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Background: Halo nevi (HN) are benign melanocytic nevi surrounded by a depigmented area (halo). This study aims to evaluate the dermoscopic features of HN and their changes during digital dermoscopic follow-up and to investigate the frequency of the halo phenomenon in a series of melanomas. Observations: In a retrospective study, digital dermoscopic images of HN from patients who attended the Pigmented Skin Lesions Clinic of the Department of Dermatology, Medical University of Graz, between October 1, 1997, and March 31, 2004, were reviewed and classified by dermoscopic morphologic criteria. For HN that were followed up with digital dermoscopy, the percentages of changes in the size of the nevus and halo components were calculated. In addition, digital dermoscopic images of histopathologically confirmed melanomas obtained from the same database were reviewed for the presence of an encircling halolike depigmentation. We classified 138 HN in 87 patients (mean age, 22.4 years). The most common dermoscopic structures were the globular and/or homogeneous patterns in more than 80% of HN. Follow-up of 33 HN revealed considerable size reduction of the nevus component, but this was not associated with significant structural changes. Of a total of 475 melanomas, only 2 revealed an encircling halo, but both displayed clear-cut melanoma-specific patterns according to dermoscopy. Conclusions: Halo nevi exhibit the characteristic dermoscopic features of benign melanocytic nevi, represented by globular and/or homogeneous patterns that are typically observed in children and young adults. Halo nevi reveal considerable changes of area over time during digital dermoscopic follow-up, albeit their structural patterns remain unchanged. For this reason and because melanoma with halolike depigmentation, despite being rare, additionally exhibits melanoma-specific dermoscopic criteria, the role of digital dermoscopic follow-up in the diagnosis of HN is insignificant.

Early melanomas in patients with two MC1R red hair variants may be difficult to diagnose definitively by dermoscopy because, in our limited experience, they show fewer colours and structures and have a lower TDS. In such melanomas, subtle atypical vessels and other changes detected by digital image follow up may be useful to confirm the diagnosis of melanoma. An integrated approach including clinical history and dermoscopic data (also considering additional information, such as the presence of atypical vessels) should be utilized in evaluating these high-risk patients. Further studies are necessary to confirm our suggestion.

The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had 2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. ' 2007 Wiley-Liss, Inc.Key words: melanoma; CDKN2A; MC1R; G101W Germline mutations within the coding region of the CDKN2A gene (9p21) have been observed in affected members of melanoma-prone families. 1,2 G101W is one of the most common CDKN2A missense mutations identified to date. It is the most common mutation observed in Italy, Spain, and France. G101W also has a high occurrence in the United States. Similar to most of the other frequent recurrent CDKN2A mutations, G101W appears to have resulted from a single mutational event. Previous evaluation of 20 melanoma-prone families with G101W mutations from France, Italy, and the United States provided compelling evidence for a single genetic origin for G101W; the mutation was estimated to have originated about 97 generations ago (1 LODunit support interval 70-133 generations). 3 Although CDKN2A mutations confer substantial risk for melanoma, not all carriers of mutations develop melanoma. Other host/ clinical, environmental, and genetic factors also modulate risk. It is well known that the incidence of melanoma varies worldwide and even in the context of familial melanoma, penetrance of CDKN2A mutations differs between Europe and the United States. 4 These differences could be related to different genetic backgrounds or to variation in host/clinical characteristics and/or sun behavior. Pr...

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%).Electronic supplementary materialThe online version of this article (doi:10.1186/1897-4287-12-20) contains supplementary material, which is available to authorized users.

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Background: The ‘gold standard’ for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability. Objectives: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions. Methods: This study used the database of MelaFind®, a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics. Results: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non-melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients ≥40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76). Limitations: The data were limited by the inclusion/exclusion criteria of the MelaFind® study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians. Conclusions: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current ‘gold standard’ is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients.