ARTICLE

Vitamin D Deficiency as a Potentially Modifiable Risk

Factor for Thyroid Cancer

Michael Roskies, BSc, Yalon Dolev, MD, Derin Caglar, MD, Michael P. Hier, MD, FRCSC,Alex Mlynarek, MD, FRCSC, Agnieszka Majdan, MD, FRCPC, and Richard J. Payne, MD, FRCSC

ABSTRACT

Background: Vitamin D, classically involved in calcium homeostasis, has garnered recent interest for its potential role in cancer

prevention and therapy. Although few risk factors have been established in the development of well-differentiated thyroid

carcinoma, some would argue that no clear modifiable risk factor exists. Our study is one of the first to explore the relationship

between vitamin D deficiency and thyroid cancer.

Methods: This retrospective cohort study was done at a university-affiliated thyroid cancer centre. In 2010, 212 patients

undergoing thyroidectomy had their preoperative 25-hydroxyvitamin D3 levels recorded in addition to the final pathologies of their

resected thyroid nodule. The patients were stratified based on vitamin D status; vitamin D deficiency (VDD), reflecting levels under

the established threshold of 37.5 nmol/L; and vitamin D sufficiency (VDS), reflecting levels above it. The primary outcome of

malignancy rate was used to compare the proportion of malignant nodules in the VDD versus the VDS groups.

Results: The malignancy rate rises when comparing the VDS and VDD groups, from 37.5 (33 of 88) to 75% (9 of 12), respectively,

corresponding to a relative risk of 2.0 (p 5 .03, 95% CI 1.07–2.66).

Conclusion: This is the first study to demonstrate the inverse relationship between VDD and well-differentiated thyroid

carcinoma. Larger prospective studies are needed to replicate these results. Should this happen, VDD may be the first modifiable risk

factor for thyroid cancer.

SOMMAIRE

Contexte: La vitamine D, bien connue pour son role dans l’homeostase du calcium, suscite de l’interet depuis quelque temps

pour son role possible dans la prevention et le traitement du cancer. Bien que peu de facteurs de risque aient ete mis en evidence

dans l’apparition du carcinome bien differencie de la thyroıde, certains font valoir qu’il n’existe pas de facteur de risque nettement

modifiable. La presente etude est l’une des premieres a examiner le lien entre la carence en vitamine D et le cancer de la thyroıde.

Methode: Cette etude de cohortes retrospective a ete menee dans un centre de traitement du cancer de la thyroıde, rattache a

une universite. Ont ete consignes le taux preoperatoire de 25(OH)D3 ainsi que les resultats definitifs de l’examen histopathologique

des nodules thyroıdiens excises chez 212 patients ayant subi une thyroıdectomie en 2010. Les patients ont ete classes en fonction du

taux de vitamine D; ainsi, une carence (CVD) a ete definie comme une valeur inferieure au seuil etabli de 37.5 nmol/L, et la suffisance

(SVD), comme une valeur superieure a cette limite. Le taux de malignite, principal critere d’evaluation, a servi de point de

comparaison entre les groupes CVD et SVD quant a la proportion de nodules malins.

Resultats: Une augmentation du taux de malignite a ete constatee entre les groupes SVD et CVD; en effet, celui-ci est passe de

37.5 (33 a 88) a 75% (9 a 12), respectivement, ce qui correspond a un risque relatif (RR) egal a 2.0 (p 5 .03; IC 5 1.07–2.66).

Conclusions: Il s’agit de la premiere etude dans laquelle une relation inverse a ete etablie entre la CVD et le carcinome bien

differencie de la thyroıde. Des etudes prospectives, de grande taille, s’imposent afin de reproduire les resultats. Si les donnees

devaient se confirmer, la carence en vitamine D pourrait etre consideree comme le premier facteur de risque modifiable du cancer de

la thyroıde.

Key words: risk factor, thyroid malignancy, vitamin D deficiency

Michael Roskies: Faculty of Medicine, McGill University; Yalon Dolev,

Michael P. Hier, Alex Mlynarek, and Richard J. Payne: Department of

Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis Jewish

General Hospital; Derin Caglar: Department of Pathology, McGill

University; and Agnieszka Majdan: Department of Endocrinology,

McGill University, Montreal, QC.

DOI 10.2310/7070.2011.110174

# 2012 The Canadian Society of Otolaryngology-Head & Neck Surgery

Address reprint requests to: Dr Richard J. Payne, Room L4.08, Royal

Victoria Hospital-MUHC, 687 Pine Ave W, Montreal, Quebec, Canada

H3A 1A1.

160 Journal of Otolaryngology-Head & Neck Surgery, Vol 41, No 3 (June), 2012: pp 160–163

25-H ydroxyvitamin D3 (25(OH)D3), classically

involved in calcium homeostasis, has gar-

nered interest recently for its potential role in cancer

prevention and therapy as it exerts effects on cell

proliferation, differentiation, apoptosis, and angiogenesis.

In vitro models have shown that knocking out the vitamin

D receptor (VDR) has predisposed subjects to cancerous

lesions of the breast, skin, blood, and more.1 Indeed,

epidemiologic research has followed and has demonstrated

an inverse relationship between vitamin D deficiency

(VDD) and cancers of the prostate, colon, and breast.2–4

As a direct result, many have started to incorporate this

inexpensive, easily accessible single supplement into their

daily lives. Even Health Canada continues to increase its

recommended daily allowance of vitamin D, up 200 IU in

the past 5 years.

The literature is devoid of research showing an

association between VDD and thyroid carcinoma.

Although few risk factors for thyroid cancer have been

established (ie, age, sex, previous radiation exposure, and

family history), some would argue that no modifiable risk

factor exists. Our study aimed to explore the relationship

between differentiated thyroid cancer and serum vitamin

D level in patients undergoing thyroidectomy. Specifically,

this study is one of the first to test for a relationship

between VDD and malignant thyroid disease.

Methods

Data Collection

A comprehensive database was created on all patients

undergoing thyroidectomy at a university-affiliated

thyroid cancer centre in 2010. The study was subject to

review and approved by the research ethics board at our

institution. Patient variables such as age, sex, serum

25(OH)D3 levels, and final pathology were recorded for

all 212 subjects. Included in the study were all patients

undergoing total or completion thyroidectomy. Excluded

were those patients undergoing subtotal thyroidectomy

or concomitant parathyroidectomy and those with

incomplete files (ie, laboratory results or final pathology

was not returned or done). The remaining 100 patients

were then assigned to the ‘‘malignant’’ or the ‘‘benign’’

group as determined by their final pathologic specimen

results. Included under the malignant heading were well-

differentiated papillary, follicular, anaplastic, and

Hurthle cell carcinomas. The benign group represented

infectious etiologies, benign adenomas, and micropapil-

lary carcinomas.

Data Analysis

The vitamin D threshold of 37.5 nmol/L established in the

third National Health and Nutrition Examination Survey

(NHANES III)5 was used to stratify for VDD below the

threshold and vitamin D sufficiency (VDS above it,

respectively. Our primary outcome of malignancy rate

was used to represent the proportion of patients in the

VDD group versus those in the VDS group who had a

malignant diagnosis. Analysis using chi-square testing was

done on independent variables presented in proportions

(ie, sex and vitamin D status), whereas a t-test was

employed for the mean ages between the groups. A value

of p , .05 was considered significant. The results were

verified by a trained and blinded statistician at our

institution.

Results

Of the 100 patient final pathologies collected, 42 were

malignant and 58 were benign. The overall VDD rate of

the cohort was 12%. Baseline characteristics are provided

in Table 1. Among the 88 patients in the VDS group, 33

had a malignant diagnosis, and of the 12 in the VDD

group, 9 had a malignant diagnosis. The increase in the

malignancy rate from 37.5 to 75% in the VDD and VDS

groups, respectively, corresponds to a relative risk of 2.0

(p 5 .03, 95% CI 5 1.07–2.66) (Figure 1). The mean ages

of 43.25 years in the deficient group and 48.27 years in the

sufficient group did not differ significantly, nor did the

proportion of females in both groups (77% vs 88.5%,

respectively).

Discussion

Observational studies in the 1940s first demonstrated that

people living at higher latitudes were predisposed to

certain cancers. Later studies have shown increased

mortality from cancer in populations exposed to less

ultraviolet B light.6 After undergoing activation in the skin

Table 1. Demographic Characteristics of Subjects Considered

Vitamin D Deficient or Vitamin D Sufficient Undergoing

Thyroidectomy

Characteristic

Vitamin D

Deficient

Vitamin D

Sufficient

p Value(n 5 12) (n 5 88)

Sex (% Female) 77 88.5 .24

Mean age (yr) 43.25 48.27 .10

Roskies et al, Vitamin D Deficiency as Modifiable Risk Factor for Thyroid Cancer 161

via sunlight and then subsequent hydroxylations in the

liver and kidney, the active form of vitamin D,

1,25(OH)D3, has been shown to act on calcium home-

ostasis, muscle function, the immune system, and

cardiovascular health. It is believed that 3% of our genome

is under the influence of vitamin D, and many of these

genes are involved in essential cell regulatory mechanisms

that, when disrupted, may result in carcinogenesis.7

Thyroid cancer increased in incidence at a rate of 6.5%

per year between 1988 and 2005.8 Many have pointed to

superior detection techniques as the source for these

numbers; however, it has been shown that even the larger

thyroid cancer nodules (. 4 cm or . 6 cm) have been

increasing in incidence as well.9 Although increased

surveillance and detection explain some of this perceived

increase, it is likely that there has been a ‘‘true’’ increase in

thyroid carcinoma. Diverse causes, including genetic and

environmental ones, have been proposed; this study aimed

to explore the latter by studying the association between

VDD and well-differentiated thyroid cancer. Interestingly,

this rise in thyroid cancer has corresponded to a similarly

increasing rate of VDD in the United States.10

Our study demonstrates that patients who are VDD are

two times as likely to have a malignant nodule compared

those with adequate serum vitamin D levels. It has been

established that the VDR is universally expressed in all

nucleated cells and that many tissues outside the kidney

express its activating enzyme, 1a-hydroxylase. The thyroid

gland has been shown to express both the VDR and 1a-

hydroxylase, and the thyroid hormone shares the same

nuclear mechanism of action as vitamin D. We hypothe-

size that perhaps vitamin D is able to bind to its receptor

in the thyroid gland, become activated, and exert its effects

locally to protect against carcinogenesis as vitamin D has

been shown to arrest thyroid carcinoma cell growth in

vitro.11

The major limitation of this study is that the results

only indicated if a nodule requiring excision is more likely

to be benign or malignant; thus, we cannot apply it to the

general population as a whole. Larger prospective cohort

studies are needed to replicate these results before VDD is

established as a risk factor for thyroid carcinoma. Other

factors, such as supplementation trends, race, and chronic

conditions, affecting the absorption of vitamin D need to

be further explored as well.

Conclusion

To our knowledge, this is the first study that shows an

association between VDD and thyroid cancer in human

subjects. One previously published article showed no

significant difference in the rates of VDD and the

incidence of thyroid carcinoma12; however, in vitro models

suggest that the link may exist.10 Our study shows that of

patients undergoing thyroidectomy, those with serum

vitamin D levels , 37.5 nmol/L had a greater malignancy

rate than those with serum levels above this threshold. We

hypothesize that because the thyroid gland expresses both

the VDR and its activating enzyme, it is the ideal

microenvironment for vitamin D to exert its anticarcino-

genic effects. Should future prospective studies replicate

these results, VDD may be the first modifiable risk factor

established for thyroid cancer, thus creating the potential

for disease prevention and outcome modification.

Acknowledgement

Financial disclosure of authors and reviewers: None

reported.

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Figure 1. Malignancy rate in vitaminD sufficient ($ 37.5 nmol/L) versusvitamin D deficient (, 37.5 nmol/L)patients undergoing thyroidectomy ata university-affiliated thyroid cancercentre.

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Roskies et al, Vitamin D Deficiency as Modifiable Risk Factor for Thyroid Cancer 163

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