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Research Updates

Update on Cutaneous T-Cell Lymphoma (CTCL) Pathogenesis and Therapy

Michael Girardi, Karen Taraszka Hastings

Tuesday, February 06, 2007

Cutaneous T-cell lymphoma (CTCL), a malignancy of activated, typically CD4+ T lymphocytes, is characterized by three major activities: (1) skin homing, (2) clonal dominance, and (3) immunogenicity. CTCL tumor burden correlates with prognosis and can be categorized as limited patch/plaque (<10% of the skin), extensive patch/plaque (≥10% of the skin), tumor CTCL, and erythrodermic CTCL (≥80% of the skin). Erythrodermic CTCL is often seen in conjunction with peripheral blood involvement, as in the Sézary syndrome (SS). An understanding of the pathogenesis of CTCL, in conjunction with assessment of tumor burden, guides therapeutic decision-making and identifies targets for the development of future treatments.

CTCL Pathogenesis Features

Skin Homing

CTCL cells use mechanisms of normal immunosurveillance of the skin to migrate to and reside in the skin. Benign and malignant skin-homing T cells express cutaneous lymphocyte-associated antigen (CLA),1 which mediates rolling and tethering to E-selectin on dermal post-capillary venules.2 Two integrin ligand pairs involved in lymphocyte homing are α4β1 and αLβ2 on the T lymphocyte binding to VCAM-1 and the ICAM family on the endothelium, respectively.3 In late stages of CTCL and SS, circulating malignant T lymphocytes lose expression of α4 (CD49d), a component of lymphocyte homing.4 Chemokine receptor interactions are essential for lymphocyte homing in the dermal endothelium and epidermotrophism. For example, CCR4 and its ligand CCL17 are expressed in normal skin and in lesions of CTCL and SS.5, 6 Expression of integrin αEβ7 on CTCL cells is important for retention in the epidermis via interaction with E-cadherin.7

Clonal Dominance

CTCL arises from clonal expansion of T lymphocytes, as demonstrated by expression of a specific T-cell receptor (TCR).8, 9 By displaying markers and cytokine production characteristics of activated T cells, CTCL cells resist apoptosis, expand, and adversely affect normal T cells. CTCL cells commonly express several activation markers, including the interleukin (IL)-2α receptor (CD25).10 Following IL-2 receptor stimulation, activated T cells undergo phosphorylation of Jak/STAT intracellular signaling proteins.11-14 Activated CTCL cells may also have significant regulatory effects on the host's normal T cells. For example, CTCL cells may produce IL-10 or TGFβ , both of which can substantially inhibit cell-mediated immunity.15 In addition, CTCL cells may induce profound deficiencies within the normal repertoire of peripheral T cells, further contributing to the immunodeficient state of this malignancy.16 As CTCL patients often succumb to infections or secondary malignancies, therapies that spare toxicity to the normal lymphocytes are warranted.17


CTCL cells express antigens, including the clonotypic TCR, which may be recognized by an anti-tumor response. Prognosis and response to therapy may be influenced by the CD4/CD8 ratio, and immunosuppressive medications such as cyclosporine may result in rapid disease progression. On the contrary, interventions that stimulate the normal immune system and/or inhibit T-regulatory (Treg) activities that may down-regulate anti-tumor immunity have a substantial role in the therapy of CTCL.

CTCL Therapeutic Options

Treatment decisions are based on the tumor burden, patient immune status, and the therapy reaching the malignant T cells and their supporting environment.

Limited Patch/Plaque CTCL

Limited patch/plaque disease is treated with skin-directed therapies, including phototherapy and topical agents. Phototherapy (PUVA/UVB) three times per week at 90% of phototoxic dose18, 19, topical nitrogen mustard (mechlorethamine),20 carmustine (BCNU) 20-40 mg% in an ointment base daily21, and bexarotene gel22 are effective treatments for limited patch/plaque disease. Although there are no data on long-term mortality, itching and pain are reduced with these treatments, which help morbidity. Bexarotene is a member of a subclass of retinoids that preferentially bind retinoid X receptors (RXRs). Retinoic acid receptors (RARs) typically bind RXRs to form RAR-RXR heterodimers that are capable of activating gene expression of cell-surface receptors, structural proteins, and other key mediators of cellular function. Bexarotene has direct effects on the expanding population of malignant cells in CTCL by inhibiting proliferation, inducing differentiation, and promoting apoptosis.23, 24 Topical class I corticosteroids twice daily are used in the treatment of CTCL. However, in the absence of long-term studies, this treatment may best be viewed as a palliative therapy or for the treatment of nondescript lesions.25 Zackheim et al.'s study involving large doses of clobetasol did not show as good a result as phototherapy. Additionally, local radiotherapy may be utilized.26

Extensive Patch/Plaque CTCL

Similar to limited patch/plaque disease, extensive patch/plaque disease can be managed with skin-directed therapies such as phototherapy and nitrogen mustard. Use of topical carmustine is limited by systemic toxicity (cytopenia) and irritant dermatitis. Other whole body and systemic modalities can be used, including oral bexarotene, methotrexate, total skin electron beam therapy (TSEBT), and alfa interferon. Oral bexarotene can produce partial improvement of cutaneous disease across all stages of CTCL without compromising immune status and is useful as an adjunctive treatment.27, 28 Oral methotrexate 15-30 mg every week can achieve partial (22%) and complete (12%) remission in patients with extensive patch/plaque disease.29 TSEBT involves delivering electrons with an energy of 3-9 MeV to the skin with less than 5% traveling beyond 2 cm.30 Typically, 1-2 Gy are delivered per treatment with greater than 20 Gy delivered over a period of 9-12 weeks. TSEBT generates a complete response in 50-75% of patients with extensive patch/plaque disease and is also useful in more advanced disease.31-33 Immune-stimulating cytokine therapy with alfa interferon can be effective in extensive patch/plaque disease as well as more advanced disease.34

Tumor CTCL

Treatment of tumor stage disease utilizes treatments previously discussed, including skin-directed therapies, TSEBT, oral bexarotene, denileukin diftitox, and alfa interferon with the addition of local radiotherapy for treatment of tumors.35, 36 The activated phenotype of CTCL cells with aberrant expression of CD25 makes CTCL cells a somewhat selective target for biologic therapy with denileukin diftitox, a recombinant fusion protein of diphtheria toxin conjugated to IL-2.37

Erythrodermic CTCL / SS

Extracorporeal photochemotherapy (ECP, also known as photopheresis) given every 4 weeks is an effective therapy for erythrodermic presentations of CTCL alone or in combination with TSEBT or alfa interferon.38, 39 ECP involves harvesting a small portion of circulating cells, exposing them to UVA light in the presence of 8-methoxypsoralen and a plastic surface, and reinfusing cells to stimulate a therapeutic response.40 ECP simultaneously renders circulating malignant T cells apoptotic and induces differentiation of peripheral monocytes to dendritic cells,41 thereby providing the key cellular components for a tumor cell vaccine. Thus, it is proposed that ECP may take advantage of unique determinants on the malignant T cells, including TCR42, 43 and other tumor antigens,44, 45 to induce an anti-tumor immune response.46 Alfa interferon can be used as monotherapy or in combination with PUVA or ECP for erythrodermic CTCL.47 Patients with systemic disease may benefit from cytotoxic chemotherapy such as chlorambucil along with prednisone.48 For advanced, unresponsive disease with nodal or visceral involvement or transformation to a large-cell lymphoma, allogeneic hematopoietic stem cell transplant can be used to achieve remission and improve survival.49


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