Pathophysiology
Clinical meaning
Melanoma arises from malignant transformation of melanocytes, pigment-producing cells in the basal layer of the epidermis. UV radiation (both UVA and UVB) causes direct DNA damage through cyclobutane pyrimidine dimer formation and indirect damage through reactive oxygen species. Key genetic mutations include BRAF V600E (present in ~50% of melanomas), NRAS, and loss of CDKN2A tumor suppressor. Unlike other skin cancers, melanoma has high metastatic potential even from thin primary lesions, spreading through lymphatic and hematologic routes to lungs, liver, brain, and bone. Breslow depth (tumor thickness in millimeters) is the strongest prognostic factor. Basal cell carcinoma (BCC), the most common skin cancer, arises from aberrant hedgehog signaling pathway activation and rarely metastasizes. Squamous cell carcinoma (SCC) carries intermediate metastatic risk.