24.21D ). During this stage, melanoma cells do not have the capacity to invade and metastasize. With time, a vertical growth phase supervenes, in which the tumor grows downward into the deeper dermal layers as an expansile mass lacking cellular maturation (
Fig. 24.21E ). This event often is heralded by the development of a nodule in a previously flat lesion and correlates with the emergence of metastatic  potential.
DNA sequencing of familial and sporadic cases, including cases that appear to have arisen from benign nevi, has provided important insights into the molecular pathogenesis of melanoma (
Fig. 24.22 ). The initiating event appears to be an activating mutation in BRAF or (less commonly) RAS. In the vast majority of cases, this produces only a benign nevus unless other mutations are superimposed. Sequencing of nevi with “atypical” morphologic features suggestive of melanoma as well as melanomas in the radial phase of growth (melanoma in situ) has shown that they commonly harbor mutations that activate the expression of telomerase, which is proposed to serve as an antidote to senescence (the usual fate of benign nevi). With additional mutations or epigenetic aberrations that lead to loss of
Fig. 24.21 Possible steps in the development of melanoma. (A) Normal skin shows only scattered melanocytes. (B) Lentiginous melanocytic hyperplasia. (C) Lentiginous compound nevus with abnormal architecture and cytologic features (dysplastic nevus). (D) Early or radial growth phase melanoma (large dark cells in epidermis) arising in a nevus. (E) Melanoma in vertical growth phase with metastatic potential. Note that no melanocytic nevus precursor is identified in most cases of melanoma. They are believed to arise de novo, perhaps all using the same pathway.
Telomerase Loss of Loss of activation p16 p53, PTEN
Melanoma, Melanoma, (e.g., nevus) atypia
Fig. 24.22 Molecularevolutionofcutaneousmelanoma.Themostimportantdrivermutationsandtheoverallmutationalburden(pointmutationsandgenomiccopy-numbervariations)atvarioushistologicphasesofmelanocyticlesionprogressionareindicated.Notethatasthetumormetastasizestointernalsites,UVlight–inducedDNAdamageleadingtopointsubstitutionsceases,andcopynumberchangesrelatedtoaneuploidyincrease.
CDNK2A and its encoded tumor suppressor p16, the tumor shifts to the invasive vertical phase of growth. Throughout this cutaneous phase of tumor evolution, exposure to UV light adds to the mutational burden and increases the chances of tumor progression. Finally, with additional mutations in genes such as tumor suppressors TP53 and PTEN, the tumor acquires the capacity for metastasis. This phase is marked by the appearance of aneuploidy and genomic copy number alterations, which add to the genetic heterogeneity of the evolving tumor.
By contrast, the less common melanomas that arise in non–sun-exposed acral and mucosal sites follow different molecular courses. The most common initiating mutation in these tumors is a gain-of-function mutation in the KIT receptor tyrosine kinase. Similarly, melanomas arising the uvea of the eye also have a distinct set of driver gene mutations, most notably mutually exclusive mutations that activate the GTP-binding proteins GNAQ or GNA11.