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Background: Differentiated thyroid cancer (DTC) is the most common pediatric endocrine malignancy. The utility of ultrasound (US) surveillance after initial treatment has not been clearly delineated. We sought to evaluate the clinical utility of US for the detection of residual or recurrent disease in pediatric patients with thyroid cancer beginning 1 year after initial therapy. Methods: This is a retrospective cohort study of pediatric patients (<19 years) diagnosed with DTC between 1998 and 2022 whose response to therapy (RTT) one year after initial treatment (thyroidectomy ± radioactive iodine) was excellent or indeterminate. We evaluated the association between sonographic and biochemical findings (thyroglobulin [Tg] and Tg antibodies [TgAb]) at one year with the subsequent diagnosis of residual/recurrent structural disease in the neck (SDN). Results: In total, 112 patients had 1-year RTT that was excellent ( n = 61, 54.5%) or indeterminate ( n = 51, 45.5%). Median length of subsequent follow-up was 6.4 (interquartile range 3.8-8.9) years. Overall, 683 surveillance neck US were performed, with a mean ± standard deviation of 1.0 ± 0.4 US per patient per year. Of 61 patients with excellent RTT, none developed SDN during follow-up. Eighteen patients (29.5%) had a false-positive indeterminate or abnormal US finding. Of 51 patients with indeterminate RTT, 9 (17.6%) developed SDN during follow-up. SDN was detected by US in 7/9 cases (77.8%). SDN was detected by I-123 scan, but not by US, in two cases (22.2%), both with abnormal Tg/TgAb. 7/9 (77.8%) cases of SDN were detectable by Tg/TgAb. Overall, fine-needle aspiration (FNA) was performed in 17/112 (15.2%) patients and diagnosed SDN in six patients. Overall, 11/112 patients (9.8%) underwent FNA but were not diagnosed with SDN. Conclusions: In pediatric DTC patients with excellent response to initial therapy, the utility of serial US surveillance is limited by the low risk of SDN and frequent false-positive US findings. In children with indeterminate RTT, SDN occurs in a significant proportion and may be detected by US or by abnormal Tg/TgAb levels. These patients may benefit from the combination of US and biochemical surveillance.

Thyroid cancer is rare in children but its incidence is increasing. Recent data have clarified important similarities and differences between thyroid cancers originating in childhood and in adulthood. The genetic drivers of pediatric thyroid cancers are similar to those in adult tumors but comprise more gene fusions and fewer point mutations. Clinically, despite frequent metastatic spread, pediatric thyroid cancer has an excellent prognosis and mortality is rare. Therefore, treatment approaches must weigh carefully the morbidity of thyroid cancer treatments against their benefits. Current key questions include which children require total thyroidectomy rather than more limited-and safer-lobectomy, and in which children does the benefit of radioactive iodine therapy outweigh its risk of inducing a secondary malignancy. Finally, molecular therapies targeting genetic drivers of thyroid cancer now provide effective treatment for children with progressive, radioiodine-refractory disease, as well as opportunities to explore novel neoadjuvant uses that facilitate therapeutic surgery or radioactive iodine., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: It is uncertain whether the presence of autoimmune thyroiditis (AIT) increases the risk of thyroid cancer in children with thyroid nodules. This study evaluated the association between AIT and thyroid cancer in pediatric patients with thyroid nodules. Methods: A cross-sectional study was performed of pediatric patients (<19 years old) with a thyroid nodule (≥1 cm) who underwent fine-needle aspiration in an academic pediatric thyroid center. AIT was defined by the presence of thyroid autoantibodies or diffusely heterogeneous sonographic echotexture. The primary outcome was diagnosis of thyroid cancer. The association of AIT with thyroid cancer was evaluated with univariable and multivariable logistic regression. Associations of AIT with subject and nodule characteristics were also assessed. Results: Four hundred fifty-eight thyroid nodules in 385 patients (81% female) were evaluated at a median age of 15.5 years (interquartile range 13.5-17.0). Thyroid cancer was present in 108 nodules (24%). AIT was present in 95 subjects (25%) and was independently associated with an increased risk of thyroid cancer (multivariable odds ratio [OR] 2.19, 95% confidence interval [CI] 1.32-3.62). Thyroid cancer was also independently associated with younger age, nodule size, and solitary nodules, but was not associated with serum thyrotropin concentration. AIT was not associated with the likelihood of subjects undergoing thyroid surgery ( p  = 0.17). AIT was less commonly associated with follicular thyroid carcinoma than with papillary thyroid carcinoma (OR 0.22, CI 0.05-1.06). Among papillary thyroid carcinomas, AIT was strongly associated with the diffuse sclerosing variant (OR 4.74, CI 1.33-16.9). AIT was not associated with the extent of local, regional, or distant disease at thyroid cancer diagnosis. Conclusions: AIT is independently associated with an increased risk of thyroid cancer in children with thyroid nodules. These findings suggest that the evaluation of thyroid autoantibodies and thyroid echotexture may inform thyroid cancer risk assessment and surgical decision-making in children with thyroid nodules.

Introduction: Ultrasound screening for thyroid cancer is recommended in familial adenomatous polyposis (FAP). This study investigated the prevalence of thyroid neoplasia in children with FAP., Methods: Cross-sectional study of children with FAP at an academic hospital. Clinical and ultrasound data were analyzed for the prevalence of thyroid nodules and cancer., Results: Of 37 children with FAP, 8 (22%) had thyroid nodules and 2 (5%) had thyroid cancer. Nodules (30%) and cancer (9%) were more common among female subjects and rare among male subjects., Discussion: Thyroid ultrasound screening in adolescence may benefit female subjects with FAP but has limited utility in male subjects., (Copyright © 2022 by The American College of Gastroenterology.)

Background: Thyroid nodules with atypia of undetermined significance (AUS) are challenging to manage because of their intermediate risk of malignancy. Subclassification of atypia can refine malignancy risk in adult AUS nodules but has not been evaluated in children., Methods: This was a retrospective cohort study of pediatric patients (<19 years old) who underwent fine-needle aspiration (FNA) of a thyroid nodule with resulting AUS cytology. Atypia was subclassified as nuclear only, architectural only, nuclear and architectural, or oncocytic. The primary outcome was the association between atypia subtype and malignancy. A secondary outcome was the association of atypia subtype with repeat FNA cytology., Results: Sixty-eight AUS nodules in 61 patients were analyzed. The median age at FNA was 16.2 years (range, 9.8-18.9 years). Twenty-four nodules (35%) were malignant. Nuclear atypia only was present in 17 nodules (25%), architectural atypia only was present in 27 nodules (40%), nuclear and architectural atypia was present in 20 nodules (29%), and predominantly oncocytic features were present in 4 nodules (6%). The presence of nuclear atypia was associated with a significantly increased rate of malignancy (22 of 37 [59%] vs 2 of 31 [6.5%]; P < .001), whereas architectural atypia was not associated with malignancy (P = .8). Repeat FNA was performed in 42 of 68 nodules (62%). In nodules with initial nuclear and architectural atypia, benign repeat cytology had a high false-negative rate (3 of 6; 50%)., Conclusions: Pediatric AUS nodules with nuclear atypia have a high rate of malignancy, but architectural atypia is not associated with malignancy. In nodules with nuclear atypia, repeat FNA may inform clinical decisions regarding the need for resection. In the absence of suspicious clinical features, nodules without nuclear atypia might be considered for observation rather than resection or repeat FNA., (© 2022 American Cancer Society.)

Context: Total thyroidectomy is recommended for children with papillary thyroid carcinoma, partly because of a high prevalence of bilateral disease. Identifying characteristics that predict bilateral disease might identify candidates for more limited surgery., Objective: Investigate associations of preoperative or histopathological characteristics with bilateral disease in children with differentiated thyroid cancer., Methods: Retrospective cohort study (1998-2020) at 2 academic hospitals. Patients <19 years who underwent total thyroidectomy for differentiated thyroid cancer were included. Clinical, sonographic, and histopathological characteristics were evaluated. The presence of bilateral disease on histopathology was assessed by univariable analysis and multivariable logistic regression., Results: One hundred and fifteen subjects were analyzed (90% with papillary carcinoma). Median (range) age at diagnosis was 15.0 (8.1-18.9) years. Bilateral disease was present in 47/115 subjects (41%). Bilateral disease was associated with solid parenchyma, calcifications, irregular margins, and abnormal lymph nodes detected by ultrasound, Bethesda class V/VI cytology, papillary histology, tumor multifocality in the primary lobe, extrathyroidal extension, lymphovascular invasion, and nodal metastases. In multivariable analysis, only multifocality in the primary lobe was independently associated with bilateral disease (OR 7.61, 95% CI 2.44-23.8, P < .001). Among clinically node-negative subjects with papillary carcinoma who did not have tumor multifocality in the primary lobe, bilateral disease was present in 5/32 (16%)., Conclusions: In children with differentiated thyroid cancer, tumor multifocality in the primary lobe is associated with bilateral disease and should prompt consideration of completion thyroidectomy after initial lobectomy. Clinically node-negative children with tumors that are unifocal in the primary lobe have a low likelihood of contralateral disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Surgical resection is recommended for cytologically indeterminate pediatric thyroid nodules due to their intermediate malignancy risk. We evaluated the utility of ultrasound characteristics for refining malignancy risk to inform the management of these nodules., Design: Retrospective cohort study (2004-2019)., Methods: We analyzed consecutive thyroid nodules with indeterminate fine-needle aspiration cytology (Bethesda category III, IV, or V) in pediatric patients (<19 years). We assessed the association of demographic and sonographic characteristics with malignancy risk among all indeterminate nodules and within each Bethesda category., Results: Eighty-seven cytologically indeterminate nodules were identified in 78 patients. Bethesda category was III in 56 nodules (64%), IV in 12 (14%), and V in 19 (22%). The malignancy rate was 46/87 (53%) overall, and 23/56 (41%), 8/12 (75%), and 15/19 (79%) in Bethesda III, IV, and V nodules, respectively. Malignancy rate was higher in solitary nodules (67% vs 37%, P = 0.004) and nodules with irregular margins (100% vs 44%, P < 0.001) or calcifications (82% vs 43%, P = 0.002). American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) risk level TR5 was associated with a higher rate of malignancy than lower TI-RADS risk levels (80% vs 42%, P = 0.002). Within individual Bethesda categories, TI-RADS risk level was not associated with malignancy. No sonographic feature had a negative predictive value for malignancy greater than 80%., Conclusions: In pediatric thyroid nodules with indeterminate cytology, some sonographic features - including higher ACR TI-RADS risk level - are associated with malignancy, but these associations are unlikely to alter clinical management in most cases.

Context: Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear., Objective: Determine the prevalence and natural history of thyroid disease in children with PHTS., Methods: Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease., Results: Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed., Conclusion: Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: The present review summarizes recent advances in the diagnosis and management of patients with congenital hypothyroidism., Recent Findings: Although most newborn screening strategies are designed to detect severe primary hypothyroidism that presents shortly after birth, some infants display a pattern of delayed TSH rise despite normal initial newborn screening. Recent studies suggest that delayed TSH rise may be more common and more severe than previously recognized. Although much less common than primary hypothyroidism, central congenital hypothyroidism is as likely to be of moderate or severe degree, which has implications for its detection and treatment. The discovery of new genetic causes of central congenital hypothyroidism, including the X-linked genes IGSF1, TBL1X, and IRS4, has begun to expand our understanding of thyroid axis regulation. Recent long-term data indicate that current treatment recommendations for congenital hypothyroidism result in grossly normal neurocognitive outcomes even in severely affected patients, and that overtreatment may not be as harmful as previously suspected. Liquid levothyroxine is now commercially available in the United States, but more studies are needed to determine optimal dosing using this formulation., Summary: Prompt identification and adequate treatment of patients with congenital hypothyroidism is critical to optimize outcomes. New information continues to accumulate about how to improve detection of congenital hypothyroidism in specific subgroups of infants (particularly those with delayed TSH rise and central hypothyroidism) and about treatment of patients with this disorder.

Background The American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) is a recognized tool for management of thyroid nodules in adults but has not been validated in pediatric patients. Purpose To assess the performance of the ACR TI-RADS criteria for guiding decisions on whether to biopsy thyroid nodules in pediatric patients in a single referral center. Materials and Methods In this retrospective study, a database of thyroid nodules in patients younger than 19 years who underwent fine-needle aspiration (FNA) biopsy between January 2004 and July 2017 was analyzed. ACR TI-RADS criteria were applied to each nodule, and an ACR TI-RADS score was created to determine how the nodule would be managed. The number of nodules that would be biopsied with FNA on the basis of ACR TI-RADS was compared with the total number of nodules biopsied with FNA in this clinic to determine if the use of ACR TI-RADS would have changed the rate of FNA (eg, decreased the number of procedures) and whether that change would have affected the timely diagnosis of cancer. Results A total of 314 patients (mean age, 14.9 years; age range, 2-18 years; 28 prepubertal patients; 286 postpubertal patients; 260 female patients) were evaluated. In these 314 patients, 404 thyroid nodules were scored, of which 19.1% (77 of 404) were malignant. Most cancers were papillary carcinoma (68 [88.3%] of 77). The use of ACR TI-RADS criteria for management of nodules in this pediatric study sample would have resulted in 17 (22.1%) of 77 cancers being missed at the patient's initial visit. Conclusion Use of the current American College of Radiology Thyroid Imaging Reporting and Data System criteria for management of pediatric thyroid nodules is inadequate because a high percentage of cancers would be missed at the initial encounter. © RSNA, 2019.

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (<19 years) and adult (≥19 years) patients. Results: Four hundred thirty pediatric thyroid nodules and 13,415 adult nodules were analyzed. Pediatric nodules were more likely to be malignant than adult nodules (19% vs. 12%, p  = 0.0002). Within cytological categories, malignancy rates were higher in pediatric nodules than in adult nodules that were cytologically nondiagnostic (11% vs. 4%, p  = 0.03), atypia of undetermined significance (AUS; 44% vs. 22%, p  = 0.004), or suspicious for follicular neoplasm (SFN; 71% vs. 28%, p  = 0.001). There were no significant differences between children and adults in the types of thyroid cancers diagnosed in these cytological categories. Among cytologically benign nodules, the difference in malignancy rates was statistically significant but clinically minimal (0.7% vs. 1%, p  = 0.001). Malignancy rates did not differ between children and adults among nodules with cytology suspicious for papillary carcinoma (73% vs. 68%, p  = 0.67) or positive for malignancy (97% vs. 95%, p  = 1). Among the subset of nodules that were resected, the malignancy rate was higher in children than in adults only in nodules that were SFN (71% vs. 36%, p  = 0.007). Conclusions: Among thyroid nodules that are cytologically AUS, SFN, or nondiagnostic, malignancy rates are higher in children than in adults. These discrepancies likely represent true differences in malignancy risk between pediatric and adult patients, rather than differences in cytological interpretation. Our findings provide pediatric-specific data to inform the optimal management of thyroid nodules in children, which may differ from that of adult nodules with equivalent cytology.

Context: In neonates, iatrogenic hypothyroidism can result from topical or IV iodine exposure. Data on intralymphatic iodine exposure, risk factors for disease severity, and timing of hypothyroidism are limited., Case Descriptions: We report 4 cases of premature neonates with previously normal thyroid function tests (TFTs) who developed hypothyroidism after intralymphatic iodinated contrast. Patients 1 and 2, premature infants with complex medical histories, had chylous effusions and high-volume chest tube output requiring imaging with lymphangiograms on day of life (DOL) 97 and DOL 43, respectively. They developed severe, primary hypothyroidism with TSH of 335.7 mIU/mL (reference range, 1.7 to 9.1) on DOL 111 and TSH of 470.2 mIU/mL (reference range, 1.7 to 9.1) on DOL 68. Patient 3 had prenatally diagnosed fetal hydrops manifesting with chylous effusions and high-volume chest tube output. The infant underwent lymphangiography on DOL 90 and was noted to have an elevated TSH of 13.35 mIU/mL (reference range, 1.7 to 9.1) 4 days later with spot urine iodine of 1742 µg/L (normal, <200). Patient 4 had a lymphatic malformation and underwent sclerotherapy with doxycycline with intralymphatic iodine exposure on DOL 4 and was found to have a TSH of 16.7 µU/mL (reference range, 1.7 to 9.1) 3 days later with spot urine iodine of 228,712 µg/L (normal, <200). The TFT results for all patients improved after levothyroxine administration., Conclusion: Intralymphatic iodine should be considered a major risk factor in the development of iatrogenic primary hypothyroidism, especially in premature neonates soon after exposure. Close monitoring of TFTs is imperative to avoid potential long-term adverse outcomes in this population.

Context: Most pediatric thyroid nodules are cytologically benign, but few data exist to guide treatment., Objective: To describe the natural history and outcomes of cytologically benign, pediatric thyroid nodules., Design: Cohort study., Setting: Multidisciplinary thyroid clinic at an academic medical center., Patients: Consecutive pediatric patients (≤18 years old) with cytologically benign thyroid nodules evaluated between 1998 and 2016., Results: Cytologically benign nodules (N = 237) in 181 patients were followed by ultrasound (median follow-up, 3.4 years; range, 0.5 to 13.9 years) or to resection. Thyroid cancer was diagnosed in six nodules (2.5%), and all six patients were disease free after median follow-up of 4.9 years. Malignancy was more common in nodules >4 cm (15.4%; P = 0.037) or that grew during follow-up (6.0%; P = 0.048). The likelihood of nodule growth (±SE) was 15% ± 3%, 24% ± 4%, and 49% ± 10% at 6, 12, and 24 months, respectively. Among nodules >2 cm, those with ≥25% cystic content grew more slowly than nodules <25% cystic; nodules <2 cm grew similarly regardless of cystic content., Conclusion: Benign cytology in pediatric thyroid nodules has a low false-negative rate similar to that in adults, and prognosis is excellent in the rare cases of malignancy. Resection of nodules >4 cm, combined with surveillance of smaller nodules and repeated aspiration for growth, detects most false-negative results. Follow-up ultrasound in 12 months is appropriate for most cytologically benign pediatric nodules, but delaying surveillance up to 24 months may be reasonable in large, predominantly cystic nodules.

Purpose To determine the relationship between demographic and sonographic characteristics of thyroid nodules and malignancy in a pediatric population. Materials and Methods All thyroid nodules in patients younger than 19 years that underwent ultrasound (US)-guided fine-needle aspiration biopsy between January 2004 and July 2017 were retrospectively identified. Age, sex, and background appearance of the thyroid gland were recorded for each patient, and sonographic characteristics and pathologic diagnosis were recorded for each nodule. Demographic and sonographic characteristics were assessed to determine which were associated with malignancy. Categorical and continuous variables and interobserver variability were assessed. Results A total of 404 nodules in 314 patients (82.8% female) (age range, 2-18 years; mean age, 14.9 years) were analyzed. A total of 77 nodules (19.1%) were malignant, the majority of which were papillary thyroid carcinoma (n = 68 [88.3%]). The likelihood of malignancy did not differ between boys and girls (27.8% vs 22.7%, P = .64), nor did it differ between prepubertal and pubertal patients (18.8% vs 19.1%, P > .99). The cancer rate in patients with a solitary nodule was higher than that in patients with multiple nodules (29.4% vs 14.2%, P = .003). Sonographic characteristics associated with malignant nodules included larger size, solid parenchyma, taller-than-wide shape, presence of speckled calcifications, lack of a smooth margin, and presence of abnormal lymph nodes. Interobserver variability for assessment of sonographic characteristics ranged from moderate to very strong. Conclusion In children with thyroid nodules, solitary nodules, larger nodule size, solid parenchyma, taller-than-wide shape, speckled calcifications, irregular margins, and abnormal lymph nodes raise concern for malignancy., (© RSNA, 2018.)

Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants.