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Malignant Melanoma: Vitamin D Status as a Risk and Prognostic Factor – Meta-analyses and Systematic Review

SINAN HADDAD, JULIUS JOHANNES WEISE, STEFAN WAGENPFEIL, THOMAS VOGT and JOERG REICHRATH
Anticancer Research January 2025, 45 (1) 27-37; DOI: https://doi.org/10.21873/anticanres.17390

Abstract

Background/Aim: Solar ultraviolet radiation represents the most important environmental risk factor for skin cancer. However, vitamin D synthesis from sun exposure has been reported to exert anti-carcinogenic effects on melanocytes in vitro. This justifies the ongoing debate whether vitamin D status can be considered a risk and prognostic for primary cutaneous malignant melanoma. The aim of this study was to assess the relevance of the vitamin D status for melanoma risk and prognosis. Materials and Methods: A systematic review and meta-analyses were conducted using Medline (via PubMed) and ISI (Web of Science). Results: Nine meta-analyses were conducted to assess the association between vitamin D status and melanoma risk, as well as prognosis (Breslow thickness, mitotic rate, tumor stage, and ulceration status). Patients with melanoma had significantly lower mean 25(OH)D levels compared to healthy controls, and there was a non-significant trend toward an increased melanoma risk in patients with vitamin D deficiency (≤20 vs. >20 ng/ml). Subgroup analyses of Southern European studies showed significant results. Low serum levels were significantly associated with greater Breslow thickness, the presence of mitoses, and ulcerated primary tumors, but not with higher tumor stage. We observed significantly increased risks for thicker tumors, mitotic tumors, and higher tumor stages in vitamin D-deficient patients. Conclusion: This study demonstrates an association between low vitamin D status and both increased melanoma risk and worsened prognosis, further contributing to the growing body of evidence supporting the tumor-protective role of vitamin D.

Key Words:

Solar UV radiation represents the most important environmental risk factor for skin cancer, and it has been shown to cause various forms of damage, including oxidative stress, cell cycle alterations, base modifications, strand breaks, and the formation of mutagenic photoproducts (1-4). While chronic UV exposure rather contributes to the development of non-melanoma skin cancer, significant findings indicate an increased risk of melanoma associated with intermittent exposure and sunburn (3, 5-7). UV exposure is also responsible for the development of UV-induced nevi, which also correlate with increased melanoma risk. Approximately 60-70% of all cutaneous melanoma are estimated to be caused by UV radiation (8). However, UV-B-induced cutaneous vitamin D synthesis has been reported to exert anti-carcinogenic (anti-proliferative, anti-angiogenic and pro-apoptotic) effects on melanocytes and keratinocytes in vitro (9-12). Vitamin D has also been associated with a lower risk of colorectal, breast, bladder, and prostate cancer, while suppressing proliferation and promoting the differentiation of melanoma cells (13, 14). This anti-tumor effect is mediated not only by the vitamin D receptor (VDR), that has been described as a tumor suppressor in the skin, but also by other nuclear receptors, including peroxisome-proliferator-activated receptor (PPAR) (15). Research findings have shown that vitamin D is involved in different cancer signaling pathways, e.g., Hedgehog signaling pathway or enzymes involved in nucleotide excision repair (16). Vitamin D enhances the activity of superoxide dismutase, the expression of GADD45 mRNA and p53, which are important components of the mechanisms protecting against DNA damage (11). Vitamin D metabolites have been shown to inhibit proliferation and induce differentiation of melanoma cells (11, 17). Tumor invasion and angiogenesis are suppressed via an IL-8-regulated pathway, through the inhibition of endothelial cell proliferation and down-regulation of VEGF (12). Although malignant melanoma accounts for only 1% of all skin cancer cases after basal cell carcinoma and squamous cell carcinoma, it is responsible for 90% of deaths caused by skin cancer (18). Early diagnosis is particularly important, as the 5-year survival rate drops dramatically to approximately 25% after metastasis (13). Thus, identifying potential risk and prognostic factors is of utmost importance. With these meta-analyses, we provide evidence to enhance our understanding of the UVB-vitamin-D-cancer-hypothesis proposed by the Garland brothers, which suggests higher cancer incidence and mortality with decreased vitamin D serum levels from sun exposure (19).

Materials and Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a transparent and comprehensive synthesis of the available evidence. This ensured that all relevant aspects, such as study selection and appraisal, data extraction, statistical analysis, and risk of bias assessment, were conducted in accordance with the guidelines and were comprehensively documented (20).

Search strategy for study identification. The systematic literature search in Medline (via PubMed) and ISI (Web of Science) databases was completed on December 31, 2022. The databases were searched using the following English search terms and keywords or combinations thereof (so-called MeSH terms): “Vitamin D”, “Vitamin D3, “25(OH)D3”, “25-Hydroxyvitamin D”, “25-Hydroxycholecalciferol”, “Vitamin D serum level”, “malignant melanoma”, “skin cancer”, “melanoma skin cancer”, “melanoma prognosis”, “melanoma mitotic rate”, “melanoma risk”, “skin cancer risk”, “Breslow thickness”, “Breslow’s depth”, “tumor thickness”, “melanoma tumor thickness”, “melanoma stage”, “melanoma tumor stage”, “melanoma ulceration”. In case of any questions, Professor Dr. Jörg Reichrath was consulted. If a study appeared suitable for the meta-analysis, the full text was read.

Selection and exclusion criteria. Studies were included based on the following selection criteria: languages German or English, study design (Randomized controlled trials, cohort studies, case-control studies), objective (the association between vitamin D status/vitamin D deficiency/vitamin D serum levels and the incidence and prognosis of malignant melanoma), cutoff value for vitamin D deficiency (≤20 ng/ml), effect measure [odds ratio (OR), relative risk (RR), standardized mean difference]. If necessary, the specified effect measure was converted to the one required for this meta-analysis or it was calculated from the raw data of the study. Studies were excluded based on the following criteria: Publications in a language other than German and English, Case reports, Review articles, animal studies. We preferred prospective and retrospective cohort and case-control observational studies. Studies without an identifiable control group were excluded. Studies with Vitamin D measurements >12 months after diagnosis were excluded. Studies without precise definition of vitamin D deficiency at <20 ng/ml were not evaluated, as were studies with arbitrarily defined vitamin D value intervals. The collection of data on prognostic factors (mitotic rate, tumor stage, ulceration status, and vertical tumor thickness) had to be precise and transparently reported.

Data extraction. The data from the eligible studies were merged into multiple Excel tables, which included all relevant parameters for the meta-analyses. In the absence of data, the authors of the respective study were contacted, and a request was made to provide the necessary information.

Risk of bias. We used the Newcastle-Ottawa Scale (NOS) as a tool for assessing study quality in meta-analyses (20). The included studies were further examined for their level of evidence according to the Oxford Centre for Evidence-Based Medicine (OCEBM) (21).

Statistical methods. The pooled odds ratio was used as the overall effect estimator along with respective 95% confidence interval (CI). Due to the rare occurrence of malignant melanoma (and cancer in general), the pooled odds ratio approximates the risk ratio (RR) under the “rare disease assumption” by Cornfield (OR≈RR) (22, 23). Thus, in this meta-analysis, it serves as a relative risk estimator. For the analysis of the association between melanoma risk and vitamin D status, unadjusted “crude” odds ratios were utilized. Similarly, the analysis concerning melanoma prognosis and vitamin D deficiency was conducted. The analysis for melanoma risk compared mean vitamin D values between melanoma patients and healthy controls. The analysis for melanoma prognosis compared the means of respective groups. This allowed the calculation of the standardized mean difference (SMD) as the overall effect estimator along with respective 95%CIs. The means for the analysis of melanoma risk were unadjusted, and mostly unadjusted for prognosis, except for two studies (24). However, to obtain a clinically relevant vitamin D value (in ng/ml) and to enhance understanding of the meta-analysis results, we performed a back-transformation of SMD values into the original unit of ng/ml (20). The statistical computations were conducted using the Metafor package in R 4.3.1 statistical software. For summarizing results of meta-analyses graphically, we used forest plots. Heterogeneity was assessed using the Cochran’s Q test and its p-value (with heterogeneity assumed at two-sided significance level of p<0.05), along with the I2 index. A random-effects meta-analysis (RE model) was performed using a restricted maximum likelihood estimator (REML) for both summary risk and standardized mean difference (SMD) estimates. Potential publication bias was assessed using funnel plot and Egger’s test (Supplementary Material). In the presence of heterogeneity, sensitivity analyses were performed to explore its causes (Supplementary Material). Initially, when there were sufficient studies in the analysis, moderation analyses were performed regarding the characteristics: geographical location, sex, and study quality (assessed using the NOS). If a moderation analysis showed a significant influence of a moderating variable on the relationship between the variables, specific subgroup analyses were conducted (Supplementary Material).

Results

Search results and study characteristics. Using the search terms defined in section 2.1, we identified 602 papers in Medline (via PubMed) and ISI (Web of Science). All were included in our initial screening. Due to incompatible content [e.g., white skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) other vitamins, etc.], 421 papers were excluded, and abstracts from the remaining 181 were reviewed. We excluded 116 papers due to lack of relevance or failure to meet our inclusion criteria. Full texts of the remaining 65 papers were reviewed, and 39 were excluded due to methodological inadequacy. Thus, we identified 26 relevant studies to include in the analyses on the association between the risk and prognosis of malignant melanoma and vitamin D (7, 14, 18, 24-46). See Supplementary Material for further details on study characteristics.

A flow diagram illustrating our literature search according to PRISMA guidelines is provided in Figure 1. In summary, the time span between the first published study in 2009 and the most recent in 2021 was 12 years. Three studies were conducted in North America, one in South America, and three others in Australia. The majority, 19 studies, were from Europe. Most studies did not differentiate by sex. Exclusively female participants were only included in the study by Kwon et al. (2018), while Major et al. (2012) focused solely on male subjects (32, 35). Regarding the assessment of study quality, evidence level, and recommendation grade, most studies scored 5 or more out of a maximum of 9 points on the Newcastle-Ottawa Assessment Scale. Kwon et al.’s study scored 5 points. Twenty-five out of 26 studies with evidence grades above 5 were considered of high quality and provided a solid foundation for analysis and reliability of results. We categorized risk of bias using the NOS as follows: ≥5 indicates low risk of bias, <5 indicates high risk of bias. All studies were individually assessed according to Oxford Centre for Evidence-based Medicine guidelines, with most studies at evidence level 3b and recommendation grade B. The included studies are predominantly individual case-control studies (level 3b) or individual cohort studies (2b), with recommendation grade B (12, 23).

Figure 1.
Figure 1.

Flow chart summarizing the literature review process for the meta-analyses (source: www.prisma-statement.org).

Melanoma risk: Meta-analysis of mean vitamin D levels. This analysis compared 13 studies regarding the mean serum vitamin D levels between melanoma patients and healthy controls (Figure 2). The standardized mean difference was −0.4 (95%CI=−0.74 to −0.06), with a p-value of 0.02. This indicates that the mean vitamin D levels of melanoma patients are significantly lower than those of healthy controls. According to Cohen et al. (21), the difference in vitamin D levels can be considered small but significant. This corresponds to a difference of −4.6 ng/ml (95%CI=−8.5 to −0.7) between melanoma patients and healthy controls after back-transformation of SMD values into the original unit of ng/ml.

Figure 2.
Figure 2.

Forest plot showing reduced mean vitamin D levels in melanoma patients vs. healthy controls. I2: 97.6%; Q: 402, p<0.0001.

Melanoma risk: Meta-analysis of vitamin D status <20 ng/ml. This meta-analysis examined associations related to actual vitamin D deficiency, defined as a serum level <20 ng/ml. It includes 11 studies with data on patients’ vitamin D status (<20 ng/ml) compared to controls (Figure 3). The pooled odds ratio was 1.79 (95%CI=0.95-3.37) with a p-value of 0.07. Based on the results of the meta-analysis, it can be inferred that patients with a vitamin D status <20 ng/ml (vitamin D deficiency) have a higher risk of melanoma compared to patients without vitamin D deficiency; however, this association is not statistically significant.

Figure 3.
Figure 3.

Forest plot showing a higher risk for melanoma development in patients with vitamin D deficiency (≤20 ng/ml). I2: 93.9%, Q: 124, p<0.0001.

Melanoma prognosis. Analysis of tumor thickness and mean Vitamin D levels. The serum vitamin D levels of melanoma patients were compared between tumors >1 mm thick and ≤1 mm thick across nine studies (Figure 4). To determine whether there is a significant association between tumor thickness and vitamin D levels, the standardized mean difference was calculated for the categories >1 mm vs. ≤1 mm. The standardized mean difference yielded a value of −0.14 (95%CI=−0.22 to −0.07) with a p-value of 0.0002. This indicates that the vitamin D levels for melanoma patients with thicker tumors (>1 mm) are significantly lower than those with tumors ≤1 mm thick. According to Cohen’s criteria, this difference can be considered small but significant (20). After back-transformation of SMD values into the original unit of ng/ml, this corresponds to a difference of −1.4 ng/ml (95%CI=−2.2 to −0.7), when comparing the groups based on tumor thickness (>1 mm vs. ≤1 mm).

Figure 4.
Figure 4.

Forest plot showing reduced mean vitamin D levels in melanoma patients with tumors >1 mm thick compared to those with tumors ≤1 mm thick. I2: 34.6%, Q: 10.8, p=0.2.

Analysis of ulceration status and mean vitamin D levels. The serum vitamin D levels of melanoma patients were compared between ulcerated and non-ulcerated tumors across four studies (Figure 5). To determine whether there is a significant association between ulceration status and vitamin D levels, the standardized mean difference was calculated for the category ulceration (yes vs. no). The standardized mean difference yielded a value of −0.2 (95%CI=−0.3 to −0.11) with a p-value of <0.0001. This indicates that the vitamin D levels for melanoma patients with ulceration are significantly lower than those without ulceration. According to Cohen’s criteria, this difference can be considered small but significant (20). After back-transformation of SMD values into the original unit of ng/ml, this corresponds to an approximate difference of −1.9 ng/ml (95%CI=−2.85 to −1.0) when comparing the ulcerated and non-ulcerated groups.

Figure 5.
Figure 5.

Forest plot showing reduced mean vitamin D levels in melanoma patients with ulcerated vs. nonulcerated tumors. I2: 0%, Q: 1, p=0.8.

Analysis of mitotic rate and mean vitamin D levels. This analysis compared the mean serum vitamin D levels of melanoma patients with and without histological evidence of mitoses across four studies (Figure 6). The standardized mean difference yielded a value of −0.3 (95%CI=−0.57 to −0.02) with a p-value of 0.03. This suggests that the vitamin D levels for melanoma patients with mitoses are significantly lower than those without mitoses. According to Cohen’s criteria, this difference is considered small but significant (20). In ng/ml, this corresponds to an approximate difference of −2.6 ng/ml (95%CI=−0.17 to −4.87) when comparing the groups with mitoses vs. without mitoses.

Figure 6.
Figure 6.

Forest plot showing reduced mean vitamin D levels in melanoma patients with mitotic vs. non-mitotic tumors. I2: 62.4% Q: 8.9, p=0.03.

Analysis of melanoma stage and mean vitamin D levels. This analysis compared the mean serum vitamin D levels of melanoma patients across seven studies categorized into high vs. low melanoma stages (Figure 7). The standardized mean difference yielded a value of −0.33 (95%CI=−0.69 to 0.03) with a p-value of 0.08. This indicates that the vitamin D levels for melanoma patients with higher stages tend to be lower than those with lower melanoma stages, though this trend does not reach statistical significance (95%CI=−0.69 to 0.03). According to Cohen’s criteria, the difference is considered small (20). In ng/ml, this corresponds to an approximate difference of −3.05 ng/ml (95%CI=−6.3 to 0.27) when comparing the categories high vs. low tumor stages. Please note that several tumor stages may be included in the categories “high” and “low” due to the small number of studies.

Figure 7.
Figure 7.

Forest plot showing lower mean vitamin D levels in patients with higher melanoma stage. I2: 90.3, Q: 47.5, p<0.0001.

Analysis of tumor thickness and vitamin D status ≤20 ng/ml. This analysis focused on vitamin D status ≤20 ng/ml, investigating associations related to actual vitamin D deficiency (Figure 8). Five studies were included in this meta-analysis, examining the occurrence of high tumor thickness in melanoma patients with vitamin D status ≤20 ng/ml (vitamin D deficiency) versus >20 ng/ml. The pooled odds ratio was 1.86 (95%CI=1.23-2.8) with a p-value of 0.003. The results are graphically represented in a Forest Plot with corresponding weights in a random-effects model. From the results of the meta-analysis (n=5 studies), it can be inferred that melanoma patients with vitamin D deficiency are significantly more likely to have high Breslow tumor thickness compared to patients without vitamin D deficiency.

Figure 8.
Figure 8.

Forest plot showing a higher risk for thicker melanomas in patients with vitamin D deficiency (≤20 ng/ml). I2: 0%, Q: 2.7, p=0.6.

Analysis of mitotic rate and vitamin D status ≤20 ng/ml. This analysis focuses on vitamin D status ≤20 ng/ml, examining associations related to actual vitamin D deficiency (Figure 9). Three studies were included in this meta-analysis, investigating the occurrence of mitotic rate (≥1/mm2) in melanoma patients with vitamin D status ≤20 ng/ml (vitamin D deficiency) compared to those without deficiency. The pooled odds ratio (OR) was 2.02 (95%CI=1.21-3.36) with a p-value of 0.007. The results are visually represented in a Forest Plot with corresponding weights in a random-effects model. From the results of the meta-analysis (n=3 studies), it can be inferred that melanoma patients with vitamin D deficiency are twice as likely to have a higher mitotic rate compared to patients without vitamin D deficiency.

Figure 9.
Figure 9.

Forest plot showing a higher risk for mitotic tumors vs. nonmitotic tumors in patients with vitamin D deficiency (≤20 ng/ml). I2: 0%, Q: 0.6, p=0.75.

Analysis of melanoma stage and vitamin D status ≤20 ng/ml. This meta-analysis included 4 studies examining the prevalence of vitamin D status ≤20 ng/ml (vitamin D deficiency) among melanoma patients with low and high tumor stages (Figure 10). The pooled odds ratio was 1.54 (95%CI=1.01-2.36) with a p-value of 0.046. The results are graphically depicted in a Forest Plot with corresponding weights in the random-effects model. From the meta-analysis results (n=4 studies), it can be inferred that melanoma patients with vitamin D deficiency are 1.5 times more likely to have a higher tumor stage compared to patients without vitamin D deficiency.

Figure 10.
Figure 10.

Forest plot showing a higher risk for high stage tumors vs. low stage tumors in patients with vitamin D deficiency (≤20 ng/ml). I2: 0%, Q: 3.5, p=0.31.

Sensitivity analyses and conclusion. There was a tendency for low serum vitamin D levels and actual vitamin D deficiency to be associated with an increased risk of melanoma and a worsened melanoma prognosis. No significance was found in the individual analyses of vitamin D deficiency and melanoma risk or in the analysis of mean vitamin D levels and melanoma stage.

Due to the small number of studies (n<10), it was not possible to evaluate the risk of publication bias for every analysis. In the sensitivity analysis (see Supplementary Material), significance was found in the meta-analyses concerning vitamin D deficiency and melanoma risk, vitamin D serum levels and melanoma risk, vitamin D levels and mitotic rate, and vitamin D levels and melanoma stage, with geographical location as a moderator. Regarding overall melanoma risk (i) and prognostic factors mitotic rate (ii) and tumor stage (iii), the subgroup of studies from Southern Europe (i, ii) and Central Europe (iii) was significant. Table I summarizes the final study results.

View this table:
Table I.

Summary of meta-analyses.

Discussion

UV radiation and genetic components influence the occurrence of malignant melanoma, whereas the role of vitamin D is far less understood. Some of this knowledge gap can be attributed to the complex pathophysiological interplay between UV radiation and vitamin D. The fact that melanoma can appear anywhere on the skin, not just in sun-exposed areas, and in other organs, suggests the presence of other risk factors that need to be identified (47). In recent years, the antineoplastic effects of vitamin D have been increasingly researched. Since the 1980s, through the work of Garland et al., vitamin D is no longer viewed merely as a calciotropic hormone but rather as a biomarker for cancer risk (42). Vitamin D has been shown to be antiproliferative and to counteract malignant tumor growth both in vitro and in vivo. An activated VDR inhibits tumor cell proliferation and induces cell apoptosis. Moreover, it interacts with growth factors, cell adhesion, metastasis, and autophagy processes (9, 11, 12). These properties underpin the recognition of the VDR as a tumor suppressor, also against UV-induced carcinogenesis, as demonstrated by the work of Ellison et al., who found a rapid UV-induced carcinogenesis in VDR knockout mice (48). Genetic variants of the VDR have also been linked to the development and pathogenesis of malignant melanoma (49).

Furthermore, sunburns and intermittent, intense sun exposure – particularly before the age of 18 – increase the risk of melanoma. Numerous studies have shown that there is a positive correlation between intense, intermittent sun exposure and the risk of melanoma, whereas this correlation cannot be established for continuous sun exposure (5). On the contrary, an inverse relationship has been observed for long-term, continuous sun exposure (50). The fact that the incidence rate of melanomas in areas with intermittent sun exposure exceeds the incidence rate in areas with chronic sun exposure seems to support this observation (51). Thus, the protective effects of ultraviolet radiation seem to outweigh its mutagenic impacts. However, chronic sun exposure also increases melanoma risk, especially for the Lentigo-Maligna-subtype, which occurs in older individuals. These melanomas, predominantly found in the head and neck region, account for only approximately 10% of all melanomas, and their pathogenesis may differ fundamentally from proximal melanomas (52).

The complex interplay between UV radiation and malignant melanoma, as suggested by our sensitivity analyses (Supplementary Material), is also reflected in the following observations: In Australia and the US, the highest incidence rates are found near the equator (in regions of low latitude) (53). These areas also have the highest UV indices, leading to intense UV exposure and increased risks of sunburn.

In Europe, however, the situation is surprisingly opposite: the highest incidence rates are observed in Northern Europe, while Southern, Central, and Eastern Europe have the lowest rates; the mortality rates follow the same pattern. Scandinavia is markedly different from the Mediterranean region (6, 8, 54, 55).

This observation aligns with the results of our subgroup/moderator analyses (Supplementary Material), showing particularly significant results in studies from Southern Europe (analyses of melanoma risk and prognosis – mitotic rate).

Generally, while the Celtic skin type is associated with an increased risk of skin cancer (53), it can be hypothesized that the darker skin type (mixed/Mediterranean type), the overall healthier lifestyle of Southern Europeans (such as the fish- and vegetable-rich Mediterranean diet, increased daily physical activity), the observance of rest periods during peak UV indices (“siesta” tradition, “pranzo”), different sun exposure patterns, and other conceivable factors might explain this correlation.

This raises the question of whether chronic, moderate sun exposure behavior towards UVB might be protective (19, 56-59).

Study limitations. There are various methods available for measuring serum vitamin D levels. Different methods have different precision (60). In the included studies, immunoassays [CLIA (LIAISON-25-OH Vitamin D immunoassay) and ELISA] as well as HPLC-MS were used. Since only one study in our meta-analysis used ELISA (25-OH-D-Euroimmunkit) and eight studies used HPLC-MS, with some studies combining these methods, precise differentiation is considered particularly difficult.

The timing of data collection (e.g., seasons, seasonal weather conditions, etc.) at the time of diagnosis must also be taken into account. For example, on the Northern Hemisphere, higher sun exposure and consequently higher vitamin D serum levels can be expected in the summer. Still, serum levels of cases and controls were comparable (in each analysis) as long as the data collection occurred within the same period. Further influencing factors include the different collection sites, degrees of pigmentation/skin types, use of sunscreen products, prevailing cultures, and ethnicities (56).

Reverse causality must also be considered: it can be assumed that melanoma itself reduces vitamin D levels. The disease condition may regulate vitamin D levels not only through sun avoidance or social withdrawal of patients after therapy begins (61) but also by impairing vitamin D synthesis in the liver in cases of liver metastases (14).

Overall, melanoma as a tumor itself seems to reduce the concentration of vitamin D, as vitamin D is considered a “negative acute-phase reactant” (62). It is inversely related to C-reactive protein CRP, which is itself an independent prognostic factor for malignant melanoma and is associated with a deterioration in melanoma-specific survival. Further studies will show whether a high vitamin D level during the progression of the disease (i.e., at a later stage) remains protective and continues to exert anti-carcinogenic effects. Hutchinson et al. reported that there might be a balance between the anti-carcinogenic effects of vitamin D on tumor cells and its immunosuppressive effects on the immune system (63). The serum levels at which this balance becomes relevant remain unknown.

To investigate a possible causal relationship between vitamin D status and malignant melanoma, high-quality prospective studies with large numbers of participants are needed, which are not yet available.

Conclusion

In summary, our results show a trend towards an increased melanoma risk and a worsened prognosis in patients with malignant melanoma. A true vitamin D deficiency seems to significantly worsen the prognosis of malignant melanoma (measured by all recognized prognostic factors), while a significant association between vitamin D deficiency and melanoma risk has not been established. This meta-analysis is consistent with findings from experimental research on the anticancer properties of vitamin D, including inhibition of proliferation, induction of differentiation and apoptosis of melanoma cells, and inhibition of invasion and angiogenesis of tumor cells. Therefore, it is essential to further elucidate the role of UV radiation in melanoma, as our results suggest potential protective effects of UV radiation, possibly through immunomodulatory mechanisms or, as Berwick et al. hypothesized, through the moderating effect of vitamin D on melanin production and the associated increase in DNA repair capacity.

Footnotes

  • Received August 14, 2024.
  • Revision received September 28, 2024.
  • Accepted September 30, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Malignant Melanoma: Vitamin D Status as a Risk and Prognostic Factor – Meta-analyses and Systematic Review
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