Purpose: The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. Patients and Methods: In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. Results: BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. Conclusion: In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

In 1948, Sophie Spitz¹ described a series of “melanomas of childhood” as lesions fulfilling the biologic as well as the histopathologic criteria of malignancy. Indeed, just 1 year later, Arthur C. Allen² included juvenile melanomas in the category of the benign melanocytic lesions. The lesion was originally thought to occur largely in children,^1,2 but it is now well recognized that more than half of Spitz nevus cases are detected in patients older than 14 years,³ and about one fourth of the cases occur in patients older than 30 years.^4-6 A Spitz nevus usually presents as a solitary lesion on the lower extremities or the face.^7,8 In its classic clinical appearance it is pink-red because of the scarcity of melanin; however, tan, brown, and even black pigmented Spitz nevi (PSN) are common as well.