R. van Doorn

Recommendations for treatment in folliculotropic mycosis fungoides : report of the Dutch Cutaneous Lymphoma Group

Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin‐directed therapies (SDTs). Recent studies distinguished indolent (early‐stage FMF) and more aggressive (advanced‐stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined.

Array-CGH analysis of cutaneous anaplastic large cell lymphoma.

This chapter describes a study in which the pattern of numerical chromosomal alterations in cutaneous anaplastic large cell lymphoma (C-ALCL) tumor samples was defined using array-based comparative genomic hybridization (CGH). First, the array-based CGH technique applied is outlined in detail. Next, its application in the analysis of C-ALCL tumor specimens is described. This approach resulted in the identification of highly recurrent chromosomal alterations in C-ALCL that include gain of 7q31 and loss on 6q16-6q21 and 13q34, each affecting 45% of the patients. The pattern characteristic of C-ALCL differs markedly from chromosomal alterations observed in other CTCL such as mycosis fungoides and Sézary syndrome and yielded several candidate genes with potential relevance in the pathogenesis of C-ALCL.

Complete remission of skin lesions in a patient with subcorneal pustular dermatosis (Sneddon-Wilkinson disease) treated with antimyeloma therapy: Association with disappearance of M-protein

Subcorneal pustular dermatosis (SPD), or Sneddon–Wilkinson disease, is a rare pustular skin disease that follows a chronic relapsing course. A well‐known association exists between SPD and IgA monoclonal gammopathy of undetermined significance (MGUS), which exists in up to 40% of cases. SPD has also been observed in patients with IgA myeloma. In SPD, direct and indirect immunofluorescence studies do not reveal in vivo bound IgA to the epithelial cell surface, in contrast to IgA pemphigus, which has similar clinicopathological features. Here we describe the case of a male patient with SPD and a concurrent IgA MGUS who had been treated with dapsone for 20 years with frequent relapses. Following development of multiple myeloma, the patient was treated with intensive antimyeloma treatment consisting of high‐dose melphalan with autologous stem cell transplantation. This resulted in a complete remission of the myeloma with disappearance of the M‐protein. In addition, a sustained remission of SPD was achieved without further treatment. Twenty‐eight months after melphalan therapy the M‐protein reappeared in the serum, and 2 months later SPD reappeared with histopathologically proven skin lesions at predilection sites. Presence and absence of skin lesions was found to correlate with the presence and absence of the M‐protein in the serum. This is the first report of antimyeloma therapy inducing a long‐lasting remission in SPD. The findings in this patient strongly suggest a causal role for circulating IgA antibodies in the pathogenesis of SPD. Antimyeloma treatment should be considered in patients with IgA MGUS‐associated SPD refractory to other therapies.

Mycosis fungoides: promoter hypermethylation predicts disease progression.

The development and progression of malignant diseases is driven by the acquisition of not only genetic, but also epigenetic alterations. The term epigenetics has been used to describe heritable changes in gene expression resulting from changes in chromatin structure without alterations in the primary DNA sequence. DNA methylation is the most studied epigenetic mechanism and refers to the addition of a methyl group to a cytosine nucleotide occurring in a CG dinucleotide. Approximately half of human gene promoters contain so-called CpG islands, genomic regions with high CG dinucleotide density, which are usually unmethylated. However, in cancer cells dozens to hundreds of promoter CpG islands become aberrantly methylated, which is often associated with transcriptional silencing of affected genes. Promoter CpG island hypermethylation demonstrates tumour-type-specific patterns and can contribute to the malignant phenotype of cells by inactivating tumour suppressor genes. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is known to have a highly variable disease course. Whereas most patients who present with erythematous plaques have stable disease for years, a subset of patients experiences rapid disease progression with development of skin tumours and extracutaneous dissemination of tumour cells. Several tumour suppressor genes have previously been found to be silenced through promoter hypermethylation in MF, including CDKN2A, BCL7A and MLH1, pointing to the relevance of epigenetic mechanisms in its pathogenesis. In a study published in this issue of BJD, Gerardo Ferrara and colleagues examined the occurrence of promoter hypermethylation of 12 selected genes in early-stage MF skin lesions. Frequent hypermethylation of several genes such as CDKN1B and IGF2 was noted. Remarkably, the frequency of promoter hypermethylation of this gene panel was observed to be higher in patients with early-stage lesions who would go on to experience disease progression than in patients with a stable disease course. The authors found that in particular promoter hypermethylation of the peroxisome proliferatoractivated receptor-c gene (PPARG) in early-stage MF skin lesions was predictive of disease progression. The PPARG gene encodes a nuclear receptor regulating lipid metabolism that is normally expressed by T lymphocytes. Promoter hypermethylation of this potential tumour suppressor gene was associated with transcriptional repression. This study demonstrates that the frequency and pattern of promoter hypermethylation is associated with the propensity of MF to progress. The prognostic significance of promoter hypermethylation of PPARG and other genes might be applied in the clinic. In addition, this study supports the notion that epigenetic deregulation acts as a driving force in MF, which is in line with the efficacy of epigenetic drugs such as the histone deacetylase inhibitor vorinostat in this T-cell malignancy. If epigenetic inactivation of PPARG might have a causal role in disease progression, then pharmacological agonists of the protein might have a therapeutic effect by limiting MF aggressiveness. This study clearly shows the clinical potential of detecting epigenetic alterations in MF. We can expect that future genome-wide analysis of DNA methylation in MF will reveal more diagnostic and prognostic biomarkers, which should be confirmed in large patient cohorts.

Epidermal growth factor receptor inhibitor‐associated rash prevented by oral tetracyclines

en-Aguinaga S, J auregui Presa I, Aguinaga-Ontoso E et al. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. Br J Dermatol 2016; 175:1153–65. 4 Maurer M, Weller K, Bindslev-Jensen C et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report. Allergy 2011; 66:317–30. 5 Abajian M, Curto-Barredo L, Krause K et al. Rupatadine 20 mg and 40 mg are effective in reducing the symptoms of chronic cold urticaria. Acta Derm Venereol 2016; 96:56–9. 6 Krause K, Spohr A, Zuberbier T et al. Up-dosing with bilastine results in improved effectiveness in cold contact urticaria. Allergy 2013; 68:921–8. 7 Magerl M, Pisarevskaja D, Staubach P et al. Critical temperature threshold measurement for cold urticaria: a randomized controlled trial of H (1)-antihistamine dose escalation. Br J Dermatol 2012; 166:1095–9. 8 Siebenhaar F, Degener F, Zuberbier T et al. High-dose desloratadine decreases wheal volume and improves cold provocation thresholds compared with standard-dose treatment in patients with acquired cold urticaria: a randomized, placebo-controlled, crossover study. J Allergy Clin Immunol 2009; 123:672–9. 9 Zhao ZT, Ji CM, Yu WJ et al. Omalizumab for the treatment of chronic spontaneous urticaria: a meta-analysis of randomized clinical trials. J Allergy Clin Immunol 2016; 137:1742–50 e4. 10 Grattan CE, O’Donnell BF, Francis DM et al. Randomized doubleblind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 2000; 143:365–72. 11 Vena GA, Cassano N, Colombo D et al. Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006; 55:705–9. 12 McBayne TO, Siddall OM. Montelukast treatment of urticaria. Ann Pharmacother 2006; 40:939–42. 13 Weller K, Groffik A, Church MK et al. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol 2014; 133:1365–72, 72 e1–6.

The value of clinical characteristics for the diagnosis of melanoma in patients presenting at a pigmented lesion clinic

DEAR EDITOR, Previous research has identified risk factors for developing a melanoma. The aim of this study was to assess to what extent established clinical risk factors for melanoma are associated with the immediate diagnosis of melanoma in patients referred to a pigmented lesion outpatient clinic (PLC) by their GP. This study was performed at the PLC of the dermatology department of Leiden University Medical Center, Leiden, the Netherlands. Between April 2011 and April 2015, all consecutive patients aged > 18 years who were referred to the outpatient clinic for the evaluation of a pigmented lesion were included. Phenotypical risk factors for melanoma, such as hair and eye colour, skin type, total number of naevi, number of atypical naevi and number of solar lentigines, were recorded with the use of a standardized form by the treating physician. 3,5 Patients were also questioned on sun exposure, episodes of sunburn, and personal or family history of melanoma. All patients underwent a full-body skin examination. All lesions that were clinically suspicious for melanoma or nonmelanoma skin cancer were excised and histologically evaluated by an expert pathologist. Patients in whom melanoma was diagnosed were considered as cases and all other patients were considered as controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for melanoma were calculated according to the presence and absence of each clinical risk factor for melanoma. In addition, the risk of melanoma diagnosis was assessed for the combination of a history of melanoma and each phenotypical risk factor separately. The diagnoses of invasive melanoma and melanoma in situ were not only combined in most analyses, but also analysed individually. All statistical analyses were performed with SPSS for Windows, release 20.0 (IBM, Armonk, NY, U.S.A.). During the study period, 2314 patients [905 men and 1409 women; mean age 42 years (range 18–91)] visited the PLC. Overall, 106 patients (4%) were diagnosed with melanoma: 91 had an invasive melanoma and 15 had a melanoma in situ. Sun exposure and sunburn were not associated with an immediate melanoma diagnosis (Table 1). The risk of melanoma diagnosis was increased for all phenotypical risk factors, especially actinic keratosis (OR 2 9, 95% CI 1 7–5 1) and personal history of melanoma (OR 4 7, 95% CI 3 0–7 5). The risk associated with actinic keratosis was independent of the (atypical) naevus count (OR 3 3, 95% CI 1 8–6 1) in patients who had < 100 naevi and fewer than five atypical naevi. Similarly, the OR of having > 100 naevi and more than five atypical naevi were 1 9 (95% CI 1 0–3 7) and 1 7 (95% CI, 0 8-3 3), respectively, in patients with no actinic keratosis. Sensitivity analyses in which patients with other skin malignancies were excluded from the control group (n = 78, data not shown), and analyses in which invasive melanoma was considered separately, yielded similar results. However, actinic keratosis (OR 1 2, 95% CI 0 2–9 6) and personal history of melanoma (OR 0 8, 95% CI 0 1–6 1) were not associated with an increased risk of melanoma in situ. When the combination of a personal history of melanoma and each phenotypical risk factor was assessed (Table 2), patients with a history of melanoma and > 100 naevi (OR 12 0, 95% CI 4 7–30 2), and patients with a history of melanoma and skin type I or II (OR 8 7, 95% CI 4 0–18 8) were at particularly high risk (Table 2). In clinical practice, information on risk factors for melanoma is obtained to assess a patient’s lifetime risk of melanoma. However, to our knowledge, this is the first study to show which established risk factors for melanoma can be used to identify patients with a pigmented lesion at highest immediate risk of melanoma diagnosis at the actual moment of clinical presentation. This information is important as current diagnostic tools (e.g. the ABCDE rule, dermatoscopy) do not take a patient’s background risk of melanoma into account. Combining diagnostic tools with easily obtainable information on clinical risk factors may help clinicians to make outpatient visits more effective by preselecting those patients at highest risk. The risk estimates for melanoma diagnosis in patients with a pigmented lesion, especially among patients with a previous melanoma, are striking when one considers that the same phenotypical risk factors predict the risk of melanoma in the general population. This suggests that these phenotypical risk factors are useful for assessing both the immediate and future risk of melanoma diagnosis in the general population, as well as in patients with a higher a priori melanoma risk. We did not find an association between sun exposure or sunburn and the risk of melanoma diagnosis at clinical presentation. A possible explanation is that all pigmented lesions and not just melanoma are associated with sun exposure. Alternatively, despite thorough questioning on sun exposure (i.e. sunbathing, gardening, outdoor activities and professions) it is possible that patients underestimated or under-reported their level of sun exposure, making levels of sun exposure falsely similar in patients and controls. This would also explain why more