Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.

Dysplastic nevi are melanocytic lesions that represent an intermediate stage between common nevus and melanoma. Histopathological distinction of dysplastic nevus from melanoma can be challenging and there is a requirement for molecular diagnostic markers. In this study, we examined promoter CpG island methylation of a selected panel of genes, identified in a genome-wide methylation screen, across a spectrum of 405 melanocytic neoplasms. Promoter methylation analysis in common nevi, dysplastic nevi, primary melanomas, and metastatic melanomas demonstrated progressive epigenetic deregulation. Dysplastic nevi were affected by promoter methylation of genes that are frequently methylated in melanoma but not in common nevi. We assessed the diagnostic value of the methylation status of five genes in distinguishing primary melanoma from dysplastic nevus. In particular, CLDN11 promoter methylation was specific for melanoma, as it occurred in 50% of primary melanomas but in only 3% of dysplastic nevi. A diagnostic algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13, and GNMT genes was validated in an independent sample set and helped distinguish melanoma from dysplastic nevus (area under the curve 0.81). Melanoma-specific methylation of these genes supports the utility as epigenetic biomarkers and could point to their significance in melanoma development.

NIR and skin impedance spectroscopic measurements for studying the effect of coffee and alcohol on skin, and dysplastic naevi.

BACKGROUND/PURPOSE: Near infrared and impedance spectroscopy can be used for clinical skin measurements and need to be evaluated for possible confounding factors; (i) are skin conditions of the patient and the subsequent skin measurements influenced by alcohol and/or coffee consumption and (ii) are measurements of dysplastic naevi (DN) reproducible over time and significantly different compared to reference skin. METHODS: Near infrared and skin impedance spectroscopic data were analysed multivariately. In the first study, the skin characteristics of 15 healthy individuals were examined related to body location, gender, individual differences, and consumption of coffee or alcohol. The second study included five patients diagnosed with dysplastic naevi syndrome. Measurements were taken on DN and reference skin over time. RESULTS: In the first study, body location and gender had a major influence on measurement scores. Inter-individual skin characteristics and coffee or alcohol effects on skin characteristics were of minor importance. In the second study, it was shown that DN can be differentiated from reference skin and the measurements are stable over time. CONCLUSIONS: Moderate consumption of alcohol and coffee did not influence the results of the measurements. It is possible to follow, stable or changed, characteristics of DN over time.

Objective follow-up of atypical melanocytic skin lesions: a retrospective study.

Various authors have suggested that information from longitudinal observation (follow-up) of dynamic changes in atypical melanocytic pigmented skin lesions (MPSL) could enable identification of early malignant melanoma escaping initial observation due to an absence of specific clinical and dermoscopic features. The aim of our retrospective study was to determine the existence of numerical variables regarding changes in MPSL that could be useful to differentiate early melanomas and atypical nevi. The study was carried out in two Italian dermatology Centres. Digital dermoscopy analyzers (DB-Mips System) were used to evaluate dermoscopic images of 94 equivocal pigmented skin lesions under observation for 6-12 months and then excised because of changes across time (29 melanomas and 65 nevi). The analyzer evaluates 49 parameters grouped into four categories: geometries, colours, textures and islands of colour. The ROC curve designed on the 49 digital dermoscopy analysis parameters showed good accuracy. At sensitivity (SE) = specificity (SP), it correctly classified 89.3% of cases. When objective pigmented skin lesion parameters were considered together with their objective changes over 6-12 months, a decisive increase in discrimination capacity was obtained. At SE = SP accuracy was 96.3%. Analysis of the parameters of our model and statistical analysis enabled us to interpret/identify the most significant factors of modification and differentiation of lesions, providing quantitative insights into the diagnosis of equivocal MPSL and demonstrating the utility of objective/numerical follow-up.

The molecular basis of melanomagenesis and the metastatic phenotype.

The last two decades have seen spectacular advances in our understanding of the biology of melanoma and, in particular, have elucidated the mechanisms operative in disease initiation and progression. With respect to the former, the genetics of melanoma and in particular the impact of genetic defects on dysregulation of the cell cycle are key issues in malignant transformation and are a major focus of this review. With respect to the latter, consideration also is given to the acquisition of growth factor autonomy and the capacity for invasion and metastasis from the standpoint of cell adhesion, motility, and matrix digestion. These events have specific morphologic correlates that will be briefly addressed. Where relevant, we will address certain of the modern pharmacogenetic strategies that flow from these novel observations concerning melanoma biology.

Dysplastic pointillist nevus.

BACKGROUND: Three cases of pointillist nevus, which is a distinctive clinical type of benign melanocytic nevus with variegated pigment, have been described in the literature to date. OBSERVATIONS: A 24-year-old man presented with an acquired melanocytic lesion composed of multiple tiny pigmented dots. Dermoscopy revealed multiple brown globules on a reddish skin-colored background, and histologic examination demonstrated architectural disorder with cytologic atypia. Conclusion To the best of our knowledge, we report a case of dysplastic pointillist nevus.

The melanoma-specific XMEL antigen is expressed in dysplastic naevi.

We have previously shown that a novel monoclonal antibody, XMEL, exhibited reactivity with deep primary melanomas while showing no reactivity with other tumours and normal tissue. XMEL was raised against a part of the extracellular domain of Xmrk, a growth factor receptor presumed to mediate melanoma formation in the Xiphophorus fish model. Here we investigate the range of XMEL immunohistochemical reactivity in paraffin sections from human common acquired and dysplastic naevi of both junctional and compound type. The strongest reactivity was observed with the compound dysplastic naevi. We conclude that the antigen recognized by XMEL acts early in the cascade of genetic alterations underlying progression into malignant melanoma. Our results also support the notion that the dysplastic naevus may play a role in progression of human malignant melanoma and may indeed represent the precursor stage.

Atypical mole syndrome: a brief overview for the primary care physician.

Early detection of melanoma and identification of potential markers or precursor lesions can substantially improve survival. Several risk factors have been identified in the pathogenesis of this potentially lethal cancer. Numerous reports in the literature have confirmed a subset of persons with an increased risk of developing melanoma. These patients are identified by a distinctive clinical phenotype depicted by unusually appearing melanocytic nevi (moles) in association with an increased number of total body nevi. They may have a family history of atypical moles or melanoma. In order to facilitate the recognition of such individuals by the non-dermatologist, a brief overview and salient features of the atypical mole syndrome are presented.

El nevo de Clark. Correlación clínica-microscópica-histológica / Clark' nevus. Clinical-microscopical-histological correlation

El nevo de Clark, antes llamado nevo ®displásico¼, es una de las lesiones melanocíticas más controvertidas y difíciles de diagnosticar. Representa también un precursor del melanoma. Con el fin de mejorar nuestro conocimiento acerca de sus características clínicas y de contar con mejores recursos para su diagnóstico, se llevó a cabo un estudio prospectivo en el que se pusieron en juego los criterios clínicos, los criterios al alcance del microscopio de superficie y los criterios histológicos. Se colectaron 70 lesiones pertenecientes a 48 pacientes. Los criterios clínicos de asimetría y pigmento bajo el microscopio de superficie, que en la histología se corresponden con clavas interpapilares más o menos elongadas en las que existen grupos de melanocitos. Es factible diagnosticar melanomas incipientes dentro del nevo de Clark. Se logró detectar a seis portadores del síndrome de los nevos de Clark, tres con melanoma y tres sin esta lesión. Puede concluirse que la identificación y el diagnóstico del nevo de Clark, con o sin melanoma asociado, es susceptible de mejorarse considerablemente con el uso del microcopio de superficie

El nevo de Clark ("displásico") en México / Clark's nevus in Mexican population

Se presenta una casuística de 100 nevos de Clark reunidos a lo largo de 37 meses en 3 diferentes laboratorios de patología, con el fin de conocer cuál es su frecuencia y forma de presentación en una muestra de la población mexicana. Se encuentra que es mucho menos frecuente de lo que se informa en otros países; se presenta en personas de piel blanca y predominantemente en el tronco. Encontramos en un 4 por ciento de su asociación con melanoma maligno, pero aparentemente ninguno de los casos estudiados es portador del síndrome Familiar. Es posible suponer que el gen que determina esta enfermedad no es común en la población mestiza, que es la que predomina en México. Se revisan los conceptos actuales sobre esta lesión y el síndrome que puede constituir.

Normal reactivation of plasmid DNA inactivated by UV irradiation by lymphocytes from individuals with hereditary dysplastic naevus syndrome.

Hereditary dysplastic naevus syndrome (DNS) is a familial disorder characterized by dysplastic naevi and an approximately 85-fold increased risk of developing malignant cutaneous melanoma. Cell lines from individuals with DNS have shown hypermutability following exposure to UV irradiation. The cause of this hypermutability is unknown, and no DNA repair defect has been identified. We have studied the capacity of lymphocytes from individuals with DNS to reactivate the chloramphenicol acetyltransferase gene in transfected plasmids that had been inactivated by UV irradiation. We found no difference in plasmid reactivation between lymphocytes from individuals with DNS and those obtained from healthy control persons matched for sex, age and smoking habits. This finding indicates that DNS is not associated with a significant quantitative defect in nucleotide excision repair of DNA.

Cutaneous response to ultraviolet radiation-induced erythema in patients with type A dysplastic nevi.

The effects of an exposure to 6 times the minimal erythemal dose of ultraviolet radiation (UV) were studied using a visual scale and a tri-stimulus colorimeter in 12 sun-tolerant (skin types III and IV) patients with type A dysplastic nevus syndrome. In such individuals, the melanocytic system would be susceptible to neoplastic transformation induced by sunlight. The cutaneous response to a marked UVB erythema has been shown to identify the high-risk patients prone to light-induced skin cancer. This study indicates that the UVB cutaneous susceptibility of patients with type A dysplastic nevi is not significantly different from control subjects, in terms of erythemal and tanning response.