Overview of Cutaneous T-Cell Lymphomas.

Non-Hodgkin's lymphoma (NHL) encompasses a diverse collection of systemic and primary cutaneous lymphomas. Cutaneous T-cell lymphomas (CTCLs) represent about 13% of all NHLs, which are further subdivided into a heterogeneous group with vastly different presentations and histologic features. Diagnosis requires integration of clinical, pathologic, and molecular features. Among CTCLs, mycosis fungoides and Sézary syndrome are the most prevalent. Treatment is aimed at limiting morbidity and halting disease progression. Hematopoietic stem cell transplantation is the only therapy with curative intent.

Blood classification and blood response criteria in mycosis fungoides and Sézary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force.

Our current mycosis fungoides (MF) and Sézary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sézary counts but results from our EORTC survey confirm these are rarely performed in patch/plaque/tumour MF, and there is a trend towards using flow cytometry to measure blood-class. Accurately assigning blood-class effects overall stage and the 'global response' used to measure treatment responses in MF/SS and hence impacts management. The EORTC Cutaneous Lymphoma Task Force Committee have reviewed the literature and held a Workshop (June 2017) to agree a definition of blood-class according to flow cytometry. No large study comparing blood-class as defined by Sézary count with flow cytometry has been performed in MF/SS. The definition of blood-class by flow cytometry varies between publications. Low-level blood involvement occurs in patch/plaque/tumour much less than erythroderma (p < 0.001). The prognostic relevance of blood involvement (B1 or B2) in patch/plaque/tumour is not known. Studies have not shown a statistically worse difference in prognosis in erythrodermic MF patients with low-level blood involvement (IIIB) versus those without (IIIA), but Sezary patients who by definition have a leukaemic blood picture (staged IVA1 or higher) have a worse prognosis. For consistency flow, definition for blood-class must be an objective measurement. We propose absolute counts of either CD4+CD7-or CD4+CD26-where B0<250/µL, B1 = 250/µl-<1000/µL and B2≥1000/µL plus a T-cell blood clone. Fluctuations between B0 and B1 should not be considered in the treatment response criteria until further prognostic information is known.

[Treatment of mycosis fungoides and Sézary syndrome]. / Therapie der Mycosis fungoides und des Sézary-Syndroms.

Adequate therapeutic management of cutaneous T-cell lymphoma (CTCL) requires the identification of the exact CTCL stage and entity within the current WHO classification. There is no curative therapy for CTCL yet, so that treatment currently aims at improving symptoms and quality of life as well as reducing relapse rates. The treatment has to be stage-adapted. Therapeutic options comprise skin-directed as well as systemic treatment. In early stages, phototherapy and local steroids are the first-line therapeutic options. For the therapy of higher stages, interferon alpha and the RXR-specific retinoid bexarotene are used as first-line medications. Second-line treatment comprises monochemotherapy with agents like gemcitabine or liposomal doxorubicine. Nevertheless, the high relapse rates in higher stages make novel alternative treatment options necessary. As future therapy, especially the fusion protein brentuximab-vedotin directed against CD30 shows promising potential in clinical studies.

Sézary syndrome without erythroderma: A review of 16 cases at Mayo Clinic.

BACKGROUND: Sézary syndrome (SS) is characterized by erythroderma with leukemic involvement. In atypical SS, leukemic involvement is present without erythroderma. Little is known about the presentation, prognosis, and outcome in these patients. OBJECTIVE: We sought to describe our experience with patients with SS without erythroderma. METHODS: We retrospectively identified patients with SS, but without erythroderma, at Mayo Clinic from 1976 to 2010. Patients all met criteria for high blood tumor burden. Their clinical characteristics, disease course, and prognosis were reviewed and compared with a previously described cohort of 176 patients with SS from this institution. RESULTS: Among 16 patients identified, all had cutaneous findings consistent with cutaneous T-cell lymphoma, most commonly erythematous patches (n = 6) and plaques (n = 12). All 16 patients were deceased at the time of the study. Median time from diagnosis of SS without erythroderma to the date of death was 3.6 years (range, 0.5-8.7 years). Survival was not different between patients with SS with and without erythroderma (hazard ratio 1.58; 95% confidence interval 0.94-2.66; P = .08). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: Leukemic involvement may confer shortened survival in patients with SS, because the presence of erythroderma did not affect survival. These atypical cases could potentially be more accurately described using the TNMB classification.

Evaluation, Diagnosis, and Staging of Cutaneous Lymphoma.

Primary cutaneous lymphomas (PCLs) are an extremely heterogeneous group of non-Hodgkin lymphomas that manifest in the skin. Their diagnosis is complex and based on clinical lesion type and evaluation of findings on light microscopic examination, immunohistochemistry and molecular analysis of representative skin biopsies. The evaluation, classification, and staging system is unique for mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma (CTCL) versus the other subtypes of Non-MF/Non-SS CTCL and the subtypes of cutaneous B-cell lymphoma (CBCL). Since current treatment is stage-based, it is particularly important that the correct diagnosis and stage be ascertained initially. The purpose of this article is to review the current evaluation, diagnosis, classification, staging, assessment techniques, and response criteria for the various types of both T-cell and B-cell PCLs.

Actualización en diagnóstico y manejo de micosis fungoide y síndrome de Sézary / Update on diagnosis and management of mycosis fungoides and Sézary's syndrome

Los linfomas cutáneos primarios consisten en una proliferación anormal de linfocitos T o B que muestran tropismo por la piel, sin evidenciarse compromiso extra cutáneo al momento del diagnóstico. Se dividen en linfomas de células T (75 por ciento-80 por ciento) y linfomas de células B (20 por ciento-25 por ciento). La micosis fungoide es una neoplasia de estirpe T y constituye el linfoma cutáneo primario más frecuente. Su presentación clínica clásica consiste en 3 etapas: parche, placa y tumor. Sin embargo, tiene múltiples variantes y un amplio diagnóstico diferencial, por lo que para su diagnóstico se requiere una estricta correlación entre la clínica y la histopatología. El síndrome de Sézary, por su parte, es considerado la variante leucémica de los linfomas cutáneos primarios y forma parte del diagnóstico diferencial de las eritrodermias. En esta revisión profundizaremos en los principales aspectos de la clínica, histopatología, criterios diagnósticos y tratamiento de la micosis fungoide y el síndrome de Sézary.

Primary cutaneous lymphomas represent an abnormal proliferation of T or B-cells with skin-homing ability, with no evidence of extra cutaneous disease at the time of diagnosis. They are divided in T-cell lymphomas (75 percent-80 percent) and B-cell lymphomas (20 percent-25percent). Mycosis fungoides (MF) is a T-cell malignancy, being the most common lymphoma. Classic MF presents 3 clinical phases: patch, plaque and tumor stage. However, it has numerous variants and a wide range of differential diagnosis, so that precise clinicopathologic correlation is necessary for make a correct diagnosis. Sézary syndrome is an aggressive leukemic primary cutaneous T-cell lymphoma variant and it is part of the spectrum of erythroderma. In this review we will analyze the main aspects about clinical presentation, histopathology, diagnosis and treatment of mycosis fungoides and Sézary syndrome.

A practical approach to accurate classification and staging of mycosis fungoides and Sézary syndrome.

Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin's lymphomas. Of which, mycosis fungoides (MF) and Sézary syndrome (SS) are two of the most common forms. Careful, clear classification and staging of these lymphomas allow dermatologists to commence appropriate therapy and allow correct prognostic stratification for those patients affected. Of note, patients with more advanced disease will require multi-disciplinary input in determining specialist therapy. Literature has been summarized into an outline for classification/staging of MF and SS with the aim to provide clinical dermatologists with a concise review.

Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.

Histopathologic diagnosis of lymphomatous versus inflammatory erythroderma: a morphologic and phenotypic study on 47 skin biopsies.

Erythroderma may be secondary to a cutaneous T-cell lymphoma (CTCL) and various other erythrodermic inflammatory dermatoses (EID), and their histopathologic distinction is often difficult. The aim of this study was to determine if morphological parameters, namely: the presence of b-catenin, and JunB (previously shown to be expressed by CTCL cells), the epidermal CD8:CD3 ratio, and CD30 expression may help in the histopathologic diagnosis of erythroderma, especially in differentiating CTCL and EID. We retrospectively reviewed a series of 47 skin biopsies from patients with erythroderma (18 CTCL and 29 EID). The diagnosis of each case was established using clinical, biological and histopathologic data. After a blind assessment of the hematoxylin--eosin--safran stained slides, a correct diagnosis of the underlying cause of erythroderma was made only in 31% of cases. A correct differential diagnosis between lymphoma and EID was done with certainty in 57% of cases. Various morphologic and phenotypic parameters were then recorded and we compared their frequency in the CTCL versus the EID group. With the exception of atypical lymphocytes, the moderate to high density of dermal infiltrates and Pautrier microabcesses, only found in CTCL, no morphologic parameter was found to be specific of CTCL, although single lymphocytes epidermotropism, telangiectasias, and slight lymphocytic dermal infiltrate were significantly more frequent in EID. A low (<10%) CD8:CD3 ratio in the epidermal lymphocytic infiltrate and dermal CD30+ lymphocytes were significantly more frequent in CTCL. JunB expression by lymphocytes was specific of CTCL, but was inconstant in our series (17%). We found ß-catenin expression in a minority of cases from both the CTCL and EID groups. Among EID, dermal suprapapillary thinning was specific of psoriasis. Neutrophils exocytosis and edema of papillary dermis were significantly more frequent in psoriasis, and spongiosis was more frequent in eczema. In conclusion, few morphological and phenotypical parameters are helpful in making a differential diagnosis between erythrodermic CTCL and EID using paraffin embedded skin biopsies.

Perspectiva histórica de los linfomas cutáneos a través de actas Dermo-Sifiliográficas / Cutaneous Lymphoma in Actas Dermo-Sifiliográficas: A Historical Perspective

Repasamos la historia de los linfomas cutáneos a través de los artículos referidos al tema en la revista Actas Dermo-Sifiliográficas. Aproximadamente 100 años después de que Alibert describiera el primer paciente con micosis fungoide en 1806, comienzan a aparecer casos sobre el tema en Actas. Veremos cómo a lo largo del siglo que lleva publicándose la Revista ha ido cambiando el concepto, la clasificación y el tratamiento de esta enfermedad, que aún hoy en día sigue siendo un reto para el dermatólogo (AU)

This article reviews the history of cutaneous lymphomas through the articles published on this subject in the journal Actas Dermo-Sifiliográficas. Approximately 100 years after Alibert published the first description of a patient with mycosis fungoides in 1806, reports of cutaneous lymphoma cases began to appear in Actas. These articles reflect how the definition, classification, and treatment of this disease, which continues to pose a challenge for dermatology, have evolved over the 100-year lifespan of the journal (AU)

Primary cutaneous lymphomas: a population-based descriptive study of 71 consecutive cases diagnosed between 1980 and 2003.

Although primary cutaneous lymphomas (PCL) are the second most common group of extra-nodal non-Hodgkin lymphomas, few epidemiological data are available in the literature, and most of them are provided by large databases from population-based cancer registries in the US or patients attending a single institution. We conducted this study to investigate the epidemiological and clinical features of PCL diagnosed in the department of Doubs from 1980 to 2003. Data were collected from the Doubs cancer registry from 1980 to 2003. Seventy-one patients with PCL were investigated. 82% were cutaneous T-cell lymphoma (CTCL) and 18% were cutaneous B-cell lymphoma (CBCL). Among CTCL, mycosis fungoides (MF) represented 58% and Sezary syndrome 10%. The standardised incidence rate of PCL was 0.42 for 100 000 person-years and significantly increased from 0.21 in 1980-1984 to 0.70 in 2000-2003 (p <0.05). The incidence rate of CTCL was 0.34 for 100 000 person-year and significantly increased from 0.2 to 0.57 (p <0.05). For MF and CBCL, the incidence rates were 0.20 and 0.08, respectively and did not vary significantly from 1980-1984 to 2000-2003. Five-year survival was 64.5% for PCL patients similar to MF patients. Our results provide updated data on the incidence of PCL in France.

Primary cutaneous B-cell lymphomas - clinicopathological, prognostic and therapeutic characterisation of 54 cases according to the WHO-EORTC classification and the ISCL/EORTC TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome.

Clinical, prognostic and therapeutic features of 54 primary cutaneous marginal zone B-cell lymphoma (pcMZL), follicle centre lymphoma (pcFCL) and diffuse large B-cell lymphoma, leg type (pcDLBL) were analysed applying the WHO-EORTC classification for cutaneous lymphomas and the new TNM staging scheme of the International Society of Cutaneous Lymphomas. Solitary (T1) or regionally clustered (T2) tumors were observed in pcMZL and pcFCL. Disseminated tumors (T3 stage) were found in 26% of patients with pcMZL and in one patient with pcDLBL. A complete remission was achieved in 41% of the patients. Three of 7 patients (43%) with pcDLBL died due to lymphoma. The new TNM staging system is easily applicable for disease documentation, but our relatively small number of patients in each T stage does not allow the assessment of its prognostic value. Surgical excision or radiotherapy is highly effective in pcMZL and pcFCL.

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma.

BACKGROUND: Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM (tumor, (lymph) node, metastasis) classification for non-mycosis fungoides cutaneous lymphomas. OBJECTIVE: We aimed to characterize the clinical features including new TNM classification for non-mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. RESULTS: Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. LIMITATIONS: The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. CONCLUSIONS: Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).

The ISCL/EORTC recommends revisions to the Mycosis Fungoides Cooperative Group classification and staging system for cutaneous T-cell lymphoma (CTCL). These revisions are made to incorporate advances related to tumor cell biology and diagnostic techniques as pertains to mycosis fungoides (MF) and Sézary syndrome (SS) since the 1979 publication of the original guidelines, to clarify certain variables that currently impede effective interinstitution and interinvestigator communication and/or the development of standardized clinical trials in MF and SS, and to provide a platform for tracking other variables of potential prognostic significance. Moreover, given the difference in prognosis and clinical characteristics of the non-MF/non-SS subtypes of cutaneous lymphoma, this revision pertains specifically to MF and SS. The evidence supporting the revisions is discussed as well as recommendations for evaluation and staging procedures based on these revisions.

TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).

Currently availabel staging systems for non-Hodgkin lymphomas are not useful for clinical staging classification of most primary cutaneous lymphomas. The tumor, node, metastases (TNM) system used for mycosis fungoides (MF) and Sézary syndrome (SS) is not appropriate for other primary cutaneous lymphomas. A usable, unified staging system would improve the communication about the state of disease, selection of appropriate management, standardization of enrollment/response criteria in clinical trials, and collection/analysis of prospective survival data. Toward this goal, during the recent meetings of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC), the representatives have established a consensus proposal of a TNM classification system applicable for all primary cutaneous lymphomas other than MF and SS. Due to the clinical and pathologic heterogeneity of the cutaneous lymphomas, the currently proposed TNM system is meant to be primarily an anatomic documentation of disease extent and not to be used as a prognostic guide.

The spectrum of cutaneous lymphomas in Japan: a study of 62 cases based on the World Health Organization Classification.

BACKGROUND: The relative incidence of malignant lymphoma subtypes differs according to geographic location. This study investigated the epidemiology of cutaneous lymphoma subtypes in Japan and compared it with other countries. METHODS: Sixty-two patients with cutaneous lymphoma attending the Department of Dermatology, National Hospital Organization Hokkaido Cancer Center were reviewed. The World Health Organization classification of hematopoietic and lymphoid malignancies was adopted. RESULTS: Of the 62 patients, 31 had primary cutaneous lymphoma (PCL) and 31 had secondary cutaneous lymphoma (SCL). T- and natural killer (NK)-cell lymphoma accounted for 80% of PCL, of which, mycosis fungoides accounted for almost 35%. Of the 31 patients with secondary cutaneous lymphoma, 17 patients (54%) had T- and NK-cell lymphoma, including nine adult T-cell leukemia/lymphoma patients, and 14 patients (46%) had B-cell lymphoma, including 11 diffuse large B-cell lymphoma patients. The majority of patients with SCL and NK-cell lymphoma with primary or secondary skin lesions had a poor outcome. CONCLUSIONS: PCL in this study showed a similar incidence to that of other institutions in Japan, while also demonstrating different frequencies from that of other countries, suggesting that the relative frequency of different PCL subtypes differ according to geographical location, similar to previous reports of systemic malignant lymphoma.

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome.

Several reviews and guidelines on the management of mycosis fungoides and Sézary syndrome (MF/SS) have been published; however, treatment strategies for patients with MF/SS vary from institution to institution and no European consensus has yet been established. There are few phase III trials to support treatment decisions for MF/SS and treatment is often determined by institutional experience. In order to summarise the available evidence and review 'best practices' from each national group, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force met in September 2004 to establish European guidelines for the treatment of MF/SS. This article reviews the treatment regimens selected for inclusion in the guidelines and summarises the clinical data for treatments appropriate for each stage of MF/SS. Guideline recommendations are presented according to the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine. Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy. Patients with advanced disease should be encouraged to participate in clinical trials and maintenance of quality of life should be paramount.

Staging and management of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) accounts for two-thirds of cases of primary cutaneous lymphoma. Most variants of CTCL are indolent lymphoma, the most common being mycosis fungoides. In addition, Sézary syndrome, the leukaemic variant, has an aggressive clinical course. Accurate diagnosis and staging is critical in determining the prognosis of those with CTCL. The tumour, node, metastasis and blood stage needs to be documented and used to determine an overall stage from IA to IVB. Management of patients should be carried out by a multidisciplinary team. A full clinical examination should be made at all visits. Thorough investigations are needed at diagnosis and should be repeated during disease progression to allow initial staging and restaging. Treatment of patients with early-stage disease (IA-IIB) should be limited to skin-directed therapy. More advanced or resistant disease may be treated with systemic therapies such as extracorporeal photopheresis, immunotherapy, monoclonal antibody therapy, novel retinoids or chemotherapy, and where possible, patients should be entered into clinical trials.

The new World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas.

The WHO-EORTC classification of cutaneous lymphomas is a good start to unifying nomenclature, a necessity before coherent consensus diagnoses can be made. There are three provisional diagnoses in this new classification that are not covered in detail in this review because they are rare diseases that still require further study for definitive classification. Much remains to be elucidated about cutaneous lymphomas, but understanding of the major entities within the new classification is an important first step in understanding these diverse diseases.