Stage Mycosis Fungoides Research Articles

Flow Cytometric Analysis of T, B, and NK Cells Antigens in Patients with Mycosis Fungoides.

We retrospectively analyzed the clinicopathological correlation and prognostic value of cell surface antigens expressed by peripheral blood mononuclear cells in patients with mycosis fungoides (MF). 121 consecutive MF patients were included in this study. All patients had peripheral blood flow cytometry as part of their first visit. TNMB and histopathological staging of the cases were retrospectively performed in accordance with International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) criteria at the time of flow cytometry sampling. To determine prognostic value of cell surface antigens, cases were divided into two groups as stable and progressive disease. 17 flow cytometric analyses of 17 parapsoriasis (PP) and 11 analyses of 11 benign erythrodermic patients were included as control groups. Fluorescent labeled monoclonal antibodies were used to detect cell surface antigens: T cells (CD3+, CD4+, CD8+, TCRαβ +, TCRγδ +, CD7+, CD4+CD7+, CD4+CD7−, and CD71+), B cells (HLA-DR+, CD19+, and HLA-DR+CD19+), NKT cells (CD3+CD16+CD56+), and NK cells (CD3−CD16+CD56+). The mean value of all cell surface antigens was not statistically significant between parapsoriasis and MF groups. Along with an increase in cases of MF stage statistically significant difference was found between the mean values of cell surface antigens. Flow cytometric analysis of peripheral blood cell surface antigens in patients with mycosis fungoides may contribute to predicting disease stage and progression.

Hypertrophic lichen sclerosus sine sclerosis: clues to histopathologic diagnosis when presenting as psoriasiform lichenoid dermatitis.

The histopathologic diagnosis of lichen sclerosus (LS) is usually facilitated by a subepidermal zone of sclerosis. In the absence of sclerosis, LS mostly presents itself as a psoriasiform lichenoid dermatitis that may be difficult to distinguish from other diseases. We sought to assess histopathologic findings that allow recognition of LS in the absence of sclerosis. We studied 28 criteria in 100 biopsy specimens of LS from genital or perianal skin, including 55 cases with marked sclerosis, 16 cases with mild sclerosis confined to foci of the papillary dermis and 29 cases without sclerosis. Fifteen cases each of the early plaque stage of mycosis fungoides, lichen planus and lichen simplex chronicus were studied for comparison. Some histopathologic hallmarks of LS were seen chiefly in sclerotic lesions and, therefore, did not contribute to the diagnosis of difficult cases, such as dissolution of elastic fibers. Others were seen rarely in non-sclerotic lesions but might be helpful in individual cases, including follicular hyperkeratosis and thickening of the basement membrane. Findings that were more common and may be utilized as clues to the histopathologic diagnosis of non-sclerotic LS include tiny foci of homogenized tissue in dermal papillae, marked fibrosis with thickening of the papillary dermis, marked thickening of individual collagen fibers, lymphocytes aligned in rows between those fibers, necrotic keratinocytes, often with preserved pyknotic nuclei, in all reaches of the epidermis, including the cornified layer, clustering of necrotic keratinocytes above elongated dermal papillae and vertical columns of parakeratosis with distinct dyskeratotic parakeratotic cells. In the absence of sclerosis, histopathologic diagnosis of LS depends on findings that are less distinctive. Nonetheless, a constellation of those findings allows a specific diagnosis to be made.

A Cutaneous Lymphoma International Consortium 'CLIC’ study of Prognostic Parameters in Advanced Stages of Mycosis Fungoides and Sezary Syndrome: Progress Towards Establishing a Prognostic Index to Augment Clinical Staging

Background: Cutaneous T cell lymphoma (CTCL) is a rare/orphan disease. Mycosis fungoides (MF) and Sézary syndrome (SS) are the major subtypes. Most patients with MF present in early stages (IA-IIA) with a good prognosis. However a third present in advanced stages (IIB-IVB) with a median survival of 1-5yrs. Clinical management is stage-based; however there is wide range of outcome within clinical stages. Currently, we lack evidence based prognostic information for further stratification that can optimize clinical management or be applied in therapeutic trials. Published prognostic studies in MF/SS have largely been single centre. A retrospective study from the UK & a US site proposed a potential prognostic model for MF/SS (Benton et al Eur J Cancer 2013;49:2859-68) but is limited in power and lacking standardised definitions. Due to the small numbers of patients presenting with advanced stage disease only a large collaboration would power a study to determine prognostic parameters with international relevance. Towards this aim, we have established an international collaborative alliance, the Cutaneous Lymphoma International Consortium (CLIC), to acts as an efficient conduit where well-defined parameters and end-points are used to design studies. This retrospective CLIC study tests selected prognostic parameters against survival in advanced stages of MF/SS in order to determine power and identify prognostic markers that impact globally and may be used in future prospective studies to establish an international prognostic index.Methods: We reviewed the literature of prognostic markers in MF/SS and identified 11 candidate clinical, pathological, and laboratory parameters; 1) stage, 2) age, 3) male sex, 4) modified skin weighted assessment tool score (MSWAT), histological features of 5) folliculotropism, 6) CD30 positivity, 7) proliferation index (%Ki-67 staining) & 8) large cell transformation(LCT), 9) leucocyte/lymphocyte count, 10) LDH & 11) identical T-cell clone in blood & skin. Data were collected on patients presenting with advanced stages of MF/SS (IIB-IVB) diagnosed after the new staging system [Olsen et al. Blood. 2007;110:1713-22].Results: Twenty-five international sites (16 EU, 6 US, 1 Australian, 1 Asian, 1 South American) identified 1249 MF/SS patients presenting with advanced stage disease since 2007. Patients with complete staging and outcome data (91% 1147 patients) were included in the analyses. MSWAT was not tested due to incompleteness of data (26%). Data completeness for the other 9 prognostic variables ranged from 38-100%. Median survival for this advanced stage cohort was 65 months with 2 and 5 year survival of 79% and 53%, respectively. The median survival for Stage IIB and III was not reached (restricted mean survival was 63 months in both stage IIB & III), median survival for stage IVA was 47 months and 44 months in stage IVB (Fig 1). In univariate analysis 4/9 variables were significantly associated with decreased survival including age>60 years (data 100% complete, p<0.001), LCT in skin (data 87% complete, p=0.007), elevated LDH (data 71% complete, p<0.001) and raised leucocytes (data 68% complete, p=0.004). In multivariate analysis including these 4 variables only age >60 (p=0.08) and LDH (p=0.008) were significant. According to stage; age>60, LDH & LCT were associated with a worse survival in stage IIB, in stage III only age & LDH and in stage IVA LDH & a raised leucocyte count were significant.Conclusion: This study has proven the ability of the CLIC to work cohesively, as the first large-scale international collaboration in CTCL. The current staging system shows similar survival in stage IIB and III disease (Fig 1) highlighting the need for further refinement within these stages. Our analysis found age>60yrs & LDH are independent prognostic parameters with potential relevance in advanced stages of MF/SS. This study has highlighted the need for prospective data collection due the intrinsic flaws of retrospective analysis including missing data, lack of standard definitions rendering some data unusable and potential bias in more complete data in aggressive subtypes. Future prospective studies with well-defined criteria and more complete data collection will be required to better identify parameters of prognostic significance and to test their utility towards building a prognostic index model. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sézary Syndrome (SS)

Introduction: The majority of patients with refractory, advanced stage MF or SS have a life expectancy less than 5 years. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed allogeneic transplant in 29 patients as a prospective clinical study using a novel non-myeloablative preparative regimen to provide prolonged disease control.Patient and Transplant Regimen: This cohort included 11 patients with MF and 18 patients with SS. The median age was 62 years (range 20-75). These patients were heavily treated with a median number of prior systemic therapies of 5 (range 2-13). The median time from diagnosis to transplant was 33 months (range 9-147). Five patients had stage IIB disease and 24 patients (83%) had stage IV disease (21 with IVA and 3 with IVB). All 11 patients with MF had evidence of large cell transformation. All patients had active disease at the time of preparative regimen (skin: 100%, blood: 62%, lymph node: 62%). The patients received total skin electron beam therapy (TSEBT, 24-36 Gy) as part of preparative regimen for skin disease control, immediately followed by total lymphoid irradiation (TLI, 8 Gy) and rabbit anti-thymocyte globulin (ATG). All patients received G-CSF mobilized peripheral blood hematopoietic cells from either an HLA-matched related (n=11), HLA-matched unrelated (n=13) or HLA-mismatched unrelated (n=5) donor. Cyclosporine or tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. The entire protocol required only a 5-day inpatient stay during the infusion of ATG.Results: As planned, all patients received their allograft infusion as outpatient. Patients tolerated the immediate post-transplant period extremely well. Fifteen patients required hospital admission within 100 days after transplant, with a median length of hospital stay of 4 days. The most common cause for admission was delayed ATG reaction. At day +90, full donor chimerism (donor CD3+ > 95%) was achieved in 10 patients (34%) and mixed chimerism was found in 14 patients (48%). Of these 14 patients, 9 of them subsequently achieved full donor chimerism and 1 had secondary graft rejection. Five patients (17%) had primary graft rejection (donor < 5%). Three of the 6 with graft rejection received a second transplant after experiencing disease progression. The incidence of GVHD in our study was considerably lower than reported in other studies using reduced intensity regimens. The cumulative incidence of grade II-IV acute GVHD was 21%. Five patients had grade II acute GVHD (4 skin, 1 GI) and 1 had fatal grade IV acute GVHD (GI). The cumulative incidence of extensive chronic GVHD at 1 and 2 years was 13% and 23%, respectively. One death was attributed to complications of chronic GVHD.At 3-month post transplant, 19 patients achieved a complete response and 7 had a partial response (ORR 90%). Two patients experienced disease progression immediately after transplant, and 1 patient had stable disease. The median post-transplant follow-up for the entire cohort was 22.2 months and for the surviving patients was 24.5 months. The 2-year OS and PFS were 76% (95% CI, 54–88%) and 50% (95% CI, 28–68%), respectively. Among the surviving 21 patients, 81% (n=17) were in CR at last follow-up (16 with durable CR lasting >1 year). Of the 8 deaths in this study cohort, 3 were from NRM, each due to acute GVHD, complications related to chronic GVHD, or secondary malignancy (B-cell acute lymphoblastic leukemia). The 1-year cumulative NRM was 3%. High-throughput sequencing (HTS) of TCRß CDR3 was used for minimal residual disease (MRD) monitoring (Sci. Transl. Med.5:214ra171, 2013) (ImmunoSEQ, Adaptive Biotech). Of the 24 patients assessed, 11 patients (46%) achieved molecular remission in the blood after transplant. The median time to achieve molecular remission in the blood was 60 days (range 30-540). Of these 11 patients, 10 of them also achieved molecular remission in the skin. The 2-year OS and PFS for patients who achieved molecular remission were 86% (95% CI, 34–98%) and 71% (95% CI, 26–92%), respectively.Conclusion: We have developed an effective novel preparatory regimen with low transplant related mortality for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. Using the utmost sensitive TCRß HTS method to assess MRD, we were able to demonstrate a potentially curative therapy with molecular remission in this patient population. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors, Staging and Treatments in Advanced Stage Mycosis Fungoides and Sézary Syndrome

Introduction:Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by skin infiltration of neoplastic T lymphocytes. Mycosis fungoides (MF), and its leukemic variant Sézary syndrome (SS), are characterized by clonal proliferation of CD4+/CD45R0+ effector or central memory CD4+ T cells, respectively, with partial loss of mature T-cell antigens.Objectives: To evaluate prognostic factors including risk of disease progression from initial presentation and treatment in a prospectively collected, single center cohort of 168 advanced MF/SS patients 168 patients evaluated from 2007 to the present.Methods:The prognostic variables effecting overall survival (OS) were examined in a unique prospectively collected cohort of 168 advanced stage MF and SS patients evaluated at MD Anderson Cancer Center (Houston,TX) from 2007 to 2014. Kaplan–Meier estimates were used to determine median OS, progression-free survival (PFS), and disease-specific survival (DSS). Cox proportional hazards regression model assessed prognostic factors.Results: Advanced patients included 97 MF (58%) and 71 SS (42%) patients with 106 (63%) males and 62 (37%) females. The median survival was 2.47 years (95% CI: 1.85 to 3.30). The range of the OS time was 7.21 years. The one-year survival rate was 76.9% (std error: 3.5%). The two-year survival rate was 57.2% (std error: 4.4%). The five-year survival rate was 30.9% (std error: 5.7%). The seven-year survival rate was 13.3% (std error: 9.9%). There were 79 (47%) deaths from any cause and 89 (53%) were alive at the end of analysis. Median OS for MF was 2.47 yrs and for SS was 2.19 yrs. The median OS for patients with large cell transformation (LCT) was 2.19 yrs, similar to OS of SS patients. Median overall survival of patients > 65 years was 1.73 years compared to 4.36 years in patients < 65 yrs of age (p=.0005). In patients with nodal disease, the median OS for N3 was 1.09 yrs, N2; 0.79 yrs compared to 2.90 yrs in Nx patients (p= <0.0001). DSS for MF was 2.85 yrs; SS was 3.15 yrs. Most patients died from disease: stage IVB 47%, IIB 38% vs stage III only 9%. In patients with various levels of blood involvement, median OS with B2 (>1000 SS) was 2.19 yrs and B1 (< 1000 and > 250) was 2.56 yrs. In the median OS and DSS for patients with a positive clone in the blood was 1.09 and 1.55 yrs respectively. In patients without a clone in blood, median OS and DSS were 2.09 and 4.36 yrs and not clinically significant. Elevated LDH levels were clinically significant p=0.04 with median OS 2.47 yrs. Expression of CD30 or CD25 was not significant for any of the two survival outcomes. Of 168 patients, 115 were treated with systemic therapies: including extracorporeal photopheresis (ECP), retinoids, interferons, targeted monoclonal antibodies, chemotherapy, total body skin electron beam, and stem cell transplant. The overall response rate (ORR) for all systemic therapies was 46% (n=52/115) with a complete response (CR) of 9% (n=10), partial response (PR) was 37% (n= 42) and 38% (n=44/115) had progressive disease (PD). ORR with ECP was 41% (n=30/74), SCT was 97% (n=16/17), retinoids was 30% (n=19/63). The ORR for single agent chemotherapy was 18% (n=20/112), multiple agent chemotherapy was 11% (n=12/112).Conclusions:By univariate analysis, risk factors associated with disease progression or death included advanced age, lymph node involvement, and elevated LDH. The follow-up period was limited. The impact of treatments on prognosis has not been determined and apart from stem cell transplantation complete responses are rarely seen. DisclosuresNo relevant conflicts of interest to declare.

Efficacy of Low‐Dose Ultraviolet A‐1 Phototherapy for Parapsoriasis/Early‐Stage Mycosis Fungoides

Efficacy of Low‐Dose Ultraviolet A‐1 Phototherapy for Parapsoriasis/Early‐Stage Mycosis Fungoides

Expression of helper T cell master regulators in inflammatory dermatoses and primary cutaneous T-cell lymphomas: Diagnostic implications

Mycosis fungoides (MF) is a neoplasm of skin-homing CD4(+) helper T (TH) lymphocytes with dysregulation of TH1 and TH2 immunity. Diagnosis of MF is challenging, as there is significant morphologic overlap with other dermatologic entities. We investigated diagnostic utility of TH1- and TH2-specific markers, T-bet, and GATA-3, respectively, in MF and its reactive and neoplastic mimics. Immunohistochemical staining for CD3/T-bet and CD3/GATA-3 was performed on inflammatory dermatoses (n = 56), MF (n = 37), Sezary syndrome (SS; n = 8), and cutaneous anaplastic large cell lymphoma (C-ALCL; n = 14). Inflammatory dermatoses showed epidermal T cells predominantly expressing GATA-3, except psoriasis, which exhibited a mixed GATA-3/T-bet staining. In contrast, neoplastic T cells in patch stage MF showed markedly increased T-bet positivity with minimal GATA-3 expression. Plaque stage MF had amixed T-bet/GATA-3 phenotype, whereas tumor stage MF and SS exhibited diffuse GATA-3 expression. C-ALCL lacked significant staining for both markers. Sample size was relatively small. A predominance of T-bet(+) T cells in the epidermis support patch stage MF over dermatitis. A predominance of GATA-3(+) Tcells in the dermis support CD30(+) MF with large cell transformation over C-ALCL. These stains donotallow distinction between dermatitis and cutaneous infiltrates of SS.

Identified early stage mycosis fungoides from psoriasis and atopic dermatitis using non-invasive color contrast enhancement by LEDs lighting

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma (CTCL) and may progress internally over time. MF is clinically categorized as poorly defined areas of erythema, flat patches, thin plaques, and tumors. The diagnosis of early stage of MF (patch and early plaque mycosis fungoides) has been a major diagnostic challenge in dermatology because of the lack of highly characteristic immunophenotypical markers and the heterogeneity of clinical presentations of MF. In this study, the spectrum of each picture element of the patient’s skin image was obtained by multi-spectral imaging technology (MSI). Spectra of normal or pathological skin were collected from 30 patients (10 early stage MF, 10 psoriasis vulgaris, and 10 atopic dermatitis). An algorithm combined with multi-spectral imaging and color reproduction technique is applied to find the best enhancement of the difference between normal and abnormal skin regions. Accordingly, an illuminant with specific intensity ratio of red, green, and blue LEDs is proposed, which has optimal color enhancement for MF detection. Compared with the fluorescent lighting commonly in the use now, the color difference between normal and inflamed skin can be improved from 11.8414 to 17.4002 with a 47 % increase, 8.7671 to 12.8544 with a 26.3 % increase, and 11.0735 to 17.2634 with a 34.3 % increase for MF, psoriasis, and atopic dermatitis patients, respectively, thus making medical diagnosis more efficient, so helping patients receive early treatment.

P11.08 * CENTRAL NERVOUS SYSTEM LYMPHOMA IN A PATIENT WITH MYCOSIS FUNGOIDES

Mycosis fungoides (MF), the most common malignant T-cell lymphoma of the skin with an annual incidence of 4.2 cases per million in the United States, usually evolves slowly over many years. Extracutaneous manifestations of MF are observed in 50-75% of cases, typically occurring in patients with advanced infiltration of other organs. The incidence of central nervous system (CNS) involvement in MF was reported to be 14% in autopsy series and less than 1.6% in clinical cohorts particularly in patients with large-cell transformation of MF. A 67-year-old woman was diagnosed with plaque stage MF in 1990 after having developed disseminated, well demarcated, erythematous macules and plaques on the trunk. The patient reported that psoriasiform skin lesions had been present over the past 35 years. Treatment consisted of topical corticosteroids, systemic psoralen plus ultraviolet A, acitretin and interferon, resulting in a complete remission since 2007, without further treatment. In April 2013, the patient presented with a 2-month history of cognitive deficits and bifrontal headache, followed by rapidly decreasing visual acuity with central and peripheral visual field defects. Magnetic resonance imaging (MRI) showed thickening of the optic chiasm and both optic nerves with homogeneous contrast medium enhancement and space-occupying effect on the hypothalamus. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis of 107 cells/µl, no lymphoma cells were detected, CSF protein was elevated (116 mg/dl), glucose and lactate were normal. A subsequent brain biopsy confirmed the diagnosis of a diffuse large-cell lymphoma of the B-cell type. Despite preoperatively started dexamethasone treatment the patient experienced severe visual loss. Following 4 cycles of chemotherapy containing high-dose methotrexate and cytarabine according to the IELSG protocol and 2 cycles of methotrexate monotherapy from May until October 2013, clinical examination showed marked visual improvement, consistent with almost complete resolution of the MRI abnormalities. Due to pituitary gland insufficiency the patient needs further hormone replacement therapy. This case illustrates the importance of considering CNS lymphoma in the context of MF, even after long-term remission of the disease limited to the skin. To the best of our knowledge, this is the first description of a primary CNS B-cell lymphoma secondary to MF.

Transforming growth factor-β1 gene polymorphism in mycosis fungoides.

Dysregulation in transforming growth factor (TGF)-β1 signalling pathways has been linked to cancer. To study the association between single nucleotide polymorphisms (SNPs) of the TGF-β1 gene and mycosis fungoides (MF). Using restriction fragment length polymorphism analysis, SNPs in the TGF-β1 gene were studied in 55 patients with MF of different stages and in 100 apparently healthy controls. A significant difference was found between patients and controls in distribution of the different TGF-β1 genotypes, with mutant forms (T/C, T/T) encountered significantly more often in patients with MF (P<0.001). The heterozygous genotype (T/C) was significantly associated with patch stage MF, whereas the homozygous genotype (T/T) was significantly associated with tumour stage (stage IIb) MF (P=0.001), although this study included only a small number of these patients. Mutant TGF-β1 genotypes are significantly associated with MF in Egyptian patients, with the homozygous genotype (T/T) having a stronger association with tumour stage (stage IIb).

Thymocyte selection-associated high mobility group box gene (TOX) is aberrantly over-expressed in mycosis fungoides and correlates with poor prognosis.

Mycosis fungoides (MF) often mimics the common chronic inflammatory skin diseases and is difficult to be diagnosed with certainty, partly because of the lack of well-characterized molecular markers. Previously, we discovered that TOX, a key T cell development regulator,was aberrantly over-expressed in early stage MF. In the current multi-center study involving two independent patient cohorts, we determined the prevalence of TOX over-expression in the full spectrum of MF skin biopsies, and tested if TOX expression levels correlated with long term clinical outcomes. We examined TOX expression levels in 113 MF biopsies. We found that the MF biopsies expressed higher TOX mRNA than the controls in both cohorts (17.9 fold in cohort 1, P = 0.002; 5.8 fold in cohort 2, P < 0.0001). In addition, thicker skin lesions such as plaques and tumors expressed even higher TOX levels than thinner patches. Further, TOX over-expression differentiated MF from the controls (area under the curve [AUC]=0.87, P < 0.0001). Finally, high TOX mRNA levels correlated with increased risks of disease progression (P = 0.003) and disease-specific mortality (P = 0.008). In conclusion, TOX may be a useful marker for improving MF diagnosis and prognostication.

Interventions for mycosis fungoides: critical commentary on a Cochrane Systematic Review.

The authors performed a systematic review of randomized controlled trials (RCTs) on interventions for any stage of typical mycosis fungoides (MF). They searched electronic databases including the Cochrane Central Register of Controlled Trials, Medline, Embase, and the Latin American and Caribbean Health Science Information database, and included reports from conference proceedings and unpublished data without language restrictions. The authors also searched trial registries affiliated with the U.S.A., Australia, the World Health Organization and the European Organisation of Research and Treatment of Cancer for studies on 'mycosis fungoides' or 'cutaneous T-cell lymphoma'. These searches were supplemented by correspondence with the groups or individuals who conducted the RCTs. The authors included RCTs with participants who were 18years of age or older, that had staging information, and in which >90% of patients had biopsy-proven typical CD4+ MF. Data on treatment and outcome of participants, including information on stage of MF, therapy, quality of life, remission or improvement, duration of remission, survival, adverse effects and toxicity were obtained from included studies. Primary outcomes were adverse effects and quality of life. Secondary outcomes were clearance of at least 90% of surface area involvement, improvement of at least 50% of surface area involvement, survival rate, relapse rate and disease-free interval. The authors also recorded potentially significant participant-related prognostic factors, such as age and sex, and tumour-related prognostic factors, such as histological subtype and systemic involvement. From 407 unique references, 14 RCTs were included with a total of 675 patients. These trials included skin-directed therapies [topical peldesine, topical imiquimod, topical hypericin, intralesional interferon (IFN)-α, psoralen ultraviolet A (PUVA) therapy, electron-beam therapy (EBT) and local radiation], systemic therapies [extracorporeal photopheresis (ECP), denileukin diftitox, bexarotene] and combination therapies (injected transfer factor with concomitant topical nitrogen mustard use). Only one meta-analysis of two studies comparing PUVA with IFN-α vs. PUVA alone could be performed, and no significant differences between the two therapies were found. Two studies on intralesional IFN-α vs. placebo were included in the review and provided opposing results, but were not examined by meta-analysis due to differences in their study design. The remainder of the Cochrane analysis reviewed outcomes of individual RCTs. There were statistically significant differences in improvement or clearance for five therapeutic regimens. One trial of topical hypericin vs. placebo found a relative benefit of hypericin, risk ratio (RR) for improvement 7·00, 95% confidence interval (CI) 1·01-48·54, P≤0·028. A trial comparing ECP with PUVA demonstrated significantly better improvement in the PUVA group (RR 0·07, 95% CI 0·00-1·00, P≤0·002). An RCT examining 'conservative', stepwise escalation from topical nitrogen mustard to 'combination therapy' with EBT and cyclophosphamide, doxorubicin, etoposide and vincristine chemotherapy found that combination therapy was superior in clearance (RR 2·18, 95% CI 1·10-4·33, P≤0·03) and improvement (RR 1·40, 95% CI 1·12-1·74, P≤0·003). However, there were no statistically significant differences in survival rates at a median follow-up of 75months. A comparison of subcutaneously injected IFN-α and acitretin vs. subcutaneously injected IFN-α and PUVA found increased clearance with IFN-α and PUVA (RR 0·54, 95% CI 0·35-0·84, P≤0·005). There were also significant reductions in grade III, severe adverse events on the World Health Organization scale; events requiring discontinuation; and neurological disorders in the IFN-α plus PUVA group. Finally, a trial comparing active vs. inactivated transfer factor found significant differences between the groups, favouring inactivated transfer factor (Fisher's exact test, P≤0·03, RR 0·09, 95% CI 0-0·61). The original study authors speculated that their results reflected a better initial prognosis for the group receiving inactivated transfer factor. None of the interventions assessed showed significant long-term benefit. Despite significantly superior clearance rates in four trials, participants in those studies had high relapse rates. This review of RCTs for MF interventions led to more questions than answers due to a dearth of adequately powered RCTs. Only one meta-analysis could be performed. The remaining review was based on single trials, many of which assessed infrequently used treatments or regimens and are not reflective of current clinical practices. Only two of the 14 RCTs assessed patient health-related quality-of-life outcomes.

A Review of Survival in Mycosis Fungoides

The objectives of this study are to review prior publications of survival for patients with mycosis fungoides (MF), to perform some analyses on the consolidated data, and then to consider the implications of the results. The data for this study comprise 18 survival curves derived from seven prior publications of long-term survival in relatively large series of patients with MF. Altogether, the study uses results from over 5,000 patients. To examine fatality, the study uses hazard functions derived from the survival curves. The analyses demonstrate significant variability in survival between different groups who have studied MF, and the results document that for most patients the diagnosis of MF has little impact on fatality. Although MF is considered a cutaneous lymphoma, that is, a malignancy, it may be time to reconsider low stages of MF as precursors to malignancy analogous to the precursors to malignancies of other types or organs.

Quantitation of tumour development correlates with prognosis in tumour stage (stage IIB) mycosis fungoides

Patients with mycosis fungoides (MF) tumour stage IIB disease show considerable variation in the number of tumours and time interval between each tumour occasion. To quantify the extent of tumour formation in patients with stage IIB MF and correlation with survival. The variability in tumour development of 46 patients with stage IIB MF was quantified by calculating a frailty score with the use of a statistical frailty model, based on both the number of tumours developed during follow-up and the time interval between each tumour occasion. The prognostic value of the frailty scores and the number of tumours at 6 and 12months after first tumour development were studied. Frailty scores varied between 0·05 and 6·94. Patients with high frailties (>1·0, n=14) had the worst disease-specific survival (DSS) and overall survival (OS), compared with patients in the low frailty group (0-0·35, n=17) and medium frailty group (0·35-1·0, n=15). Differences in DSS and OS between the three frailty groups were highly significant (both P<0·001). The number of tumours that developed within 6months after the diagnosis of MF stage IIB was prognostic for subsequent DSS and OS (P<0·001 and P=0·021, respectively). The number of tumours and time interval between tumour formation differs greatly among patients with stage IIB MF and these differences correlate with survival. Patients with an adverse prognosis can be identified by quantifying the number of tumours that develop within 6months after diagnosis of MF stage IIB.

Efficacy of Low‐Dose Ultraviolet A‐1 Phototherapy for Parapsoriasis/Early‐Stage Mycosis Fungoides

Mycosis fungoides (MF) and parapsoriasis (PP) are major dermatologic conditions for which phototherapy continues to be a successful and valuable treatment option. UVA-1 phototherapy is effective in the management of cutaneous T-cell mediated diseases. The aim of the study was to evaluate the efficacy and safety of low-dose UVA-1 phototherapy for the management of PP/early-stage MF. A total of 30 patients, diagnosed with MF (n:19) or PP (n:11) were enrolled to the study. All patients were managed with low-dose UVA-1 (20 or 30 J cm(-2)). Response was assessed clinically and immunohistochemically. UVA-1 treatment led to clinical and histological complete remission (CR) in 11 of 19 MF patients (57.9%), partial remission (PR) in three of 19 (15.8%), after a mean cumulative dose of 1665 (range, 860-3120) J cm(-2) and mean number of 73 exposure (range, 43-107) sessions. Five patients with PP (45.5%) showed CR, and PR was observed in six patients with PP (54.5%) after a mean cumulative dose of 1723 (range, 1060-3030) J cm(-2) and mean number of 74 exposure (range, 53-101) sessions. We conclude that low-dose UVA-1 therapy seems to be an effective, safe, and well-tolerated treatment option for patients with PP/early-stage MF.

Mycosis fungoides with CD20 expression: report of two cases and review of the literature

CD20 expression is exceedingly rare in T-cell lymphomas. Most published cases have been diagnosed as peripheral T-cell lymphomas, not otherwise specified. Only 18 cases of CD20-positive mycosis fungoides (MF) have been previously reported. Here, we describe two cases of CD20-positive MF. Patient 1 was an 84-year-old woman who presented with a 5-year history of multiple pruritic erythematous papules coalescing into thin plaques over 80% of her body surface area. She expired after developing tumors and large cell transformation. Patient 2 was a 67-year-old woman with a long-standing history of tumor stage MF with large cell transformation. She developed a nodular plaque while receiving topical and systemic therapy. In both cases, the neoplastic T-cells demonstrated a CD4-positive immunophenotype with loss of pan-T-cell markers and a monoclonal T-cell receptor gamma gene rearrangement. CD20 was expressed by a significant population of the neoplastic T-cells, but these T-cells lacked expression of other B-cell markers, including CD79a, CD19 and PAX5. This report adds to and summarizes the small body of literature describing CD20-positive MF, and discusses diagnostic and clinical implications.

Mycosis Fungoides With Large Cell Transformation and T Follicular Helper Phenotype

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is usually characterized by a T-helper phenotype of neoplastic cells. Several clinical, histopathologic, and phenotypic variants of the disease have been described. We report on a case of MF in tumor stage with neoplastic cells expressing a T-follicular helper phenotype, characterized by positivity for PD-1, Bcl-6, and CXCL-13. Retrospective analysis of the first diagnostic biopsy of patch stage MF revealed a similar phenotype. This review addresses the clinical, histopathologic, phenotypic, differential diagnostic, and prognostic features of typical and of less conventional cases of MF.

CD20+ Mycosis Fungoides

Mycosis fungoides (MF) is the most common of the family of cutaneous T-cell lymphomas, accounting for 65% of all cases of cutaneous T-cell lymphomas. The classic phenotypic profile is one defined by CD4+ T cells showing a reduction in the expression of CD7 and CD62L. There are 3 previous reports describing CD20 expression in MF. The cell surface antigen CD20 is a transmembrane glycosylated phosphoprotein expressed in the early stages of B-cell development before differentiation into plasma cells. Two male patients, aged 14 and 44 years, presented with persistent truncal plaques up to 8 cm of 1 and 4 years duration, respectively. A third patient, an 80-year-old female, presented with a 1-year history of progressive nodules involving the head and neck area. Cases 1 and 2 both responded to topical treatment modalities. The biopsies in cases 1 and 2 showed features typical of plaque stage MF, whereas case 3 was compatible with follicular MF with tumor stage transformation. Phenotypically, the aberrant cell populace demonstrated a CD4+, CD7-, and CD62L- phenotype; at variance with classic MF was the expression of CD20. Although there were a few PAX5-positive staining cells, definitive colocalization studies were negative. Other B-cell markers and heavy chain immunoglobulin rearrangement were not detected. There are a growing number of reports describing T-cell lymphomas and leukemias with CD20 expression. Of the 6 CD20+ MF cases reported in the literature to date, 3 have been associated with a more aggressive clinical course; all but one case have occurred in males.

Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

Mycosis fungoides (MF) is the most common variant of primary cutaneous T-cell lymphoma, and decreased forkhead box P3 (FoxP3) expression has been reported in MF late stages. Hypoxia-inducible factor 1 alpha (HIF-1α) may regulate FoxP3 expression; however, it is unknown whether HIF-1α is expressed in the CD4(+) T cells of MF patients and how it could affect the expression of FoxP3. Therefore, we evaluated the expression of HIF-1α and FoxP3 in CD4(+) T cells obtained from the skin lesions of MF patients. We found increased cell proliferation and an increase in CD4(+) T cells with an aberrant phenotype among early stage MF patients. HIF-1α was overexpressed in these CD4(+) T cells. In addition, we found a decrease in the percentage of FoxP3(+) cells both in the skin of MF patients, when compared with control skin samples, and with disease progression. In addition, a negative correlation was established between HIF-1α and FoxP3 expression. Skin HIF-1α expression in MF patients correlated with the extent of the affected area and increased with the disease progression. Finally, we showed that ex vivo inhibition of HIF-1α degradation increases the percentage of FoxP3(+) T cells in skin lesions. Our results suggest that overexpression of HIF-1α affects the levels of FoxP3 in MF patients, which could have relevant implications in terms of disease outcome.

Genetic markers associated with progression in early mycosis fungoides

Mycosis fungoides (MF) is a rare, but potentially devastating malignancy. It classically presents with cutaneous patches and plaques and can progress to tumours on the skin with lymph node, blood and visceral involvement. While most patients with MF have a relatively benign disease course, a subset of patients will develop progressive disease that is often fatal. The aim of this study was to identify genetic markers in early MF limited to the skin (stages IA-IIA) that distinguish those patients who will have progressive disease from those who will not, so that early appropriate treatment may be instituted. The study includes 18 patients who were diagnosed with early stage MF at the time of biopsy and had follow-up to determine which patients developed progressive disease. RNA was extracted from skin biopsy specimens and analysed for expression of CD3, FOXP3, IFNγ, Interleukin (IL)-4, IL-13, KIR3DL2, MICB, PLS3 and STAT4 by quantitative real-time polymerase chain reaction. Reduced expression of FOXP3 and STAT4 and increased expression of IL-4 relative to CD3 expression levels were significantly associated with MF progression. Further studies will be needed to fully assess the usefulness of these genetic markers to predict disease progression and guide treatment options in patients diagnosed with early MF.