Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

SIMPLE SUMMARY: In the last few years, the field of cutaneous T-cell lymphomas has experienced major advances. In the context of an active translational and clinical research field, next-generation sequencing data have boosted our understanding of the main molecular mechanisms that govern the biology of these entities, thus enabling the development of novel tools for diagnosis and specific therapy. Here, we focus on mycosis fungoides and Sézary syndrome; we review essential aspects of their pathophysiology, provide a rational mechanistic interpretation of the genomic data, and discuss the current and upcoming therapies, including the potential crosstalk between genomic alterations and the microenvironment, offering opportunities for targeted therapies. ABSTRACT: Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.