TSH level as a risk factor of thyroid malignancy for nodules in euthyroid patients| ACTA Otorhinolaryngologica Italica

Abstract

Objective. With the increased prevalence of incidental thyroid cancer, determining the predictors of thyroid malignancy has become a source of debate. This study aimed to determine the impact of thyroid stimulating hormone (TSH) levels on rates of thyroid cancer in euthyroid patients.
Methods. A retrospective study included 421 patients who underwent thyroidectomy at a tertiary hospital between 2016 and 2020. Patients’ demographics, history of cancer, preoperative workup and final histology reports were obtained. The study sample was divided into two groups based on the final histopathology (benign vs malignant). The two groups were compared using the appropriate statistical tests to determine the predictors of thyroid cancer in euthyroid patients.
Results. TSH levels were significantly higher in patients with malignant nodules compared to those with benign nodules (1.94 vs 1.62, p = 0.002). It was 1.54 times more likely for thyroid nodules to be malignant when TSH levels were higher (p = 0.038). Meanwhile, larger nodules (> 4 cm) were significantly more prevalent in benign nodules (43.1%) than in malignant nodules (21.1%). Larger nodules decreased the possibility of thyroid cancer by 24% (OR = 0.760, p-value = 0.004).
Conclusions. High TSH levels in euthyroid patients were significantly correlated with the risk of thyroid malignancy. In addition, as Bethesda category proceeded toward malignancy, TSH levels increased. High TSH levels and small nodule diameters can be used as additional parameters in predicting thyroid cancer in euthyroid patients.

Introduction

Thyroid nodules are common in clinical practice; however, their incidence varies according to the diagnostic methods ¹. Epidemiological studies have shown a 2-6% prevalence on physical examination, 19-68% using high-resolution ultrasound and 36-50% in autopsy series ^1,2. The incidence of thyroid cancer is rising with the increased detection rates of non-palpable thyroid nodules ². The risk factors for thyroid malignancy in thyroid nodules include age (> 70 years), male gender, radiation exposure, family history, compressive symptoms, cervical lymphadenopathy, rapid growth and fixed-hard nodules ³.

With the increased rate of incidental thyroid cancer, finding the best available diagnostic method has been a subject of debate. Fine needle aspiration (FNA) using the Bethesda System for Reporting Thyroid Cytopathology has been the initial diagnostic method of choice for the past two decades ⁴. However, FNA has its limitations, being nondiagnostic and inconclusive in 20-25% of cases, necessitating further evaluation ⁵. Laboratory and molecular markers have also been reported to be of prognostic and predictive value. Thyroid stimulating hormone (TSH) has been evaluated as a predictor of malignancy in thyroid nodules, showing that a higher serum concentration of TSH is associated with an increased risk of thyroid cancer ^6-10.

Although there are multiple studies on the association between TSH level and thyroid malignancy, those investigating this relationship in euthyroid patients are limited. Therefore, this study aims to determine the influence of TSH levels on the incidence of thyroid cancer in euthyroid patients.

Methods

Study design and subjects

A retrospective study included all patients who underwent hemithyroidectomy or total thyroidectomy at King Abdulaziz Medical City in Riyadh, Saudi Arabia (SA), from 2016 to 2020. The indications for thyroidectomy were based on the American Thyroid Association (ATA) management guidelines (2015) ¹. Patients with hypothyroidism, hyperthyroidism, history of radioactive iodine treatment, or thyroid medication use were excluded from the study. A total of 421 patients met our criteria and were included in the study.

Data collection

The patients’ electronic records were reviewed using the hospital’s health care information system. The data collection flowsheet included patients’ demographics (i.e., age, gender, height, and weight), history of cancer, thyroid function tests, FNA finding, nodule diameter and final histopathology.

Statistical analysis

Data were analysed using Statistical Package for the Social Sciences (SPSS^®) version 25. Categorical data were summarised and reported as frequencies and proportions, while continuous variables were summarised and reported as means and standard deviations (SD). The study sample was divided into two groups based on final histopathology (benign vs malignant). Categorical and continuous variables were compared using chi-square test and independent T-test, respectively. All the variables were included in a multivariable logistic regression model to determine the predictors of thyroid malignancy in euthyroid nodules. A p-value < 0.05 was considered as statistically significant.

Results

The study included 421 patients with thyroid patients. The mean age of patients was 45.93 (± 14.3) years, and females represented most of our sample (80.3%). The mean TSH level was 1.84 (± 1.0) mIU/L, and almost two-thirds of patients (63.9%) had a TSH level less than 2 mIU/L (63.9%). Final surgical histopathology showed a benign pathology in one-third of cases (32.5%) and malignant in almost two-thirds of the patients (67.5%). Table I demonstrates the demographic and clinical characteristics of all patients.

The mean TSH level was significantly higher in malignant thyroid nodules compared to benign nodules (1.94 vs 1.62, p-value = 0.002). A TSH level > 2 mIU/L was significantly more common in malignant than in benign thyroid nodules (39.4 vs 29.2%, p-value = 0.040). Large nodules (≥ 4 cm) were more common in benign than in malignant nodules (43.1 vs 21.1%, p-value = 0.000). Moreover, the mean nodule diameter and mean body mass index (BMI) were significantly larger in patients with benign thyroid nodules than in malignant nodules (3.88 vs 2.74, p-value = 0.000, and 31.65 vs 30.33, p-value = 0.043, respectively). Table II shows the differences between benign and malignant thyroid nodules.

Table III illustrates the predictors of thyroid cancer in euthyroid patients in multivariable regression analysis. A higher TSH level increased the likelihood of malignancy in thyroid nodules by 1.54 times (p-value = 0.038). Moreover, larger nodules decreased the possibility of thyroid cancer by 24% (OR = 0.760, p-value = 0.004). Age, gender, BMI, history of cancer and free thyroxine (FT4) levels were not associated with the final histopathology of thyroid nodules in multivariable regression analysis.

Table IV and Figure 1 demonstrate the relationship between the TSH level and Bethesda system category. TSH level was significantly correlated with the Bethesda system category (p-value = 0.001). It showed that the higher the Bethesda category, the higher the TSH level.

Discussion

Thyroid nodules are common clinical findings, with a prevalence reaching 70%. Most thyroid nodules are benign, while the incidence of malignancy is around 5% ¹¹. Multiple clinical, pathological, laboratory and radiological factors have been proposed to differentiate benign from malignant nodules; however, the reported predictors are inconclusive.

TSH is a major regulator of thyroid function. Multiple studies have evaluated it as a predictor of malignancy in thyroid nodules with conflicting results ^6-10,12. Most studies have shown that a higher serum concentration of TSH is associated with an increased risk of thyroid cancer. However, studies investigating this relationship in euthyroid patients are limited ¹³. In the present study, the TSH levels were higher in malignant compared to benign nodules. TSH levels within the higher end of the reference range increased the likelihood of thyroid malignancy by 1.54 times. Baser et al. evaluated 1433 patients who underwent thyroidectomy and reported that malignant thyroid nodules had elevated TSH levels compared to the benign group (p < 0.001) ¹³. The TSH level threshold above which the risk of thyroid malignancy increases was 1 mIU/L ¹⁴. Conflicting these studies, Castro et al. reported that serum TSH level was not associated with increased risk of malignancy among 327 thyroid lesions suspicious for follicular neoplasm or Hürthle cell neoplasms ¹². Singh et al. found no association between Hashimoto’s thyroiditis, which has high TSH levels, and the incidence of malignancy in a meta-analysis conducted in 1999 ¹⁵. Moreover, Holm et al. found that patients with uncontrolled hypothyroidism had no increased risk of thyroid malignancy after two decades of follow-up ¹⁶.

It is unclear whether higher TSH levels increase the malignant potential of the thyroid nodules or whether the malignant nodules produce higher levels of TSH. It is suggested that TSH modulates the thyroid cell function, growth and expression of specific proteins after binding to its receptors of the follicular cells. This leads to the continuous stimulation and proliferation of the thyroid nodules by high TSH levels, which results in cellular alternations and modulation of thyroidal gene expression ^17,18. Animal experiments on mice and golden hamsters showed that TSH stimulation is associated with thyroid malignancy, as overstimulation of TSH leads to hyperplasia and, eventually, thyroid cancer ⁶. Moreover, this hypothesis is supported by the fact that patients with well-differentiated thyroid cancer benefit from TSH suppressive treatment with levothyroxine as it decreases disease progression, recurrence rates, and cancer-related mortality ¹⁹. On the other hand, recent genetic studies aimed to search for sequence variants that link TSH with thyroid malignancy. Two variants, located on 9q22.33 and 14q13.3, have been associated with thyroid cancer; both have also been associated with low serum TSH ²⁰. Moreover, an inverse relationship between TSH receptor mRNA and cancer progression was documented by Shi et al. ²¹.

TSH level was measured for each Bethesda category separately in the present study. TSH level significantly correlated with the Bethesda system category. The higher the Bethesda category, the higher the TSH level was, and the highest levels were found in the malignant categories (V-VI). Similarly, Baser et al. reported that TSH levels increased gradually as the Bethesda category did, rising from Bethesda category II to VI ¹³.

Malignant thyroid nodules are smaller in diameter than benign in the present study. Moreover, our study showed the large nodule diameter (> 4 cm) decreased the possibility of thyroid cancer by 24%. Our findings correlate with Castro et al. and Baser et al., who reported that smaller nodules were more frequently seen in patients with malignancy ^12,13. On the other hand, Sahin et al. and Chung et al. found no association between the diameter of the thyroid nodule and its malignant potential ^22,23.

In addition to TSH, low FT4 levels were reported as an independent predictor of thyroid malignancy in the literature ²⁴. Our study had no significant association between FT4 levels and thyroid malignancy. Extremes of age and male gender were also reported to increase the risk of thyroid malignancy ³. However, we did not find a significant correlation between age and gender with thyroid malignancy. A meta-analysis by Zhao et al. found that obesity is significantly associated with an increased risk of thyroid cancer ²⁵. In our study, univariate analysis showed a significant association between high BMI and the risk of thyroid malignancy; however, multivariate analysis did not support this finding.

Our study has a few limitations, such as being a retrospective single-centre study which may limit its generalisability. Moreover, it only included patients who underwent thyroidectomies. Patients with Bethesda categories I-III who did not have other indications for surgical intervention were not included in the study. However, this is the first study to evaluate the association between TSH levels and thyroid malignancy in euthyroid patients from Saudi Arabia.

Conclusions

High TSH levels in euthyroid nodules were significantly associated with the risk of thyroid malignancy. In addition, as Bethesda category proceeded toward malignancy, TSH levels increased. High TSH levels and small nodule diameters can be used as additional parameters in predicting thyroid cancer in euthyroid patients.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

AKA, LOH, AMA, AAA: drafted the initial manuscript and worked on the data acquisition; AKA: analyzed and interpreted the data, wrote and edited the manuscript; MA, AAA: assisted with data interpretation and reviewed and revised the manuscript. All authors read and approved the submitted version of the manuscript to be published.

Ethical consideration

The institutional review board (IRB) of King Abdullah International Medical Research Center (KAIMRC) approved the study (KIMARC, NRC21R/364/09).

The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s Declaration of Helsinki.

Written informed consent was obtained from each participant/patient for study participation and data publication.

Figures and tables

Figure 1.Mean TSH levels in different Bethesda system categories (II-VI).

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