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Journal of Surgical Oncology 2009;100:111–114
Prognostic Impact of Lymphatic Invasion in Patients With
Node-Negative Gastric Cancer
DAISUKE ICHIKAWA, MD,* TAKESHI KUBOTA, MD, SHOJIRO KIKUCHI, MD, HITOSHI FUJIWARA, MD,HIROTAKA KONISHI, MD, MASAHIRO TSUJIURA, MD, HISASHI IKOMA, MD, MASAYOSHI NAKANISHI, MD,
KAZUMA OKAMOTO, MD, CHOHEI SAKAKURA, MD, TOSHIYA OCHIAI, MD,YUKIHITO KOKUBA, MD, AND EIGO OTSUJI, MD
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
Background and Objectives: This study investigated the prognostic impact of lymphatic invasion on the outcome of patients with node-negative
gastric cancer.
Methods: A total of 828 patients with node-negative gastric cancer who underwent curative gastretomy were reviewed retro-
spectively. The clinicopathological features and prognoses of patients with lymphatic invasion were compared to those of patients without
such invasion.
Results: The total rate of lymphatic invasion was 18.2% in node-negative gastric cancers, with a significant difference between early gastric
cancers (9.8%) and advanced gastric cancers (49.2%). The presence of lymphatic invasion correlated significantly with tumor location, size and
depth of tumor (P< 0.01). Lymphatic invasion was significantly associated with a poorer overall survival in node-negative gastric cancer patients
on univariate analysis (P< 0.001) as well as multivariate analysis (P< 0.01).
Conclusions: Lymphatic invasion provides additional useful information that could be applied to identify patients at high risk for recurrence who
might be candidates for adjuvant therapies in patients with node-negative gastric cancers.
J. Surg. Oncol. 2009;100:111–114. � 2009 Wiley-Liss, Inc.
KEY WORDS: lymphatic vessel; survival; prognostic factors; invasion
INTRODUCTION
Although the incidence of gastric cancer has decreased significantly
over the past several decades, it remains the second most common
cause of cancer-related deaths worldwide [1]. Since the lymph node
metastasis is one of the most important prognostic factors, both of
the two main staging systems for gastric cancer, the Union
Internationale Contre le Cancer (UICC) and the Japanese Classification
of Gastric Carcinoma (JCGC), defines the stage of the disease
based mainly on status of lymph node metastasis and depth of wall
invasion [2,3].
However, lymphatic invasion has also been recognized as a
significant prognostic factor, strongly associated with potential lymph
node metastasis [4–7]. We have sometimes encountered gastric cancer
patients showing discrepancy between the status of lymph node
metastasis and the degree of lymphatic invasion. Therefore, lymphatic
invasion of tumor cells does not necessarily indicate the lymph node
metastases.
Large-scale randomized studies have recently demonstrated that
post-operative adjuvant chemotherapy is the standard of care after
curative surgery in patients with stage II and III gastric cancers [8,9].
However, since the two main staging systems that are currently
applied to gastric cancer do not include the degree of lymphatic
invasion in the staging system, lymphatic invasion generally is not
included in the determination of whether adjuvant chemotherapy is
indicated or not.
This study investigated the frequency of discrepancy between the
degree of lymphatic invasion and the status of lymph node metastases,
and the clinical significance of lymphatic invasion without lymph node
metastasis in patients with gastric cancer.
MATERIALS AND METHODS
Patients
Between 1974 and 2006, a total of 2,599 patients with gastric
cancer underwent surgical resection at Kyoto Prefectural University of
Medicine Hospital. Of these patients, 828 patients (31.9%) histo-
logically proven node-negative gastric cancer, who underwent curative
gastrectomy with lymph node dissection, were enrolled in this
retrospective study.
The clinicopathological features of these node-negative gastric
cancer patients were retrospectively reviewed using the hospital
database. The presence of lymphatic vessel invasion was determined
by routine hematoxylin and eosin staining of the resected specimens,
and immunostaining using D2-40 antibody (Nichirei, Tokyo, Japan) as
needed. The degree of lymphatic invasion was divided into four
grades according to the Japanese Classification of Gastric Carcinoma
(JCGC): ly0(no lymphatic invasion), ly1(minimal lymphatic invasion),
ly2(moderated lymphatic invasion), ly3(marked lymphatic invasion).
Other histological features were also classified according to the
JCGC [3].
*Correspondence to: Dr. Daisuke Ichikawa, MD, Division of DigestiveSurgery, Department of Surgery, Kyoto Prefectural University of Medicine,465 Kajii-cho, Kamigyo-ku, Kyoto 6028566, Japan. Fax: 81-75-251-5522.E-mail: ichikawa@koto.kpu-m.ac.jp
Received 29 November 2008; Accepted 14 April 2009
DOI 10.1002/jso.21311
Published online 27 May 2009 in Wiley InterScience(www.interscience.wiley.com).
� 2009 Wiley-Liss, Inc.
Follow-up consisted of blood examinations, radiological examina-
tions of the gastrointestinal tract, endoscopic procedures, computed
tomography, and ultrasonography. Follow-up procedures were per-
formed every 3 months for at least 2 years, and continued periodically
for at least 5 years.
Statistical Analysis
Survival rates were calculated by the Kaplan–Meier method, with
the date of gastrectomy as the starting point. Differences in survival
were examined by log-rank test. Multivariate analysis of prognostic
factors related to survival was performed using the Cox proportional
hazard mode. The significance of differences was accepted at P< 0.05.
RESULTS
Clinicopathologic Findings
The mean patient age was 60.9 years (range 22–91), and the
male:female ratio was 2.1:1. The median tumor size was 36mm (range
5–272mm). Six hundred fifty-one of 828 patients (78.6%) had early
gastric cancer (T1). Among the 828 node-negative gastric cancer
patients, lymphatic invasion was present in 151 patients (18.2%), with
a significant difference between early gastric cancer (T1: 9.8%) and
advanced gastric cancer (T2,3: 49.2%; Table I). Other factors, such as
tumor location and tumor size, also correlated significantly with the
presence of lymphatic invasion. However, clinicopathologic factors
such as age, sex, and histological type were not found to be associated
with the presence of lymphatic invasion (Table I).
The 151 patients with lymphatic invasion were classified into three
groups according to the JCGC; 100 patients as ly1, 45 patients as ly2
and 6 patients as ly3. Since only 6 patients were classified as ly3, ly2
and ly3 were grouped into one category (ly2,3) for the further
prognostic study. Meanwhile, all patients showing lymphatic invasion
were classified into one category (ly1,2,3) for further prognostic study
of early node-negative gastric cancers, since there were only 8 patients
in ly2 and no patients in ly3 in the early gastric cancer group.
Survival
Figure 1 shows the survival curves for each group according to the
lymphatic invasion grade. The lymphatic invasion was a significant
prognostic factor on univariate analysis (P< 0.0001). Then, the
survival curves for patients in each early and advanced gastric cancer
are shown in Figure 2. In early gastric cancers, the presence of
lymphatic invasion was a significant prognostic factor (P< 0.05).
Lymphatic invasion greater than ly2 was a significant prognostic factor
in advanced gastric cancers (P< 0.05).
As well as lymphatic invasion, univariate analyses demonstrated that
age, tumor size, and depth of tumor were also significant prognostic
factors of patients with node-negative gastric cancer, but sex, tumor
location, and histological type were not (Table II). Next, these significant
prognostic factors and lymphatic invasion were analyzed by multivariate
analysis. Lymphatic invasion was an independent prognostic factor, as
were age and depth of tumor (Table III).
DISCUSSION
The lymphatic metastasis of tumor cells consists of a highly
complex series of mechanisms as follows; (1) invasion to the stromal
tissues and penetration into the lymphatic vessels; (2) release of tumor
cells from the primary tumor mass; (3) dissemination within the
lymphatic circulating system; (4) adhesion of the tumor cells to the
lymphatic endothelium in lymph nodes; and (5) formation of tumor
deposit [10,11]. Although the details of these steps remain unknown,
the step in which the tumor cells enter the lymphatic flow is the most
important for lymph node metastases. In fact, the lymphatic invasion
has been reported to associate with lymph node metastases [12,13].
We, however, sometimes experienced node-negative gastric cancer
patients with histological findings of lymphatic invasion in the
primary tumors.
There should be several reasons for the discrepancy between
findings of lymphatic invasion and status of lymph node metastasis.
First, there is good likelihood that latent lymph node metastasis existed
between each pair of a sectional plane on routine histological
examinations. Second is the possibility that there might be micro-
metastasis detected by only immunohistochemistry but not by routine
hematoxylin and eosin staining. Another possibility is that the tumor
cells entering the lymphatic flow did not have the ability to adhere to
lymphatic endothelium and develop metastatic deposit in lymph node.
Miyazaki et al. [14] reported that galectin-3 might be involved in
Journal of Surgical Oncology
TABLE I. Clinicopathological Features With or Without Lymphatic
Invasion in Patients With Node-Negative Gastric Cancer
Lymphatic invasion
P valueNegative Positive
Age
<65 413 91
�65 264 60 NS
Sex
Male 457 103
Female 220 48 NS
Location
Upper 94 36
Middle 342 62
Lower 228 53 <0.01
Unknown 13
Size
<3 cm 389 36
�3 cm 288 115 <0.001
Depth
T1 587 64
T2T3 90 87 <0.001
Histology
Diff. 387 82
Undiff. 289 69 NS
Unknown 1
Fig. 1. Survival curve of patients with node-negative gastriccancer according to lymphatic invasion. The lymphatic invasion wasa significant prognostic factor by univariate analysis.
112 Ichikawa et al.
developing lymph node metastasis in gastric cancer. PRL-3 was also
reported to play important roles in lymph node metastasis [15]. These
factors on primary tumor cells might be involved partly in the
discrepancy.
In the present study, we evaluated the lymphatic invasion by routine
hematoxylin and eosin staining and immunostaining as needed.
Immunostaining was mainly performed to distinguish lymphatic
invasion from blood vessel invasion in the present study. In the present
study, the overall incidence of lymphatic invasion was 18.2% in node-
negative patients, similar to that in previous reports [4]. Lymphatic
invasion was a significant prognostic factor in node-negative gastric
cancer on both univariate and multivariate analyses. Since the
incidences and degrees significantly differed between early gastric
cancers and advanced gastric cancers, we examined the survival impact
separately in each group. In the node-negative early gastric cancer
group, the presence of lymphatic invasion, even minimal lymphatic
invasion (ly1), was a significant prognostic factor. Two patients who
died from recurrences had each developed peritonitis carcinomatosa,
which is an uncommon recurrence pattern for post-operative patients
Journal of Surgical Oncology
Fig. 2. Survival curve of patients with N0 early gastric cancer (A) and N0 advanced gastric cancer (B) according to lymphatic invasion. Thepresence of lymphatic invasion was a significant prognostic factor in node-negative early gastric cancer (P< 0.05). Lymphatic invasion greaterthan ly2 was a significant prognostic factor in node-negative advanced gastric cancer (P< 0.05).
TABLE II. Prognostic Significance by Univariate Analysis of Variables for
Patients With Node-Negative Gastric Cancer
Variables
No. of
patients
5-year
survival (%) P value
Age
<65 504 95.4
�65 324 92.5 <0.05
Sex
Male 560 94.2
Female 268 94.5 NS
Location
Upper 130 92.6
Middle 404 95.8
Lower 281 92.7 NS
Unknown 13
Size
<3 cm 425 96.9
�3 cm 403 91.3 <0.01
Depth
T1 651 92.7
T2T3 177 82.0 <0.001
Histology
Diff. 469 94.2
Undiff. 358 94.4 NS
Unknown 1
Ly
0 677 97.1
1 100 88.8
2, 3 51 69.4 <0.001
TABLE III. Prognostic Significance by Multivariate Analysis of Variables
for Patients With Node-Negative Gastric Cancer
Risk ratio
95% confidence
interval P value
Age
<65 1 <0.01
�65 3.137 1.457–6.753
Size
<3 cm 1 NS
�3 cm 1.184 0.459–3.054
Depth
T1 1 <0.001
T2T3 6.977 2.575–18.904
Ly <0.01
0 1
1 1.651 0.542–5.030
2, 3 4.818 1.889–12.288
Lymphatic Invasion in Gastric Cancer 113
with early gastric cancers. Peritoneal dissemination might have arisen
from tumor cells exfoliated from lymphatic vessels during surgery.
However, the survival of patients with minimal lymphatic invasion
(ly1) was similar to that of those without lymphatic invasion in patients
with node-negative advanced gastric cancers. When we examined the
prognostic impact of lymphatic invasion on multivariate analysis,
because some factors other than tumor stage were also significant
prognostic factors on univariate analysis, lymphatic invasion was a
significant prognostic factor on multivariate analysis again.
Other findings in the present study were that the histological type
did not correlate with either lymphatic invasion or survival in patients
with node-negative gastric cancers. Because lymph node metastasis
was more frequent in undifferentiated gastric cancer [13], the high
frequency of lymph node metastasis in undifferentiated gastric cancer
might depend on the ability of tumor cells to adhere to the lymphatic
endothelium in lymph nodes and form tumor deposits. Other
interesting finding was that tumor location also correlated significantly
with the presence of the lymphatic invasion. The reason is not known
exactly, however, because the tumors located in the upper-third tended
to be more advanced T-stage compared to those of other regions in the
present study (data not shown), the differences might effect the
frequency of the lymphatic invasion.
CONCLUSIONS
In conclusion, the present study clearly demonstrated the prognostic
impact of lymphatic invasion in patients with node-negative gastric
cancer. Intensive chemotherapy and close follow-up should be
recommended for node-negative gastric cancer with lymphatic
invasion, especially those showing moderate or marked lymphatic
invasion.
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Journal of Surgical Oncology
114 Ichikawa et al.
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