Traditional lymph node stage (N stage) has limitations in advanced gastric remnant cancer (GRC) patients; therefore, establishing a new predictive stage is necessary.

To explore the predictive value of positive lymph node ratio (LNR) according to clinicopathological characteristics and prognosis of locally advanced GRC.

Seventy-four patients who underwent radical gastrectomy and lymphadenectomy for locally advanced GRC were retrospectively reviewed. The relationship between LNR and clinicopathological characteristics was analyzed. The survival analysis was performed using Kaplan-Meier survival curves and Cox regression model.

Number of metastatic LNs, tumor diameter, depth of tumor invasion, Borrmann type, serum tumor biomarkers, and tumor-node-metastasis (TNM) stage were correlated with LNR stage and N stage. Univariate analysis revealed that the factors affecting survival included tumor diameter, anemia, serum tumor biomarkers, vascular or neural invasion, combined resection, LNR stage, N stage, and TNM stage (all P < 0.05). The median survival time for those with LNR0, LNR1, LNR2 and LNR3 stage were 61, 31, 23 and 17 mo, respectively, and the differences were significant (P = 0.000). Anemia, tumor biomarkers and LNR stage were independent prognostic factors for survival in multivariable analysis (all P < 0.05).

The new LNR stage is uniquely based on number of metastatic LNs, with significant prognostic value for locally advanced GRC, and could better differentiate overall survival, compared with N stage.

Gastric remnant cancer (GRC) is currently defined as carcinoma in the remnant stomach following partial gastrectomy, regardless of the disease being benign or malignant[1]. According to the Chinese surgeons’ consensus opinion for the definition of gastric stump cancer (2018 edition), GRC is defined as carcinoma arising in the remnant stomach ≥ 5 years after gastrectomy for benign disease, or ≥ 10 years after gastrectomy for gastric cancer. GRC has been reported to represents 1%-3% of all gastric cancers[2-4]. According to the American Joint Committee on Cancer (AJCC) traditional lymph node (LN) stage (N stage) of gastric cancer has been well explored[5-7]. However, the evaluation of N stage in GRC remains uncertain, which is mainly because the number of LNs required to ensure accuracy needs to be at least 15[7,8]. Indeed, surgery for GRC usually fails to retrieve the 15 LNs necessary for the initial operation[5,9].

Since traditional N stage has its limitation in GRC patients, establishing a new predictive stage is necessary. Positive LN ratio (LNR) is defined as the ratio of the number of metastatic LNs to the total number of LNs retrieved. In patients with gastric cancer, LNR might be more appropriate than N stage in predicting clinicopathological characteristics and prognosis[10-12]. However, the value of LNR stage in patients with GRC remains unclear. The purpose of this study was to evaluate the impact of LNR on clinicopathological characteristics and prognosis in patients with GRC.

GRC was first described in 1922 by Balfour[15]. The prevalence of GRC continues to increase because of the long latency period after prior gastric surgery, including that for peptic ulcer or gastric cancer[16]. However, the clinicopathological characteristics and prognosis of GRC, especially the values of LN metastasis or N stage, are still controversial[3,5,7,8]. Our results showed that, compared with N stage, LNR stage was not related to the number of retrieved LNs and, according to the multivariable analysis, it played an independent role in prognosis.

Some studies have shown that the number of dissected LNs was significantly lower in patients with GRC, especially in patients with initial malignant cancer. This aspect was considered to be related to LN dissection during primary gastrectomy[6,17]. In the present study, the mean number of retrieved LNs and the proportion of patients with < 15 was similar to those reported in previous studies[5-7,9]. Although theses values did not differ significantly between the two groups, our series displayed a trend: The patients that underwent initial surgery for benign disease had more retrieved LNs and a lower proportion.

LN metastasis plays an important role in both gastric cancer and GRC. Since N stage seems inaccurate for the evaluation, other studies are suggesting an alternative to N stage, which is dependent on the absolute number of metastatic LNs required for GRC[5,9]. In our study, we found that the new LNR stage is uniquely based on the number of metastatic LNs. Other studies have demonstrated that this new staging system might be more accurate in predicting survival in different cancers, including primary gastric cancer, regardless of the number of retrieved LNs[10,18,19]. Thus, the value of LNR stage in GRC, due to its unique characteristics, is worthy of exploration.

The prognosis of GRC remains controversial. Some studies have reported that GRC shows similar prognosis to primary gastric cancer[20-22], whereas others have argued that the prognosis for GRC is worse[3,9,23]. In our study, we only enrolled patients with locally advanced GRC and 73.9% (67/74) of the patients were stage II or stage III. The survival rate was similar to that in other reports[5,9].

Other studies have confirmed that tumor size, combined resection, N stage, LNR stage and TNM stage were linked to prognosis, while the number of retrieved LNs had no effect[5-7,9]. GRC has higher rates of combine resection and the prognostic value is highly debated. Some studies have demonstrated that this factor has no influence[5,24], but others have reported a worse outcome[7,20]. In contrast, we were unable to demonstrate the predictive value of T stage, which may be due mainly to two factors: (1) we excluded patients with T1 stage; and (2) patients with T2 and T3 stage were combined as a whole cohort. With respect to the influence of primary disease and histological types on prognosis, we concluded that they do not affect survival. Kung et al[16] reported that prognosis was better in patients with initial malignant disease because of the regular follow-up. Son et al[5] reported that previous malignant disease meant poor 5-year survival rate. In addition, histological types were considered not to affect survival as their influence was reported as inconsistent in different studies[6,16].

Despite reports of worse outcomes in patients with vascular or neural invasion, this evidence remains unclear, due to the limited number of cases[16,25,26]. Our study demonstrated that anemia was an independent predictor of GRC. The estimated rate of preoperative anemia was 27%-44% in gastric cancer and predicted poor prognosis[27]. Due to lifelong vitamin B₁₂ deficiency and iron absorption disorders due to gastrectomy[28], anemia may be more common in GRC. The rate of anemia was 55.4% in our cohort, being defined as hemoglobin < 90 g/L. This implies the need to improve nutritional status.

The abnormal rate of tumor biomarker level was 36.5% in our study. A correlation has been commonly observed between serum tumor biomarkers and prognosis and diagnosis of gastric cancer[29-31], but no consensus has been reached. Deng et al[30] reported that high serum tumor biomarker level was possibly a poor prognostic factor. A recent Chinese study with 92 GRC cases indicated that patients with high CEA level had an equivalent prognosis. Few studies have evaluated the association between serum tumor biomarker levels and GRC; therefore, more data are needed to clarify this aspect.

In the present cohort, we tried to demonstrate the superiority of LNR stage for GRC. Some studies have demonstrated that the prognostic ability of a new staging system (using the ratio of the number of metastatic LNs to the number of retrieved LNs) has not improved[5,7]. We confirmed some advantage of LNR stage in predicting median survival time in different groups. As shown in Figure 2, patients with N3 stage had a longer median survival time compared to those with N2 stage, while median survival time decreased with the increase of LNR stage. Moreover, LNR stage was still an independent predictive factor considering the multivariable analysis, but N stage and TNM stage (which is largely related to N stage) were not. Notwithstanding the limited number of cases and the diverse entry criteria, our results suggest that LNR stage has a better prognostic performance in all patients and those with different stages of GRC. This suggests that LNR stage is an ideal and effective staging system for patients with GRC, but whether the same staging system is suitable for all patients is still an open question.

There were several limitations to this study. First, GRC is a rare disease, and 74 cases are not sufficient to identify an optimal staging system. Second, it was a retrospective study conducted in single center. Third, overall survival is most significant in evaluating the prognosis of cancer patients[32,33]. Only the 5-year survival rate and median survival time were assessed, and we did not include disease-free survival. Therefore, it is crucial to perform future studies with large sample sizes in multiple institutions.

This study showed the limitation of traditional N staging. LNR stage was not correlated with the number of LNs dissected and had a better prognostic value. It might be more reliable than N stage in patients with GRC.