Mind your head: two cases of mucosal metastasis of BRAF-mutated melanoma of the scalp

Mucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after a malignant melanocytic mucosal lesion with a BRAF mutation was found, the primary cutaneous source was identified and clonality confirmed between the lesions. In both cases, primary lesions occurred on the scalp, an often-overlooked site. Both lesions showed signs of regression implying that in due time these lesions could have been fully regressed and might never have been detected. In that case, the metastatic mucosal lesion would erroneously be identified as a BRAF-mutated mucosal melanoma. These cases give warrant; a careful dermatological inspection should be instigated when confronted with a BRAF-mutated mucosal melanoma. We hypothesize that some BRAF-mutated mucosal melanomas might actually represent metastases of regressed cutaneous melanomas.MTG4Molecular tumour pathology - and tumour genetic

Current knowledge on biomarkers for contact sensitization and allergic contact dermatitis.

Contact sensitization is common and affects up to 20% of the general population. The clinical manifestation of contact sensitization is allergic contact dermatitis. This is a clinical expression that is sometimes difficult to distinguish from other types of dermatitis, for example irritant and atopic dermatitis. Several studies have examined the pathogenesis and severity of allergic contact dermatitis by measuring the absence or presence of various biomarkers. In this review, we provide a non-systematic overview of biomarkers that have been studied in allergic contact dermatitis. These include genetic variations and mutations, inflammatory mediators, alarmins, proteases, immunoproteomics, lipids, natural moisturizing factors, tight junctions, and antimicrobial peptides. We conclude that, despite the enormous amount of data, convincing specific biomarkers for allergic contact dermatitis are yet to be described

Stratum corneum biomarkers for inflammatory skin diseases

This thesis focusses on development of biomarkers, obtained by a non-invasive sampling method, for skin inflammatory diseases relevant for occupational settings; irritant contact dermatitis (ICD), allergic contact dermatitis (ACD) and atopic dermatitis (AD). In various studies, in which different methods were used, several biomarkers related to the skin barrier function and local inflammation were investigated. These biomarkers include: filaggrin degradation products known as natural moisturizing factors (NMF), corneocyte morphology quantified in a dermal topographical index (DTI) and a large set of inflammatory mediators. The developed biomarkers have been applied to monitor therapy efficacy, assessment of disease severity and to differentiate ICD from ACD. Next to their use in clinical practice, the biomarkers were used to provide more insight in the role of skin barrier malfunction and local inflammatory mediators in the pathogenesis of these skin disorders

Validation of automated positive cell and region detection of immunohistochemically stained laryngeal tumor tissue using digital image analysis.

OBJECTIVES: This study aimed to validate a digital image analysis (DIA) workflow for automatic positive cell detection and positive region delineation for immunohistochemical hypoxia markers with a nuclear (hypoxia-inducible factor 1α [HIF-1α]) and a cytoplasmic (pimonidazole [PIMO]) staining pattern. MATERIALS AND METHODS: 101 tissue fragments from 44 laryngeal tumor biopsies were immunohistochemically stained for HIF-1α and PIMO. QuPath was used to determine the percentage of positive cells and to delineate positive regions automatically. For HIF-1α, only cells with strong staining were considered positive. Three dedicated head and neck pathologists scored the percentage of positive cells using three categories (0: 33%;). The pathologists also delineated the positive regions on 14 corresponding PIMO and HIF-1α-stained fragments. The consensus between observers was used as the reference standard and was compared to the automatic delineation. RESULTS: Agreement between categorical positivity scores was 76.2% and 65.4% for PIMO and HIF-1α, respectively. In all cases of disagreement in HIF-1α fragments, the DIA underestimated the percentage of positive cells. As for the region detection, the DIA correctly detected most positive regions on PIMO fragments (false positive area=3.1%, false negative area=0.7%). In HIF-1α, the DIA missed some positive regions (false positive area=1.3%, false negative area=9.7%). CONCLUSIONS: Positive cell and region detection on biopsy material is feasible, but further optimization is needed before unsupervised use. Validation at varying DAB staining intensities is hampered by lack of reliability of the gold standard (i.e., visual human interpretation). Nevertheless, the DIA method has the potential to be used as a tool to assist pathologists in the analysis of IHC staining

Supplementary Material for: Stratum Corneum Tape Stripping: Monitoring of Inflammatory Mediators in Atopic Dermatitis Patients Using Topical Therapy

<i>Objective:</i> The aim of this study was to explore the tape strip sampling technique in the assessment of stratum corneum levels of inflammatory mediators in a clinical trial setting. <i>Methods:</i> Thirty-eight inflammatory mediators were analyzed by a multiplex-assay in the stratum corneum, collected by adhesive tapes before and after 6 weeks of therapy, in mild and moderate atopic dermatitis (AD) patients (n = 90). Treatment was a ceramide- and magnesium-containing emollient. <i>Results:</i> Twenty-four mediators could quantitatively be determined. The Th2 mediators interleukin (IL)-4, IL-13, CCL2 (monocyte chemotactic protein-1), CCL22 (macrophage-derived chemokine), and CCL17 [thymus and activation-regulated chemokine (TARC)] were significantly decreased after therapy as well as IL-1β, IL-2, IL-8 (CXCL8), IL-10, acute-phase protein serum amyloid A, C-reactive protein, and vascular adhesion molecule-1. The decrease of CCL17 and IL-8 was correlated with the decrease in disease severity in a subgroup of moderate AD individuals. <i>Conclusion:</i> Stratum corneum tape stripping offers a minimally invasive approach for studying local levels of immunomodulatory molecules in the skin. CCL17 (TARC) and IL-8 were found to be the most promising biomarkers of AD and might be useful for investigating the course of skin diseases and the effect of local therapy

Stratum corneum profiles of inflammatory mediators in patch test reactions to common contact allergens and sodium lauryl sulfate

Background: Recent studies have demonstrated allergen-specific differences in the gene expression of inflammatory mediators in patch tested skin. Objectives: To determine levels of various inflammatory mediators in the stratum corneum (SC) after patch testing with common contact allergens and the skin irritant sodium lauryl sulfate (SLS). Methods: In total, 27 individuals who had previously patch tested positive to nickel, chromium, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) or para-phenylenediamine were retested and then patch tested with SLS and petrolatum, with petrolatum serving as the patch test control. At 72 h, the test sites were clinically graded and the SC samples collected on adhesive tape. Results: The levels of 18 of the 32 quantified mediators differed significantly from that of the control patches for at least one of the tested substances. SLS and MCI/MI induced the largest number of immunomediators. Interleukin (IL)-16 levels were significantly higher in patch test reactions in all allergens than they were in the controls, while no significant difference was detected for SLS. Furthermore, a strong negative correlation was found between strength of patch test reaction and IL-1α levels. Conclusions: Cytokine profiles in the SC of patch tested skin did not show a distinct allergen-specific pattern. However, MCI/MI induced a larger and wider immune response than the other allergens, perhaps due to its potency as an irritant. The levels of IL-16 were significantly increased in patch test reactions to allergens but not to SLS; thus, they may help clinicians to differentiate between allergic contact dermatitis and irritant contact dermatitis