Skin Cancer Prevention and Early Detection: A Comprehensive Evidence-Based Review

Skin cancer is the most commonly diagnosed cancer in the United States and is estimated to be the most common cancer in Europe, though exact nonmelanoma skin cancer (NMSC) figures remain unavailable due to inconsistent cancer registry reporting. Approximately 5.4 million keratinocyte carcinomas and over 100,000 invasive melanomas are diagnosed annually in the US alone, with an estimated 92% of melanoma cases attributable to ultraviolet (UV) radiation exposure. This review synthesizes the current evidence for skin cancer prevention and early detection across three domains: primary prevention, chemoprevention, and early detection strategies. For primary prevention, daily broad-spectrum sunscreen (SPF >=30) remains the cornerstone intervention, supported by randomized controlled trial (RCT) evidence demonstrating a 73% reduction in invasive melanoma (HR 0.27; 95% CI 0.08-0.97) and a 39% reduction in squamous cell carcinoma (SCC) incidence. Protective clothing, shade-seeking behavior, and avoidance of indoor tanning are also recommended by the AAD, USPSTF, NCCN, and ASCO. For chemoprevention, the strongest evidence supports nicotinamide (vitamin B3) 500 mg twice daily, which reduced new NMSCs by 23% (P = 0.02) in a phase 3 RCT of high-risk immunocompetent patients, and topical 5-fluorouracil, which reduced cSCC risk by 75% at 1 year. Topical DNA repair enzymes (T4 endonuclease V) have demonstrated efficacy in [xeroderma pigmentosum](/rare-disease/xeroderma-pigmentosum) patients, and oral acitretin reduces keratinocyte carcinomas by 56% in organ transplant recipients. Polypodium leucotomos extract shows promise as a photoprotective adjunct but lacks cancer endpoint data. Omega-3 fatty acids, vitamin D3, and NSAIDs have suggestive preclinical or observational data but lack RCT evidence of skin cancer reduction. Topical tretinoin failed to reduce keratinocyte carcinoma incidence in the largest RCT (VATTC, n = 1,131), though it may contribute to combination field therapy regimens - a distinction that reflects the fundamental difference between clearing existing dysplastic clones (field therapy) and preventing de novo carcinogenesis (chemoprevention). For early detection, the 2023 USPSTF found insufficient evidence to recommend universal visual skin cancer screening, though risk-stratified screening is widely endorsed. The ABCDE mnemonic and the "ugly duckling" sign remain the most widely used clinical tools for identifying suspicious melanocytic lesions. Dermoscopy performed by trained clinicians increases diagnostic sensitivity for melanoma from 76% to 92% and specificity from 75% to 95%. Total body photography with sequential digital dermoscopy is associated with detection of thinner melanomas (0.47-0.55 mm vs. 0.60-1.8 mm) and lower rates of invasive disease, particularly in high-risk patients. Artificial intelligence-assisted diagnostic tools show promise but require further validation. Patient education in skin self-examination, teledermatology for rapid triage, and same-day or next-day lesion-directed appointments represent practical strategies to reduce diagnostic delay. Germany's nationwide population-based screening program has not demonstrated a clear melanoma mortality benefit at the population level, reinforcing the value of targeted, risk-adapted screening approaches over universal screening.