Joan-Anton Puig-Butille

Dermoscopic features of melanomas associated with MC1R variants in Spanish CDKN2A mutation carriers

Background  The presence of at least one MC1R gene variant is associated with a reduction in age at melanoma diagnosis in families with CDKN2A mutations.

Correlation among dermoscopy, confocal reflectance microscopy, and histologic features of melanoma and basal cell carcinoma collision tumor.

Reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has been shown to enhance secondary evaluation of melanocytic lesions by allowing for in vivo visualization of microscopic structures and cellular details of the epidermis and superficial dermis at almost histologic resolution. RCM has been used to image various skin conditions, including benign and malignant pigmented lesions, amelanotic melanoma, BCC, and actinic keratosis.

Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population

Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored.

Dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma

The identification of BRAF mutations in melanoma led to the development and implementation of new and effective therapies. Few clinical and histological features have been associated with this mutational status.

Mutational status of naevus-associated melanomas

The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus.

Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom

BackgroundMutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence.MethodsPopulation-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4.ResultsThe prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations.ConclusionsThere is a low probability (<2%) of detecting a germline CDKN2A mutation in people with melanoma except for those with a strong family history of melanoma (≥2 affected relatives, 25%), three or more primary melanomas (29%), or more than one primary melanoma who also have other affected relatives (27%).

Field Cancerisation Improvement with Topical Application of a Film-Forming Medical Device Containing Photolyase and UV Filters in Patients with Actinic Keratosis, a Pilot Study

Background: Actinic keratoses (AKs) are considered to be a ‘field of cancerization’ consisting of a histologically abnormal epithelium adjacent to tumour tissue. Treatment of the ‘field of canceri-zation’ is important for the prevention of neoplasm progression. UV radiation, especially UVB, produce genotoxic photoproducts such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photo-products (6-4PPs) in DNA, being major players in skin cancerization. The potential use of DNA photolyases in skin cancer prevention is increasingly being demonstrated. Topical application of a liposome formulation containing CPD photolyase onto human skin provides protection against UV-B-induced damages. Objectives: To assess the effects of topical application of a medical device (Eryf-AK) containing a DNA-repair enzyme, photolyase, encapsulated in liposomes and UV filters, on cancerization field in actinic keratosis (AK). Methods: 13 AK patients were included. Clinical, dermoscopic, and reflectance confocal microscopy (RCM) assessments, as well as skin biopsies, before and after a 4-week treatment were performed. Patients used Eryf-AK twice daily or only a sunscreen (3:1) with a similar sun protection factor (SPF) for one month. Results: Erythema and scaling improved with Eryf-AK. RCM showed a reduction in scaling, detached corneocytes and polygonal nucleated cells in the stratum corneum (p=0.004, p=0.018, and p=0.021), an improvement of the atypical honeycomb pattern, and a decreased number of round nucleated cells at the spinous granulous layer (p<0.0005 and p=0.019) with Eryf-AK while no improvement was noted with the sunscreen product. The mean RCM score for AK significantly improved from 0.78 to 0.27 (p=0.002) with Eryf-AK. Histological clearance of AK in 4 cases and an improvement with a focal AK associated with inflammation in 3 additional patients were also observed with Eryf-AK. A decrease in p21 expression (p=0.042) and a tendency to decrease PCNA expression was also observed with Eryf-AK (p=0.076). Conclusion: Our results show a benefit from Eryf-AK in the treatment of AK cancerisation field. The improvement was demonstrated clinically, by RCM, histologically and by immunohistochemistry. An improvement was also observed in the two patients with xeroderma pigmentosum, suggesting a benefit from this topical treatment in patients with this rare genetic disorder.

Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF.

Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease.

Association between dermoscopic and reflectance confocal microscopy features of cutaneous melanoma with BRAF mutational status

Melanomas harbouring common genetic mutations might share certain morphological features detectable with dermoscopy and reflectance confocal microscopy. BRAF mutational status is crucial for the management of metastatic melanoma.

Association Between Confocal Morphologic Classification and Clinical Phenotypes of Multiple Primary and Familial Melanomas.

Importance The improved knowledge of clinical, morphologic, and epidemiologic heterogeneity of melanoma in the context of multiple primary and familial melanomas may improve prevention, diagnosis, and prognosis of melanoma. Objective To characterize reflectance confocal microscopy (RCM) morphologic patterns of melanomas in multiple primary and familial melanomas. Design, Setting, and Participants In this cross-sectional, retrospective study, patients in a hospital-based referral center were recruited from March 1, 2010, through August 31, 2013; data analysis was conducted from September 1, 2013, through May 31, 2014. Consecutive primary melanomas, documented by dermoscopic and confocal examination, from multiple primary and familial melanomas with known CDKN2A mutational status were studied. Main Outcomes and Measures Epidemiologic, genetic, dermoscopic, and histologic data were evaluated according to an RCM morphologic classification: dendritic cell, round cell, dermal nest, combined, and nonclassifiable types. Results Fifty-seven melanomas from 50 patients (28 women [56%] and 49 white patients [98%]) were included: 23 dendritic cell (40%), 21 round cell (37%), 2 dermal nests (4%), 2 combined (4%), and 9 nonclassifiable (16%). The median (SD) age of the participants was 53.0 (16.9) years (interquartile range, 41.8-71.2 years), and the median (SD) age at the first melanoma was 46.0 (17.1) years (interquartile range, 35.8-61.5 years). Dendritic cell melanoma was characterized by older age at diagnosis, phototypes 2 and 3, more intense solar exposure, and moderate to severe solar lentigines; it was the most prevalent confocal type in facial lesions and was associated with the lentigo maligna histologic subtype. Round cell melanomas were identified more often in the familial context and in individuals with phototype 1 skin types; RCM features, such as junctional thickening, dense dermal nests, and nucleated cells within papillary dermis, were more frequently found in this subtype. Dermal nest and combined melanoma were associated with the absence of pigmented network on dermoscopy and thicker tumors on histologic analysis. Nonclassifiable type was associated, by RCM, with the absence of pagetoid cells on confocal examination and lower frequency of marked atypia on melanocytes in the basal cell layer; it presented with lower ABCD Total Dermoscopy Scores and RCM scores compared with the other types. CDKN2A mutation carriers may develop any RCM type of melanoma. Conclusions and Relevance Different routes to develop melanoma can be identified according to RCM morphologic classification, with dendritic cell melanomas being associated with chronic sun damage and round cell melanoma with early age at onset and phototype 1 in the context of multiple primary and familial melanomas. The morphologic expression of melanomas via dermoscopy and confocal examination varies according to differences in tumor stage and biological behavior.