Abstract

Peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of postthymic T-cell lymphomas with >30 distinct subtypes associated with varied clinicopathological features. Unfortunately, the overall survival of the major PTCL subtypes is dismal and has not improved for decades; thus, there is an urgent unmet clinical need to improve diagnosis, therapies, and clinical outcomes. The diagnosis is often challenging, requiring a combinatorial evaluation of clinical, morphologic, and immunophenotypic features. PTCL pathobiology is difficult to investigate due to enormous intertumor and intratumor heterogeneity, limited tissue availability, and the paucity of authentic T-cell lymphoma cell lines or genetically faithful animal models. The application of transcriptomic profiling and genomic sequencing has markedly accelerated the discovery of new biomarkers, molecular signatures, and genetic lesions, and some of the discoveries have been included in the revised World Health Organization or International Consensus Classification. Genome-wide investigations have revealed the mutational landscape and transcriptomic profiles of PTCL entities, defined the cell of origin as a major determinant of T-cell lymphoma biology, and allowed for the refinement of biologically and clinically meaningful entities for precision therapy. In this review, we prioritize the discussion on common nodal PTCL subtypes together with 2 virus-associated T-cell and natural killer cell lymphomas. We succinctly review normal T-cell development, differentiation, and T-cell receptor signaling as they relate to PTCL pathogenesis and biology. This review will facilitate a better biological understanding of the different PTCL entities and their stratification for additional studies and target-directed clinical trials.