Insights Into the Molecular and Cellular Underpinnings of Cutaneous T Cell Lymphoma

Abstract

Cutaneous T cell lymphoma (CTCL) is a rare malignancy of skin-homing T lymphocytes. Advances in whole exome sequencing have identified a vast number of both single nucleotide variants (SNVs) and genomic copy number alterations (GCNAs) as driver mutations present in CTCL cells. These alterations cluster within several key pathways - T cell/NF-κB/JAK-STAT activation, cell cycle dysregulation/apoptosis, and DNA structural dysregulation affecting gene expression - allowing the maintenance of a population of proliferating, activated malignant T lymphocytes. While much of the clinical spectrum, genetic alterations, and oncogenic behavior of CTCL have been elucidated, little is known about the etiology that underlies CTCL malignant transformation and progression. Herein, we review the epidemiology, clinical presentation, and pathophysiology of CTCL to provide a perspective on CTCL pathogenesis. We outline a series of alterations by which mature, activated T lymphocytes are endowed with apoptosis resistance and cutaneous persistence. Subsequent genomic alterations including the loss of chromosomal structural controls further promote proliferation and constitutive T cell activation. CTCL cells are both malignant cells and highly functional T cells that can have major cutaneous and immunologic effects on the patient, including the suppression of cell-mediated immunity that facilitates malignant cell expansion. A deeper understanding of the molecular and cellular underpinnings of CTCL can help guide clinical management as well as inform prognosis and therapeutic discovery.

Keywords: CTCL; Mycosis fungoides; Sézary syndrome; cutaneous T cell lymphoma.

Figure 1

Alterations in the development of malignant CTCL cells of mycosis fungoides and Sézary syndrome. Activated skin-homing T cells in the skin are met with mutagenic insults, and along with changes in the aging immune system, result in T cell apoptosis resistance and cutaneous persistence. Subsequent genomic alterations including the loss of chromosomal structure controls further promote proliferation and selection of genomic copy number alterations (GCNAs) and single nucleotide variants (SNVs) that promote malignant CTCL behavior. (figure created with biorender.com)

Figure 2

Cutaneous manifestations of mycosis fungoides (MF) and Sézary syndrome (SS). (A) Asymmetric patches and plaques in classic MF. (B) Hypopigmented, (C) follicular, and (D) ulcerated plaque lesions in MF. (E-F) Erythroderma of SS.