Gastric cancer, one of the most common malignant neoplasms in the world, results in the death of thousands every year, especially in China [1, 5, 15]. After curative resection of gastric cancer was implemented, the possibility to extend survival has been a topic of exploration for investigators globally, as extending life is always a consistent goal. Thus, the factors that influence prognosis after curative resection in gastric cancer have been extensively studied. Indisputably, lymph node stage (N stage) is one of the foremost prognostic factors [16,17,18]. Many studies have shown that the 5-year survival rate of gastric cancer patients with positive lymph nodes is significantly lower than in those without lymph node metastasis. Moreover, as the number of lymph node metastases increases, prognosis gradually decreases. Not only metastasis lymph node stage but also the total number of lymph nodes examined is an important factor that influences prognosis. It has been demonstrated that the number of lymph nodes is an independent prognostic factor and a larger number of lymph nodes can lead to a higher 5-year overall survival rate [19,20,21,22,23,24]. The TNM staging system, a tool to evaluate prognosis of patients who had curative resection of gastric cancer, is current and accepted comprehensively by surgeons. In the 7th Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) tumor, lymph node, metastasis (TNM) staging system published in 2010, metastatic lymph nodes are essential in prognostication. However, properly classifying lymph node metastasis is limited by the number of lymph nodes. This system requires that at least 15 lymph nodes be examined postoperatively to obtain precise N staging, in order to avoid inaccurate staging. When the number of lymph nodes is > 15, the number of lymph node metastases is more accurate in assessing prognosis. However, if the number of lymph nodes is insufficient, the phenomenon of stage migration occurs [4, 5, 8, 10]. In addition, increasing the number of lymph nodes examined can lead to a higher 5-year survival rate. Hence, obtaining more lymph nodes from the postoperative specimen was deemed to be necessary and useful. Most surgeons follow the UICC/AJCC guide and remove a sufficient number of lymph nodes. Nevertheless, there are still some reasons that lead to fewer than 15 lymph nodes being obtained at surgery. Insufficiency of the technique itself, surgeon experience, or the lymph nodes in the specimen being too small may be reasons leading to a lesser number of lymph nodes being examined [7, 25]. Thus, many investigators have investigated finding a method to reduce that phenomenon. In recent years, LNR has been provided superior prognostic information over the N category according to the TNM classification in breast, colon, and rectal cancer . Some investigators have proposed that LNR could be a new prognostic indicator and have demonstrated LNR to be an independent prognostic factor in gastric cancer. It has also been attested that the LNR may reduce the phenomenon of stage migration [10, 13, 27,28,29].
We aimed to determine the prognostic significance of the metastatic LNR as a new tool to evaluate prognosis of patients with curative gastrectomy. In our study, we found that tumor grade, T stage, N stage, TNM stage, and LNR were the factors that influenced prognosis of patients according to the univariate analysis. Patients with a better differentiated pathological type, an earlier stage of T staging, N staging, and TNM staging, and a lower LNR have improved survival rates. However, when all nine factors are entered into the Cox proportional-hazards model, the multivariable analysis showed that only grade, T stage, N stage, and LNR showed statistical significance. LNR still had statistical significance in both the univariate and multivariable analysis. Thus, our study again demonstrated that LNR was an independent prognostic factor. With increased LNR, OS decreases. Thus, LNR may have value for evaluating prognosis. LNR could become a new tool to estimate prognosis in patients who undergo curative gastrectomy.
Although LNR is an independent prognostic factor, further research is required. We have evaluated the influence of LNR on prognosis in group 1 (LN ≥ 15) and group 2 (LN < 15). In our study, we set cut-off values (0, 0.13, and 0.4) based on N stage of the TNM staging system. The advantages of and reasons for choosing this cut-off value were convenience and ease, which should be important characteristics for any prognostic system used by physicians. Ultimately, we divided all patients in each group into four subgroups (R0, R1, R2, and R3) according to LNR, respectively.
In group 1, there were 178 patients, who were divided into the following four subgroups: r0 (LNR = 0), r1 (0 < LNR ≤ 0.13), r2 (0.13 < LNR ≤ 0.4), and r3 (LNR > 0.4). We compared the four subgroups with regard to survival time, and the univariate analysis showed statistical significance between the four subgroups. Patients in the r0 group had a maximal median survival time of 60.0 months, and the median survival time of patients in the r3 group was minimal (14.0 months). Thus, we considered that when LN ≥ 15, the LNR had value in evaluating prognosis of patients with curative gastrectomy and the median survival time decreased with increasing LNR. In group 2, we still obtained a statistically significant result between r0 (LNR = 0), r1 (0 < LNR ≤ 0.13), r2 (0.13 < LNR ≤ 0.4), and r3 (LNR > 0.4). The univariate analysis showed that different LNRs can lead to different prognoses.
It appeared that LNR may be a prognostic indicator for patients, regardless of number of lymph nodes examined, according to our study results. However, we did not think that the method of grouping that divided all patients into four groups was suitable for group 2. On the one hand, we had a small sample size and the number of patients with LN < 15 examined was only 43. On the other hand, when the number of lymph nodes examined was less than 15, increasing or decreasing the number by one lymph node would lead to a larger variation of LNR. For example, when the number of metastatic lymph nodes increased by one for patients with five lymph nodes examined, the LNR would increase by 0.2. But the LNR would increase by only 0.07 when the total number of lymph nodes examined was 15. Thus, it would be imprecise for prognostication if we divided the patients with fewer than 15 lymph nodes into too many subgroups.
Finally, we decided to divide our patients into two subgroups: LNr1 and LNr2. The cut-off value was chosen in this way: we compared all four subgroups of LNR, regardless of the number of lymph nodes examined. We compared R0 with R1, R2, and R3 and found that R3 had the largest significant statistical difference compared with R0. Ultimately, we chose 0.4 as the cut-off value and divided patients with LN < 15 examined into two subgroups. The univariate analysis showed a statistically significant result (Fig. 3). And the median survival time of patients with LNR that greater than 0.4 was 20.5 months. The other patients who had an LNR less than or equal to 0.4 had a higher median survival time (47.0 months). That result meant that LNR had value in evaluating prognosis of patients with fewer than 15 lymph nodes examined and the median survival time decreased with increasing LNR.
The TNM staging system has some disadvantages that could be improved. LNR, as a new research direction, has been shown to have value in estimating prognosis. Our study demonstrated that LNR was an independent prognostic factor. Either in patients with greater than or equal to 15 LN examined, or fewer than 15 LN, LNR could estimate prognosis and OS was shown to decrease with increasing LNR. We found that there was no correlation between LNR and the total number of harvested LNs. In other words, patients with identical LNR, even with differing numbers of detected metastatic nodes, will have a similar outcome. Conversely, among patients with the same number of metastatic nodes, those with a higher LNR will have an unfavorable outcome . Thus, the LNR could be a new prognostic indicator to enhance the TNM staging system.