Cutaneous T-cell lymphoma

While the etiology of MF/SS remains unclear, theories include causative genomic alterations and infectious agents.

Genomic alterations

A high incidence of complex chromosomal structural rearrangement has been demonstrated in patients with cutaneous T-cell lymphomas (CTCL), with more than 65% of patients exhibiting at least one chromothripsis-like rearrangement (evidence of >10 copy number states on a single chromosome).[12] Chromosomal aberrations most often occur on chromosomes 8, 10, and 17.[12][13]

Evidence suggests that there are at least 55 potential driver mutations and 14 biologically relevant pathways, including T-cell activations, migration and differentiation; chromatin modification, cell cycle, survival and proliferation; and DNA damage response.[12][14][15]

No inherited germ-line mutations have been identified in the etiology of MF/SS, but people with psoriasis and atopic dermatitis, which exhibit familial inheritance, may be at a higher risk for these malignancies.[16][17][18]

Infectious agents

Infectious agents have been investigated as potential causative agents in CTCL, including Staphylococcus aureus, retro-viruses, herpes-viruses, polyomavirus, and human T-cell lymphotropic virus 1.[19][20] Studies have failed to find a consistent association between these infectious agents and CTCL. However, there is evidence to suggest that the most frequently clonally expanded T-cell receptor beta variable (TRBV) gene in SS is TRBV20-1, which is associated with the recognition of S aureus.[13]S aureus has been demonstrated to act as a superantigen and stimulate the proliferation of malignant T cells in patients with MF/SS.[21][22]

CTCLs exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers.[23]

MF/SS are thought to be malignancies of memory T cells. Typically they develop from skin-tropic memory CD41 T-cells, although CD81, and CD4-, CD8- subtypes may also be observed, which depend on dendritic cells for survival and proliferation.[24][25][26][27] Malignant cells display a T-helper cell type 2 (Th2) cytokine profile with increased production of IL-4, IL-5, and IL-13.[28]

Some evidence suggests that different T-cell surface phenotypes and molecular profiles are present in MF and SS, supporting the theory that they originate from distinct memory T-cell subsets: the skin resident memory T cell in MF, and the skin-tropic central memory T cell in SS.[29] However, phylogenetic analysis raises the possibility that MF may develop without a common ancestral T cell clone. One study detected the ultraviolet marker signature 7 mutations in the blood of patients with SS, which may imply a role of UV exposure in CTCL pathogenesis.[23]

WHO-EORTC 2018 classification of cutaneous (T-cell and NK-cell) lymphomas[2]

The European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas is based on distinct disease entities with predictable behavior, treatment responses, and prognoses.

Mycosis fungoides (MF), subtypes, and variants
- Folliculotropic MF
- Pagetoid reticulosis
- Granulomatous slack skin

Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
Subcutaneous panniculitis-like T-cell lymphoma
Extranodal natural killer/T-cell lymphoma, nasal type
Chronic active Epstein-Barr virus infection
Primary cutaneous peripheral T-cell lymphoma, rare subtypes
- Primary cutaneous gamma-delta T-cell lymphoma
- Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)
- Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoproliferative disorder (provisional)
- Primary cutaneous acral CD8+ T-cell lymphoma (provisional)
Primary cutaneous peripheral T-cell lymphoma, not otherwise specified

Pathophysiology

Classification

WHO-EORTC 2018 classification of cutaneous (T-cell and NK-cell) lymphomas[2]