title: Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer.
abstract: 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).
  
  
  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).
  
  
  CONCLUSIONS
  The histologic subclassification and TILs can be used to predict RFS and DFS for patients with EBVaGC.
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Kyungpook National University.
authors.forename: B W
authors.initials: BW
authors.lastname: Kang
authors.affiliation: Departments of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: A N
authors.initials: AN
authors.lastname: Seo
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Kyungpook National University.
authors.forename: S
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Departments of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: H I
authors.initials: HI
authors.lastname: Bae
authors.affiliation: Gastroenterology, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: S W
authors.initials: SW
authors.lastname: Jeon
authors.affiliation: Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: O K
authors.initials: OK
authors.lastname: Kwon
authors.affiliation: Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: H Y
authors.initials: HY
authors.lastname: Chung
authors.affiliation: Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine.
authors.forename: W
authors.initials: W
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Institute of Microorganisms and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Kyungpook National University jkk21c@knu.ac.kr.
authors.forename: J G
authors.initials: JG
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: Epstein–Barr virus-associated gastric cancer; gastric cancer; host immune reaction; prognosis; tumor-infiltrating lymphocytes