The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.53 Feskanich et al23 examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.
Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.54 Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.54 Vitamin D receptors are expressed on keratinocytes and melanocytes.55 Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.56 In a mouse model, Ellison et al56 found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.
Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.57-60 Eide et al57 studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).57 An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.58 This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).58 Furthermore, Park et al60 looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al63 performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.
Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.64 It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.64,65
Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.67,68 Human studies have not consistently shown these effects. Vural et al50 investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,42 which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).