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Vitamin D Level and Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma Risk

      Various associations between serum vitamin D levels and skin cancer have been reported. In this issue, van der Pols et al. observed that baseline 25-hydroxyvitamin D (25OHD) levels above 75nmol/L were associated with an increased incidence of basal cell carcinoma and melanoma, and a nonstatistically significant decreased incidence of squamous cell carcinoma. Complex factors including sun exposure, skin phototype, and anticarcinogenic and procarcinogenic effects of vitamin D are potential causes of the observed associations.

      Commentary

      Serum 25-hydroxyvitamin D (25OHD) levels reflect available body stores of vitamin D obtained from UV exposure, diet, and supplements. Circulating vitamin D is hydroxylated in the liver to 25OHD, and then in kidneys or in other cell types including keratinocytes, to the active form, calcitriol (1,25(OH)2D). Vitamin D–mediated gene transcription influences calcium and phosphorus regulation, immune function, angiogenesis, cellular growth, differentiation, and apoptosis (
      • Holick M.F.
      Vitamin D deficiency.
      ). In this issue,
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      report a positive association between baseline vitamin D levels and basal cell carcinoma (BCC) and melanoma incidence and a negative association with squamous cell carcinoma (SCC) incidence.

      Serum vitamin D level and skin cancer risks

      The literature contains many reports of associations between vitamin D levels and chronic diseases and malignancies (
      • Reddy K.K.
      • Gilchrest B.A.
      What is all this commotion about vitamin D?.
      ). Anticarcinogenic and procarcinogenic actions of vitamin D have also been discussed. Although associations have been made between low-normal vitamin D levels and studied diseases, high-normal vitamin D levels have also been associated with disease, including prostate and pancreatic cancers (
      • Tuohimaa P.
      • Tenkanen L.
      • Ahonen M.
      • et al.
      Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries.
      ;
      • Stolzenberg-Solomon R.Z.
      • Vieth R.
      • Azad A.
      • et al.
      A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers.
      ). Associations between vitamin D levels and risk of skin cancer have been examined in several studies (
      • Asgari M.M.
      • Tang J.
      • Warton M.E.
      • et al.
      Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma.
      ;
      • Tang J.Y.
      • Parimi N.
      • Wu A.
      • et al.
      Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men.
      ;
      • Eide M.J.
      • Johnson D.A.
      • Jacobsen G.R.
      • et al.
      Vitamin D and nonmelanoma skin cancer in a health maintenance organization cohort.
      ;
      • Lamberg A.L.
      • Olesen A.B.
      • Jensen A.O.
      Hip fracture history and risk of nonmelanoma skin cancer: a Danish population-based study.
      ;
      • Liang G.
      • Nan H.
      • Qureshi A.A.
      • et al.
      Pre-diagnostic plasma 25-hydroxyvitamin D levels and risk of non-melanoma skin cancer in women.
      ).
      The study by
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      assesses the association between baseline serum 25OHD levels and skin cancer risk, as determined by prospective incidence of histologically confirmed skin cancer in 1,191 adults for 11 years after serum 25OHD measurement at the end of winter. Odds ratios (ORs) were adjusted for multiple factors, including age, sex, personal or family history of skin cancer, skin color, and usual time spent outdoors. Recorded but not included in the analysis were vitamin D intake and supplement use, number of nevi, skin aging, body mass index, sunscreen use, physical activity, presence of other medical conditions, calcium intake, and smoking status. Socioeconomic status was not reported.
      In subjects with a history of skin cancer, 25OHD levels above 75nmol/L were associated with increased incidence of BCC (OR 1.51, 95% confidence interval (CI) 1.1–2.07, P=0.01) and melanoma (OR 2.71, 95% CI 0.98–7.48, P=0.05) and with reduced incidence of SCC (OR 0.67, 95% CI 0.44–1.03, P=0.07). Interestingly, those who did not have a history of skin cancer before baseline 25OHD measurement did not show an association of vitamin D level with skin cancer risk. Vitamin D levels were highly correlated with self-reported time spent outdoors in the 6 months preceding serum 25OHD measurement and during follow-up. Childhood or previous adulthood sun exposure habits, although likely influencing skin cancer risk, were not examined. Those who reported more than half of their time spent outdoors had vitamin D levels averaging 76nmol/L, generally overlapping with the group that displayed higher risks for BCC and melanoma and a lower risk for SCC.
      Previous studies have found confirmatory and conflicting results (Table 1). Most have had primarily female subjects and have suggested that BCC and SCC incidences increase with vitamin D levels. The prospective Nurses’ Health study found baseline 25OHD levels to be associated with increased BCC (OR 2.07) and SCC (OR 3.77) incidences when comparing 25OHD >78–85 with <50nmol/L and adjusting for multiple factors (
      • Liang G.
      • Nan H.
      • Qureshi A.A.
      • et al.
      Pre-diagnostic plasma 25-hydroxyvitamin D levels and risk of non-melanoma skin cancer in women.
      ). BCC was associated with vitamin D levels only when 25OHD samples collected outside of summer were examined;
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      also used non-summer 25OHD levels. Vitamin D levels were similar at 3 and 10 years in the Nurses’ Health Studies, suggesting that baseline 25OHD measurements were reasonable markers of long-term 25OHD levels (
      • Kotsopoulos J.
      • Tworoger S.S.
      • Campos H.
      • et al.
      Reproducibility of plasma and urine biomarkers among premenopausal and postmenopausal women from the Nurses’ Health Studies.
      ). Sun exposure remains a likely confounding factor in most studies, with the authors concluding that 25OHD levels likely reflect sun exposure habits and therefore predict risk for nonmelanoma skin cancer. A second prospective study in 3,233 low-bone-density, white individuals, mostly female, also found positive correlations between baseline 25OHD levels (>37.5nmol/L) and increased risk for both BCC and SCC (OR 1.7–2.2), citing sun exposure as a likely causative factor (
      • Eide M.J.
      • Johnson D.A.
      • Jacobsen G.R.
      • et al.
      Vitamin D and nonmelanoma skin cancer in a health maintenance organization cohort.
      ).
      • Asgari M.M.
      • Tang J.
      • Warton M.E.
      • et al.
      Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma.
      also found that vitamin D levels correlated with BCC risk (OR 2.09, 95% CI 0.95–4.58, P=0.11). In addition, a large Danish study reported reduced incidence of BCC, but not SCC, in those with hip fracture histories (OR 0.90) hypothesized to result from reduced sun exposure (
      • Lamberg A.L.
      • Olesen A.B.
      • Jensen A.O.
      Hip fracture history and risk of nonmelanoma skin cancer: a Danish population-based study.
      ).
      Figure thumbnail fx1
      Table 1Serum vitamin D levels and skin cancer risk
      InvestigatorMethodsPopulationAssociated 25OHD level (nmol/L)Reference 25OHD level (nmol/L)BCC risk (OR, 95% CI)SCC risk (OR, 95% CI)Melanoma risk (OR, 95% CI)Regression analysis variables
      • Liang G.
      • Nan H.
      • Qureshi A.A.
      • et al.
      Pre-diagnostic plasma 25-hydroxyvitamin D levels and risk of non-melanoma skin cancer in women.
      Baseline serum 25OHD; prospective incidence of BCC, SCC; 8–19-year follow-upNurses’ Health Study, 4,641 women, no history of skin cancer before 25OHD collection>78–85<50OR 2.07
      In subjects with 25OHD collection in non-summer months.
      (1.52–2.80), P<0.01
      OR 3.77 (1.70–8.36), P<0.01Age, season, local UVB index, lab batch, hair color, skin pigmentation, sunburn tendency and number; sun exposure not studied
      • Eide M.J.
      • Johnson D.A.
      • Jacobsen G.R.
      • et al.
      Vitamin D and nonmelanoma skin cancer in a health maintenance organization cohort.
      Baseline serum 25OHD; incidence of BCC, SCC; mean 10-year follow-upHMO, 90% women, 3,233 white, low bone density, immunocompetent subjects≥37.5<37.5OR 1.7 (1.0–2.9), P<0.05OR 1.7 (0.7–4.0), P>0.05Age, sex, season, NMSC anatomic location; smoking and BMI not adjusted
      • Asgari M.M.
      • Tang J.
      • Warton M.E.
      • et al.
      Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma.
      Baseline 25OHD; BCC incidence; 4–21-year follow-upNorthern California HMO, 220 patients, 220 controls, 52% male≥75<25OR 3.61 (1.00–13.10), P=0.03BMI, smoking, education, sun exposure, X-ray exposure, history of skin cancer
      • Lamberg A.L.
      • Olesen A.B.
      • Jensen A.O.
      Hip fracture history and risk of nonmelanoma skin cancer: a Danish population-based study.
      Case–controls with hip fracture history; BCC and SCC prevalence69,000 BCC patients and 11,000 SCC patients, age 40+, Danish cancer registryOR 0.90 (0.85–0.94)OR 1.07 (0.98–1.17)Age, sex, chronic disease, socioeconomic status
      Newton-Bishop et al. (2009)25OHD level 3–6 months after melanoma diagnosis; Breslow thickness, relapse, and death; median follow-up 4.7 yearsLeeds Melanoma Cohort; 872 subjects>61≤ 41.3Relapse-free survival HR 0.57 (0.33–0.97); Mean 25OHD 56 vs. 49nmol/l in MM<0.75 vs. >3mm depth, P=0.002Age, sex, BMI, season, VDR status, Townsend score, tumor site, Breslow thickness, supplement use
      • Tang J.Y.
      • Parimi N.
      • Wu A.
      • et al.
      Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men.
      Baseline serum 25OHD; prospective incidence of self-reported NMSC (BCC, SCC not separately specified); 5-year follow-upOsteoporotic fractures study; 930 community-dwelling white men, age >65 years>75<40NMSC OR 0.53 (0.30–0.93), P=0.026NMSC OR 0.53 (0.30–0.93), P=0.026Age, BMI, season, latitude, physical activity, smoking
      • Tang J.Y.
      • Xiao T.Z.
      • Oda Y.
      • et al.
      Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas.
      Calcium and vitamin D supplementation (1,000mg/400IU daily); prospective incidence of BCC, SCC, melanoma; mean 7-year follow-upWHI study cohort; 36,282 postmenopausal women; age 50–79 yearsNo difference; HR 1.02 (0.95–1.07)No difference; HR 1.02 (0.95–1.07)HR 0.43
      In subjects with a history of nonmelanoma skin cancer; subjects with a history of melanoma were excluded from the study.
      (0.21–0.90), P=0.038
      Age, geographic region, physical activity, smoking, education, socioeconomic status, nutrient intake
      • Freedman D.M.
      • Looker A.C.
      • Chang S.C.
      • et al.
      Prospective study of serum vitamin D and cancer mortality in the United States.
      Baseline serum 25OHD; prospective cancer mortality; up to 12-year follow-upNHANES study, 16,818 subjectsNone observedNo difference in melanoma mortalitySex, race, smoking, BMI, latitude, physical activity
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      Baseline serum 25OHD; prospective incidence; 11-year follow-upAustralian skin cancer prevention study cohort; 1,191 adult men and women, mean age 54 years>75≤75OR 1.51
      In subjects with a history of skin cancer.
      (1.10–2.07), P=0.01
      OR 0.67
      In subjects with a history of skin cancer.
      (0.44–1.03), P=0.07
      OR 2.71
      In subjects with a history of skin cancer.
      (0.98–7.48), P=0.05
      Age, sex, family history of skin cancer, skin color, usual time outdoors; BCC and SCC further adjusted for neck elastosis, back freckling, propensity to sunburn
      Abbreviations: BCC, basal cell carcinoma; BMI, body mass index; CI, confidence interval; HMO, health maintenance organization; HR, hazard ratio; 25OHD, 25-hydroxyvitamin D; MM, malignant melanoma; NHANES, National Health and Nutrition Examination Survey; NMSC, nonmelanoma skin cancer; OR, odds ratio; SCC, squamous cell carcinoma; VDR, vitamin D receptor; WHI, Women’s Health Initiative.
      1 In subjects with 25OHD collection in non-summer months.
      2 In subjects with a history of nonmelanoma skin cancer; subjects with a history of melanoma were excluded from the study.
      3 In subjects with a history of skin cancer.
      One study in elderly men reported contrary results from most other studies, finding baseline 25OHD levels >75nmol/L to be associated with decreased risk for nonmelanoma skin cancer (OR 0.53, P=0.026, BCC or SCC not separately specified) (
      • Tang J.Y.
      • Parimi N.
      • Wu A.
      • et al.
      Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men.
      ). Subjects with skin cancers diagnosed at or after 25OHD collection were included, leading the authors to suggest that sun avoidance as a result of skin cancer diagnosis could explain the reduced skin cancer incidence. With some similarity,
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      have reported a reduced risk for SCC, although not statistically significant, in those with a history of skin cancer and vitamin D levels >75nmol/L. It appears that postdiagnosis sun avoidance was a less likely factor in the findings of van der Pols et al., as sun exposure adjustments were made. Together, evidence suggests that vitamin D levels of 38–85nmol/L may be a marker for increased BCC risk in susceptible individuals and are variably associated with increased or decreased SCC incidence.
      In addition to an observed increased risk for BCC,
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      also found 25OHD levels >75nmol/L to be a marker of increased melanoma incidence. Particular melanoma subtypes, depths, and patient outcomes were not described. UV exposure again represents a confounding factor. Sunburn has been strongly associated with increased melanoma risk, and chronic or occupational UV exposures are associated with increased head and neck melanomas, although also with reduced overall melanoma risk (OR 0.67) (
      • Newton-Bishop J.A.
      • Chang Y.M.
      • Elliott F.
      • et al.
      Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate.
      ).
      Reported associations between vitamin D level and melanoma prognosis have been variable. A prospective study of 17,000 NHANES subjects followed for up to 12 years found no association between 25OHD levels and melanoma mortality (
      • Freedman D.M.
      • Looker A.C.
      • Chang S.C.
      • et al.
      Prospective study of serum vitamin D and cancer mortality in the United States.
      ). However, in a small study, higher 25OHD levels at the time of melanoma diagnosis, although generally below 75nmol/L, were associated with reduced Breslow thickness (mean 56nmol/L in melanomas <0.75mm) and with independently reduced risks for relapse and death (highest tertile 25OHD >61nmol/L, hazard ratio (HR) 0.79 for relapse-free survival per 20nmol/L, P=0.01) (
      • Newton-Bishop J.A.
      • Beswick S.
      • Randerson-Moor J.
      • et al.
      Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma.
      ). A valuable large intervention study, the Women’s Health Initiative (WHI), found that postmenopausal women with a history of nonmelanoma skin cancer who received 1,000mg calcium and 400IU vitamin D daily displayed a 57% reduced incidence (P=0.04) of melanoma.

      Procarcinogenic and anticarcinogenic effects of vitamin D on skin cancer

      Several of the factors that affect serum 25OHD levels likely contribute to skin cancer risk, including sun exposure habits, latitude, diet, supplement intake, age, body mass index, skin color, vitamin D receptor (VDR) polymorphisms, chronic diseases, and socioeconomic status. Associations of vitamin D levels with additional risk factors may also be a contributing factor, including immunosuppression, human papillomavirus infection, and smoking. Sun exposure remains the most suspicious confounding or cofactor. Although investigators have adjusted for multiple factors in published studies, all major factors have not been analyzed and the possibility of complete and accurate adjustment for these multiple complex factors remains improbable.
      Despite many confounding factors, the interesting finding by
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      of reduced SCC incidence in individuals with 25OHD >75nmol/L and the findings of the WHI reporting reduced melanoma incidence in women with a history of nonmelanoma skin cancer taking 400IU vitamin D daily, encourage evaluation of the cellular effects of vitamin D on skin carcinogenesis.
      Keratinocytes are one of the few cell types possessing both 1-α- and 25-hydroxylase and are thus able to produce calcitriol locally (
      • Lehmann B.
      • Tiebel O.
      • Meurer M.
      Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents-a preliminary study.
      ). Variations in serum 25OHD levels within the normal range are not known to result in variations in calcitriol levels, and hence it remains uncertain whether variations in normal serum 25OHD levels cause changes in cellular calcitriol levels, VDR activation, or gene activity. Cutaneous VDR activation appears generally to reduce growth and proliferation through upregulation of the MEK/ERK and PI3K/Akt pathways, as well as of calbindin, IGFBP, E-cadherin, and β3 integrin. BCL2, IL1, IL12, TNF-α, IFN-γ, EGFR, and telomerase are downregulated (
      • Field S.
      • Newton-Bishop J.A.
      Melanoma and vitamin D.
      ).
      Mice lacking the VDR develop increased nonmelanoma skin cancers and display reduced NF-κB and p53 expression (
      • Field S.
      • Newton-Bishop J.A.
      Melanoma and vitamin D.
      ). Furthermore, VDR polymorphisms have been associated with variations in BCC, SCC, and melanoma risk (
      • Kostner K.
      • Denzer N.
      • Koreng M.
      • et al.
      Association of genetic variants of the vitamin D receptor (VDR) with cutaneous squamous cell carcinomas (SCC) and basal cell carcinomas (BCC): a pilot study in a German population.
      ). Vitamin D appears to mitigate UV damage in vitro by reducing cyclobutane pyrimidine dimer (CPD) formation, improving CPD repair, inducing antioxidant metallothionein, and reducing UVB-induced apoptosis. Antiproliferative effects have been observed in some melanoma and basal cell carcinoma lines (
      • Tang J.Y.
      • Fu T.
      • Leblanc E.
      • et al.
      Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the Women’s Health Initiative randomized controlled trial.
      ).
      Vitamin D may also influence skin cancer through effects on immune cells. Calcitriol appears to suppress T helper type 1 (Th1) and increase Th2 and regulatory T-cell responses, which may reduce immune surveillance of skin cancer (
      • Bikle D.D.
      Vitamin D regulation of immune function.
      ). However, innate immunity is promoted, including Toll-like receptor induction, which may improve anticancer responses (
      • Bikle D.D.
      Vitamin D regulation of immune function.
      ).

      Clinical recommendations

      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      have confirmed previously observed positive associations between vitamin D level and BCC risk and have suggested a positive association with melanoma and negative association with SCC incidence. Large and complex confounding factors limit clinically applicable conclusions on the cause of the observed associations. Although anticarcinogenic and procarcinogenic actions of vitamin D in skin have been described, the ultimate balance of effects of serum 25OHD concentrations on skin cancer remains unknown. Intervention studies are more likely than association studies to identify opportunities for effective health interventions. Clinical risk assessment, prevention methods, or treatment modalities for BCC or SCC appear unlikely to change significantly on the basis of vitamin D level. However, on the basis of the positive effect of vitamin D supplementation in reducing melanoma incidence in the WHI study, investigation into the optimal serum 25OHD range for prevention or treatment of melanoma through intervention studies may provide information that can improve clinical outcomes.
      Current evidence suggests that it may be prudent to avoid both vitamin D deficiency (<25–50nmol/L) and high-normal vitamin D levels (>75nmol/L) in patients at risk for skin cancer, particularly by avoiding excessive UV exposures. Although
      • van der Pols J.C.
      • Russell A.
      • Bauer U.
      • et al.
      Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community.
      found that SCC incidence reduced when 25OHD levels were above 75nmol/L, other studies have found increased SCC risks, and these levels have further been associated with pancreatic and prostate cancers.
      The recommendation by the Institute of Medicine for serum 25OHD targets of 50–75nmol/L appears prudent and is supported by skin cancer association studies (
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.
      ). In addition, modest vitamin D supplementation (400IU) may be beneficial in reducing melanoma incidence in patients with a history of nonmelanoma skin cancer. Vitamin D levels have been associated with both higher and lower rates of disease depending on the disease studied; therefore, overall health should be considered when selecting a serum vitamin D goal in the context of skin cancer management. Because UV exposure remains a well-known skin carcinogen, oral calcitriol presents the safest and most reliable supplementation method.

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