Evaluation of children with solid thyroid nodules: a single-center experience

Introduction

Thyroid nodules are less common in children compared to adults [1]. However, the risk of malignancy in pediatric thyroid nodules is significantly higher [1], 2]. Recent studies have reported an increasing incidence of both thyroid nodules and thyroid cancer in children and adolescents [3]. Risk factors for thyroid nodules and thyroid cancer include a family history of thyroid disease, exposure to radiation, obesity, history of thyroid disorders, iodine deficiency, elevated serum thyroid-stimulating hormone (TSH) levels, and various genetic syndromes [4], 5].

Solid thyroid nodules should be carefully evaluated due to the risk of differentiated thyroid carcinoma [5]. Detailed history-taking, physical examination, thyroid ultrasonography (US), and fine-needle aspiration biopsy (FNAB) are essential diagnostic tools that guide the assessment of malignancy risk and management strategies [1]. Ultrasonographic features suggestive of malignancy in children include microcalcifications, irregular margins, hypoechogenicity, solid composition, increased intranodular vascularity, larger nodule size, and the presence of abnormal lymph nodes [1], 2], 4]. FNAB under US guidance is indicated for nodules exhibiting high-risk sonographic features [2]. Concurrent biopsy of suspicious lymph nodes in the lateral neck compartments should be performed alongside the thyroid nodule biopsy to determine the necessity and extent of lateral neck dissection [2]. Detection of elevated thyroglobulin levels in FNAB washout fluid is suggestive of malignancy in cytologically indeterminate lymph nodes [5], 6]. Cytological findings from FNAB are classified into six categories according to the Bethesda System [7]. Indeterminate cytology (Bethesda categories 3, 4, and 5) carries a higher risk of malignancy in children compared to adults [2]. Although pediatric management strategies are generally guided by established clinical guidelines [3], 8], the diagnostic and surgical approach to thyroid nodules in children requires consideration of distinct features that differ from adult cases [9].

The aim of this study is to investigate the clinical and laboratory characteristics of pediatric patients with thyroid nodules, evaluate the ultrasonographic and cytological features of the nodules to identify malignancy risk factors, and determine the frequency of malignancy based on Bethesda categories in cases undergoing FNAB.

Materials and methods

After approval of the study protocol by the local ethics committee, the medical records of pediatric and adolescent patients who were evaluated for thyroid nodules at our hospital between January 2020 and December 2025 were retrospectively reviewed. Demographic, laboratory, imaging, and biopsy findings of the patients were assessed. All procedures were conducted in accordance with the Declaration of Helsinki for research involving human subjects. Due to the retrospective nature of the study, informed consent was waived.

Purely cystic thyroid nodules were excluded from the study, as they are presumed not to carry a risk of malignancy. Only the data of purely solid or cystic thyroid nodules with a solid component were analyzed. In our clinic, nodules with a diameter of ≥10 mm and/or suspicious ultrasonographic features at the time of diagnosis or during follow-up are evaluated via FNAB. Suspicious sonographic features other than size include microcalcifications, irregular margins, hypoechogenicity, solid composition, increased intranodular blood flow, and abnormal lymph nodes. A nodule with irregular margins is defined as one that exhibits microlobulations, spiculations, or an infiltrative, jagged border with the surrounding thyroid parenchyma.

Cytological results were reported in accordance with the Bethesda System for Reporting Thyroid Cytopathology, which classifies thyroid fine-needle aspiration specimens into six categories: Category 1 indicates a non-diagnostic or unsatisfactory cytological specimen; Category 2 corresponds to benign findings; Category 3 represents atypia of undetermined significance (AUS) or a follicular lesion of undetermined significance (FLUS); Category 4 includes cases suggestive of a follicular neoplasm or suspicious for a Hürthle cell neoplasm; Category 5 is used for specimens that are suspicious for malignancy; and Category 6 denotes cytological features diagnostic of malignancy. Patients were evaluated for treatment options in a multidisciplinary tumor board based on clinical, imaging, and cytological findings. In patients who underwent surgery, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the FNAB cytology categories were calculated.

For statistical analysis, the Statistical Package for the Social Sciences (SPSS) version 22.0 for Windows (IBM Inc., Chicago, IL, USA) was used. Quantitative variables were reported as mean±standard deviation (SD) or median (range), depending on data distribution. Categorical variables were expressed as absolute and relative (%) frequencies. Pearson’s chi-square test or Fisher’s exact test was used for comparison of categorical variables, while the Mann–Whitney U test was used for continuous variables. A p-value of <0.05 was considered statistically significant.

Results

A total of 67 patients with solid thyroid nodules were evaluated in the study, of whom 56 (84 %) were female. FNAB was performed in 53 patients (79 %). The median age of the biopsied patients was 16.1 years (5.5–18.0), and the male-to-female ratio was 10/43. Ultrasonographic characteristics of the nodules identified in these cases are summarized in Table 1. Among the patients who underwent FNAB, two had coexisting Graves’ disease, and five were diagnosed with Hashimoto’s thyroiditis.

Of the 53 thyroid biopsy specimens evaluated, 13 cases (24.5 %) were classified as Bethesda Category 1 (non-diagnostic), 25 cases (47.2 %) as Category 2 (benign), 10 cases (18.9 %) as Category 3 (atypia of undetermined significance/follicular lesion of undetermined significance), 4 cases (7.5 %) as Category 5 (suspicious for malignancy), and 1 case (1.9 %) as Category 6 (malignant). Following these biopsy results, surgery was performed in 13 patients, and papillary thyroid carcinoma (PTC) was identified in 10 of them (77 %). Postoperative complications occurred in two patients: one with transient and one with permanent hypoparathyroidism. Among patients who underwent surgery, malignancy was confirmed in all cases categorized as Bethesda Category 5 (n = 4) and Category 6 (n = 1), yielding a malignancy rate of 100 % for these groups. In Category 3 (n = 7), the malignancy rate was 57.1 %, while in Category 2 (n = 2), it was 50 %. Further details are presented in Figure 1. In one patient with a benign cytology (Category 2), an increase in nodule size during follow-up prompted a second FNAB, which was reported as Category 3. Subsequent surgery confirmed the diagnosis of PTC. Another patient initially classified as Category 2 underwent surgery at an external center and was also diagnosed with PTC.

Figure 1:

Distribution of patients who underwent fine-needle aspiration biopsy (FNAB) according to the Bethesda classification and pathological outcomes of those who underwent surgery. PTC: Papillary thyroid carcinoma.

During follow-up, repeat biopsies were obtained in 4 out of 13 patients with initial Category 1 cytology and in 7 out of 25 patients with initial Category 2 cytology. One patient with two consecutive non-diagnostic (Category 1) FNAB results was re-biopsied a third time, yielding a Category 3 result. Surgery was performed, and PTC was confirmed histologically. Among the patients initially classified as Category 2, two were re-biopsied, both yielding Category 3 results. Surgery was performed in both cases, and one was found to have PTC (see Figure 1). When evaluating the predictive ability of FNAB, comparing Bethesda Categories 2 (benign) and 3–6 (indeterminate/suspicious/malignant), our study found a sensitivity of 81.8 % and a specificity of 66.6 % for the initial FNAB. Among the 10 patients with Bethesda Category 3 who underwent surgery, the frequency of PTC was 60 %. In our study, the positive predictive value (PPV) and negative predictive value (NPV) of FNAB for Bethesda categories 3–6 in predicting malignancy were both calculated as 75 %; confidence interval (CI), 53 %–97 %.

Among patients diagnosed with PTC, four had ultrasonographic findings indicating four or more suspicious features. Another four patients exhibited three suspicious features, and three patients had two such features. Notably, in one case, the decision to pursue malignancy workup was based solely on an increase in nodule size, in the absence of other suspicious sonographic characteristics. Clinical features of patients diagnosed with PTC are summarized in Table 2.

When comparing patients with malignant and non-malignant histopathological results after surgery, the presence of microcalcifications, increased intranodular vascularization, purely solid nodule composition, and solitary nodule were significantly more frequent ultrasonographic features in the malignancy group.

Discussion

In this study, the relationship between cytopathological findings and postoperative histopathological diagnoses was evaluated in pediatric and adolescent patients with solid thyroid nodules. In particular, ultrasonographic findings suggestive of malignancy were found to be important guiding factors in the surgical decision-making process, especially in cases diagnosed with PTC, including those with non-diagnostic, benign, or indeterminate cytopathology.

The approach to thyroid nodules in children differs from that in adults [4]. In adults, the Thyroid Imaging Reporting and Data System (TIRADS) was developed to reduce the frequency of FNAB by assigning scores based on nodule composition, echogenicity, shape, margin characteristics, and echogenic foci [10]. In children, TIRADS has a reported positive predictive value of 71.7 % and a negative predictive value of 80.0 % [4]. However, in pediatric thyroid nodules, using TIRADS alone can result in false-negative rates of up to 22 % [4]. Therefore, for children with benign FNAB results, annual thyroid ultrasound is recommended, and FNAB should be repeated or surgical excision should be considered for nodules that grow or develop suspicious features on ultrasound [3]. In contrast, studies in adults suggest that nodule growth does not necessarily predict malignancy and recommend discontinuing follow-up after three years following a benign FNAB result [11], 12].

The 2015 guidelines of the American Thyroid Association (ATA) on thyroid nodules and differentiated thyroid cancer in children state that the risk of malignancy in pediatric nodules (22 %–26 %) is higher than in adults (5 %–10 %) and that there is a strong female predominance (5:1) [3]. Consistent with the literature, malignancy was detected in approximately one-fifth of the cases that underwent FNAB in our study. In previous studies, a female predominance of 65 %–82 % has been reported among cases who underwent FNAB [1], 13], 14], which was also observed in our case series.

Ultrasound features such as microcalcifications, irregular margins, hypoechoic pattern, and increased intranodular vascularity are known risk factors for malignancy in thyroid nodules [15]. These features have been reported in malignant nodules at frequencies of 45 %–48 % for irregular margins, 48 %–55 % for abnormal lymph nodes, and 45 %–70 % for microcalcifications [1], 15]. In our study, these ultrasound risk features were rarely observed in patients whose postoperative histopathology was benign, supporting the high sensitivity of these features in ruling out malignancy.

A recent study evaluating the ultrasound characteristics of six patients with papillary thyroid carcinoma found ≥2 malignant features in five patients [16]. However, that study did not provide data on margin irregularity. In contrast, most patients in our study demonstrated ≥3 ultrasound features suggestive of malignancy.

In the literature, the cytopathological distribution of FNAB results in pediatric and adolescent thyroid nodules is reported as follows: Bethesda Category 1 (non-diagnostic) 7 %–10 %, Category 2 (benign) 43 %–64 %, Category 3 (atypia of undetermined significance) 16 %–63 %, Category 4 (follicular neoplasm/suspicious for follicular neoplasm) 0 %–28 %, Category 5 (suspicious for malignancy) 9 %–14 %, and Category 6 (malignant) 2 %–6 % [13], 14], 17]. In our study, Category 3 accounted for approximately one-fifth of all FNAB results, and more than half of these patients were diagnosed with PTC following surgery. During the study period, we did not have any patients with pathology results of category 4.

The reported malignancy rate in Bethesda Category 2 nodules in pediatric patients ranges from 4 % to 25 % [7], 13], 14], 18]. In one adult study including 6,317 benign nodules, 570 underwent surgery, and 90 % had benign histopathology [19]. Current literature data and our findings indicate that benign cytology results for solid thyroid nodules are less common in children and adolescents compared to adults. In pediatric and adolescent patients, malignancy rates in Category 3 range from 22 % to 44 % [7], 13], 17], 18], whereas in adults, these rates are much lower as 5 %–15 % [20]. In our cohort, malignancy rates in Categories 2 and 3 were notably higher than those observed in adult populations. Reported pediatric malignancy rates for Categories 4, 5, and 6 are 30–75 %, 74–100 %, and 97–100 %, respectively [7], 13], 14], 17], 18]. In this study, malignancy was detected in all patients with FNAB results corresponding to Bethesda Categories 5 and 6, consistent with existing literature.

The 2015 ATA guidelines recommend surgical intervention in the case of indeterminate or suspicious FNAB results [3]. The reported sensitivity and specificity of FNAB in the pediatric population range from 91 to 96 % and 50 to 65 %, respectively [13], 14]. The positive predictive value of FNAB is reported as 76 %–91 %, and the negative predictive value as 75 %–85 % in the literature [13], 14]. Our study findings are consistent with these data, showing similar sensitivity, specificity, and predictive values for FNAB in the pediatric population.

Follow-up and possible repeat FNAB may be required in patients with initially benign cytology. In our cohort, two patients with initial benign FNAB results were later diagnosed with PTC after surgery due to nodule growth during follow-up. These findings emphasize the importance of close monitoring of thyroid nodules and considering surgical options in suspicious cases, even when cytology is benign.

The primary limitations of this study are its retrospective, single-center design and relatively small sample size, which may limit the generalizability and statistical power of the findings. Further prospective, multicenter studies with larger patient populations are needed to validate these results.

In conclusion, this study emphasizes that the assessment of thyroid nodules in children and adolescents necessitates a distinct approach from that used in adults. Due to the higher risk of malignancy in the pediatric population, the presence of suspicious ultrasound features plays a pivotal role in guiding surgical decision-making, even when FNAB results are benign or indeterminate. Consequently, the evaluation of pediatric thyroid nodules should involve a multidisciplinary team, and surgical excision should be considered in cases where clinical or radiological suspicion of malignancy persists.