Pathophysiology
Clinical meaning
Melanoma arises from malignant transformation of melanocytes, the pigment-producing cells derived from neural crest cells that reside in the basal layer of the epidermis. Oncogenic mutations โ most commonly BRAF V600E (present in approximately 50% of cutaneous melanomas) โ constitutively activate the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway, driving uncontrolled melanocyte proliferation, resistance to apoptosis, and tumor progression. Melanoma staging follows the American Joint Committee on Cancer (AJCC) TNM system: T classification is determined by Breslow depth (tumor thickness in millimeters measured from the granular layer of the epidermis to the deepest invasive melanoma cell) and the presence or absence of ulceration โ Breslow depth is the single most important prognostic factor for localized disease. N classification assesses regional lymph node involvement via sentinel lymph node biopsy (SLNB), recommended for melanomas greater than 0.8 mm or with ulceration; microsatellite and in-transit metastases also affect nodal staging. M classification identifies distant metastatic disease, with serum LDH as an additional prognostic biomarker in stage IV. Stage groupings range from stage 0 (melanoma in situ) through stage IV (distant metastasis), with 5-year...