Abstract
Objective
To assess the effect of preoperative subclinical hypothyroidism on prognosis and 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.
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 . This unique event triggered investigation into whether hypothyroidism had a prognostic effect on metastatic cancer, and several preclinical studies revealed that thyroid hormone deprivation slowed solid tumour growth rates, whereas thyroid hormone supplementation increased them . 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 ανβ3-bearing cells . Such cells are usually tumour cells or dividing endothelial or vascular smooth muscle cells . However, investigators suggest that, in thyroid carcinoma, the thyroid-stimulating 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 . 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 .
Interestingly, several recent studies suggest that Hashimoto’s thyroiditis (HT) increases the risk for papillary thyroid carcinoma (PTC) . 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 . In addition, Hercbergs et al. reported apparent tumour stimulation with thyroid hormone and complete remission of tumour for clinical hypothyroidism in anaplastic thyroid carcinoma . 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 thyroid-related medication including antithyroid drugs or levothyroxine; (5) regular follow-up over more than a 60-month period after initial thyroid surgery.
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 . 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 . Subclinical hyperthyroidism was defined as a decrease in serum TSH level below the reference range, with normal serum free T4 and T3 concentrations . 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 were best suited for estimating the effect of preoperative TSH concentration on PTC.
2.3
Review of histopathological parameters
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 131 I 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 Chi-square 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 disease-free 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 levels. With regard to the results, p values were 2-sided throughout and statistical significance was defined as p < 0.05.
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 thyroid-related medication including antithyroid drugs or levothyroxine; (5) regular follow-up over more than a 60-month period after initial thyroid surgery.
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 . 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 . Subclinical hyperthyroidism was defined as a decrease in serum TSH level below the reference range, with normal serum free T4 and T3 concentrations . 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 were best suited for estimating the effect of preoperative TSH concentration on PTC.
2.3
Review of histopathological parameters
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 131 I 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 Chi-square 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 disease-free 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 levels. With regard to the results, p values were 2-sided throughout and statistical significance was defined as p < 0.05.
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