The Effect of ThyroidߚStimulating Hormone on Stage of Differentiated Thyroid Carcinoma

Abstract Introduction Thyroid cancer is the most common endocrine malignancy, and it has the fastest increase rate in incidence in both sexes, with a yearly increase of 3% over the last decade. Thyroid‐stimulating hormone (TSH) is the main driver for the thyroid gland to produce thyroid hormone. The main purpose of this study was to assess the relationship between serum TSH level and the stage of malignancy in patients with differentiated thyroid cancer. Methods This cross‐sectional study was performed on 77 patients with thyroid cancer. The demographic characteristics, TSH level and stage of malignancy were recorded for all patients in the data collection form. The data analysis was conducted by descriptive statistics using SPSS 20.0 software. Results The results show a significant relationship (p‐value = .025) between the malignancy stage and serum TSH level. The mean TSH level in patients of stage 3 (5.70 ± 2.03) was significantly higher than patients in stage 2 (2.58 ± 0.52) and stage 1 (2.33 ± 0.28). No significant relationship was observed between the age of patients and serum TSH level. Although the mean serum TSH level in men (3.61 ± 0.98) was higher than in women (2.52 ± 0.25), the difference was not statistically significant. Conclusions According to the results of this study, serum TSH level can be considered as a predictor of the stage of differentiated thyroid cancer. Therefore, it can be used to predict the likelihood of cancer and improve the outcome and extent of thyroidectomy in patients with thyroid cancer.

history of neck irradiation, male gender and age of younger than 20 years or more than 70 years. [5][6][7][8] In order to inform DTC management, different staging systems have been developed within the past decades. 9 American Joint Committee on Cancer (AJCC) proposed the tumour-nodemetastasis (TNM) staging system for predicting the prognosis of DTC in clinical practice. 10 In this study, we classified the thyroid cancer cases based on the most updated version of the TNM system (8 th edition), which is one of the most popular staging systems across the world. Although understanding the risk factors of thyroid cancer is still controversial, 11 researchers found a significant relationship between thyroid cancer and exposure to ionizing radiation, family history of thyroid cancer, history of benign thyroid disease, age and gender. [12][13][14][15] Thyroid-stimulating hormone (TSH), also known as thyrotropin is the main driver for the thyroid gland to produce thyroid hormone. 16 In recent years, many studies tried to assess the relationship between the serum TSH level and the risk of thyroid cancer, many of them concluded that higher serum TSH level leads to a higher risk of thyroid cancer. [17][18][19][20][21][22] Nevertheless, several studies conflicted with this conclusion and reported that no significant relationship was found between thyroid cancer and TSH serum level. 23 All in all, the relationship between serum TSH levels and thyroid cancer is still poorly understood and not clear, 22,24,25 Therefore, to gain more insights, we looked at the association between the serum TSH level and stage of malignancy in patients with thyroid cancer.

| MATERIAL S AND ME THODS
In this prospective study, Clinicopathologic characteristics of 100 patients with confirmed thyroid cancer who were referred to the endocrine clinic in Kerman, Iran in early 2019 were gathered. After reviewing the collected data, we excluded the patients who took any thyroid medication within 3 months prior to the collection of data and those who had incomplete preoperational information. Finally, the total number of 77 patients (12 men and 65 women) were included in this study.
In the process of data collection, various variables were recorded including age, sex, family history of thyroid cancer, history of neck radiotherapy, history of former benign thyroid disease, preoperative serum TSH, Triiodothyronine (T3), fine needle aspiration (FNA) results, histology, size of nodules and surgical pathology report. The study was confirmed by the Ethics Committee of Kerman University of Medical Sciences (permission number: 9600878). The patients were assured that their information will be remained confidential and only being used for research purposes.

| Statistical analysis
Statistical relevance of the recorded risk factors for thyroid cancer was calculated by Student's t-test and Pearson chi-square test for continuous variables and categorical variables respectively.
Moreover, we calculated means, standard deviations, frequency and relative frequency for the descriptive statistics. The statistical analysis was conducted using IBM SPSS Statistics 20.0. 26 In addition, we considered a p-value of less than 0.05 statistically significant.

| RE SULTS
In this study, a total number of 77 patients (65 out of which were female) with DTC were staged based on tumour-node-metastasis. The age distribution of the subject group shows that 2 (2.5%) patients were under 20 years old, 37 (48.1%) patients were 20-40 years old, 34 (44.2%) patients were 41-60 years old, and 4 (5.2%) patients were over 60 years old.
The minimum and maximum mean serum TSH levels were associated with the age groups older than 60 years and between 20 and 40 respectively (Table 2). However, the relationship between the age of patients and serum TSH level was not statistically significant (p = .920).
Furthermore, the effect of age on malignancy staging is shown in Table 2 where most of the patients within all malignancy stages were 20-60 years old. The statistical analysis indicated that the relationship between age and malignancy staging was not significant (p = .364).
Although the mean serum TSH level in men (3.61 ± 0.98) was higher than the mean in women (2.52 ± 0.25), the difference was not statistically significant (Table 3).

| DISCUSS ION
The relationship between serum TSH level and the malignancy of Thyroid cancer has been confirmed in many studies, 11,27,28 Haymart et al. 29 have also shown that when TSH level was less than 0.06 mIU/L the risk of Thyroid cancer was 16%, while it was 52% for the TSH levels of 5.00 mIU/L or greater. Moreover, both frequency and stage of thyroid cancer are perceived to be in association with the serum TSH level. 30 In the present study, we found a significant relationship between serum TSH level and the stage of malignancy; where the higher stages of malignancy were associated with the higher average serum TSH level. In a study by Haymart et al. 29 32,33 In another study, the malignancy prevalence was found to be significantly higher in patients younger than 40 years old in comparison to the 40-49 year group. 24 This observation is not consistent with many other cancers that are generally more common in people older than 40 years old. In our study, although the mean age of patients with stage III was higher than the mean age of patients in stage I and II, this difference was not statistically significant (p = .364).
In addition, this study showed that women were more likely to be diagnosed with thyroid cancer than men, and this finding is compatible with similar studies, 31,34 for example in the study by Oberman et al. 34 81% of the detected patients were female. However, no significant relationship between gender and stage of malignancy was identified in this study. One of the limitations in our study is the low number of patients in advanced stages (III and IV) that can limit the ability to find a significant relationship between the malignancy stage and age/gender.
In order to assess the patients with thyroid nodules, one of the initial required lab tests is recommended to be the serum TSH level. 35 Moreover, the TSH level is not only an important factor of thyroid disease but also a beneficial tool for clinical thyroid cancer management. 17,35,36 Although previous studies have shown that serum TSH level is an independent predictor of thyroid malignancy, 19 no optimal TSH cut-off value has been recognized for anticipating the thyroid cancer risk. 17

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interests.

E TH I C A L A PPROVA L
The study was confirmed by the Ethics Committee of Kerman University of Medical Sciences (permission number: 9600878).

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets collected and analysed during the current study are not publicly available due to individual privacy concerns but are available from the corresponding author on reasonable request.