Aim: A debate in scientific communities currently exists between balancing the positive and negative effects of solar UV exposure. On one side, solar UV represents a significant environmental risk factor for cutaneous carcinogenesis, requiring stringent sun protection practices. On the opposing side, it is the principal method of vitamin D synthesis, with deficiency being increasingly associated with several independent diseases, including internal malignancies. For dermatologists, this issue presents a particular conundrum, which is further complicated by a hypothesised role for vitamin D in skin cancer protection. Our aim was to perform a comprehensive search, critical appraisal and summary of all current literature regarding the role of vitamin D in melanoma in order to better inform this discussion and identify current gaps in knowledge.
Method: A literature search of the following medical databases (OVID, PubMed, Medline, Cochrane and Embase) to identify current literature (2012–2017) pertaining to vitamin D and melanoma was conducted using the search terms ´vitamin D, vitamins, cholecalciferol, ergocalciferol, vitamin D3, sunshine vitamin, 1,25(OH)2D3, 25(OH)D, calcitriol, melanoma, skin cancer, cutaneous carcinogenesis, photocarcinogenesis, melanocytes.
Results: In vitro experiments have demonstrated that 1,25(OH)2D3 stimulates melanocyte maturation, differentiation, upregulates VDR expression and is anti-proliferative. Additionally, it has been implicated in altering the melanoma micro-environment through angiogenic effects and interfering with melanoma-stromal interactions, which have significant bearing on melanoma metastases. This reflects the multimodal tumour suppressor activities of vitamin D metabolites, similarly observed with other cell types. In keeping with this proposed role, genetic studies into VDR polymorphisms and melanoma risk have identified Bsml and Fok1 as predominant at risk genotypes. However, the association between vitamin D on melanoma risk and outcomes has not been as clearly evidenced in clinical studies, which have yielded conflicting results due to heterogeneity and limitations in study design. Despite this, one vital reproducible association across several studies has been the strong inverse relationship between low 1,25(OH)2D3 levels and Breslow thickness, a strong prognostic factor for melanoma survival. Although no direct causality has been established, this important finding indicates the essential need for randomized control studies to investigate the association further.
Conclusion: Impressively, several tumour suppressor mechanisms have been suggested and successfully demonstrated in vitro. However, bridging the gap between experimental studies and clinical trials has proved difficult. The majority of studies we evaluated failed to show a protective effect of higher 25(OH)D levels on cutaneous melanoma incidence. Nevertheless, a critical and reproducible finding by several independent studies has shown that 25(OH)D blood levels appear to be inversely associated with Breslow thickness. The exact clinical implications are yet unclear. Trials assessing whether 25(OH)D represents a prognostic marker or if higher levels improve melanoma outcomes, have yielded inconsistent results. Adequately powered interventional studies are urgently required. At present most dermatology guidelines recommend testing skin cancer patients for vitamin D deficiency and treating appropriately. Optimal levels of vitamin D have yet to be established.