Pediatric thyroid cancer: Recent developments.

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.

Autoimmune Thyroiditis and Risk of Malignancy in Children with Thyroid Nodules.

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.

Thyroid Nodules in Children With Familial Adenomatous Polyposis.

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.

Subtype of atypia on cytology and risk of malignancy in pediatric thyroid nodules.

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.

Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition.

PURPOSE: Multigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined. METHODS: Clinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants ("pathogenic variants") were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk. RESULTS: Of 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone. CONCLUSIONS: A high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under-recognized component of cancer predisposition syndromes.

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Predictors of Bilateral Disease in Pediatric Differentiated Thyroid Cancer.

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.

Clinical utility of sonographic features in indeterminate pediatric thyroid nodules.

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.

Relationship of Preoperative Thyroid Dysfunction to Clinical Outcomes in Pediatric Cardiac Surgery.

CONTEXT: Thyroid function may be assessed in children before cardiac surgery because of concerns that hypothyroidism or thyrotoxicosis might adversely affect cardiac function perioperatively. However, the relationship between preoperative thyroid dysfunction and surgical outcomes is unknown. OBJECTIVE: Determine the relationship between preoperative thyroid dysfunction and outcomes of pediatric cardiac surgery. METHODS: Retrospective cohort study (January 2005 to July 2019). SETTING: Academic pediatric hospital. PATIENTS: All patients <19 years old who underwent cardiac surgery with cardiopulmonary bypass and had thyrotropin (TSH) measured within 14 days preoperatively. Exclusion criteria included neonates (≤30 days), preoperative extracorporeal life support, salvage operations, or transplantation procedures. MAIN OUTCOME MEASURES: Subjects were stratified by preoperative TSH concentration (mIU/L): low (<0.5), normal (0.5-5), mildly high (5.01-10), or moderately high (>10). Outcomes were compared among subjects with normal TSH (control) and each group with abnormal TSH concentrations. The primary outcome was 30-day mortality. Secondary outcomes included time to extubation, intensive care unit and hospital length of stay, and operative complications. RESULTS: Among 592 patients analyzed, preoperative TSH was low in 15 (2.5%), normal in 347 (58.6%), mildly high in 177 (29.9%), and moderately high in 53 (9.0%). Free thyroxine was measured in 77.4% of patients and was low in 0 to 4.4% of subjects, with no differences among TSH groups. Thirty-day mortality was similar among TSH groups. There were no differences in any secondary outcome between patients with abnormal TSH and patients with normal TSH. CONCLUSION: Preoperative mild to moderate subclinical hypothyroidism was not associated with adverse postoperative outcomes in children undergoing cardiopulmonary bypass procedures.

Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome.

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.

Undernutrition and Pubertal Timing in Female Survivors of Medulloblastoma and Other Embryonal Tumors.

CONTEXT: Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. OBJECTIVE: To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. DESIGN, SETTING, AND PATIENTS: Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children's Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. MAIN OUTCOME MEASURES: Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. RESULTS: The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (ß = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. CONCLUSIONS: Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

Assessment of American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) for Pediatric Thyroid Nodules.

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.

A Novel ALK Fusion in Pediatric Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered with CCDC6 in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel CCDC6-ALK fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel CCDC6-ALK fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of ALK fusions seen in MTC, including the first pediatric case of ALK translocated MTC. This novel fusion with CCDC6 has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with ALK fusion MTC has important therapeutic implications.

Differences in Thyroid Nodule Cytology and Malignancy Risk Between Children and Adults.

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.

COINCIDENT SUPPURATIVE THYROIDITIS AND GRAVES DISEASE IN A PATIENT WITH INFECTED BRANCHIAL CLEFT CYST.

OBJECTIVE: Acute suppurative thyroiditis (AST) is frequently caused by anatomic abnormalities, including branchial cleft cysts. Patients with AST are typically euthyroid, but thyrotoxicosis may occur. Thyroid antibodies are usually not present in AST. Our objective is to describe a teenage male who presented with concomitant suppurative thyroiditis and Graves disease (GD). METHODS: We report a case of an infected left branchial cleft cyst with AST and concurrent GD in an adolescent male. Thyroid function tests and thyroid imaging were used for diagnostic evaluation, and the patient was managed with antibiotics, analgesia, and surgery. RESULTS: A 17-year-old male with a history of an infected left fourth branchial cleft cyst presented with recurrence of neck pain, odynophagia, and fever. Serum labs showed thyrotoxicosis and elevated thyroid antibodies and inflammatory markers. Magnetic resonance imaging showed an abscess adjacent to the left thyroid lobe. Symptoms resolved after antibiotic therapy, but laboratory tests showed persistent subclinical thyrotoxicosis. Four months later, he underwent excision of the branchial cleft cyst and left thyroid lobe. Two months after surgery, evaluation showed overt thyrotoxicosis with laboratory tests confirming GD. Methimazole was initiated and thyroid function subsequently normalized. CONCLUSION: This patient manifested a rare coincidence of AST due to a branchial cleft cyst and autoimmune thyroid disease. Further studies are needed to determine if there is any relationship between AST and development of thyroid autoimmunity. Assessment of thyroid autoimmunity may be considered in patients with prior or recurrent AST.

Natural History and Outcomes of Cytologically Benign Thyroid Nodules in Children.

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.