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ORIGINAL ARTICLE
Year : 2022 | Volume
: 30
| Issue : 2 | Page : 32-37
Sunlight: Friend or foe? A natural source of vitamin D or a risk factor for cutaneous malignancy?
Zeynep Gulsum Guc1, Hasan Guc2
1 Department of Medical Oncology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey
2 Department of Plastic, Reconstructive and Aesthetic Surgery, Tepecik Training and Research Hospital, Izmir, Turkey
Correspondence Address:
Dr. Zeynep Gulsum Guc
Department of Medical Oncology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir
Turkey
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/tjps.tjps_66_21
Objective: We assessed the relationship between serum 25 hydroxyvitamin D (OH) D levels and the presence of malignancy in patients who underwent surgery for cutaneous skin lesions. Materials and Methods: Three-hundred and ninety-eight patients operated on for cutaneous lesions, had serum 25 (OH) D levels on file, had no known parathyroid pathology, did not concomitantly take bisphosphonate or Vitamin D supplement, and had accessible pathology results were reviewed upon their consent for the retrospective analysis of their data. Demographic characteristics, diagnosis dates, lesion localizations, pathology results, and serum 25 (OH) D levels were noted. Optimal cutoff value for Vitamin D levels was calculated with receiver operating characteristic (ROC) curve analysis and pathology results of the excised lesions and patient characteristics were analyzed according to this value. Results: ROC analysis showed 90% sensitivity and 64% specificity for vitamin D levels of 18.64 ng/ml (area under the curve [AUC] = 0.905; 95% confidence interval 0.87–0.93, P < 0.001). Review of lesions for pathological characteristics showed 207 (52%) benign and 191 (48%) malignant. While no significant relationship was observed between gender and vitamin D levels, a significant difference was identified between advanced age and low Vitamin D levels and the presence of malignancy (P < 0.001). The one-way analysis of variance and Bonferroni's post hoc analysis revealed higher incidences of malignant lesions in the group with low serum 25 (OH) D levels (P < 0.001), in patients aged 65+ years (P < 0.001), in cases localized to the head and neck (P = 0.026), and in males (P = 0.047). Conclusion: We identified a statistically significant relationship between low serum 25 (OH) D levels and the development of cutaneous malignancy.
Keywords: 25 (OH) D levels, skin cancers, sunlight, Vitamin D deficiency, vitamin D
Skin cancer is the most common type of malignancy. While there is a noteworthy increase in the incidences across the world, about 3.5 million new patients are diagnosed with skin cancer every year in the US.[1] Whereas its most lethal subtype is malignant melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have extremely important effects on quality of life.[2] The main etiological factor for these cancers is ultraviolet radiation (UVR) from the sun.
As a fat-soluble micronutrient, Vitamin D is found in two natural forms, namely ergocalciferol (Vitamin D2) and cholecalciferol (Vitamin D3). About 90% of Vitamin D is synthesized in the skin where 7-dehydrocholesterol is converted to Vitamin D3 upon exposure to UVR. The remaining 10% can be taken exogenously from diet or supplements.[3] Vitamins D2 and D3 are then metabolized in the liver to 25-hydroxyvitamin D (25 (OH) D). In the kidneys, the metabolic active form of vitamin D, 1-alpha is converted to 25-dihydroxyvitamin D3. 25 (OH) D represents its main circulating form and reflects the state of vitamin D.[4]
As well as its positive effects on bone health, Vitamin D has a role in many biological functions, such as immune system modulation, and antiangiogenic and antiproliferative effects.[5],[6] Low Vitamin D levels have been shown to play a role in the development and progression of various diseases, including autoimmune diseases, respiratory tract infections, Type 1 and Type 2 diabetes mellitus, hypertension, cardiovascular diseases, neuromuscular disorders, and cancer.[7]
The effects of Vitamin D are largely associated with the presence and activity of the nuclear Vitamin D receptor (VDR). A member of the steroid nuclear receptor superfamily, VDR, is expressed in a wide range of cells and tumors and is an intracellular receptor and a protein that acts as a transcription factor.[8] Abnormal activity of this receptor, which is found in many cell types, can hinder the effectivity of vitamin D even at normal levels.[9] In fact, to perform its biological functions, it binds to 1,25 (OH) 2D3 VDR and heterodimerizes with the retinoid X receptor.[10] This heterodimeric complex communicates with the nucleus. It is involved in the expression of more than 900 genes related to cell cycle progression, differentiation, and apoptosis.[11],[12],[13]
In the absence of VDR, DNA damage repair is restricted, which results in the accumulation of mutations in the DNA. In the absence of VDR in the epidermis, on the other hand, hedgehog and beta-catenin pathways, which are important steps of carcinogenesis, are activated. As a result, the long noncoding RNA shifts toward an oncogenic profile.[14] While current studies based on this information have shown a protective effect of Vitamin D on different types of cancer, the data on the relationship between Vitamin D and skin cancers remain contradictory.[15] UVR from sunlight is both the main risk factor for skin cancers and responsible for the synthesis of vitamin D which has many important roles in maintaining overall health. The aim of this study was to review the 25 (OH) D levels of patients who were operated on for cutaneous lesions and compare the 25 (OH) D levels of benign and malignant cases in an attempt to contribute to clarifying this contradiction.
Materials and MethodsPatients
The institutional and national research committees' ethical standards, as well as the 1964 Declaration of Helsinki and its later revisions, were observed in all studies involving human participants. Ethics committee approval for the study was obtained from the University's Ethics Committee. Files of all patients who presented to the plastic surgery outpatient clinic from August 2019 to December 2020 and were operated on for cutaneous lesions were scanned. Out of 1810 patients who met the above criteria, those who had their serum 25 (OH) D levels recorded in their files at the time of surgery, had no known parathyroid pathology, did not concomitantly take bisphosphonate or Vitamin D supplement, and whose pathology results were accessible were included in the study upon their consent for the retrospective analysis of their data. Since 25 (OH) D levels could vary depending on the month tested, only the patients who were diagnosed and tested for Vitamin D levels in the winter months (November through February) were included in the study to ensure consistency. Demographic characteristics of patients, their diagnosis date, localization of lesion, pathology results, and serum 25 (OH) D levels were noted. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for Vitamin D levels. Pathology results of the excised lesions and patient characteristics were analyzed according to this cutoff value.
Statistical analysis
The Statistical Package for the Social Sciences for Windows 20.0 (SPSS, Inc., Chicago, IL, USA) was used for analysis. Descriptive statistics summarized frequencies and percentages for categorical, mean, and standard deviation for continuous variables. Categorical variables were compared with the independent samples t-test and categorical parameters with the Chi-squared test. ROC curve analysis was used to determine the optimal cutoff point for Vitamin D levels. After determining the cutoff point, we calculated the sensitivity, specificity, and positive and negative predictive values. The one-way analysis of variance (ANOVA) was used to compare the continuous parameters of the groups according to 25 (OH) D levels, and the groups that presented a difference were identified with Bonferroni's post hoc analysis. P < 0.05 was considered statistically significant.
ResultsThe mean age of the 398 patients included in the study was 56 (18–106) years, and 171 were female (43%) and 227 were male (57%). When grouped by age, 270 patients (67.8%) were found younger than 65 years, while 128 were aged 65 years or above at the time of their diagnosis.
According to their localizations, excised lesions were in the head and neck in 325 (81.7%) patients, in the limb in 45 (11.3%), and in the torso in 28 (7%) patients. With respect to their pathological characteristics, 207 lesions (52%) were benign and 191 (48%) were malignant. Of the malignant lesions, the most common type was BCC diagnosed in 147 patients (76.8%), followed by SCC in 37 patients (19.3%) and malignant melanoma in 7 patients (3.9%). Characteristics of patients by gender are given in [Table 1].
The mean 25 (OH) D level of patients was 13.64 ng/ml (range: 1–43.85). Optimal cutoff value of the Vitamin D level was calculated with the ROC curve analysis [Figure 1] (AUC = 0.905; 95% confidence interval 0.87–0.93, P < 0.001). The ROC analysis provided 90% sensitivity and 64% specificity for this cutoff value. Taking 18.64 ng/ml 25 (OH) D as the cutoff point, patients were divided into two groups: those with a low Vitamin D level and those with a normal Vitamin D level.
Figure 1: Receiver operating characteristic curve analysis performed for the Vitamin D level cutoff valueAnalysis of the correlation between Vitamin D levels and genders using the Chi-square test showed no statistical difference between males and females in terms of Vitamin D levels (P = 0.479). When Vitamin D levels were compared with respect to the histopathological nature of the lesions, Vitamin D levels were seen to be significantly lower in patients with malignant lesions (P < 0.001). An analysis based on age groups revealed that patients aged 65+ years had statistically significantly lower Vitamin D levels (P < 0.001) [Table 2].
Table 2: Patient characteristics according to vitamin D levels and histopathological groupsA significant correlation was found between the pathological characteristics of the excised lesions and the age groups, with a higher malignancy rate in the 65+ age group (P < 0.001). An analysis in terms of gender showed that histopathologically malignant lesions were more common among male patients (P = 0.041) [Table 2].
One-way ANOVA on the correlation between the pathological condition and groups revealed significant differences in terms of Vitamin D levels, age groups, lesion localizations, and genders (P < 0.001). Bonferroni's post hoc analysis done to determine the groups that showed a difference revealed a higher malignancy rate in the low 25 (OH) D level group (P < 0.001), the 65+ age group (P < 0.001), among patients with head-and-neck localization (P = 0.026), and among males (P = 0.047).
DiscussionOur study has shown that 25 (OH) D levels can predict malignancy in excised cutaneous lesions. Analysis of Vitamin D levels and pathologies of cases, both done in comparable timeframes and in homogeneously distributed age groups, showed significantly lower Vitamin D levels in the presence of cancer.
Since UVR plays a key role both in the pathogenesis of skin cancers and in Vitamin D synthesis, there are conflicting data on the relationship between cutaneous malignancies and Vitamin D. Despite the many studies investigating the relationship between Vitamin D and cancer, confounding variables, differences among the geographic characteristics of each community, and small sample sizes make it challenging to draw meaningful and valid conclusions. Also considering the characteristics of the geography we live in, in their daily practice, clinicians often emphasize that many patients should avoid UVR to prevent the development of skin cancers such as SCC, BCC, melanoma. Given that Vitamin D plays a role in carcinogenesis by means of various mechanisms and about 90% of this Vitamin is synthesized in the skin when 7-dehydrocholesterol is converted to Vitamin D3 during exposure to UVR, it is reasonable to assume that Vitamin D levels may decrease if the necessary replacements are not provided as part of a strategy to protect from UV. Similar to other reports in the literature, we, too, found that cutaneous malignancies, especially BCC, were more common in individuals with low Vitamin D levels.
While Vitamin D has pleiotropic effects such as cell growth and cell differentiation, it also plays a role in regulating apoptosis and the tumor-immune system and performs these tasks through VDR.[16],[17] Neoplastic cells contain VRDs. When the 25 (OH) D level is high due to the 1 alpha-hydroxylase enzymes they contain, the cells form 1,25 (OH) 2D, which has the characteristics of a tumor suppressor. They have reducing effects on proliferation, invasion, angiogenesis, metastasis, and increasing effects on differentiation and apoptosis.[18] After completing its task in a malignant cell, 1,25 (OH) 2D starts its own destruction process by stimulating the CYP24 gene. Vitamin 1,25 (OH) 2D, which acts on the malignant cell, does not enter circulation and does not affect the calcium metabolism.[19],[20],[21]
Prospective and retrospective studies have shown that both the incidence and the mortality of solid tumors, such as colon CA, prostate CA, and lung CA, increase when 25 (OH) D level is low.[22],[23],[24],[25] In our study, we found a higher rate of malignancy (especially in BCC histology) among the cutaneous lesions excised from patients with lower Vitamin D levels. A prospective study by Ince et al. showed that Vitamin D replacement reduced the recurrence of BCC.[26]
The protective role of VDR in epithelial tumor formation has been demonstrated in different studies. In VDR null mice, different skin tumors, mostly SCC, were seen after UVB exposure.[27],[28] Activation of the sonic hedgehog (SHH) signaling pathway is involved in the pathogenesis of BCC, which is the most common skin cancer. The SHH's membrane receptor on the skin is PTCH1, and SHH in the absence of PTCH1. It inhibits smoothened (SMO), which is another membrane protein, triggering carcinogenesis.[29],[30] VDR plays a key role in regulating SHH signaling in the epidermis.[31]
Our study, consistent with the literature, showed a higher incidence of cutaneous malignancy among older and male patients. Furthermore, Vitamin D levels were low in this group of patients, as consistent with the pathogenetic mechanisms indicated in carcinogenesis. In their case–control study, they conducted in an elderly male population, Tang et al. found that increased plasma preVitamin D levels were both associated with lower incidences of nonmelanoma skin tumors and supported lower metastasis incidences and better survival in the presence of tumors.[32] Another case–control study conducted in melanoma patients also found low Vitamin D levels to be associated with melanoma.[33]
Although we could not assess it in our study, VDR polymorphism is reported to cause skin cancers by reducing the effectiveness of Vitamin D. The most studied VDR small nucleotide polymorphisms in skin cancers are Taq1, Bsm1, Apa1, and Fok1.[34]
In contrast to the data we obtained in our study, there are studies in the literature reporting that the risk of malignancy increased as Vitamin D levels increased in both melanoma and nonmelanoma cutaneous cancers.[35] In a commentary reviewing nine clinical studies, Reddy[36] reported to have identified contradictory associations between serum Vitamin D levels and skin cancer in these studies; however, also added that in some studies, BCC and melanoma were more prevalent in patients with higher Vitamin D levels, particularly the study by van der Pols et al.,[37] as also reported by Reddy, indicated that 25 (OH) D levels >75 nmol/L were associated with an increase in the incidences of BCCs and melanomas, and a statistically nonsignificant decrease in the incidence of SCCs.
A recently published systematic review which reports a meta-analysis of the dose–response relationship in prospective studies has criticized some of these studies, indicating that they are limited to small numbers of cases, and lack dose–response and subgroup analyses.[38] Another recent pooled analysis of 25 studies showed that low Vitamin D levels were associated with higher Breslow thickness and mortality rates in melanoma patients.[39]
High-intensity UVB exposure is known to initiate carcinogenesis in the skin by triggering cutaneous inflammation and DNA damage.[40] 95%–98% of UVB radiation can be absorbed with sunscreens with a protection factor. However, studies have shown that sunscreens could reduce the active synthesis of Vitamin D in the skin.[41] The Institute of Medicine, therefore, recommends a daily intake of 600 International Unit Vitamin D to patients who are recommended to reduce UV exposure and use sunscreen. Studies have shown that oral Vitamin D intake did not increase the risk of malignancy.[42],[43]
While different results are reported by meta-analyses and retrospective studies in the literature, advanced knowledge on the molecular properties and importance of Vitamin D has helped an increase in the number of randomized controlled trials. A phase III randomized controlled trial, in which the contribution of Vitamin D supplementation to relapse-free survival in malignant melanoma patients is the primary endpoint, is planned to end in September 2023.[44] We believe it will be such clinical trials that show us the path toward mitigating the paradox between low serum 25 (OH) D levels and cutaneous malignancy. We hope our study will contribute to the literature on this path.
Our study has some limitations. The first is its retrospective design. Nevertheless, care was taken to ensure standardization and reduce the number of parameters that could affect the results, and, to that end, only patients who had available pathology reports, had no known parathyroid pathology, did not concomitantly take bisphosphonate or Vitamin D supplement, and had their serum 25 (OH) D levels tested in November through February were included in the study. These criteria have led to a decrease in the number of eligible patients. Another limitation of our study is an outcome of its retrospective nature, in which only the basal Vitamin D levels were measured. It would be healthier to assess the association between Vitamin D levels and/or deficiencies, and cutaneous malignancy through repeating measurements.
ConclusionTo conclude, our study showed a statistically significant association between low serum 25 (OH) D levels and cutaneous malignancy, particularly BCC. Exposure of the skin to sunlight and synthesis of Vitamin D from 7-dehydrocholesterol are the major sources of Vitamin D. UVB, on the other hand, is known to be the most important risk factor in the development of cutaneous malignancy, and patients are advised to avoid sunlight. This paradox can be mitigated by regularly testing serum 25 (OH) D3 levels and giving Vitamin D3 replacement in patients who are advised to avoid exposure to UVR.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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