Targetable alterations in primary extranodal diffuse large B-cell lymphoma.

Primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) is a heterogeneous subgroup of DLBCL. We investigated the prevalence and prognostic value of surface expression of PD-L1, PD1, and CD30, copy number of 9p24.1 (PD-L1 region), and mutations in MYD88 , CD79B , CARD11 , and BTK in a cohort of 116 patients, localized in the mediastinum (PMBL, n  = 12), ear, nose and throat (ENT, n  = 28), central nervous system ( n  = 29), testis ( n  = 7), breast ( n  = 4), stomach ( n  = 10), bone ( n  = 8), spleen ( n  = 2), and skin ( n  = 16). PD-L1 expression is most frequent in PMBL (92%), followed by lymphomas originating in the stomach (57%), ENT (23%), and skin (18%). PD1 was expressed at low levels in less than 13% of PE-DLBCL, while CD30 expression was found in 58% of PMBL. Mutation analysis revealed an unexpectedly high frequency of MYD88 and CD79B mutations in ENT lymphomas (46% and 50%, respectively). CARD11 mutations are rare but more frequently found in gastric lymphomas (30%), suggesting BTK resistance. Thirty-four of 113 (30%) of the lymphomas harbored both MYD88 and CD79B mutations. Lower overall and progression-free survival rates were found for cases with MYD88 , CD79B , and BTK mutations. These data confirm the biologic singularity of PE-DLBCLs and provide some suggestions for targeted therapies.