Evolving insights in the pathogenesis and therapy of cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)

Abstract

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment.

Figure 1

Summary of cytokine expression and cellular changes seen in the early and late stages of MF/SS. The different stages of MF/SS are shown with the corresponding extent of T cell infiltration of the skin by CD4⁺ and CD8⁺ T cells. There are more CD8⁺ T cells relative to the atypical CD4⁺ tumour cells in the early skin stages of MF/SS. In more advanced disease with tumours, there are fewer CD8⁺ T cells. The level of cytokine expression for Th1, Th2, and IL17 is shown in the bottom panel. The increase in expression of immune suppressive molecules in more advanced stages of MF/SS is shown.

Figure 2

Model for immunoediting in relation to MF/SS stage. The progression of MF/SS is illustrated as impacted by the level of tumour immunity present and underlying genetic alterations that contribute to tumour sculpting to stimulate progression to more advance stages of the disease.