Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients

Mycosis fungoides and Sézary syndrome: demographic, clinical, histopathological, immunopathological, molecular, laboratory and evolutionary characterization of the cohort observed at the cutaneous lymphomas outpatient clinic of the Division of Clinical Dermatology of the Hospital das Clínicas of the University of São Paulo Medical School between 1989 and 2018

INTRODUÇÃO: Micose fungoide (MF) é o linfoma cutâneo de células T mais prevalente, e a síndrome de Sézary (SS) é uma variante leucêmica agressiva. A variação geográfica das características da MF/SS é grande. Não há estudo abrangendo uma grande coorte de pacientes com MF/SS no Brasil. OBJETIVOS: Descrever as características demográficas, clínicas, histopatológicas, imunopatológicas, moleculares, laboratoriais e evolutivas de uma grande coorte de pacientes com MF/SS em um serviço de saúde público terciário no Brasil. Correlacionar variantes, subtipos, estágios e sobrevida com os dados demográficos, clínicos, histopatológicos, imunopatológicos, moleculares e laboratoriais. MÉTODOS: Estudo observacional de coorte retrospectivo a partir de banco de dados e prontuários médicos. Foram analisados pacientes diagnosticados com MF/SS avaliados no ambulatório de linfomas cutâneos da Divisão de Clínica Dermatológica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, entre 1989 e 2018; e foram coletados dados demográficos, clínicos, histopatológicos, imunopatológicos, moleculares e laboratoriais no momento do diagnóstico. Foram analisados os tratamentos ao longo do seguimento e o estado do paciente na última avaliação. RESULTADOS: Dentre 856 pacientes com linfomas cutâneos de células T/NK, 78,6% (673/856) apresentavam MF e 6,3% (54/856) SS. Houve 51,2% (372/727) de pacientes masculinos e 48,8% (355/727) femininos. A mediana de idade ao diagnóstico foi de 51,8 anos. Dentre os pacientes com MF, 41,8% (281/673) apresentavam a forma de Alibert-Bazin, com formação de patches, placas e tumores; 4,9% (33/673) apresentavam a variante foliculotrópica; 1,8% (12/673) a cútis laxa granulomatosa; e 0,3% (2/673) a reticulose pagetoide. Além destas variantes, outros subtipos incluíram 14,1% (95/673) pacientes com MF eritrodérmica, 10,8% (73/673) com MF hipocromiante, 10,8% (73/673) com MF poiquilodérmica, 0,6% (4/673) com MF granulomatosa, 0,3% (2/673) com MF papulosa, 0,1% (1/673) com MF hipercrômica, e 14,4% (97/673) com formas mistas em que mais de uma variante ou subtipo foram observados no mesmo paciente. O achado histológico mais frequente foi o epidermotropismo/exocitose de linfócitos, observado em 96,2% (563/585) dos casos. Porém, 20,4% (70/343) dos pacientes com MF e 35,1% (13/37) dos pacientes com SS tiveram biópsias cutâneas iniciais inespecíficas. Acometimento linfonodal, de medula óssea e visceral raramente foram observados. A presença de população monoclonal de linfócitos T foi detectada na pele em 52,8% (93/176) dos pacientes com MF e 78,6% (22/28) com SS; no sangue em 23,6% (43/182) dos pacientes com MF e 93,7% (30/32) com SS; e no linfonodo 62,5% (15/24) dos pacientes com MF e 83,3% (15/18) com SS. De acordo com o estadiamento, 62,4% (413/662) apresentavam estágio inicial (estágios IA a IIA) no momento do diagnóstico, e 37,6% (249/662) apresentavam estágio avançado (estágio IIB a IVB). A sobrevida global em 5 anos foi de 82,7%. Após análise multivariada, diagnóstico de SS, MF foliculotrópica, MF eritrodérmica, estadiamento, idade (>= 60 anos), aumento da desidrogenase láctica e transformação para linfoma de grandes células conferiram um pior prognóstico. CONCLUSÕES: Esta é a maior coorte brasileira e latino-americana de pacientes com MF/SS. As características demográficas, clínicas, histopatológicas, imunopatológicas, moleculares, laboratoriais e evolutivas estiveram de acordo com a maioria dos estudos norte-americanos, europeus e asiáticos. Fatores associados a pior prognóstico descritos na literatura também foram observados no presente trabalho.INTRODUCTION: Mycosis fungoides (MF) is the most prevalent cutaneous T-cell lymphoma, and Sézary syndrome (SS) is an aggressive leukemic variant. Geographical variation of MF/SS characteristics is large. There is no study covering a large cohort of patients with MF/SS in Brazil. OBJECTIVES: To describe the demographic, clinical, histopathological, immunopathological, molecular, laboratory and evolutionary characteristics of a large cohort of patients with MF/SS in a tertiary public health service in Brazil. To correlate variants, subtypes, stages, and survival with demographic, clinical, histopathological, immunopathological, molecular, and laboratory data. METHODS: Retrospective observational cohort study from database and medical records. Patients diagnosed with MF/SS evaluated in the cutaneous lymphomas outpatient clinic of the Division of Clinical Dermatology of the Hospital das Clínicas of the University of São Paulo Medical School, between 1989 and 2018, were analyzed; and demographic, clinical, histopathological, immunopathological, molecular, and laboratory data were collected at the time of diagnosis. The treatments during the follow-up and the patient\'s condition in the last evaluation were analyzed. RESULTS: Among 856 patients with cutaneous T/NK cell lymphomas, 78.6% (673/856) had MF and 6.3% (54/856) SS. There were 51.2% (372/727) of male and 48.8% (355/727) of female patients. The median age at diagnosis was 51.8 years. Among patients with MF, 41.8% (281/673) had the Alibert-Bazin form, with the formation of patches, plaques, and tumors; 4.9% (33/673) had the folliculotropic variant; 1.8% (12/673) the granulomatous slack skin; and 0.3% (2/673) the pagetoid reticulosis. In addition to these variants, other subtypes included 14.1% (95/673) patients with erythrodermic MF, 10.8% (73/673) with hypopigmented MF, 10.8% (73/673) with poikilodermatous MF, 0.6% (4/673) with granulomatous MF, 0.3% (2/673) with papular MF, 0.1% (1/673) with hyperpigmented MF, and 14.4% (97/673) with mixed forms when more than one variant or subtype were observed in the same patient. The most frequent histological finding was epidermotropism/exocytosis of lymphocytes, observed in 96.2% (563/585) of the cases. However, 20.4% (70/343) of the patients with MF and 35.1% (13/37) of the patients with SS had non-specific initial skin biopsies. Lymph node, bone marrow, and visceral involvement were rarely observed. The presence of a monoclonal T-lymphocyte population was detected on the skin in 52.8% (93/176) of the patients with MF and 78.6% (22/28) with SS; on the blood in 23.6% (43/182) of the patients with MF and 93.7% (30/32) with SS; and on the lymph node in 62.5% (15/24) of the patients with MF and 83.3% (15/18) with SS. According to staging, 62.4% (413/662) had early-stage disease (stages IA to IIA) at the time of diagnosis, and 37.6% (249/662) had advanced-stage disease (stage IIB to IVB). The overall 5-year survival was 82.7%. After multivariate analysis, diagnosis of SS, folliculotropic MF, erythrodermic MF, clinical stage, age (>= 60 years), increased lactate dehydrogenase, and large cell transformation conferred a worse prognosis. CONCLUSIONS: This is the largest Brazilian and Latin American cohort of patients with MF/SS. Demographic, clinical, histopathological, immunopathological, molecular, laboratory, and evolutionary characteristics were in agreement with most North American, European, and Asian studies. Factors associated with a worse prognosis described in the literature were also observed in the present study

Additional file 1: of A case report of erythroderma in a patient with borderline leprosy on reversal reaction: a result of the exacerbated reaction?

Immunohistochemistry staining for Foxp3, IL-4, IL-17 and IFN-γ of the biopsies of skin lesions. Material and methods for the immunohistochemistry stainings. (DOCX 16 kb

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment