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

Ann Oncol. 2016 Mar;27(3):494-501. doi: 10.1093/annonc/mdv610. Epub 2015 Dec 16.


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.

Keywords: Epstein–Barr virus-associated gastric cancer; gastric cancer; host immune reaction; prognosis; tumor-infiltrating lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy
  • Adenocarcinoma / virology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Disease-Free Survival
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / virology
  • Female
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / therapy
  • Stomach Neoplasms / virology*
  • Treatment Outcome


  • Biomarkers, Tumor