Primary Large B-Cell Lymphomas of Immune-Privileged Sites With IRF4 Rearrangement: Clinicopathological and Molecular Characterization.

Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is an aggressive B-cell lymphoma arising in the central nervous system, vitreoretina, and testis, whereas the molecular features of IP-LBCL with IRF4 rearrangement (IP-LBCL-IRF4-R) remain poorly characterized. Here, we report seven cases of IP-LBCL-IRF4-R, all showing IRF4 rearrangement confirmed by fluorescence in situ hybridization. The cohort included six males and one female, with a median age of 58 years (range, 34-73 years); all patients were immunocompetent. Tumors involved the central nervous system (n = 4) and testis (n = 3). With a median follow-up of 10 months (range, 3-45 months), all patients were alive. Histologically, all IP-LBCL-IRF4-R cases showed diffuse proliferation of medium-to-large B cells with centroblast-like and/or immunoblast-like morphology. Immunophenotypically, one case was classified as the germinal center B-cell subtype and six as the non-germinal center B-cell subtype. Five cases showed BCL2/C-MYC double expression, and all seven cases were negative for Epstein-Barr virus-encoded small RNA. IRF4 rearrangement was detected in all seven cases by break-apart probes, and an IGH::IRF4 fusion was detected in only one case; three cases harbored BCL6 rearrangements, and no BCL2 or MYC rearrangements were detected. Next-generation sequencing identified recurrent mutations in IRF4 and PIM1 (6/7, 85.7% each), followed by MYD88 (5/7, 71.4%) and BTG1, CD79B, and LRP1B (3/7, 42.9% each). LymphGen 2.0 classified five cases as the MCD subtype and two as Other. Our study highlights IRF4 rearrangement as a rare genetic event in IP-LBCL and provides further insights into the molecular diversity of this entity.