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Cutaneous T-cell lymphomas (CTCLs) are rare forms of non-Hodgkin's lymphoma of T-cell origin that occur mainly in the skin. The most common form is mycosis fungoides (MF), but Sézary syndrome (SS), a more aggressive form of CTCL, is another relevant subgroup. Due to the rare nature of the disease, population-based studies of the epidemiology and disease burden and insights into care delivery are limited.Based on an anonymized, age and sex-adjusted routine dataset comprising approximately five million people with statutory health insurance, a retrospective, longitudinal healthcare research study was conducted over a six-year period (2012-2017).In 55 % of patients with MF and SS, the initial diagnosis was documented in an outpatient setting; in 59 % of cases by a dermatologist. Immunophenotyping by flow cytometry is considered an important investigative tool for the detection and follow-up surveillance of blood involvement of cutaneous lymphomas, as the disease stage is the most important prognostic factor in MF and SS; this was performed in only 10 % of patients. The first-line treatment was topical (76 %), in particular with corticosteroids (66 %).The findings from this healthcare research point to the need for increased guideline-based care.

BACKGROUND: Accurate Sezary cell detection in peripheral blood of mycosis fungoides/Sezary syndrome (MF/SS) patients by flow cytometry can be difficult due to overlapping immunophenotypes with normal T cells using standard markers. We assessed the utility of programmed death-1 (PD-1/CD279), a transmembrane protein expressed in some hematopoietic cells, for identification and quantitation of circulating Sezary cells among established markers using flow cytometry. METHODS: 50 MF/SS and 20 control blood samples were immunophenotyped by flow cytometry. Principal component analysis (PCA) assessed contributions of antigens to separation of abnormal from normal T cell populations. PD-1 was assessed over time in blood and bone marrow of available MF/SS cases. RESULTS: Normal CD4+ T cells showed dim/intermediate to absent PD-1 expression. PD-1 in Sezary cells was informatively brighter (≥1/3 log) than internal normal CD4+ T cells in 39/50 (78%) cases. By PCA, PD-1 ranked 3(rd) behind CD7 and CD26 in population separation as a whole; it ranked in the top 3 markers in 32/50 (64%) cases and 1(st) in 4/50 (8%) cases when individual abnormal populations were compared to total normal CD4+ T cells. PD-1 clearly separated Sezary from normal CD4+ T cells in 15/26 (58%, 30% of total) cases with few and subtle alterations of pan T-cell antigens/CD26 and was critical in 6 (12% of total), without which identification and quantification were significantly affected or nearly impossible. PD-1 remained informative in blood/bone marrow over time in most patients. CONCLUSIONS: PD-1 significantly contributes to accurate flow cytometric Sezary cell assessment in a routine Sezary panel.

Cutaneous T-cell lymphomas (CTCL) result from the infiltration and proliferation of a population of T cells in the skin, inducing changes in the activity of both T cells and surrounding skin cells. In the CTCL microenvironment, cell interactions mediated by cell signaling pathways are altered. Defining changes in cell signaling enables to understand T-cell deregulations in the CTCL microenvironment and thus the progression of the disease. Moreover, characterizing signaling networks activated in CTCL stages can lead to consider new molecular biomarkers and therapeutic targets. Focusing on mycosis fungoides (MF), the most frequent variant of CTCL, and Sézary syndrome (SS), its leukemic variant, this review highlights recent molecular and genetic findings revealing modifications of key signaling pathways involved in (1) cell proliferation, cell growth, and cell survival such as MAP kinases and PI3K/Akt; (2) immune responses derived from TCR, TLR, JAK/STAT, and NF-kB; and (3) changes in tissue conditions such as extracellular matrix remodeling, hypoxia, and angiogenesis. Alterations in these signaling networks promote malignant T-cell proliferation and survival, T-cell migration, inflammation, and suppression of immune regulation of malignant T cells, making a skin microenvironment that allows disease progression. Targeting key proteins of these signaling pathways, using molecules already available and used in research, in clinical trials, and with other disease indications, can open the way to different therapeutic options in CTCL treatment.

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of mature CD4-positive T-cell lymphoid cells associated with retrovirus human T-lymphotropic virus type-1 (HTLV-1) with a wide clinical and pathologic spectrum. We report a case of a 53-year-old African man who presented with fever and skin eruptions on the trunk composed of non-itchy erythematous reticulated macules and papules initially suspected for viral exanthem or drug rash. Skin punch biopsy showed a dermal T-cell lymphoid infiltrate with epidermotropism. The patient developed generalized lymphadenopathy and his peripheral blood showed lymphocytosis with atypical lymphocytes with convoluted nuclei. Our initial diagnosis was mycosis fungoides with Sézary syndrome. However, some clinical and histopathologic features were unusual. The acute onset, lack of previous skin lesions, the histomorphologic features of the dermal, nodal and peripheral blood lymphocytes and the geographic origin of the patient raised the suspicion of other T-cell lymphomas, particularly ATLL. This was confirmed by a positive anti-HTLV-1 serology. Our final diagnosis was acute variant ATLL. Different T-cell lymphomas can involve the skin with overlapping clinical, histomorphologic and immunohistochemical features. Some clinical and pathologic features should alarm dermatologists and pathologists to the possibility of ATLL particularly in patients from HTLV-1 endemic geographic areas.

BACKGROUND Sezary syndrome is a leukaemic variant of cutaneous T-cell lymphoma with poor prognosis. With the exception of stem cell transplantation, current treatments for SS are not curative. Rather, they aim at reducing disease burden and improving quality of life. Yet, pruritus - the major cause for impaired quality of life in these patients - is notoriously difficult to treat. Thus, supportive treatments addressing agonizing pruritus are urgently needed. OBJECTIVES To explore the clinical and immunological effects of type 2 cytokine blockade with dupilumab as supportive treatment in Sezary syndrome. METHODS A Sezary syndrome patient with stable disease but intractable pruritus was treated with dupilumab in combination with continued extracorporeal photopheresis. Close clinical and immunological monitoring on blood and skin samples from the patient was performed over 44 weeks. In vitro assays with patient's lymphoma cells were performed to address effects of dupilumab on Sezary cell's response to Th2 cytokines. RESULTS Clinically, dupilumab treatment induced rapid and sustained reduction in itch and improvement of skin and lymph node involvement. In both blood and skin, a reduction in Th2 bias was observed. Intriguingly, lymphocyte counts and Sezary cells in blood increased and later stabilized under dupilumab treatment. In vitro, dupilumab abrogated the anti-apoptotic and activating effects of Th2 cytokines on Sezary cells. CONCLUSIONS In this Sezary patient, inhibition of IL-4 and IL-13 signalling was associated with striking clinical benefit in terms of quality of life, pruritus and use of topical corticosteroids. While safety remains an important concern, our data support the future exploration of Th2 modulation for supportive care in Sezary Syndrome.

Introducing a sensitive and specific peripheral blood flow cytometric assay for Sézary syndrome and mycosis fungoides (SS/MF) requires careful selection of assay design characteristics, and translation into a laboratory developed assay through development/optimization, validation, and continual quality monitoring. As outlined in a previous article in this series, the recommended design characteristics of this assay include at a minimum, evaluation of CD7, CD3, CD4, CD8, CD26, and CD45, analyzed simultaneously, requiring at least a 6 color flow cytometry system, with both quantitative and qualitative components. This article provides guidance from an international group of cytometry specialists in implementing an assay to those design specifications, outlining specific considerations, and best practices. Key points presented in detail are: (a) Pre-analytic components (reagents, specimen processing, and acquisition) must be optimized to: (i) identify and characterize an abnormal population of T-cells (qualitative component) and (ii) quantitate the abnormal population (semi/quasi-quantitative component). (b)Analytic components (instrument set-up/acquisition/analysis strategy and interpretation) must be optimized for the identification of SS/MF populations, which can vary widely in phenotype. Comparison with expert laboratories is strongly encouraged in order to establish competency. (c) Assay performance must be validated and documented through a validation plan and report, which covers both qualitative and semi/quasi-quantitative assay components (example template provided). (d) Ongoing assay-specific quality monitoring should be performed to ensure consistency.

Background Deregulation of signal transducer and activator of transcription (STAT) signaling is known to participate in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). However, published results regarding STAT expression in different stages of CTCLs are conflicting. The aim of the study was to define the pattern of STAT expression in skin and detect any differences between pruritic and nonpruritic patients but also different stages of disease. Methods Thirty-nine skin biopsies from CTCL patients and 24 biopsies from healthy volunteers were taken. Immunohistochemical staining for STAT 3, 5a, 5b, and 6 was performed in formalin-fixed paraffin-embedded sections of mycosis fungoides (MF) and Sezary syndrome (SS) specimens. Results We found increased expression of STAT proteins in CTCL: MF and SS skin in comparison to the control group. STAT5 but also STAT6 and to a lesser extent STAT3 seems to be constitutively activated in MF and SS. Moreover, also downregulation of STAT5b protein in advanced-stage CTCL appears to contribute to its pathogenesis. There were no significant associations between expression of STATs and pruritus severity. Conclusions Our results confirm the possible pathogenetic role of STATs in CTCL. STATs seem to be a promising target for new effective therapeutic agents in CTCL.

BACKGROUND Given the severe symptom burden and chronic nature of mycosis fungoides (MF) and Sezary syndrome (SS), effective assessment of quality of life (QoL) is essential to guiding patient-centred care in this population. In this study, we aim to provide a comprehensive assessment of QoL in early- and advanced-stage MF/SS and to assess the correlation of traditional measures of clinical severity with QoL measures. METHODS Between July 2017 and April 2019, outpatients at an academic medical centre with either MF/SS (n = 115) or general dermatology concerns (n = 115) completed generic and dermatology-specific QoL instruments [Health Utilities Index Mark 3 (HUI3), RAND 36-Item Short-Form Health Survey (SF-36), Skindex-29, visual analogue scale for itch (VAS itch) and 5-D pruritus scale]. The mean scores of MF/SS patients were compared to that of controls using multivariable regression models adjusted for demographics and medical comorbidities. Cluster analysis of the QoL instruments and clinical severity measures (e.g. stage and body-surface-area involvement) was performed. RESULTS Patients with MF/SS scored significantly worse than controls on all QoL instruments used, with advanced-stage (IIB-IVB) disease having the worst QoL impairment. Early-stage (IA-IIA) and advanced-stage MF/SS patients had significantly reduced overall health status (HUI3; P

Cell adhesion molecule 1 (CADM1) is aberrantly expressed by T-cell neoplasms such as adult T-cell leukemia/lymphoma (ATLL) and mycosis fungoides (MF). We studied the expression of CADM1 and its splicing variants in Sézary syndrome (SS), MF, other cutaneous T-cell lymphoma (CTCL), and cell lines derived from T- and B-cell lymphomas. Soluble CADM1 was measured in the patients' sera. CADM1+ cells in the blood and skin lesions were examined by flow cytometry and immunostaining, respectively. Soluble CADM1 was measured by ELISA, and the splicing variants of CADM1 transcripts were determined by reverse transcriptase-polymerase chain reaction, followed by sequencing. As a result, circulating CADM1+ cells were significantly increased in seven out of 10 patients with SS, ranging from 7.9% to 74.5% of the CD3+CD4+ fractions (median 33.7%; cut-off value 6.5%). The percentages of CADM1+ cells were usually less than those of circulating Sézary cells. CADM1 was expressed, to various degrees, in six of nine T-cell lines derived from SS, MF, ATLL, and anaplastic large cell lymphoma (ALCL), but negative in B-cell lymphoma-derived cell lines. CADM1+ cells were present in the skin infiltrates of MF, SS, ATLL and ALCL. Serum levels of soluble CADM1 were not significantly elevated in SS/MF. Three major splicing variants of CADM1 expressed by neoplastic T-cells contained different combinations of the exons 7, 8, 9 and 11, including a putative oncogenic variant composed of exons 7-8-9-11. In conclusion, CADM1 is frequently expressed in Sézary cells and cell lines from CTCL.

The prevalence of atopy was investigated in 20 patients with Sézary syndrome (SS), 20 patients with plaque phase mycosis fungoides (MF), 9 patients with primary cutaneous marginal zone lymphoma (pcMZL) and 8 patients with primary cutaneous follicle center lymphoma (pcFCL) with the Phadiatop multi-allergen test. The relationship among serologic atopy, IgE reactivity against Staphyloccocal enterotoxin superantigens, and serum total IgE (IgE-t) levels and their prognostic implications in SS was investigated. Phadiatop test was positive in 45%, 15%, 33% and 0% of samples of SS, MF, pcMZL and pcFCL, respectively. IgE-t levels were also increased in SS, pcMZL and marginally MF. No correlation was found with patients' history of atopic disorders. Staphylococcal superantigen-specific IgE ≥ 0.35 kUa/L, most often against toxic shock syndrome toxin-1, was detected in 40% of Sézary samples followed by MF (20%). In the absence of serologic atopy (negative Phadiatop test), IgE-t levels for patients with SS and MF were not significantly higher than controls whereas the levels for pcMZL remained high. Furthermore, even with a negative Phadiatop test, IgE-t values were higher in sera of patients with SSAg-IgE ≥ 0.35 kUa/L vis-à-vis0.35 kUa/L across all diagnostic categories including controls albeit the difference was statistically significant only for SS. The presence of specific IgE antibodies ≥ 0.35 kUa/L, IgE-t122 kU/L or eosinophils500/µL had no impact on survival of patients with SS. These results indicate that a pathogenic link may exist between an atopic diathesis and development of SS and possibly pcMZL.

BACKGROUND Limited information exists regarding survival of Asian patients with mycosis fungoides (MF) and Sezary syndrome (SS). OBJECTIVE To evaluate the epidemiology, outcome and prognostic factors of these patients. METHODS A retrospective review of MF/SS cases diagnosed from 2000 to 2011 at a tertiary referral dermatology centre in Singapore was performed. RESULTS Of 246 patients, 63% were male and the median age at diagnosis was 49 years. 73.2% were Chinese, 12.6% Indian, 6.9% Malay and 7.3% Caucasian. A total of 239 patients (97.2%) had MF and seven had SS. Median follow-up duration was 6.3 years, and median duration of symptoms at diagnosis was 13 months. For patients with MF, the majority had early disease (92.8% stage IA-IIA). 3.8% were stage IIB, 1.7% stage III and 1.7% stage IV. Complete response to treatment occurred in 78.2%, partial response in 9.6%, persistent but non-progressive disease in 10.0% and disease progression in 4.1% of patients. Large cell transformation occurred in 4.1% of patients. Mean overall survival during this study was 12.7 years, with death occurring in 2.5% of patients (all ≥stage IIB at diagnosis). For patients with SS, 71.4% presented with stage IVA disease, 28.6% stage IVB. Complete response to treatment occurred in 14.2%, persistent but non-progressive disease in 28.6% and disease progression in 57.2% of patients. Mean overall survival was 3.3 years within this study, with death occurring in 42.9% of SS patients. Prognostic factors associated with favourable recurrence-free survival were male gender (P = 0.008), early disease stage (T1) at diagnosis (P

Cutaneous T-cell Lymphoma's (CTCL) are a rare, heterogeneous group of T-cell lymphomas that primarily manifest in the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are considered the classic types of CTCL. The diverse manifestation of CTCL results in a wide range of symptoms with a possible mild to severe impact on Quality of Life (QoL) depending on the disease stage. Previous studies on QoL in CTCL patients report diverse patient populations and use many different QoL instruments. In the current literature, a clear overview on the influence of the different stages of disease (early MF, late-stage MF/SS or total group) on the QoL is lacking. Therefore, a systematic search of the literature was conducted using the PubMed, Embase, PsycINFO and Web of Science databases. Studies were included if they described QoL in patients with MF and SS retrieved by standardized instruments or qualitative interviews. In total, 24 studies were included using 18 different questionnaires to report on dermatology-specific, cancer-specific and generic QoL. The effect on QoL was found to be greater in patients with late-stage disease as compared to early stage disease, with significant impairments on functional, emotional and physical domains. Nonetheless, even in patients with limited disease, QoL was mildly to moderately affected. Overall, pruritus was the most frequent reported and most bothersome symptom. Significant influence of the disease on daily life activities were found, not only in patients but also on caregivers and family. This broad, structured overview on QoL in MF and SS patients underlines the influence of disease stage on QoL, and therefore, recommends future studies to distinguish between disease stages when reporting results. Furthermore, this overview can inform clinicians in clinical practice by creating awareness of QoL deficits according to disease stage.

Sezary syndrome (SS) is an extremely rare form of cutaneous T-cell lymphoma (incidence 0.01 cases/100,000 person-years) associated with debilitating morbidity and poor overall prognosis.1,2 For patients with relapsed or treatment-refractory SS, traditional therapies are limited and predominantly palliative.1 Multiple prior single-center studies suggest allogeneic hematopoietic stem-cell transplantation (HSCT) with total-skin electron beam (TSEB) may offer durable remission to a subset of these patients.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).

Sézary syndrome (SS) is defined by erythroderma and circulating atypical T cells, with or without lymphadenopathy. Recently, Thompson et al. identified a distinct population of SS patients with an atypical presentation: a high blood tumor burden of Sézary cells fulfilling criteria for SS but without fulfilling the criteria for erythroderma at the diagnosis. Here, we report a case of a 49-year-old Japanese man with SS who did not present with erythroderma initially, but exhibited erythematous itchy papules symmetrically located on the legs and arms. We also reviewed reported cases of SS without initial erythroderma. The skin manifestations at diagnosis varied from patches to tumors often seen in mycosis fungoides, and other rarer findings such as excoriation, palmoplantar keratoderma and alopecia. Pruritus was reported in most patients (86%), unlike early mycosis fungoides, and could be the main clue to the diagnosis of SS. Notably, three patients were reported to have presented with papular lesions, similar to our case. Little is known about why skin lesions in SS without erythroderma vary and why these cases did not exhibit erythroderma initially. Attenuated stimulation by colonized Staphylococcus aureus, impairment in recruitment of malignant T cells and suppression of inflammatory response induced by malignant T cells with regulatory phenotype may be associated with skin manifestations. Further studies are necessary to elucidate the etiology of this entity.

Background The aim of this study was to determine the relative frequency of primary cutaneous lymphoma (PCL) in Argentina according to the new World Health Organization (WHO)-European Organization for the Research and Treatment of Cancer (EORTC) classification system. Methods A total of 416 patients from 21 dermatology services were included during a 5-year period (2010-2015); these patients were classified using WHO-EORTC criteria. Results There were 231 (55.2%) males and 185 (44.8%) females; the male-to-female ratio was 1.35. The median age of the patients was 57 years (range, 0-90 years). Most patients were Caucasian (79%), and only 16% of patients were registered as Amerindian. Most patients (387/416, 93%) had cutaneous T-cell lymphoma (CTCL); 28 patients (6.7%) were diagnosed with cutaneous B-cell lymphoma (CBCL). The most frequent CTCL subtypes, in decreasing order of prevalence, were mycosis fungoides (MF), including its variants (75.7%); CD30+ primary cutaneous lymphoproliferative disorders (7.2%); and Sezary syndrome (SS) (3.1%). Cutaneous follicle center lymphoma was the most common CBCL subtype (2.9%). In the subset of patients ≤20 years of age, the most common condition was MF (57%), followed by extranodal NK-T nasal-type lymphoma (14%). Conclusions This study revealed relatively higher rates of MF and lower rates of CBCL in Argentinean patients that have been reported in American and European countries.

BACKGROUND: Advanced age at diagnosis is considered a poor prognostic factor in mycosis fungoides (MF) and Sézary syndrome (SS). OBJECTIVE: To evaluate the outcomes and prognostic factors in patients diagnosed at an advanced age (≥65 years) with MF/SS. METHODS: Survival, progression rates and various clinical and histopathological variables were studied in a group of 174 elderly patients diagnosed with MF/SS between 1992 and 2015 at a single referral cancer center in the United States. Kaplan– Meier estimates were used to determine survival and progression and Cox proportional hazards regression univariate and multivariate models were used to identify prognostic factors. RESULTS: Of 174 elderly patients, 76.4% were diagnosed with early-stage (clinical stages IA-IIA) and 23.6% with late-stage MF/SS (IIB-IV). Advanced age was associated with poor overall survival, but not with disease-specific survival (DSS) or progression free survival (PFS). Gender, increasing clinical stage, T and B classifications, elevated lactate dehydrogenase (LDH) levels, and development of large cell transformation (LCT) were significant predictors of poor survival or disease progression. Patients with early-stage MF and

Primary cutaneous T-cell lymphoma (CTCL) comprises the second most common group of extra-nodal non-Hodgkin's lymphoma. They represent incurable primary extra-nodal lymphomas of major T cells, uniformly present in the skin with 1%-2% risk of systemic dissemination in mycosis fungoides (MF), which represents the most common subtype of CTCL. In general, long-term antigen stimulation is thought, through key cytokine signalling pathways, to induce an inflammatory response with T-cell proliferation, leading to a clonal malignant T cell with continuous expansion. However, in recent years, using data harvested from high-throughput transcriptional profiling, substantial advances in the understanding of the molecular pathogenesis were made to understand the complex pathogenesis of CTCL. In this review, the actual data are summarised.

Background Mogamulizumab (Mog) is a defucosylated, therapeutic monoclonal antibody, targeting CCR4 and was first approved in Japan for the treatment of adult T-cell leukaemia/lymphoma (ATLL), followed by cutaneous T-cell lymphoma and peripheral T-cell lymphoma. Objective To retrospectively investigate development of photosensitivity in patients with mycosis fungoides and other T-cell neoplasms after treatment with Mog. Methods We treated seven cutaneous lymphoma patients with Mog. Upon combination treatment with narrow-band UVB, we noticed that four patients developed photosensitivity dermatitis following Mog therapy, including two cases of mycosis fungoides, one case of adult T-cell leukaemia/lymphoma and one case of EB virus-associated T-cell lymphoproliferative disorder. Phototest was performed with UVA and UVB, and immunohistochemical staining for CD4, CD8 and Foxp3 was conducted in both photosensitivity and lymphoma lesions. Results Phototest revealed that the action spectrum of the photosensitivity was UVB in three cases and both UVB and UVA in one case. Histopathologically, the photosensitive lesions were characterized by a lichenoid tissue reaction with a CD8+ T cell-dominant infiltrate, sharing the feature with chronic actinic dermatitis, an autoreactive photodermatosis with a cytotoxic T-cell response. Foxp3+ regulatory T cells (Tregs) were decreased in the photosensitivity lesions compared with the lymphoma lesions. Conclusion Increased incidence of photosensitivity reaction was observed during Mog treatment. Decreased number of Tregs in the lesional skin suggests that this reaction is possibly induced by autoreactive cytotoxic T cells.

Angiogenesis is an important step to support progression of malignancies, including mycosis fungoides (MF) and Sézary syndrome (SS). Vascular endothelial growth factor (VEGF)-A, a key player in angiogenesis, is secreted by tumor cells of MF/SS and its expression levels in lesional skin correlated with disease severity. In this study, we examined serum VEGF-A levels in MF/SS patients. Serum VEGF-A levels were elevated in patients with erythrodermic MF/SS and the levels decreased after treatment. Importantly, serum VEGF-A levels positively correlated with markers for pruritus. We also found that VEGF-A upregulated mRNA expression of thymic stromal lymphopoietin by keratinocytes. Taken together, our study suggests that VEGF-A can promote progression and pruritus in MF/SS. Inhibition of VEGF-A signaling can be a therapeutic strategy for patients with erythrodermic MF/SS.

Disease overview Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sezary Syndrome (SS). Diagnosis The diagnosis of MF or SS requires the integration of clinical and histopathologic data. Risk-adapted therapy TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk-adapted,” multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Background The comprehensive genetic alterations underlying the pathogenesis of Sezary syndrome (SS) remains largely unknown. Previous studies showed that alterations of tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) are frequent in SS. In this study, we characterized the mutation and polymorphisms of A20 in a case with SS and compared with the genetic feature of A20 in T-cell acute lymphoblastic leukemia (T-ALL). Methods Using a novel approach based on the combination of fine-tiling array comparative genomic hybridization ( and ligation-mediated polymerase chain reaction (LM-PCR) to identify SS clone, the polymorphisms in the A20 gene (promoter, exons 2-9 [coding region] and 3'UTR) were detected by PCR and sequencing. Results The malignant SS clone was identified as TCR Vα2-Jα22 rearrangement without deletion at the A20 loci (6q23-27 region) in the SS case. Six polymorphisms were identified, all of them are belonging to single nucleotide polymorphisms (SNPs) that are recorded in genebank: rs5029924, rs5029937, rs2230926, rs582757 and rs77191406, while rs2307859 was not identified in the SS sample, which is found in all T-ALL. The alteration pattern of A20 in this case seemed different from the T-ALL samples, in contrast, it is similar to the alteration of A20 in samples from rheumatoid arthritis or systemic lupus erythematosus with poor clinical outcome and cancer developing. Conclusions The genetic alteration of A20 in the SS case was different from the T-ALL samples and similar to the cases with refractory autoimmune disease and related to tumorigenesis. The findings lead to discuss whether such SNPs of A20 may link the refractory autoimmune inflammation and the tumorigenesis.

Existing therapies for Sézary syndrome (SS) are limited in efficacy and in disease control, and patients have very poor prognosis. Here, we report a case report of a patient who has a 16-year history of SS and related treatments (both standard and experimental). In particular, two drugs, one conventional (gemcitabine) and one experimental (mogamulizumab), were able to induce long lasting response. Patient refused to undergo allogeneic stem cell transplantation. After eleven lines of therapeutic approaches, the patient is in very good partial response and free of therapy at the latest available follow-up.

Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and "down-staging" effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS.

Background Primary cutaneous lymphomas (PCL) are a group of extranodal non-Hodgkin lymphomas presenting with no evidence of extracutaneous disease at the time of diagnosis. Few longitudinal studies of PCL have been conducted, particularly in South American populations. Our objective was to describe the behavior of PCL and evaluate patient survival in a cohort of patients from southern Brazil. Methods We conducted a retrospective cohort study of all patients with a histopathological diagnosis of PCL receiving care at a tertiary referral center in southern Brazil from 2000 to 2012. Clinical, laboratory, and histopathological data, treatment variables, and survival curves were analyzed. Results Eighty-nine patients with PCL were included, with a mean age at diagnosis of 58.9 years. Cutaneous T-cell and natural killer (NK) cell lymphomas (CTCL/NKCL) accounted for 78.4% of cases and cutaneous B-cell lymphomas (CBCL) for 21.6%; 57.4% of patients with CTCL/NKCL and 50% of patients with CBCL were male. Half of all cases were mycosis fungoides (MF). The 5-year survival rate was 74.8% for MF, 61% for Sezary syndrome, 87.5% for primary cutaneous CD30+ lymphoproliferative disorders, and 88.9% for primary cutaneous follicle center lymphoma. Conclusions In this cohort of patients with PCL from southern Brazil, CTCL/NKCL was more prevalent than CBCL, and the MF subtype was predominant. Survival curves were similar to those reported in the literature, except for Sezary syndrome, which had a better prognosis in this sample.

Mycosis fungoides and Sézary syndrome are T-helper (Th)2-skewed cutaneous lymphomas. The clinical course of mycosis fungoides is classically indolent, manifesting as patches, plaques and tumors. Along with their progression, Th2 dominance tends to be accelerated. In this review, we discuss the epidemiology, clinicopathogenetic features and therapeutic approaches in mycosis fungoides and Sézary syndrome.

CCR4 is expressed on tumor cells of mycosis fungoides (MF) and Sézary syndrome (SS). In MF, most infiltrating cells in patches and plaques express CXCR3, while tumor cells express CCR4 in advanced stages. Poteligeo Test IHC (CCR4 staining kit) is a newly developed staining kit that can examine the presence of CCR4 expressed on tumor cells of adult T-cell leukemia/lymphoma, peripheral T-cell lymphoma and cutaneous T-cell lymphoma before treatment of anti-CCR4 antibody using paraffin-embedded samples. In this study, we analyzed CCR4 expression in lesional skin of MF, SS, atopic dermatitis (AD) and psoriasis with this new kit. CCR4 was expressed on infiltrating cells in lesional skin of patch, plaque, tumor MF and SS, and the number of positive cells increased as the disease progressed. Immunohistochemistry with frozen sections also showed some positive cells scattered in the dermis, although the quality was not high enough to quantify positive cells. There were significant positive correlations between CCR4(+) cells and serum lactate dehydrogenase levels. Interestingly, CCR4(+) cells were also detected in AD skin, whose number was larger than that in psoriatic skin. Previous studies showed only scattered CCR4(+) cells in skin samples by standard immunohistochemical staining. The new, sensitive CCR4 staining kit has revealed that CCR4 is expressed on infiltrating cells in lesional skin of early MF and AD as well as advanced MF and SS. These cells can be therapeutic targets for patients who are resistant to standard treatments.

Tumor genesis and development are driven by a combination of intrinsic events such as oncogene activation and tumor-suppressor gene inactivation, and extrinsic events that are dependent on the interaction with the stroma. Different types of growth factors, cytokines and chemokines secreted by the surrounding stromal cells are thought to play key roles in solid tumor progression. Accumulating evidence indicates that the immunological milieu plays an essential role in tumor development, not only in solid tumors, but also in hematopoietic malignancies. Understanding the interactions between tumor cells and microenvironment in mycosis fungoides (MF) and Sézary syndrome (SS) could provide a basis for the development of new treatments for these diseases that are sometimes resistant to current therapies. This article focuses on the wide variety of cell types and immunological milieus, affecting the characteristic features of MF and SS, such as skin-homing of tumor cells, T-helper type 2-dominant tumor microenvironment, accumulation of dermal dendritic cells, epidermal hyperplasia, angiogenesis and pruritus.

Background We examined the course of cutaneous T-cell lymphoma (CTCL), which has been associated with chronic lymphocytic leukemia (CLL) in patients with CLL. Materials and methods A search was conducted of the master diagnosis index at our institution to identify patients with both CLL and CTCL from 1980 to 2010. A retrospective chart review was then conducted. Results Of the 14 patients with CTCL and CLL, eight had mycosis fungoides (MF; two with patch stage, two with plaque stage, two with tumor stage, and two with erythrodermic stage), four had Sezary syndrome, one had natural killer cell lymphoma involving the skin, and one had peripheral T-cell lymphoma involving the skin. Eight had concurrent diagnoses, five received a CLL diagnosis first, and one received a CTCL diagnosis first. Ten patients were deceased at the time of data abstraction due to unknown causes (n = 4), lymphoma (n = 2), pneumonia (n = 2), MF (n = 1), or respiratory failure (n = 1). Of the nine patients with concurrent or prior CTCL, seven were deceased, with a median time to death of 10.2 months (range, 6–89 months). Of the five patients with CLL prior to CTCL, three were deceased at 18, 27, and 47 months, respectively, after the CTCL diagnosis. The median survival for the two groups was 12 and 47 months, respectively. Conclusions Patients with CTCL concurrent with or prior to CLL have a worse overall survival than patients with CLL in whom CTCL later develops. Larger studies are needed.

Isoprenylcysteine (IPC) molecules modulate G-protein-coupled receptor signalling. The archetype of this class is N-acetyl-S-farnesyl-l-cysteine (AFC). Topical application of AFC locally inhibits skin inflammation and elicitation of contact hypersensitivity in vivo. However, the mechanism of these anti-inflammatory effects is not well understood. Dermal microvascular endothelial cells (ECs) are involved in inflammation, in part, by secreting cytokines that recruit inflammatory cells. We have previously shown that the sympathetic nerve cotransmitter adenosine-5'-triphosphate (ATP) and adenosine-5'-O-(3-thio) triphosphate (ATP?S), an ATP analogue that is resistant to hydrolysis, increase secretion of the chemokines CXCL8 (interleukin-8), CCL2 (monocyte chemotactic protein-1) and CXCL1 (growth-regulated oncogene a) by dermal microvascular ECs. Production of these chemokines can also be induced by the exposure to the proinflammatory cytokine TNFa. We have now demonstrated that AFC dose-dependently inhibits ATP-, ATP?S- and TNFa-induced production of CXCL1, CXCL8 and CCL2 by a human dermal microvascular EC line (HMEC-1) in vitro under conditions that do not affect cell viability. Inhibition of ATP?S- or TNFa-stimulated release of these chemokines was associated with reduced mRNA levels. N-acetyl-S-geranyl-l-cysteine, an IPC analogue that is inactive in inhibiting G-protein-coupled signalling, had greatly reduced ability to suppress stimulated chemokine production. AFC may exert its anti-inflammatory effects through the inhibition of chemokine production by stimulated ECs

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment.

Background Molluscum contagiosum (MC) is caused by a DNA virus of the poxvirus group. It is common in children, and is also found in sexually active adults and HIV-seropositive patients. Cellular immunity is essential to controlling MC virus infection. We report the first observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo. Case report A woman aged 70 presented with aggravation of Sezary syndrome diagnosed in 2009 and treated with topical corticosteroids. The examination showed a generalized pruritic exanthem and multiple flesh-coloured papules from 1 to 3 mm, spread over the entire skin surface and surrounded by a white halo. Histological examination of a lesion showed the presence of infected cells with intracytoplasmic inclusions infected in an acanthotic epidermis, surrounded by a melaninopenic hypomelanosis with a normal melanocyte density. There was no inflammatory character. The diagnosis of multiple molluscum contagiosum was given, the application of clobetasol propionate was suspended and treatment with chlorambucil 4 mg/day and prednisone 0.5 mg/kg/day was started. The evolution of the rash and pruritus was rapidly favourable. After 3 months, the rash and pruritus had regressed. There was no molluscum contagiosum or clear halo. Conclusion We report the original observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo, without inflammation, eczema or disappearance of melanocytes. This halo could be due to the secretion of a protein by molluscum contagiosum inhibiting inflammation around this MC. To our knowledge, this phenomenon reported in a patient with severe atopic dermatitis associated with Sezary syndrome has not previously been described.

Background: FoxP3 is the most specific available marker for regulatory T cells (Tregs). Tumor-associated FoxP3-positive Tregs have been identified in various neoplasms, including cutaneous T-cell lymphoma (CTCL). FoxP3 expression in CTCL varies across groups; few studies have compared CTCL with inflammatory conditions. Methods: Lesional skin biopsies from 20 patients with CTCL [13 mycosis fungoides (MF); 7 Sezary syndrome (SS)] and 22 with inflammatory dermatoses (11 spongiotic; 11 lichenoid or interface) were examined for FoxP3 expression by immunohistochemistry. Epidermal FoxP3-positive lymphocytes were counted as a percentage of the total epidermal CD3-positive T-cell population. Results: FoxP3-positive T cells composed the minority of infiltrate in all major categories. Lower numbers of epidermal FoxP3-positive T cells were observed in CTCL, particularly MF, than in inflammatory dermatoses (P < .001). CTCL neoplastic T cells did not express FoxP3. Conclusion: FoxP3-positive T cells are less frequently encountered in MF than in inflammatory dermatoses. FoxP3-positive T cells occur in higher proportions in the dermis than in the epidermis and probably correlate with coexisting inflammatory components. CTCL neoplastic cells do not typically express a Treg phenotype and are associated with low numbers of FoxP3-positive Tregs in the infiltrate. FoxP3 expression by immunohistochemistry may aid histologic evaluation of these conditions. Wada DA, Wilcox RA, Weenig RH, Gibson LE. Paucity of intraepidermal FoxP3-positive T cells in cutaneous T-cell lymphoma in contrast with spongiotic and lichenoid dermatitis.