In Epstein-Barr virus-associated gastric carcinoma a high density of CD66b-positive tumor-associated neutrophils is associated with intestinal-type histology and low frequency of lymph node metastasis.

Abstract

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent intratumoral lymphocyte infiltration, with some infiltration by other types of inflammatory cells, such as neutrophils. In this study, the significance of tumor-associated neutrophils (TANs) and cytotoxic T lymphocytes (CTLs) was investigated in EBVaGC. CD66b-positive TANs and CD8-positive CTLs in surgically resected EBVaGC tissues were evaluated by immunohistochemistry and digital imaging analysis. Cut-off values were determined with receiver operating characteristic curve analyses. Forty-two of 77 cases (55%) had some infiltration of TANs (CD66b-positive areas >0.5%, TAN(+)) and 35 (45%) had scant infiltration (TAN(-)). Thirty-five cases (45%) had more CTLs (CD8-positive area >18%, CTL-high) and 42 (55%) had fewer (CTL-low). There was no correlation between CD66b- and CD8-positive areas in the tumor (P=0.453). TAN(+) correlated with intestinal-type histology (P=0.048) and low frequency of lymph node metastasis (P=0.023), while CTL-low with upper location (P=0.030) and advanced invasion depth (pT2 or greater) (P=0.006). Disease-specific survival was not significantly correlated with TANs or CTLs. Multivariate logistic regression analysis revealed TAN(-) to be independently associated with lymph node metastasis (P=0.036). None of the cases of TAN(+) early EBVaGC with submucosal invasion showed lymph node metastasis (95% confidence interval 0-13.3%). When compared with 24 EBV-negative gastric carcinomas, EBVaGC had significantly more CTLs (P<0.001), while there was no difference in the number of TANs. TANs in EBVaGC may suppress lymph node metastasis, and absence of TANs might suggest careful follow-up or additional therapy in cases of post-endoscopic resection.