LAG-3 in Diffuse Large B-Cell Lymphoma: Immunohistochemical Expression Patterns and Clinicopathological Correlations

Background/Objectives: Lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint molecule that may contribute to immune escape in diffuse large B-cell lymphoma (DLBCL). This study aimed to characterize LAG-3 expression in neoplastic cells and tumor-infiltrating lymphocytes (TILs) and to investigate its associations with clinicopathological features and clinical outcome. Methods: This retrospective, single-center study included 210 patients with DLBCL diagnosed between 2007 and 2019. LAG-3 expression was evaluated immunohistochemically in whole-tissue sections. Tumor-cell expression was assessed according to the percentage and intensity of positive cells, while LAG-3-positive TILs were quantified as the mean number of positive lymphocytes per high-power field (HPF). Associations with clinicopathological parameters, treatment response, overall survival, and progression-free survival (PFS) were analyzed. Results: LAG-3 staining of varying intensity was observed in neoplastic cells in 177 cases (84.3%), and 82 cases (39.0%) were classified as LAG-3 positive using a 10% tumor-cell cut-off. The median number of LAG-3-positive TILs was 5/HPF. Male patients showed a higher percentage of LAG-3-positive tumor cells than female patients (p = 0.039). Moderate-to-strong tumor-cell staining was significantly more frequent in cases with >5 LAG-3-positive TILs/HPF than in those with ≤5 TILs/HPF (p = 0.018). LAG-3 expression parameters were not significantly associated with treatment response or overall survival. Univariate Cox regression analysis also showed no significant association between overall survival and LAG-3-positive TIL count, tumor-cell LAG-3 percentage, or staining intensity. Exploratory PFS analysis in 66 evaluable patients also showed no significant association with LAG-3 expression parameters. Conclusions: LAG-3 expression in DLBCL occurs in both neoplastic cells and TILs. The association between increased LAG-3-positive TILs and stronger tumor-cell expression supports further investigation of LAG-3 across both cellular compartments. No significant association with overall survival was observed in this cohort; however, the limited number of survival events precludes definitive conclusions regarding its prognostic significance. Further studies using standardized assessment methods and larger, clinically well-characterized cohorts are warranted.