malignant melanoma

Malignant melanoma originates from melanocytes, the pigment-producing cells derived from neural crest, typically in the epidermis but also found in mucosa, eyes (uveal melanoma), and meninges. Major risk factors include intense intermittent UV exposure, fair skin (Fitzpatrick I-II), dysplastic nevus syndrome, family history, and immunosuppression. Four major clinical/histologic subtypes: superficial spreading (most common), nodular (most aggressive, vertical growth phase early), lentigo maligna (in chronically sun-damaged skin, elderly), and acral lentiginous (occurs on palms/soles/nail beds, most common subtype in darker-skinned individuals, NOT UV-related). Molecular pathogenesis frequently involves BRAF V600E mutation (~50%), NRAS mutations, and c-KIT mutations (especially in acral/mucosal types). Diagnosis uses the ABCDE mnemonic and confirmed via excisional biopsy with histopathology assessing Breslow depth (thickness in mm, most important prognostic factor) and Clark level (anatomic layer invaded). Ulceration and mitotic rate also affect staging (AJCC TNM). Metastasis occurs via lymphatics (sentinel lymph node biopsy is prognostic) and hematogenously to lung, liver, brain, and bone. Treatment: wide local excision with margins based on Breslow depth, sentinel lymph node biopsy for intermediate-depth tumors. For metastatic/unresectable disease: BRAF/MEK inhibitors (vemurafenib, dabrafenib + trametinib) for BRAF-mutant tumors, immune checkpoint inhibitors (anti-PD-1: pembrolizumab, nivolumab; anti-CTLA-4: ipilimumab) have revolutionized treatment. Melanoma is highly immunogenic, making it a paradigm for immunotherapy research. Key associations: S-100 and HMB-45 are immunohistochemical markers used in diagnosis. High-yield boards fact: melanoma is the deadliest skin cancer despite being less common than basal cell or squamous cell carcinoma, due to its metastatic potential.