Pathogenesis

  • ~90% of melanomas are sporadic
  • MAPK pathway is activated in most → BRAF, MEK, and ERK kinase activity → cell growth, proliferation, and migration
    • B-RAF mutations (~60%), associated with earlier age, non-chronically sun damaged, 80% of mutation = V600E
    • N-RAS (~20%) mutations, late age, congenital melanocytic nevi (CMN)
    • Note: CDKN2A mutation seen in FAMMM syndrome activate MAPK
  • cKIT mutation: Mucosal ~40%, acral ~35%, chronic sun damaged skin ~25-30% risk. Activation of cKIT receptor leads to signaling downstream MAPK and/or PI3K.
  • GNAQ, GNA11 mutations: ~90% uveal melanoma, also seen in nevus of Ota (~15% uveal melanoma), blue nevi ± malignant (65-75%), and Sturge-Weber
  • MITF: Amplified in 20% of melanomas, important in melanocyte survival and function, worse prognosis. Germline mutation increases risk of multiple nevi % melanoma.
  • Other genes and pathways of importance include genes seen in familial melanomas

  • Antigens recognized by CD8+ T cell or Ab:
  1. Mutant tumor antigens (e.g. mutant p16);
  2. Common tumor-specific antigens of cancer / testis family (e.g. MAGE-1, MAGE-3, NY-ESO-1);
  3. Cell type-specific differentiation antigens (e.g. tyrosinase, PMEL17 / gp100, MART-1 / Melan-A)
  • Melanoma specific CD8+ T cell activation → eliminate tumor cells
  • Melanoma cells upregulate CTLA-4 and PD-1, PD-L1 → reduce T-cell activation, apoptosis of tumor antigen-specific T cells, inhibit regulatory T cell apoptosis
  • Advanced melanoma: loss of tumor-specific antigens, loss of MHC class I molecules, release of IL-10 and TGF-β

  • Benign melanocytic nevi
  • Atypical nevi
  • Primary malignant melanoma – RADIAL growth = E-cadherin
  • Secondary malignant melanoma – VERTICAL growth = N-cadherin (loss of E-cadherin)
  • Metastatic malignant melanoma

Only 30% melanoma arise from precursor nevi