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\begin{document}

\title{Presence of hypothyroidism and thyroiditis does not improve the
performance of ultrasound screening for thyroid nodules in patients with
obesity}



\author[1]{Gabriel Gimenez-Perez}%
\author[1]{Assumpta Recasens}%
\author[2]{Sandra Chicharro}%
\author[1]{Olga Simo}%
\author[2]{Jesus Murillo}%
\author[1]{Ignasi Castells}%
\affil[1]{Hospital General de Granollers}%
\affil[2]{Fundació Privada Hospital de Mollet}%


\vspace{-1em}



  
  \date{March 12, 2025}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Purpose: It has been suggested, on a theoretical basis, that ultrasound
screening of thyroid nodules in obese patients with additional risk
factors (family history, thyroiditis or high thyrotropin) might be
cost-effective for the early detection and treatment of thyroid cancer.
The present study evaluates if this approach can be validated in a real
clinical setting. Methods: Patients with obesity attended in
hospital-based clinics were evaluated for risk factors of thyroid cancer
and ultrasound screened for thyroid nodularity. Detected nodules were
evaluated according to current guidelines. Results: A total of 429
patients were evaluated (70.2\% women, mean age 49.1\selectlanguage{ngerman}±11.0, mean body
mass index 42.6±5.8 kg/m2). Risk factors were present in 129 (30.1\%)
patients. Thyroid nodules with indication for fine needle aspiration
biopsy were detected in 69 (16.1\%). We did not find differences in the
risk of harbouring thyroid nodules according to the presence of risk
factors (no risk factors 16.6\%, risk factors 14.1\%, p = 0.64). No
single risk factor conferred an increased risk for thyroid nodules
During the screening procedure 4 cases of thyroid cancer were detected,
none of them with the evaluated risk factors. Conclusion: The present
study, has been unable to demonstrate that the use of known risk factors
for thyroid cancer is helpful to discriminate obese patients with higher
risk of harbouring thyroid nodules.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{INTRODUCTION}

Obesity is a well-established risk factor for numerous diseases,
including different types of cancer {[}1, 2{]}. Various studies and
meta-analyses have observed an increase in the incidence of
differentiated thyroid cancer in overweight and obese individuals
{[}3{]}. Additionally, it has been suggested that obesity is associated
to more aggressive forms of papillary cancer {[}4{]}, to more advanced
stages at diagnosis {[}5{]} and to higher rates of disease persistence
after treatment {[}6{]}. However, these associations have not been
replicated in other studies {[}\emph{7} {]}.

Ultrasound screening of thyroid cancer is not recommended in
asymptomatic individuals with no specific risks for the disease {[}8{]},
however, some controversy exists about the benefits and risks of the
screening in high risk populations such as radiation exposure {[}9,
10{]} and autoimmune thyroid diseases {[}11{]}. Obesity may be also
considered a risk factor for thyroid cancer {[}12{]}, and although the
screening of thyroid cancer in obese individuals is not considered
justified {[}13{]}, data about the feasibility of early detection of
thyroid cancer by systematic ultrasound assessment and its effects on
the prognosis of thyroid cancer in patients with obesity are lacking
{[}13{]}.

In order to justify a specific cancer screening approach, it must be
demonstrated that it is beneficial, that it lacks of significant harm
and that it is cost-effective {[}14{]}. Recently, Cham et al {[}15{]},
evaluated the cost-effectiveness of US screening of thyroid cancer in
obese individuals. In their study, using data from published reports and
US costs, the authors concluded that US screening of thyroid cancer in
selected obese patients with risk factors (family history of thyroid
cancer, radiation exposure, Hashimoto's thyroiditis, and/or elevated
thyrotropin (TSH)) was cost-effective. However, the study was based on
published reports and has not been experimentally validated in actual
obese patients.

The objective of the current study is to evaluate if a strategy of US
screening of thyroid nodules in obese patients with risk factors, can be
validated in a real clinical setting.

\textbf{MATERIALS AND METHODS}

Patients from the obesity and diabetes clinics of two Endocrinology
Units (Hospital General de Granollers and Hospital de Mollet), older
than 18 years and with obesity, defined as a body mass index (BMI) [?] 30
kg/m\textsuperscript{2}, were asked to participate.

After signing the informed consent, patients were examined clinically
and a thyroid US and the determination of serum
anti-thyroperoxidase~antibodies (TPOAb) and TSH levels were planned.

Exclusion criteria were the inability to understand the study, the
presence of personality traits in which the practice of thyroid US and
the possible detection of nodular pathology could generate an undue
anxiety, and the presence of previously other known autoimmune diseases,
thyroid nodules or thyroid cancer. Specifically, patients with obesity
who consulted for suspected functional or nodular thyroid disease were
not included in the present study.

Thyroid US were performed and interpreted by experienced
endocrinologists using an Esaote Mylab9 scanner (Hospital de Granollers)
or a Siemens Sonoline G40 scanner (Hospital de Mollet) both equipped
with a high-resolution linear transducer (7.5--14 MHz).

Serum TPOAb were measured in an Immulite 2000 XPi Immunoassay System
(Siemens Healthcare GmbH, Erlangen Germany) and expressed as IU/ml.
Normal values for TPOAb were \textless{}35 IU/ml. Serum TSH was measured
in a Cobas e170 analyser (Roche Diagnostics LTd, Rotkreuz, Switzerland;
normal values 0.3-4.2 \selectlanguage{greek}μ\selectlanguage{english}IU/ml).

Patients were classified according to neck palpation (i.e. abnormal vs.
normal) and the presence of the pre-specified risk factors, i.e. family
history of thyroid cancer, radiation exposure, Hashimoto's thyroiditis
and elevated TSH or treated hypothyroidism. Patients were considered as
harbouring Hashimoto's thyroiditis if TPOAb levels were higher than the
upper limit of reference. Likewise, TSH levels were considered high if
they exceeded the upper normal reference value.

Thyroid nodules detected by thyroid US were classified as specified by
the current guidelines of the American Thyroid Association (ATA)
{[}16{]} and fine needle aspiration biopsy (FNAB) was indicated
accordingly, with the exception of subcentimeter nodules with a high
suspicion echographic pattern where FNAB was also considered. FNABs were
performed and processed using standard protocols {[}17{]} and were
evaluated by the Department of Pathology of Hospital de Granollers using
the Bethesda reporting system {[}18{]}. Surgical treatment was planned
according to current guidelines {[}16{]}. In a post-hoc analysis nodules
were classified following the TI-RADS classification of the American
College of Radiology (ACR) {[}19{]}.

Follow-up of nodules not subjected to surgery and of those without
indication of FNAB was performed at discretion of the attending
physician.

Data are presented as number (n) and standard deviation (SD) or
percentages with 95\% confidence intervals (CI) when appropriate. The
differences in the frequency of thyroid nodules between groups were
analysed with Pearson's Chi-squared test at a significance level of
p\textless{}0.05. To test for differences between the present results
and those previously hypothesized we used inference statistics for one
sample using as reference the proportions stated by Cham et al {[}15{]}.
Analyses were performed using free online statistical packages
(https://www.socscistatistics.com and
https://www.medcalc.org/calc/test\_one\_proportion.php).

The study was approved by the research committees of the participating
centres. No specific funding was received for the development of the
study.

\textbf{RESULTS}

During the study period, participation was offered to a total of 506
patients, of whom 429 were valid for evaluation. Figure 1 depicts the
flow diagram of the study and the classification of the evaluated
patients according to their risk factors. The final population consisted
of 301 (70.2\%) women and 128 (29.8\%) men with a mean age of 49.1\selectlanguage{ngerman}±11.0
years and a BMI of 42.6±5.8 kg/m\textsuperscript{2}. Morbid obesity
(BMI\selectlanguage{english}[?]40 kg/m\textsuperscript{2}) was present in 283 (66.2\%) patients.
As shown, 129 (30.1\%; CI 25.9-34.6) patients were classified as having
one or more risk factors for thyroid cancer. Abnormal palpation was
present in 38 (8.9\%; CI 6.5-11.9) individuals. Elevated
TSH/hypothyroidism was the most prevalent risk factor (19.6\%; CI
16.1-23.6). Prevalence of risk factors was significantly higher among
women (34.4\% vs 17.4\%; P\textless{}0.001). Radiation exposure was not
present in any patient.

Sixty-nine (16.1\%; CI 12.8-19.9) patients harboured thyroid nodules
with indication for FNAB according to the ATA guideline {[}16{]}. This
value was significantly higher than expected (10\%; P\textless{}0.0001)
{[}15{]}\emph{.} Prevalence of thyroid nodules was significantly higher
in women (18.9\% vs 9.4\%; P=0.014). Patients with thyroid nodules were
significantly older (54.2\selectlanguage{english}?10.0 vs. 48.2\selectlanguage{english}?12.1; P\textless{}0.005). Body
mass index was not different between patients with or without thyroid
nodules (P=0.49).

Sixty-three patients underwent FNAB. Table 1 shows the FNAB results, the
corresponding US risk categories and the final surgical diagnosis when
available. Initially, six nodules received a Bethesda 3 diagnosis, which
was confirmed in a second FNAB in 2 cases; the second FNAB of the four
remaining nodules rendered a Bethesda 2 diagnosis.

Six patients were lost for follow-up before performing the FNAB; two of
these nodules were classified as high suspicion pattern according to the
ATA guideline (moderately suspicious according to ACR) with a maximum
diameter of 12 mm.

Four patients were operated on the basis of cytological results with 3
final cases of papillary thyroid cancer and one case of nodular
hyperplasia (cytological diagnosis: Bethesda 4). The clinical and
pathological characteristics of papillary thyroid cases are shown in
Table 2. An additional case was operated despite a benign FNAB result on
the basis of mild local symptoms with a final result of nodular
hyperplasia.

In 111 (25.9\%) patients, thyroid nodules with no indication of FNAB
were found. In 48 (43.2\%) patients follow-up sonographies were
performed after a median time of 14 months. During follow-up, 26 months
after the initial screening, we detected enlarged suspicious
lymphadenopathies in a 47yr old male patient with a hypoechoic isthmic
nodule of 8mm. The final diagnosis was papillary thyroid carcinoma
(multicentric, infiltrative follicular variant) pT1bN1bM0 with a largest
nodule of 11mm. At first evaluation, TSH was normal and TPOAbs were
undetectable. Therefore, risks of malignancy were 0.93\% (CI 0.02-1.84)
for the entire screened cohort; 2.2\% (CI 0.9-5.5) for patients with
thyroid nodules and 5.8\% (CI 2.3-14.0) for those nodules with
indication of FNAB.

Table 3 depicts the percentage of thyroid nodules according to thyroid
palpation and risk factors. As shown, the presence of an abnormal
palpation was associated with a significantly higher prevalence of
thyroid nodules, whereas the prevalence of thyroid nodules was not
dependent on the presence of risk factors. Additional comparisons
considering as risk factor a TPOAb level above 100 IU/ml and excluding
patients with treated hypothyroidism did not find significant
differences between groups in the prevalence of thyroid nodules.

Table 4 shows the prevalence of thyroid nodules according to the
individual risk factors. The presence of thyroid nodules was, again, not
dependent on the presence of any of the assessed risk factors.

\textbf{DISCUSSION}

In the present study, we have not been able to demonstrate that the use
of established risk factors for thyroid cancer is useful to discriminate
obese patients with a higher risk of harbouring thyroid nodules and,
therefore candidates to rule out thyroid cancer.

No professional medical society recommends population-based screening
for thyroid cancer {[}20{]}, and in the cases where this strategy has
been implemented it has rendered no benefit in clinical terms {[}21{]}.
However, there is a continued increase in thyroid cancer prevalence in
most countries that is generally considered as overdiagnosis and
overtreatment {[}22{]} and probably indicates, among other reasons, a
continued non-judicious use of thyroid ultrasound in some clinical
settings {[}23, 24{]}. Our aim in this study was to analyse the
effectiveness of a screening strategy advocated as cost-effective and
therefore recommendable from a theoretical framework {[}15{]}, adding
knowledge to the sensible use of thyroid ultrasound. Our data do not
support the advocated strategy and therefore supports the current
recommendations in asymptomatic obese adults {[}13{]}.

A significant difference between the theoretical framework used in the
seminal study {[}15{]} and our actual results is the prevalence of risk
factors. The main discrepancy lies in our higher prevalence of
hypothyroidism. Although the prevalence of high TSH may be different in
different populations {[}25, 26{]}, the reported prevalences, also for
treated hypothyroidism {[}27{]}, are generally lower than in our study.
A possible explanation for our higher prevalence could be the presence
of obesity itself, since it has been reported that high TSH levels are
more prevalent in obese patients, at least in children and adolescents
{[}28{]} and morbid obese patients {[}29{]}. The prevalence of TPOAb was
similar to some other studies {[}26{]} but again higher than usually
expected.

Different studies have shown an association between thyroid cancer and
the presence of autoimmune thyroiditis {[}30, 31{]} or higher TSH levels
{[}32{]}. Although these associations are not a constant finding {[}33,
34{]}, some authors have suggested a role for periodic US to detect
thyroid malignancy in these situations {[}30{]}. In our population the
presence of these potential risk factors was not associated to an
increased risk of thyroid nodularity or cancer. We can hypothesize that
this finding may be due to a different relevance of these factors in the
obese population, specially the higher incidence of high TSH. In this
sense it has been argued that higher TSH levels in obese patients are
not an evidence of thyroid dysfunction but, rather, an adaptation
process {[}35{]}. Interestingly, in a recent report, thyroid nodules
were less common in children and adolescents with autoimmune thyroiditis
or high TSH than in their counterparts {[}36{]}.

The percentage of thyroid nodules with indication for FNAB was higher
than expected {[}15{]}. This result is in line with other authors'
results {[}37{]} and suggests that the prevalence of thyroid nodularity
in the obese population is probably higher than in the non-obese
population.

Several meta-analyses have found an association of obesity with an
increased thyroid cancer risk {[}3{]}. Although the present study was
not designed nor powered to evaluate the incidence of thyroid cancer or
the utility of generalized US screening for its detection in obese
patients, we found an incidence above the reported incidence rates for
the general population {[}8{]} although in line with other populations
where a systematic screening has been performed {[}21{]}. Most detected
thyroid cancers in our study were of low risk and good prognosis and
since any screening strategy should counterbalance potential health
benefits with the risk of generating an excess in diagnosis, treatment
and costs {[}8, 21{]}, it does not seem that any screening strategy of
thyroid cancer in obese individuals will be cost-effective and, in any
case, the use of the assessed risk factors is not useful.

Furthermore, this screening strategy results in the detection of a
considerable number of nodules without indication for FNAB that could be
subjected to follow-up increasing~resource use and costs and generating
anxiety for patients without any noticeable benefit.

Our study has some limitations. We designed the study to detect
differences in the incidence of thyroid nodules and not thyroid cancer,
which is the final purpose of the screening strategy. However, detection
of thyroid nodules is the first step in the diagnosis of most thyroid
cancers {[}16{]} and therefore the absence of an increased incidence of
thyroid nodules in the obese population with additional risk factors
makes the screening strategy ineffective.

Some variability may rise from the fact that ultrasound was not
performed centrally. However, the use of a specific classification
system might have reduced the effects of this limitation {[}38{]}.

Additionally, we used as a surrogate for the presence of thyroiditis the
positivity of TPOAb. Although other serological markers can be used,
TPOAbs are considered the best serological marker to establish a
diagnosis of Hashimoto's thyroiditis {[}39{]}. However, an association
between thyroid cancer and anti-thyroglobulin antibodies (TgAb) has been
reported {[}31{]}, and therefore we cannot rule out that the use of
TgAbs would have changed the results.

Also, the population studied is predominantly morbid obese patients,
which may not be representative of other obese populations. It seems
reasonable, however, to consider that our study focuses on the obese
population at highest risk of cancer and in which the effect of
additional risk factors should be more evident. Moreover, BMI was not
different between patients without or with thyroid nodules.

Furthermore, there is some risk of selection bias. For unknown reasons,
not all obese patients attended were offered participation and, this
fact may have selected the population finally evaluated. Additionally,
we decided to exclude patients with other autoimmune diseases. The
reason for doing so, was to not overestimate de prevalence of high
TPOAbs as it is known that the prevalence of thyroid autoimmunity is
increased in the presence of other autoimmune disorders {[}40{]}.

Despite these limitations, the number of patients evaluated give us
confidence that the results are reliable and therefore we can conclude
that the use of the studied risk factors (specifically TSH and TPO) is
not useful to discriminate obese patients with a higher risk of
harbouring thyroid nodules.

\textbf{DECLARATIONS}

\textbf{Funding}

No funding was received for conducting this study

\textbf{Conflicts of interest}

The authors have no relevant financial or non-financial interests to
disclose

\section*{Ethics approval}

{\label{ethics-approval}}

Approval was obtained from the research committees of the participating
centres. The procedures used in this study adhere to the tenets of the
Declaration of Helsinki.

Informed consent was obtained from all individual participants included
in the study

\section*{Authors' contributions}

{\label{authors-contributions}}

GGP designed the study protocol and drafted the manuscript. AR, SC, OS,
JM and IC reviewed and amended the study protocol. All authors were
involved in the acquisition and treatment of data and read and approved
the final manuscript.

\section*{Data availability}

{\label{data-availability}}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

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Endocrinol Invest.} 2008;31:861-5.

\textbf{Table 1. FNAB results, US risk categories (ATA and ACR
classification) and final diagnosis}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
FNAB result\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
ATA classification suspicion level (n)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
ACR classification suspicion level (n)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Final diagnosis ( n)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bethesda 6\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
3 (4.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
High = 2 Intermediate = 1\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
High= 2 Moderate = 1\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Papillary carcinoma = 3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bethesda 4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Intermediate = 1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate = 1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Thyroid hyperplasia = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bethesda 3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Intermediate = 2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Moderate = 2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bethesda 2\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
55 (79.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
High = 10 Intermediate =18 Low = 24 Very low = 3\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
High = 6 Moderate = 22 Mild = 18 Not suspicious/benign = 9\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Thyroid hyperplasia = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Bethesda 1\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Intermediate = 1 Very low = 1\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Moderate = 1 Not suspicious/benign = 1\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Not performed\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6 (8.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
High = 2 Intermediate = 2 Low = 2\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Moderate = 4 Mild = 2\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

FNAB: Fine needle aspiration biopsy. ATA: American Thyroid Association.
ACR: American College of Radiology.

\textbf{Table 2. Clinical and pathological characteristics of screen
detected papillary cancers}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Sex\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
TNM (AJCC 8th ed)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Other characteristics\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Case 1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
56\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
38.3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
pT1bN0 (16mm)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Classical\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
53\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
43.2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
pT1bN0 (13mm)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Classical Multicentric\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case 3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
37.9\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
pT1bN0 (13mm)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Classical Multicentric Focal infiltration of perithyroidal soft
tissue\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Case 4\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
48.9\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
pT1bN1bM0 (11 mm)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Infiltrative follicular Multicentric Infiltration of fat perithyroidal
tissue Lymph node metastasis in 12 out of 18 lymph nodes\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{+} detected during follow-up

BMI: body mass index



\textbf{Table 3. Prevalence of thyroid nodules according to risk
categories}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& THYROID NODULES WITH INDICATION FOR FNAB n (\%; CI) & PAPILLARY
THYROID CANCER (n)\tabularnewline
\midrule
\endhead
Abnormal palpation (n=38) & 18 (47.4; 32.5-62.7)\textsuperscript{*} &
1\tabularnewline
With risk factors (independent of palpation) (n=129) & 19 (14.7;
9.6-21.9)\textsuperscript{**} & 0\tabularnewline
No risks factors (independent of palpation) (n=300) & 50 (16.7;
12.9-21.3) & 3\tabularnewline
\bottomrule
\end{longtable}

FNAB: fine needle aspiration biopsy. CI: 95\% confidence
intervals.\textsuperscript{*}p\textless{}0.0001 vs. normal
palpation;\textsuperscript{**}p=0.62 vs. no risks factors (independent
of palpation)

\textbf{Table 4. Prevalence of thyroid nodules according to individual
risk factors}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
& Family history of thyroid cancer & Family history of thyroid cancer &
Treated hypothyroidism & Treated hypothyroidism & TSH \textgreater{} 4.2
\selectlanguage{greek}μ\selectlanguage{english}IU/ml or treated hypothyroidism & TSH \textgreater{} 4.2 \selectlanguage{greek}μ\selectlanguage{english}IU/ml or
treated hypothyroidism & TPOAb \textgreater{}35 IU/ml & TPOAb
\textgreater{}35 IU/ml & TPOAb \textgreater{}100 IU/ml & TPOAb
\textgreater{}100 IU/ml\tabularnewline
\midrule
\endhead
& YES n = 4 & NO n= 425 & YES n=33 & NO n=396 & YES n=84 & NO n=345 &
YES n=72 & NO n=357 & YES n=31 & NO n=398\tabularnewline
Thyroid nodules with indication for FNAB (n (\%)) & 1 (25.0\%) & 68
(16.0\%) & 1 (3.0\%) & 68\textsuperscript{*} (17.2) & 9 (10.7\%) & 60
(17.4\%) & 15 (20,8\%) & 54 (15.1\%) & 8 (25.8\%) & 61
(15.3\%)\tabularnewline
Papillary thyroid cancer (n) & 0 & 3 & 0 & 3 & 0 & 3 & 0 & 3 & 0 &
3\tabularnewline
\bottomrule
\end{longtable}

TSH: thyrotropin; TPOAb: serum
anti-thyroperoxidase~antibodies;\textsuperscript{*}P=0.034

\textbf{FIGURE LEGENDS}

Figure 1. Flow diagram of the study\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1IJCP/Figure1IJCP}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

