Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer

Background: This study explored the prognostic impact of tumor-infiltrating lymphocytes (TILs) and investigated whether three histologic subtypes (lymphoepithelioma-like carcinoma, carcinoma with Crohn's disease-like lymphoid reaction, and conventional-type adenocarcinoma) could stratify a prognostic subset for patients with Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). Materials and methods: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. The evaluation of the percentage of intratumoral (iTu-) and stromal (str-) TILs was carried out, and the cases were also subclassified into three histologic subtypes as noted above. Results: Among the 120 patients, 73 patients (60.8%) and 60 patients (50.0%) were determined as str-TIL-positive and iTu-TIL-positive, respectively. In a univariate analysis, str-TIL-positivity was significantly associated with longer recurrence-free survival (RFS; P ≥ 0.002) and disease-free survival (DFS; P ≥ 0.008), yet not overall survival (OS; P ≥ 0.145). While iTu-TIL-positivity has a tendency of favorable outcome indicator for DFS and OS, but statistically significant differences were not shown, respectively (RFS, P ≥ 0.058; DFS, P ≥ 0.151; OS, P ≥ 0.191). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, lymphatic invasion, perineural invasion, and venous invasion; histologic subtype, WHO classification, and str-TIL-positivity were independently or tentatively associated with favorable RFS (hazard ratio [HR] ≥ 12.193, 95% confidence interval [95% CI] 1.039-143.055, P ≥ 0.047) or DFS (HR ≥ 4.836, 95% CI 0.917-25.525, P ≥ 0.063). Conclusion: The histologic subclassification and TILs can be used to predict RFS and DFS for patients with EBVaGC.