Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content +++ Incidence ++ 91,270 estimated new cases of malignant melanoma in the United States in 2018. 9,320 estimated deaths from melanoma in the United States in 2018. 20% to 30% of melanomas are located in the head and neck region. Alarming increases in incidence (5% per year) and mortality (2% per year). Highest incidence in areas with high sun-exposure and populations with fair skin (eg, Australia). +++ Risk Factors ++ Sun-exposure Frequent, intermittent exposure to intense sunlight appears to be the highest risk factor. Ultraviolet light causes a photochemical reaction in DNA, leading to the formation of pyrimidine (thymine and cytosine) dimers. Ultraviolet B (290-310 nm). More potent cause of DNA damage Ultraviolet A (320-400 nm). More abundant in natural sunlight than UVB Can also cause oxidative DNA damage Visible light may also contribute to the pathogenesis. Sunscreen is protective. Should be labeled “broad spectrum,” that is, protection against both UVA and UVB light Should be at least sun protection factor (SPF) 15, and preferably 30 or greater Tanning beds Produce mostly UVA radiation, but some models increase UVB fraction. Evidence supports an increased risk of malignant melanoma with use of tanning beds. Fair skin (Fitzpatrick type I), blond or red hair Family history of melanoma Freckling of the upper back History of three or more blistering sunburns before the age of 20 years History of three or more years at an outdoor job as a teenager Presence of actinic keratoses +++ Hereditary Syndromes ++ Familial melanoma/dysplastic nevus syndrome Multiple atypical moles Lifetime risk of melanoma approaches 100% Genetic defect = CDKN2A gene at chromosome 9p21, which encodes p16(INK4a) and p14ARF Xeroderma pigmentosa Autosomal recessive 1000-fold increased risk of skin cancer, often before the age of 10 Early onset freckling (before 2 years of age) Caused by a heterogeneous group of defects in the nucleotide excision repair pathway → cannot appropriately repair the constant DNA damage (specifically, thymine dimers) caused by UV exposure +++ Molecular Biology of Sporadic Melanoma ++ Ras-Raf-Mek-Erk pathway Important pathway in regulation of cell proliferation. Activating NRAS mutations are the most common Ras family mutations. Activating BRAF mutations are found in 50% to 70% of cutaneous melanomas. Several BRAF inhibitors and MEK inhibitors approved by the Food and Drug Administration (FDA) to treat malignant melanomas with activating mutations in BRAF. c-kit Tyrosine kinase receptor for stem cell factor. Activating mutations and amplifications cause constitutive activation of growth and proliferation pathways. More commonly found in melanoma unrelated to sun-exposure, namely, acral or mucosal melanoma. Imatinib: A combined Abelson murine leukemia viral oncogene (ABL), c-kit, platelet-derived growth factor receptor (PDGFR) inhibitor, very successful in treating GI stromal tumors, and chronic myelogenous leukemias. Imatinib or other kit inhibitors may have activity in melanomas with activating c-kit mutations (more common in acral lentiginous and mucosal melanomas). Mutation burden and neo-antigens Based on The Cancer Genome Atlas ... Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. Please click ‘Continue’ to continue the affiliation switch, otherwise click ‘Cancel’ to cancel signing in. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products. Subscribe: Institutional or Individual Sign In Username Error: Please enter User Name Password Error: Please enter Password Forgot Password? Forgot Username? Sign in via OpenAthens Sign in via Shibboleth You already have access! Please proceed to your institution's subscription. Create a free a profile for additional features.