Should the left gastric artery lymph node be considered as the predictive lymph node for extra-gastric lymph node metastases?

Introduction

Gastric cancer (GC) has a tendency toward lymphatic metastasis due to the abundant lymphatic vessels in the stomach wall. Lymphadenectomy has an important clinical impact, and the extent of lymphadenectomy may directly influence the patients’ survival outcome after radical gastronomy. The No. 7 station (along the left gastric artery) is a specific anatomic lymph node (LN) station located between peri-gastric LNs and other extra-gastric LNs in GC patients. In theory, the No. 7 LN station is not defined as one of the peri-gastric LN stations based on its anatomical location, despite the high incidence of metastatic incidents occurring close to the peri-gastric LN stations (1,2). According to the latest Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) guidelines for GC (3), No. 7 station LNs should be considered while evaluating the extent of D2 lymphadenectomy. However, in the latest edition of the Japanese Gastric Cancer Treatment Guidelines (the 3^rd edition) and the 14^th edition of the Japanese General Rules for Gastric Cancer Study, the No. 7 LN station was assigned to the range of both D1 plus and D2 lymphadenectomy (4,5). That is to say, GC patients with cT1N0M0 stage disease might undergo different lymphadenectomies in different countries. Therefore, the clinical significance of the No. 7 station for GC patients remains controversial according to the current literature (1,6-9).

In order to evaluate precisely the range of LN metastasis, the concept of sentinel LNs (SLNs) arised, which was defined as the first draining LNs that obtain lymphatic flow from a primary tumor (10). The concept of SLNs is gradually being accepted and applied to GC, and novel techniques for SLN mapping have been developed, such as methods using dyes or radioisotopes (11-13). However, identifying specific SLNs in cases of GC is challenging, due to the complexity of lymphatic drainage from the gastric area (14,15). And SLNs seldom provides much benefit to predict the extra-gastric LN station or distant metastasis. Thus, new predictive factors are needed to identify the extra-gastric LN or distant metastasis. On the other hand, multiple recent studies have reported that the No. 7 LN station was the most common extra-gastric LN station to be involved in metastasis, regardless of tumor location (16-18). Taking anatomical location and high incidence of metastatic incidents of No. 7 LN station into account, we hypothesized that the No. 7 station should be on the main lymph routine and be a predictive LN for extra-gastric LN metastases. However, few studies have evaluated whether the No. 7 LN station might be considered as the predictive marker for determining the extent of lymphadenectomy in GC patients.

In this study, we aimed to demonstrate the prognostic impact of the No. 7 LN station and to validate whether the No. 7 LN should be considered as the predictive LN for other extra-gastric LN metastases in GC patients.

We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-19-4786a).

Methods

Patients

Between January 2003 and December 2011, a total of 1,923 GC patients who underwent R0 gastrectomy at Tianjin Medical University Cancer Institute and Hospital. The clinicopathologic date and fellow-up records of 1,923 GC patients were retrospectively reviewed after receiving Institutional Review Board approval. Eligibility criteria included: (I) proven histologically primary gastric carcinoma; (II) curative gastrectomy with pathologically negative resection margins (R0 resection); (III) remaining alive at the initial hospital stay and the first postoperative month. The exclusion criteria were: (I) distant metastases or peritoneal dissemination; (II) skip LN metastases; (III) posterior (No. 8p, No. 12b/p, No. 13, and No. 14v) or para-aortic (No. 16a2, and No. 16b1) LNs metastases; (IV) history of gastrectomy or other malignancies; (V) history of neoadjuvant chemotherapy; and (VI) loss of follow up.

Ultimately, 1,586 patients in total were included in this study (Figure S1). Of these 1,586 GC patients, 897 (56.56%) presented LN metastases, and 235 (14.82%) presented the No. 7 LN metastases. According to the range of LN involved, all included patients with LN involvement were divided into three groups of cases: (I) LN metastases limited to peri-gastric area (peri-gastric group), (II) peri-gastric LN metastases with only No. 7 LN metastases (No. 7 group), and (III) peri-gastric LN metastases with other extra-gastric LN metastases (extra-gastric group).

Figure S1 Patients flow diagram: eligibility criteria and exclusion criteria in this study. GC, gastric cancer; LN, lymph node.

The study was approved by Tianjin Medical University Cancer Institute and Hospital ethics committees (No. bc2019087). All patients provided written informed consent before any enrolling procedures were initiated.

Surgical management

All included patients underwent the curative gastrectomy with lymphadenectomy for GC. Curative resection was defined as the complete absence of grossly visible tumor tissue and pathologically negative resection margins. The pT stage and pN stage were according to AJCC TNM staging system (19). The nodes staging system was defined according to the 13^th edition of JCGC (Japanese Gastric Cancer Association, JCGC) (20). Peri-gastric LN stations were defined as n1-tire (from No. 1 to No. 6) LN station, whereas LN stations along the left gastric artery (No. 7), along the common hepatic artery (No. 8a), the celiac axis (No. 9), the splenic hilar(No. 10), splenic artery (No. 11) and the proper hepatic artery (No. 12a) were defined as extra-gastric LN stations. Skip LN metastases were defined as the presence of a metastatic LN in an extra-gastric area without peri-gastric LN involvement (21).

Follow-up

After curative surgery for GC, all patients were followed-up every 3 or 6 months for 2 years, and annually, thereafter, until death or deadline. The median follow-up time for the entire cohort was 33 months (range, 2 to 148 months). The deadline of follow-up in this study was December 2015. At every visit, patients underwent ultrasonography, computed tomography, chest radiography, and endoscopy. Overall survival (OS) served as the primary end-point, and was defined as the time interval between the date of surgery and the date of either death as a result of GC or the last follow-up. During the follow-up period, 1,229 patients (77.49%) died.

Propensity score matching (PSM)

To overcome possible selection bias, one-to-one matching using PSM was performed in this study (22,23). The propensity score, defined as the conditional probability of patients being treated given the covariates, could be used to balance the covariates in two groups and therefore reduce such bias (24,25). It had also been reported that potential confounding variables that could be unrelated to the exposure but related to the outcome should be included in the propensity score model, and that this would decrease the variance of an estimated exposure effect without increasing the bias (26). The propensity scores were estimated by using a non-parsimonious multiple logistic regression model. In this study, the No. 7 LN metastases were significant correlated with pN stage (spearman r=0.424, P<0.001). Therefore, the following covariates were selected for the calculation of the propensity score: gender, age, tumor location, tumor size, pT stage, Borrmann type, Lauren type, vasculolymphatic invasion, neurological invasion and adjuvant chemotherapy.

Statistical analysis

The χ² or Fisher’s exact test used for categorical variables, and a t test was used for continuous variables. Factors that showed significant difference in the univariate analysis (P<0.05) were included in the multivariate analysis. Multivariate analysis was performed using a logistic regression model for the evaluation of the predictive risk factors. OS was determined using the Kaplan-Meier method, and a log-rank test was used to evaluate significance. Multivariate analyses of OS were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) through the Cox regression model. In all statistical analyses, significance was defined as P<0.05 (two-sided). All statistical analyses were performed using the statistical analysis program package SPSS version 24.0 (SPSS, Chicago, IL, United States).

Results

Survival analysis of the No. 7 station LN metastases

The prognostic impact of the No. 7 station LN metastases in patients was determined. During the follow-up, 1,229 patients died and 357 patients remained alive. Kaplan-Meier analyses showed a significant difference in terms of prognosis between the No. 7 LN-negative (no metastasis) and the No. 7 LN-positive (metastases) patients (HR 1.795, 95% CI: 1.545–2.086, P<0.001, Figure 1A). The median survival time of No. 7 LN-negative and No. 7 LN-positive patients was 38±1.757 vs. 18±1.730 months. That survival difference was also significant after stratification by pTNM stage (III stage with vs. without the No. 7 LN metastases: HR 1.225, 95% CI: 1.043–1.439, P=0.014, Figure 1B). Although the small-scale samples resulted in the non-significant difference in patients with II stage (II stage with vs. without the No. 7 metastases, HR 1.392, 95% CI: 0.763–2.539, P=0.281), the potential tendency of survival difference might be observed in the Figure 1B.

Figure 1 Kaplan-Meier curves for overall survival (A) between patients with No. 7 LN metastasis and patients without No. 7 LN metastasis; (B) after adjustment by pTNM stage. LN, lymph node. No. 7 LN, LN along the left gastric artery. No. 7 (+), with No. 7 LN metastasis; No. 7 (−), without No. 7 LN metastasis; HR, hazard ratio; CI, confidence interval.

PSM among peri-gastric, the No. 7 and extra-gastric group

Table 1 showed the clinical characteristics of GC patients of peri-gastric group and the No. 7 group. Before PSM, some significant differences were observed between two groups: tumor location (P<0.001), and Borrmann type (P=0.119). The differences between peri-gastric and the No. 7 groups were well balanced after PSM: tumor location (P=0.858), and Borrmann type (P=0.425). Ultimately, 138pairs patients were analyzed after PSM. As Table 2 showed, the differences between the No. 7 and extra-gastric group were also immensely reduced after PSM: tumor location (before vs. after: P<0.001 vs. P=0.125), tumor size (before vs. after: P=0.104 vs. P=0.286), pT stage (before vs. after: P=0.071 vs. P=0.106), and Borrmann type (before vs. after: P<0.001 vs. P=0.207). Ultimately, 113 pair patients were enrolled after PSM.

Table 1 Clinical characteristics of patients of peri-gastric group and No. 7 group before and after propensity score matching
Full table

Table 2 Clinical characteristics of patients of No. 7 group and extra-gastric group before and after propensity score matching
Full table

Prognostic analysis before and after PSM

The prognostic analysis among peri-gastric, the No. 7 and extra-gastric groups was performed (Figure 2A). During the follow-up, the survival rates of these three groups were respectively: 15.4% (81/524), 13.04% (21/161) and 10.38% (22/212). And the median survival time were respectively: 24±1.381, 18±2.819, and 18±1.266 months. Before matching, Kaplan-Meier curve showed a significant difference in terms of prognosis between the No. 7 group and peri-gastric group (HR 1.227, 95% CI: 1.014–1.484, P=0.035, Figure 2B), but no significant difference in survival outcomes between the No. 7 group and extra-gastric group (HR 1.084, 95% CI: 0.872–1.349, P=0.467, Figure 2C). After PSM, the OS was also significantly poorer in the No. 7 group compared with peri-gastric group (HR 1.360, 95% CI: 1.051–1.761, P=0.020, Figure 2D). Similarly, the close survival rate between No. 7 group and extra-gastric group (HR 1.123, 95% CI: 0.851–1.482, P=0.411, Figure 2E) was observed after PSM.

Figure 2 Kaplan-Meier curves for overall survival (A) among peri-gastric group, No. 7 group and extra-gastric group; (B) between peri-gastric group and No. 7 group before PSM; (C) between No. 7 and extra-gastric group before PSM; (D) between peri-gastric group and No. 7 group after PSM; (E) between No. 7 and extra-gastric group after PSM. PSM, propensity score matching; LN, lymph node; No. 7 LN, LN along the left gastric artery; HR, hazard ratio; CI, confidence interval.

Survival analysis for patients with extra-gastric LN metastases except the No. 7 LN

Patients in the extra-gastric group were further subdivided into two subgroups: 138 (37.00%) patients with extra-gastric LN except No. 7 LN metastases (No. 8a, No. 9, No. 10, No. 11, or No. 12a), and 74 (19.84%) presented with both the No. 7 LN and other extra-gastric LN metastases (Figure 3A).Patients without the No. 7 LN metastases failed to be elucidated to be significantly associated with the higher survival rate compared to other subgroups of patients (Figure 3B), which indicated the No. 7 LN should not be considered as the predictive LN for the extra-gastric LN metastases.

Figure 3 Survival analysis for patients with extra-gastric LN metastases. (A) Patients with extra-gastric LN metastases were subdivided into three subgroups: patients with only No. 7 LN metastases, patients with extra-gastric LN except No. 7 LN metastases, and patients with both No. 7 LN and other extra-gastric LN metastases; (B) Kaplan-Meier curves for overall survival among three subgroups. LN, lymph node; No. 7 LN, LN along the left gastric artery; HR, hazard ratio; CI, confidence interval.

Correlation analysis of risk factors for the No. 7 LN metastases

Among 1,586 patients, 235 (14.82%) presented with the No. 7 LN metastases. The median number of the No. 7 LNs examined was 2 (range, 1 to 27). As shown in Table 3, the univariate analysis showed that the No. 7 LN metastases were significantly related with thirteen clinicopathologic characteristics: tumor location (P=0.014), tumor size (P=0.027), number of LNs examined (P<0.001), pT stage (P=0.003), pN stage (P<0.001), Lauren type (P=0.024), No. 1 LN metastatic status (P<0.001), No. 2 LN metastatic status (P<0.001), No. 3 LN metastatic status (P<0.001), No. 4sa LN metastatic status (P=0.018), No. 4sb LN metastatic status (P<0.001), No. 5 LN metastatic status (P<0.001) and No. 6 LN metastatic status (P<0.001). However, pN stage [odds ratio (OR) 2.358, 95% confidence interval (CI): 1.840 to 3.022, P<0.001], No. 3 LN metastatic status (OR 2.089, 95% CI: 1.097 to 3.980, P=0.025), and No. 5 LN metastatic status (OR 2.023, 95% CI: 1.021 to 4.010, P=0.043) were identified as independent risk factors for the No. 7 LN metastases by using the multivariate logistic analysis.

Table 3 Univariate and multivariate correlation analysis for the No. 7 LN metastases
Full table

Discussion

In this study, we found that the OS rate of patients with metastases in the No. 7 station in addition to peri-gastric stations was significantly lower than that of patients with metastases in only peri-gastric LN stations. Nevertheless, the survival rate for patients with peri-gastric and No. 7 station metastases was not significantly different from the survival rate for patients with peri-gastric and other extra-gastric LN metastases. Furthermore, among patients with both peri-gastric and extra-gastric LN metastases, there was no significant difference in survival rate between those with and without No. 7 station metastases. Metastasis in the No. 7 station did not appear to be essential for the development of other extra-gastric LN metastases, indicating that it should not be considered a predictive marker for predicting the invasion extent. Based on survival rate, the No. 7 station seems more closely aligned with the extra-gastric rather than peri-gastric stations.

LN metastases are extremely crucial for evaluating the prognostic outcomes of GC patients, and the precision of LN station staging is critical for deciding the treatment and for evaluating the OS. LN metastases in local peri-gastric area are mainly spreading via complicated lymphatic network and might fellow some orders from N1 station to N2 station LN, which gives us potential opportunities to find some mark LN stations to predict the extent of LN metastases and lymphadenectomy. Nevertheless, the skip LNs were reported as the presence of a metastatic LN in an extra-gastric area without peri-gastric LN involvement, which fortunately were relatively rare. In our entire 1923 GC patients, we observed the lower occurrence rate (65/1923, 3.38%) of skip metastases and highest frequency (32/65, 49.23%) of skip metastases of No. 7 LN station (Figure S2), which was consistent with most studies (27,28). As many previous studies reported (29,30), we found survival rate of patients with skip metastases was close to that of patients with only peri-gastric LN metastases (HR 0.965, 95% CI: 0.910–1.022, P=0.225), whereas was significantly superior than that of NO. 7 group (HR 0.910, 95% CI: 0.839–0.986, P=0.021). Considering the specific clinical characteristic of skip metastases and the high frequency of skip metastases of No. 7 LN station, our study excluded this subgroup patients to obtain precise conclusion.

Figure S2 Survival analysis for patients with skip LN metastases. LN, lymph node; No. 7 LN, LN along the left gastric artery; HR, hazard ratio; CI, confidence interval.

Currently, dissection of the No. 7 LN is deemed a part of the D1 LN dissection range (4), instead of the D2 dissection range (as per the previous definition) (20). In this study, the metastatic incident rate of the No. 7 LN station was 14.82% (235/1,586) in the entire cohort, which was the 3^rd highest metastatic incident rate among all LN stations, only ranking lower than the rates of the No. 3 (544/1,586) and No. 6 (301/1,170) LN stations. Therefore, the No. 7 LN station might be considered as the main route of lymphatic drainage from the gastric area. Our previous study also reported a high metastatic incident rate in the No. 7 LN station in GC patients (2). Other researchers have similarly reported that the metastatic incident rate of the No. 7 LN station was comparable to or even higher than that of the peri-gastric LN stations (1,31). This high metastatic incident rate might be the reason that the No. 7 LN station was reclassified in the range of D1 LN dissection in the 3^rd edition of the Japanese Gastric Cancer Treatment Guidelines and in the 14^th edition of the Japanese General Rules for Gastric Cancer Study (4,5). However, it is still controversial whether the prognostic implication of the No. 7 LN station is similar to that of the peri-gastric LN stations or other extra-gastric LN stations and whether the No. 7 station might be considered as an SLN for extra-gastric LN metastases in GC patients.

In the entire cohort, No. 7 LN metastases showed a significant impact on OS rate (P<0.001). After stratification by pTNM stage, we observed similar results in patients with pIII stage (P=0.014). We also observed a similar non-significant trend in pII stage patients (shown in the Figure 1B), which might be a result of the small sample size of these GC patient subgroups. Our results were consistent with those reported by Chen (32). Nevertheless, another study reported contrasting results after adjustment for pN stage, because two-thirds of their patient population received preoperative therapy to downstage the pN stage (33). Furthermore, the small sample size might limit the credibility of the results of that study. In despite of those limitations, we also observed some tendency of poor outcome in patients with No .7 LN metastases (with No. 7 LN metastases vs. without No. 7 LN metastases, 3-year survival rate: N1, 75% vs. 79%; N2, 40% vs. 80%; N3, 20% vs. 33%). Thus, we could not deny that No. 7 LN station metastases might have a significant influence on the prognosis of GC patients.

To obtain more precise results, PSM was performed to balance the confounding factors between two groups. Both before and after PSM, the survival outcome of patients with No. 7 LN station metastases was similar to that of patients with extra-gastric LN station metastases (Figure 2C,E) and significantly poorer than that of patients with only peri-gastric LN station metastases (Figure 2B,D). Our results were consistent with those reported by Chen et al. (32). However, Murayama et al. reported that the prognostic impact of the No. 7 LN station was similar to that of peri-gastric LNs in patients with six or fewer positive LNs (6). This converse conclusion might be achieved result from enriching patients with lack of positive LNs. Based on our findings, we believe that the No. 7 LN station should be included in the range of D2 lymphadenectomy. If No. 7 LN involvement is highly suspected during the operation, D2 lymphadenectomy might be required. However, our study showed that metastases to extra-gastric LNs other than the No. 7 LN was observed in 37% (138/373) of patients, and this subgroup did not show a superior survival outcome. This result indicated that No. 7 LN metastasis was not essential for extra-gastric LN metastases and that the No. 7 LN should not be considered as the SLN for extra-gastric LN metastases. Further prospective large-scale studies are warranted to confirm this conclusion.

The results of multivariate analysis showed pN stage (P<0.001), No. 3 LN metastases (P=0.025), and No. 5 LN metastases (P=0.043) were independent risk factors for No. 7 LN metastases. Chen et al. also reported that metastases to the No. 7 LN station were associated with pN stage, pTNM stage, and No. 3 LN metastases, which is mostly consistent with our findings (32). In addition, previous studies have reported that No. 7 LN metastases are associated with aggressive biological behavior, such as large tumor size and vasculolymphatic invasion (34,35). These findings indicated that the No. 7 station might be a part of a crucial lymphatic route.

This study has several limitations. First, the endpoint in this study was OS; we did not investigate disease-free survival. Second, our study had a single-center retrospective design. Third, our study had a relatively small sample size. Third, the patients lost to follow up were excluded in this study, lesser than 10% of entire cohort, which might cause small amount of selection bias. Thus, there is a need for a multicenter study with a larger sample size to confirm our findings.

Conclusions

In conclusion, our study indicated the No. 7 LN station should be reclassified in the D2 dissection range due to its prognostic impact similar to that of extra-gastric LN station. If No. 7 LN involvement is highly suspected during the operation, D2 lymphadenectomy might be required. Nonetheless, our study proposed that the No. 7 LN station should not be considered a SLN as it does not appear to be essential for extra-gastric LN metastasis.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Funding: This study was supported by grants from the Programs of National Natural Science Foundation of China [grant number 81572372 to JD], National Key Research and Development Program “major chronic non-infectious disease research” [grant number 2016YFC1303202 to HL], National Key Research and Development Program “precision medicine research” [grant number 2017YFC0908304 to JD].

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-19-4786a

Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-19-4786a

Peer Review File: Available at http://dx.doi.org/10.21037/atm-19-4786a

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-19-4786a). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by Tianjin Medical University Cancer Institute and Hospital ethics committees (No. bc2019087). All patients provided written informed consent before any enrolling procedures were initiated.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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