Clinical, cytological and ultrasonographic features of incidental thyroid cancer in a hospital‐based study in vietnam

Abstract Introduction Thyroid nodules are common diseases of the endocrine system, with a 5% prevalence rate in the general population. This study aimed to identify prevalence, clinical, cytological and ultrasonographic features of incidental thyroid cancer and its associated factors in Vietnam. Methods This cross‐sectional descriptive study consisted of 208 patients with incidental thyroid nodules detected by ultrasound at the Endocrinology Department, Bach Mai Hospital, Hanoi, Vietnam between November 2019 and August 2020. Clinical information, sonography characteristics of thyroid nodules, results of fine‐needle aspiration biopsy (FNAB), postoperative pathology and lymph node metastasis were collected. A multiple logistic regression model was used to estimate factors associated with thyroid cancer. Results A total of 272 thyroid nodules (from 208 participants) were included in this study. The mean age was 47.2 ± 12.0 (years). The rate of incidental thyroid cancer patients detected was 17.3%. Nodules <1 cm in size were significantly more prevalent for malignant nodules. The size of more than half of thyroid cancer nodules was 0.50–0.99 cm. Postoperative pathology of all nodules with Bethesda V and VI was papillary thyroid cancer which was consistent with cytological results. 33.3% of thyroid cancer patients have lymph node metastasis. The regression model showed that thyroid cancer was more likely to occur at a younger age (≤ 45 years vs. >45 years, OR 2.8; 95% CI: 1.3–6.1), taller‐than‐wide nodules (OR 6.8; 95% CI: 2.3–20.2) and hypo‐echoic nodules (OR 5.2; 95% CI: 1.7–15.9). Conclusion The study showed that the prevalence of incidental thyroid cancers was 17.3%, of which 100% was papillary carcinoma. People under the age of 45 and the presence of ultrasound characteristics, such as taller‐than‐wide and hypoechoic nodules increased risk for malignancy.


| INTRODUC TI ON
Thyroid nodules are common diseases of the endocrine system, with a 5% prevalence rate in the general population. 1 Although 85%-93% of thyroid nodules are benign, they may become potentially malignant, which has become the fastest-growing cancer.
A thyroid incidentaloma is an unexpected, asymptomatic thyroid nodule discovered incidentally during examination for an unrelated condition. The incidence of thyroid incidentaloma varies depending on different imaging modalities. Previous studies reported that the rate of thyroid incidentaloma was 67% with neck ultrasonography imaging, 2 0.84% of carotid ultrasonography, 3 15% with computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, 4,5 3.45% of cervical spine or face/orbit MRIs, 5.84% of chest CTs with contrast, and 5.14% of chest CTs without contrast, 3 1%-2% with fluorodeoxyglucose (FDG) positron emission tomography 6,7 and 5% of time-resolved magnetic resonance angiography (TRMRA) examinations. 8 Vietnam has witnessed a rapid increase in the incidence of thyroid cancer. The age-standardized incidence rate of thyroid cancer was 2.4 per 100,000 during 1996-2000 and dramatically increased to 7.5 per 100,000 during 2011-2015. 9 With the development of imaging technologies, the probability that asymptomatic thyroid nodules will be discovered is increasing. In the absence of accurate clinical signs or predictors of malignancy, many of the nodules will require fine-needle aspiration biopsy (FNABs), which appears not to be cost-effective and diagnostic challenges, for example indeterminate and non-diagnostic cytology.
Clinical evaluations and sonographic variables should be used in combination to determine whether the clinician should proceed with further confirmatory tests or with periodical follow-up. 10,11 Highrisk clinical features such as young age, single nodularity and male sex were established risk factors for malignant thyroid nodules. 12 The ultrasound findings of micro-calcifications, absence of a halo, hypo-echogenicity and irregular nodular margins all increase cancer risk 13,14 The 5-year survival rates for thyroid cancers are nearly 100% for localized tumours, 97% for tumours with regional metastases and 57.3% for distant staged tumours. 15 Early detection of thyroid cancers can have a significant positive effect on prognosis and impact treatment decisions. 16 The aim of this study was to describe the prevalence, clinical, cytological and ultrasonographic features of incidental thyroid nodules and to assess the independent predictors of thyroid cancer in Vietnam.

| Study design and setting
The study was designed as a cross-sectional investigation including 208 subjects with incidental thyroid nodules, who presented to the  Mai Hospital. After training, these physicians were re-tested before starting the study to confirm the results were similar. Each patient had an ultrasound and FNA biopsy by one of these three endocrinologists.

* Pathology results after surgery
All patients with Bethesda V and VI were performed thyroidectomy in three hospitals, which were Bach Mai Hospital, Vietnam National Cancer Hospital and National Hospital of Endocrinology. The postoperative pathology results were evaluated using the WHO 2017 classification. 21

| Statistical methods
The analysis was performed with SPSS 20. Descriptive statistics were used: continuous variables were presented as mean ± standard deviation (SD) and categorical variables as frequency and percentage. Proportions were compared by using Chi-squared tests with continuity correction or Fisher's exact test when appropriate, continuous variables were compared by using Student's t-tests. Univariate logistic regression was performed on general factors and other potential factors that can be associated with thyroid cancer based on the literature such as the size of a thyroid nodule, and ultrasonographic features. Only variables that had a p-value <.2 on univariate analysis were selected for multivariate analysis. Multivariate analyses were conducted with logistic regression, the results were presented as an odds ratio (OR) with a 95% confidence interval (CI). All values of p < .05 were considered statistically significant.

| RE SULTS
A total of 272 thyroid nodules (from 208 participants) were included in this study. The mean age was 47.2 ± 12.0 (years). The proportion of patients with thyroid cancer detected was 17.3%.
The rate of thyroid cancer in the age group ≤45 (years) was statistically significantly higher than that in the age group >45 (years) ( Table 1).
The sonographic characteristics of those with cancer versus non-cancer ones were compared in Table 2

| DISCUSS ION
To our knowledge, the current study is the first work to mention incidental thyroid nodules in a hospital-based study in Vietnam. The results showed that the rate of thyroid cancer was 17.3% out of 208 patients with thyroid nodules detected incidentally on ultrasound.
Thyroid cancer patients were mostly aged ≤45 and most of the nodules with diameter ranged from 0.50 to 0.99 cm. The sonographic features of nodules associated with a high risk of malignancy were those with taller-than-wide dimensions and hypo-echogenicity. Many studies have attempted to show that certain sonographic features are associated with a higher risk of malignancy, especially in nonpalpable thyroid nodules to avoid unnecessary FNA or surgery. [31][32][33] In our study, the ultrasonographic features of nonpalpable nodules suggesting the highest malignancy odds ratios were taller-than-wide dimensions (OR 6.8, 95% CI 2.3-20.2) and hypoechogenicity (OR 5.2, 95% CI 1.7-15.9). Meanwhile, a study by Kang HW et al. 32 indicated that the ultrasound features of solid echogenic structures, blurred margins and calcifications showed significant diagnostic value in detecting malignancy in incidental thyroid nodules.
In fact, blurred margin, calcification, hypo-echogenicity and tallerthan-wide and solid echo structures are all suggestive of cancer and have a high TIRADS score. 18 However, in small thyroid nodules, ultrasonography may be more difficult to detect features such as calcifications and blurred margins than taller-than-wide and hypoechoic.  should recommend ultrasound-guided FNA to screen for malignancy for incidentally detected thyroid nodules, even when the nodule size is <1 cm, with sonography features suspicious on such as taller-thanwide dimensions and hypo-echogenicity in patients ≤45 years of age.
Our result had a majority of women (87%) who are at the highest risk of developing thyroid cancer earlier (those were most often in their 40s or 50s at diagnosis) than men (often in their 60s or 70s). 35 This finding may also be related to the role of oestrogen levels, its receptors and gynaecological diseases requiring oestrogen replacement therapy in the proliferation, migration and invasion of thyroid cancer. 36

Type of cancer n (%)
Lymph node metastasis n (%) The difference may be due to the immigration and acculturation of these Asian ethnic groups (e.g. goitrogenic exposure, diet, weight and body mass index and menstruation and reproductive events), which can have a strong effect on the development of PTC. In terms of diet, Iodine deficiency is thought to be associated with the follicular and anaplastic histotypes whereas iodine excess is related to the papillary histotype. 45 Molecular alterations (including the BRAF mutations and rearrangements) were identified mainly in PTC but rare in the follicular thyroid cancer (FTC). 46,47 Previous studies showed that the percentage of BRAF-positive PTCs in iodine-sufficient areas was higher than in iodine-deficient areas. 48,49 Vietnam is a country with a long coastline and the national program to prevent Iodine deficiency disorders has been implemented since 1993, which can lead to iodine excess associated with the predominance of papillary thyroid cancer in our study. 50 It should be noted that our study has not found any follicular thyroid cancer. Interestingly, the FTC exhibits other differences in sonographic features compared to those in the PTC. The latter is more likely to be iso-to hyperechoic, noncalcified, wider-than-tall nodules with well-defined margins. 51 In contrast, the results in our study with PTC nodules had the ultrasound features of hypo-echogenicity, micro-calcifications, taller-than-wide dimensions and blurred margins. In addition, in the study of Al-Hakami H et al, 52 follicular carcinoma was mostly found in nodules with a size of 4 cm, on the other hand, the largest nodules in our study were 2.4 cm.
There are some strengths and limitations to our study. This has been the first study in Vietnam to discover random thyroid nodules. We found it possible to use ultrasound-a cost-effective and easily accessible tool-to detect thyroid cancer with great accuracy and relevance in developing countries. However, this was a crosssectional study that could not show a causal relationship between risk factors and outcomes. Therefore, it is essential for further studies to explore these issues.

| CON CLUS ION
In writing -original draft (equal); writing -review and editing (equal).

ACK N OWLED G EM ENT
We would like to express our deepest gratitude for the great support of the Endocrinology Department, Bach Mai Hospital during research implementation.

FU N D I N G S TATEM ENT
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

CO N FLI C T O F I NTE R E S T S TATE M E NT
The author reports no conflicts of interest in this work.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets of this study are available from the corresponding author on reasonable request.