Poor prognosis in Epstein–Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype
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.
KeywordsGastric cancer with lymphoid stroma Immune checkpoint Tumor-infiltrating lymphocyte Epstein–Barr virus
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C3078).
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflict of interest.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.
Informed consent to be included in the study, or the equivalent, was obtained from all patients.
- 3.Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, et al. Host inflammatory response predicts survival of patients with Epstein–Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139(84–92):e2.Google Scholar
- 4.Nakamura S, Ueki T, Yao T, Ueyama T, Tsuneyoshi M. Epstein–Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer. 1994;73:2239–49.CrossRefPubMedGoogle Scholar
- 5.Lim H, Park YS, Lee JH, Son DH, Ahn JY, Choi KS, et al. Features of gastric carcinoma with lymphoid stroma associated with Epstein–Barr virus. Clin Gastroenterol Hepatol. 2015;13(1738–44):e2.Google Scholar
- 36.Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–7.CrossRefPubMedGoogle Scholar