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Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY 3 4 ( 2 0 13 ) 31 2–3 1 9
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Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma Dongbin Ahn, MD a,⁎, Jin Ho Sohn, MD, PhD a , Jae Hyug Kim, MD a , Chang Min Shin, MD a , Jae Han Jeon, MD b , Ji Young Park, MD, PhD c a b c
Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Korea Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
ARTI CLE I NFO
A BS TRACT
Article history:
Objective: To assess the effect of preoperative subclinical hypothyroidism on prognosis and
Received 13 September 2012
on the tumour's clinicopathological features at initial diagnosis of papillary thyroid carcinoma (PTC). Materials and methods: 328 patients who underwent surgery for PTC between January 2001 and December 2006 were enrolled in this study. Of these, we compared 35 patients with preoperative subclinical hypothyroidism with 257 patients who were euthyroid before the operation, with respect to clinicopathological characteristics and prognosis. Results: No significant differences were observed in tumour size, extrathyroidal extension, and multifocality between subclinical hypothyroidism and euthyroid patients. Patients with subclinical hypothyroidism had a considerably lower percentage of lymph node metastasis than did euthyroid patients (8.6% vs. 21.8%, p = 0.068). Although preoperative subclinical hypothyroidism decreased the risk of lymph node metastasis at 0.313 of odds ratio in the multivariate analysis, its significance was not verified (95% confidence internal, 0.089–1.092; p = 0.068). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than did preoperative euthyroid patients, for both recurrence (2.9% vs. 14.0%, p = 0.099) and 7-year disease-free survival (97.1% vs. 87.8%, p = 0.079), during the 82-month mean follow-up period. However, even as thyroid-stimulating hormone (TSH) concentration increased, there were no consistent relationships observed between the TSH levels and the prognostic parameters. Conclusion: We could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters, indicating that subclinical hypothyroidism with elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in PTC. © 2013 Elsevier Inc. All rights reserved.
1.
Introduction
In 1993, Hercbergs reported complete sustained regression of metastatic non-small cell lung cancer in a man who had lapsed
into a myxoedema coma and was subsequently resuscitated [1]. This unique event triggered investigation into whether hypothyroidism had a prognostic effect on metastatic cancer, and several preclinical studies revealed that thyroid hormone
⁎ Corresponding author. Department of Otolaryngology-Head and Neck Surgery, Kyungpook National University Hospital, 50 Samduck 2-Ga, Jung-Gu, Daegu 700-712, Korea. Tel.: + 82 53 200 5777; fax: +82 53 423 4524. E-mail address: [email protected] (D. Ahn). 0196-0709/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2012.12.013
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deprivation slowed solid tumour growth rates, whereas thyroid hormone supplementation increased them [2,3]. A plasma membrane receptor for thyroid hormone, integrin αvβ3, is the basis for a nongenomic mechanism of the hormonal actions that appear to contribute to proliferation of integrin ανβ3bearing cells [4–6]. Such cells are usually tumour cells or dividing endothelial or vascular smooth muscle cells [5,7]. However, investigators suggest that, in thyroid carcinoma, the thyroidstimulating hormone (TSH) stimulates the development of thyroid malignancy and that elevated serum TSH is associated with a higher incidence of thyroid cancer and advanced tumour stage, despite the fact that elevated TSH level typically signifies hypothyroidism, with deprivation of thyroid hormone [8]. This is contrary to the effect of hypothyroidism on other solid tumours, such as lung, prostate, and breast tumours, in which clinical or subclinical hypothyroidism ostensibly reduced cancer risk and resulted in better outcomes [9]. Interestingly, several recent studies suggest that Hashimoto's thyroiditis (HT) increases the risk for papillary thyroid carcinoma (PTC) [10–12]. Considering that HT is the most common cause of clinical primary hypothyroidism and that elevated TSH is much more frequently found in individuals with HT than in the general population, these findings also support a role for TSH in the occurrence of thyroid carcinoma. Ironically, however, most studies investigating the clinical relationship between HT and PTC report a better prognosis for PTC concurrent with HT compared with PTC alone, regardless of elevated TSH levels in some HT patients [10,13]. In addition, Hercbergs et al. reported apparent tumour stimulation with thyroid hormone and complete remission of tumour for clinical hypothyroidism in anaplastic thyroid carcinoma [9]. In summary, the results of studies concerning the effect of thyroid hormones (L-thyroxine [T4], triiodo-L-thyronine [T3]), and TSH on tumorigenesis vary among tumours and centres, thus contributing to ongoing uncertainty about their effect. In addition, it remains unclear whether the predominant effect of hypothyroidism on malignant tumours ensues from decreased thyroid hormone or elevated TSH. In the present study, we stratified the thyroid function status of our patients at the time of initial diagnosis of PTC and assessed the effect of preoperative subclinical hypothyroidism on prognosis and the tumour's presenting clinicopathological features.
2.
Materials and methods
2.1.
Patients
Between January 2001 and December 2006, 973 thyroid surgeries were performed at our institution. Of these, 328 patients met the following inclusion criteria and were retrospectively evaluated in our study: (1) thyroid surgery performed as initial treatment; (2) histologically confirmed PTC; (3) accessible medical records with preoperative results for thyroid function tests including serum TSH, free T4, and T3 levels; (4) no history of known thyroid disease and thyroidrelated medication including antithyroid drugs or levothyroxine; (5) regular follow-up over more than a 60-month period after initial thyroid surgery.
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Of the 973 cases, 129 (13.3%) cases were excluded because they were revision surgeries for recurrent thyroid carcinoma, and 156 (16.0%) because they involved other subtypes of thyroid carcinoma, such as follicular (7.3%, 71/973), medullary (2.3%, 22/973), and anaplastic carcinomas (1.2%, 12/973), or benign tumours (5.2%, 51/973). A total of 228 (23.4%) patients were excluded because they had previously been diagnosed with nonsurgical thyroid disease or had taken thyroid-related medication before the preoperative thyroid function tests were performed. The remaining 132 (13.6%) of 973 patients were excluded due to insufficient follow-up; inadequate medical records; or absence of preoperative serum TSH, free T4, or T3 levels. Finally, 328 patients were eligible for analysis in our study. The cohort of 328 patients enrolled in our study comprised 50 men and 278 women, with a mean age of 47.0 years at the time of diagnosis of PTC. Thyroid lobectomy with isthmusectomy was performed in 38 patients, while total thyroidectomy with or without neck dissection was performed in 290 patients. Total thyroidectomy with central neck dissection and without lateral compartment neck dissection was performed in 33 patients. Total thyroidectomy with comprehensive neck dissection including central neck dissection such as radical neck dissection, modified radical neck dissection, and selective neck dissection of level II to V was performed in 42 patients, with 5 patients undergoing bilateral neck dissection.
2.2. Classification according to preoperative thyroid function status In accordance with standard practice in our institution's laboratory, the reference range of TSH, free T4, and T3 concentration was defined as 0.45 to 4.5 mIU/L, 0.8 to 2.0 ng/ dL, and 0.6 to 1.9 ng/mL, respectively [14,15]. The 328 patients were classified into 5 categories according to preoperative thyroid function status as follows; euthyroid, subclinical hypothyroidism, subclinical hyperthyroidism, overt hypothyroidism, and overt hyperthyroidism. Euthyroid status was defined as normal levels of serum TSH, free T4, and T3. Subclinical hypothyroidism was defined as an elevation in serum TSH level above the upper limit of reference range, with normal free T4 concentrations [14,15]. Subclinical hyperthyroidism was defined as a decrease in serum TSH level below the reference range, with normal serum free T4 and T3 concentrations [14,15]. Overt hypothyroidism was defined as an elevation in serum TSH and free T4 concentrations, and overt hyperthyroidism was defined as a decrease in serum TSH, free T4, and T3 concentrations. To assess the effect of subclinical hypothyroidism on PTC, we compared the 35 patients with subclinical hypothyroidism with the 257 euthyroid patients for clinicopathological characteristics and prognosis. Because most patients with established clinical or overt hypothyroidism have been treated with thyroid hormone supplement prior to the diagnosis of PTC and/or have had regular thyroid evaluations including thyroid ultrasonography, they would introduce an important bias into analysing the effect of preoperative thyroid function status on the time of detection and clinical features of PTC. Therefore, we decided that patients with subclinical thyroid dysfunction
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were best suited for estimating the effect of preoperative TSH concentration on PTC.
2.3.
levels. With regard to the results, p values were 2-sided throughout and statistical significance was defined as p < 0.05.
Review of histopathological parameters
3. The histopathological parameters of each patient were blindly determined by 1 co-author specializing in thyroid pathology (JY Park). All pathological slides were reviewed for primary tumour size, presence of multifocal disease, extrathyroidal extension (ETE), cervical lymph node (LN) metastasis, and coexisting HT. Pathologic staging was redefined according to the Tumor, Lymph Node, and Metastasis (TNM) staging system of the 6th edition of the International Union Against Cancer and the American Joint Committee on Cancer (UICC/AJCC).
2.4.
Treatment protocol for papillary thyroid carcinoma
All patients underwent surgery performed by the 2 experienced head and neck surgeons. The concrete principle of thyroid surgery was as follows. Thyroid lobectomy with isthmusectomy was performed only when the following criteria were met: the cancer was an intrathyroidal, unifocal microcarcinoma (< 1 cm in diameter), with no cervical lymph node involvement. In the other cases, total thyroidectomy was primarily performed. Central neck dissection was performed when enlarged LN was seen in preoperative imaging study or the surgical field of vision with 2.5× loupes, or was detected by palpation of the central neck region. When metastasis to the lateral compartment of the neck was identified in the preoperative evaluation or in follow-up examination after initial thyroid surgery, comprehensive neck dissection was performed from level II to VI. Radioactive iodine remnant ablation was performed using 100–150 mCi 131I with the same indications as those for total thyroidectomy.
2.5.
Statistical analyses
SPSS for Windows (version 12.0; SPSS, Chicago, IL, USA) was used to analyse the data. Continuous data are represented as mean ± standard deviation. To compare continuous variables, age, tumour size, and concentrations of TSH, free T4 and T3 according to thyroid function status were tested using an independent t-test. The association between subclinical hypothyroidism and prognostic variables was assessed using a Chi-square test or Fisher's exact test for age ≥ 45 years, sex, primary tumour size ≥ 1-cm diameter, ETE, multifocality, LN metastasis, and concurrent HT. LN metastasis according to various clinicopathological factors such as age ≥ 45 years, sex, primary tumour size ≥ 1-cm diameter, ETE, multifocality, and subclinical hypothyroidism was also assessed using the Chisquare or Fisher's exact test. Multivariate analysis was performed by binary logistic regression. The Kaplan–Meier method with a log-rank test was used to determine diseasefree survival rate during the follow-up period. Correlation analysis was performed to evaluate whether a linear relationship existed between TSH levels and continuous variables such as age and tumour size. For categorical variables such as ETE, multifocality, LN metastasis, and recurrence, p value for trend was used to assess the linear relationship with TSH
Results
3.1. Thyroid function status at the time of diagnosis of PTC Of 328 patients with PTC, 257 (78.4%) had normal thyroid function. A total of 64 patients (19.5%) had subclinical thyroid dysfunction, 35 of them (10.7%) with subclinical hypothyroidism and 29 (8.8%) with subclinical hyperthyroidism. Since we excluded patients with a history of known thyroid disease or thyroid-related medication, overt thyroid dysfunction including hypothyroidism and hyperthyroidism was documented in only 7 patients (2.1%) (Fig. 1).
3.2. Do patients with subclinical hypothyroidism have aggressive clinicopathological features of PTC compared with patient who are euthyroid? The clinicopathological factors of 257 patients with preoperative euthyroid state and 35 patients with subclinical hypothyroidism were compared (Table 1). With respect to thyroid function test, the mean concentration of TSH was 1.86 mIU/L in the euthyroid group and 6.86 mIU/L in the subclinical hypothyroidism group. This difference was statistically significant (p < 0.001). Although concentrations of free T4 and T3 were lower in the subclinical hypothyroidism patients than in the euthyroid patients, the difference did not reach statistical significance (1.03 vs. 1.21 ng/dL, p = 0.168 in free T4 and 1.08 vs. 1.23 ng/dL, p = 0.377 in T3, respectively). Patients with subclinical hypothyroidism were similar to the euthyroid group with regard to mean age (48.1 vs. 46.6 years, p = 0.537), proportion of male gender (14.3% vs. 16.0%, p = 0.799), mean primary tumour size (1.6 vs. 1.7 cm, p = 0.547), ETE (62.9% vs. 53.7%, p = 0.307), multifocality (42.9% vs. 30.0%, p = 0.123), and concurrent HT (31.4% vs. 22.6%, p = 0.247), and stage (p = 0.081). Although a considerably lower percentage of LN metastasis was found in patients with subclinical hypothyroidism compared with euthyroid patients (8.6% vs. 21.8%, p = 0.068), the difference did not reach statistical significance.
Fig. 1 – Thyroid function status at the time of diagnosis of papillary thyroid carcinoma.
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Table 1 – Clinicopathological characteristics according to preoperative thyroid function status. Euthyroid group (n = 257)
Subclinical hypothyroidism group (n = 35)
p-value
1.86 ± 0.92 1.21 ± 0.72 1.23 ± 1.03 46.6 ± 13.0 144 (56.0%) 41:216 1.7 ± 1.3 172 (66.9%) 138 (53.7%) 77 (30.0%) 56 (21.8%) 58 (22.6%)
6.86 ± 3.29 1.03 ± 0.24 1.08 ± 0.22 48.1 ± 12.6 19 (54.3%) 5:30 1.6 ± 1.1 21 (60.0%) 22 (62.9%) 15 (42.9%) 3 (8.6%) 11 (31.4%)
<0.001 0.168 0.377 0.537 0.845 0.799 0.547 0.417 0.307 0.123 0.068 0.247
159 (61.9%) 16 (6.2%) 60 (23.3%) 22 (8.6%)
23 (65.8%) 0 (0.0%) 12 (34.2%) 0
0.081
Thyroid function test TSH (mIU/L) Free T4 (ng/dL) T3 (ng/dL) Age (years) ≥45 Sex (male:female) Primary tumour size (cm) ≥1 Extra-thyroidal extension Multifocal disease Lymph node metastasis Concurrent Hashimoto's thyroiditis Stage I II III IV
3.3. Is subclinical hypothyroidism associated with the incidence of LN metastasis?
3.4. Recurrence and survival differences between patients with preoperative euthyroid status and subclinical hypothyroidism
Table 2 lists the univariate and multivariate clinicopathological factors associated with LN metastasis at the initial diagnosis of PTC. LN metastasis at initial diagnosis was significantly associated with patient age ≥ 45 years (p = 0.047), primary tumour size ≥ 1 cm (p = 0.001), and ETE (p < 0.001) in univariate analysis. Although the proportion of male gender was considerably higher in patients with LN metastasis and subclinical hypothyroidism was frequently found in patients without LN metastasis, these differences were not statistically significant (p = 0.060 and p = 0.068, respectively). On multivariate analysis including variables with p < 0.2 on univariate analysis, male gender (odds ratio = 2.198; 95% confidence interval, 1.012–4.772; p = 0.046), tumour size ≥ 1 cm (odds ratio = 2.554; 95% confidence interval [CI], 1.158–5.631; p = 0.020), and ETE (odds ratio = 2.882; 95% CI, 1.458–5.699; p = 0.002) were significantly associated with LN metastasis at the time of initial diagnosis. Preoperative subclinical hypothyroidism was found to decrease the risk of LN metastasis at 0.313 of odds ratio, however, its significance was not verified (95% CI, 0.089–1.092; p = 0.068).
During the mean 82-month follow-up period, recurrence occurred in 36 (14.0%) of 257 euthyroid patients and only 1 (2.9%) of 35 patients with subclinical hypothyroidism. This difference was not statistically significant (p = 0.099). Overall, 4 (1.6%) patients with euthyroid status died, but only 2 (0.8%) of these deaths were due to PTC or related complications. All patients with subclinical hypothyroidism were alive at the time of the present evaluation (Table 3). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than the euthyroid patients, although the difference between the 2 groups did not reach statistical significance in 7-year disease-free survival rates (p = 0.079, Fig. 2).
3.5. Trends in prognostic parameters with respect to TSH level We subdivided all the patients into 4 categories according to TSH levels (0.45–2.4 mIU/L; 2.5–4.5 mIU/L; 4.6–6 mIU/L; > 6
Table 2 – Clinicopathological factors associated with lymph node metastasis at initial diagnosis: univariate and multivariate analysis.
Age ≥ 45 years Male Primary tumour size ≥ 1 cm Extra-thyroidal extension Multifocal disease Subclinical hypothyroidism ⁎ Statistically significant.
Univariate
Multivariate
Odds ratio
Confidence interval 95%
0.047 ⁎ 0.060 0.001 ⁎ <0.001 ⁎ 0.166 0.068
0.097 0.046 ⁎ 0.020 ⁎ 0.002 ⁎ 0.241 0.068
0.597 2.198 2.554 2.882 1.473 0.313
0.325–1.099 1.012–4.772 1.158–5.631 1.458–5.699 0.770–2.818 0.089–1.092
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Table 3 – Recurrence and survival according to preoperative thyroid function status.
Follow-up period (months) Recurrence Death Disease-specific 7-year disease-free survival rate
Euthyroid group (n = 257)
Subclinical hypothyroidism group (n = 35)
p-value
82.8 ± 21.5 36 (14.0%) 4 (1.6%) 2 (0.8%) 87.8%
82.0 ± 14.3 1 (2.9%) 0 (0.0%) 0 (0.0%) 97.1%
0.761 0.099 1.000 1.000 0.079
mIU/L) and examined the prognostic parameters to evaluate whether there is any positive or negative relationship corresponding to an increase in TSH level. Pearson's correlation coefficients (r) for age and tumour size with TSH level were 0.026 and − 0.066, respectively, indicating that there were only ignorable linear relationships (Fig. 3). P values for trend in ETE, multifocality, LN metastasis, and recurrence were 0.087, 0.051, 0.254, and 0.076, respectively (Fig. 4). Generally, age, ETE, and multifocality show a rising trend with respect to an increase in TSH concentrations, whereas primary tumour size, LN metastasis, and recurrence show a decreasing trend. However, none of these parameters had statistically significant associations with TSH concentrations.
4.
Discussion
come this limitation, we deemed that patients with incidentally found subclinical thyroid dysfunction were best suited for estimating relationships between preoperative thyroid function status and thyroid cancer, although studying patients with clinical or overt thyroid dysfunction might yield clearer results. The prevalence of subclinical hypothyroidism is about 4% to 10% in those without known thyroid disease [15]. The prevalence increases with age; subclinical hypothyroidism is found in up to 20% of women older than 60 years of age [15,16]. In our study of patients with PTC, the prevalence of subclinical hypothyroidism was 10.7%, which is comparable to the rate in the general population without thyroid disease, suggesting that PTC may not affect thyroid gland function. With respect to the aetiology of the subclinical hypothyroidism of our patients, Hashimoto's thyroiditis, which is the most common
Although numerous studies have reported the effects of subclinical hypothyroidism on the cardiovascular system, metabolic syndrome, and neuropsychiatric disease, it is an unfamiliar subject to oncologist, particularly those studying thyroid cancers. Because most patients with established clinical or overt hypothyroidism should be treated with thyroid hormone supplements regardless of diagnosis of thyroid cancer, it is difficult to evaluate the absolute effect of preoperative hypothyroidism on thyroid cancer. To over-
Fig. 2 – Kaplan–Meier curves for disease-free survival according to preoperative thyroid function status.
Fig. 3 – Mean age (A) and tumour size (B) according to the thyroid-stimulating hormone (TSH) concentration. r = Pearson's correlation coefficient.
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Fig. 4 – Incidence of extrathyroidal extension (ETE) (A), multifocality (B), lymph node (LN) metastasis (C), and recurrence (D) according to thyroid-stimulating hormone (TSH) concentration. Ptrend = p value for trend.
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cause of clinical hypothyroidism, was also supposed to be the most important cause of subclinical hypothyroidism: concurrent Hashimoto's thyroiditis was more common in patients with subclinical hypothyroidism than in euthyroid subjects in this study. Although consumption of iodine in seafood, such as fish, sushi, and seaweed, could also be an important cause of subclinical hypothyroidism in our country, the diets of euthyroid subjects and subclinical hypothyroidism patients enrolled in our study did not likely differ in this respect, because most of them belonged to the same community. Recently, several studies reported that elevated TSH is associated with a higher incidence of thyroid cancer and advanced-stages, regardless of age [8,17,18]. A study evaluating 554 patients with well-differentiated thyroid cancer found that TSH ≥ 2.5 mIU/L was associated with a higher incidence of ETE and lateral LN metastasis [8]. In a study of 10,178 patients subjected to fine needle aspiration, patients with PTC cytology exhibited significantly higher concentrations of TSH than did those with benign thyroid disease [18]. However, these studies had some limitations. Some reports did not take thyroid hormone (T4 and T3) concentrations into consideration, despite the fact that elevated TSH usually denotes decreased thyroid function, while others patients with varying thyroid function, such as hyperthyroidism, hypothyroidism, and euthyroidism, preventing a clear answer for whether elevated TSH increases the risk for thyroid carcinoma or advancedstages compared with euthyroid status [8,18]. To overcome these limitations, we restricted our analysis to patients with subclinical hypothyroidism thus eliminating any bias introduced by effects of endogenous and exogenous thyroid hormone, and compared them directly to patients with euthyroid status. In our study, there were no significant differences in tumour size, ETE, and multifocality between euthyroid patients and those with subclinical hypothyroidism. Patients with subclinical hypothyroidism had a considerably lower incidence of LN metastasis than did the euthyroid group, although the difference was not statistically significant. This result contradicts previously reported studies on the role of TSH in thyroid cancer; however, well-known parameters predicting tumour aggressiveness, such as male gender, primary tumour size ≥ 1 cm, and ETE, were well correlated with LN metastasis on multivariate analysis, demonstrating the reliability of our study [8]. The results of our study could support the hypothesised role of clinical or subclinical hypothyroidism in solid tumours other than thyroid cancer. In a study evaluating breast cancer patients and 1250 controls, women with untreated hypothyroidism or goitre had a significantly reduced incidence of breast cancer [19]. In a study of renal cell carcinoma, the objective remission rate and median survival duration were significantly better in patients with subclinical hypothyroidism than in euthyroid patients [20]. In addition, hypothyroidism was associated with a delayed onset of cancer, smaller tumour size, and less likelihood for metastatic disease in several oncological studies [9,21]. In our study, although it was not statistically significant, there was a trend toward older age, smaller tumours, and lower incidence of LN metastasis at the time of diagnosis of PTC in patients with subclinical hypothyroidism. Furthermore, considering that the recurrence rate of
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PTC after total thyroidectomy followed by radioactive iodine ablation and TSH suppression treatment is reported as 10%– 20%, our findings of a 7-year disease-free survival rate of 97.1% in PTC patients with subclinical hypothyroidism is remarkably low [22,23]. This survival rate represents a better outcome compared with the 87.8% disease-free survival of euthyroid patients, although statistical significance was not verified. However, it is difficult to conclude that elevated TSH or subclinical hypothyroidism is associated with better prognostic factors. We were unable to find a consistent linearcorrelation between the degree of elevated TSH and prognostic parameters such as age, tumour size, multifocality, ETE, LN metastasis and recurrence. In addition, as interval between the development of subclinical hypothyroidism and the development of and surgery for PTC was difficult to estimate and might vary between patients, time-correlation between duration of subclinical hypothyroidism and better or worse prognostic factors could not be verified. Because thyroid tumour cells reportedly have cell surface receptor for thyroid hormone on integrin alphaVbeta3, like other solid tumour cells, thyroid hormone could act as a growth factor for thyroid cancers, including papillary and follicular thyroid carcinoma [7]. In addition, tetraiodothyroacetic acid, which is an antagonist at the integrin receptor and blocks the binding of agonist thyroid hormone analogue, was found to arrest growth of medullary thyroid carcinoma in the thyroid gland. Therefore, it is problematic to insist that elevated TSH level independently contributes to tumorigenesis and progression of thyroid cancer, without considerations for thyroid function status. In fact, TSH was not elevated in patients with micro-PTC in a recent study, indicating that is not likely involved in the de novo oncogenesis of PTC, and the prevalence of subclinical hypothyroidism in our study was similar to that found in the general population [24]. Our study has some potential limitations, including the small sample size of subclinical hypothyroidism patients and insufficient follow-up duration. Moreover, because the overall prognosis of PTC is remarkably excellent, it is difficult to analyze recurrent and survival differences between subgroups of PTC [10]. Our study did not directly evaluate whether elevated TSH increases the incidence of PTC as it was based on patients undergoing thyroid surgery as treatment for this malignancy. In addition, although it is not statistically significant, there was a trend for subclinical hypothyroidism patients to have lower concentrations of free T4 and T3 than did the euthyroid group; thus, the effect of endogenous thyroid hormone cannot be excluded completely. Despite these limitations, the results of our study suggest that elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis. Although the p-values did not meet our criteria for statistical significance, these results would possibly change with additional patients and an increased follow-up period.
5.
Conclusion
Elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in the patients with PTC. In spite of elevated TSH levels, subclinical hypothyroidism could
be associated with better prognosis in PTC as did in other solid tumours. However, we could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters. A prospective randomised control study of the general and subclinical hypothyroidism population should be performed in the future to further explore these questions.
REFERENCES
[1] Hercbergs A, Leith JT. Spontaneous remission of metastatic lung cancer following myxedema coma—an apoptosis-related phenomenon? J Natl Cancer Inst 1993;85:1342–3. [2] Hercbergs A. The thyroid gland as an intrinsic biologic response-modifier in advanced neoplasia—a novel paradigm. In Vivo 1996;10:245–7. [3] Theodossiou C, Skrepnik N, Robert EG, et al. Propylthiouracilinduced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 1999;86:1596–601. [4] Lin HY, Sun M, Tang HY, et al. L-Thyroxine vs. 3,5,3′-triiodo-Lthyronine and cell proliferation: activation of mitogenactivated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 2009;296:C980–91. [5] Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31:139–70. [6] Yalcin M, Dyskin E, Lansing L, et al. Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 2010;95: 1972–80. [7] Lin HY, Tang HY, Shih A, et al. Thyroid hormone is a MAPKdependent growth factor for thyroid cancer cells and is antiapoptotic. Steroids 2007;72:180–7. [8] Kim SS, Lee BJ, Lee JC, et al. Preoperative serum thyroid stimulating hormone levels in well-differentiated thyroid carcinoma is a predictive factor for lateral lymph node metastasis as well as extrathyroidal extension in Korean patients: a single-center experience. Endocrine 2011;39: 259–65. [9] Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010;17:432–6. [10] Ahn D, Heo SJ, Park JH, et al. Clinical relationship between Hashimoto's thyroiditis and papillary thyroid cancer. Acta Oncol 2011;50:1228–34. [11] Larson SD, Jackson LN, Riall TS, et al. Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway. J Am Coll Surg 2007;204:764–73 [discussion 73–5]. [12] Repplinger D, Bargren A, Zhang YW, et al. Is Hashimoto's thyroiditis a risk factor for papillary thyroid cancer? J Surg Res 2008;150:49–52. [13] Kim EY, Kim WG, Kim WB, et al. Coexistence of chronic lymphocytic thyroiditis is associated with lower recurrence rates in patients with papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2009;71:581–6. [14] Col NF, Surks MI, Daniels GH. Subclinical thyroid disease: clinical applications. JAMA 2004;291:239–43. [15] Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–38. [16] Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160: 526–34. [17] Fiore E, Rago T, Latrofa F, et al. Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI N E AN D SUR G E RY 3 4 ( 2 0 13 ) 31 2–3 1 9
[18]
[19]
[20]
[21]
of treatment with L-thyroxine. Endocr Relat Cancer 2011;18: 429–37. Fiore E, Rago T, Provenzale MA, et al. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role. Endocr Relat Cancer 2009;16:1251–60. Hoffman DA, McConahey WM, Brinton LA, et al. Breast cancer in hypothyroid women using thyroid supplements. JAMA 1984;251:616–9. Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011;117:534–44. Cristofanilli M, Yamamura Y, Kau SW, et al. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated
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with a reduced incidence of primary breast carcinoma. Cancer 2005;103:1122–8. [22] Sato N, Oyamatsu M, Koyama Y, et al. Do the level of nodal disease according to the TNM classification and the number of involved cervical nodes reflect prognosis in patients with differentiated carcinoma of the thyroid gland? J Surg Oncol 1998;69:151–5. [23] Ahn D, Lee SJ, Park SK, et al. Is comprehensive neck dissection a sole choice for the treatment of recurrent papillary thyroid carcinoma in the lateral neck? Korean J OtorhinolaryngolHead Neck Surg 2011;54:62–8. [24] Gerschpacher M, Gobl C, Anderwald C, et al. Thyrotropin serum concentrations in patients with papillary thyroid microcancers. Thyroid 2010;20:389–92.
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Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma Dongbin Ahn, MD a,⁎, Jin Ho Sohn, MD, PhD a , Jae Hyug Kim, MD a , Chang Min Shin, MD a , Jae Han Jeon, MD b , Ji Young Park, MD, PhD c a b c
Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Korea Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
ARTI CLE I NFO
A BS TRACT
Article history:
Objective: To assess the effect of preoperative subclinical hypothyroidism on prognosis and
Received 13 September 2012
on the tumour's clinicopathological features at initial diagnosis of papillary thyroid carcinoma (PTC). Materials and methods: 328 patients who underwent surgery for PTC between January 2001 and December 2006 were enrolled in this study. Of these, we compared 35 patients with preoperative subclinical hypothyroidism with 257 patients who were euthyroid before the operation, with respect to clinicopathological characteristics and prognosis. Results: No significant differences were observed in tumour size, extrathyroidal extension, and multifocality between subclinical hypothyroidism and euthyroid patients. Patients with subclinical hypothyroidism had a considerably lower percentage of lymph node metastasis than did euthyroid patients (8.6% vs. 21.8%, p = 0.068). Although preoperative subclinical hypothyroidism decreased the risk of lymph node metastasis at 0.313 of odds ratio in the multivariate analysis, its significance was not verified (95% confidence internal, 0.089–1.092; p = 0.068). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than did preoperative euthyroid patients, for both recurrence (2.9% vs. 14.0%, p = 0.099) and 7-year disease-free survival (97.1% vs. 87.8%, p = 0.079), during the 82-month mean follow-up period. However, even as thyroid-stimulating hormone (TSH) concentration increased, there were no consistent relationships observed between the TSH levels and the prognostic parameters. Conclusion: We could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters, indicating that subclinical hypothyroidism with elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in PTC. © 2013 Elsevier Inc. All rights reserved.
1.
Introduction
In 1993, Hercbergs reported complete sustained regression of metastatic non-small cell lung cancer in a man who had lapsed
into a myxoedema coma and was subsequently resuscitated [1]. This unique event triggered investigation into whether hypothyroidism had a prognostic effect on metastatic cancer, and several preclinical studies revealed that thyroid hormone
⁎ Corresponding author. Department of Otolaryngology-Head and Neck Surgery, Kyungpook National University Hospital, 50 Samduck 2-Ga, Jung-Gu, Daegu 700-712, Korea. Tel.: + 82 53 200 5777; fax: +82 53 423 4524. E-mail address: [email protected] (D. Ahn). 0196-0709/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2012.12.013
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deprivation slowed solid tumour growth rates, whereas thyroid hormone supplementation increased them [2,3]. A plasma membrane receptor for thyroid hormone, integrin αvβ3, is the basis for a nongenomic mechanism of the hormonal actions that appear to contribute to proliferation of integrin ανβ3bearing cells [4–6]. Such cells are usually tumour cells or dividing endothelial or vascular smooth muscle cells [5,7]. However, investigators suggest that, in thyroid carcinoma, the thyroidstimulating hormone (TSH) stimulates the development of thyroid malignancy and that elevated serum TSH is associated with a higher incidence of thyroid cancer and advanced tumour stage, despite the fact that elevated TSH level typically signifies hypothyroidism, with deprivation of thyroid hormone [8]. This is contrary to the effect of hypothyroidism on other solid tumours, such as lung, prostate, and breast tumours, in which clinical or subclinical hypothyroidism ostensibly reduced cancer risk and resulted in better outcomes [9]. Interestingly, several recent studies suggest that Hashimoto's thyroiditis (HT) increases the risk for papillary thyroid carcinoma (PTC) [10–12]. Considering that HT is the most common cause of clinical primary hypothyroidism and that elevated TSH is much more frequently found in individuals with HT than in the general population, these findings also support a role for TSH in the occurrence of thyroid carcinoma. Ironically, however, most studies investigating the clinical relationship between HT and PTC report a better prognosis for PTC concurrent with HT compared with PTC alone, regardless of elevated TSH levels in some HT patients [10,13]. In addition, Hercbergs et al. reported apparent tumour stimulation with thyroid hormone and complete remission of tumour for clinical hypothyroidism in anaplastic thyroid carcinoma [9]. In summary, the results of studies concerning the effect of thyroid hormones (L-thyroxine [T4], triiodo-L-thyronine [T3]), and TSH on tumorigenesis vary among tumours and centres, thus contributing to ongoing uncertainty about their effect. In addition, it remains unclear whether the predominant effect of hypothyroidism on malignant tumours ensues from decreased thyroid hormone or elevated TSH. In the present study, we stratified the thyroid function status of our patients at the time of initial diagnosis of PTC and assessed the effect of preoperative subclinical hypothyroidism on prognosis and the tumour's presenting clinicopathological features.
2.
Materials and methods
2.1.
Patients
Between January 2001 and December 2006, 973 thyroid surgeries were performed at our institution. Of these, 328 patients met the following inclusion criteria and were retrospectively evaluated in our study: (1) thyroid surgery performed as initial treatment; (2) histologically confirmed PTC; (3) accessible medical records with preoperative results for thyroid function tests including serum TSH, free T4, and T3 levels; (4) no history of known thyroid disease and thyroidrelated medication including antithyroid drugs or levothyroxine; (5) regular follow-up over more than a 60-month period after initial thyroid surgery.
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Of the 973 cases, 129 (13.3%) cases were excluded because they were revision surgeries for recurrent thyroid carcinoma, and 156 (16.0%) because they involved other subtypes of thyroid carcinoma, such as follicular (7.3%, 71/973), medullary (2.3%, 22/973), and anaplastic carcinomas (1.2%, 12/973), or benign tumours (5.2%, 51/973). A total of 228 (23.4%) patients were excluded because they had previously been diagnosed with nonsurgical thyroid disease or had taken thyroid-related medication before the preoperative thyroid function tests were performed. The remaining 132 (13.6%) of 973 patients were excluded due to insufficient follow-up; inadequate medical records; or absence of preoperative serum TSH, free T4, or T3 levels. Finally, 328 patients were eligible for analysis in our study. The cohort of 328 patients enrolled in our study comprised 50 men and 278 women, with a mean age of 47.0 years at the time of diagnosis of PTC. Thyroid lobectomy with isthmusectomy was performed in 38 patients, while total thyroidectomy with or without neck dissection was performed in 290 patients. Total thyroidectomy with central neck dissection and without lateral compartment neck dissection was performed in 33 patients. Total thyroidectomy with comprehensive neck dissection including central neck dissection such as radical neck dissection, modified radical neck dissection, and selective neck dissection of level II to V was performed in 42 patients, with 5 patients undergoing bilateral neck dissection.
2.2. Classification according to preoperative thyroid function status In accordance with standard practice in our institution's laboratory, the reference range of TSH, free T4, and T3 concentration was defined as 0.45 to 4.5 mIU/L, 0.8 to 2.0 ng/ dL, and 0.6 to 1.9 ng/mL, respectively [14,15]. The 328 patients were classified into 5 categories according to preoperative thyroid function status as follows; euthyroid, subclinical hypothyroidism, subclinical hyperthyroidism, overt hypothyroidism, and overt hyperthyroidism. Euthyroid status was defined as normal levels of serum TSH, free T4, and T3. Subclinical hypothyroidism was defined as an elevation in serum TSH level above the upper limit of reference range, with normal free T4 concentrations [14,15]. Subclinical hyperthyroidism was defined as a decrease in serum TSH level below the reference range, with normal serum free T4 and T3 concentrations [14,15]. Overt hypothyroidism was defined as an elevation in serum TSH and free T4 concentrations, and overt hyperthyroidism was defined as a decrease in serum TSH, free T4, and T3 concentrations. To assess the effect of subclinical hypothyroidism on PTC, we compared the 35 patients with subclinical hypothyroidism with the 257 euthyroid patients for clinicopathological characteristics and prognosis. Because most patients with established clinical or overt hypothyroidism have been treated with thyroid hormone supplement prior to the diagnosis of PTC and/or have had regular thyroid evaluations including thyroid ultrasonography, they would introduce an important bias into analysing the effect of preoperative thyroid function status on the time of detection and clinical features of PTC. Therefore, we decided that patients with subclinical thyroid dysfunction
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were best suited for estimating the effect of preoperative TSH concentration on PTC.
2.3.
levels. With regard to the results, p values were 2-sided throughout and statistical significance was defined as p < 0.05.
Review of histopathological parameters
3. The histopathological parameters of each patient were blindly determined by 1 co-author specializing in thyroid pathology (JY Park). All pathological slides were reviewed for primary tumour size, presence of multifocal disease, extrathyroidal extension (ETE), cervical lymph node (LN) metastasis, and coexisting HT. Pathologic staging was redefined according to the Tumor, Lymph Node, and Metastasis (TNM) staging system of the 6th edition of the International Union Against Cancer and the American Joint Committee on Cancer (UICC/AJCC).
2.4.
Treatment protocol for papillary thyroid carcinoma
All patients underwent surgery performed by the 2 experienced head and neck surgeons. The concrete principle of thyroid surgery was as follows. Thyroid lobectomy with isthmusectomy was performed only when the following criteria were met: the cancer was an intrathyroidal, unifocal microcarcinoma (< 1 cm in diameter), with no cervical lymph node involvement. In the other cases, total thyroidectomy was primarily performed. Central neck dissection was performed when enlarged LN was seen in preoperative imaging study or the surgical field of vision with 2.5× loupes, or was detected by palpation of the central neck region. When metastasis to the lateral compartment of the neck was identified in the preoperative evaluation or in follow-up examination after initial thyroid surgery, comprehensive neck dissection was performed from level II to VI. Radioactive iodine remnant ablation was performed using 100–150 mCi 131I with the same indications as those for total thyroidectomy.
2.5.
Statistical analyses
SPSS for Windows (version 12.0; SPSS, Chicago, IL, USA) was used to analyse the data. Continuous data are represented as mean ± standard deviation. To compare continuous variables, age, tumour size, and concentrations of TSH, free T4 and T3 according to thyroid function status were tested using an independent t-test. The association between subclinical hypothyroidism and prognostic variables was assessed using a Chi-square test or Fisher's exact test for age ≥ 45 years, sex, primary tumour size ≥ 1-cm diameter, ETE, multifocality, LN metastasis, and concurrent HT. LN metastasis according to various clinicopathological factors such as age ≥ 45 years, sex, primary tumour size ≥ 1-cm diameter, ETE, multifocality, and subclinical hypothyroidism was also assessed using the Chisquare or Fisher's exact test. Multivariate analysis was performed by binary logistic regression. The Kaplan–Meier method with a log-rank test was used to determine diseasefree survival rate during the follow-up period. Correlation analysis was performed to evaluate whether a linear relationship existed between TSH levels and continuous variables such as age and tumour size. For categorical variables such as ETE, multifocality, LN metastasis, and recurrence, p value for trend was used to assess the linear relationship with TSH
Results
3.1. Thyroid function status at the time of diagnosis of PTC Of 328 patients with PTC, 257 (78.4%) had normal thyroid function. A total of 64 patients (19.5%) had subclinical thyroid dysfunction, 35 of them (10.7%) with subclinical hypothyroidism and 29 (8.8%) with subclinical hyperthyroidism. Since we excluded patients with a history of known thyroid disease or thyroid-related medication, overt thyroid dysfunction including hypothyroidism and hyperthyroidism was documented in only 7 patients (2.1%) (Fig. 1).
3.2. Do patients with subclinical hypothyroidism have aggressive clinicopathological features of PTC compared with patient who are euthyroid? The clinicopathological factors of 257 patients with preoperative euthyroid state and 35 patients with subclinical hypothyroidism were compared (Table 1). With respect to thyroid function test, the mean concentration of TSH was 1.86 mIU/L in the euthyroid group and 6.86 mIU/L in the subclinical hypothyroidism group. This difference was statistically significant (p < 0.001). Although concentrations of free T4 and T3 were lower in the subclinical hypothyroidism patients than in the euthyroid patients, the difference did not reach statistical significance (1.03 vs. 1.21 ng/dL, p = 0.168 in free T4 and 1.08 vs. 1.23 ng/dL, p = 0.377 in T3, respectively). Patients with subclinical hypothyroidism were similar to the euthyroid group with regard to mean age (48.1 vs. 46.6 years, p = 0.537), proportion of male gender (14.3% vs. 16.0%, p = 0.799), mean primary tumour size (1.6 vs. 1.7 cm, p = 0.547), ETE (62.9% vs. 53.7%, p = 0.307), multifocality (42.9% vs. 30.0%, p = 0.123), and concurrent HT (31.4% vs. 22.6%, p = 0.247), and stage (p = 0.081). Although a considerably lower percentage of LN metastasis was found in patients with subclinical hypothyroidism compared with euthyroid patients (8.6% vs. 21.8%, p = 0.068), the difference did not reach statistical significance.
Fig. 1 – Thyroid function status at the time of diagnosis of papillary thyroid carcinoma.
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Table 1 – Clinicopathological characteristics according to preoperative thyroid function status. Euthyroid group (n = 257)
Subclinical hypothyroidism group (n = 35)
p-value
1.86 ± 0.92 1.21 ± 0.72 1.23 ± 1.03 46.6 ± 13.0 144 (56.0%) 41:216 1.7 ± 1.3 172 (66.9%) 138 (53.7%) 77 (30.0%) 56 (21.8%) 58 (22.6%)
6.86 ± 3.29 1.03 ± 0.24 1.08 ± 0.22 48.1 ± 12.6 19 (54.3%) 5:30 1.6 ± 1.1 21 (60.0%) 22 (62.9%) 15 (42.9%) 3 (8.6%) 11 (31.4%)
<0.001 0.168 0.377 0.537 0.845 0.799 0.547 0.417 0.307 0.123 0.068 0.247
159 (61.9%) 16 (6.2%) 60 (23.3%) 22 (8.6%)
23 (65.8%) 0 (0.0%) 12 (34.2%) 0
0.081
Thyroid function test TSH (mIU/L) Free T4 (ng/dL) T3 (ng/dL) Age (years) ≥45 Sex (male:female) Primary tumour size (cm) ≥1 Extra-thyroidal extension Multifocal disease Lymph node metastasis Concurrent Hashimoto's thyroiditis Stage I II III IV
3.3. Is subclinical hypothyroidism associated with the incidence of LN metastasis?
3.4. Recurrence and survival differences between patients with preoperative euthyroid status and subclinical hypothyroidism
Table 2 lists the univariate and multivariate clinicopathological factors associated with LN metastasis at the initial diagnosis of PTC. LN metastasis at initial diagnosis was significantly associated with patient age ≥ 45 years (p = 0.047), primary tumour size ≥ 1 cm (p = 0.001), and ETE (p < 0.001) in univariate analysis. Although the proportion of male gender was considerably higher in patients with LN metastasis and subclinical hypothyroidism was frequently found in patients without LN metastasis, these differences were not statistically significant (p = 0.060 and p = 0.068, respectively). On multivariate analysis including variables with p < 0.2 on univariate analysis, male gender (odds ratio = 2.198; 95% confidence interval, 1.012–4.772; p = 0.046), tumour size ≥ 1 cm (odds ratio = 2.554; 95% confidence interval [CI], 1.158–5.631; p = 0.020), and ETE (odds ratio = 2.882; 95% CI, 1.458–5.699; p = 0.002) were significantly associated with LN metastasis at the time of initial diagnosis. Preoperative subclinical hypothyroidism was found to decrease the risk of LN metastasis at 0.313 of odds ratio, however, its significance was not verified (95% CI, 0.089–1.092; p = 0.068).
During the mean 82-month follow-up period, recurrence occurred in 36 (14.0%) of 257 euthyroid patients and only 1 (2.9%) of 35 patients with subclinical hypothyroidism. This difference was not statistically significant (p = 0.099). Overall, 4 (1.6%) patients with euthyroid status died, but only 2 (0.8%) of these deaths were due to PTC or related complications. All patients with subclinical hypothyroidism were alive at the time of the present evaluation (Table 3). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than the euthyroid patients, although the difference between the 2 groups did not reach statistical significance in 7-year disease-free survival rates (p = 0.079, Fig. 2).
3.5. Trends in prognostic parameters with respect to TSH level We subdivided all the patients into 4 categories according to TSH levels (0.45–2.4 mIU/L; 2.5–4.5 mIU/L; 4.6–6 mIU/L; > 6
Table 2 – Clinicopathological factors associated with lymph node metastasis at initial diagnosis: univariate and multivariate analysis.
Age ≥ 45 years Male Primary tumour size ≥ 1 cm Extra-thyroidal extension Multifocal disease Subclinical hypothyroidism ⁎ Statistically significant.
Univariate
Multivariate
Odds ratio
Confidence interval 95%
0.047 ⁎ 0.060 0.001 ⁎ <0.001 ⁎ 0.166 0.068
0.097 0.046 ⁎ 0.020 ⁎ 0.002 ⁎ 0.241 0.068
0.597 2.198 2.554 2.882 1.473 0.313
0.325–1.099 1.012–4.772 1.158–5.631 1.458–5.699 0.770–2.818 0.089–1.092
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Table 3 – Recurrence and survival according to preoperative thyroid function status.
Follow-up period (months) Recurrence Death Disease-specific 7-year disease-free survival rate
Euthyroid group (n = 257)
Subclinical hypothyroidism group (n = 35)
p-value
82.8 ± 21.5 36 (14.0%) 4 (1.6%) 2 (0.8%) 87.8%
82.0 ± 14.3 1 (2.9%) 0 (0.0%) 0 (0.0%) 97.1%
0.761 0.099 1.000 1.000 0.079
mIU/L) and examined the prognostic parameters to evaluate whether there is any positive or negative relationship corresponding to an increase in TSH level. Pearson's correlation coefficients (r) for age and tumour size with TSH level were 0.026 and − 0.066, respectively, indicating that there were only ignorable linear relationships (Fig. 3). P values for trend in ETE, multifocality, LN metastasis, and recurrence were 0.087, 0.051, 0.254, and 0.076, respectively (Fig. 4). Generally, age, ETE, and multifocality show a rising trend with respect to an increase in TSH concentrations, whereas primary tumour size, LN metastasis, and recurrence show a decreasing trend. However, none of these parameters had statistically significant associations with TSH concentrations.
4.
Discussion
come this limitation, we deemed that patients with incidentally found subclinical thyroid dysfunction were best suited for estimating relationships between preoperative thyroid function status and thyroid cancer, although studying patients with clinical or overt thyroid dysfunction might yield clearer results. The prevalence of subclinical hypothyroidism is about 4% to 10% in those without known thyroid disease [15]. The prevalence increases with age; subclinical hypothyroidism is found in up to 20% of women older than 60 years of age [15,16]. In our study of patients with PTC, the prevalence of subclinical hypothyroidism was 10.7%, which is comparable to the rate in the general population without thyroid disease, suggesting that PTC may not affect thyroid gland function. With respect to the aetiology of the subclinical hypothyroidism of our patients, Hashimoto's thyroiditis, which is the most common
Although numerous studies have reported the effects of subclinical hypothyroidism on the cardiovascular system, metabolic syndrome, and neuropsychiatric disease, it is an unfamiliar subject to oncologist, particularly those studying thyroid cancers. Because most patients with established clinical or overt hypothyroidism should be treated with thyroid hormone supplements regardless of diagnosis of thyroid cancer, it is difficult to evaluate the absolute effect of preoperative hypothyroidism on thyroid cancer. To over-
Fig. 2 – Kaplan–Meier curves for disease-free survival according to preoperative thyroid function status.
Fig. 3 – Mean age (A) and tumour size (B) according to the thyroid-stimulating hormone (TSH) concentration. r = Pearson's correlation coefficient.
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Fig. 4 – Incidence of extrathyroidal extension (ETE) (A), multifocality (B), lymph node (LN) metastasis (C), and recurrence (D) according to thyroid-stimulating hormone (TSH) concentration. Ptrend = p value for trend.
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cause of clinical hypothyroidism, was also supposed to be the most important cause of subclinical hypothyroidism: concurrent Hashimoto's thyroiditis was more common in patients with subclinical hypothyroidism than in euthyroid subjects in this study. Although consumption of iodine in seafood, such as fish, sushi, and seaweed, could also be an important cause of subclinical hypothyroidism in our country, the diets of euthyroid subjects and subclinical hypothyroidism patients enrolled in our study did not likely differ in this respect, because most of them belonged to the same community. Recently, several studies reported that elevated TSH is associated with a higher incidence of thyroid cancer and advanced-stages, regardless of age [8,17,18]. A study evaluating 554 patients with well-differentiated thyroid cancer found that TSH ≥ 2.5 mIU/L was associated with a higher incidence of ETE and lateral LN metastasis [8]. In a study of 10,178 patients subjected to fine needle aspiration, patients with PTC cytology exhibited significantly higher concentrations of TSH than did those with benign thyroid disease [18]. However, these studies had some limitations. Some reports did not take thyroid hormone (T4 and T3) concentrations into consideration, despite the fact that elevated TSH usually denotes decreased thyroid function, while others patients with varying thyroid function, such as hyperthyroidism, hypothyroidism, and euthyroidism, preventing a clear answer for whether elevated TSH increases the risk for thyroid carcinoma or advancedstages compared with euthyroid status [8,18]. To overcome these limitations, we restricted our analysis to patients with subclinical hypothyroidism thus eliminating any bias introduced by effects of endogenous and exogenous thyroid hormone, and compared them directly to patients with euthyroid status. In our study, there were no significant differences in tumour size, ETE, and multifocality between euthyroid patients and those with subclinical hypothyroidism. Patients with subclinical hypothyroidism had a considerably lower incidence of LN metastasis than did the euthyroid group, although the difference was not statistically significant. This result contradicts previously reported studies on the role of TSH in thyroid cancer; however, well-known parameters predicting tumour aggressiveness, such as male gender, primary tumour size ≥ 1 cm, and ETE, were well correlated with LN metastasis on multivariate analysis, demonstrating the reliability of our study [8]. The results of our study could support the hypothesised role of clinical or subclinical hypothyroidism in solid tumours other than thyroid cancer. In a study evaluating breast cancer patients and 1250 controls, women with untreated hypothyroidism or goitre had a significantly reduced incidence of breast cancer [19]. In a study of renal cell carcinoma, the objective remission rate and median survival duration were significantly better in patients with subclinical hypothyroidism than in euthyroid patients [20]. In addition, hypothyroidism was associated with a delayed onset of cancer, smaller tumour size, and less likelihood for metastatic disease in several oncological studies [9,21]. In our study, although it was not statistically significant, there was a trend toward older age, smaller tumours, and lower incidence of LN metastasis at the time of diagnosis of PTC in patients with subclinical hypothyroidism. Furthermore, considering that the recurrence rate of
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PTC after total thyroidectomy followed by radioactive iodine ablation and TSH suppression treatment is reported as 10%– 20%, our findings of a 7-year disease-free survival rate of 97.1% in PTC patients with subclinical hypothyroidism is remarkably low [22,23]. This survival rate represents a better outcome compared with the 87.8% disease-free survival of euthyroid patients, although statistical significance was not verified. However, it is difficult to conclude that elevated TSH or subclinical hypothyroidism is associated with better prognostic factors. We were unable to find a consistent linearcorrelation between the degree of elevated TSH and prognostic parameters such as age, tumour size, multifocality, ETE, LN metastasis and recurrence. In addition, as interval between the development of subclinical hypothyroidism and the development of and surgery for PTC was difficult to estimate and might vary between patients, time-correlation between duration of subclinical hypothyroidism and better or worse prognostic factors could not be verified. Because thyroid tumour cells reportedly have cell surface receptor for thyroid hormone on integrin alphaVbeta3, like other solid tumour cells, thyroid hormone could act as a growth factor for thyroid cancers, including papillary and follicular thyroid carcinoma [7]. In addition, tetraiodothyroacetic acid, which is an antagonist at the integrin receptor and blocks the binding of agonist thyroid hormone analogue, was found to arrest growth of medullary thyroid carcinoma in the thyroid gland. Therefore, it is problematic to insist that elevated TSH level independently contributes to tumorigenesis and progression of thyroid cancer, without considerations for thyroid function status. In fact, TSH was not elevated in patients with micro-PTC in a recent study, indicating that is not likely involved in the de novo oncogenesis of PTC, and the prevalence of subclinical hypothyroidism in our study was similar to that found in the general population [24]. Our study has some potential limitations, including the small sample size of subclinical hypothyroidism patients and insufficient follow-up duration. Moreover, because the overall prognosis of PTC is remarkably excellent, it is difficult to analyze recurrent and survival differences between subgroups of PTC [10]. Our study did not directly evaluate whether elevated TSH increases the incidence of PTC as it was based on patients undergoing thyroid surgery as treatment for this malignancy. In addition, although it is not statistically significant, there was a trend for subclinical hypothyroidism patients to have lower concentrations of free T4 and T3 than did the euthyroid group; thus, the effect of endogenous thyroid hormone cannot be excluded completely. Despite these limitations, the results of our study suggest that elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis. Although the p-values did not meet our criteria for statistical significance, these results would possibly change with additional patients and an increased follow-up period.
5.
Conclusion
Elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in the patients with PTC. In spite of elevated TSH levels, subclinical hypothyroidism could
be associated with better prognosis in PTC as did in other solid tumours. However, we could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters. A prospective randomised control study of the general and subclinical hypothyroidism population should be performed in the future to further explore these questions.
REFERENCES
[1] Hercbergs A, Leith JT. Spontaneous remission of metastatic lung cancer following myxedema coma—an apoptosis-related phenomenon? J Natl Cancer Inst 1993;85:1342–3. [2] Hercbergs A. The thyroid gland as an intrinsic biologic response-modifier in advanced neoplasia—a novel paradigm. In Vivo 1996;10:245–7. [3] Theodossiou C, Skrepnik N, Robert EG, et al. Propylthiouracilinduced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 1999;86:1596–601. [4] Lin HY, Sun M, Tang HY, et al. L-Thyroxine vs. 3,5,3′-triiodo-Lthyronine and cell proliferation: activation of mitogenactivated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 2009;296:C980–91. [5] Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31:139–70. [6] Yalcin M, Dyskin E, Lansing L, et al. Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 2010;95: 1972–80. [7] Lin HY, Tang HY, Shih A, et al. Thyroid hormone is a MAPKdependent growth factor for thyroid cancer cells and is antiapoptotic. Steroids 2007;72:180–7. [8] Kim SS, Lee BJ, Lee JC, et al. Preoperative serum thyroid stimulating hormone levels in well-differentiated thyroid carcinoma is a predictive factor for lateral lymph node metastasis as well as extrathyroidal extension in Korean patients: a single-center experience. Endocrine 2011;39: 259–65. [9] Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010;17:432–6. [10] Ahn D, Heo SJ, Park JH, et al. Clinical relationship between Hashimoto's thyroiditis and papillary thyroid cancer. Acta Oncol 2011;50:1228–34. [11] Larson SD, Jackson LN, Riall TS, et al. Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway. J Am Coll Surg 2007;204:764–73 [discussion 73–5]. [12] Repplinger D, Bargren A, Zhang YW, et al. Is Hashimoto's thyroiditis a risk factor for papillary thyroid cancer? J Surg Res 2008;150:49–52. [13] Kim EY, Kim WG, Kim WB, et al. Coexistence of chronic lymphocytic thyroiditis is associated with lower recurrence rates in patients with papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2009;71:581–6. [14] Col NF, Surks MI, Daniels GH. Subclinical thyroid disease: clinical applications. JAMA 2004;291:239–43. [15] Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–38. [16] Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160: 526–34. [17] Fiore E, Rago T, Latrofa F, et al. Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI N E AN D SUR G E RY 3 4 ( 2 0 13 ) 31 2–3 1 9
[18]
[19]
[20]
[21]
of treatment with L-thyroxine. Endocr Relat Cancer 2011;18: 429–37. Fiore E, Rago T, Provenzale MA, et al. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role. Endocr Relat Cancer 2009;16:1251–60. Hoffman DA, McConahey WM, Brinton LA, et al. Breast cancer in hypothyroid women using thyroid supplements. JAMA 1984;251:616–9. Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011;117:534–44. Cristofanilli M, Yamamura Y, Kau SW, et al. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated
319
with a reduced incidence of primary breast carcinoma. Cancer 2005;103:1122–8. [22] Sato N, Oyamatsu M, Koyama Y, et al. Do the level of nodal disease according to the TNM classification and the number of involved cervical nodes reflect prognosis in patients with differentiated carcinoma of the thyroid gland? J Surg Oncol 1998;69:151–5. [23] Ahn D, Lee SJ, Park SK, et al. Is comprehensive neck dissection a sole choice for the treatment of recurrent papillary thyroid carcinoma in the lateral neck? Korean J OtorhinolaryngolHead Neck Surg 2011;54:62–8. [24] Gerschpacher M, Gobl C, Anderwald C, et al. Thyrotropin serum concentrations in patients with papillary thyroid microcancers. Thyroid 2010;20:389–92.