Superficial spreading melanoma arising from a dysplastic nevus

Finnish Study Finds Fewer Melanoma Cases Among Regular Users of Vitamin D Editors’ note:  Please consult your health care provider before initiating any vitamin supplementation, including Vitamin D as potentially serious side effects are possible. Interview with:
Prof. Ilkka T Harvima

Department of Dermatology
University of Eastern Finland and Kuopio University Hospital
Kuopio, Finland What is the background for this study?

Response: The North Savo Skin Cancer Program in Eastern Finland was launched in 2017, and it aims at reducing the incidence, morbidity and mortality caused by skin cancers, such as basal cell carcinoma, squamous cell carcinoma and melanoma. A part of this program constituted a follow-up project of patients with an assessed risk of skin cancer. There are also several other parts, such as analysis of skin cancer material reposited in the Biobank of Eastern Finland (see the enclosed BMC Cancer 2021 reference), public information, education of general physicians and medical students etc.

In 2021, we published the article in BMC Cancer (enclosed), where we attempted to clarify the reasons for the relatively high melanoma mortality in relation to its incidence in this region (North Savo) of the country. By using the biobank material we also published an article in 2022 showing that melanoma and melanoma in situ associate with keratinocytic premalignant lesions and keratinocyte skin carcinomas (Suhonen V, Siiskonen H, Suni M, Rummukainen J, Mannermaa A, Harvima IT. Malignant and in situ subtypes of melanoma are associated with basal and squamous cell carcinoma and its precancerous lesions. Eur J Dermatol 2022 Apr 1;32(2):187-194. doi: 10.1684/ejd.2022.4221.).

The follow-up study of about 500 subjects is ongoing (COVID-19 caused pretty much trouble for the recruitment). This is focused on finding risk factors and biomarkers for skin cancers and carcinogenesis.

The first study on these follow-up patients was published in 2021 (Komulainen J, Siiskonen H, Harvima IT. Association of elevated serum tryptase with cutaneous photodamage and skin cancers. Int Arch Allergy Immunol 2021;182(11):1135-1142. doi: 10.1159/000517287.).

The article on vitamin D just recently published in Melanoma Research on Dec 28, 2022, is the second one.

The third work in pipeline deals with the association of atopic disorders with skin cancers, and the manuscript is under revision.

So, these provide with some background for the article in Melanoma Research. Actually, we thought that vitamin D use might associate with skin photoaging, actinic keratoses and carcinogenesis, but the only, though very important, finding was its association with melanoma. We have not focused our research just on vitamin D only, but it looks like we need to go further. What are the main findings?

Response:  There are fewer melanoma cases among regular users of vitamin D than among non-users. In addition, the skin cancer risk class (the subjects were classified to low, moderate, or high) as assessed by experienced dermatologists was significantly lower among regular than non-users.

We divided the subjects into 3 groups based on their self-reported use of vitamin D supplement: no use, occasional use, regular use. This is the way how a doctor tries to clarify this issue when examining a patient. In half of the subjects in each group, we analyzed serum calcidiol and confirmed that, indeed, the answers were in a dose-dependent fashion associated with serum calcidiol level. So, this classification system seems to be quite useful for clinical practice.

In the logistic regression analysis, the odds ratio was 0.447 among regular users and 0.523 among occasional users. Therefore, a dose-dependency was noted, again: the risk (odds ratio) of melanoma decreased from 1 (non-users) -> 0.523 (occasional users) -> 0447 (regular users). Of course, the causality between vitamin D use and melanoma can not be shown in this type of cross-sectional study. Hopefully, the follow-up program enlightens this matter in the near future.

One point we would like to bring out, too. Serum calcidiol alone may not necessarily be a good marker of skin cancer risk. Human skin itself expresses CYP27A1 (that produces calcidiol from vitamin D) and CYP27B1 (that produces biologically very active calcitriol from calcidiol). Moreover, human skin expresses CYP24A1 that can inactivate vitamin D and its metabolites. The balance between their expression may determine the end level of vitamin D/metabolites within cutaneous microenvironment. What should readers take away from your report?

Response: We still need to follow the recommendations in each country on the dose of vitamin D supplement. However, in countries with a short daylight in winter, like in Finland, one might consider a higher dose of vitamin D, perhaps some 20-50 micrograms a day. The dose should not reach/exceed 100 micrograms because toxicity may take place. This is important to note because there are always people in populations who get too excited at scientific articles and consequently may take too high doses with resultant toxic effects. What recommendations do you have for future research as a results of this study?

Response:  In order to obtain solid results, a double-blind placebo-controlled study with different doses of vitamin D should be designed. These types of studies are expensive, large and long-lasting, perhaps with some 5-year follow-ups


Kanasuo E, Siiskonen H, Haimakainen S, Komulainen J, Harvima IT. Regular use of vitamin D supplement is associated with fewer melanoma cases compared to non-use: a cross-sectional study in 498 adult subjects at risk of skin cancers. Melanoma Res. 2022 Dec 28:CMR.0000000000000870. doi: 10.1097/CMR.0000000000000870. Epub ahead of print. PMID: 36580363.

Our references are below:

Kaukinen A, Pelkonen J, Harvima IT. Mast cells express CYP27A1 and CYP27B1 in epithelial skin cancers and psoriasis. Eur J Dermatol 2015; 25:548-555. doi: 10.1684/ejd.2015.2645.

Kaukinen A, Siiskonen H, Pelkonen J, Harvima IT. Immunoreactivity to CYP24A1, but not vitamin D receptor, is increased in mast cells of keratinocyte skin cancers. Eur J Dermatol 2017; 27:590-598. doi: 10.1684/ejd.2017.3132.

Furthermore, the mutations in the genes of these CYP enzymes and vitamin D receptor may have an impact on their levels and effect.

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