Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [T_FH] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n = 22; 34%) and PTCL-TBX21 (n = 41; 66%), and a significant association (P < .02) with overall survival was reaffirmed. Histopathologic assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared with PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (P < .05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4⁺CD8^- and associated with significantly higher LEF1, MYC, and CD30 expression (P < .05). PTCL-TBX21 displayed a more diverse biomarker profile with the following 2 subgroups: one expressing cytotoxic antigens and enriched in CD8⁺CD4^- or CD8^-CD4^- phenotype, and another lacking cytotoxic markers but showing a CD4⁺CD8^- phenotype with increased ICOS expression, but devoid of other T_FH markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma gene signature, had more Epstein-Barr encoding region-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of angioimmunoblastic T-cell lymphoma (P < .01). This study highlights the unique morphologic and phenotypic variations within the newly identified PTCL subtypes and should enable a more precise diagnosis and tailored therapeutic strategies in the future.