Introduction
Article Outline
Cutaneous T-cell lymphoma (CTCL) is generally classified as a type of non-Hodgkin’s lymphoma and represents a spectrum of diseases involving malignant clonal helper T lymphocytes of the CD4 phenotype. CTCL is the most common type of primary cutaneous lymphoma, representing 65% of cases of skin lymphoma. It is approximately twice as common in men as in women, while blacks have twice the incidence of whites.
The cause of CTCL is unknown. Several theories of the etiology of CTCL have been postulated, including exposure to environmental, genetic, and infectious agents. Early epidemiologic studies suggested a causative role of environmental exposure to chronic antigenic stimulation (eg, industrial chemicals, metals, and herbicides/pesticides), but these findings have not been substantiated by more recent case-control studies.1, 2
Studies have also hypothesized a retroviral cause of CTCL. The human T-cell lymphotropic virus type-1 (HTLV-1) was found to have a causal relation to adult T-cell leukemia/lymphoma. However, most CTCL patients are negative for the virus and the known HTLV-1 epidemiologic patterns have not been observed in CTCL.
Other implicated risk factors include genetic predisposition, radiation exposure, and pre-existing malignancies, although there are little supporting data.3 However, there is some evidence to suggest that immunosuppression is a risk factor for CTCL, including cases of documented CTCL arising in organ transplant recipients,4 treated lymphoma patients,5 and patients infected with the human immunodeficiency virus.6
To make a diagnosis of CTCL, specific clinicopathologic features must be identified, including skin biopsies showing epidermotropism with atypical mononuclear cells. Molecular studies can also help to support the diagnosis. Most CTCL cases show the expression of the CD4 antigen and a loss of CD7 and CD26. Tumor cells also show clonal T-cell receptor gene rearrangements. These clonal rearrangements can be identified using Southern blot analysis or polymerase chain reaction analysis.
Treatment of CTCL depends on the stage of disease. Traditional CTCL treatment regimens include skin-directed therapies such as psoralen with UVA irradiation (PUVA), retinoids, topical chemotherapy with mechlorethamine (nitrogen mustard) and carmustine (BCNU), and electron beam radiation, as well as systemic therapies such as chemotherapy, photopheresis, and interferons.
Conservative approaches using skin-directed therapy are the preferred first-line treatments for early stage CTCL.7 Combination therapies are appropriate for those with disease resistant to skin-directed therapies. Topical nitrogen mustard or PUVA is often used to prolong the effects of radiation treatment; while the addition of interferon or retinoids to PUVA therapy significantly reduces the cumulative UVA dose to achieve response and may also prolong the duration of response. Furthermore, in late stages of disease, chemotherapy alone as either single or multi-agent chemotherapy tends to be associated with a short duration of response and significant adverse effects, although there has been some success combining some single agents (such as deoxycofomycin) with immunotherapies (such as interferon).
A new class of drugs that have shown efficacy in CTCL are the retinoid X receptor (RXR) retinoids. These agents bind to RXR elements in transcriptional units and modulate gene expression. Bexarotene is the first systemic retinoid X-receptor-selective retinoid to be approved by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bexarotene gel has been shown to be effective in clinical trials for stage IA or IB CTCL.8, 9 Evidence is also emerging that combining oral bexarotene with psoralen and UVA therapy may also be effective in treating patients with advanced CTCL.
Another novel class of targeted antineoplastic agents is represented by an interleukin-2 receptor (IL-2R)-specific ligand fusion protein (DAB389IL-2, denileukin diftitox), which may be potentially selective for IL-2R-expressing cancers. Denileukin diftitox has shown promising results in the treatment of CTCL as a single agent and is being pursued in combination therapies.
This evidence-based, peer-reviewed supplement based on the proceedings of a closed expert symposium, provides an up-to-date insight into the epidemiology, etiology, and evolving pharmacotherapy of cutaneous T-cell lymphoma.
References
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- Successfully treated Hodgkin’s disease followed by mycosis fungoides (Case report and review of the literature) . Cutis . 1987;39:291–296
- . Cutaneous T-cell lymphoma and human immunodeficiency virus (The spectrum broadens) . Arch Dermatol . 1991;127:1045–1047
- A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides . N Engl J Med . 1989;321:1784–1790
- Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma . Arch Dermatol . 2001;137:581–593
- Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma (multinational phase II-III trial results) . J Clin Oncol . 2001;19:2456–2471
This supplement was supported by an unrestricted educational grant from Zeneus Pharma Ltd.
Prof Foss is a member of the speakers’ bureau for Ligand Pharmaceuticals. Dr Whittaker has served as a consultant to Zeneus, Genmab, and Ligand.
PII: S0093-7754(05)00508-7
doi:10.1053/j.seminoncol.2005.12.014
© 2006 Elsevier Inc. All rights reserved.
