Mycosis Fungoides
Description
Mycosis fungoides is a malignant T-cell lymphoma of the skin, first reported (and named) by Alibert (1835).
Sezary syndrome is a leukemic variant of mycosis fungoides defined by erythroderma with greater than 80% of the skin showing redness, adenopathy and greater than 1,000 circulating Sezary cells/microliter with a CD4+CD26- or CD4+CD7- phenotype. Sezary cells have a type 2 helper T cell cytokine profile. Sezary syndrome has a median overall survival time of only 2.4 years in patients with Sezary cells at a density of greater than 10,000 cells/microliter or 5.4 years in patients with 1,000-10,000 Sezary cells/microliter. Mycosis fungoides and Sezary syndrome are the most common cutaneous T-cell lymphomas. Sezary syndrome can arise de novo or can appear following years of chronic mycosis fungoides. Both are thought to arise from clonal expansion of CD4+ helper T cells responding to chronic antigen stimulation (summary by Wang et al., 2015).
InheritanceSandbank and Katzenellenbogen (1968) observed mycosis fungoides in brother and sister. Cameron (1933) reported the condition in mother and daughter. Shelley (1980) observed mycosis fungoides in father and daughter and reviewed the sparse reports of other familial occurrences.
Hodgkin disease (236000) and various lymphomas also show familial aggregation. Greene et al. (1982) found that of 526 consecutive patients with cutaneous T-cell lymphomas, 21 had first-degree relatives with lymphoproliferative or hematopoietic malignancies--29 such malignancies in 21 kindreds. Hodgkin disease accounted for a third, with various leukemias (11 cases), non-Hodgkin lymphoma (5 cases), and multiple myeloma (3 cases) accounting for the rest.
Molecular GeneticsWang et al. (2015) presented a multiplatform genomic analysis of 37 patients with Sezary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53 (191170), CARD11 (607210), CCR4 (604836), PLCG1 (172420), CDKN2A (600160), ARID1A (603024), RPS6KA1 (601684), and ZEB1 (189909). Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1, encoding a transcriptional repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases.
Da Silva Almeida et al. (2015) performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sezary syndrome and 17 patients with other cutaneous T cell lymphomas (CTCLs). These analyses identified a distinctive pattern of somatic copy number alterations in Sezary syndrome, including highly prevalent chromosomal deletions involving the TP53, RB1 (614041), PTEN (601728), DNMT3A (602769), and CDKN1B (600778) tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, 612839; CREBBP, 600140; KMT2D, 602113; KMT2C, 606833; BRD9 (618465); SMARCA4, 603254; and CHD3, 602120) and signaling, including MAPK1 (176948), BRAF (164757), CARD11, and PRKG1 (176894) mutations driving increased MAPK, NF-kappa-B (see 164011), and NFAT (see 600490) activity upon T cell receptor stimulation.