10.14639/0392-100X-N2288
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 (&gt; 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.
text/xml
1827-675X
2288
en
Abdulaziz A. Alsalem
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
Bethesda classification
TSH level as a risk factor of thyroid malignancy for nodules in euthyroid patients
Text.Serial.Journal
https://www.actaitalica.it/
43
Thyroid
2023-05-16
2022-08-26
2023-05-19
2023-05-19
183-188
1
Abdulaziz A. Alsalem
2023/05/16
10.14639/0392-100X-N2288
183
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
1827-675X
Bethesda classification
en
188
TSH level as a risk factor of thyroid malignancy for nodules in euthyroid patients
https://www.actaitalica.it/article/download/2288/987
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:183-188; doi: 10.14639/0392-100X-N2288




Thyroid


TSH level as a risk factor of thyroid malignancy
for nodules in euthyroid patients
Analisi dei valori di TSH come fattori di rischio per malignità di noduli tiroidei
in pazienti eutiroidei
Abdulaziz K. Alaraifi1,2, Mohammed Alessa1,3, Leen O. Hijazi1,2, Areej M. Alayed4, Abdulaziz A. Alsalem1,2
1
 Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, King Abdulaziz Medical City, Ministry of National Guard
Health Affairs, Riyadh, Saudi Arabia; 2 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 3 Department
of Otolaryngology-Head and Neck Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 4 College of Medicine,
King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia


SUMMARY
Objective. With the increased prevalence of incidental thyroid cancer, determining the pre-
dictors of thyroid malignancy has become a source of debate. This study aimed to deter-
mine 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, pre-
operative 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,               Received: August 26, 2022
larger nodules (> 4 cm) were significantly more prevalent in benign nodules (43.1%) than          Accepted: January 8, 2023
in malignant nodules (21.1%). Larger nodules decreased the possibility of thyroid cancer
by 24% (OR = 0.760, p-value = 0.004).                                                             Correspondence
Conclusions. High TSH levels in euthyroid patients were significantly correlated with the         Leen O. Hijazi
risk of thyroid malignancy. In addition, as Bethesda category proceeded toward malignan-          Division of Otolaryngology-Head and Neck
cy, TSH levels increased. High TSH levels and small nodule diameters can be used as ad-           Surgery, Department of Surgery, King Abdulaziz
ditional parameters in predicting thyroid cancer in euthyroid patients.                           Medical City, Ministry of National Guard-Health
                                                                                                  Affairs, Riyadh 11426, Saudi Arabia
KEY WORDS: thyroid cancer, TSH, thyroid nodule, euthyroid patients, Bethesda
                                                                                                  Tel. +96 6556209291
classification
                                                                                                  E-mail: Leenhijazi96@gmail.com

RIASSUNTO
                                                                                                    How to cite this article: AlaraifiAK, Alessa M,
Obiettivo. Alla luce dell’incremento di incidenza dei tumori tiroidei, la ricerca di potenziali
                                                                                                    Hijazi LO, et al. TSH level as a risk factor of
fattori predittivi di malignità ha acquisito sempre più importanza. Il presente studio è volto      thyroid malignancy for nodules in euthyroid pa-
a determinare l’impatto dei livelli di ormone tireostimolante (TSH) sull’incidenza di carci-        tients. Acta Otorhinolaryngol Ital 2023;43:183-
noma tiroideo in pazienti eutiroidei.                                                               188. https://doi.org/10.14639/0392-100X-N2288
Metodi. È stato condotto uno studio retrospettivo su 421 pazienti sottoposti a tiroidecto-
mia in un ospedale di riferimento nel periodo dal 2016 al 2020. Sono stati raccolti i dati        © Società Italiana di Otorinolaringoiatria
demografici, anamnesi oncologica, indagini pre-operatorie ed esame istologico definitivo.         e Chirurgia Cervico-Facciale
La popolazione in studio è stata suddivisa in due gruppi sulla base dell’esito dell’esame
istologico (benigno vs maligno). I due gruppi sono stati confrontati statisticamente per                         OPEN ACCESS
determinare i fattori predittivi di malignità tiroidea in pazienti eutiroidei.
Risultati. I livelli di TSH si sono dimostrati significativamente maggiori nei pazienti affetti   This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
da tumori maligni rispetto ai benigni (1,94 vs 1,62, p = 0,002). In particolare, valori elevati
                                                                                                  Commercial-NoDerivatives 4.0 International) license. The
di TSH sono associati ad aumento della probabilità che un nodulo tiroideo si riveli maligno       article can be used by giving appropriate credit and mentio-
di 1,54 volte (p = 0,038). Noduli > 4 cm sono stati maggiormente riscontrati in pazienti con      ning the license, but only for non-commercial purposes and
lesioni benigne (43,1%) che in pazienti con tumori maligni (21,2%). La presenza di noduli         only in the original version. For further information: https://
grandi ha ridotto la probabilità di carcinoma tiroideo del 24% (OR = 0,760, p-value = 0,004).     creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                          183
A.K. Alaraifi et al.




Conclusioni. Alti valori di TSH in pazienti eutiroidei si sono dimostrati correlabili alla presenza di tumori maligni. Inoltre, la progressione
nella classificazione di Bethesda verso la malignità ha rivelato un rispettivo incremento dei valori di TSH. Alti livelli di TSH e noduli di piccole
dimensioni possono essere utilizzati come parametri aggiuntivi nel predire la presenza di carcinoma tiroideo in pazienti eutiroidei.
PAROLE CHIAVE: carcinoma tiroideo, nodulo tiroideo, TSH, pazienti eutiroidei, classificazione di Bethesda



Introduction                                                                Data collection
                                                                            The patients’ electronic records were reviewed using the
Thyroid nodules are common in clinical practice; however,
                                                                            hospital’s health care information system. The data collec-
their incidence varies according to the diagnostic methods 1.
Epidemiological studies have shown a 2-6% prevalence on                     tion flowsheet included patients’ demographics (i.e., age,
physical examination, 19-68% using high-resolution ultra-                   gender, height, and weight), history of cancer, thyroid func-
sound and 36-50% in autopsy series 1,2. The incidence of                    tion tests, FNA finding, nodule diameter and final histopa-
thyroid cancer is rising with the increased detection rates of              thology.
non-palpable thyroid nodules 2. The risk factors for thyroid
malignancy in thyroid nodules include age (> 70 years),                     Statistical analysis
male gender, radiation exposure, family history, compres-                   Data were analysed using Statistical Package for the So-
sive symptoms, cervical lymphadenopathy, rapid growth                       cial Sciences (SPSS®) version 25. Categorical data were
and fixed-hard nodules 3.                                                   summarised and reported as frequencies and proportions,
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                     Table I. Demographic and clinical characteristics of the study cohorts.
System for Reporting Thyroid Cytopathology has been the                      Variables                                     Statistics (n = 421)
initial diagnostic method of choice for the past two dec-                    Age (mean ± SD)                                  45.93 (± 14.3)
ades 4. However, FNA has its limitations, being nondiag-                     Age (n%)
nostic and inconclusive in 20-25% of cases, necessitating                       < 55 years                                     294 (69.8%)
further evaluation 5. Laboratory and molecular markers                          ≥ 55 years                                     127 (30.2%)
have also been reported to be of prognostic and predictive                   Gender (n%)
value. Thyroid stimulating hormone (TSH) has been evalu-
                                                                                Male                                           83 (19.7%)
ated as a predictor of malignancy in thyroid nodules, show-
                                                                                Female                                        338 (80.3%)
ing that a higher serum concentration of TSH is associated
                                                                             BMI (mean ± SD)                                  30.76 (± 6.3)
with an increased risk of thyroid cancer 6-10.
                                                                             Personal history of cancer (n%)
Although there are multiple studies on the association
                                                                                Yes                                             33 (7.8%)
between TSH level and thyroid malignancy, those inves-
tigating this relationship in euthyroid patients are limited.                   No                                             388 (92.2%)
Therefore, this study aims to determine the influence of                     Surgery (n%)
TSH levels on the incidence of thyroid cancer in euthyroid                      Total thyroidectomy                            335 (79.6%)
patients.                                                                       Hemithyroidectomy                              64 (15.2%)
                                                                                Completion hemithyroidectomy                    22 (5.2%)
                                                                             TSH (mean ± SD)                                   1.84 (± 1.0)
Methods
                                                                             TSH (n%)
                                                                                ≤ 2 mIU/L                                     269 (63.9%)
Study design and subjects                                                       > 2 mIU/L                                     152 (36.1%)
A retrospective study included all patients who underwent                    FT4 (mean ± SD)                                  12.51 (± 1.5)
hemithyroidectomy or total thyroidectomy at King Ab-                         Nodule diameter (mean ± SD)                      3.11 (± 2.0)
dulaziz Medical City in Riyadh, Saudi Arabia (SA), from
                                                                             Nodule diameter (n%)
2016 to 2020. The indications for thyroidectomy were based
                                                                                < 4 cm                                         302 (71.7%)
on the American Thyroid Association (ATA) management
                                                                                ≥ 4 cm                                         119 (28.3%)
guidelines (2015) 1. Patients with hypothyroidism, hyperthy-
                                                                             Final histopathology (n%)
roidism, history of radioactive iodine treatment, or thyroid
medication use were excluded from the study. A total of 421                     Benign                                         137 (32.5%)
patients met our criteria and were included in the study.                       Malignant                                      284 (67.5%)




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                                                                                                             Association between TSH levels and thyroid malignancy




Table II. Patient demograhics and selected characteristics of benign and malignant thyroid nodules.
 Variables                               Benign              Malignant           P-value            Odd Ratio                    95% LCI            95% UCI
                                        (n = 137)             (n = 284)
 Age (mean ± SD)                              45.24 (± 13.4)         46.27 (± 14.64)           0.489           1.005              0.991              1.020
 Age (n%)
   < 55 years                                   99 (72.3%)             195 (68.7%)             0.451           1.189              0.758              1.865
   ≥ 55 years                                   38 (27.7%)              89 (31.3%)
 Gender (n%)
   Male                                        28 (20.4%)              55 (19.4%)              0.796           0.935              0.562              1.555
   Female                                      109 (79.6%)             229 (80.6%)
 BMI (mean ± SD)                              31.65 (± 6.04)          30.33 (± 6.33)          0.043*           0.967              0.991              0.999
 History of cancer (n%)
   Yes                                           7 (5.1%)               26 (9.2%)              0.148           1.872              0.791              4.426
   No                                          130 (94.9%)             258 (90.8%)
 TSH (mean ± SD)                               1.62 (± 1.0)            1.94 (± 1.0)           0.002*           1.401              1.126              1.744
 TSH (n%)
   ≤ 2 mIU/L                                    97 (70.8%)             172 (60.6%)            0.040*           1.579              1.019              2.448
   > 2 mIU/L                                    40 (29.2%)             112 (39.4%)
 FT4 (mean ± SD)                              12.62 (± 1.55)          12.45 (± 1.51)          0.300            0.933              0.817              1.064
 Nodule diameter (mean ± SD)                   3.88 (± 1.83)           2.74 (± 1.91)          0.000*           0.740              0.663              0.827
 Nodule diameter (n%)
   < 4 cm                                       78 (56.9%)             224 (78.9%)            0.000*           0.354              0.228              0.551
   ≥ 4 cm                                       59 (43.1%)              60 (21.1%)
* Significant at p < 0.05; UCI: upper confidence interval; LCI: lower confidence interval.



while continuous variables were summarised and re-                                           p-value = 0.002). A TSH level > 2 mIU/L was significantly
ported as means and standard deviations (SD). The study                                      more common in malignant than in benign thyroid nodules
sample was divided into two groups based on final histo-                                     (39.4 vs 29.2%, p-value = 0.040). Large nodules (≥ 4 cm)
pathology (benign vs malignant). Categorical and contin-                                     were more common in benign than in malignant nodules
uous variables were compared using chi-square test and                                       (43.1 vs 21.1%, p-value = 0.000). Moreover, the mean nod-
independent T-test, respectively. All the variables were                                     ule diameter and mean body mass index (BMI) were signifi-
included in a multivariable logistic regression model to                                     cantly larger in patients with benign thyroid nodules than in
determine the predictors of thyroid malignancy in euthy-                                     malignant nodules (3.88 vs 2.74, p-value = 0.000, and 31.65
roid nodules. A p-value < 0.05 was considered as statisti-                                   vs 30.33, p-value = 0.043, respectively). Table II shows the
cally significant.                                                                           differences between benign and malignant thyroid nodules.
                                                                                             Table III illustrates the predictors of thyroid cancer in eu-
                                                                                             thyroid patients in multivariable regression analysis. A
Results
                                                                                             higher TSH level increased the likelihood of malignancy in
The study included 421 patients with thyroid patients. The                                   thyroid nodules by 1.54 times (p-value = 0.038). Moreover,
mean age of patients was 45.93 (± 14.3) years, and females                                   larger nodules decreased the possibility of thyroid cancer
represented most of our sample (80.3%). The mean TSH                                         by 24% (OR = 0.760, p-value = 0.004). Age, gender, BMI,
level was 1.84 (± 1.0) mIU/L, and almost two-thirds                                          history of cancer and free thyroxine (FT4) levels were not
of patients (63.9%) had a TSH level less than 2 mIU/L                                        associated with the final histopathology of thyroid nodules
(63.9%). Final surgical histopathology showed a benign pa-                                   in multivariable regression analysis.
thology in one-third of cases (32.5%) and malignant in al-                                   Table IV and Figure 1 demonstrate the relationship be-
most two-thirds of the patients (67.5%). Table I demonstrates                                tween the TSH level and Bethesda system category. TSH
the demographic and clinical characteristics of all patients.                                level was significantly correlated with the Bethesda system
The mean TSH level was significantly higher in malignant                                     category (p-value = 0.001). It showed that the higher the
thyroid nodules compared to benign nodules (1.94 vs 1.62,                                    Bethesda category, the higher the TSH level.



                                                                                                                                                              185
A.K. Alaraifi et al.




Table III. Predictors of thyroid cancer in euthyroid patients in logistic regression analysis.
      Variable                      Odds Ratio                             P-value                              95% LCI                   95% UCI
 TSH level                                   1.544                                 0.038*                        1.024                     2.329
 Nodule diameter                             0.760                                 0.004*                        0.630                     0.918
 BMI                                         0.967                                 0.083                         0.931                     1.004
 FT4                                         0.890                                 0.109                         0.771                     1.026
 Older age                                   1.004                                 0.754                         0.978                     1.031
 Male gender                                 1.058                                 0.844                         0.604                     1.852
* Significant at p < 0.05; UCI: upper confidence interval; LCI: lower confidence interval.



Table IV. Mean TSH levels in different Bethesda system categories (II-VI).
      Variable              II (n = 128)           III (n = 79)            IV (n = 38)                    V (n = 53)       VI (n = 123)        P-value
 TSH (mean ± SD)                  1.57 (± 0.93)             1.77 (± 0.95)              1.91 (± 1.1)      2.01 (± 0.99)     2.07 (± 1.0)        0.001*




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



Discussion                                                                                    TSH is a major regulator of thyroid function. Multiple
                                                                                              studies have evaluated it as a predictor of malignancy in
Thyroid nodules are common clinical findings, with a                                          thyroid nodules with conﬂicting results 6-10,12. Most studies
prevalence reaching 70%. Most thyroid nodules are be-                                         have shown that a higher serum concentration of TSH is
nign, while the incidence of malignancy is around 5% 11.                                      associated with an increased risk of thyroid cancer. How-
Multiple clinical, pathological, laboratory and radiological                                  ever, studies investigating this relationship in euthyroid
factors have been proposed to differentiate benign from                                       patients are limited 13. In the present study, the TSH levels
malignant nodules; however, the reported predictors are                                       were higher in malignant compared to benign nodules.
inconclusive.                                                                                 TSH levels within the higher end of the reference range



186
                                                                                Association between TSH levels and thyroid malignancy




increased the likelihood of thyroid malignancy by 1.54          thyroid cancer by 24%. Our findings correlate with Castro
times. Baser et al. evaluated 1433 patients who under-          et al. and Baser et al., who reported that smaller nodules
went thyroidectomy and reported that malignant thyroid          were more frequently seen in patients with malignancy 12,13.
nodules had elevated TSH levels compared to the benign          On the other hand, Sahin et al. and Chung et al. found no
group (p < 0.001) 13. The TSH level threshold above which       association between the diameter of the thyroid nodule and
the risk of thyroid malignancy increases was 1 mIU/L 14.        its malignant potential 22,23.
Conflicting these studies, Castro et al. reported that se-      In addition to TSH, low FT4 levels were reported as an
rum TSH level was not associated with increased risk of         independent predictor of thyroid malignancy in the litera-
malignancy among 327 thyroid lesions suspicious for fol-        ture 24. Our study had no significant association between
licular neoplasm or Hürthle cell neoplasms 12. Singh et         FT4 levels and thyroid malignancy. Extremes of age and
al. found no association between Hashimoto’s thyroiditis,       male gender were also reported to increase the risk of thy-
which has high TSH levels, and the incidence of malig-          roid malignancy 3. However, we did not find a significant
nancy in a meta-analysis conducted in 1999 15. Moreover,        correlation between age and gender with thyroid malig-
Holm et al. found that patients with uncontrolled hypo-         nancy. A meta-analysis by Zhao et al. found that obesity
thyroidism had no increased risk of thyroid malignancy          is significantly associated with an increased risk of thyroid
after two decades of follow-up 16.                              cancer 25. In our study, univariate analysis showed a signifi-
It is unclear whether higher TSH levels increase the ma-        cant association between high BMI and the risk of thyroid
lignant potential of the thyroid nodules or whether the         malignancy; however, multivariate analysis did not support
malignant nodules produce higher levels of TSH. It is           this ﬁnding.
suggested that TSH modulates the thyroid cell function,         Our study has a few limitations, such as being a retrospec-
growth and expression of specific proteins after binding to     tive single-centre study which may limit its generalisabil-
its receptors of the follicular cells. This leads to the con-   ity. Moreover, it only included patients who underwent
tinuous stimulation and proliferation of the thyroid nod-       thyroidectomies. Patients with Bethesda categories I-III
ules by high TSH levels, which results in cellular alter-       who did not have other indications for surgical interven-
nations and modulation of thyroidal gene expression 17,18.      tion were not included in the study. However, this is the
Animal experiments on mice and golden hamsters showed           first study to evaluate the association between TSH levels
that TSH stimulation is associated with thyroid malignan-       and thyroid malignancy in euthyroid patients from Saudi
cy, as overstimulation of TSH leads to hyperplasia and,         Arabia.
eventually, thyroid cancer 6. Moreover, this hypothesis is
supported by the fact that patients with well-differentiated
                                                                Conclusions
thyroid cancer benefit from TSH suppressive treatment
with levothyroxine as it decreases disease progression,         High TSH levels in euthyroid nodules were significantly
recurrence rates, and cancer-related mortality 19. On the       associated with the risk of thyroid malignancy. In addition,
other hand, recent genetic studies aimed to search for se-      as Bethesda category proceeded toward malignancy, TSH
quence variants that link TSH with thyroid malignancy.          levels increased. High TSH levels and small nodule diam-
Two variants, located on 9q22.33 and 14q13.3, have been         eters can be used as additional parameters in predicting
associated with thyroid cancer; both have also been as-         thyroid cancer in euthyroid patients.
sociated with low serum TSH 20. Moreover, an inverse re-
lationship between TSH receptor mRNA and cancer pro-            Conflict of interest statement
gression was documented by Shi et al. 21.                       The authors declare no conflict of interest.
TSH level was measured for each Bethesda category
separately in the present study. TSH level significantly        Funding
correlated with the Bethesda system category. The higher        This research did not receive any specific grant from fund-
the Bethesda category, the higher the TSH level was, and        ing agencies in the public, commercial, or not-for-profit
the highest levels were found in the malignant categories       sectors.
(V-VI). Similarly, Baser et al. reported that TSH levels
increased gradually as the Bethesda category did, rising        Author contributions
from Bethesda category II to VI 13.                             AKA, LOH, AMA, AAA: drafted the initial manuscript
Malignant thyroid nodules are smaller in diameter than be-      and worked on the data acquisition; AKA: analyzed and
nign in the present study. Moreover, our study showed the       interpreted the data, wrote and edited the manuscript; MA,
large nodule diameter (> 4 cm) decreased the possibility of     AAA: assisted with data interpretation and reviewed and



                                                                                                                                187
A.K. Alaraifi et al.




revised the manuscript. All authors read and approved the                          noma. Otolaryngol Head Neck Surg 2016;154:256-262. https://doi.
submitted version of the manuscript to be published.                               org/10.1177/0194599815618388
                                                                              11
                                                                                   Davies L, Welch HG. Increasing incidence of thyroid cancer in the
                                                                                   United States, 1973-2002. JAMA 2006;295:2164-2167. https://doi.
Ethical consideration                                                              org/10.1001/jama.295.18.2164
The institutional review board (IRB) of King Abdullah In-                     12
                                                                                   Castro MR, Espiritu RP, Bahn RS, et al. Predictors of malignancy
ternational Medical Research Center (KAIMRC) approved                              in patients with cytologically suspicious thyroid nodules. Thyroid
the study (KIMARC, NRC21R/364/09).                                                 2011;21:1191-1198. https://doi.org/10.1089/thy.2011.0146
The research was conducted ethically, with all study pro-
                                                                              13
                                                                                   Baser H, Topaloglu O, Tam AA, et al. Higher TSH can be used as an
                                                                                   additional risk factor in prediction of malignancy in euthyroid thyroid
cedures being performed in accordance with the require-                            nodules evaluated by cytology based on Bethesda system. Endocrine
ments of the World Medical Association’s Declaration of                            2016;53:520-529. https://doi.org/10.1007/s12020-016-0919-4
Helsinki.                                                                     14
                                                                                   Adhami M, Michail P, Rao A, et al. Anti-thyroid antibodies and TSH
Written informed consent was obtained from each partici-                           as potential markers of thyroid carcinoma and aggressive behavior in
                                                                                   patients with indeterminate fine-needle aspiration cytology. World J
pant/patient for study participation and data publication.                         Surg 2020;44:363-370. https://doi.org/10.1007/s00268-019-05153-1
                                                                              15
                                                                                   Singh B, Shaha AR, Trivedi H, et al. Coexistent Hashimoto’s thyroidi-
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