Refining gastric cancer staging: examining the interplay between number and anatomical location of metastatic lymph nodes - a retrospective multi-institutional study

Patient demographic and clinicopathological characteristics

The patients’ clinicopathological characteristics are shown in Table 1. The total cohort consisted of 7,181 (66.7%) male individuals, with a mean age of 61.16 ± 11.95 years, and a mean body mass index (BMI) of 23.68 ± 3.31 kg/m2. Of the 10,772 patients, 2,449 (22.7%) underwent total gastrectomy, 6,880 (63.9%) underwent D2 or higher lymphadenectomy, and 3,591 (33.3%) had with node-positive disease. OS was compared according to pathological stage and revealed a decline in survival with increasing disease severity (Supplementary Fig. 1).

Table 1 Patient characteristics according to lymph node metastasisFig. 3figure 3

Analysis of the overall survival of the three lymph node metastasis groups according to the N stage. A: N1 stage, B: N2 stage, C: N3a stage, D: N3b stage. Patients in the far-extragastric group (group FE) had significantly lower survival rates in N1 and N2 stages

Compared with the total patient group, node-positive patients had a higher proportion of individuals aged 65 years or older, a greater prevalence of patients with a poor performance status, and a lower average BMI. Additionally, these patients underwent more invasive surgeries and radical lymphadenectomies (beyond D2), and had a higher proportion of total gastrectomy cases than in the total cohort. Notably, the node-positive subgroup exhibited a significantly higher disease severity. The sex distribution was comparable between the groups (Table 1).

Table 2-1 Multivariate analysis of factors contributing to OS of N1 caseTable 2-2 Multivariate analysis of factors contributing to OS of N2 caseTable 2-3 Multivariate analysis of factors contributing to OS of N3a caseTable 2-4 Multivariate analysis of factors contributing to OS of N3b caseComparison of survival according to anatomic location of lymph node metastasesComparison of survival between the perigastric and extragastric lymph node metastasis groups across nodal stages

OS was compared between group P and the extragastric groups according to the N stage; there was no significant difference in 5-year survival rates (5YOS) at different nodal stages. In N1, the 5YOS in group P and extragastric groups was 82.4% and 75.5%, respectively, with no significant disparity (P = 0.091). Similar findings were observed in N2 (65.0 vs. 64.3, P = 0.162), N3a (55.0 vs. 49.4, P = 0.136) and N3b (33.9 vs. 25.9, P = 0.690). Therefore, in each N stage, there was no significant difference in patient survival between group P and the extragastric group (Supplementary Fig. 2).

Fig. 4figure 4

Comparison of survival according to the primary cancer location: Primary lesion at upper location. A: N1 stage, B: N2 stage, C: N3a stage, D: N3b stage. The far-extragastric group (group FE) had significantly lower overall survival, specifically in the N2 stage

Fig. 5figure 5

Comparison of survival according to the primary cancer location: Primary lesion at middle and/or lower location. A: N1 stage, B: N2 stage, C: N3a stage, D: N3b stage. The far-extragastric group (group FE) had significantly lower overall survival, specifically in the N2 stage

Comparison of overall survival between three lymph node metastasis groups

The characteristics of the Three LNM groups were compared. There were no significant differences in baseline characteristics such as age, sex, and ECOG. Group FE had a significantly higher rate of open approach and total gastrectomy, and was confirmed to have performed more lymphadenectomy of D2 or higher. Additionally, compared to group P, it was confirmed that the disease severity of groups NE and FE was relatively advanced disease (Supplementary Table 1).

The OS of the three LNM groups (P, NE, and FE) was analyzed according to the N stage. In N1, the 5YOS was 82.4% for group P, 77.9% for group NE, and 63.8% for group FE; the difference was significant (P = 0.013). Similarly, in N2, the 5YOS was 65.0%, 71.0%, and 46.8%, respectively (P < 0.001). However, the difference in OS in N3 between the three groups was not significant. These findings demonstrated that patients in group FE had significantly lower survival rates in N1 and N2 (Fig. 3).

Univariate and multivariate analysis of factors related to survival including three lymph node Metastasis groups

In the univariate analysis for the N1 stage, significant factors included age, sex, ECOG, BMI, approach method, lymphadenectomy extent, T stage, TNM stage, and LNM group. Through multivariate analysis, it was confirmed that the hazard ratio (HR) of group FE compared to group P was 2.457, surpassing other significant baseline variables such as age, sex, ECOG, and BMI. In the multivariate analysis of the N2 stage, group FE was established as a statistically significant factor, along with age, ECOG, and TNM stage. However, it did not exhibit significance in N3a and N3b stages (HR, CI, p-value; 1.024, 0.767–1.366, 0.873 / 1.153, 0.884–1.506, 0.293), respectively (Table 2-1, 2-2, 2-3, 2-4).

Comparison of survival according to cancer location

We conducted an analysis according to the primary cancer location. The lesions were classified as upper, middle, or lower lesions. Subsequently, we compared the survival outcomes among the three groups. Irrespective of the cancer location, group FE had significantly lower OS rates, specifically in N2. However, for the remaining N stages except N2, there were no significant difference in survival based on the specific cancer location in relation to the MLN groups (Figs. 4 and 5).

Comparison of survival according to extent of Surgery

We also conducted an analysis based on the extent of surgery and lymph node dissection range. Firstly, when total gastrectomy was performed, the 5YOS for group P, group NE, and group FE were as follows (N1: 75.6 vs. 66.9 vs. 61.7), (N2: 59.9 vs. 68.6 vs. 36.2), and (N3a: 67.9 vs. 61.4 vs. 23.4). These results confirmed the notably lower survival rates in group FE. For patients who underwent subtotal gastrectomy, a statistically significant outcome was observed (N3a: 40.4 vs. 29.9 vs. 28.4) (Supplementary Figs. 3 and 4). Similarly, an analysis was conducted based on the extent of lymph node dissection, revealing significantly lower OS rates in group FE exclusively in the N2 stage. This trend was observed both in the range below D1 plus (N2: 71.7 vs. 62.6 vs. 31.7) and in the range above D2 (N2: 57.7 vs. 53.8 vs. 45.7) (Supplementary Figs. 5 and 6).

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