AIM: To elucidate the potential impact of examined lymph nodes (eLNs) on long-term survival of node-negative gastric cancer patients after curative surgery.

METHODS: A total of 497 node-negative gastric cancer patients who underwent curative gastrectomy between January 2000 and December 2008 in our center were enrolled in this study. Patients were divided into 4 groups according to eLNs through cut-point analysis. Clinicopathological features were compared between ≤ 15 eLNs group and > 15 eLNs group and potential prognostic factors were analyzed. The Log-rank test was used to assess statistical differences between the groups. Independent prognostic factors were identified using the Cox proportional hazards regression model. Stratified analysis was performed to investigate the impact of eLNs on patient survival in each stage. Overall survival was also compared among the four groups. Finally, we explored the recurrent sites associated with eLNs.

RESULTS: Patients with eLNs > 15 had a better survival compared with those with eLNs ≤ 15 for the entire cohort. By the multivariate survival analysis, we found that the depth of invasion and the number of eLNs were the independent predictors of overall survival (OS) of patients with node-negative gastric cancer. According to the cut-point analysis, T2-T4 patients with 11-15 eLNs had a significantly longer mean OS than those with 4-10 eLNs or 1-3 eLNs. Patients with ≤ 15 eLNs were more likely to experience locoregional and peritoneal recurrence than those with > 15eLNs.

CONCLUSION: Number of eLNs could predict the prognosis of node-negative gastric cancer, and dissection of > 15 eLNs is recommended during lymphadenectomy so as to improve the long-term survival.

Lymph node metastasis is one of the most important prognostic factors for gastric cancer patients following curative resection[1,2]. It is generally accepted that patients could benefit from a standardized approach of lymphadenectomy in terms of a higher overall survival (OS)[3-5]. At present, the category based on the absolute number of metastatic lymph nodes has been adopted by the Union for International Cancer Control (UICC) and American Joint Commission for Cancer as the N stage of the tumour, node, metastasis (TNM) classification since 1997 and the examination of no less than 15 regional lymph nodes was recommended for nodal metastatic status determination according to the latest version[6-8]. The 7^th edition of the TNM classification designates node-negative (N0) disease as any gastric cancer with all examined lymph nodes (eLNs) negative, regardless of the total number of eLNs. Several studies have found that the prognosis of node-negative gastric cancer patients was associated with the number of dissected lymph nodes[9,10]. However, there is still controversy over how many nodes should be removed and examined when performing a radical gastrectomy for node-negative gastric cancer patients[9-11]. Therefore, the aim of the present study was to determine the optimal number of eLNs required for curative surgery. Furthermore, we intend to explore an appropriate classification based on the count of eLNs for precise prediction of the prognosis of gastric cancer patients with node-negative metastasis after curative surgery.

Although several new staging methods have been proposed to evaluate the prognosis of gastric cancer, the TNM staging system based on the count of positive lymph nodes is still widely used, for the number of positive lymph nodes reflects well the prognosis[15-17]. It was reported that gastric cancer patients might be staged incorrectly because of an insufficient number of eLNs[18]. Large population studies from various institutions and countries demonstrated that there was a significant association between the number of eLNs and the OS of patients, so the latest TNM staging system recommends that no less than 15 lymph nodes should be examined for the accuracy of N staging[6-8]. Meanwhile, the same edition staging system designates node-negative disease as any gastric cancer with all eLNs negative, regardless of the total number of eLNs, thus the present study was designed to determine the optimal number of lymph nodes required for curative surgery for node-negative gastric cancer.

Adachi et al[19] pointed out that the clinicopathologic characteristics and prognosis of node-negative gastric cancer patients were similar to those of patients with early gastric cancer. Several studies showed that in patients with node-negative gastric cancer, the 5- and 10-year OS rates varied from 72% to 92% and 88% to 93%, respectively, and these patients had a significantly better survival than the patients with node-positive gastric cancer[20-24]. In this study, the 5-YSR was 67.2%, which was lower than that observed in studies in Japan and Korea due largely to the lower proportion of patients with early stage disease (6.8%) in our study. Our previous study found that the node-positive gastric cancer patients had a better OS with an increased count of negative lymph nodes retrieved[17]. This phenomenon was also observed in the studies about node-negative gastric cancer. There are several possible explanations for this observation. First, there may have been lymph node metastases that were missed during dissection or pathological examination in node-negative patients who had ≤ 15 eLNs, which may cause inappropriate understaging. More eLNs should increase the opportunity to find metastatic lymph nodes, which could reduce the influence of inappropriate understaging[25-27]. Second, micrometastasis was considered to play an important role in prognosis of gastric cancer patients. Patients with micrometastasis were reported to have an especially high risk of recurrence[10]. It was reported that 17%-32% of node-negative gastric cancer patients were identified by routine histologic examination, and micrometastasis was detected by immunohistochemical and molecular examinations. Therefore, dissection of adequate negative lymph nodes could improve the prognosis of node-negative gastric cancer patients by reducing micrometastasis. Third, several studies have confirmed that lymphovascular invasion is associated with poor survival in gastric cancer patients[28,29]. More eLNs means dissection of potential lymphovascular invasion, which may improve prognosis by reducing recurrence. In addition, it is speculated that patients with more lymph nodes in the specimen have better immune response against the tumor, and smaller LNs were correlated with decreased immune response in gastrointestinal cancer[32]. Strong immune status also contributes to good prognosis.

Son et al[33] investigated 10010 patients with gastric cancer, and the results showed that the majority of patients with ≤ 15 eLNs had T1 tumors (64.2%) or pN₀ disease (81.3%). Consequently, the patients with no more than 15 eLNs had a significantly worse prognosis after they underwent standard curative lymphadenectomy, compared with patients with > 15 eLNs. Our data revealed that there were significant survival differences between the patients who had > 15 eLNs and ≤ 15 eLNs by cut-point analysis. By the multivariate analyses, we found that the number of eLNs is an independent prognostic factor that was associated with a worse prognosis. In this study, 66.6% of patients had ≤ 15 eLNs, which contributed to the lower OS of the entire cohort. The main reasons for examination of ≤ 15 eLNs after curative gastrectomy were deemed to be the inaccurate lymph node dissection or examination[34-36]. These inaccuracies most likely occur by inexperienced surgeons or pathologists[37]. In addition, the inaccurate lymph node dissection was considered to be closely related to host clinicopathologic status and immunologic response[38,39]. Besides, patient^，s comorbidities, the intrinsic number of LNs, and lymphovascular invasion status may play a role in inadequate LN dissection and assessment. Therefore, it is important to evaluate the prognostic value for patients with ≤ 15 eLNs. In this study, we performed cut-point analysis and determined 3 cut-off points to classify all patients into 4 subgroups as 1-3, 4-10, 11-15, and ≥ 16 eLNs, which can not only reflect the distribution of eLNs, but also demonstrate the correlation between the prognosis of patients and the number of eLNs intuitively.

Gastrectomy with lymphadenectomy remains the standard treatment option for gastric cancer, while it is often performed without an accurate knowledge of nodal status. Sentinel lymph node (SLN) is defined as the first LN to receive drainage by a primary tumor. Therefore, the status of SLN could predict the overall status of LN metastasis. As extensive lymphadenectomies are not without complications, limited gastric resections without an extended lymphadenectomy have been applied to the selected patients with early gastric cancer according to the status of SLN[40]. For early N0 gastric cancer, SLN should be used in selected patients for less invasive surgical approaches, while it is not easy to predict accurately the status of LN metastasis through SLN because lymphatic drainage is complex for advanced N0 disease, so the extended lymphadenectomy is still essential for advanced gastric cancer. In addition to the number of eLNs, the depth of tumor invasion was identified as one of the most important prognostic indicators of node-negative gastric cancer in the present study, which was similar to other studies[9,20-23,33]. The number of eLNs was reported to be associated with depth of invasion. Compared with the patients who had less than 6 eLNs, patients who had 6-10 eLNs, 11-15 eLNs, and ≥ 16 eLNs had a significantly lower chance of death in T2-4 disease, while the gastric cancer specific survival among different eLNs groups had no statistical difference in T1 stage, because patients with stage T1 disease have a small number of cases and a higher 5-YSR[9].

Based on our results, patients with > 15 eLNs had better prognosis than those with ≤ 15 eLNs in T2-T4 stages. Patients with ≤ 15 eLNs should be divided into 3 groups as 1-3 eLNs, 4-10 eLNs, and 11-15 eLNs for acquisition of significant statistical differences among the subgroups of patients in T2-T4 stages. Recently, Huang et al[22] suggested that the D2 lymphadenectomy should involve 15 nodes for pT1-T2 disease and 20 nodes for pT₃-T₄ disease. However, it is difficult to determine accurately the T stage before surgery. From our results, we suggested that patients with node-negative gastric cancer following curative dissection should have more than 15 eLNs. It should be considered as a necessary supplement to the TNM staging system.