114 30 89 51 [120]

8 22 9 12 8 [36]

12 4 10 5 [76]

[87]

1 2 [95]

3 28 20 [25]

4 13 0 [63]

[17]

22 23 [47]

21 17 [106]

15 4 5 12 1 [111]

2 2 0 5 7 20 1 6 1 2 0 12 0 4 5 12 [86]

21 5 [54]

26 95 12 6 13 35 1 54 [32]

62 23 [44]

7 5 [77]

43 16 9 28 22 [55]

63 109 123 [80]

5 37 13 [80]

[113]

[113]

ADC: Adenocarcinoma; L: Lymphatic; N: Lymph node; SCC: Squamous cell cancer; sm: Submucosal; V: Vascular.

Five-year view with long-term results comparable to the established surgical

Diagnosis and treatment of submucosal esophageal cancer will
remain an important challenge in the future. The need for
a more accurate staging of this entity and a more thorough
understanding of factors enhancing pathways of lymph node
metastasis are pressing, as is the demand for a molecular-level
explanation of risk factors. Further improvements in nodal stag-
ing with better imaging devices and predictive markers will play
a decisive role in view of decision-making processes between
endoscopic versus surgical resections and consecutive treatment
algorithms. Future prospective randomized studies will have to
prove whether patients diagnosed with submucosal (T1b) esoph-
ageal cancer will be oncologically adequately treated by endo-
scopic resection or less-invasive and limited surgical procedures
data. Administration of neoadjuvant therapy may be discussed
in cases of sm3 depth of infiltration and vascular invasion in
future trials.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
This manuscript contains parts of the doctoral MD thesis of Ursula
Polotzek.
No writing assistance was utilized in the production of this manuscript.

www.expert-reviews.com 379
 Review Gockel, Sgourakis, Lyros et al.
Key issues
• In our review, the percentage of lymph node metastasis in submucosal cancer was 37% in surgically resected specimens.
• Lymph node (N), lymphatic (L) and vascular (V) involvement in patients with sm3 lesions was 54, 69 and 47%, respectively, regarding
both histologic entities.
• Submucosal squamous cell cancer (SCC) had an overall more aggressive presentation, compared with adenocarcinoma (ADC; N+: 45 vs
26%; L+: 57 vs 37%; V+: 40 vs 18%).
• The rates of nodal metastasis for sm1 and sm2 were higher in SCC compared with ADC, whereas N+ status for sm3 was similar in both
entities (>50%).
• While endoscopic therapy may be adequate in selected patients with ‘low-risk’ sm1 ADC, submucosal SCC necessitates esophageal
resection and systematic lymphadenectomy owing to its aggressive nature and tendency for early metastasis.
References
Papers of special note have been highlighted as:
• of interest
1 Fujishiro M, Kodashima S, Goto O
et al. Successful en bloc resection of
superficial esophageal cancer treated by
endoscopic submucosal dissection with a
splash needle. Endoscopy 40(Suppl. 2),
E81–E82 (2008).
2 Fujishiro M, Yahagi N, Nakamura M et al.
Successful outcomes of a novel endoscopic
treatment for GI tumors: endoscopic
submucosal dissection with a mixture of
high-molecular-weight hyaluronic acid,
glycerin, and sugar. Gastrointest. Endosc.
63(2), 243–249 (2006).
3 Kakushima N, Yahagi N, Fujishiro M,
Kodashima S, Nakamura M, Omata M.
Efficacy and safety of endoscopic
submucosal dissection for tumors of the
esophagogastric junction. Endoscopy 38(2),
170–174 (2006).
4 Atkins BZ, Shah AS, Hutcheson KA et al.
Reducing hospital morbidity and mortality
following esophagectomy. Ann. Thorac.
Surg. 78(4), 1170–1176; discussion
1170–1176 (2004).
5 Bollschweiler E, Baldus SE, Schröder W
et al. High rate of lymph-node metastasis in
submucosal esophageal squamous-cell
carcinomas and adenocarcinomas.
Endoscopy 38(2), 149–156 (2006).
6 Hölscher AH, Bollschweiler E,
Schneider PM, Siewert JR. Early
adenocarcinoma in Barrett’s oesophagus.
Br. J. Surg. 84(10), 1470–1473 (1997).
7 Nigro JJ, Hagen JA, DeMeester TR et al.
Prevalence and location of nodal metastases
in distal esophageal adenocarcinoma
confined to the wall: implications for
therapy. J. Thorac. Cardiovasc. Surg. 117(1),
16–23; discussion 23–15 (1999).
8 Stein HJ, Feith M, Bruecher BL, Naehrig J,
Sarbia M, Siewert JR. Early esophageal
cancer: pattern of lymphatic spread and
prognostic factors for long-term survival
380
after surgical resection. Ann. Surg. 242(4),
566–573; discussion 573–565 (2005).
• Early squamous cell cancer has more
aggressive lymphatic spread compared
with early adenocarcinoma.
9 Stein HJ, Feith M, Mueller J, Werner M,
Siewert JR. Limited resection for early
adenocarcinoma in Barrett‘s esophagus.
Ann. Surg. 232(6), 733–742 (2000).
10 Manner H, May A, Pech O et al. Early
Barrett’s carcinoma with ‘low-risk’
submucosal invasion: long-term results of
endoscopic resection with a curative intent.
Am. J. Gastroenterol. 103(10), 2589–2597
(2008).
• Long-term results of endoscopic
resection in submucosal (sm1)
‘low-risk’ adenocarcinoma.
11 Buskens CJ, Westerterp M, Lagarde SM,
Bergman JJ, Ten KFJ, van Lanschot JJ.
Prediction of appropriateness of local
endoscopic treatment for high-grade
dysplasia and early adenocarcinoma by EUS
and histopathologic features. Gastrointest.
Endosc. 60(5), 703–710 (2004).
12 Westerterp M, Koppert LB, Buskens CJ
et al. Outcome of surgical treatment for
early adenocarcinoma of the esophagus or
gastro-esophageal junction. Virchows Arch.
446(5), 497–504 (2005).
13 Eguchi T, Nakanishi Y, Shimoda T et al.
Histopathological criteria for additional
treatment after endoscopic mucosal
resection for esophageal cancer: analysis of
464 surgically resected cases. Mod. Pathol.
19(3), 475–480 (2006).
14 Matsubara T, Ueda M, Abe T, Akimori T,
Kokudo N, Takahashi T. Unique
distribution patterns of metastatic lymph
nodes in patients with superficial
carcinoma of the thoracic oesophagus.
Br. J. Surg. 86(5), 669–673 (1999).
15 Takubo K, Aida J, Sawabe M et al. Early
squamous cell carcinoma of the
oesophagus: the Japanese viewpoint.
Histopathology 51(6), 733–742 (2007).
16 Akiyama H, Tsurumaru M, Udagawa H,
Kajiyama Y. Radical lymph node dissection
for cancer of the thoracic esophagus.
Ann. Surg. 220(3), 364–372; discussion
372–363 (1994).
17 Altorki NK, Lee PC, Liss Y et al.
Multifocal neoplasia and nodal metastases
in T1 esophageal carcinoma: implications
for endoscopic treatment. Ann. Surg.
247(3), 434–439 (2008).
18 Amano T, Matsumoto T, Hayashi T et al.
Subepithelial extension of squamous cell
carcinoma in the esophagus:
histopathological study using D2–40
immunostaining for 108 superficial
carcinomas. Pathol. Int. 57(12), 759–764
(2007).
19 Ancona E, Rampado S, Cassaro M et al.
Prediction of lymph node status in
superficial esophageal carcinoma.
Ann. Surg. Oncol. 15(11), 3278–3288
(2008).
20 Araki K, Ohno S, Egashira A, Saeki H,
Kawaguchi H, Sugimachi K. Pathologic
features of superficial esophageal squamous
cell carcinoma with lymph node and distal
metastasis. Cancer 94(2), 570–575 (2002).
21 Benasco C, Combalia N, Pou JM,
Miquel JM. Superficial esophageal
carcinoma: a report of 12 cases.
Gastrointest. Endosc. 31(2), 64–67 (1985).
22 Bogomoletz WV, Molas G, Gayet B,
Potet F. Superficial squamous cell
carcinoma of the esophagus. A report of 76
cases and review of the literature. Am. J.
Surg. Pathol. 13(7), 535–546 (1989).
23 Bonavina L, Ruol A, Ancona E,
Peracchia A. Prognosis of early squamous
cell carcinoma of the esophagus after
surgical therapy. Dis. Esophagus 10(3),
162–164 (1997).
24 Brücher BL, Stein HJ, Werner M,
Siewert JR. Lymphatic vessel invasion is an
independent prognostic factor in patients
with a primary resected tumor with
esophageal squamous cell carcinoma.
Cancer 92(8), 2228–2233 (2001).
Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)

25 Cen P, Hofstetter WL, Correa AM et al.
Lymphovascular invasion as a tool to
further subclassify T1b esophageal
adenocarcinoma. Cancer 112(5),
1020–1027 (2008).
26 Chen YJ, Lee MD, Chen PH. Diagnosis
and treatment of superficial oesophageal
carcinoma. J. Gastroenterol. Hepatol.
12(12), 778–784 (1997).
27 Chibana Y, Fujii S, Ichikawa K et al.
Tumor cell dissociation score highly
correlates with lymph node metastasis in
superficial esophageal carcinoma.
J. Gastroenterol. Hepatol. 20(9), 1371–1378
(2005).
28 Chino O, Makuuchi H, Shimada H,
Machimura T, Mitomi T, Osamura RY.
Assessment of the proliferative activity of
superficial esophageal carcinoma using
MIB-1 immunostaining for the Ki-67
antigen. J. Surg. Oncol. 67(1), 18–24
(1998).
29 Conio M, Repici A, Cestari R et al.
Endoscopic mucosal resection for
high-grade dysplasia and intramucosal
carcinoma in Barrett’s esophagus:
an Italian experience. World J.
Gastroenterol. 11(42), 6650–6655 (2005).
30 De Baecque C, Potet F, Molas G,
Flejou JF, Barbier P, Martignon C.
Superficial adenocarcinoma of the
oesophagus arising in Barrett’s mucosa
with dysplasia: a clinico-pathological study
of 12 patients. Histopathology 16(3),
213–220 (1990).
31 Endo M. Endoscopic resection as local
treatment of mucosal cancer of the
esophagus. Endoscopy 25(9), 672–674
(1993).
32 Endo M, Kawano T. Detection and
classification of early squamous cell
esophageal cancer. Dis. Esophagus 10(3),
155–158 (1997).
33 Endo M, Yoshino K, Kawano T, Nagai K,
Inoue H. Clinicopathologic analysis of
lymph node metastasis in surgically
resected superficial cancer of the thoracic
esophagus. Dis. Esophagus 13(2), 125–129
(2000).
34 Endo M, Yoshino K, Takeshita K,
Kawano K. Analysis of 1,125 cases of early
esophageal carcinoma in Japan.
Dis. Esophagus 4(2), 71–76 (1991).
35 Fujita H, Sueyoshi S, Yamana H et al.
Optimum treatment strategy for
superficial esophageal cancer: endoscopic
mucosal resection versus radical
esophagectomy. World J. Surg. 25(4),
424–431 (2001).
www.expert-reviews.com
Lymph node metastasis in submucosal esophageal cancer
36 Goseki N, Koike M, Yoshida M.
Histopathologic characteristics of early
stage esophageal carcinoma. A comparative
study with gastric carcinoma. Cancer 69(5),
1088–1093 (1992).
37 Gotohda N, Nishimura M, Yoshida J, Nagai
K, Tanaka N. The pattern of lymphatic
metastases in superficial squamous cell
carcinoma of the esophagus.
Hepatogastroenterology 52(61), 105–107
(2005).
38 Hagen JA, DeMeester SR, Peters JH,
Chandrasoma P, DeMeester TR. Curative
resection for esophageal adenocarcinoma:
analysis of 100 en bloc esophagectomies.
Ann. Surg. 234(4), 520–530; discussion
530–521 (2001).
39 Haruma K, Tokutomi T, Tsuda T,
Yoshihara M, Sumii K, Kajiyama G.
Superficial esophageal carcinoma: a report
of 27 cases in Japan. Am. J. Gastroenterol.
86(12), 1723–1728 (1991).
40 Higuchi K, Tanabe S, Koizumi W et al.
Expansion of the indications for endoscopic
mucosal resection in patients with
superficial esophageal carcinoma. Endoscopy
39(1), 36–40 (2007).
41 Himeno S, Yasuda S, Shimada H,
Tajima T, Makuuchi H. Evaluation of
esophageal cancer by positron emission
tomography. Jpn. J. Clin. Oncol. 32(9),
340–346 (2002).
42 Hölscher AH, Bollschweiler E,
Schneider PM, Siewert JR. Prognosis of
early esophageal cancer. Comparison
between adeno- and squamous cell
carcinoma. Cancer 76(2), 178–186
(1995).
43 Hui AM, Itabashi M, Kato H,
Tachimori Y, Watanabe H, Hirota T. Flow
cytometric DNA analysis of submucosal
carcinoma of the esophagus. Jpn. J. Clin.
Oncol. 24(1), 26–31 (1994).
44 Ide H, Nakamura T, Hayashi K et al.
Esophageal squamous cell carcinoma:
pathology and prognosis. World J. Surg.
18(3), 321–330 (1994).
45 Igaki H, Kato H, Tachimori Y et al.
Clinicopathologic characteristics and
survival of patients with clinical Stage I
squamous cell carcinomas of the thoracic
esophagus treated with three-field lymph
node dissection. Eur. J. Cardiothorac. Surg.
20(6), 1089–1094 (2001).
46 Igaki H, Kato H, Tachimori Y,
Nakanishi Y. Cervical lymph node
metastasis in patients with submucosal
carcinoma of the thoracic esophagus.
J. Surg. Oncol. 75(1), 37–41 (2000).
Review
47 Ikeda Y, Ozawa S, Ando N, Kitagawa Y,
Ueda M, Kitajima M. Meanings of c-erbB
and int-2 amplification in superficial
esophageal squamous cell carcinomas.
Ann. Thorac. Surg. 62(3), 835–838
(1996).
48 Ikeguchi M, Saito H, Katano K,
Tsujitani S, Maeta M, Kaibara N.
Clinicopathologic significance of the
expression of mutated p53 protein and the
proliferative activity of cancer cells in
patients with esophageal squamous cell
carcinoma. J. Am. Coll. Surg. 185(4),
398–403 (1997).
49 Inoue A, Moriya H, Katada N et al.
Intratumoral lymphangiogenesis of
esophageal squamous cell carcinoma and
relationship with regulatory factors and
prognosis. Pathol. Int. 58(10), 611–619
(2008).
50 Isono K, Sato H, Nakayama K. Results of a
nationwide study on the three-field lymph
node dissection of esophageal cancer.
Oncology 48(5), 411–420 (1991).
51 Izbicki JR, Hosch SB, Pichlmeier U et al.
Prognostic value of immunohistochemically
identifiable tumor cells in lymph nodes of
patients with completely resected
esophageal cancer. N. Engl. J. Med.
337(17), 1188–1194 (1997).
52 Kato H, Tachimori Y, Mizobuchi S,
Igaki H, Ochiai A. Cervical, mediastinal,
and abdominal lymph node dissection
(three-field dissection) for superficial
carcinoma of the thoracic esophagus.
Cancer 72(10), 2879–2882 (1993).
53 Kim DU, Lee JH, Min BH et al.
Risk factors of lymph node metastasis in
T1 esophageal squamous cell carcinoma.
J. Gastroenterol. Hepatol. 23(4), 619–625
(2008).
54 Kimura H, Konishi K, Maeda K et al.
Flow cytometric analysis and
immunohistochemical staining for the p53
protein and proliferating cell nuclear
antigen in submucosal carcinoma of the
esophagus. Hepatogastroenterology. 46(25),
285–289 (1999).
55 Kitamura K, Ikebe M, Morita M,
Matsuda H, Kuwano H, Sugimachi K.
The evaluation of submucosal carcinoma of
the esophagus as a more advanced
carcinoma. Hepatogastroenterology. 40(3),
236–239 (1993).
56 Kodama M, Kakegawa T. Treatment of
superficial cancer of the esophagus:
a summary of responses to a
questionnaire on superficial cancer of the
esophagus in Japan. Surgery 123(4),
432–439 (1998).
381
 Review Gockel, Sgourakis, Lyros et al.
57 Kuwano H, Kitamura K, Baba K et al.
Determination of the resection line in early
esophageal cancer using intraoperative
endoscopic examination with Lugol
staining. J. Surg. Oncol. 50(3), 149–152
(1992).
58 Kuwano H, Masuda N, Kato H,
Sugimachi K. The subepithelial extension
of esophageal carcinoma for determining
the resection margin during
esophagectomy: a serial histopathologic
investigation. Surgery 131(1 Suppl.),
S14–S21 (2002).
59 Larghi A, Lightdale CJ, Memeo L,
Bhagat G, Okpara N, Rotterdam H. EUS
followed by EMR for staging of high-grade
dysplasia and early cancer in Barrett’s
esophagus. Gastrointest. Endosc. 62(1),
16–23 (2005).
60 Lerut T, Nafteux P, Moons J et al.
Three-field lymphadenectomy for
carcinoma of the esophagus and
gastroesophageal junction in 174 R0
resections: impact on staging, disease-free
survival, and outcome: a plea for adaptation
of TNM classification in upper-half
esophageal carcinoma. Ann. Surg. 240(6),
962–972; discussion 972–964 (2004).
61 Little SG, Rice TW, Bybel B et al.
Is FDG-PET indicated for superficial
esophageal cancer? Eur. J. Cardiothorac.
Surg 31(5), 791–796 (2007).
62 Liu J, Wang Q, Li B et al. Superficial
carcinomas of the esophagus and gastric
cardia. A clinicopathological analysis of
141 cases. Chin. Med. J. (Engl.) 108(10),
754–759 (1995).
63 Liu L, Hofstetter WL, Rashid A et al.
Significance of the depth of tumor invasion
and lymph node metastasis in superficially
invasive (T1) esophageal adenocarcinoma.
Am. J. Surg. Pathol. 29(8), 1079–1085
(2005).
64 Maish MS, DeMeester SR. Endoscopic
mucosal resection as a staging technique to
determine the depth of invasion of
esophageal adenocarcinoma. Ann. Thorac.
Surg. 78(5), 1777–1782 (2004).
65 Makuuchi H, Shimada H, Mizutani K
et al. Clinical pathological analysis of
surgically resected superficial esophageal
carcinoma to determine criteria for
deciding on treatment strategy. Diagn.
Ther. Endosc. 3(4), 211–220 (1997).
66 Mannell A, Becker PJ. Evaluation of the
results of oesophagectomy for oesophageal
cancer. Br. J. Surg. 78(1), 36–40 (1991).
67 Matsumoto M, Natsugoe S, Okumura H
et al. Overexpression of vascular
endothelial growth factor-C correlates with
382
lymph node micrometastasis in submucosal
esophageal cancer. J. Gastrointest. Surg.
10(7), 1016–1022 (2006).
68 Nabeya K, Hanaoka T, Li S, Nyumura T.
What is the ideal treatment for early
esophageal cancer? Endoscopy 25(9),
670–671 (1993).
69 Nagawa H, Kaizaki S, Seto Y, Tominaga O,
Muto T. The relationship of macroscopic
shape of superficial esophageal carcinoma
to depth of invasion and regional lymph
node metastasis. Cancer 75(5), 1061–1064
(1995).
70 Nakajima Y, Nagai K, Miyake S, Ohashi K,
Kawano T, Iwai T. Evaluation of an
indicator for lymph node metastasis of
esophageal squamous cell carcinoma
invading the submucosal layer. Jpn. J.
Cancer Res. 93(3), 305–312 (2002).
71 Nakano S, Baba M, Natsugoe S et al.
Detection of lymph node metastasis using
desmoglein 1 expression in superficial
esophageal cancer in relation to the
endoscopic mucosal resection.
Dis. Esophagus 11(3), 157–161 (1998).
72 Natsugoe S, Matsumoto M, Okumura H
et al. Prognostic factors in patients with
submucosal esophageal cancer.
J. Gastrointest. Surg. 8(5), 631–635 (2004).
73 Nishimaki T, Tanaka O, Suzuki T,
Aizawa K, Watanabe H, Muto T. Tumor
spread in superficial esophageal cancer:
histopathologic basis for rational surgical
treatment. World J. Surg. 17(6), 766–771;
discussion 771–762 (1993).
74 Noguchi H, Naomoto Y, Kondo H et al.
Evaluation of endoscopic mucosal resection
for superficial esophageal carcinoma. Surg.
Laparosc. Endosc. Percutan. Tech. 10(6),
343–350 (2000).
75 Nozoe T, Saeki H, Ohga T, Sugimachi K.
Clinicopathological features of early
esophageal squamous cell carcinoma with
subsequent recurrence. Dis. Esophagus
15(2), 145–148 (2002).
76 Ohno S, Mori M, Tsutsui S et al. Growth
patterns and prognosis of submucosal
carcinoma of the esophagus. A pathologic
study. Cancer 68(2), 335–340 (1991).
77 Paraf F, Flejou JF, Pignon JP, Fekete F,
Potet F. Surgical pathology of
adenocarcinoma arising in Barrett’s
esophagus. Analysis of 67 cases. Am. J.
Surg. Pathol. 19(2), 183–191 (1995).
78 Peters FP, Kara MA, Rosmolen WD et al.
Endoscopic treatment of high-grade
dysplasia and early stage cancer in Barrett’s
esophagus. Gastrointest. Endosc. 61(4),
506–514 (2005).
79 Rice TW, Blackstone EH, Goldblum JR
et al. Superficial adenocarcinoma of the
esophagus. J. Thorac. Cardiovasc. Surg.
122(6), 1077–1090 (2001).
80 Rice TW, Zuccaro G, Adelstein DJ,
Rybicki LA, Blackstone EH, Goldblum JR.
Esophageal carcinoma: depth of tumor
invasion is predictive of regional lymph
node status. Ann. Thorac. Surg. 65(3),
787–792 (1998).
81 Rösch T, Sarbia M, Schumacher B et al.
Attempted endoscopic en bloc resection of
mucosal and submucosal tumors using
insulated-tip knives: a pilot series.
Endoscopy 36(9), 788–801 (2004).
82 Ruol A, Parenti A, Zaninotto G et al.
Intestinal metaplasia is the probable
common precursor of adenocarcinoma in
Barrett esophagus and adenocarcinoma of
the gastric cardia. Cancer 88(11),
2520–2528 (2000).
83 Sabik JF, Rice TW, Goldblum JR et al.
Superficial esophageal carcinoma.
Ann. Thorac. Surg. 60(4), 896–901;
discussion 902 (1995).
84 Saha AK, Sutton CD, Sue-Ling H,
Dexter SP, Sarela AI. Comparison of
oncological outcomes after laparoscopic
transhiatal and open esophagectomy for T1
esophageal adenocarcinoma. Surg. Endosc.
23(1), 119–124 (2009).
85 Sako A, Kitayama J, Kaisaki S, Nagawa H.
Hyperlipidemia is a risk factor for
lymphatic metastasis in superficial
esophageal carcinoma. Cancer Lett. 208(1),
43–49 (2004).
86 Scheil-Bertram S, Lorenz D, Ell C,
Sheremet E, Fisseler-Eckhoff A. Expression
of a-methylacyl coenzyme A racemase in
the dysplasia carcinoma sequence associated
with Barrett’s esophagus. Mod. Pathol.
21(8), 961–967 (2008).
87 Schmidt LW, Dean PJ, Wilson RT.
Superficially invasive squamous cell
carcinoma of the esophagus. A study of
seven cases in Memphis, Tennessee.
Gastroenterology 91(6), 1456–1461 (1986).
88 Schröder W, Wirths K, Gutschow C et al.
Transthoracic esophagectomy after
endoscopic mucosal resection in patients
with early esophageal carcinoma.
J. Gastrointest. Surg. 13(2), 223–229
(2009).
89 Shami VM, Villaverde A, Stearns L et al.
Clinical impact of conventional
endosonography and endoscopic
ultrasound-guided fine-needle aspiration
in the assessment of patients with
Barrett’s esophagus and high-grade
dysplasia or intramucosal carcinoma who
Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)

have been referred for endoscopic ablation
therapy. Endoscopy 38(2), 157–161
(2006).
90 Shima I, Sasaguri Y, Kusukawa J et al.
Production of matrix metalloproteinase-2
and metalloproteinase-3 related to
malignant behavior of esophageal
carcinoma. A clinicopathologic study.
Cancer 70(12), 2747–2753 (1992).
91 Shimada H, Nabeya Y, Matsubara H et al.
Prediction of lymph node status in patients
with superficial esophageal carcinoma:
analysis of 160 surgically resected cancers.
Am. J. Surg. 191(2), 250–254 (2006).
92 Shimoyama S, Imamura K, Takeshita Y
et al. The useful combination of a higher
frequency miniprobe and endoscopic
submucosal dissection for the treatment of
T1 esophageal cancer. Surg. Endosc. 20(3),
434–438 (2006).
93 Shiozaki H, Doki Y, Yamana H, Isono K.
A multi-institutional study of
immunohistochemical investigation for the
roles of cyclin D1 and E-cadherin in
superficial squamous cell carcinoma of the
esophagus. J. Surg. Oncol. 79(3), 166–173
(2002).
94 Soehendra N, Binmoeller KF, Bohnacker S
et al. Endoscopic snare mucosectomy in the
esophagus without any additional
equipment: a simple technique for resection
of flat early cancer. Endoscopy 29(5),
380–383 (1997).
95 Soga J, Tanaka O, Sasaki K, Kawaguchi M,
Muto T. Superficial spreading carcinoma of
the esophagus. Cancer 50(8), 1641–1645
(1982).
96 Sugimachi K, Ohno S, Matsuda H,
Mori M, Matsuoka H, Kuwano H.
Clinicopathologic study of early stage
esophageal carcinoma. Br. J. Surg. 76(7),
759–763 (1989).
97 Tabira Y, Kitamura N, Yoshioka M et al.
Significance of three-field
lymphadenectomy for carcinoma of the
thoracic esophagus based on depth of
tumor infiltration, lymph nodal
involvement and survival rate.
J. Cardiovasc. Surg. 40(5), 737–740 (1999).
98 Tachibana M, Hirahara N, Kinugasa S,
Yoshimura H. Clinicopathologic features of
superficial esophageal cancer: results of
consecutive 100 patients. Ann. Surg. Oncol.
15(1), 104–116 (2008).
99 Tachibana M, Yoshimura H, Kinugasa S
et al. Clinicopathological features of
superficial squamous cell carcinoma of the
esophagus. Am. J. Surg. 174(1), 49–53
(1997).
www.expert-reviews.com
Lymph node metastasis in submucosal esophageal cancer
100 Tajima Y, Nakanishi Y, Ochiai A et al. 110
Histopathologic findings predicting
lymph node metastasis and prognosis of
patients with superficial esophageal
carcinoma: analysis of 240 surgically 111
resected tumors. Cancer 88(6), 1285–
1293 (2000).
101 Takeo Y, Yoshida T, Shigemitu T, Yanai H,
Hayashi N, Okita K. Endoscopic mucosal
resection for early esophageal cancer and 112
esophageal dysplasia. Hepatogastroenterology
48(38), 453–457 (2001).
102 Takubo K, Takai A, Takayama S,
Sasajima K, Yamashita K, Fujita K.
Intraductal spread of esophageal squamous 113
cell carcinoma. Cancer 59(10), 1751–1757
(1987).
103 Tauchi K, Kakudo K, Machimura T,
Makuuchi H, Mitomi T. Superficial
esophageal carcinoma. With special
reference to basaloid features. Pathol. Res. 114
Pract. 186(4), 450–454 (1990).
104 Toh Y, Baba K, Ikebe M, Adachi Y,
Kuwano H, Sugimachi K. Endoscopic
ultrasonography in the diagnosis of an early
esophageal carcinoma. Hepatogastroenterology 115
40(3), 212–216 (1993).
105 Tomita N, Matsumoto T, Hayashi T et al.
Lymphatic invasion according to D2–40
immunostaining is a strong predictor of
nodal metastasis in superficial squamous 116
cell carcinoma of the esophagus: algorithm
for risk of nodal metastasis based on
lymphatic invasion. Pathol. Int. 58(5),
282–287 (2008).
106 Tsutsui S, Kuwano H, Yasuda M et al.
Extensive spreading carcinoma of the 117
esophagus with invasion restricted to the
submucosa. Am. J. Gastroenterol. 90(10),
1858–1863 (1995).
107 van Sandick JW, van Lanschot JJ,
Ten Kate FJ et al. Pathology of early
invasive adenocarcinoma of the esophagus
or esophagogastric junction: implications
for therapeutic decision making. Cancer 118
88(11), 2429–2437 (2000).
108 Wang GQ, Jiao GG, Chang FB et al.
Long-term results of operation for
420 patients with early squamous cell
esophageal carcinoma discovered by 119
screening. Ann. Thorac. Surg. 77(5),
1740–1744 (2004).
109 Wang VS, Hornick JL, Sepulveda JA,
Mauer R, Poneros JM. Low prevalence of
submucosal invasive carcinoma at
esophagectomy for high-grade dysplasia or 120
intramucosal adenocarcinoma in Barrett’s
esophagus: a 20-year experience.
Gastrointest. Endosc. 69(4), 777–783
(2009).
Review
Watanabe M, Kuwano H, Araki K et al.
Prognostic factors in patients with
submucosal carcinoma of the oesophagus.
Br. J. Cancer 83(5), 609–613 (2000).
Yoshikane H, Tsukamoto Y, Niwa Y et al.
Superficial esophageal carcinoma:
evaluation by endoscopic ultrasonography.
Am. J. Gastroenterol. 89(5), 702–707
(1994).
Yoshinaka H, Shimazu H, Fukumoto T,
Baba M. Superficial esophageal carcinoma:
a clinicopathological review of 59 cases.
Am. J. Gastroenterol. 86(10), 1413–1418
(1991).
Gockel I, Domeyer M, Sgourakis GG et al.
Prediction model of lymph node metastasis
in superficial esophageal adenocarcinoma
and squamous cell cancer including D2–40
immunostaining. J. Surg. Oncol. 100(3),
191–198 (2009).
Kato H, Tachimori Y, Watanabe H,
Yamaguchi H, Ishikawa T, Itabashi M.
Superficial esophageal carcinoma. Surgical
treatment and the results. Cancer 66(11),
2319–2323 (1990).
Natsugoe S, Aikou T, Yoshinaka H et al.
Lymph node metastasis of early stage
carcinoma of the esophagus and of the
stomach. J. Clin. Gastroenterol. 20(4),
325–328 (1995).
Nozoe T, Kakeji Y, Baba H, Maehara Y.
Two-field lymph-node dissection may be
enough to treat patients with submucosal
squamous cell carcinoma of the thoracic
esophagus. Dis. Esophagus 18(4), 226–229
(2005).
Ruol A, Merigliano S, Baldan N et al.
Prevalence, management and outcome of
early adenocarcinoma (pT1) of the
esophago-gastric junction. Comparison
between early cancer in Barrett’s esophagus
(type I) and early cancer of the cardia
(type II). Dis. Esophagus 10(3), 190–195
(1997).
Shima I, Sasaguri Y, Kakegawa T et al.
Treatment for superficial esophageal cancer
based on histological features and gross
appearance. Int. J. Oncol. 5, 315–320
(1994).
Sugimachi K, Ikebe M, Kitamura K,
Toh Y, Matsuda H, Kuwano H. Long-term
results of esophagectomy for early
esophageal carcinoma.
Hepatogastroenterology 40(3), 203–206
(1993).
Sugimachi K, Kitamura K, Matsuda H,
Mori M, Kuwano H, Ide H. Proposed new
criteria for early carcinoma of the
esophagus. Surg. Gynecol. Obstet. 173(4),
303–308 (1991).
383
 Review Gockel, Sgourakis, Lyros et al.
121 The Japanese Society for Esophageal
Diseases. Guidelines for Clinical and
Pathologic Studies on Carcinoma of the
Esophagus (9th Edition). Tokyo, Japan
(2001).
122 May A, Gunter E, Roth F et al. Accuracy of
staging in early oesophageal cancer using
high resolution endoscopy and high
resolution endosonography: a comparative,
prospective, and blinded trial. Gut 53(5),
634–640 (2004).
384
123 Pech O, May A, Gunter E, Gossner L,
Ell C. The impact of endoscopic
ultrasound and computed tomography on
the TNM staging of early cancer in
Barrett’s esophagus. Am. J. Gastroenterol.
101(10), 2223–2229 (2006).
124 Yoon YC, Lee KS, Shim YM, Kim BT,
Kim K, Kim TS. Metastasis to regional
lymph nodes in patients with esophageal
squamous cell carcinoma: CT versus FDG
PET for presurgical detection prospective
study. Radiology 227(3), 764–770 (2003).
125 Vieth M, Ell C, Gossner L, May A,
Stolte M. Histological analysis of endoscopic
resection specimens from 326 patients with
Barrett’s esophagus and early neoplasia.
Endoscopy 36(9), 776–781 (2004).
Website
201 March JH. Oxford Centre for Evidence-
Based Medicine – Levels of Evidence (2009)
www.cebm.net/index.aspx?o=1025
Expert Rev. Gastroenterol. Hepatol. 5(3), (2011)