Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations.

Mutations in N-ras exon 2 codon 61 were studied in formalin-fixed human melanoma metastases. DNA fragments including codon 61 were amplified by polymerase chain reaction (PCR) and mutational analysis was performed by oligonucleotide hybridization (ODN), allele specific PCR and PCR combined with single strand conformation polymorphism analysis (SSCP). Thirty metastases from 25 patients with 'spontaneous' cutaneous melanoma were compared with 35 metastases from 17 patients with 'hereditary' cutaneous melanoma. The frequency of mutations as measured by PCR/ODN was significantly higher in patients with hereditary melanoma (mutations in 24% versus 59%, p < 0.05). The most frequent mutations were C/A transversions to lysine (AAA). The occurrence of lysine mutations was, in addition, studied by allele specific polymerase chain reaction. Again, the mutation frequency was significantly higher in metastases from patients with hereditary melanoma. PCR/SSCP finally enabled the isolation of lysine mutant alleles and nucleotide sequence analysis which confirmed the presence of the mutated codon 61. The relatively higher frequency of N-ras mutations in tumours from patients with hereditary melanoma may be related to the hypermutability described in hereditary melanoma and dysplastic naevus syndrome. The results support an involvement of N-ras mutations in the molecular pathogenesis of melanoma.

Morphometric, DNA, and proliferating cell nuclear antigen measurements in benign melanocytic lesions and cutaneous malignant melanoma.

Morphometric, DNA, and proliferating cell nuclear antigen (PCNA) measurements were taken of benign melanocytic tumors and malignant melanomas. Significant differences between lesion groups according to Krushell-Wallis analysis were found in terms of mean nuclear area, coefficient of variation (cv) of nuclear area, cv of nuclear shape nuclear contour index (NCI), mean and cv of nucleolar area, DNA 2.5 c and 5 c exceeding rates, and PCNA positivity. A logistic regression analysis with respect to banal nevi versus primary malignant melanoma showed that the cv of nuclear area and the DNA 2.5 c exceeding rate were significant independent predictors. Nuclear polymorphism, i.e., the cv of nuclear shape NCI, was larger in metastasizing primary melanomas than in thin nonmetastasizing primary melanomas. PCNA positivity was occasionally increased in keratinocytes adjacent to nevi or melanomas. Larger values for nuclear area, DNA aneuploidy, and PCNA positivity were found in thick malignant melanomas and melanoma metastases than in benign melanocytic lesions and thin malignant melanomas. Morphometry, DNA content, and PCNA positivity thus seem to reflect different stages in tumor progression of malignant melanoma.

The accuracy of skin self-examination for atypical nevi.

We conducted a validation study to assess laypersons' ability to self-report atypical nevi. Study subjects were drawn from a large population-based cohort of middle-aged Swedish women who had responded to a previous health survey. The health survey questionnaire included color photographs of atypical nevi. Respondents were asked to examine their lower extremities for similar lesions. We invited 500 survey respondents to participate in a physician-conducted skin examination; 400 (80%) subjects agreed. We compared the results of skin self-examination for atypical nevi to the results of the physician-conducted skin examination. Using methods developed for this study, we estimated sensitivity as 29% and specificity as 85%. Positive predictive value was 20%; negative predictive value was 90%. We estimated that 12% of Swedish women have atypical nevi on the lower extremities. Although these findings suggest poor accuracy of skin self-examination for atypical nevi, our results may have been adversely affected by limiting self-examination to the legs and by the severity of atypical nevi shown in the comparison photographs used by survey respondents.