Serum 25-Hydroxyvitamin D Level Does Not Affect the Aggressiveness and Prognosis of Papillary Thyroid Cancer

Abstract

Background:

Vitamin D deficiency has been known to be associated with the aggressiveness and prognosis of several cancers. This study evaluated the effect of preoperative serum vitamin D levels on the aggressiveness and prognosis of papillary thyroid cancer (PTC).

Methods:

In total, 820 patients with PTC were enrolled. 25-hydroxyvitamin D levels were measured in blood samples before surgery. Clinical, pathologic, and recurrence data were accessed to examine the prognostic effects of vitamin D. Patients were categorized into four quartiles by preoperative serum vitamin D levels.

Results:

Of the enrolled patients, 795 (97%) had insufficient vitamin D levels (<30 ng/mL). Vitamin D levels showed positive correlations with age and body mass index (BMI), and negative correlations with serum thyrotropin levels and antithyroid peroxidase antibody titers. The association between vitamin D quartile and the risks of extrathyroidal invasion, lymph node metastasis, advanced cancer stages (III or IV), and risk of recurrence were not significant after adjusting for age, sex, BMI, preoperative ionized calcium, and parathyroid hormone. Additionally, serum vitamin D was not associated with recurrent or persistent PTC.

Conclusion:

Serum vitamin D levels are not associated with either disease aggressiveness or poor outcomes among patients with PTC and vitamin D insufficiency.

Introduction

Vitamin D has been known to be essential for bone mineralization by regulating calcium and phosphate metabolism (1). In addition to skeletal action, vitamin D levels have also been associated with several malignancies, including breast, colon, and prostate cancer (2). Previous epidemiological studies have reported an association between low serum vitamin D and increased risk of colorectal (3), breast (4), and prostate (5) cancer. Additionally, low vitamin D levels have been associated with high mortality and low disease-free survival rates in patients with colorectal cancer, breast cancer, and lymphoma (6). However, a small pilot study found no association between vitamin D levels and occurrence of thyroid cancer (7). Recently, Kim et al. reported that low serum vitamin D is associated with poor clinicopathological findings in female patients with papillary thyroid cancer (PTC) (8).

Calcitriol (1,25-OH Vitamin D₃) is a potent activated form of vitamin D and is converted from 25-hydroxyvitamin D₃ by cytochrome P450 enzyme CYP27B1 in the kidney (9). The action of vitamin D is mediated by the vitamin D receptor (VDR), a ligand-regulated nuclear hormone receptor. In previous studies, VDR expression has been reported in normal thyroid tissue as well as thyroid cancer tissue (10,11). VDR expression was shown to be higher in differentiated thyroid cancer tissue than normal thyroid tissue, but decreased expression was observed in cases of local or distant metastasis (11), suggesting the possibility of a local impact of calcitriol on thyroid cancer at an early stage. Another enzyme, CYP24A1, catabolizes calcitriol into the inactive 1α, 24,25(OH)₃D and 24,25(OH)₂D, and it was found to be increased in PTC (12). Furthermore, overexpression of CYP24A1 showed a strong correlation with the presence of the BRAF^V600E mutation (12). These molecular findings suggest that vitamin D might have antitumor activities in thyroid cancer cells.

25-hydroxyvitamin D₃ is the circulating form of vitamin D and is usually measured in the blood to monitor vitamin D levels in human subjects. Deficiency of vitamin D is defined as serum 25(OH)D₃ of <20 ng/mL, and vitamin D insufficiency is defined as a level of 21–29 ng/mL (13). Vitamin D insufficiency is very common in Korea, and vitamin D deficiency was found in 47.3% of males and 64.5% of females in the 2008 Korea National Health and Nutrition Examination Survey (KNHANES) (14). In addition, PTC has recently become a very common cancer in Korea. Therefore, this study evaluated the associations of preoperative serum vitamin D levels on the aggressiveness and prognosis of PTC in patients with vitamin D insufficiency.

Materials and Methods

Study population

Patients were retrospectively enrolled who underwent a total thyroidectomy and had pathologically confirmed PTC at the Chung-Ang University Hospital (Seoul, Korea) between May 2011 and April 2014. Among these patients, those who were followed for more than one year at the hospital were included. A blood sample for preoperative evaluation was obtained one to two weeks prior to the thyroid surgery. Subjects who had any prior cancer history, daily vitamin D supplementation, or a disease that would affect serum vitamin D levels were excluded from the study. In total, 820 patients met the inclusion criteria. These patients' medical records were retrospectively reviewed to obtain information about their age at diagnosis, sex, anthropometric data, preoperative parathyroid hormone (PTH), ionized calcium, 25-hydroxyvitamin D, thyroid function tests, thyroid autoantibodies (anti-thyroglobulin and thyroid peroxidase [TPO] antibodies), clinicopathologic characteristics, disease-free status, and vitamin D supplementation after thyroid surgery. This study was approved by the Institutional Review Board of the Chung-Ang University Hospital.

Measurement of 25-hydroxyvitamin D

Serum 25-hydroxyvitamin D levels were measured using a chemiluminescent immunoassay with an ADVIA Centaur Vitamin D Total assay (Siemens Healthcare Diagnostics, Inc., New York, NY). Vitamin D values <4 ng/mL were undetectable and were assigned to be 4 ng/mL. The intra- and inter-assay coefficients of variation were 5.1% and 4.4%, respectively. In addition to using vitamin levels as a continuous variable, 25-hydroxyvitamin D was treated as a categorical variable, and the season-adjusted vitamin D level was calculated. This was calculated by adding residuals from a locally weighted polynomial regression of 25-hydroxyvitamin D on the month of blood draw to the overall mean value. The patients were divided into four groups based on their seasonally adjusted vitamin D levels.

Statistical analyses

All of the statistical analyses were performed with IBM SPSS Statistics for Windows v20 (IBM Corp., Armonk, NY). To compare their clinicopathological features, a chi-square test was used for categorical variables, or Student's t-test for continuous variables. Pearson's correlation method was used to check the correlation between serum vitamin D and other parameters. Logistic regression analyses were used to evaluate the effect of vitamin D on the aggressiveness of thyroid cancer. Additionally, to identify the effect of vitamin D on disease-free survival, Cox proportional hazard models were used with or without multivariate analysis, using age at diagnosis, sex, body mass index, preoperative PTH, ionized calcium, thyrotropin (TSH), and vitamin D supplementation. A p-value of <0.05 was considered to be statistically significant.

Results

Clinicopathologic characteristics according to vitamin D level

In total, 820 patients diagnosed with PTC were included in the study. The median follow-up period was 35.0 months (range 12.9–151.5 months). The mean adjusted serum vitamin D level was 14.5 ± 6.3 ng/mL. Because most patients (97.3%) showed vitamin D insufficiency (<30 ng/mL), patients were divided into four groups according to season-adjusted serum vitamin D levels, and baseline characteristics were compared between each quartile group (Table 1). In the fourth quartile group, the age of the patients at diagnosis of thyroid cancer was significantly older, and there were significantly more males. Preoperative serum TSH and anti-TPO antibody titers were significantly higher in the first quartile group. When the correlations between age, body mass index (BMI), serum TSH, anti-TPO antibodies, and adjusted serum vitamin D levels were analyzed, age and BMI showed positive correlations with adjusted serum vitamin D levels (Table 2). In contrast, serum TSH and anti-TPO antibodies showed negative correlations with adjusted serum vitamin D levels. Other clinicopathologic parameters were not significantly different between each quartile group.

Table 1.

Clinicopathological Characteristics According to Quartiles of Adjusted Serum 25-Hydroxyvitamin D

	Total (N = 820)	Quartile 1 (<9.9; N = 205)	Quartile 2 (9.9–13.1; N = 205)	Quartile 3 (13.2–17.6; N = 205)	Quartile 4 (17.7–44.0; N = 205)	p-Value
Adjusted vitamin D (ng/mL)	14.5 ± 6.3	7.9 ± 1.6	11.6 ± 1.0	15.2 ± 1.3	23.2 ± 5.1	<0.001
Vitamin D supplementation after thyroid surgery (%)	419 (51.1)	110 (53.7)	96 (46.8)	113 (55.1)	100 (48.8)	0.284
Age at thyroid surgery (years)	46.7 ± 12.4	45.2 ± 11.9	45.3 ± 12.7	46.0 ± 11.6	50.4 ± 12.7	<0.001
Sex, male (%)	172 (21.0)	24 (11.7)	40 (19.5)	48 (23.4)	60 (29.3)	<0.001
Body mass index (kg/m²)	24.0 ± 3.6	23.6 ± 3.4	24.0 ± 3.9	24.0 ± 3.6	24.4 ± 3.4	0.128
Preoperative TSH (μIU/mL)	1.99 ± 1.70	2.20 ± 1.85	2.12 ± 2.20	1.94 ± 1.31	1.70 ± 1.24	0.016
Preoperative TPO antibody (IU/mL)	232.4 ± 680.9	338.80 ± 843.95	284.10 ± 768.22	142.96 ± 502.17	159.80 ± 519.85	0.009
Positivity of TPO antibody (%)	132 (16.8)	41 (20.4)	32 (16.4)	25 (12.9)	34 (17.3)	0.256
Preoperative PTH (pg/mL)	50.19 ± 21.07	56.24 ± 24.87	48.84 ± 17.23	51.18 ± 22.62	44.46 ± 16.84	<0.001
Preoperative ionized Ca (mg/dL)	4.82 ± 0.25	4.80 ± 0.25	4.83 ± 0.24	4.81 ± 0.27	4.87 ± 0.26	0.025
Tumor size (cm)	0.95 ± 0.70	0.94 ± 0.69	0.91 ± 0.62	0.98 ± 0.82	0.95 ± 0.63	0.783
Multiplicity (%)	346 (42.2)	88 (42.9)	79 (38.5)	90 (43.9)	89 (43.4)	0.673
Extrathyroidal invasion (%)	299 (36.5)	64 (31.2)	75 (36.6)	79 (38.5)	81 (39.5)	0.303
Perineural invasion (%)	60 (7.3)	19 (9.3)	15 (7.4)	14 (6.9)	12 (5.9)	0.619
Lymphatic invasion (%)	31 (3.8)	7 (3.4)	6 (2.9)	9 (4.4)	9 (4.4)	0.828
Lymph node metastasis						0.588
Central (%)	311 (37.9)	80 (39.4)	69 (34.3)	85 (41.9)	77 (38.3)
Lateral (%)	81 (9.9)	19 (9.4)	18 (9.0)	24 (11.8)	20 (10.0)
Thyroiditis (%)	311 (37.9)	84 (41.2)	77 (37.7)	70 (34.1)	80 (39.2)	0.513
BRAF mutation (%)^a	430 (83.8)	96 (85.7)	113 (83.4)	111 (83.5)	110 (82.1)	0.889
T stage, 3 or 4 (%)	301 (36.7)	63 (30.7)	76 (37.1)	83 (40.5)	79 (38.5)	0.194
N stage, 1 (%)	391 (47.7)	99 (48.5)	87 (43.7)	108 (53.5)	97 (48.7)	0.282
M stage, 1 (%)	8 (1.0)	3 (1.5)	2 (1.0)	3 (1.5)	0 (0.0)	0.387
Radioactive iodine therapy (%)	442 (53.9)	110 (53.7)	100 (48.8)	115 (56.4)	117 (57.9)	0.265
Risk of recurrence^b						0.597
Low risk	313 (38.2)	83 (40.5)	89 (43.4)	72 (35.1)	76 (37.1)
Intermediate risk	438 (53.4)	108 (52.7)	100 (48.8)	115 (56.1)	116 (56.6)
High risk	61 (7.4)	14 (6.8)	16 (7.8)	18 (8.8)	13 (6.3)

Numbers and percentages of BRAF mutation were calculated for patients who were tested with a BRAF mutation analysis before surgery.

Risk of recurrence was defined by the American Thyroid Association (ATA) guidelines (22).

Ca, calcium; PTH, parathyroid hormone; TPO, thyroid peroxidase; TSH, thyrotropin.

Table 2.

Correlations of Adjusted Serum 25-Hydroxyvitamin D Levels with Age, Body Mass Index, and Thyroid Function Tests

Variables	N	Pearson correlation	p-Value
Age	820	0.216	<0.001
Body mass index	820	0.073	0.036
TSH	818	−0.107	0.002
fT4	818	0.053	0.127
Anti-TPO antibody	786	−0.091	0.011

fT4, free thyroxine.

Effect of serum vitamin D on the aggressiveness or prognosis of PTC

To evaluate the effect of serum vitamin D on the aggressiveness of PTC, binary logistic regression analysis was performed for each quartile of serum vitamin D (Table 3). Advanced cancer stages (III or IV), extrathyroidal invasion, lateral lymph node metastasis, and stratification of the risk of recurrence did not significantly differ between the serum vitamin D quartiles.

Table 3.

Logistic Regression Analysis of the Effect of 25-Hydroxyvitamin D on the Aggressiveness of Thyroid Cancer

	Model 1			Model 2
	OR	CI	p-Value	OR	CI	p-Value
Extrathyroidal invasion
Quartile 1	0.737	0.486–1.117	0.150	0.799	0.520–1.226	0.304
Quartile 2	0.936	0.624–1.404	0.749	0.975	0.647–1.471	0.906
Quartile 3	0.973	0.651–1.454	0.893	1.023	0.679–1.541	0.915
Quartile 4	1	Ref		1	Ref
Lateral lymph node metastasis
Quartile 1	0.965	0.488–1.907	0.918	1.182	0.586–2.358	0.641
Quartile 2	0.862	0.435–1.710	0.672	0.944	0.471–1.892	0.871
Quartile 3	1.138	0.598–2.165	0.694	1.318	0.683–2.546	0.410
Quartile 4	1	Ref		1	Ref
Stage 3/4
Quartile 1	0.858	0.512–1.437	0.560	0.907	0.532–1.546	0.720
Quartile 2	0.634	0.377–1.065	0.085	0.649	0.382–1.100	0.108
Quartile 3	0.902	0.545–1.492	0.684	0.939	0.630–1.571	0.810
Quartile 4	1	Ref		1	Ref
Intermediate and high risk of recurrence by ATA classification (22)
Quartile 1	0.872	0.578–1.317	0.516	0.934	0.611–1.482	0.753
Quartile 2	0.749	0.497–1.127	0.165	0.782	0.517–1.182	0.243
Quartile 3	1.040	0.687–1.573	0.853	1.094	0.718–1.666	0.677
Quartile 4	1	Ref		1	Ref

Model 1 was adjusted for age (<45 and ≥45 years) and sex; model 2 was adjusted for the variables in model 1 plus BMI, preoperative ionized calcium, and PTH.

CI, confidence interval; OR, odds ratio.

The effect of serum vitamin D on recurring or persistent disease of PTC was also evaluated using Cox regression analysis. As shown in Table 4, serum vitamin D had no significant effect on the recurrence or persistence of PTC in multivariate analysis.

Table 4.

Risk of Recurring or Persistent Disease According to the Quartile of 25-Hydroxyvitamin D by Cox Proportional Hazard Analysis

	Quartile 1		Quartile 2		Quartile 3		Quartile 4
Variable	HR	CI	HR	CI	HR	CI	HR	CI	p-Value
Unadjusted	0.584	0.156–2.185	0.526	0.126–2.206	1.193	0.364–3.912	1	Ref	0.559
Adjusted for
Age	0.566	0.149–2.143	0.511	0.121–2.163	1.166	0.353–3.849	1	Ref	0.545
Body mass index	0.613	0.164–2.295	0.537	0.128–2.249	1.242	0.378–4.079	1	Ref	0.564
Preoperative PTH	0.540	0.140–2.081	0.508	0.121–2.135	1.142	0.345–3.776	1	Ref	0.530
Preoperative iCa	0.684	0.182–2.570	0.560	0.134–2.349	1.398	0.426–4.595	1	Ref	0.539
Preoperative TSH	0.608	0.162–2.277	0.547	0.130–2.295	1.216	0.370–3.993	1	Ref	0.588
Sex (male)	0.656	0.173–2.494	0.551	0.131–2.312	1.222	0.373–4.010	1	Ref	0.635
Tumor size	0.529	0.141–1.984	0.528	0.126–2.215	0.739	0.207–2.648	1	Ref	0.753
Extrathyroidal invasion	0.629	0.168–2.357	0.519	0.124–2.177	1.165	0.355–3.820	1	Ref	0.613
Lymph node metastasis	0.572	0.153–2.146	0.533	0.127–2.242	0.900	0.272–2.981	1	Ref	0.744
Distant metastasis	0.515	0.136–1.954	0.489	0.116–2.062	0.974	0.285–3.325	1	Ref	0.588
Thyroiditis	0.593	0.159–2.219	0.353	0.068–1.821	1.184	0.361–3.887	1	Ref	0.418
BRAF mutation	0.431	0.078–2.395	0.196	0.022–1.765	0.772	0.172–3.463	1	Ref	0.464
Radioactive iodine therapy	0.579	0.154–2.167	0.550	0.131–2.307	1.075	0.327–3.542	1	Ref	0.661
Vitamin D supplementation	0.608	0.162–2.274	0.524	0.125–2.196	1.254	0.381–4.120	1	Ref	0.537
Multivariate^a	0.798	0.198–3.212	0.614	0.145–2.602	1.521	0.453–5.110	1	Ref	0.584

Adjusted for age, sex, body mass index, preoperative PTH, iCa, TSH, and vitamin D supplementation.

HR, hazard ratio.

Since papillary thyroid microcarcinoma has an excellent prognosis, subgroup analyses were performed to evaluate the impact of the tumor, i.e. ≤1 cm or ≥1 cm. However, it was found that preoperative vitamin D levels were not associated with either the aggressiveness or the prognosis in larger PTCs (Supplementary Tables S1, S2 and S3; Supplementary Data are available online at www.liebertpub.com/thy).

Discussion

In this study, preoperative serum vitamin D levels were not associated with the aggressiveness or prognosis of PTC in vitamin D insufficiency. These results are discordant with previous studies that reported that lower preoperative serum vitamin D levels were associated with poor clinicopathological features in female patients with PTC (8). Several explanations were considered for the differences in findings between those studies and the current study.

First, vitamin D might not truly impact the aggressiveness or prognosis of thyroid cancer. To exclude other confounding factors that affect the aggressiveness or prognosis of thyroid cancer, the analysis was repeated in subjects without thyroiditis or in the female population. However, the results still did not differ in aggressiveness or prognosis across vitamin D levels in subjects without thyroiditis or who were female (data not shown).

Second, because only 10% of patients had vitamin D sufficiency in the fourth quartile group, there were not enough patients to represent higher levels of vitamin D. If there was a concentration-dependent effect of vitamin D, the first quartile group should have shown the most aggressive characteristics and poorest prognosis. However, the second quartile group had more advanced T stages (3 or 4), lymph node metastasis, and extrathyroidal invasion than the fourth quartile in the study by Kim et al. (8). Therefore, this discordant result might suggest that other factors besides vitamin D affect the aggressiveness or prognosis of thyroid cancer.

In addition, there is a possibility that VDR polymorphisms may affect the influence of active vitamin D on thyroid carcinomas. In a previous study, VDR polymorphisms were associated with follicular thyroid cancer (15). VDR polymorphisms have also been associated with breast cancer progression (16) and the risk of advanced prostate cancer (17). More studies will be needed to confirm the effect of VDR polymorphisms on the prognosis of thyroid cancer.

Study results have also been inconsistent concerning the effect of vitamin D on other cancers, such as colon, breast, and prostate cancer. A meta-analysis showed a decreased risk of colorectal cancer in patients with high serum vitamin D levels (18). In breast and prostate cancer, the results were inconclusive. One meta-analysis showed no significant association between vitamin D levels and risk and progression of prostate cancer (19). In breast cancer, vitamin D supplementation did not reduce the incidence of breast cancer in postmenopausal women (20). In contrast, another meta-analysis for breast cancer showed that the risk of breast cancer decreased with increasing vitamin D levels of 27–34 ng/mL (21). Therefore, considering the above results, it is still difficult to draw any conclusions about the effect of vitamin D on thyroid and other cancers.

This study has several limitations. First, there is a possibility of selection bias. The study subjects were enrolled from one hospital (Chung-Ang University Hospital) retrospectively, and most of them lived in an urban area. Therefore, more subjects with vitamin D deficiency were included in the study. Another limitation is the relatively short follow-up period. Because PTC is generally an indolent cancer with a favorable long-term survival rate, a longer duration of follow-up will be needed to evaluate a more accurate prognosis by vitamin D level status. In addition, only 2.7% of patients were vitamin D sufficient. Therefore, the possibility that different results would have been obtained if the fourth quartile group had included more vitamin D sufficient patients cannot be excluded. Lastly, because the months of serum vitamin D measurement varied and serum vitamin D was measured only once, each subject's vitamin D levels might not be representative. To overcome this limitation season-adjusted vitamin D levels were calculated.

Despite these limitations, this study is meaningful because there is a lack of research on the effect of vitamin D on the aggressiveness or prognosis of PTC. To confirm the exact effect of vitamin D on thyroid cancer, a randomized controlled trial will be needed in the future.

In summary, preoperative serum vitamin D levels were not found to be associated with aggressiveness or prognosis of PTC in patients with vitamin D insufficiency.

Footnotes

Acknowledgments

This work was supported by Chung-Ang University Research Grants in 2014.

Author Disclosure Statement

The authors declare that no competing financial interests exist.

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