Poor prognosis in Epstein-Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype.

Abstract

Gastric cancer with lymphoid stroma (GCLS) is pathologically characterized by poorly developed tubular structures with a prominent lymphocytic infiltration. Its clinical and prognostic features differ in patients positive and negative for Epstein-Barr virus (EBV) infection. This study analyzed the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and the density of tumor-infiltrating lymphocytes (TILs) including CD3+and CD8+T cells, as well as their prognostic significance in patients with GCLS. The study included 58 patients with GCLS (29 EBV+ and 29 EBV-) who underwent curative resection. Expression of CD3, CD8, PD-1, and PD-L1 in tumor cells and TILs was analyzed using a quantitative multispectral imaging system (Opal™), with these results validated by immuno-histochemical assays for PD-L1 on whole slide sections. The proportion of tumors overexpressing PD-L1 (31.0 vs. 0%, P=0.002), TIL density (4548 vs. 2631/mm2, P<0.001), and intra-tumoral CD8+ T-cell density (2650 vs. 1060/mm2, P<0.001) were significantly higher in EBV+ than in EBV- GCLS. In addition, CD8+/CD3+ T-cell ratio was higher in EBV+ than in EBV- GCLS (55.3 vs. 35.8%, P<0.001). Lower TIL density, defined as<1350/mm2, was a significant negative factor of survival. Despite histopathological similarity, quantitative multispectral imaging revealed differences in the tumor immune micro-environment between EBV+ and EBV- GCLS, indicating that the underlying pathogenesis differs in these two disease entities. TIL density may be a prognostic marker in patients with GCLS.