We explored the prognostic significance of MSC in patients with advanced gastric cancer. Even after stratification by T stage or final stage using the Eighth TNM Classification, the patients with MSC had a poorer prognosis than the patients without MSC, except for those with early stage disease. Furthermore, MSC was an independent prognostic factor for OS. These results suggest that MSC can be used to further stratify patients of identical T stage and final TNM stage. Therefore, MSC has utility for predicting the prognosis of patients with advanced gastric cancer.
Several studies have shown that MSC has a poor prognosis. Wang et al.  reported that pT3 MSC (+) patients had a similar prognosis to pT4a patients. Sang et al.  showed that pT2-3 MSC (+) patients had a similar survival rate to pT4a MSC (–) patients. However, in those studies, the effects of MSC on the final pathological stage, the combination of T stage and lymph node metastasis, were not evaluated. Bando et al.  reported that the magnitude of serosal changes predicted peritoneal recurrence of gastric cancer; they also showed that pT2 patients with marked macroscopic serosal invasion had a poorer prognosis than pT3 and pT4 patients with little or no macroscopic serosal invasion. However, that study involved only about one-third the number of patients as compared to our present study. In addition, this study also included patients who underwent D3 (para-aortic) lymph node dissection, and the R2 resection rate was 32%. In contrast, our study involved strict eligibility to accurately verify the impact of MSC on the patients with resectable advanced gastric cancer.
Intraoperative MSC is determined based on the color of, and morphological differences between, the tumoral and adjacent normal surface of the serosa. In this study, MSC was found in pT2 and pT3 tumors, suggesting that it reflects not only the tumor itself but also reactions to it, such as inflammation. In pT4 cases, MSC may be negative when the tumor shows only slight invasion of the serosa without inflammation. Therefore, MSC-positive cases may have either a substantial tumor volume at the serosal surface or accompanying inflammation. Recently, it has been known that inflammatory reactions play important roles in the growth of tumors. Both cancer cells and the surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to form an inflammatory tumor microenvironment that promotes tumor growth, angiogenesis, and metastasis [11, 12]. Our study showed that the rate of peritoneal recurrence was higher in MSC-positive than -negative pT2–T4 patients with negative lavage cytology (Table 4). This means that tumor cells can directly invade the serosa or cause serosal changes indirectly, such as by inducing inflammation, which can in turn cause peritoneal changes at distant sites even if intraoperative lavage cytologic analysis yielded a negative result. Previous studies also showed that the invasion area of the tumors at the serosal surface, and the magnitude of serosal change, are risk factors for peritoneal metastasis and prognosis [13, 7].
Most important finding in our present study is that not only MSC is an independent prognostic factor, similar to pT and pN, but also that MSC further stratifies the prognosis in patients with late-stage gastric cancer after stratifying by final TNM stage. This may lead to more efficacious postoperative adjuvant therapies, including switching from single to dual agents. Also, confirmation of the presence of MSC by staging laparoscopy may influence the selection of treatments such as preoperative chemotherapy in the future.
On the other hand, there was no marked difference in survival between MSC (+) and MSC (–) pStage IB and IIA patients. The stage IB group included only T2N0 cases, and the stage IIA group included T3N0 and T2N1 cases. MSC was not associated with peritoneal metastasis when pT2 and pT3 patients had no nodal metastasis. Peritoneal dissemination is established by detachment cancer cells from the gastric serosa and attachment to, and growth at, the peritoneum. And another mechanism of peritoneal dissemination is the release of tumor cells via lymphatic channels . Pathologically serosa-negative (T2 or T3) tumor is thought to occur peritoneal dissemination from tumors with some degree of lymph node metastases.
Although the Kaplan–Meier curves of MSC (+) and MSC (−) stage IIIC patients were clearly dissociable, the difference in OS was not significant. This is likely because of the small number of MSC (−) cases included in the stage IIIC group (n = 20). In other words, cases having pT3 or pT4 tumor with extensive lymph node metastasis (7 ≤ N) classified as pStage IIIC almost show MSC (+). Accurate verification of the impact of MSC on Stage IIIC will require further cases.
This study had several limitations. First, it used a retrospective design and included patients treated at only a single cancer center. Therefore, a multicenter, prospective study is required to validate the present results. Second limitation is that the MSC-positive rate may be different in other hospitals. Sang et al.  reported the diagnostic accuracy for MSC to be 82.1%, with 87.1% sensitivity and 81.1% specificity. Our results showed a diagnostic accuracy of 74.6%, sensitivity of 78.7% and specificity of 72.3%. Although the difference was not large, there are some discrepancies for diagnosing MSC, depending on the institution and country.