Sinonasal DLBCL: Molecular Profiling Identifies Subtypes with Distinctive Prognosis and Targetable Genetic Features.

Primary sinonasal diffuse large B -cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient -tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene -expression profiling, cytogenetics, and next -generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell -of -origin (COO) was 68 (58%) activated B -cell (ABC), 44 (38%) germinal center B -cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression -free survival (PFS) and lymphoma -specific mortality (LSM) in both the overall cohort (5 -year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5 -year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD -L1 expression and copy -number alterations were rare. All lymphomas were Epstein -Barr virus -negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B -cell and toll -like receptor signaling therapy.