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602
Risk Factors for Lymph Node Metastasis from
lntramucosal Gastric Carcinoma
Takekazu Yamao, M.D.'
Kuniaki Shirao, M.o.'
Hiroyuki Ono, M.D.'
Hitoshi Kondo, M.D?
Daizo Saito, M.D?
Hajime Yamaguchi, M.D.*
Mitsuru Sasako, M.D?
Takeshi Sano, M . D . ~
Atsushi Ochiai, M.D.3
Shigeaki Yoshida, M.D?
' Department of Internal Medicine, National
Cancer Center Hospital, Tokyo, Japan.
* Department of Surgery, National Cancer Center Hospital, Tokyo, Japan.
Department of Pathology, National Cancer
Center Hospital, Tokyo, Japan.
Department of Internal Medicine, National
Cancer Center Hospital East, Chiba. Japan.
BACKGROUND. Although regional lymph node metastasis from intramucosal early
gastric carcinoma (EGC) is rare, it is very important to clarify the characteristics
of patients having lyniph nodal metastases in order to determine appropriate
therapy.
METHODS. The authors investigated 1196 patients with solitary intramucosal EGC
who underwent resection at the National Cancer Center Hospital in Tokyo, with
special reference to lymph node metastases. Eight clinicopathologic factors (age,
sex, tumor: size, location, macroscopic type, histologic type, histologic ulceration
of the tumor, and lymphatic vessel invasion) were investigated by univariate and
multivariate analyses for their possible relationship to lymph node metastasis.
RESULTS. Lymph node metastases were found in 43 patients (3.5%). Univariate
analysis revealed that younger age (< 5 7 years), macroscopic depressed type, larger
tumor size ( 2 30 mm), undifferentiated histologic type, histologic ulceration of
the carcinoma, and lymphatic vessel invasion had a significant association with
regional lyniph node metastasis. Multivariate analysis revealed that lymphatic vessel invasion, histologic ulceration of the tumor, and larger size ( 2 3 0 mm) were
independent risk factors for regional lymph node metastasis. The incidence of
lymph node metastasis from intramucosal EGC negative for these 3 risk factors
was only 0.36% (1 in 277 patients).
CONCLUSIONS. Lymphadenectomy is unnecessary for patients with small intramucosal EGC with neither histologic ulceration of the tumor nor lymphatic vessel
invasion because the incidence of regional lymph node metastasis is extremely
low in those patients. The therapeutic options for such patients would be local
resection or endoscopic resection. Cancer 1996; 77502-6.
0 1996 American Cancer Society.
KEYWORDS: early gastric carcinoma, regional lymph node metastasis, multivariate
analysis, risk factor, lymphadenectomy, endoscopic treatment.
E
The work was supported in part by a Grant-inAid for Cancer Research (5-18 and 7-34) from
Ministry of Health and Welfare, Japan.
Address for reprints: Takekazu Yamao, M.D.,
Department of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku,
Tokyo 104, Japan.
Received April 20, 1995; revision received June
27, 1995; accepted June 27, 1995.
0 1996 American Cancer Society
arly gastric carcinoma (EGC)is defined as that confined to the mucosa
or submucosa regardless of the presence or absence of regional lymph
node metastasis.' As a result of diagnostic development, including X-ray
and endoscopy, the detection of EGC has been increasing in Japan. The
prognosis of patients with EGC has improved with surgical treatment.'
Gastrectomy with complete removal of primary and secondary lymph
nodes has been the standard operation for EGC in Japan."' This surgical
strategy provides an excellent therapeutic outcome; the 5-year survival
rate after curative gastrectomy is more than 90% in Japan.',"' Although
one of the most important factors for the prognosis of patients with EGC
is the presence or absence of regional lymph node metastasis,"-" the
incidence of metastasis of intramucosal EGC is approximately 3% and is
20% in submucosal EGC.l3-Ifi Thus, it should be possible to modify the
therapeutic strategy for intramucosal EGC, taking into consideration the
Nodal Metastasis of Early Gastric CarcinomaNarnao et al.
risk of surgery and quality of life for the patients. The
purpose of this study is to clarify independent risk factors
for regional lymph node metastasis from intramucosal
EGC that would be useful for therapeutic determination.
603
TABLE I
Relationship between Clinicopathologic Factors and Regional Lymph
Node Metastasis from Intramucosal EGC, and Univariate Analysis
Results
Regional lymph node metastases
MATERIALS AND METHODS
Patients and Specimens
A total of 2265 patients with EGC underwent gastrectomy
at the National Cancer Center Hospital in Tokyo between
1963 and 1993. The resected stomachs were opened along
the greater or lesser curvatures, pinned on a plate, and
fixed in formalin. The specimens containing the tumors
and the surrounding gastric wall were cut into multiple
slices, principally parallel to the lesser curvature, at an
interval of 5 mm. Dissected lymph nodes were also fixed
in formalin, cut into two, and embedded in paraffin. Each
slice embedded in paraffin was prepared for histologic
examination. All microscopic sections were stained with
hematoxylin and eosin. All histologic examinations were
made by pathologists.
Of the 1196 specimens proven to be solitary intramucosal cancer, 43 (3.5%) revealed regional lymph node metastasis histologically. The distribution of positive lymph
nodes in all 43 specimens was to primary lymph nodes
( n l ) in 31 (72%), secondary lymph nodes (1121 in 7 (16%),
and unknown in 5 (12%),according to the Japanese Classification of Gastric Cancer outlined by the Japanese Research Society for Gastric Cancer.” Eight clinicopathologic factors were investigated by means of univariate and
multivariate analyses for their possible association with
lymph node metastasis. Each factor was divided into 2 or
3 subgroups: age younger than 57 years or 57 years or
older (the mean age of the patients was 57 years); sex;
location of the primary lesion as either C (upper third of
stomach), M (middle third of stomach), or A (lower third
of stomach), according to the Japanese Classification; l 7
macroscopic type (protruded type or depressed type); tumor size smaller than 30 mm or 30 mm or larger in diameter (the mean diameter of the tumor was 30 mm in diarneter); histologic type (differentiated type or undifferentiated type); histologic ulceration of the tumor (negative
0 1 positive); and lymphatic vessel invasion (negative or
positive). The primary lesions were classified macroscopically according to the Japanese Classification” as follows:
Type I (protruded type), IIa (superficial elevated type),
1Ib (flat type), IIc (superficial depressed type), and Ill (excavated type). In the current analysis, we defined macroscopic protruded type as Type I, Type Ha, or combined
type with Type I or Type Ha, such as Ha plus IIc type,
and defined macroscopic depressed type as Type IIb, IIc,
111, or combined type with Type IIb, IIc, or 111, such as IIc
plus 1Ib or IIc plus 111. As for the histologic classification,
tubular adenocarcinoma and papillary adenocarcinoma
were classified as differentiated type, and poorly differen-
Clinicopathologicfactor
Negative
Positive
Percentage
“of positive”
P
value
Age (yr)
4 7
257
Sex
Male
Female
Location in stomach
C (upper third)
M (middle third]
A (lower third)
Macroscopic type
Protruded
Depressed
Unknown*
554
599
30
13
5.1%
2.1%
0.005
754
399
25
18
3.2%
3.3%
0.327
103
683
367
)
1.970
3.5%
0.536
25
16
4.201
7
0.8%
4.3%
<n.ooi
41
620
517
16
12
31
l.9%
5.7%
<o.nni
667
486
12
31
1.8%
6.0%
m n i
416
i2l
16
2
31
0.48%
5.4%
<n.ooi
1036
30
3
235
912
6
Size (inin)
<30
230
Unknown’
Histological type
Differentiated
Undifferentiated
Histological ulceration
Negative
Positive
Unknown*
Lymphatic vessel invasion
Negative
Positive
Unknown*
6
3.7%
33.3%
<0.001
111
EGC early gastric carcinoma.
’ Unknown cases were excluded from statistical analysis
tiated adenocarcinoma, mucinous adenocarcinoma, and
signet ring cell carcinoma were classified as undifferentiated type.
Statistical Analysis
The SAS program (SAS Institute, Inc., SAS Campus Drive,
Cary, NC) was used for all analyses. The association of
lymph node metastasis with clinicopathologic variables
was assessed using a simple chi-square test. Multivariate
analysis was carried out using a logistic model with a
stepwise method. A level of P < 0.05 was taken as significant.
RESULTS
Univariate Analysis of Risk Factors for Regional Lymph
Node Metastasis from lntramucosal EGC
The associations between clinicopathologic factors and
the presence or absence of lymph node metastasis are
604
CANCER February 15, 1996 / Volume 77 / Number 4
TABLE 2
Independent Risk Factors for Regional Lymph Node Metastasis from
lntramucosal EGC
Clinicopathologicfactor
(observed value)
Lymphatic vessel invasion
(negative or positive)
Histologic ulceration
(negative or positive)
Size of lesion (c30 nini
or 2 30 mml
Relative risk
(95%C.I.*)
S.E.**
P
value
14.33 (2.98-68.841
0.8007
0.0009
6.09 (1.38-26.821
0.7564
0.0169
3.11 (1.4-7.57)
0.4177
0.0038
tCL: rarl, gasirir c~ircit~i)n~~i:
(:I: ciinfidcnce i n l e n d SE: standard rrriit
summarized in Table 1. Age younger than 57 years, macroscopic depressed type, tumor size larger than 30 m m
in diameter, undifferentiated histologic type, histologic
ulceration of the tumor, and lymphatic vessel invasion
had a significant association with lymph node metastasis
by chi-square test.
Multivariate Analysis of Risk Factors for Regional Lymph
Node Metastasis from lntramucosal EGC
We chose six clinicopathologic factors (age, macroscopic
type, tumor size, histologic type, histologic ulceration of
the tumor, and lymphatic vessel invasion) that had a significant association for lymph node metastasis in the univariate analysis described above. As shown in Table 2,
the independent risk factors for regional lymph node nietastases were found to be lymphatic vessel invasion, a
tumor size larger than 30 nim in diameter, and histologic
ulceration of the tumor. The incidence of regional lymph
node metastases of intramucosal EGC specimens that
were negative for these 3 risk factors was only 0.36% (one
of 277 specimens).
DISCUSSION
The presence or absence of regional lymph node nietastasis is one of the most important factors for the prognosis
of patients with EGC.""' Lymph node metastasis of intramucosal EGC is rare. I n general, lymph node metastasis of intramucosal EGC has been thought to be an exceptional event. Although the number of resected EGCs has
increased in Japan, the clinicopathologic characteristics
of intramucosal EGC with regional lymph node metastasis have been unclear because of their low incidence.
Although gastrectoniy with lymph node dissection has
been the standard treatment for EGC in Japan,"-bpatients
with EGC who are free of regional lymph node metastasis
can be cured without lymph node dissection. In addition,
with the recent developinent of endoscopic mucosal resection for EGC, patients with n o lymph nodal metastasis
can be treated using endoscopy without increasing the
risk of recurrence."' Thus, considering the low incidence of lymph node metastasis, the risk of surgery, and
quality of life for the patients, there is much to be said
for modifying the therapeutic strategy for the cure of intramucosal EGC on the basis of patients' risk factors for
regional lymph node metastasis. This is the first report
with reference to risk factors for lymph node metastasis
of intramucosal EGC by multivariate analysis of a large
number of patients in a single institution.
In this study, regional lymph node metastases were
found in 3.5% of intramucosal carcinomas, which was
not much different from previous reports.''-'b Sano et al.
reported 14 cases (3.3%)of intramucosal gastric carcinomas with lymph node meta~tases.'~
They noted that 12
of the 14 lesions were of the macroscopically depressed
type and were accompanied by histologic ulceration of
the tumor and that one was a large (55 m m in diameter)
protruded type. Furthermore, no difference was found in
the distribution of histologic types. Korenaga et al. reported that lymph node metastasis was found in 11 of
568 cases (1.9%) of intramucosal EGC and that all lesions
were larger than 20 mm in diameter." Nine lesions were
of the undifferentiated type and six were accompanied by
histologic ulceration of the tumor. In the present study,
similar findings were observed in the characteristics of
intramucosal carcinoma with lymph node metastasis.
Lymph node metastases were significantly associated
with a younger age, macroscopically depressed lesion,
larger tumor size, undifferentiated histologic type, histologic ulceration of the tumor, and lymphatic vessel invasion in the iinivariate analysis.
Furthermore, multivariate analysis revealed that lymphatic vessel invasion, histologic ulceration of the tumor,
and larger tumor size were independent risk factors for
lymph node metastases of intramucosal EGC. It is readily
understandable that lymphatic vessel invasion is one of
the risk factors for lymph node metastases because its
presence indicates that cancer cells have already permeated to lymph flow. Lymphatic vessels are few in the mucosal layer, whereas the submucosal layer is rich in them.
The existence of histologic ulceration within the tumor
indicates the destruction of the muscularis mucosa that
acts as a barrier against the lymphatic vessel invasion.
The speculation proposed by Sane'" makes it plausible
that the destruction of the muscularis mucosa by histologic ulceration could cause a n interchange between the
lymph flow in the mucosa and submucosa, which could
result in a n increase in the risk of regional lymph node
metastasis. Additionally, the breakdown of the muscularis
mucosa also means the possibility that a preceding invasion to the submucosal layer has already occurred.
The results of multivariate analyses of risk factors
provide useful information in the clinical decision-mak-
Nodal Metastasis of Early Gastric Carcinornaflarnao et al.
ing processes. In the present study, lymphatic vessel invasion, histologic ulceration of the tumor, and larger tumor
diameter were the independent risk factors for regional
lymph node metastasis from intramucosal EGC. The present findings theoretically provide useful information for
the determination of how extensively lymphadenectomy
should be performed in individual patients with intramucosal EGC. The incidence of regional lymph node metastases in intramucosal EGC that was negative for lymphatic vessel invasion, histologic ulceration of the tumor,
and a tumor less than 30 m m in diameter was 3.8% (40
metastases of 1076 tumors), 0.48% (2 metastases of 418
tumors) and 1.9% (12 metastases of 632 tumors) respectively (‘Table 1). The incidence of lymph node metastases
of intramucosal EGC in which tumor size was less than
30 m m in diameter with neither histologic ulceration of
the tumor nor lymphatic vessel invasion was only 0.36%
(1 of 277). Thus, the conventional view that gastrectomy
with extensive lymphadenectomy should be the standard
surgical procedure for every EGC may be thrown into
question because the incidence of regional lymph node
metastasis is extremely low in patients with intramucosal
EGC who are negative for those risk factors. Even without
Iymphadenectomy, patients without those risk factors
can be highly curable and may be good candidates for
local resection, preserving the function of the cardia and
the pylorus. ‘Those same patients also may be good candidates for endoscopic resection, especially if they have
surgical risks such as cardiovascular disorders or renal
fiilure.
‘Ihe clinical issue is the selective performance of surgery without lymphadenectomy or endoscopic resection
for patients with EGC who are free of lymph node metastasis. The appropriate selection of patients applicable to
the aforementioned therapeutic strategies depends o n
how accurately diagnosis can be made for depth of invasion, tumor size, histologic ulceration of the tumor, and
lymphatic vessel invasion. The size of the primary lesion
can be determined by routine endoscopy and the histologic ulceration of the tumor can be estimated by routine
endoscopy and endoscopic ultrasonography by detecting
any sign of converging folds or submucosal
Conversely, lymphatic vessel invasion and minute submucosal invasion cannot be diagnosed without histologic
examination of the primary tumor. However, endoscopic
“strip biopsy” or endoscopic mucosal resection (EMR),
introduced by Tada et al.,L’should provide more accurate
information on the primary lesion because histologic
evaluations are possible in the specimens resected endoscopically. Because the specimens resected by EMR include the submucosal layer, we can evaluate by histologic
examination not only the depth of tumor invasion but
also lymphatic vessel invasion and histologic ulceration
of the tumor. Therefore, by combining these clinical data,
605
it should be possible to select patients with EGC who
are likely to be free of regional lymph node metastasis.
Furthermore, EMR can be not only the diagnostic procedure described above but also a radical treatment for
selected patients with EGC who are negative for these risk
factors. When the primary lesion is completely removed
endoscopically and the resected specimen is histalogically revealed to be free of these risk factors, EMR can be
a curative treatment. It appears that EMR is an important
diagnostic procedure for therapeutic determination of
small EGC and could be a first choice of treatment for
patients with surgical risk.
We conclude that the independent risk factors for
regional lymph node metastasis of intramucosal EGC are
larger tumor size, histologic ulceration of the tumor, and
lymphatic vessel invasion, and that because of the extremely low incidence of lymph node metastasis, a
lymphadenectomy is unnecessary for patients with EGC
who are negative for these factors. The therapeutic options for such patients would be local resection or endoscopic resection.
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