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

Kang BW, Seo AN, Yoon S, Bae HI, Jeon SW, Kwon OK, etal.

Ann Oncol. 2016 Mar;27(3):494-501

Editorial comment from Professor Florian Lordick:
The Cancer Genome Atlas (TCGA) network has divided gastric cancer into four distinct molecular subtypes, one of which being associated with the presence of Epstein-Barr-Virus (EBV) in gastric carcinoma cells. This subtype constitutes 5-10% of gastric cancers according to the current literature and seems to be associated with a somewhat better prognosis. EBV-associated gastric cancer often displays heavily infiltrating lymphoid elements and is also associated with inflammatory stroma and a rich cytokine milieu. 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 -associated gastric cancer. In an analysis of 120 patients with EBV-associated gastric cancer, stroma-TIL-positivity was significantly associated with longer recurrence-free survival (P = 0.002) and disease-free survival (P = 0.008), yet not overall survival. This is the first study that assessed the prognostic value of TILs in EBV-associated gastric cancer. The current findings support the concept that TILs can exert an antitumor effect through the host cellular immune response. Thus, the TILs in EBV-associated gastric cancer could be a stratification parameter and prognostic factor for predicting patient outcome. Further investigation is needed to determine the precise biologic significance of the inflammatory response in EBV-associated gastric cancer, as the authors conclude.

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).

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.

©The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

©PubMed Central


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