Vitamin D (VD) is a prohormone obtained mainly from exposure to ultraviolet B (UVB) radiation and diet (fig. 1).1 VD plays an essential role in bone health and immunity. Furthermore, VD has an antineoplastic effect by regulating cell proliferation, differentiation, migration, and apoptosis (table 1).2,3 VD has been associated with a lower risk of colorectal, breast, and prostate cancer.4 However, this association is controversial in the case of skin cancer (SC).5,6

Figure 1.

Vitamin D metabolism (panel A) and structure of activated vitamin D (calcitriol or 1,25-dihydroxycholecalciferol; C27H44O3) (panel B).

Panel A. Vitamin D metabolism. Vitamin D can be obtained through the diet, or by cutaneous conversion via UVB, which transforms provitamin D3 (synthesized at skin level) into previtamin D3. The first hepatic step converts it to calcidiol or 25-hydroxyvitamin D through hepatic 25-hydroxylase. The second step, which occurs at renal level, converts it into the active metabolite, 1,25-dihydroxycholecalciferol or calcitriol through renal 1-hydroxylase. This mechanism is regulated, among others, by serum levels of calcium, phosphorus, and parathyroid hormone. Calcitriol acts through intracellular vitamin D receptors (VDR), which activate the transcription and translation process of messenger RNA by synthesizing vitamin D-dependent proteins, with their corresponding activity based on the target cell. The excretion of vitamin D through bile is mediated by the activity of renal 24-hydroxylase, which converts calcitriol into calcitroic acid.

Panel B. Structure of activated vitamin D. Note that vitamin D must undergo 2 different hydroxylations to be activated: activation #1 (green circle) occurs in the liver forming 25-hydroxycholecalciferol, or calcidiol; activation #2 (red circle) occurs in the kidney forming 1,25-dihydroxycholecalciferol or calcitriol, which is the active form.

Source: own elaboration and data obtained with permission from Navarro-Triviño et al.5

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Since 2009, 25-hydroxyvitamin D or colecalciferol (25VD) has been quantified to recognize VD levels. According to the National Academy of Medicine (NAM), 25VD levels >20 ng/mL are sufficient for optimal health, while the American Endocrine Society (AES) suggests levels >30 ng/mL; insufficient levels range between 20 ng/mL and 30 ng/mL, and deficient levels are those <20 ng/mL.5 In recent years, VD deficiency and insufficiency have been regarded as having “pandemic proportions.” Up to 70% of the European population may have insufficient levels, even in countries with high sun exposure, such as Mediterranean regions.7 Some authors attribute this phenomenon to reduced sunlight exposure and/or diets low in VD-rich foods.8 However, other authors consider the cutoff of 20 ng/mL or 30 ng/mL too high, which would explain why most of the European population has low VD levels without accompanying symptoms.8 Recently, considering the contradictory evidence on the utility of measuring and supplementing VD, the U.S. Preventive Services Task Force has ill-advised measuring and supplementing VD levels in healthy individuals, something that should only be done in patients at risk of osteoporosis or fractures.9

As previously noted, the relationship between VD and SC is controversial, and the evidence is often contradictory.5,6 In this article, we will be reviewing the association between VD and the development and prognosis of SC.

We conducted a narrative review of currently available literature. Searches were conducted in Spanish and English across Medline and Google Scholar from September through October 2023 using the terms “vitamin D,” “calcitriol,” “colecalciferol,” “skin cancer,” “melanoma,” “squamous cell carcinoma,” “basal cell carcinoma,” “immunotherapy,” “supplementation,” “response to targeted therapy,” and “response to immunotherapy.” The search included articles from January 1st, 2000 through September 1st, 2023. Prospective and retrospective studies with ≥ 10 patients, and systematic reviews (SRs) and meta-analyses (MAs), were included. Articles were screened based on their abstracts and selected based on their relevance. Two authors (MMP and DMC) conducted the search and selected the articles.

The association between VD levels and skin cancer is as controversial as the association between VD supplementation and decreased SC, or its prognosis. Currently, there are no established criteria or recommendations in the main guidelines on the management of SC, and we lack standardized recommendations on the measurement or supplementation of VD in patients at risk or suffering from SC.

Regarding NMSC, numerous studies have reported a direct association between BCC and 25VD levels.6,11,12,14–17,19–21 This relationship has also been reported in cutaneous squamous cell carcinoma.6,12,14,15,17,19–21 This is surprising, given the growing evidence supporting VD supplementation vs other types of cancer, such as colorectal or lung cancer.51 This may possibly be explained by the direct relationship between 25VD levels and sun exposure, a crucial risk factor for the development of NMSC.21

As for the association between melanoma and VD levels, the analyzed studies differ on whether there is a direct, or inverse association, or no association whatsoever. Although most studies report that low levels of VD or VD supplementation could reduce the risk of melanoma,13,17,25–31,33–35,37–41,43–45 we found inconclusive studies,24,32,36 and even some that positively correlate VD levels with the risk of melanoma or worse prognosis.16,20,42

The role of vitamin D receptor (VDR) and melanoma has been studied recently: some studies suggest that certain polymorphisms in the VDR gene could be associated with a higher risk of melanoma.52 A recent retrospective study (703 melanomas) stated that higher levels of VDR expression independently protected vs melanoma-related death, both primary and metastatic. Tumors with high rates of VDR expression showed increased anti-tumor immune activity and reduced proliferative pathways, particularly Wnt-β-catenin signaling. In this study, VD deficiency was associated with lower survival in primary melanoma, especially when VDR levels were low. These findings suggest a causal relationship between VD-VDR signaling and melanoma survival.53

For the relationship between VD levels or supplementation and immunotherapy in melanoma, there are studies showing that low VD levels would correlate with a lower antitumor response to immunotherapy48,54 or even a higher rate of adverse effects.47 Currently, VD supplementation in melanoma patients has a grade B recommendation (probably an effective recommendation), with a level evidence IIb (cohort studies and case-control studies), although current evidence is still scarce.5 As a matter of fact, the National Comprehensive Cancer Network (NCCN) guidelines do not take a stance on this matter,55 nor does the European Society for Medical Oncology (ESMO) guidelines,56 or the 8th edition of the American Joint Committee on Cancer (AJCC).57 New studies are needed to evaluate the value of VD supplementation in melanoma patients.

A recent retrospective study with 663 patients evaluated whether melanoma patients were at increased risk of developing other non-cutaneous cancers after a previous diagnosis of melanoma. A total of 34 non-cutaneous tumors were found, and the multivariate analysis concluded that age older than 60 years (HR, 3.4; 95%CI, 1.5-7.6) and nodular subtype of melanoma (HR, 2.2; 95%CI, 1-4.8) were directly associated with the appearance of other non-cutaneous tumors, but not VD levels.58

Our review has multiple limitations: it is a narrative–not a systematic one–review; many studies included are retrospective and/or use several methodologies to measure variables and outcomes, which complicates data comparison. These factors hinder the generalization of findings and conclusions, underscoring the need for properly designed prospective studies with prolonged follow-up.

The association between VD and SC is a complex one. Adequate or even elevated levels of VD could be associated with a higher risk of NMSC, especially BCC. As for melanoma, the relationship is uncertain, with contradictory results. However, most studies state that higher levels of VD or VD supplementation could reduce the risk of melanoma and are associated with melanomas of better prognosis. Similarly, elevated levels of VD or VD supplementation could be associated with a better antitumor response and fewer adverse effects with melanoma immunotherapy. In conclusion, to date, there is still insufficient evidence to recommend VD supplementation in patients at risk of NMSC or melanoma. However, normal levels of VD could be associated with better therapeutic responses and prognosis in melanoma. Prospective studies of high methodological quality are required to clarify the role of VD and its supplementation in SC and develop clinical guidelines accordingly.

None declared.