Abstract
Melanoma accounts for 1.7% of global cancer diagnoses and is the fifth most common cancer in the US. Melanoma incidence is rising in developed, predominantly fair-skinned countries, growing over 320% in the US since 1975. However, US mortality has fallen almost 30% over the past decade with the approval of 10 new targeted or immunotherapy agents since 2011. Mutations in the signaling-protein BRAF, present in half of cases, are targeted with oral BRAF/MEK inhibitor combinations, while checkpoint inhibitors are used to restore immunosurveillance likely inactivated by UV radiation. Although the overall 5-year survival has risen to 93.3% in the US, survival for stage IV disease remains only 29.8%. Melanoma is most common in white, older men, with an average age of diagnosis of 65. Outdoor UV exposure without protection is the main risk factor, although indoor tanning beds, immunosuppression, family history and rare congenital diseases, moles, and obesity contribute to the disease. Primary prevention initiatives in Australia implemented since 1988, such as education on sun-protection, have increased sun-screen usage and curbed melanoma incidence, which peaked in Australia in 2005. In the US, melanoma incidence is not projected to peak until 2022–2026. Fewer than 40% of Americans report practicing adequate protection (sun avoidance from 10 a.m.–4 p.m. and regular application of broad-spectrum sunscreen with an SPF > 30). A 2-4-fold return on investment is predicted for a US sun-protection education initiative. Lesion-directed skin screening programs, especially for those at risk, have also cost-efficiently reduced melanoma mortality.
Highlights
Melanoma is a malignancy of melanocytes, melanin producing cells in the basal layer of the epidermis
Acral lentiginous melanoma, which arises from the glabrous skin of the palms, soles, and nailbeds is more likely to arise in darker-skinned ethnicities
Mortality rates have fallen thanks to advances in targeted and immunotherapies, though those diagnosed with stage IV disease still have a dismal survival rate
Summary
Melanoma is a malignancy of melanocytes, melanin (pigment) producing cells in the basal layer of the epidermis. The incidence of melanoma has increased in developed, predominantly fair-skinned countries over the past decades [4]. The incidence of melanoma has increased in developed, predominantly fair-skin2noefd countries over the past decades [4]. UV exposure is the primary risk factor for melanoma of the skin, though this effect is heavily modulated by genetics, melanin, and UV wavelengths. The location of UV-induced mutations, i.e., cancer’s molecular profile, varies highly with melanoma subtype, prognosis, and response to treatment. BRAF is more commonly mutated in younger patients with more nevi and sun exposure and those with superficial-spreading melanoma (SSM) (up to 50%) and is targeted with BRAF + MEK small molecular inhibitors as a front-line treatment [16,17,18]. While eumelanin’s scattering of UV rays protects against DNA damage, it decreases cutaneous vitamin D3 production, which explains why homo sapiens who left Africa for higher latitudes (with less UV exposure) were selected for phaeomelanin and lighter skin [11,21,22]
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