Background: The accuracy of digital epiluminescence microscopy (D-ELM) as an adjunct to clinical examination for the diagnosis of pigmented skin lesions (PSLs) has seldom been evaluated. Objective: To compare the accuracy of the combined clinical/D-ELM (C/D-ELM) examination with that of the clinical examination alone. Methods: A total of 3,372 PSLs from 1,556 consecutive patients referred to a skin cancer clinic underwent clinical examination and a combined C/D-ELM examination. The reference diagnosis was established using the histology report of known surgical excisions plus a cancer-registry-based follow-up (duration 18 months) of benign C/D-ELM diagnoses. The two diagnostic approaches were compared for sensitivity, predictive value and false-positive rate. Results: The series included 55 melanomas and 43 basal cell carcinomas. About 50% of malignant misdiagnosed cases were identified solely through the cancer registry. The C/D-ELM diagnosis showed a greater sensitivity for melanoma <0.76 mm thick (83 vs. 46% for clinical examination alone; ratio, 1.82) and basal cell carcinoma (79 vs. 49%; ratio, 1.62), a greater predictive value for melanoma (81 vs. 53%; ratio, 1.53) and a reduced total false-positive rate (0.3 vs. 0.9%; ratio, 0.31). Conclusion: D-ELM showed a potential to improve the clinical diagnosis of PSL.

Background: Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease. Methods: A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16 ^CDKN2A , BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16 ^CDKN2A genes. Results: For melanoma susceptibility, investigations at germline level indicated that p16 ^CDKN2A was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16 ^CDKN2A gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16 ^CDKN2A silencing). Conclusion: Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.

Background: Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Methods: Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. Results: Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. Conclusions: Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.

Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).

Cutaneous malignant melanoma is a heterogeneous disease, being the consequence of specific genetic alterations along several molecular pathways. Despite the increased knowledge about the biology and pathogenesis of melanoma, the incidence has grown markedly worldwide, making it extremely important to develop preventive measures. The beneficial role of correct nutrition and of some natural dietary compounds in preventing malignant melanoma has been widely demonstrated. This led to numerous studies investigating the role of several dietary attitudes, patterns, and supplements in the prevention of melanoma, and ongoing research investigates their impact in the clinical management and outcomes of patients diagnosed with the disease. This article is an overview of recent scientific advances regarding specific dietary compounds and their impact on melanoma development and treatment.