Failure of Senescence in the Dysplasia–Melanoma Sequence: Demonstration Using a Tissue Microarray and a Revised Paradigm for Melanoma

In order to correlate changes in morphology to changes in molecular attributes, we constructed a tissue microarray of thin and thick melanomas selected to represent progression from dysplasia to early and advanced melanoma. Hematoxylin and eosin (H&E) staining and immunohistology with antibodies to cyclin D1, p16, Ki67, and Bcl-2 were performed. Observations were interpreted using a revised paradigm for the dysplasia–melanoma sequence in which the early steps of melanomatous growth develop in an accretive fashion similar to the growth of the common acquired nevus. The co-expression of cyclin D1 and p16 persisted from dysplasia to early melanomatous vertical growth. Malignant transformation characterized by absence of p16 and presence of increased cyclin D1 and increased Ki67 and confirmed by clinically documented metastasis occurred during the process of evolving melanomatous vertical growth. The interplay of mutated BRAF, cyclin D1, and p16 with anti-apoptosis and failure of senescence may account for the existence of nevi and dysplastic nevi and for their relationship to melanoma, and may indirectly account for the infrequency of nevi in the lentiginous melanomas that lack mutated BRAF. These observations suggest a need for more detailed study of transformation to malignancy in the various subsets of melanoma.