Characterization of DLBCL with a PMBL gene expression signature

Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in non-mediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent a distinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 - proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealed close associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin (GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleural disease, and bone/bone marrow involvement was observed in three cases. However, while clinically distinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulation of immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes being significantly more frequently affected than in GCB-DLBCL and bf-PMBL. Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and genetic features, and potential implications for gene expression- and mutation-based subtyping of aggressive B-cell lymphoma and related targeted therapies.