R0 resection with D2 lymphadenectomy is significantly associated with improved survival outcome and widely used as a standard treatment for advanced gastric cancer patients in Eastern countries, especially China and Japan[9, 12, 13]. CnLNs (nos. 8, 9, and 11p) located in the extraperigastric area are included in the extent of D2 lymph node dissection for gastric cancer patients and routinely resected in clinical practice. Through pathologists’ hard work, tumors were staged correctly according to the TNM classification. To date, the definition of N stage was based on the number of positive lymph nodes. The later the N stage is, the poorer the prognosis. Few studies have focused on the location of positive lymph nodes and its impact on survival outcome in gastric cancer patients[5, 8]. However, whether the special locations of metastatic lymph nodes was associated with poor survival outcome of the patients treated with D2 lymphadenectomy remain controversial. In the present study, we found that CnLN metastasis was an independent prognostic factor for survival outcome in gastric cancer patients, especially when more than three positive CnLNs were observed (p = 0.001).
Ikoma et al defined “central lymph node” as common hepatic artery, celiac artery, and proximal splenic artery LNs (station nos. 8, 9, and 11p). In our study, CnLN metastasis was relatively common (29.0%) (21.9% in no. 8 LNs, 8.4% in no. 9 LNs, and 5.4% in no. 11p LNs) and was significantly associated with poor survival outcome. And in this trial, larger tumor size (p < 0.001), more frequent lymphatic vessel invasion (p < 0.001), signet ring cell histology (p = 0.014), and more advanced pathological T stage (p = 0.013) were significantly related to CnLNs metastasis. In the subgroup analysis, we found that CnLN metastasis was associated with shorter 5-year DFS in pN2 and pN3 patients (for pN2 patients: 25.9% vs 39.3%, p = 0.017; for pN3: 11.5% vs 23.4%, p = 0.005), but not showed a significant difference for pN1 patients (42.3% vs 50.6%, p = 0.326). Central lymph node metastasis is predictive of prognosis for pN2/3 patients.
For pN1 patients, CnLN metastasis was not significantly associated with survival outcome, which might be related to the low metastatic rate and the mechanism of “skip metastasis”[14, 15]. Skip metastasis was defined when LN metastasis appeared to bypass or skip tiers rather than following the lymphatic streams and was not related to the location of the primary tumor. In earlier tumor stages, tumor cell colonization might be random, and studies have shown that station nos. 1, 7, 8a, 9, and 11 were the main sites of skip metastasis. The pN1 stage patients with positive CnLNs were likely to experience skip metastasis. However, the association between skip metastasis and survival outcome in gastric cancer patients remains a matter of debate. Some studies have revealed that skip metastasis has no impact on survival[14, 16]. And our study supported this point, because CnLN metastasis in pN1 stage patients was not related to survival (p = 0.376). Skip metastasis might be the reason for which CnLN-positive pN1 patients did not experience poor survival rates, similar to pN2/3 patients.
N stage, which is stratified by the number of positive lymph nodes, is a consistent and effective method used worldwide[4, 11]. However, for patients with positive lymph nodes, the location of the metastatic LNs, especially central lymph nodes, is strongly correlated with survival[17, 18]. And in our study, we found the GC patients who located in the same N stage showed the different survival outcome because of CnLN metastasis. Especially for pN2 and pN3 stage, patients with positive CnLNs had shorter lifetime significantly. Thus, central lymph nodes metastasis could be a potential supplement to current international N stage for evaluating the prognosis of GC patients more accurately.
CnLN metastasis could be a potential predictor for prognosis and help guide postoperative treatment. Therefore, D2 lymphadenectomy and an accurate LN pathological examination are necessary for advanced gastric cancer patients. Extensive lymphadenectomy could resect the micrometastasis and decrease the recurrence rate, especially for upper gastric cancer. Some studies have reported that upper gastric carcinoma is more prone to LN metastasis, especially at station nos. 1, 2, 3, and 7, and usually metastasizes to the para-aortic lymph node through the left gastric cancer artery and splenic artery[20, 21]. Thus, surgeons should carefully examine the lymph node and decide whether they need to perform a more extensive lymphadenectomy. In contrast to Eastern countries, D1 lymphadenectomy is more common in Western countries, mainly because of its lower rates of poorly differentiated histology and proximal stomach involvement – factors that are related to poor survival. The standard range of lymphadenectomy is still under debate, but we suggest that patients with a later stage (i.e., later than T2) and with suspicious positive LNs should undergo extensive lymphadenectomy.
Extensive and high-quality dissection and an accurate lymph node stage are key factors to consider when planning postoperative treatment. Guidelines request at least 15 lymph nodes to be examined in D2 resection for accurate LN staging. And the later N stage, the more possible to metastasize to extraperigastric area following the lymphatic streams. In our study, we found that patients with more than three positive CnLNs had a poorer prognosis than the patients with one or two metastatic CnLNs (p = 0.001). Thus, in D2-resected GC patients in N2 stage or later, with positive CnLNs, especially at least three – all the variables related to a heavy lymph burden, – adjuvant chemoradiotherapy should initiate timely after surgery to eradicate micrometastasis and prolong survival. Some phase III studies have revealed that both adjuvant chemotherapy and radiochemotherapy were beneficial in preventing recurrence in D2-resected GC patients with positive LNs[23, 24]. The oxaliplatin combined with capecitabine (XELOX regimen) is commonly used as first-line postoperative adjuvant chemotherapy, especially for LN-positive gastric cancer patients, with tolerable side effects (most AEs are grade I/II) and a survival benefit (25.4–29 mo)[25–27].
There were some limitations in our study. First, our study was a retrospective analysis involving a single institution. In the future, well-designed, large sample size and multicenter studies still need to be performed. Additionally, not all patients had at least 15 examined lymph nodes, which may have caused the incurrent N stage. Secondly, therapeutic protocols and recommendations for gastric cancer patients could have evolved during the study period. Adjuvant chemotherapy had been successfully performed in the recent decade, but the proportion of the patients who received adjuvant chemotherapy was relatively low in the current cohort. This may have a potential impact on prognostic assessment of gastric cancer patients.
In conclusion, this study reported that CnLN metastasis could be regarded as a predictor for survival outcome in gastric cancer patients who underwent R0 resection and D2 lymphadenectomy. The anatomical location of positive LNs may be supplement to “N stage” for accurately prognostic evaluation. Large sample, multicenter, randomized clinical trials are still needed in the future.