The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression

We studied the prognostic importance of tumor-infiltrating regulatory T lymphocytes (Tregs) and cytotoxic T/NK lymphocytes (CTLs) in 98 diagnostic biopsy specimens from patients with classical Hodgkin lymphoma (cHL). Immunohistochemical analysis was performed for FOXP3 to identify Tregs and for granzyme B (GrB) to identify activated CTLs. Failure-free survival (FFS) and overall survival (OS) were clinical end points. Patients with fewer than 25 FOXP3+ cells per high-power field (HPF) had a mean +/- SD 5-year FFS of 64% +/- 7% vs 85% +/- 5%,for patients with 25 or more FOXP3+ cells/HPF (P =.05). A FOXP3/GrB ratio of 1 or less was associated with poor FFS (46% +/- 10% vs 86% +/- 4%; P <.001) and OS (67% +/- 10% vs 93% +/- 3%; P <.001). When prior available MAL and bcl-2 expression data were included in a multivariate analysis of all clinical and biologic factors, a FOXP3/GrB ratio of 1 or less and tumor cell expression of MAL and bcl-2 all independently predicted poor FFS. This demonstrates the importance of evaluating tumor cell markers and the tumor immune infiltrate when considering biologic prognostic markers in cHL.