Peripheral T-Cell Lymphoma, Not Otherwise Specified: Clinical Manifestations, Diagnosis, and Future Treatment

Simple Summary The intent of this paper is to critically revise the epidemiology, etiology, main clinical features, histopathology, immunophenotype, molecular characteristics, prognosis, and therapeutic options of peripheral T-cell lymphoma, not otherwise specified (PTCL_NOS). PTCL_NOS represents the commonest category of PTCL. Regarded as an exclusion diagnosis, it has a quite distinctive profile, based on the authors' experience and data from the literature. New therapeutic agents are discussed, which might improve the prognosis of this neoplasm that remains dismal based on conventional chemotherapy. Peripheral T-cell lymphoma, not otherwise specified (PTCL_NOS) corresponds to about one fourth of mature T-cell tumors, which overall represent 10-12% of all lymphoid malignancies. This category comprises all T-cell neoplasms, which do not correspond to any of the distinct entities listed in the WHO (World Health Organization) Classification of Tumours of Haematopoietic and Lymphoid Tissues. In spite of the extreme variability of morphologic features and phenotypic profiles, gene expression profiling (GEP) studies have shown a signature that is distinct from that of all remaining PTCLs. GEP has also allowed the identification of subtypes provided with prognostic relevance. Conversely to GEP, next-generation sequencing (NGS) has so far been applied to a limited number of cases, providing some hints to better understand the pathobiology of PTCL_NOS. Although several pieces of information have emerged from pathological studies, PTCL_NOS still remains a tumor with a dismal prognosis. The usage of CHOEP (cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide) followed by autologous stem cell transplantation may represent the best option, by curing about 50% of the patients whom such an approach can be applied to. Many new drugs have been proposed without achieving the expected results. Thus, the optimal treatment of PTCL_NOS remains unidentified.