Japanese Journal of Clinical Oncology, 2016, 46(1) 63–70
doi: 10.1093/jjco/hyv159
Advance Access Publication Date: 23 October 2015
Original Article
Original Article
Survival benefit of greater number of lymph
nodes dissection for advanced node-negative
gastric cancer patients following radical
gastrectomy
Hongyong He†, Zhenbin Shen†, Xuefei Wang, Jing Qin*, Yihong Sun*,
and Xinyu Qin
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
*For reprints and all correspondence: Yihong Sun, Department of General Surgery, Zhongshan Hospital, Fudan University,
Fenglin Road 180, Shanghai 200032, China. E-mail: [email protected]; Jing Qin, Department of General Surgery,
Zhongshan Hospital, Fudan University, Fenglin Road 180, Shanghai 200032, China. E-mail: [email protected]
†
Hongyong He and Zhenbin Shen contributed equally to this work.
Received 20 April 2015; Accepted 29 September 2015
Abstract
Objective: A common clinicopathological factor except for T stage that could significantly influence
the clinical outcome of advanced node-negative gastric cancer patients following radical gastrectomy was unknown. This study was designed to investigate the clinicopathological characteristics
of these patients, and to evaluate the outcome indicators and improve the risk stratification.
Methods: A total of 195 patients harboring advanced gastric adenocarcinoma with no lymph node
and distant metastases and following radical gastrectomy were retrospectively analyzed from the
prospectively collected database of Zhongshan Hospital of Fudan University between 2006 and 2010.
Results: The 3-year and 5-year overall survival rates of this study population were 85.0 and 69.6%.
Factors influencing the overall survival were the degree of tumor differentiation, the depth of invasion and the number of lymph nodes resected (LN, cutoff = 18). Lymph node was recognized as an
independent prognostic factor for overall survival of advanced node-negative gastric cancer patients,
and the prognosis of the patients with greater number of lymph nodes resected (LN ≥ 18) was significantly better than those with lymph node < 18, and only the patients with T3/T4 stage could be
significantly stratified by lymph node. Based on this condition, a new staging system named
tumor-node-metastasis staging system for T3/T4 node-negative gastric cancer was constructed,
which could have statistically different overall survival between subgroups.
Conclusions: Lymph node was an independent prognostic factor of patients with advanced nodenegative gastric cancer, and retrieval of more than 18 lymph nodes should be warranted. In addition,
these patients with lesser number of lymph nodes resected might need aggressive postoperative
treatment and closer follow-up.
Key words: lymph node dissection, node negative, gastric cancer
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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LN dissection for advanced N0 gastric cancer
Introduction
Gastric cancer is the fourth most common malignancy globally and
accounts for the second leading cause of death from cancer worldwide
(1,2). At present, D2 lymphadenectomy is the standard approach of
radical gastrectomy for resectable advanced gastric cancer both in eastern and western countries, and requests that a minimum of 15 dissected
lymph nodes be collected from gastric cancer patients for accurate histological examination and postoperative assignment of lymph node metastatic category according to the current tumor-node-metastasis (TNM)
staging system for gastric cancer of the Union for International Cancer
Control/American Joint Committee on Cancer (UICC/AJCC) manual
(3–6). However, because of the variable ideas of the different doctors
from different hospitals of different regions and the limitations of
specimen collection and examination technology of pathologists, the
number of lymph nodes resected (LN) cannot always get to the number
required according to the UICC/AJCC TNM staging manual (7,8). So,
how to evaluate the tumor stage and prognosis of these gastric cancer
patients is one of the most vital things that the surgeons have to face.
The number of lymph nodes metastases is one of the most important determinants of prognosis in patients with gastric cancer and has
been identified as a staging parameter in the UICC/AJCC TNM staging classification for carcinoma of the stomach (6). Recently, the
lymph node metastases ratio (the ratio of metastatic to examined
lymph nodes) has also been demonstrated as an independent prognostic factor of gastric cancer patients and could reduce the phenomenon
of stage migration in many previous studies (9–11). However, the
node-negative patients with advanced gastric cancer are heterogeneous and the prognosis of these patients cannot be stratified by the
number of lymph nodes metastases and/or the lymph node metastases
ratio (12). In the light of these considerations, the aim of our present
study was to evaluate the clinicopathological features of the patients
with advanced node-negative gastric cancer, and to find whether
there was a common clinicopathological factor that could significantly
influence the clinical outcome of these patients.
In the current study, we investigated the clinicopathological features of the patients with advanced node-negative gastric cancer and
their correlation with the overall survival. The results indicated that
LN was an independent prognostic factor of patients with advanced
node-negative gastric cancer. Moreover, the newly constructed staging
system for T3/T4 node-negative gastric cancer, namely TLN staging
system, could refine prognostic stratification of node-negative gastric
Figure 1. Flowchart of the inclusion process of patients analyzed in this study.
cancer patients with T3/T4 stage, and has statistically different overall
survival between subgroups.
Patients and methods
Patients
We prospectively recruited consecutive patients with gastric cancer,
collected the clinicopathological data and detailed retrospectively analyzed the clinicopathological features correlating with overall survival
and their role in refining gastric cancer prognostic stratification (13–
17). Between January 2006 and December 2010, 1058 patients underwent radical surgical resection of gastric adenocarcinoma based on the
database of patients with gastric cancer in the Department of General
Surgery of Zhongshan Hospital of Fudan University (Shanghai,
China). Selected were the patients harboring advanced gastric adenocarcinoma with no lymph node and distant metastases pathologically
analyzed at the time of surgical resection and after surgery, all resulting negative for metastases at routine hematoxylin–eosin staining. Excluded were patients with early gastric cancer, lymph node metastases,
distant metastases, gastric stump cancer, infiltration of adjacent structures (T4b) and peritoneal dissemination. In addition, patients were
excluded if they had previously been exposed to any targeted therapy,
chemotherapy, radiotherapy or intervention therapy for gastric cancer. After operation, routine chemotherapy based on 5-fluorouracil
and oxaliplatin had been given to the patients with advanced-stage
disease, but no radiation treatment was done in any of patients included in our study. As a result, from a total number of 1058 patients
submitted to radical gastrectomy (R0 resection according to the UICC/
AJCC) and D2 lymphadenectomy for T2–T4 gastric adenocarcinoma
in the period 2006–10, 195 patients were included in the final analysis
(Fig. 1). All the operations were performed by well-trained surgeons
according to the guidelines of International Gastric Cancer Association and the Japanese Gastric Cancer Association. A retrospective
review of prospectively collected data was performed, and the clinicopathological features ( patient’s age, gender, tumor localization, degree
of tumor differentiation, tumor size, depth of invasion, lymphatic vessel invasion, number of lymph nodes dissection) and the oncological
results (overall survival rate) were analyzed. The stage of gastric cancer
is classified according to the TNM staging system of the seventh UICC/
AJCC manual (6). Dissected lymph nodes were taken out and histologic evaluation was pathologically reassessed independently by two
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Jpn J Clin Oncol, 2016, Vol. 46, No. 1
gastroenterology pathologists blinded to the clinical data according to
the Japanese General Rules for Gastric Cancer Study in Surgery and
Pathology. The follow-up was conducted until 31 December 2013
or until death, and the median follow-up for the patients was 37
months (range, 1–67 months). No patients had been lost to follow-up.
Ethical approval was granted by the Clinical Research Ethics Committee of Zhongshan Hospital of Fudan University (Shanghai, China).
Signed informed consent was obtained from all patients for the
acquisition and use of anonymized clinical data.
Statistical analysis
Statistical analysis was performed with MedCalc Software (version
11.4.2.0; MedCalc, Mariakerke, Belgium) and SPSS Software
(version 17.0; SPSS Inc., Chicago, IL, USA). The statistical significance
of categorical data was evaluated using χ 2 or Fisher’s exact test.
Cumulative survival time was calculated by Kaplan–Meier method
and analyzed by log-rank test. Numbers at risk were calculated for
the beginning of each time period. The Cox proportional hazards
regression model was used to perform univariate and multivariate
analyses. Receiver operating characteristic (ROC) analysis was used
to compare the sensitivity and specificity for the prediction of overall
survival by the parameters. All P values were two sided, and
differences were considered significant at values of P < 0.05.
Results
Clinicopathological features and correlation
with overall survival
Table 1 summarizes the clinicopathological characteristics of advanced node-negative gastric cancer patients without distant metastasis enrolled in this study, and their relationship with overall survival.
Most patents were male (71.8%) and old (>60 years, 58.5%), and had
a distal-located cancer (59.5%), poor differentiation (55.4%), smaller
tumor size (≤3.5 cm, 58.5%), lymphatic vessel invasion (84.6%) and
greater number of lymph nodes resected (≥15, 72.8%). The 3-year
and 5-year overall survival rates of this study population were 85.0
and 69.6%. Factors influencing the overall survival rate were the
degree of tumor differentiation (P = 0.035) and the depth of invasion
(T stage, P < 0.001).
Table 1. Patient demographics and clinicopathological
characteristics and correlation with overall survival
Factor
No. of patients
No. of events
All patients
Age(years)a
≤60
>60
Gender
Female
Male
Localization
Proximal
Middle
Distal
Differentiation
Well
Moderate
Poor
Tumor size (cm)a
≤3.5
>3.5
T stage
T2
T3
T4
Lymphatic vessel invasion
Absent
Present
No. of LNs
<15
≥15
195
37
81
114
13
24
55
140
12
25
38
41
116
9
5
23
11
76
108
1
8
28
114
81
21
16
65
67
63
4
12
21
165
30
30
7
53
142
16
21
P*
0.186
0.739
0.417
0.035
0.822
<0.001
0.365
0.056
LNs, lymph nodes resected.
a
Split at median.
*P < 0.05 was considered statistically significant.
P value (P = 0.003). Under these conditions, LN was divided into
two groups (cutoff = 18, LN0, LNs < 18; LN1, LNs ≥ 18). According
to this criterion, approximately 39.49% (77 of 195) LN were scored
as LN0 and 60.51% (118 of 195) LN were scored as LN1 in the
patients enrolled in this study.
Best cutoff of the number of lymph nodes resected
The current TNM staging system for gastric cancer according to the
seventh UICC/AJCC cancer staging manual requires that a minimum
of 15 lymph nodes be collected from the gastric cancer patient for accurate histological examination and postoperative assignment of
lymph node metastatic category. D2 lymphadenectomy was done in
every case of this study population, and the mean number of lymph
nodes resected was 21. As shown in Table 1, LN (cutoff = 15) was
not significantly associated with the overall survival of advanced
node-negative gastric cancer patents following radical gastrectomy
(P = 0.056), but it might have the potential to stratify the advanced
node-negative patients with different prognosis. Based on this hypothesis, we further evaluated the prognostic value of the different number
of lymph nodes resected in advanced node-negative gastric cancer patients following radical gastrectomy. The area under the receiver operating characteristic curves (AUC) at different cutoff values of overall
survival time was calculated to determine the optimal cutoff value
of LN in advanced node-negative gastric cancer. As shown in Fig. 2,
the optimal value of cutoff point of LN was 18 due to its best predictive value (AUC, 0.657; 95% CI, 0.558–0.755) and the smallest
Overall survival benefit of greater number of lymph
nodes dissection
In order to estimate the clinical prognostic significance of LN that
might influence the overall survival of patients enrolled in this study,
univariate analyses for overall survival were performed. As shown in
Table 2, LN (cutoff = 18) is a significant prognostic predictor for patients with advanced node-negative gastric cancer. The prognosis of
these patients with LN ≥ 18 was significantly better than those with
LN < 18. (hazard ratio [HR], 0.383; 95% CI, 0.195–0.755; P = 0.006;
Fig. 3A). To evaluate the robustness of the prognostic value of LN,
Cox multivariate regression analyses were performed to derive risk estimates related to overall survival with the same clinicopathological
parameters that show significance in univariate analyses to control
for confounders. As shown in Table 3, LN (P = 0.001) and T stage
(P = 0.008) were both recognized as independent prognostic factors
for overall survival of advanced node-negative gastric cancer patients.
In addition, in order to determine whether LN could stratify patients
with each T-stage stratum, we evaluated the prognostic value of LN
and did stratified analyses of advanced node-negative gastric cancer
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LN dissection for advanced N0 gastric cancer
Figure 2. The optimal cutoff value of LN was obtained by ROC analysis. LN, the number of lymph nodes resected; ROC, receiver operating characteristic.
Table 2. Univariate Cox regression analyses for overall survival according to the LNs in different T stage
Factor
No. of patients
No. of events
OS (univariate)
Hazard ratio (95% CI)
All patients
LNs < 18
LNs ≥ 18
T2 stage
LNs < 18
LNs ≥ 18
T3 stage
LNs < 18
LNs ≥ 18
T4 stage
LNs < 18
LNs ≥ 18
195
77
118
37
24
13
1.000 (reference)
0.383 (0.195–0.755)
31
34
3
1
1.000 (reference)
0.351 (0.036–3.460)
24
43
8
4
1.000 (reference)
0.292 (0.088–0.974)
22
41
13
8
1.000 (reference)
0.352 (0.146–0.851)
P*
0.006
0.370
0.045
0.020
OS, overall survival; 95% CI, 95% confidence interval.
*P < 0.05 was considered statistically significant.
patients with T2 stage, T3 stage and T4 stage respectively. As shown in
Table 2, only the node-negative patients with T3 and T4 stages could
be significantly stratified by LN, the prognosis of T3/T4 stage patients
with the greater number of lymph nodes resected (LN ≥ 18) was significantly better than those with LN < 18 (P = 0.045 and P = 0.020, respectively; Fig. 3B–D). Taken together, our findings indicate that LN
may be a useful marker to predict the overall survival of advanced
node-negative patients with gastric cancer, and the patients with T3/
T4 stage did need more lymph nodes to resect, even though the lymph
nodes resected were not metastases.
Overall survival based on the TLN stage
The current TNM staging system was determined on the basis of T, N
and M stage definitions from the seventh edition of the UICC/AJCC
cancer staging manual of gastric cancer. However, there is only one
parameter, T stage, to work for node-negative gastric cancer patients
without distant metastasis, especially the advanced gastric cancer, just
because the T1 cancers are very low risk of lymph node metastasis and
recurrence. As shown in Table 2 and Fig. 3, only the node-negative patients with T3/T4 stage could be significantly stratified by LN. So
based on this condition, we put forward a new staging system, namely
TLN staging system, constructed on the basis of the same T definitions
from the seventh UICC/AJCC staging system and the aforementioned
LN definitions (LN0, LNs < 18; LN1, LNs ≥ 18) for patients with T3/
T4 node-negative gastric cancer without distant metastasis. To evaluate the performance of the TLN staging system, UICC/AJCC T3 stage
and T4 stage were stratified by LN. As shown in Table 4 and Fig. 4,
advanced node-negative gastric cancer patients with T3LN1 stage had
the best prognosis (5-year OS rate, 90.7%), whereas patients with
T4LN0 had the worse (5-year OS rate, 40.9%). In addition, the advanced node-negative patients of T4 stage with the greater number
of lymph nodes resected (LN ≥ 18) could have the better prognosis
than patients with T3 stage and LN < 18 although there was no
statistical significance (5-year OS rate, 80.5 vs 66.7%, P = 0.542,
Fig. 4A and B).
Discussion
Gastric cancer is still a universal health problem and accounts for the
second leading cause of cancer-related mortality globally (1,2,18). D2
lymphadenectomy is the standard approach of radical gastrectomy for
resectable advanced gastric cancer, and requests that a minimum of 15
dissected lymph nodes be collected from gastric cancer patient for an
adequate assessment of the N category of TNM staging system of
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Jpn J Clin Oncol, 2016, Vol. 46, No. 1
Figure 3. Kaplan–Meier analyses of overall survival according to the number of lymph nodes resected in patients with advanced node-negative gastric cancer in
(A) All patients (n = 195), (B) T2 stage (n = 65), (C) T3 stage (n = 67) and (D) T4 stage (n = 63). P value was calculated by log-rank test.
Table 3. Multivariate Cox regression analyses for overall survival
Factor
No. of patients
No. of events
OS (multivariate)
Hazard ratio (95% CI)
All patients
Differentiation
Well
Moderate
Poor
T stage
T2
T3
T4
No. of LNs
<18
≥18
195
37
11
76
108
1
8
28
1.000 (reference)
1.445 (0.148–14.090)
1.583 (0.136–18.409)
65
67
63
4
12
21
1.000 (reference)
2.767 (0.640– 11.953)
6.485 (1.523–27.620)
77
118
24
13
1.000 (reference)
0.317 (0.160–0.627)
P*
0.934
0.751
0.714
0.008
0.173
0.011
0.001
*P < 0.05 was considered statistically significant.
UICC/AJCC manual (5,6,19). The number of lymph nodes metastases
is one of the most important determinants of prognosis in patients
with gastric cancer and has been widely accepted and applied for
prognostic prediction as a staging parameter for carcinoma of the
stomach (7). However, in clinical practice, because of the variable
ideas of the different doctors from different hospitals of different
68
LN dissection for advanced N0 gastric cancer
Table 4. Log-rank test on overall survival according to the TLN stage including T stage and LNs stage
Factor
TLN stage
T3LN0
T3LN1
T4LN0
T4LN1
No. of patients
No. of events
Overall survival rate
P*
3 years (%)
5 years (%)
79.2
90.7
63.6
80.5
66.7
90.7
40.9
80.5
<0.001
24
43
22
41
8
4
13
8
LN0, lymph nodes resected <18; LN1, lymph nodes resected ≥18;
*P < 0.05 was considered statistically significant.
Figure 4. Kaplan–Meier analyses of overall survival according to T stage (A) and TLN stage (B) in advanced node-negative gastric cancer patients with the seventh
UICC/AJCC T3/4 stage. P value was calculated by log-rank test.
regions and the limitations of specimen collection and examination
technology of pathologists, the number of lymph nodes resected cannot always get to the number required even in major hospitals and
medical centers in China, especially in the patients with advanced
node-negative gastric cancer, who are lacking independent and convenient markers except for T stage which could significantly influence
the clinical outcome. This fact weakened the predictive role of TNM
staging system for the prognosis of these patients. Based on the situation above, in order to find potential outcome indicators as the supplementary of TNM staging system and provide some useful
information of prognosis for these patients, we designed this study.
In the present research, we evaluated the clinicopathological features
of the patients with advanced node-negative gastric cancer and their
correlation with the overall survival, and found that the prognosis
of the patients with greater number of lymph nodes resected (LN ≥ 18)
was significantly and independently better than those with LN < 18,
and only the patients with T3/T4 stage could be significantly stratified
by LN. Moreover, based on this condition, we put forward a new staging system, namely TLN staging system, for T3/T4 node-negative
gastric cancer, which could have statistically different overall survival
between subgroups. These results indicated that LN was an independent prognostic factor of patients with advanced node-negative gastric
cancer except for T stage, and retrieval of more than 18 lymph nodes
should be warranted. In addition, these patients with lesser number of
lymph nodes resected might need aggressive postoperative treatment
and closer follow-up.
In clinical practice, there is a wide range of the number of dissected
lymph nodes in D2 lymphadenectomy for resectable advanced gastric
cancer, which might result in stage migration (9–11,20). This phenomenon exists in reality because of various kinds of reasons, such as the
individual differences of patients with gastric cancer. All the operations in this study were performed by an experienced gastric cancer
surgery team according to the guidelines of International Gastric Cancer Association and the Japanese Gastric Cancer Association. In addition, dissected lymph nodes were taken out and histologic evaluation
was pathologically reassessed independently by two gastroenterology
pathologists blinded to the clinical data according to the Japanese
General Rules for Gastric Cancer Study in Surgery and Pathology.
Based on the above data, although we could not completely eliminate
the effect of stage migration and the number of lymph nodes dissected
might induce stage migration, the impact on stage migration is little
and acceptable. Additionally, in order to elucidate stage migration, except for the traditional indicator of lymph nodes metastases, recently,
the lymph node metastases ratio has also been demonstrated as an
Jpn J Clin Oncol, 2016, Vol. 46, No. 1
independent prognostic factor of gastric cancer patients and could
reduce the phenomenon of stage migration in many previous studies
(9–11,20). However, in the population of patients with advanced
node-negative gastric cancer, their clinical outcomes are heterogeneous and the prognosis of these patients cannot be stratified by the
number of lymph nodes metastases and/or the lymph node metastases
ratio (12). And a common clinicopathological factor except for T stage
that could significantly influence the clinical outcome of advanced
node-negative gastric cancer patients following radical gastrectomy
was unknown (21–24). So, finding a common clinicopathological
factor that could significantly influence the clinical outcome of these
patients was one of the most important and interesting things that
the surgeons have to face. Zhang et al. reported that the number of
lymph nodes retrieved was an independent prognostic factor for the
node-negative gastric cancer patients, and survival was improved as
the number of lymph nodes retrieved >15. However, the gastric cancer
patients with all T stages had been enrolled in their study, including
the early gastric cancer with fewer lymph nodes metastases and better
prognosis. In addition, most of the number of lymph nodes resected
from the patients was <15 (74 of 106, 69.8%) (25). In the present
study, we evaluated the clinicopathological features of the patients
with advanced node-negative gastric cancer and their correlation
with the overall survival, and there were 60.5% (118 of 195) of patients enrolled in this study with lymph nodes resected >18. The results
of this research indicated that LN was an independent prognostic
factor, which could provide some useful information of prognosis
for these patients.
Another factor that might result in stage migration is lymph nodes
micrometastases. Micrometastases and isolated tumor cells are small
tumor cells or clusters detected by hematoxylin–eosin staining or
immunohistochemistry using specific monoclonal antibodies (26).
The seventh TNM staging system for gastric cancer of UICC/AJCC
manual defines micrometastases as metastatic lesions ranging in size
from 0.2 to 2.0 mm and isolated tumor cells which are either single
cells or aggregates reaching the size of <0.2 mm (6). The clinical significance of lymph nodes micrometastases examination is still debated.
Many experts suspect lymph nodes micrometastases to be a key prognostic factor for recurrence and metastases in the gastric cancer patients, but the others do not agree it. Recently, a meta-analysis of
observational studies about lymph nodes micrometastases of early
and advanced gastric cancer showed that there is a positive correlation
between lymph nodes micrometastases and an unfavorable surgical
outcome in gastric cancer patients (9). However, Theresa et al. (27)
had been reported that immunohistostaining of regional lymph
nodes in node-negative gastric cancer patients led to an increased
detection of lymph nodes micrometastases with significant implications for the staging system, but there was no impact on the survival
time of these patients. Previously in vitro research indicated that some
of the isolated tumor cells will be regressed spontaneously upon resection of the primary tumor owing to the activity of natural killer cells,
whereas micrometastases continued to proliferate and eventually grew
into gross metastases (28). For the above situation, the clinical significance of station of micrometastases and isolated tumor cells in lymph
nodes dissected is not very clear. In the current study, we demonstrated
that greater number of lymph nodes dissection for advanced nodenegative gastric cancer patients following radical gastrectomy is associated with better prognosis. This maybe because that the greater number of lymph nodes dissection removed the lymph nodes or the
lymphatic vessels with potential micrometastases in the perigastric
soft tissues, which might result in the recurrence and poor prognosis
in some patients with gastric cancer, especially the patents with T3/T4
69
stage after radical gastrectomy. However, there is no denying that
there must be other reasons under these results, the potential mechanisms and profound clinical impact of LN in advanced node-negative
gastric cancer patients remains far from fully understood and merit
further investigation.
There are several limitations of this study. First, this study is a
retrospective analysis and may have some selection biases although
we collected the data from a prospectively recruited database. Second,
this study does not consider the problem of micrometastases and isolated tumor cells in lymph nodes, because the only performed histologic evaluation was the standard hematoxylin–eosin staining.
Third, there is not including the data of disease free survival in this
study. There are many factors, such as the follow-up examinations
and the postoperative treatment, might influence the disease-free survival of gastric cancer patients. And the disease-free survival data
should be collected in the future researches.
In conclusion, our results demonstrate that LN was an independent prognostic factor of patients with advanced node-negative gastric
cancer. Moreover, the newly constructed TLN staging system could refine prognostic stratification of node-negative gastric cancer patients
with T3/T4 stage, and had statistically different overall survival between subgroups. Based on these results, the advanced node-negative
patients with greater number of lymph nodes dissection would have
better prognosis than the others, who should have appropriate surveillance and aggressive postoperative treatment. However, the potential
clinical practice impact should be validated in the prospective randomized controlled clinical studies in the future.
Funding
This work was supported by grants from National Natural Science
Fund (81501999) and Fund of Zhongshan Hospital of Fudan University
(2015ZSQN44).
Conflict of interest statement
None declared.
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