How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome.

T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.

Low-Dose Intralesional Recombinant Interferon-α2b in the Treatment of Mycosis Fungoides.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is characterized by malignant CD4+ skin-homing T-cells that drive formation of cutaneous patches, plaques, and/or tumors. MF's known immunogenicity makes it an ideal candidate for local immunotherapy. Recombinant human leukocyte interferon-α2 (rIFN-α2) has well-established immunomodulatory, antiproliferative, and antitumor effects; and relatively low levels of endogenous IFN-α have been observed within MF lesions. As a systemic therapy delivered via subcutaneous (SC) or intramuscular (IM) injection, rIFN-α2 has previously shown efficacy against MF. Due to high levels of toxicity associated with the systemic dosing required for improvement of disease, rIFN-α2 has had limited use in the treatment of MF. For these reasons, we sought to deliver rIFN-2 as a local immunotherapy, and herein describe two cases of MF successfully managed with intralesional injections of low-dose rIFN-α2. With limited reporting in the medical literature, intralesional injection of rIFN-α2 has shown efficacy, but with high frequency of associated systemic side effects. Towards a better tolerated, localized immunotherapy, we initiated treatment in two MF patients with low dose (0.5 MU) rIFN-α2 per injection that led to marked responses, and subsequent dosing to 1.0 MU ultimately led to complete resolution of the treated lesions without the generalized side effects observed with systemic administration of rIFN-α2. These cases suggest that low-dose intralesional rIFN-α2 may be an efficacious and well-tolerated local immunotherapy for early stage MF, providing a therapeutic option for the management of chronic, recalcitrant lesions.

Mechanisms of itching in mycosis fungoides: grade of itching correlates with eosinophil infiltration and kallikrein 5 expression.

BACKGROUND: Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphomas (CTCL). Itching can be a major symptom for patients with CTCL, however, itching associated with MF is not relieved by conventional therapy using anti-histamines, suggesting that histamine is not the main pruritogen. Therefore, the underlying mechanisms of itching in MF patients remain unclear. OBJECTIVES: To investigate the clinical and histopathological features associated with MF-related itching. MATERIALS AND METHODS: Skin sections from MF patients and healthy subjects were used for pathophysiological analysis and evaluation of protease activity. These results were compared with the degree of itching. RESULTS: Of the MF patients, 40% did not report itching and 60% reported itching (moderate itching: 40%; strong itching: 20%). The number of eosinophils, but not mast cells, that infiltrated into skin was increased in the group with strong itching. In the skin of patients, both serine protease activity and immunoreactivity to kallikrein 5 (KLK5), a known itch mediator, increased relative to the grade of itching. CONCLUSION: These results suggest that KLK5 and eosinophil infiltration may be involved in itching in patients with MF.

[Acrally emphasized papules-a case report]. / Akral betonte Papeln ­ ein Fallbericht.

Syringotropic mycosis fungoides (STMF) is an extremely rare form of cutaneous T­cell lymphoma with 51 published cases so far. Clinically STMF is manifested similarly to folliculotropic mycosis fungoides (MF), whereby the course of STMF is much milder. Histopathologically, it shows a prominent tropism of the T­cell lymphocytic infiltrate for the eccrine epithelium. We report the case of a 65-year-old woman with multiple small papules on the feet, shinbones and back.

Correlation between mycosis fungoides and pregnancy.

OBJECTIVES: To evaluate the effect of pregnancy on the natural course of Mycosis fungoides (MF) and compare the obtained results with previous reports. METHODS: The medical records of 140 patients with cutaneous T-cell lymphoma (CTCL) treated at the University Hospital of Isfahan (the academic referral center for CTCL) Isfahan, Iran. Between 2000 and 2013 were retrospectively reviewed to retrieve all cases of pregnancy during the course of MF disease.  RESULTS: A total of 8 pregnancies were recorded. The median age of patients at the time of diagnosis was 26.7 (range 21-30 years) and pregnancy 29.4 (range 27-31 years). Most of patients had early-stage MF (Ia and Ib). All patients experienced aggravation of disease during pregnancy or immediately postpartum. Mycosis fungoides did not cause any complications during pregnancy.  CONCLUSION: Pregnancy appears to have a negative impact on the course of MF, probably due to immune system deteriorations during the pregnancy. Further studies are needed to clarify the interplay between pregnancy and MF.

Lymphomatoid papulosis: Treatment response and associated lymphomas in a study of 180 patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology. OBJECTIVE: The aim of this study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome, and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center. METHODS: Patient charts and clinical and histopathologic data of 180 patients with LyP were retrospectively assessed. RESULTS: A total of 56.7% of patients was men. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6%, and mixed subtype in 4.4% of the patients. One hundred fourteen lymphomas were observed in 93 patients, with mycosis fungoides (61.4%) and anaplastic large cell lymphoma (26.3%) being the most common forms. Risk factors for development of lymphoma included sex and histologic subtype. Number of lesions and symptom severity were not associated with lymphoma development. Patients with type D were less likely to have lymphomas. Treatment provided symptomatic relief but did not prevent progression to lymphoma. LIMITATIONS: The limitation of this study is the retrospective study design. CONCLUSION: Patients with LyP are at increased risk of associated lymphomas. Thorough patient counseling is needed and long follow-up periods are required to detect and treat secondary lymphomas.

Micosis fungoide folicular, una variante infrecuente y agresiva / Follicular mycosis fungoides, a rare and aggressive variant

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Correlations between clinical and pathological features in 17 cases of mycosis fungoides before and after transformation.

BACKGROUND: Mycosis fungoides (MF) may progress to transformed MF (T-MF), a condition with aggressive behavior. OBJECTIVES: This study was designed to compare the clinical and pathological features of biopsies in 17 cases of MF before and after transformation. METHODS: During a revision of primary cutaneous T cell lymphomas, 53 cases of MF were identified, including 17 cases of T-MF. Clinical, pathological, and immunohistochemical data for the MF patients were evaluated. Cases of T-MF and intermediate transformed (IT) MF were diagnosed according to previous criteria. The histological and immunohistochemical features of T-MF biopsies were compared with those of MF/IT-MF biopsies taken before or concomitant with transformation. RESULTS: At the initial diagnosis, three patients were found to have more advanced stages of disease: two had MF and T-MF simultaneously, and another had only oral T-MF. Four patients considered to show histological transformation maintained disease stages Ia and Ib and all remain alive. Of five patients with IT-MF at first diagnosis, all progressed to complete histological transformation, three developed tumors, and two died of disease. Four patients progressed to CD30+ large cell lymphoma, and three of these died of disease. In one of these patients, the MF biopsy showed a high level of expression of CD30 in the epidermis and dermis. CONCLUSIONS: No correlation between advanced MF and expression of CD25 and CD30, or frequency of Ki-67+ cells was found. The frequency of transformation among patients with initially non-transformed MF was high. Our findings support the emphasis given by other authors to IT-MF, a pattern of MF which is generally not considered in many studies.

The spectrum of pigmented purpuric dermatosis and mycosis fungoides: atypical T-cell dyscrasia.

We report the case of a healthy 17-year-old adolescent boy with an unremarkable medical history who presented with an asymptomatic fixed rash on the abdomen, buttocks, and legs. The rash initially developed in a small area on the right leg 2 years prior and had progressed slowly. Prior biopsies were consistent with pigmented purpura. Clinical examination revealed multiple annular purpuric patches on the abdomen, buttocks, and legs covering approximately 20% of the body surface area without lymphadenopathy or hepatosplenomegaly. Additional biopsies demonstrated changes consistent with mycosis fungoides (MF). T-cell receptor g gene rearrangements demonstrated clonality. The patient was diagnosed with stage IB MF of the pigmented purpura-like variant. The patient responded well to psoralen plus UVA therapy. It has been proposed that pigmented purpuric dermatosis (PPD) is a form of cutaneous T-cell lymphoid dyscrasia and that T-cell gene rearrangement studies should be obtained for prognostic evaluation in patients with widespread disease. In our patient, the clinical appearance of the lesions, pathologic findings, and gene rearrangement studies led to the diagnosis of MF. Until the potential for evolution of PPD to malignant disease is better understood, further evaluation of MF in patients with an unusual presentation of pigmented purpura is warranted.

Hypopigmented mycosis fungoides: a review of its clinical features and pathophysiology / Micose fungoide hipocromiante: uma revisao de seus aspectos clinicos e fisiopatologicos

Several distinct clinical forms of mycosis fungoides have been described. Hypopigmented mycosis fungoides should be regarded as a subtype of mycosis fungoides, insofar as it presents some peculiar characteristics that contrast with the clinical features of the classical form. Most patients with hypopigmented mycosis fungoides are younger than patients typically diagnosed with classical mycosis fungoides. In addition to typical dark-skinned individuals impairment, hypopigmented mycosis fungoides has also been described in Asian patients. The prognosis for hypopigmented mycosis fungoides is much better than for classical mycosis fungoides: hypopigmented mycosis fungoides is diagnosed when there are only patches of affected skin, and lesions usually will not progress beyond terminal stages, although they can persist for many years. Diagnosis should involve clinicopathologic correlation: skin biopsy analysis often reveals intense epidermotropism, characterized by haloed, large, and atypical CD8+ lymphocytes with convoluted nuclei, in contrast to mild to moderate dermal lymphocytic infiltrate. These CD8+ cells, which participate in T helper 1-mediated immune responses, prevent evolution to mycosis fungoides plaques and tumors and could be considered the main cause of the inhibition of melanogenesis. Therefore, hypopigmentation could be considered a marker of good prognosis for mycosis fungoides.

Ultimamente diferentes formas clínicas da micose fungoide têm sido descritas. A micose fungoide hipocromiante pode ser considerada um subtipo da micose fungoide, apresentando algumas características peculiares que contrastam com os achados da forma clássica da micose fungoide. A maioria dos pacientes com micose fungoide hipocromiante são mais jovens que aqueles acometidos pela micose fungoide clássica. Esta variante é descrita principalmente em indivíduos melanodérmicos (afroamericanos e asiáticos). O prognóstico é melhor que o observado para a forma clássica: ao diagnóstico, os pacientes apresentam somente "patches", que tendem a perdurar por longos períodos, sem evolução para estágios mais avançados. O diagnóstico é feito através da correlação clinicopatológica: biópsia da lesão cutânea frequentemente revela intenso epidermotropismo, caracterizado por linfócitos CD8+ atípicos, grandes, com halo e núcleo convoluto, contrastando com o infiltrado dérmico leve a moderado. Estas células CD8+, que participam do perfil de resposta T helper-1, impediriam a evolução da doença para o desenvolvimento de placas infiltradas e tumores, além de determinar a inibição da melanogênese nas lesões hipocrômicas. Portanto, a hipocromia poderia ser considerada um marcador de bom prognóstico na micose fungoide.

An unusual case of mycosis fungoides with high proliferation index and C-MYC/8q24 translocation.

Mycosis fungoides is the most common entity among all cutaneous T cell lymphomas. Herein, we report for the first time a case of mycosis fungoides in a 51-year-old man with aggressive clinical course and confirmed C-MYC/8q24 translocation. Review of the literature reveals that dermal Ki-67 proliferation index not only correlates with the type and extent of skin involvement and clinical stage, but is also an independent adverse prognostic factor. Mycosis fungoides is associated with multiple genomic abnormalities, particularly in patients with tumor stage and advanced clinical stage, and gain of C-MYC/8q24 is associated with a shorter survival. Our patient showed a high dermal Ki-67 level and concomitant C-MYC/8q24 translocation, which may account for the aggressive clinical course and refractoriness to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.

Hypopigmented mycosis fungoides: a review of its clinical features and pathophysiology.

Several distinct clinical forms of mycosis fungoides have been described. Hypopigmented mycosis fungoides should be regarded as a subtype of mycosis fungoides, insofar as it presents some peculiar characteristics that contrast with the clinical features of the classical form. Most patients with hypopigmented mycosis fungoides are younger than patients typically diagnosed with classical mycosis fungoides. In addition to typical dark-skinned individuals impairment, hypopigmented mycosis fungoides has also been described in Asian patients. The prognosis for hypopigmented mycosis fungoides is much better than for classical mycosis fungoides: hypopigmented mycosis fungoides is diagnosed when there are only patches of affected skin, and lesions usually will not progress beyond terminal stages, although they can persist for many years. Diagnosis should involve clinicopathologic correlation: skin biopsy analysis often reveals intense epidermotropism, characterized by haloed, large, and atypical CD8+ lymphocytes with convoluted nuclei, in contrast to mild to moderate dermal lymphocytic infiltrate. These CD8+ cells, which participate in T helper 1-mediated immune responses, prevent evolution to mycosis fungoides plaques and tumors and could be considered the main cause of the inhibition of melanogenesis. Therefore, hypopigmentation could be considered a marker of good prognosis for mycosis fungoides.

Peroxisome proliferator-activated receptor gamma, a possible culprit in mycosis fungoides: an immunohistochemical study.

BACKGROUND: It still remains debatable whether peroxisome proliferator-activated receptor gamma (PPARγ) is pro- or antineoplastic, and its exact role in mycosis fungoides (MF) remains unclear. OBJECTIVE: This prospective comparative study aimed to investigate the expression of PPARγ in MF and compare it with psoriatics and controls in a trial to deduce its possible role in MF. Also, we tried to clarify the relation between PPARγ and Bcl-2 in MF. METHODS: Twenty MF patients, 20 psoriatic patients and 20 controls were included. All participants underwent a skin biopsy, and immunohistochemical staining for both PPARγ and Bcl-2 were performed. Western blot analysis was performed for detection of both PPARγ and Bcl-2. RESULTS: The mean area per cent of PPARγ measured in the MF patients (57.1217±9.502417) was significantly higher (P<0.001) when compared with that of both the psoriatics (2.989±1.723) and controls (35.9357±8.1789). The mean area per cent of Bcl-2 in MF patients (9.3763±6.6328) was significantly higher (P<0.001) than that of both the psoriatics (2.35±1.35) and the controls (0.73105±0.5302)]. Our results were confirmed using the western blot analysis. We detected a highly significant positive correlation between the PPARγ and Bcl-2 mean area per cents in all patients. In our MF patients, both parameters were also positively correlated with the age of the patient, duration and stage of MF (P<0.05). CONCLUSION: Our data suggest a possible role for PPARγ in the pathogenesis of MF possibly through several mechanisms, one of which might be conferring upon the lymphoma cells, a survival advantage at least partially through up regulating Bcl-2.

Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors.

Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that play key roles in cell trafficking, cell motility, and survival. These receptors are activated by small molecular weight chemotactic cytokines called chemokines. Chemokine receptors play roles in the migration and localization of normal T cells (and other leukocytes) during physiological responses in inflamed or infected skin. In cancer cells, these receptors may also facilitate tumorigenesis, metastasis, and resistance to immune-mediated killing. This review will focus on recent data that reveal potential roles of specific chemokine receptors, including CCR4, CXCR4, and CCR10, in the pathophysiology of cutaneous T-cell lymphoma, including mycosis fungoides and Sézary syndrome.

Evaluation of the role of human herpes virus 6 and 8 in parapsoriasis.

INTRODUCTION: The aetiology of mycosis fungoides and parapsoriasis (which may be considered as an early stage of mycosis fungoides) remains debated. Previous recent studies have suspected the involvement of viral agents and particularly human herpes viruses (HHV).The aim of the present study was to screen for the presence of HHV-6 and HHV-8 genome in parapsoriasis samples. METHOD: Fifty paraffin-embedded samples from skin biopsies of parapsoriasis were retrospectively collected from archival files in our Dermatology department. Total DNA was extracted from samples using the phenol-chloroform method and the presence of viral genomes was screened using real-time PCR. RESULTS: Forty nine out of the fifty tissue samples of parapsoriasis were interpretable, they were all found negative for HHV-6 and HHV-8. DISCUSSION: This study does not confirm the suspected role of HHV-6 or -8 in parapsoriasis. HHV-8 has been the most studied virus in parapsoriasis and more widely in cutaneous lymphoproliferative diseases and our results are in agreement with most of the studies which found none or few HHV-8 in more advanced stages of cutaneous lymphoproliferative diseases. Concerning HHV-6, our study is the first one investigating the presence of this virus in lesional tissue samples of patients with parapsoriasis. In conclusion, parapsoriasis does not seem to be associated with either HHV-6 or HHV-8.

Cutaneous T-cell lymphoma presenting as a ten month history of unilateral facial swelling.

A 25-year-old fisherman presented with a ten-month history of unilateral facial swelling involving his lower lip and eyelids. The differential diagnosis for oro-facial swelling is extensive including congenital, infective, inflammatory and neoplastic processes. Biopsies revealed a cutaneous T cell lymphoma.

Emerging drugs in cutaneous T cell lymphoma.

BACKGROUND: Mycosis fungoides (MF) represents the most common type of primary cutaneous T cell-lymphomas (CTCL), which are characterized by a clonally proliferation of malignant CD4+ lymphocytes in the skin. OBJECTIVE: Skin-directed treatment regimens, like phototherapy and corticosteroids, are commonly used in early stages; systemic treatments and chemotherapies are used in advanced stages. Because conventional treatments usually end in a transient remission without curative results, there is a high need for new therapeutic strategies with acceptable side effects. METHODS: Literature and reference research was done by using the data bank PubMed, and updates of ongoing studies were taken out of ASCO and ASH annual meeting abstracts. RESULTS/CONCLUSIONS: This article gives an overview of the various medications in current use, with emphasis on emerging drugs with novel therapeutic targets.