| Background and Aim: Asia is the high-prevalence area of gastric cancer, especially in china, the incidence and mortality is the second and third place. The prognosis of gastric cancer is poor, and 5-year survival rate is less than 20%. With the development of sequencing technique, TCGA(The Cancer Genome Atlas) has proposed four new molecular characterizations gastric adenocarcinoma, including Epstein-Barr virus(EBV) positive gastric tumor, Microsatellite unstable tumor, chromosome unstable and chromosome stable tumor. Studies have illustrated that lymphocytes infiltration in tumor microenvironment(TME) related to the tumor prognosis closely, particularly in EBV positive gastric tumor. However, the infiltration of lymphocytes subgroups was not known in EBV positive gastric tumor clearly. Moreover, PD-1 and PD-L1 have become hot in gastric cancer contribute to the good clinical outcome of some solid tumors with antibodies therapy. Several studies have demonstrated that PD-L1 expression often predicted a worse survival in gastric cancer. TCGA found that PD-L1/L2 overexpressed in EBVa GC. The aim of this study was to analysis the clinical pathological features and prognosis between EBV positive and negative gastric tumor and to explore the level of lymphocytes subgroups infiltration in EBV positive and negative gastric tumor, and the relation with survival. Furthermore, we investigated the expression of PD-1 and PD-L1 in EBVa GC and all gastric cancer.Methods: Consecutive patients who underwent primary gastric tumor surgical operation from January 2007 to January 2010 were reviewed retrospectively. All patients with primary gastric tumor were included unless they had any of following conditions: previous chemotherapy before surgery, autoimmune disease and /or glucocorticoid treatment for a long time, HIV positive, lymphoma and other sources of gastric metastatic carcinoma. The tissue microarrays were used to detect EBER positive gastric tumors. Meanwhile, immunohistochemistry of CD4, CD8, Foxp3, CD80, PD-1 and PD-L1 were evaluated. Clinical, laboratory, pathological and survival information were collected(the end survival was 60 months). The data were applied to describe the clinical pathological features and analysis the prognosis of EBV positive and negative gastric tumors, to evaluate the levels of different subgroup lymphocytes and PD-1/PD-L1 expression in TME and explore the relationship with prognosis. All data were obtained by electronic medical records, clinical visits or telephone calls with patients or their relatives.Results: 571 patients were included in this study who were underwent surgery successfully. The total ratio of loss follow-up was 8.9%(51 cases). The incidence of EBV positive gastric tumor was 5.3%(32 cases). There was no significant difference in clinical pathological features between EBV positive gastric cancer and EBV negative gastric cancer. The median of overall survival was 25 months in all patients, 95% credibility interval was 22.2 to 27.8 months. A better prognosis was observed in EBV positive gastric tumor compared to EBV negative gastric tumor(p=0.003). The survival rate of EBV positive and negative gastric tumor at 1 year, 2 year, 3 year, 4 year and 5 year was 83.9%, 70.9%, 64.5%, 51.6% and 35.5% vs. 77.2%?51.3%?31.7%?23.9% and 17.0%. The results of immunohistochemistry indicated that the percentage of CD8+ EBV+ gastric tumor was 64.5% compared 27.2% in CD8+ EBV- group(p<0.001), Foxp3+ EBV+ gastric tumor was 60% compared 38.6% in Foxp3+ EBV- group(p=0.020), CD80+ EBV+ gastric tumor was 37% compared 13.1% in CD80+ EBV- group(p=0.002). PD-1+EBV+ gastric tumor was 48.0% compared 32.0% in PD-1+EBV- group(p=0.096). PD-L1+EBV+ gastric tumor was 41.9% compared 40.7% in PD-L1+EBV- group(p=0.912). The infiltration of CD4+ and PD-1+ T lymphocytes had no significant difference between two groups. The prognosis of CD8- PD-1+ gastric cancer was worse than CD8-PD-1- gastric cancer and CD8+PD-L1+ gastric cancer predicted a worse survival than CD8+PD-L1- tumor. Cox regression indicated that CD8+ lymphocytes and Foxp3+ lymphocytes infiltration predicted a better survival in gastric tumor and PD-L1 expression predicted a worse prognosis.Conclusion: EBV positive gastric tumor was a special type with a lower incidence and better survival, which might correlate with variety subgroups lymphocytes infiltration in TME. The expression of PD-1/PD-L1 had no significance between EBVa GCC and EBVn GC. CD8+ lymphocytes and Foxp3+ cells infiltration predicted a better survival in gastric tumor. While PD-L1 expression acted on an opposite role. |
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