Prognostic implications of tumor-infiltrating immune cells in primary diffuse large B-cell lymphoma of the central nervous system

Abstract

Background: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is a distinct clinicopathologic entity having poor prognosis. Tumor-associated macrophages/microglial cells (TAMs) and regulatory T-cells (Tregs) play an important role in tumor microenvironment. Macrophages can differentiate to M1 or M2 phenotype. However, little has been known about prognostic factors and role of tumor-infiltrating immune cells in primary CNS DLBCL and systemic DLBCL. Thus I investigated the prognostic implications of tumor-associated macrophages (TAMs) and regulatory T-cells (Tregs) in primary CNS DLBCL and systemic DLBCL. Methods: Immunohistochemistry was performed for CD68, CD163, CD204, and FOXP3 in 129 primary CNS DLBCL and 165 DLBCL cases. The number of positive cells was determined using image analyzer after virtual microscope scanning. Results: All of tumor-associated immune cells, tumor-infiltrating CD68 (+) TAMs, CD163 (+) or CD204 (+) M2 macrophages, and FOXP3 (+) Tregs were significantly decreased in primary CNS DLBCL compared with systemic DLBCL. However, the ratio of CD163/CD68 (+) cells or CD204/CD68 (+) cells had no significant difference according to primary site. CD163 (+) cells were tend to greater in primary CNS DLBCL associated with advanced ECOG performance status (PS, P = 0.052). FOXP3 (+) cells were decreased in advanced PS (P = 0.015), decreased IELSG prognostic index (P = 0.011), decreased Nottingham/Barcelona score (P = 0.010) and had a tendency to decrease in elevated CSF protein (P = 0.064). In systemic DLBCL, CD68 (+), CD163 (+) and CD204 (+) cells and the ratio of CD163/CD68 (+) and CD204/CD68 (+) cells were significantly greater in systemic DLBCLs associated with EBV (P = 0.005, 0.046, 0.028, 0.004 and 0.007, respectively). CD68 (+) cells were increased in systemic DLBCL patients with the age of < 60 years (P = 0.015). Survival analysis was performed among 100 primary CNS DLBCL patients. An increase in CD68 (+) cells was significantly associated with prolonged overall survival (OS) and progression-free survival (PFS) (P = 0.014 and 0.001, respectively). In contrast, an increase of CD204 (+) cells was related with shorter OS and PFS (P = 0.057 and 0.012, respectively). In multivariate analysis, a decreased CD68 (+) cells and increased CD204 (+) cells were independent predictors of shorter PFS. In 109 DLBCLs treated with R-CHOP, an increase in CD68 (+) cells was related to improved OS (P = 0.033). By contrast, an increased number of CD163 (+) cells and a higher ratio of CD163/CD68 (+) cells were significantly associated with shorter OS (P = 0.041 and 0.003) and PFS (P < 0.001 and 0.002). DLBCL patients with increased Tregs tended to have better prognosis. In multivariate analysis, an increased ratio of CD163/CD68 (+) cells was an independent predictor of shorter OS and PFS. Conclusions: These results suggest that M2 macrophages might have a lymphoma-promoting function in both primary CNS DLBCL and systemic DLBCL, and predict poor clinical outcome. In contrast, CD68 (+) TAMs might have a lymphoma-suppressor function in primary CNS DLBCL and systemic DLBCL treated with R-CHOP, and predict favorable clinical outcome. CD68 (+) TAMs plays an opposite pro-tumoral function in systemic DLBCL in absence of rituximab. The analysis of TAM profiles could be helpful for predicting prognosis of primary CNS and systemic DLBCL patients.