B-cell lymphoma-2 (BCL2) downregulation is a useful feature -supporting a neoplastic phenotype in mature T-cell lymphomas.

Normal T-cells express high levels of BCL2 protein, data regarding BCL2 expression status and its diagnostic utility in T-cell lymphoma is scarce. We evaluated BCL2 expression in a series of mature T-cell lymphoproliferations including indolent and more recently recognized entities (follicular helper T-cell (TFH) lymphomas). Sixty-six neoplastic biopsies (60 patients) representing mature nodal, extranodal and leukemia T-cell neoplasms were collected from three institutes (2 US and 1 Japan) and were compared with reactive T-cells in 8 benign tissues/blood and 9 T-cell rich B-cell proliferations. BCL2 immunostaining was performed and scored based on intensity weighted H-score (0-300). Next generation sequencing (5 cases), BCL2 gene sequencing, and real time-PCR (3 cases) were conducted. Association of H-score with overall survival (using proportional hazards modeling) was assessed in non-leukemic T-cell lymphoproliferations (TCL). Most TCLs showed significantly downregulated median BCL2 H-score (125, range 18-300) with the exception of T-cell prolymphocytic leukemia (T-PLL) and hepatosplenic T-cell lymphoma (HSTL) both of which showed uniform strong retention of BCL2 as did the 8 reactive tissues (median H-score 280; p=0.000). Notably all TFH lymphoma CD4 neoplastic T-cells, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) CD8 adipocyte-rimming T-cells and T-cell large lymphocyte leukemia (T-LGLL) with pathogenic STAT5B and TP53 mutation showed BCL2 downregulation. No BCL2 mutations were observed by NGS or sequencing with decreased BCL2 mRNA transcripts by real-time PCR. BCL2 downregulation is pervasive among many T-cell lymphoproliferations and unrelated to any mutations. There is utility for BCL2 immunostaining in some challenging situations as discussed in manuscript.