Low density of CD204-positive M2-type tumor-associated macrophages in Epstein-Barr virus–associated gastric cancer: a clinicopathologic study with digital image analysis

SummaryRecent studies suggest that CD204-positive (CD204+) M2-type tumor-associated macrophages (TAMs) are associated with the aggressive behavior of various cancers. However, the clinicopathologic significance of tumor-infiltrating CD204+ macrophages and their correlation with Epstein-Barr virus (EBV) in gastric cancer is unclear. Tissue microarrays were constructed from 119 surgically resected gastric cancer specimens (86 EBV-negative and 28 EBV-positive cases). After immunohistochemistry of CD204, the density of CD204+ cells was calculated using image analysis software, and associations between CD204 and clinicopathologic factors including patient survival were examined. High CD204+ cell density was significantly associated with several adverse prognostic factors, including older age (P = .008), advanced tumor depth (P < .001), lymph node metastasis (P < .001), presence of venous invasion (P < .001), and lymphatic invasion (P = .03). Low CD204+ cell density was significantly associated with EBV infection. Advanced tumor depth and presence of lymph node metastasis were significantly associated with high CD204+ cell density in both EBV-positive and EBV-negative subgroups. High CD204+ cell density was significantly associated with shorter cancer-specific survival (P = .0015). In conclusion, a high density of CD204+ TAMs was associated with the aggressive behavior and worse survival of gastric cancer. Low density of CD204+ TAMs was associated with infection of EBV, which may explain the favorable outcome of EBV-associated gastric carcinoma. Our results suggest that a specific immune microenvironment may be associated with the biological behavior of gastric cancer and that EBV-associated gastric carcinoma is distinctive from other gastric carcinomas in tumor immunity.