<p><strong>BACKGROUND: </strong>The recommendation for children with papillary thyroid cancer (PTC) is total thyroidectomy (TT) based on the incidence of bilateral disease. Evaluating this assumption, we reviewed the characteristics of bilateral PTC in a large cohort of children.</p>
<p><strong>METHODS: </strong>A retrospective chart review for patients surgically treated for PTC from 2009 to 2018 analyzing preoperative risk factors, ultrasound findings, and pathology results was performed. Bilateral disease was defined as pathologic PTC in the contralateral lobe, including microscopic disease.</p>
<p><strong>RESULTS: </strong>Of the 172 patients included, 38.4% had bilateral disease with 23% diagnosed postoperatively. Multifocal disease on ultrasound was associated with bilateral disease (OR 2.9, 95% CI 1.5-5.9, p = 0.002). Nodule dimension >2 cm was associated with increased risk for postoperative bilateral disease (OR 3.5, 95% CI 1.6-7.4, p = 0.001). Patients with bilateral disease were more likely to have extrathyroidal extension, lymphovascular invasion, positive central lymph nodes, and extranodal extension (p < 0.001 for all). Diffuse-sclerosing variant PTC was also associated with bilateral disease.</p>
<p><strong>CONCLUSION: </strong>Thirty-eight percent of children were diagnosed with PTC demonstrate bilateral disease. Nearly one in four have occult bilateral disease. The features that predicted bilateral disease were multifocality, widely invasive PTC on ultrasound, and the presence of lymphadenopathy. Thus, TT is the appropriate surgical approach for pediatric patients with PTC.</p>
<p><strong>TYPE OF STUDY: </strong>Clinical Research, Retrospective Review.</p>
<p><strong>LEVEL OF EVIDENCE: </strong>Level IV.</p>
<p><strong>BACKGROUND: </strong>Genetic alterations in multiple cell signaling pathways are involved in the molecular pathogenesis of thyroid cancer. Oncogene mutation testing and gene-expression profiling are routinely used for the preoperative risk management of adult thyroid nodules. In this study, we evaluated the potential value of miRNA biomarkers for the classification of pediatric thyroid lesions.</p>
<p><strong>PROCEDURE: </strong>Double-blind case-control study with 113 resected pediatric lesions: 66 malignant and 47 benign. Quantitative and qualitative molecular data generated with a 10-miRNA expression panel (ThyraMIR) and a next-generation sequencing oncogene panel (ThyGeNEXT) were compared with clinicopathological parameters.</p>
<p><strong>RESULTS: </strong>miRNAs were differentially expressed in benign versus malignant tumors with distinct expression patterns in different histopathology categories. The 10-miRNA classifier identified 39 (59%) malignant lesions with 100% specificity. A positive classifier score was associated with lymph node metastasis, extrathyroidal extension and intrathyroidal spread. Genetic alterations associated with increased risk for malignancy were detected in 35 (53%) malignant cases, 20 positive for point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, or TERT and 15 positive for gene rearrangements involving ALK, NTRK3, PPARG, or RET. The 10-miRNA classifier correctly identified 11 mutation-negative malignant cases. The performance of the combined molecular test was 70% sensitivity and 96% specificity with an area under the curve of 0.924.</p>
<p><strong>CONCLUSIONS: </strong>These data suggest that the regulatory miRNA pathways underlying thyroid tumorigenesis are similar in adults and children. miRNA expression can identify malignant lesions with high specificity, augment the diagnostic yield of mutation testing, and improve the molecular classification of pediatric thyroid nodules.</p>
<p>Hypoparathyroidism is one of the most common complications for patients undergoing total thyroidectomy. Our study's primary objective was to assess if intraoperative PTH levels correlate with parathyroid gland function recovery time in pediatric patients following total thyroidectomy. Retrospective review of pediatric patients who underwent thyroid surgery at CHOP for demographics and laboratory test values (calcium, phosphorus, and parathyroid hormone). We defined Time of Recovery (TOR) as the time difference from first intra-operative parathyroid hormone level (ioPTH) timepoint until normalization of PTH (> 10 pg/mL) post-thyroidectomy. Calcium and vitamin D supplements were weaned following normalization of calcium and phosphorous levels postoperatively. Patients were excluded if they lacked three intraoperative PTH timepoints or were missing postoperative follow-up PTH data. 65 patients (54 female), median age 15 (range 5-23 years), underwent thyroid surgery and met study inclusion criteria. The correlations of 2nd and 3rd ioPTHs with TOR were statistically significant ( < 0.05): the lower the ioPTH, the greater the recovery time. Stratifying patients into high-risk (2nd ioPTH ≤ 10 pg/mL), moderate-risk (2nd ioPTH between 10 and 20 pg/mL), and low-risk (2nd ioPTH ≥ 20 pg/mL) tertiles, the TOR decreased by orders of magnitudes from an average of 43.13 ± 76.00 to 6.10 ± 17.44 to 1.85 ± 6.20 days. These differences were statistically significant ( < 0.05). Our study results confirm the usefulness of intraoperative PTH levels to predict pediatric patient recovery post-surgery and provides useful anticipatory guidance to optimize timing and frequency of postoperative laboratory surveillance.</p>
<p>The American Joint Committee Cancer (AJCC) TNM system predicts survival in patients with differentiated thyroid cancer (DTC). In the eighth edition of the AJCC TNM, microscopic extrathyroidal extension (microETE) was removed and tumor size >4 cm was maintained in the definition of T3 disease to reduce unnecessarily aggressive therapy for adults at low risk of death from DTC. In pediatric patients where DTC survival rates are high, the AJCC TNM is used to identify patients at increased risk of persistent, postsurgical disease, to identify patients who benefit from radioactive iodine therapy. The aim of this study was to assess the correlation of microETE with cervical lymph node (LN) metastasis in pediatric patients and to determine if tumor size or microETE is more informative in predicting regional LN disease. Patients with DTC <19 years of age at the time of thyroidectomy with AJCC T3 tumors (seventh edition) and the presence of LNs on the surgical specimen were included in this retrospective chart review. Pathological findings were confirmed by pathologist review. Forty-five patients with AJCC T3 designation were included, 34 with microETE and 11 without microETE. Of those with microETE, 32 (94.1%) demonstrated regional LN metastasis compared with 5/11 patients (45.5%) without microETE ( = 0.001). In addition, microETE was associated with lateral neck LN metastasis ( = 0.004), bilateral disease ( = 0.001), and tumor multifocality ( = 0.003). Patients with microETE had smaller tumors (median = 2.5 cm, interquartile range [IQR]: 1.6-4.5) compared with patients without microETE (median = 5 cm, IQR: 4.2-5.4; = 0.02). No increased association was found between microETE and vascular invasion, distant metastasis, or persistent/recurrent disease. In pediatric patients with DTC, microETE is a strong predictor of LN metastasis when compared with tumor size. For patients who do not undergo prophylactic central neck LN dissection, the presence of microETE predicts an increased risk of postsurgical disease and should be included in future revisions of the American Thyroid Association pediatric risk stratification categories.</p>
<p><strong>BACKGROUND: </strong>Recent studies suggest improved outcomes for children undergoing thyroidectomy at high-volume pediatric surgery centers. We present outcomes after thyroid surgery at a single center and advocate for referral to high-volume centers for multidisciplinary management of these children.</p>
<p><strong>METHODS: </strong>Medical records were reviewed for all pediatric patients undergoing thyroid surgery at a single institution from 2009 through 2017. Routine recurrent laryngeal nerve and parathyroid hormone monitoring was used. Lymph node dissections were performed in appropriately selected cancer patients. Data collection focused on pathologic diagnosis, surgical technique, and surgical complications, including postoperative hematoma, neurapraxia, permanent nerve damage, hypocalcemia, and transient and permanent hypoparathyroidism.</p>
<p><strong>RESULTS: </strong>From 2009 through 2017, 464 patients underwent thyroid surgery. Median age of the cohort was 15 years (range 2-24). Thirty-three percent were diagnosed with benign nodules (n=151), 36% with papillary or follicular thyroid cancer (n=168), 27% with Graves' disease (n=124), 3% with medullary thyroid cancer (n=14), and 1.5% underwent prophylactic thyroidectomy for MEN2a (n=7). Six patients required return to the OR for hematoma evacuation including 5 patients after surgery for Graves' disease (RR 8.7, 95% CI 1.06-71.85). In sixteen cases, concern about neurapraxia resulted in laryngoscopy, revealing eleven patients with vocal cord paresis. Two of these patients demonstrated a persistent deficit at 6 months postoperatively (0.4%). Thirty-seven percent of patients had transient hypoparathyroidism (n=137), and two patients had persistent hypoparathyroidism 6 months after total thyroidectomy (0.6%). There was no significant difference in either hypocalcemia or hypoparathyroidism after total thyroidectomy based on age or diagnosis.</p>
<p><strong>CONCLUSIONS: </strong>Characterizing outcomes for pediatric patients based on diagnosis will assist in preoperative counseling for patients and their families. This high-volume center reports low complication rates after pediatric thyroid surgery, highlighting that referral to high-volume centers should be considered for children and adolescents with thyroid disease requiring surgery.</p>
<p><strong>LEVEL OF EVIDENCE: </strong>Level IV.</p>
<p><strong>Context: </strong>Adults with differentiated thyroid carcinoma (DTC) and Graves Disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in pediatric and young adults.</p>
<p><strong>Design: </strong>Single institution, retrospective longitudinal cohort study between 1997-2016.</p>
<p><strong>Participants: </strong>139 pediatric and young adults with DTC, diagnosed at median age 15 (range 5-23) years compared to 12 GD-DTC patients, median age 18 (range 12-20) years.</p>
<p><strong>Major Outcome Measures: </strong>Patient demographics, pre-operative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes.</p>
<p><strong>Results: </strong>Compared to DTC, GD-DTC were significantly older at the time of DTC diagnosis (p<0.01). GD-DTC were more likely to exhibit micro-carcinoma (p<0.01) and 2/12 (17%) demonstrated tall-cell variant PTC vs 2/139 (2%) in DTC alone (p=0.03). While DTC patients showed greater lymphovascular invasion (60% vs 25%; p=0.03), no group differences were noted in extra-thyroidal extension, regional lymph node, distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence.</p>
<p><strong>Conclusions: </strong>Concurrent DTC in pediatric GD patients is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared to DTC alone. Similar to adults, micro-carcinoma and tall-cell variant PTC is prevalent in pediatric GD-DTC. For GD-DTC patients with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment.</p>
<p><strong>Context: </strong>Thyroid nodules are increasingly recognized in children and are associated with a greater risk for thyroid cancer compared to adults. Thyroid ultrasound is the favored tool for evaluation of thyroid nodules; however, there are limited data regarding the accuracy of thyroid ultrasound to confirm features associated with a low risk of thyroid cancer in children.</p>
<p><strong>Objectives: </strong>We examined whether thyroid ultrasound is capable of accurately identifying thyroid nodules at a low risk of malignancy in children.</p>
<p><strong>Design and Setting: </strong>Using a retrospective cohort study design, we identified all children age ≤ 18 years with thyroid nodules and adequate follow up. Ultrasound images were reviewed independently by two blinded expert radiologists and ultrasound characteristics were analyzed to determine optimal predictive value and reliability.</p>
<p><strong>Patients and Results: </strong>417 subjects were found to have thyroid nodules and 152 subjects had adequate follow up; 59 (38.8%) of these were diagnosed with thyroid cancer. 236 individual nodules were evaluated. Features most consistent with benign nodules included small size, isoechoic echogenicity, partially cystic structure, sharp or non-infiltrative margins, absent Doppler flow and absent calcifications. Significant variability was found between expert interpretations of ultrasound features. Thyroid nodule composition appears to be the most sensitive and reliable feature for stratifying risk of thyroid cancer. Cumulatively, ultrasound accurately identified benign thyroid nodules in 80.9% (95% CI 74, 86.6%) of subjects.</p>
<p><strong>Conclusions: </strong>Ultrasonography is useful for the evaluation of thyroid nodules, but we found no combination of ultrasound features sufficient to exclude thyroid cancer without a biopsy.</p>
<p><strong>Context: </strong>In adults, non-invasive follicular variant papillary thyroid carcinoma (FVPTC) is considered low risk for metastasis and persistent/recurrent disease.</p>
<p><strong>Objective: </strong>The goal of this study was to assess the clinical, sonographic, and histopathological features of FVPTC in a pediatric cohort.</p>
<p><strong>Design: </strong>A retrospective review of subjects < 19 years of age with papillary thyroid carcinoma (PTC) who underwent thyroidectomy between January 2010 and July 2015.</p>
<p><strong>Setting: </strong>Multidisciplinary, academic referral center.</p>
<p><strong>Patients: </strong>Patients with FVPTC, defined as a tumor ≥1.0 cm in largest dimension with predominant follicular growth, complete lack of well-formed papillae, and nuclear features of PTC.</p>
<p><strong>Main Outcome Measure: </strong>Tumor size and location, presence of a tumor capsule, capsule and vascular invasion, lymph node and distant metastasis.</p>
<p><strong>Results: </strong>Eighteen patients with FVPTC were identified from a case cohort of 110 patients with PTC. On histopathology, 13 (72%) had unifocal nodules and 14 (78%) were completely encapsulated. Capsule invasion was frequent (9/14; 64%) and vascular invasion was found in one third of patients (6/18; 33%). No lymph node metastases were found in the 13 (72%) patients who had a central neck lymph node dissection. One patient with vascular invasion had distant metastases.</p>
<p><strong>Conclusion: </strong>When strictly defined, FVPTC in pediatric patients has a low risk for bilateral disease and metastasis. Prospective studies are needed to confirm whether lobectomy with surveillance is sufficient to achieve remission in pediatric patients with low risk FVPTC.</p>
<p><strong>BACKGROUND: </strong>Thyroid nodules are less common in pediatric patients (≤18 years) than in adults. The Bethesda System for Reporting Thyroid Cytopathology allows for individual risk stratification, but a significant number of nodules are indeterminate. Incorporating gene mutation panels and gene expression classifiers may aid in pre-operative diagnosis. The overall aim of this study was to assess the prevalence of oncogene alterations in a representative pediatric population and across a broad-spectrum of thyroid tumor diagnoses.</p>
<p><strong>METHODS: </strong>Retrospective cross-sectional evaluation of 115 archived samples, including: 47 benign [29 follicular adenoma (FA), 11 diffuse hyperplasia, 4 thyroiditis, and 3 multinodular goiter], 6 follicular thyroid cancer (FTC), 24 follicular variant of papillary thyroid cancer (fvPTC), 27 classic variant of PTC (cPTC), 8 diffuse sclerosing variant of PTC (dsvPTC) and 3 other PTC. Molecular testing was performed by multiplex qualitative PCR followed by bead array cytometry. Oncogene results were analyzed for association with age, gender, histology, lymph node metastasis and intrathyroidal spread.</p>
<p><strong>RESULTS: </strong>A mutation in one of the 17 molecular markers evaluated was found in: 2/6 (33%) FTC, 8/24 (33%) fvPTC, 17/27 (63%) cPTC, and 4/8 (50%) dsvPTC. Mutations in RAS or PAX8-PPARG were exclusive to FTC and fvPTC, BRAF was the most common mutation in cPTC (12/17; 71%) and RET-PTC was the only mutation associated with dsvPTC. Overall, a mutation was found in 32/68 (47%) malignant specimens with a single FA positive for PAX8-PPARG. The relative distribution of gene alterations in pediatric lesions was similar to adults. Presence of BRAF mutation in pediatric cPTC did not predict a more invasive phenotype.</p>
<p><strong>CONCLUSIONS: </strong>. 32/33 nodules with genetic alterations were malignant. Mutations in RAS were most frequently associated with FTC, RET-PTC rearrangements with dsvPTC and invasive fvPTC, and BRAF with cPTC. These results suggest a clinical role for mutational analysis of pediatric nodules to guide the surgical approach.</p>