In the current study, we analyzed the prognostic impact of the different number of retrieved LNs in Group 1 and 2 LNs on 1730 GC patients who underwent radical gastrectomy. We found that the optimal number of retrieved LNs for Group 1 and 2, based on the 13th edition of the JCGC, was > 13 and 9 respectively, based on which we proposed a revised nodal classification (rN). The prognostic prediction of patients classified using the rN criteria was found to be superior than those classified using the 8th UICC/AJCC GC, LNR, and LODDs criteria.
The number of retrieved LNs serves as a prognostic factor for GC as well as for postoperative survival for certain cancers [23]. The NCCN and TNM staging guidelines recommend the resection of no less than 15 LNs for radical gastrectomy [11, 24, 25]. However, the optimal number of retrieved LNs remains controversial. For example, Hayashi et al. [13] recommended retrieval of > 40 LNs after total gastrectomy for stage III patients, whereas Lu et al. [12] suggested that harvesting 21 LNs might represent a superior cut-off point for radical total gastrectomy to better determine the prognosis of the patients. Although a greater number of retrieved LNs has been associated with longer survival of patients with node-metastatic cancer, the optimal number of LNs to be examined at different stages remains unclear.
Nevertheless, almost all previous studies have focused exclusively on the number of retrieved LNs, both metastatic and non-metastatic, without proper consideration on their residing anatomic location groups [18, 26]. It has been indicated in esophageal cancer that both the location and number of metastatic LNs had important prognostic impact [27]. In GC, Zhao et al. [28] reported that the anatomical location of metastatic LNs was an important prognostic factor, especially in patients with stage pN1–N2 disease, whereas Tong et al. [29] emphasized that the classification of LNs in different locations did affect treatment and prognostic assessment. Although it is widely accepted that stage migration is related to the prognosis and the number of retrieved LNs, stage migration and survival prognostication discrepancies can occur when LNs are mostly removed from stations 1–7 as compared to other stations, based on previous studies [17, 27,28,29] and our own clinical experience. Moreover, skip metastasis of LNs or solitary metastatic LNs in GC is common, and it is necessary to retrieve Group 2 LNs to increase the probability of removing as much mLNs as possible [30, 31]. Thus, whether the number-based nodal category is superior to the revised anatomic location-based nodal category deemed worthy of investigation, and the current study intended to combine both methodologies.
Our findings showed significant associations between the number of retrieved LNs at different anatomic location groups and outcomes of patients with GC. On average, 23.8 LNs were retrieved from each patient, with more than 15 retrieved from 1177 (68.0%) of the cohort. X-tile software was employed to calculate the cut-off values of retrieved Group 1 and Group 2 LNs in predicting survival outcomes. We found that the retrieval of > 13 and > 9 LNs for Group 1 and Group 2 was associated with a relatively better prognosis. Additionally, combinations of different numbers of retrieved Group 1 and Group 2 LNs was confirmed to have different effects on the prognosis of patients classified by pN stage, as their prognosis was significantly poorer for Subgroup 2 patients than for Subgroup 1 patients, especially among those with stage pN0–N2 disease. Nevertheless, for pN3 patients, there was no significant difference observed in the prognosis between Subgroup 1 and 2. This may have been because patients needed to have a range of 7–15 and > 16 LNs retrieved to be classified as pN3a and pN3b, respectively, which mostly englobed our proposed criteria Group 1 > 13 LNs and 2 > 9 LNs; thereby possibly reflecting no significant difference with that of our proposed grouping criteria. Hence, based on the findings presented, we suggest that the importance of anatomic location groups of the retrieved LNs should not be ignored.
Notably, D2 lymphadenectomy has been accepted as an important part of radical gastrectomy and standard treatment to manage LN metastasis [5, 17, 32, 33]. However, the number of retrieved LNs is influenced by the extent of lymphadenectomy, surgical choice, the surgeon’s skill and/or the ability to examine LNs by the surgeons or pathologists. Sometimes, LNs are retrieved by pathologists who are less familiar with the anatomic locations. Therefore, it is inevitable that the number of LNs retrieved from various stations will differ among surgeons, centers, and even countries. Furthermore, it is very difficult to retrieve a sufficient number of LNs in some patients after neoadjuvant chemoradiotherapy. Under such circumstances, the examination of insufficient LNs could result in stage migration and affect the prognostic evaluation and the formulation of the optimal treatment to be given. Consequently, it is necessary and reasonable to formulate a method able to agglomerate both the number and distribution of retrieved LNs. To this end, we integrated our results into the UICC/AJCC-N staging system. In the proposed revision of the N staging system, for example, stage rN0 was limited to patients with UICC/AJCC-pN0 stage in Subgroup 1 (Table 3), whereas the N1 stage rN1 contained patients with UICC/AJCC-pN0 stage in Subgroup 2 and UICC/AJCC-pN1 stage in Subgroup 1 on the account that there was no significant prognostic difference between these two subgroups. Furthermore, after comparing LNR with LODDs staging systems, the revised N staging system demonstrated superior prognostic stratification and was found to focus more on the retrieved number of LNs in Group 1 and 2. We thought the superiority might be that we rationalized the sources of retrieved LNs and distinguished different combinations of retrieved LNs. Further, implementation of this proposed system, if properly validated, may be easier as compared to the LNR or LODDs which requires some level of mathematical calculation before use. The findings from the present study not only showed that the revised N staging system was superior and clinically feasible, but also suggest that gastric cancer surgeons should be paying more attention to the anatomic locations of the retrieved LNs as this can enable surgeons to increase the number of retrieved LNs and improve the survival prognostication of their patients.
There were several limitations in the present study that should be addressed. First, the revised N staging system was based on the analyses of data from a single institution in China, thus the results regarding the number of harvested LNs may differ among institutions. Second, our conclusions were based on data collected between 1987 and 2012 and we considered that this was a relatively long period that may have caused heterogeneity in diagnosis, treatment skills, and postoperative treatment recommendations. Third, the current study only focused on Group 1 and 2 LNs, thus it might be more precise for the N staging system to include the numbers of LNs retrieved from all LN groups mentioned in the JCGC [5]. Furthermore, it was inevitable that for patients who underwent total gastrectomy, it was easier to retrieve more than 13 LNs in the Group 1 LNs as compared to other gastric resection types. These above-mentioned limitations could have caused the deviation of patient classification and affect the conclusions of this study, to a certain extent. Hence, a prospective study recruiting more patients to validate the conclusions from the current study is to be considered in the future.