How molecular advances may improve the diagnosis and management of PTCL patients

Abstract

Peripheral T-cell lymphomas (PTCL) comprised more than 30 rare heterogeneous entities, representing 10 to 15% of adult non-Hodgkin lymphomas. Although their diagnosis is still mainly based on clinical, pathological, and phenotypic features, molecular studies have allowed for a better understanding of the oncogenic mechanisms involved and the refinement of many PTCL entities in the recently updated classifications. The prognosis remains poor for most entities (5-year overall survival < 30%), with current conventional therapies based on anthracyclin-based polychemotherapy regimen, despite many years of clinical trials. The recent use of new targeted therapies appears to be promising for relapsed/refractory patients, such as demethylating agents in T-follicular helper (TFH) PTCL. However further studies are needed to evaluate the proper combination of these drugs in the setting of front-line therapy. In this review, we will summarize the oncogenic events for the main PTCL entities and report the molecular targets that have led to the development of new therapies. We will also discuss the development of innovative high throughput technologies that aid the routine workflow for the histopathological diagnosis and management of PTCL patients.

Keywords: diagnosis; molecular diagnosis; oncogenesis; peripheral T-cell lymphoma; targeted therapy.

Figure 1

Oncogenic mechanisms of the main non-cutaneous PTCL entities. PTCL oncogenesis is a multistep process resulting from the accumulation of oncogenic events targeting epigenetics, signaling pathways (alterations of the TCR pathway is a common feature of TFH-PTCL, ATLL and certain PTCL-NOS, whereas alterations of the JAK/STAT pathway is shared by PTCL entities with a cytotoxic immunophenotype), cell cycle or apoptosis. Oncogenic viruses (HTLV1, EBV) are involved in a few specific entities. Chronic antigen stimulation may play a role as initiating event in several extranodal T or NK-cell lymphomas. Immune surveillance and crosstalk between neoplastic cells and reactive cells of the microenvironment is important, especially in AITL, where reactive cytotoxic CD8 T-cells and B-cells are associated with a poor and favorable outcome respectively. Genetic susceptibility is recognized in SPTCL, EATL and ENKTL. This figure depicts these events and their involvement for specific PTCL entities. Genes are crossed out when the alterations result in a loss of function. TFH, T follicular helper; ALCL, anaplastic large cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; ATLL, adult T-cell leukemia/lymphoma; ENKTCL, extra-nodal NK/T-cell lymphoma; HSTL, hepatosplenic T-cell lymphoma; EATL, enteropathy associated T-cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; SPTCL, subcutaneous panniculitis-like T cell lymphomas.