[Discrasia linfoide epiteliotrópica de células T. Tratamiento con radiación ultravioleta].

INTRODUCTION: T-cell lymphoid dyscrasia is a group of different, infrequent, epitheliotropic inflammatory dermatosis that precede cutaneous T-cell lymphomas. Treatment with ultraviolet radiation is safe and efficacious. OBJECTIVE: To describe responses to treatment, secondary effects and complications. METHOD: Eleven patients with different T-cell lymphoid dyscrasias were treated. Two received psoralens plus ultraviolet A radiation (PUVA) and nine narrow band ultraviolet B radiation (NB-UVB). RESULTS: Seven women and four men from 5 to 30 years-old and phototypes III and IV were included. They had hypopigmented epitheliotropic lymphoid dyscrasia, chronic pityriasis lichenoides, hypopigmented parapsoriasis and pigmented purpuric dermatoses. Two received PUVA and 9 NB-UVB. Eight achieved complete response and three partial response with 10 to 119 sessions. Any patient presented neither relapse nor progression to cutaneous T-cell lymphoma during treatment or in the follow up period after 34 to 247 sessions. Secondary effects were xerosis and mild pruritus. CONCLUSIONS: The majority of patients with T-cell lymphoid dyscrasias can be successfully and safely treated with minimal secondary effects after a variable number of sessions and periods of time with ultraviolet radiation.

INTRODUCCIÓN: Las discrasias linfoides epiteliotrópicas de células T son un grupo de dermatosis inflamatorias poco frecuentes que pueden progresar a linfomas cutáneos. El tratamiento con radiación ultravioleta ha sido descrito como seguro y eficaz. OBJETIVO: Describir la respuesta al tratamiento, sus efectos secundarios y complicaciones. MÉTODO: Se administró radiación ultravioleta A con psoralenos (PUVA) a dos pacientes y radiación ultravioleta B de banda estrecha (NB-UVB) a nueve pacientes, con diferentes discrasias. RESULTADOS: Conformaron la serie siete mujeres y cuatro hombres, con edades de 5 a 30 años y con fototipos III y IV, con diagnóstico de discrasia linfoide epiteliotrópica hipopigmentada, pitiriasis liquenoide crónica, parapsoriasis hipopigmentada y púrpura pigmentada. Dos recibieron PUVA y nueve recibieron NB-UVB. Ocho alcanzaron respuesta completa y tres respuesta parcial con 10 a 119 sesiones de tratamiento. Ningún paciente presentó reactivación de la enfermedad después de 34 a 247 sesiones, y ninguno en tratamiento o seguimiento evolucionó a linfoma cutáneo. Los efectos secundarios fueron xerosis y prurito. CONCLUSIÓN: El tratamiento de las discrasias linfoides con radiación ultravioleta es eficaz y seguro, con efectos secundarios leves y con respuestas exitosas en la mayoría de los pacientes, en tiempo y número de sesiones variables.

Allogeneic hematopoietic stem cell transplantation in Primary Cutaneous T Cell Lymphoma.

In our retrospective study, 16 patients affected by advanced cutaneous T cell lymphoma (CTCL) underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two patients (12.5%) were in complete remission (CR), nine (56.3%) in partial remission (PR), and five (31.2%) with active disease. The patients were transplanted from an HLA-identical (n = 7) from a mismatched (n = 1) or haploidentical (n = 1) sibling, from matched unrelated donor (n = 5), or from a single cord blood unit (n = 2). Conditioning regimen was standard myeloablative in 6 patients and at reduced intensity in 10. Seven patients died from non relapse mortality (NRM) and four patients relapsed or progressed, three of them achieved a second CR after donor lymphocyte infusion (DLI) or chemotherapy plus DLI. To date, with a median follow-up of 76 months (range 6-130), nine patients are alive, eight in CR, and one with active disease. Overall survival (OS) and disease-free survival (DFS) at 1 and 10 years are 61% (95% CI 40-91%) and 54% (95% CI 33-86%), 40% (95% CI 22-74%), and 34% (95% CI 16-68%), respectively. The time from diagnosis to transplant seems to influence negatively both OS (log-rank p < 0.04) and DFS (log-rank p < 0.05). Our results confirm on a long follow-up that CTCL appears particularly susceptible to the graft versus lymphoma (GVL) effect, so that allogeneic HSCT represents a possibility of cure for advanced CTCL. The timing of HSCT in the clinical course of disease remains an open issue.

Gallium maltolate inhibits human cutaneous T-cell lymphoma tumor development in mice.

Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin's lymphoma characterized by an accumulation of malignant CD4 T cells in the skin. The group IIIa metal salt, gallium nitrate, is known to have antineoplastic activity against B-cell lymphoma in humans, but its activity in CTCLs has not been elaborated in detail. Herein, we examined the antineoplastic efficacy of a gallium compound, gallium maltolate (GaM), in vitro and in vivo with murine models of CTCLs. GaM inhibited cell growth and induced apoptosis of cultured CTCL cells. In human CTCL xenograft models, peritumoral injection of GaM limited the growth of CTCL cells, shown by fewer tumor formations, smaller tumor sizes, and decreased neovascularization in tumor microenvironment. To identify key signaling pathways that have a role in GaM-mediated reduction of tumor growth, we analyzed inflammatory cytokines, as well as signal transduction pathways in CTCL cells treated by GaM. IFN-γ-induced chemokines and IL-13 were found to be notably increased in GaM-treated CTCL cells. However, immunosuppressive cytokines, such as IL-10, were decreased with GaM treatment. Interestingly, both oxidative stress and p53 pathways were involved in GaM-induced cytotoxicity. These results warrant further investigation of GaM as a therapeutic agent for CTCLs.

An evaluation of the treatment of parapsoriasis with phototherapy.

Whether parapsoriasis represents an early stage of T-cell cutaneous lymphoma is still the subject of controversy. We evaluated the efficacy of phototherapy in the treatment of parapsoriasis and its relation with TCCL. Patients diagnosed with parapsoriasis and treated with phototherapy PUVA or UVB-NB were selected. Between 1 to 8 years following treatment the evolution of their disease was evaluated. In 62 patients the cure rate was 79.3% and 17.2% showed improvement of the lesions. Only two patients developed full blown T-cell cutaneous lymphoma. Phototherapy is an excellent treatment for parapsoriasis, with high cure rates, regardless of the type of phototherapy employed. Of the 62 patients under study, parapsoriasis showed no general tendency to progress to T-cell cutaneous lymphoma.

Dendritic cells and cutaneous T-cell lymphomas.

Dendritic cells (DCs) are potent antigen-presenting cells that help orchestrate the innate and adaptive immune systems to induce tolerance and immunity. They are diversified in their phenotypes, stages of maturation, degrees of activation, and functions. Several subtypes of DCs exist among human lymphoid tissues, non-lymphoid tissues, and in peripheral blood. In the skin, three types of DCs are described: Langerhans cells (LCs), dermal dendritic cells (DDCs), and plasmacytoid dendritic cells (pDCs). In the peripheral blood, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells are well described. Dysfunctional DCs are found in many autoimmune disorders, allergies, and cancers. In this paper, we focus on DCs as related to cutaneous T cell lymphomas (CTCLs). Abnormal DC number and defective DC function are found in the blood of patients with advanced stage Sézary syndrome (SS), a leukemic variant of CTCLs. Extracorporeal photopheresis (ECP), an effective therapy for erythrodermic CTCLs, is thought to work by inducing apoptosis of tumor cells and monocytes-derived DCs. DC vaccination has been carried out successfully in some patients with CTCLs when combined with immune modifiers like toll like receptor agonists, which may enhance the function of DCs. However, DCs may perform a dual role in the pathogenesis of CTCLs. Immature DCs (langerhans cells) could promote the survival of malignant T cells. Further understanding of DCs and their role in CTCLs can help us to uncover the pathogenesis of this disease and to further explore the therapeutic uses of DCs.

Skin cancer in skin of color.

In general, skin cancer is uncommon in people of color when compared to Caucasians. When it does occur, it is often associated with increased morbidity and mortality. Differences in survival rates may be attributed to skin cancers being diagnosed at a more advanced stage, and socioeconomic factors such as lack of adequate insurance coverage and lack of transportation can function as barriers to timely diagnosis and early treatment. In addition to advanced stage at presentation, malignant skin lesions in skin of color often present in an atypical fashion. Because skin cancer prevention and screening practices historically have been lower among Hispanics, Blacks, and Asians, and given the changing demographics in the United States, interventions that are tailored to each of these groups will be needed. Public educational campaigns should be expanded to educate people of all skin types with emphasis on skin cancers occurring in areas not exposed to the sun (Byrd-Miles et al., 2007), since sunlight is not as important an etiologic factor in the pathogenesis of skin cancer in people of color. Dermatologists and primary care physicians should instruct their darker-skinned patients on how to perform routine skin self-examinations. Physicians should also encourage patients to ask their specialists such as their gynecologist, dentist, and ophthalmologist to look for abnormal pigmentation during routine exams. To reduce the burden of skin cancer, several prevention methods for all people have been strongly encouraged, including monthly self-examinations, daily use of SPF 30 or greater sunscreen, sunglasses with UV-absorbing lenses, and avoiding tanning booths (American Cancer Society, 2008) (see Table 7). In addition, recommendations for clinicians to promote the prevention of skin cancer in skin of color have also been made, including closely monitoring changing pigmented lesions on the palms and soles and hyperkeratotic or poorly healing ulcers in immunosuppressed patients (Halder & Bridgeman-Shah, 1995) (see Table 7).

Bexarotene.

Bexarotene is a selective retinoid X receptor (RXR) agonist. It binds to, and activates RXRs which function as ligand-activated transcription factors that control gene expression. This leads to modulation of cell growth, apoptosis, and differentiation. In patients with refractory or persistent early stage cutaneous T cell lymphoma (CTCL), the overall response rate was 54% after oral bexarotene 300 mg/m2/day. The overall response rate in patients with refractory or persistent advanced stage CTCL was 45% at the same dosage. An overall response rate of 63% was reported after topical bexarotene 0.1 to 1% twice daily in patients with early stage CTCL. Another trial reported an overall response rate of 44% after topical bexarotene 1% once daily escalated up to 4 times daily. Plaque elevation was significantly reduced, and the severity of moderate to severe psoriasis was substantially improved in patients receiving oral bexarotene 0.5 to 2 mg/kg/day. At clinically relevant oral dosages, bexarotene significantly decreases levels of serum thyrotropin and free thyroxine. The most common adverse events associated with oral bexarotene are hypertriglyceridemia, hypercholesterolemia, central hypothyroidism and headache. Reversible acute pancreatitis has occurred during oral bexarotene therapy. Adverse events associated with the topical formulation are limited to rash, pruritus, and pain.