Genetic and epigenetic insights into cutaneous T-cell lymphoma.

Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of non-Hodgkin T-cell lymphomas that present in the skin. In recent years, significant progress has been made in the understanding of the pathogenesis of CTCLs. Progress in CTCL classifications combined with technical advances, in particular next-generation sequencing, enabled a more detailed analysis of the genetic and epigenetic landscape and transcriptional changes in clearly defined diagnostic entities. These studies not only demonstrated extensive heterogeneity between different CTCL subtypes but also identified recurrent alterations that are highly characteristic for diagnostic subgroups of CTCLs. The identified alterations, in particular, involve epigenetic remodeling, cell cycle regulation, and the constitutive activation of targetable oncogenic pathways. In this respect, aberrant JAK-STAT signaling is a recurrent theme; however, it is not universal for all CTCLs and has seemingly different underlaying causes in different entities. A number of the mutated genes identified are potentially actionable targets for the development of novel therapeutic strategies. Moreover, these studies have produced an enormous amount of information that will be critically important for the further development of improved diagnostic and prognostic biomarkers that can assist in the clinical management of patients with CTCL. In the present review, the main findings of these studies in relation to their functional impact on the malignant transformation process are discussed for different subtypes of CTCLs.

Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection.

Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.

Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.

Results of phase 2 trials exploring the safety and efficacy of omiganan in patients with human papillomavirus-induced genital lesions.

AIMS: To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL). METHODS: Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire. RESULTS: Twenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%; P = .045) in AGW patients only. CONCLUSION: Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients.

Plaque stage folliculotropic mycosis fungoides: histopathologic features and prognostic factors in a series of 40 patients.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how patients presenting with plaques should be classified. The present study describes the histopathologic features of 40 FMF plaques. The aim of the study was to identify risk factors for disease progression and poor outcome in this group. METHODS: Clinical, histopathological, and immunophenotypical data from 40 patients with plaque stage FMF were reviewed and analysed for risk factors for disease progression and survival. RESULTS: After a median follow-up of 80 months, disease progression occurred in 20 of 40 patients. Percentage of atypical cells, cell size, percentage of Ki-67+ cells, and co-existent interfollicular epidermotropism, but not the extent of perifollicular infiltrates, were associated with disease progression and reduced survival, while extensive follicular mucinosis was associated with increased survival. CONCLUSIONS: This study underlines that FMF patients presenting with plaques represent a heterogeneous group and that a subgroup of these patients may have an indolent clinical course. It further shows that histological examination is a valuable tool to differentiate between indolent and aggressive disease.

Real-life treatment of cutaneous warts with cantharidin podophyllin salicylic acid solution.

Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty-two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p < .01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p = .7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10-point scale, median patient satisfaction score was 9.0 (interquartile range 7.8-10.0) and 8.0 (interquartile range 5.1-9.7) for children and adults respectively (p < .01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children.

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study.

Organ transplant recipients (OTRs) have a 100-fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between ß genus human papillomaviruses (ßPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003-2006 (n = 274) and cohort 2 was transplanted in 1986-2002 (n = 352). Participants were followed until death or cessation of follow-up in 2016. ßPV infection was assessed in eyebrow hair by using polymerase chain reaction-based methods. ßPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of ßPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different ßPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1-2.6). A similar risk was seen with high ßPV loads (HR 1.8, 95% confidence interval 1.2-2.8). No significant associations were seen between serum antibodies and cSCC or between ßPV and basal cell carcinoma. The diversity and load of ßPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that ßPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.

p16 immunostaining in keratinocytic neoplasia in organ transplant recipients: Bowen's disease shows a characteristic pattern.

BACKGROUND: For selecting therapy, it is important to distinguish different types of keratinocytic neoplasia. It is sometimes difficult to make histopathologic diagnosis, especially in organ transplant recipients (OTR) who develop numerous lesions. METHODS: To investigate p16 immunostaining in different types of keratinocytic neoplasia in OTR, we studied 59 actinic keratoses (AK), 51 Bowen' s disease (BD), 63 squamous cell carcinomas (SCC), 16 benign keratotic lesions (BKL) from 31 OTR patients and 25 controls (eczema and psoriasis). Tissue sections were stained for H&E and p16. We scored intensity, proportion and distribution of p16 positive lesional cells. RESULTS: In 19% of AK, 92% of BD, 35% of SCC and 12% of BKL more than 15% of lesional cells were p16-positive. In 16% of AK, 80% of BD, 18% of SCC and 13% of BKL strong p16 staining was observed. BKL, AK and SCC showed focal and patchy staining, BD showed diffuse pattern with strong staining of all atypical cells. Sparing of the basal layer was predominantly seen in BD. No control specimen showed p16-overexpression. CONCLUSIONS: p16 immunostaining shows a characteristic pattern in BD, but not in AK, SCC and BKL. It appears useful in recognizing BD, but not in differentiating between other keratinocytic neoplasia.

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment.

A proportion of human immunodeficiency virus (HIV)-infected patients develop persistent, stigmatizing human papillomavirus (HPV)-related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)-treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended.

Human Beta-papillomavirus infection and keratinocyte carcinomas.

Although the role of oncogenic human Alpha-papillomaviruses (HPVs) in the development of mucosal carcinomas at different body sites (eg cervix, anus, oropharynx) is fully recognized, a role for HPV in keratinocyte carcinomas (KCs; basal and squamous cell carcinomas) of the skin is not yet clear. KCs are the most common cancers in Caucasians, with the major risk factor being ultraviolet (UV) light exposure. A possible role for Beta-HPV types (BetaPV) in the development of KC was suggested several decades ago, supported by a number of epidemiological studies. Our current review summarizes the recent molecular and histopathological evidence in support of a causal association between BetaPV and the development of KC, and outlines the suspected synergistic effect of viral gene expression with UV radiation and immune suppression. Further insights into the molecular pathways and protein interactions used by BetaPV and the host cell is likely to extend our understanding of the role of BetaPV in KC.

One lesion, one virus: individual components of high-grade anal intraepithelial neoplasia in HIV-positive men contain a single HPV type.

BACKGROUND: High-grade anal intraepithelial neoplasia (AIN) is present in many human immunodeficiency virus (HIV)-positive men who have sex with men. The major etiologic factor is infection with an oncogenic human papillomavirus (HPV) genotype. We investigated whether individual components of high-grade AIN are caused by single HPV types. METHODS: DNA was isolated from whole-tissue sections of 31 high-grade AIN that were recovered from 21 HIV-positive men who have sex with men. The SPF10 PCR/LiPA25 HPV genotyping system was used for DNA analysis. In whole-tissue sections with multiple HPV types, polymerase chain reaction was repeated in regions of AIN sampled by laser-capture microdissection. The results were compared with HPV types in anal swabs. RESULTS: A single HPV type was observed in 15 (48%) of 31 whole-tissue sections. In an additional 14 whole-tissue sections, 1 HPV type was found in each lesion sample evaluated by laser-capture microdissection. Consequently, in 29 of 31 biopsy specimens (94%), a single HPV type was found in each lesional component studied. Two whole-tissue sections contained collision regions, each with 2 HPV types. HPV16 was presumed to be causative in 14 of 31 biopsy specimens (45%). More than half of the anal swabs did not contain all causative HPV types. CONCLUSIONS: Individual components of high-grade AIN are caused by single HPV types (the so-called one lesion, one virus concept). HPV16 is causative in <50% of cases. Anal swabs are not useful for detecting lesion-specific HPV types.

Improved detection reveals active ß-papillomavirus infection in skin lesions from kidney transplant recipients.

The aim of this study was to determine whether detection of ß-HPV gene products, as defined in epidermodysplasia verruciformis skin cancer, could also be observed in lesions from kidney transplant recipients alongside the viral DNA. A total of 111 samples, corresponding to 79 skin lesions abscised from 17 kidney transplant recipients, have been analyzed. The initial PCR analysis demonstrated that ß-HPV-DNA was highly present in our tumor series (85%). Using a combination of antibodies raised against the E4 and L1 proteins of the ß-genotypes, we were able to visualize productive infection in 4 out of 19 actinic keratoses, and in the pathological borders of 1 out of 14 squamous cell carcinomas and 1 out of 31 basal cell carcinomas. Increased expression of the cellular proliferation marker minichromosome maintenance protein 7 (MCM7), that extended into the upper epithelial layers, was a common feature of all the E4-positive areas, indicating that cells were driven into the cell cycle in areas of productive viral infections. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in actinic keratosis and the adjacent pathological epithelium of skin cancer, clearly shows that ß-HPV are actively replicating in the intraepidermal precursor lesions of kidney transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion.

Cross-sectional study of genital carcinogenic HPV infections in Paramaribo, Suriname: prevalence and determinants in an ethnically diverse population of women in a pre-vaccination era.

OBJECTIVE: Cervical cancer is caused by carcinogenic human papillomavirus (HPV) infections. Prior to the introduction of HPV vaccination in Suriname, we performed a cross-sectional study to estimate the prevalence of and determinants for genital carcinogenic HPV infections. METHODS: Women were recruited at a family planning (FP) clinic and a sexually transmitted infections (STI) clinic. Vaginal swabs were used for HPV genotyping by the SPF10 PCR-DEIA-LiPA25 system. Logistic regression was used to identify determinants for carcinogenic HPV infection. RESULTS: The prevalence of any HPV was 54.2% and of carcinogenic HPV was 27.9% among 813 women attending the FP clinic. Among the 188 women attending the STI clinic, the prevalence of any HPV (76.1%) and of carcinogenic HPV (40.4%) was significantly higher. HPV52 was the most prevalent genotype in both clinics. The prevalence of HPV16 and/or 18 was 6.4% in the FP clinic and 12.2% in the STI clinic. The following determinants were independently associated with carcinogenic HPV infection among women visiting the FP clinic: ≥2 recent partners (OR 1.53; 95% CI 1.13 to 2.06), Chlamydia trachomatis co-infection (OR 1.89; 95% CI 1.32 to 2.70), disassortative ethnic sexual mixing (OR 1.50; 95% CI 1.13 to 1.99) and ethnic group (OR 1.90; 95% CI 1.27 to 2.85 for Creole and OR 1.67; 95% CI 1.06 to 2.62 for mixed ethnicity, both compared with Hindustani). No independent determinants were found among women visiting the STI clinic. CONCLUSIONS: Carcinogenic HPV is highly prevalent among women in Suriname, and not equally distributed among ethnic groups. These data provide a baseline to assess possible shifts in the prevalence of HPV genotypes following vaccination.

Serovar D and E of serogroup B induce highest serological responses in urogenital Chlamydia trachomatis infections.

BACKGROUND: Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection (STI) worldwide. A strong link between C. trachomatis serogroup/serovar and serological response has been suggested in a previous preliminary study. The aim of the current study was to confirm and strengthen those findings about serological IgG responses in relation to C. trachomatis serogroups and serovars. METHODS: The study population (n = 718) consisted of two patient groups with similar characteristics of Dutch STI clinic visitors. We performed genotyping of serovars and used titre based and quantitative commercially available ELISA kits (medac Diagnostika) to determine specific serum IgG levels. Optical density (OD) values generated by both tests were used to calculate the IgG titres (cut-off 1:50). Analyses were conducted stratified by gender. RESULTS: We observed very significant differences when comparing the median IgG titres of three serogroups, B, C and I: in women for B vs. C: p < 0.0001 (median titres B 200 vs. C <50); B vs. I: p < 0.0001 (200 vs. 50), and in men for B vs. C: p = 0.0006 (150 vs. <50); B vs. I: p = 0.0001 (150 vs. <50); C vs. I was not significant for both sexes. Serovars D and E of serogroup B had the highest median IgG titres compared to the other serovars in both men and women: 200 and 200 vs. ≤ 100 for women and 100 and 200 vs. ≤ 75 for men, respectively. CONCLUSIONS: This study shows that B group serovars induce higher serological responses compared to the C and I group serovars in vivo in both men and women.

Severe drug eruption from oral terbinafine for mild onychomycosis-A case report from family practice and literature review: "Just an innocent little pill?"

Onychomycosis is the most prevalent nail disease and is frequently encountered in clinical practice. Despite having multiple therapeutic options, of which systemic antifungals are the most effective, treatment is not always mandatory in all patients. Especially when considering systemic treatment, the risk of adverse reactions may outweigh the potential benefits of treatment. In this case report, we present a clinical case of a 49-year-old male patient with a blank past medical history who experienced a severe drug eruption from terbinafine prescribed for mild onychomycosis that required discontinuation of terbinafine, additional evaluation, and treatment of this adverse reaction.

Association between onychomycosis and ulcerative complications in patients with diabetes: a longitudinal cohort study in Dutch general practice.

INTRODUCTION: Diabetic foot ulcers are feared complications of diabetes mellitus (DM), requiring extensive treatment and hospital admissions, ultimately leading to amputation and increased mortality. Different factors contribute to the development of foot ulcers and related complications. Onychomycosis, being more prevalent in patients with diabetes, could be an important risk factor for developing ulcers and related infections. However, the association between onychomycosis and diabetic complications has not been well studied in primary care. RESEARCH DESIGN AND METHODS: To determine the impact of onychomycosis on ulcer development and related complications in patients with diabetes in primary care, a longitudinal cohort study was carried out using routine care data from the Extramural Leiden University Medical Center Academic Network. Survival analyses were performed through Cox proportional hazards models with time-dependent covariates. RESULTS: Data from 48 212 patients with a mean age of 58 at diagnosis of DM, predominantly type 2 (87.8%), were analysed over a median follow-up of 10.3 years. 5.7% of patients developed an ulcer. Onychomycosis significantly increased the risk of ulcer development (HR 1.37, 95% CI 1.13 to 1.66), not affected by antimycotic treatment, nor after adjusting for confounders (HR 1.23, 95% CI 1.01 to 1.49). The same was found for surgical interventions (HR 1.54, 95% CI 1.35 to 1.75) and skin infections (HR 1.48, CI 95% 1.28 to 1.72), again not affected by treatment and significant after adjusting for confounders (HR 1.32, 95% CI 1.16 to 1.51 and HR 1.27, 95% CI 1.10 to 1.48, respectively). CONCLUSIONS: Onychomycosis significantly increased the risk of ulcer development in patients with DM in primary care, independently of other risk factors. In addition, onychomycosis increased the risk of surgeries and infectious complications. These results underscore the importance of giving sufficient attention to onychomycosis in primary care and corresponding guidelines. Early identification of onychomycosis during screening and routine care provides a good opportunity for timely recognition of increased ulcer risk.