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Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function MYD88 c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of MYD88 mutation and PD-1 alterations in PCNSL and the impact of Epstein–Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBVpos) PCNSL, 49% harbored MYD88 mutation, none seen in EBVpos PCNSL. MYD88 protein expression did not correlate with MYD88 mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBVpos. Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence In Situ Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. MYD88 mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBVpos PCNSL has a distinct activation mechanism, independent of genetic alterations. [ABSTRACT FROM AUTHOR]

Primary central nervous lymphoma (PCNSL) is a rare extra-nodal subtype of non-Hodgkin lymphoma and most cases are of diffuse large B-cell lymphoma histology with an aggressive presentation. The treatment of PCNSL has evolved over the years from radiation alone to multi-agent chemotherapy with the goal of minimizing long-term toxicity. Recent studies have evaluated autologous stem cell transplant as consolidation in eligible patients with success. The prognosis of relapsed disease remains poor and hence the emphasis is on effective and less toxic frontline strategies. Our growing understanding of the pathogenetic pathways in PCNSL is giving way to an exciting new era of targeted and immunotherapy options with the potential for inclusion in upfront therapy in the future. This review critically evaluates the current evidence including ongoing studies for the frontline treatment of PCNSL. [ABSTRACT FROM AUTHOR]