Acne fulminans successfully treated with cyclosporine and isotretinoin

A 15-year-old white male patient with severe acne flare was referred to our hospital. Diagnosis was acne vulgaris for the past 2 years, treated with topical antibiotics. Six months before the consultation, the lesions worsened and a diagnosis of acne conglobata was made. He was treated with isotretinoin 20 mg/day and prednisone 15 mg/day, but there was no clinical improvement. Isotretinoin dosage was increased to 30 mg/day, but 3 weeks later multiple reddish papulonodular and ulcerated lesions with hemorrhagic crusts suddenly developed on his face, neck, and trunk. The lesions were painful, and arthralgias and temperature up to 39°C were noted (Fig 1). Abnormal laboratory findings included elevated C-reactive protein levels (5 mg/dL; normal < 1 mg/dL) and leukocytosis (15,700 cells/mm3) with neutrophilia (68.8%). AF was diagnosed, and treatment with prednisone 60 mg/day and isotretinoin 20 mg/day was initially successful. Nevertheless progressive worsening was observed in the following weeks while prednisone was tapered and isotretinoin increased to 30 mg/day. He was treated with potassium permanganate baths and topical antibiotics. Oral cyclosporine 5 mg/kg/day plus isotretinoin 30 mg/day was initiated and systemic steroids were stopped. After a few weeks, the lesions improved, and 4 months later, cyclosporine was discontinued. A total dose of isotretinoin 100 mg/kg could be completed, and he presented an almost complete resolution of the inflammatory lesions with some residual scarring (Fig 2). No significant side effects or laboratory abnormalities were observed during treatment

Methylation status of the p15, p16 and MGMT promoter genes in primary cutaneous T-cell lymphomas

p15(INK4b), p16(INK4a) and O(6)-methylguanine DNA methyltransferase (MGMT) gene hypermethylation was studied in 22 patients with primary cutaneous T-cell lymphomas (CTCL). p15(INK4b) and p16(INK4a) inactivation is present in early and advanced disease and seems to be independent of disease stage. MGMT inactivation may play a pathogenetic role in a subset of CTCL

Absence of MALT1 traslocation in primary cutaneous marginal zone B-cell lymphoma

The implication of MALT1 gene in the pathogenesis of primary cutaneous marginal zone B-cell lymphomas (PCMZL) has been a matter of controversy. We examined the presence of MALT1 translocations in a series of 23 PCMZL. FISH assay with a MALT1 dual color break apart translocation probe revealed the absence of MALT1 translocations in all cases

Comparative Analysis of TCR-gamma Gene Rearrangements by Genescan and Polyacrylamide Gel-electrophoresis in Cutaneous T-cell Lymphoma

Demonstrating T-cell clonality has become an important approach supporting a diagnosis of malignant T-cell neoplasms. A comparative study between Genescan analysis, polyacrylamide gel and agarose gel electrophoresis in visualizing X-cell receptor gamma gene rearrangement was performed on 25 biopsy specimens from 18 patients with different forms of cutaneous T-cell lymphomas. Clonality was detected in 17 biopsy specimens when PCR products were evaluated by Genescan analysis. Seventeen showed discrete bands when visualized in polyacrylamide gel and 14 cases were clonal when visualized with agarose gel. In five cases, a clonal population was seen in the gels, but not with Genescan. On sequencing the PCR products we demonstrated nonclonality of these five samples. Our results confirm that PCR-Genescan is a useful, reliable and specific screening method for detecting dominant clones in patients with T-cell lymphoma

Lymphomatoid papulosis associated with mycosis fungoides. A clinicopathological and molecular study of 12 cases

The association of mycosis fungoides and a primary cutaneous CD30+ lymphoproliferative disorder has been reported and probably represents different clinical aspects of a unique T-cell monoclonal expansion. In this study, 12 patients (6 men and 6 women) presented with lymphomatoid papulosis and mycosis fungoides. A TCRgamma gene rearrangement study was performed by an automated high-resolution PCR fragment analysis method on skin biopsy specimens taken from the different clinical lesions in each patient. An indolent clinical course was observed in the majority of patients. T-cell clonality was identified in 7 of 12 lymphomatoid papulosis lesions (58%) and in 6 skin biopsies of plaque stage mycosis fungoides (50%). In each individual case, where T-cell clonality was detected, both mycosis fungoides and lymphomatoid papulosis specimens exhibited an identical peak pattern by automated high-resolution PCR fragment analysis, confirming a common clonal origin. Only one case showed a clonal TCRgamma rearrangement from the lymphomatoid papulosis lesion, which could not be demonstrated in the mycosis fungoides specimen. The demonstration of an identical clone seems to confirm that both disorders are different clinical manifestations of a unique T-cell monoclonal proliferation. Our results also seem to confirm that the association of mycosis fungoides with a primary cutaneous CD30+ lymphoproliferative disorder usually carries a favourable prognosis

A 38-year-old woman with zosteriform skin lesions

A 38-year-old white woman with no previous medical history presented to our hospital with a 7-day clinical history of skin lesions on her shoulder. She had visited Uganda for 3 weeks, where she swam in Bunyonyi Lake at the end of the first week of the trip. She remained asymptomatic until 2 weeks after her return (approximately 5 weeks after freshwater exposure), when she developed pruritic painless erythematous papules grouped on the back part of her left shoulder following the C3-C4 dermatome (Fig 1). Under clinical suspicion of cutaneous herpes zoster, oral valganciclovir was prescribed. No clinical improvement was observed, and varicella zoster virus polymerase chain reaction from a skin lesion was negative. Routine blood tests showed eosinophilia (5,200 cells/mm3, normal count below 450 cells/mm3). No parasites, cysts, or eggs were observed in excreta. Two weeks after the clinical symptoms appeared and while waiting for the results of some serological tests, a skin biopsy (Fig 2) and a specific loop-mediated isothermal amplification (LAMP) assay of the sample were performed. What is your diagnosis

MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients

Association of APOA5 and APOC3 genetic polymorphisms with severity of hypertriglyceridemia in patients with cutaneous T-Cell lymphoma treated with bexarotene

Importance: hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives: to analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants: this case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures: primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results: among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance: these results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile

FOXP1 molecular cytogenetics and protein expression analyses in primary cutaneous large B cell lymphoma, leg-type

FOXP1 protein is expressed in normal activated B cells and overexpressed in a subset of diffuse large B-cell lymphomas, including primary cutaneous large B-cell lymphomas (PCLBCL), leg type. High expression of FOXP1 has been associated to an unfavourable prognosis with independent survival significance. However, little is known regarding the mechanisms underlying the overexpression of FOXP1 in PCLBCL, leg type. Our aims were to analyze FOXP1 cytogenetic status and protein expression in a series of PCLBCL, leg type. Finally, we compared the observed results with those obtained in a group of patients with primary cutaneous follicle centre lymphoma (PCFCL). Fifteen patients with PCLBCL, leg type and nine patients with primary cutaneous follicle centre lymphoma (PCFCL) were included in the study. For each biopsy specimen, FOXP1 translocation and copy number changes were evaluated by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC). Immunohistochemistry showed FOXP1 staining in 13 PCLBCL, leg type, whereas all PCFCL were negative. FISH analysis disclosed no translocations involving FOXP1 gene in any of the cases. However, FOXP1 gene gains (3 to 4 copies) were observed in 82% of samples of PCLBCL, leg type and in 37% of PCFCL. FOXP1 expression was independent from FOXP1 translocation. Our results confirm that overexpression of FOXP1 is present in a considerable proportion of PCLBCL, leg type and might indicate an unfavourable prognosis. Mechanisms not related to translocation seem to be responsible for this overexpression

Identification of gene mutations and fusion genes in patients with Sézary Syndrome

Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease