More Research Updates

Atopic dermatitis (AD), or eczema, is one of the biggest challenges within the field of dermatology both in the clinic and in the research laboratory.

Read more

In the last several years, there has been a great deal of interest in the relationship between stem cells and cancer. In this article, Dr. Stephen Lyle considers several aspects of stem cell biology that apply to cancer, while focusing on the skin. Dr. Lyle believes that the application of advances in stem cell biology to cancer research can lead to a better understanding of what drives carcinogenesis, tumor progression, recurrence and metastasis, and that the localization of keratinocyte, melanocyte and neural crest-derived stem cells in the bulge region of the skin provides an excellent model system to study the relationship of stem cells and cancer.

Read more

Dermatologists are constantly exposed to clinical trials data at meetings, in the news, and in the medical literature.

Read more

Despite the adverse effects of ultraviolet (UV) exposure, the indoor tanning business is booming.

Read more

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

Immunogenicity

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

References

  1. Picker LJ, Michie SA, Rott LS, et al. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am J Pathol. 1990;136(5):1053-68.
  2. Picker LJ, Kishimoto TK, Smith CW, et al. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature. 1991;349(6312):796-9.
  3. Santamaria Babi LF, Moser R, Perez Soler MT, et al. Migration of skin-homing T cells across cytokine-activated human endothelial cell layers involves interaction of the cutaneous lymphocyte-associated antigen (CLA), the very late antigen-4 (VLA-4), and the lymphocyte function-associated antigen-1 (LFA-1). J Immunol. 1995;154(4):1543-50.
  4. Scala E, Russo G, Cadoni S, et al. Skewed expression of activation, differentiation and homing-related antigens in circulating cells from patients with cutaneous T cell lymphoma associated with CD7- T helper lymphocytes expansion. J Invest Dermatol. 1999;113(4):622-7.
  5. Ferenczi K, Fuhlbrigge RC, Pinkus JL, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002;119:1405-10.
  6. Kleinhans M, Tun-Kyi A, Gilliet M, et al. Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma. Blood. 2003;101(4):1487-93.
  7. Schechner JS, Edelson RL, McNiff JM, et al. Integrins alpha4beta7 and alphaEbeta7 are expressed on epidermotropic T cells in cutaneous T cell lymphoma and spongiotic dermatitis. Lab Invest. 1999;79(5):601-7.
  8. Benhattar J, Delacretaz F, Martin P, et al. Improved polymerase chain reaction detection of clonal T-cell lymphoid neoplasms. Diagn Mol Pathol. 1995;4(2):108-12.
  9. Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol. 1994;103(1):34-41.
  10. Nagatani T, Matsuzaki T, Iemoto G, et al. Comparative study of cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma. Clinical, histopathologic, and immunohistochemical analyses. Cancer. 1990;66(11):2380-6.
  11. Nielsen M, Nissen MH, Gerwien J, et al. Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3. Blood. 2002;99(3):973-7.
  12. Eriksen KW, Kaltoft K, Mikkelsen G, et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia. 2001;15(5):787-93.
  13. Brender C, Nielsen M, Kaltoft K, et al. STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. Blood. 2001;97(4):1056-62.
  14. Mao X, Lillington D, Scarisbrick JJ, et al. Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides. Br J Dermatol. 2002;147(3):464-75.
  15. Berger CL, Tigelaar R, Cohen J, et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood. 2005;105(4):1640-7.
  16. Yawalkar N, Ferenczi K, Jones DA, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood. 2003;102(12):4059-66.
  17. Kantor AF, Curtis RE, Vonderheid EC, et al. Risk of second malignancy after cutaneous T-cell lymphoma. Cancer. 1989;63(8):1612-5.
  18. Herrmann JJ, Roenigk HH Jr, Hurria A, et al. Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol. 1995;33(2 Pt 1):234-42.
  19. Boztepe G, Sahin S, Ayhan M, et al. Narrowband ultraviolet B phototherapy to clear and maintain clearance in patients with mycosis fungoides. J Am Acad Dermatol. 2005;53(2):242-6.
  20. Kim YH, Martinez G, Varghese A, et al. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol. 2003;139(2):165-73.
  21. Zackheim HS, Epstein EH Jr, Crain WR. Topical carmustine (BCNU) for cutaneous T cell lymphoma: a 15-year experience in 143 patients. J Am Acad Dermatol. 1990;22(5 Pt 1):802-10.
  22. Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol. 2003;49(5):801-15.
  23. Zhang C, Hazarika P, Ni X, et al. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res. 2002;8(5):1234-40.
  24. Cheng SX, Kupper T. A new rexinoid for cutaneous t-cell lymphoma. Arch Dermatol. 2001;137(5):649-52.
  25. Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for mycosis fungoides. Experience in 79 patients. Arch Dermatol. 1998;134(8):949-54.
  26. Micaily B, Miyamoto C, Kantor G, et al. Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys. 1998;42(2):361-4.
  27. Duvic M, Martin AG, Kim Y, et al. 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(5):581-93.
  28. Duvic M, Hymes K, Heald P, et al. 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(9):2456-71.
  29. Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol. 2003;49(5):873-8.
  30. Jones GW, Hoppe RT, Glatstein E. Electron beam treatment for cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9(5):1057-76.
  31. Reddy S, Parker CM, Shidnia H, et al. Total skin electron beam radiation therapy for mycosis fungoides. Am J Clin Oncol. 1992;15(2):119-24.
  32. Tadros AA, Tepperman BS, Hryniuk WM, et al. Total skin electron irradiation for mycosis fungoides: failure analysis and prognostic factors. Int J Radiat Oncol Biol Phys. 1983;9(9):1279-87.
  33. Hoppe RT, Cox RS, Fuks Z, et al. Electron-beam therapy for mycosis fungoides: the Stanford University experience. Cancer Treat Rep. 1979;63(4):691-700.
  34. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther. 2003;16(4):311-21.
  35. Chinn DM, Chow S, Kim YH, et al. Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys. 1999;43(5):951-8.
  36. Maingon P, Truc G, Dalac S, et al. Radiotherapy of advanced mycosis fungoides: indications and results of total skin electron beam and photon beam irradiation. Radiother Oncol. 2000;54(1):73-8.
  37. Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001;19(2):376-88.
  38. Bisaccia E, Gonzalez J, Palangio M, et al. Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous T-cell lymphoma: a 9-year retrospective study at a single institution. J Am Acad Dermatol. 2000;43(2 Pt 1):263-71.
  39. Kohn EC, Steis RG, Sausville EA, et al. Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sezary syndrome. J Clin Oncol. 1990;8(1):155-60.
  40. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. 1987;316(6):297-303.
  41. Berger CL, Xu AL, Hanlon D, et al. Induction of human tumor-loaded dendritic cells. Int J Cancer. 2001;91(4):438-47.
  42. Winter D, Fiebiger E, Meraner P, et al. Definition of TCR epitopes for CTL-mediated attack of cutaneous T cell lymphoma. J Immunol. 2003;171(5):2714-24.
  43. Berger CL, Longley J, Hanlon D, et al. The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma. Ann N Y Acad Sci. 2001;941:106-22.
  44. Theinert SM, Pronest MM, Peris K, et al. Identification of the testis-specific protein 10 (TSGA10) as serologically defined tumour-associated antigen in primary cutaneous T-cell lymphoma. Br J Dermatol. 2005;153(3):639-41.
  45. Usener D, Schadendorf D, Koch J, et al. cTAGE: a cutaneous T cell lymphoma associated antigen family with tumor-specific splicing. J Invest Dermatol. 2003;121(1):198-206.
  46. Girardi M, Berger C, Hanlon D, et al. Efficient tumor antigen loading of dendritic antigen presenting cells by transimmunization. Technol Cancer Res Treat. 2002;1(1):65-9.
  47. Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol. 2002;138(8):1054-60.
  48. Winkelmann RK, Diaz-Perez JL, Buechner SA. The treatment of Sezary syndrome. J Am Acad Dermatol. 1984;10(6):1000-4.
  49. Oyama Y, Guitart J, Kuzel TM, et al. High-dose therapy and bone marrow transplantation in cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 2003;17(6):1475-83, xi.
Back