Molecular Genetics Augment Cytopathologic Evaluation and Surgical Planning of Pediatric Thyroid Nodules.

PURPOSE: Molecular genetic testing in conjunction with cytopathology may improve prediction of malignancy in thyroid nodules, particularly those with indeterminate cytology (Bethesda III/IV). Though now commonplace in adults, pediatric data are limited. This study examines molecular genetics of pediatric nodules with correlation to cytologic and histologic classification at time of surgery and the distribution of mutations. METHODS: Retrospective chart review of 164 patients <22 years who underwent surgical resection of a thyroid nodule between 2002 and 2020 with molecular testing on fine-needle aspiration biopsy (FNA) or final histopathology. RESULTS: 85 (52 %) of 164 patients undergoing thyroid resection had available molecular genetic testing. BRAF V600E testing was performed on the FNA samples of 73 (86 %) patients and on 15 (18 %) surgical specimens; 31 (37 %) were positive. Of the remaining 54 patients, 21 had additional mutation/fusion testing. In 17 (81 %) cases, an alternate mutation/fusion was identified including 8 gene fusions, 3 DICER1 mutations, 4 NRAS mutations, one BRAF variant, and one unknown variant. BRAF, DICER1 mutations, and gene fusions predicted malignancy. Greater than 95 % of BRAF mutations were in Bethesda V/VI lesions and associated with classic variant PTC whereas fusions and DICER1 mutations clustered in Bethesda IV nodules. Bethesda III nodules harbored BRAF and NRAS mutations. In Bethesda IV nodules, a gene fusion or DICER mutation altered the surgical decision-making (upfront thyroidectomy rather than lobectomy) in 70 % of nodules submitted for genetic testing. CONCLUSION: Expanded molecular genetic testing on FNA of pediatric thyroid nodules, particularly Bethesda III/IV, may improve prediction of malignancy and augment surgical decision-making. LEVEL OF EVIDENCE: III.

Management of Pediatric Graves Disease: A Review.

Importance: The incidence of Graves disease (GD) is rising in children, and adequate care of these patients requires a multidisciplinary approach. Whether patients are seen in the context of endocrinology, nuclear medicine, or surgery, it is important to know the nuances of the therapeutic options in children. Observations: Given the rarity of GD in children, it is important to recognize its various clinical presenting signs and symptoms, as well as the tests that may be important for diagnosis. The diagnosis is typically suspected clinically and then confirmed biochemically. Imaging tests, including thyroid ultrasonography and/or nuclear scintigraphy, may also be used as indicated during care. It is important to understand the indications for and interpretation of laboratory and imaging tools so that a diagnosis is made efficiently and unnecessary tests are not ordered. Clinicians should be well-versed in treatment options to appropriately counsel families. There are specific scenarios in which medical therapy, radioactive iodine therapy, or surgery should be offered. Conclusions and Relevance: The diagnosis and treatment of pediatric patients with GD requires a multidisciplinary approach, involving pediatric specialists in the fields of endocrinology, ophthalmology, radiology, nuclear medicine, and surgery/otolaryngology. Antithyroid drugs are typically the first-line treatment, but sustained remission rates with medical management are low in the pediatric population. Consequently, definitive treatment is often necessary, either with radioactive iodine or with surgery, ideally performed by experienced, high-volume pediatric experts. Specific clinical characteristics, such as patients younger than 5 years or the presence of a thyroid nodule, may make surgery the optimal treatment for certain patients.

Pathologic Characteristics, Natural History, and Prognostic Implications of BRAFV600E Mutation in Pediatric Papillary Thyroid Carcinoma.

The BRAFV600E mutation is the most common genetic aberration in papillary thyroid cancer (PTC), found in up to 68% of PTC in adults where it is associated with aggressive features. The incidence of this mutation in pediatric PTC is less frequent, reported as 0%-20% in the past and up to 63% in one recent series. Data suggest the mutation is not associated with an aggressive course in children; however, there are limited numbers of reported case series, so the prognostic implications remain poorly understood. The aim of this retrospective study was to examine the histologic characteristics and clinical outcomes of BRAF positive pediatric PTC at a single institution. A 12-year retrospective review of all thyroidectomies performed at a tertiary medical center identified 59 pediatric cases with a surgical pathology diagnosis of PTC. Fifty patients had BRAFV600E mutation analysis data and were selected for further study. BRAFV600E mutations were present in 48% of cases (n = 24) and absent in 52% (n = 26). The molecular characteristics of the BRAF negative cases will further be evaluated in future studies. BRAF positive cases occurred in patients who were on average older than the BRAF negative patients. Classic histology PTC was present in both BRAF positive and negative cases; however, only cases with classic PTC histology were positive for the mutation. No patients died and BRAF mutation was not associated with an increased recurrence rate. Our study supports BRAFV600E is more common in children than previously thought and does not portend a more aggressive clinical course.

NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States.

BACKGROUND: An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children. METHODS: The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing. RESULTS: Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V) (600E)) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V) (600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V) (600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1). CONCLUSIONS: Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.

C-Cell Neoplasia in Asymptomatic Carriers of RET Mutation in Extracellular Cysteine-Rich and Intracellular Tyrosine Kinase Domain.

Germline mutations in RET proto-oncogene associated with multiple endocrine neoplasia type 2 (MEN2) may affect codons for the extracellular cysteine-rich (ECR) or the intracellular tyrosine kinase (ITK) domain of the transmembrane receptor tyrosine kinase protein. We compared C-cell pathology in asymptomatic carriers of RET mutation affecting the 2 domains. Twenty-two asymptomatic carriers (median age, 9.5 years), 10 with mutations in the ECR (codons 634, 611, 618, and 620) and 12 with mutations in the ITK domain (codons 804, 790, 891, and 918), underwent total thyroidectomy. C-cell hyperplasia was identified in 16 (73%), was multifocal and/or bilateral in 11, and was associated with medullary thyroid carcinoma (MTC) in 10 thyroids. When comparing the ECR and ITK groups in 21 carriers from MEN2A/familial MTC families, C-cell hyperplasia was more frequent in the former (90% versus 55%), as was multifocality (70% versus 27%) and MTC (60% versus 27%), despite the significantly younger median age in the former group (5 versus 23 years, P = .04). One asymptomatic carrier had de novo codon 918 mutation (MEN2B) and showed bilateral microcarcinoma with lymph node metastasis at presentation and progressive disease on follow-up. In conclusion, asymptomatic carriers of high-risk RET mutations affecting the ECR were significantly younger and frequently showed C-cell neoplasia, multifocality, and MTC when compared with mutations affecting the ITK domain in the MEN2A/familial MTC families. The presence of C-cell disease, its severity, and aggressiveness correlated with the mutated codon and with increasing age.

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer.

BACKGROUND: Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population exhibit differences in pathophysiology, clinical presentation, and long-term outcomes. Furthermore, therapy that may be recommended for an adult may not be appropriate for a child who is at low risk for death but at higher risk for long-term harm from overly aggressive treatment. For these reasons, unique guidelines for children and adolescents with thyroid tumors are needed. METHODS: A task force commissioned by the American Thyroid Association (ATA) developed a series of clinically relevant questions pertaining to the management of children with thyroid nodules and differentiated thyroid cancer (DTC). Using an extensive literature search, primarily focused on studies that included subjects ≤18 years of age, the task force identified and reviewed relevant articles through April 2014. Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force. RESULTS: These inaugural guidelines provide recommendations for the evaluation and management of thyroid nodules in children and adolescents, including the role and interpretation of ultrasound, fine-needle aspiration cytology, and the management of benign nodules. Recommendations for the evaluation, treatment, and follow-up of children and adolescents with DTC are outlined and include preoperative staging, surgical management, postoperative staging, the role of radioactive iodine therapy, and goals for thyrotropin suppression. Management algorithms are proposed and separate recommendations for papillary and follicular thyroid cancers are provided. CONCLUSIONS: In response to our charge as an independent task force appointed by the ATA, we developed recommendations based on scientific evidence and expert opinion for the management of thyroid nodules and DTC in children and adolescents. In our opinion, these represent the current optimal care for children and adolescents with these conditions.

The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy.

Pediatric thyroid cancer is a rare disease with an excellent prognosis. Compared with adults, epithelial-derived differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid cancer, presents at more advanced stages in children and is associated with higher rates of recurrence. Because of its uncommon occurrence, randomized trials have not been applied to test best-care options in children. Even in adults that have a 10-fold or higher incidence of thyroid cancer than children, few prospective trials have been executed to compare treatment approaches. We recognize that treatment recommendations have changed over the past few decades and will continue to do so. Respecting the aggressiveness of pediatric thyroid cancer, high recurrence rates, and the problems associated with decades of long-term follow-up, a premium should be placed on treatments that minimize risk of recurrence and the adverse effects of treatments and facilitate follow-up. We recommend that total thyroidectomy and central compartment lymph node dissection is the surgical procedure of choice for children with DTC if it can be performed by a high-volume thyroid surgeon. We recommend radioactive iodine therapy for remnant ablation or residual disease for most children with DTC. We recommend long-term follow-up because disease can recur decades after initial diagnosis and therapy. Considering the complexity of DTC management and the potential complications associated with therapy, it is essential that pediatric DTC be managed by physicians with expertise in this area.

Differentiated thyroid cancer in children: diagnosis and management.

PURPOSE OF REVIEW: Differentiated thyroid cancer is the most common endocrine malignancy in children. In 2006, the American Thyroid Association Guidelines Taskforce released detailed management recommendations for differentiated thyroid cancer, which primarily addressed the approach for treating adult patients. Children with differentiated thyroid cancer present with more advanced disease and yet have a more favorable outcome than adults. Thus optimal treatment for younger patients with differentiated thyroid cancer may differ from that for adults. RECENT FINDINGS: All available data regarding differentiated thyroid cancer treatment in children are retrospective. In the past year, several large case series have been published that strengthen the argument for total thyroidectomy at the time of diagnosis, followed by administration of radioactive iodine for remnant ablation. There have also been recent advances in understanding the genetic abnormalities associated with pediatric thyroid cancer. SUMMARY: The optimal treatment of differentiated thyroid cancer in pediatric patients continues to be debated. Recent publications from institutions around the world provide useful data regarding current approaches to this unusual disease. Further collaborative studies are needed to further refine the surgical approach, particularly the extent of lymph-node dissection, radioactive iodine dosing, and the role of genetic analysis in diagnosis and clinical approach.

The MACIS score predicts the clinical course of papillary thyroid carcinoma in children and adolescents.

MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores are employed to predict mortality for papillary thyroid carcinoma (PTC) in adults. However, this system has not been validated in children and adolescents. We hypothesized that MACIS scores would correlate with recurrent and persistent disease in children. Patients with PTC (n = 48) were divided into those with aggressive (invasive, metastasic, recurrent or persistent disease) or indolent (lacking these features) disease. Those with aggressive PTC (n = 11) had average MACIS score = 5.2 +/- 1.3, compared to 3.7 +/- 0.4 in patients with indolent disease (n = 37, p < 0.0005). A cutoff score of 4.0 provides a PPV of 29% and NPV of 94% in predicting recurrence, and a PPV of 43% and NPV of 91% in predicting persistent disease. MACIS scores may be useful in predicting outcome in the pediatric population.

Treatment of recurrent papillary thyroid carcinoma in children and adolescents.

Mortality for children with papillary thyroid carcinoma (PTC) is low (< or = 10%), but recurrence is frequent (20%). In adults, recurrent PTC has a poor prognosis (50% remission) and a high mortality (16-63%). We hypothesized that treatment of recurrent PTC would be more effective in children than in adults. We reviewed the clinical course of 42 children with PTC in remission. Seven (7/42, 17%) recurred and records were available for six. All six received RAI (median = 130 mCi), and one had a cervical node removed. Five of the six (83%) achieved remission (median duration 67 mo, range 10-99 mo), one had a second recurrence and a third remission, and one patient (17%) had persistent disease. There were no deaths. In conclusion, although we had only one child less than 10 years of age in our study, these and previous data suggest that treatment of recurrent PTC in children is generally effective.

Tumor size and extent of disease at diagnosis predict the response to initial therapy for papillary thyroid carcinoma in children and adolescents.

Treatment of papillary thyroid carcinoma (PTC) in children and adolescents is controversial. We previously showed that large tumor size, multifocal disease, and extensive disease at diagnosis predict recurrence. We examined 47 patients with PTC to determine whether these features predict response to treatment. Overall, 70% of the patients (33/47) remitted with initial treatment. 79% (15/19), of Class I, 86% (12/14) of Class II, and 100% (6/6) of Class III, but none of Class IV patients (n = 8) (p < 0.001) achieved remission. Tumor size for patients who entered remission (2.0 +/- 0.2 cm) was less than for patients with persistent disease (4.2 +/- 0.4) (p < 0.0005). Extent of disease at diagnosis correlated with the number of radioactive iodine (RAI) treatments (p = 0.022) and dose (p = 0.002) required to achieve first remission. We conclude that extensive disease at diagnosis and larger tumor size predict failure to remit after initial treatment of PTC in children and adolescents.

Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents.

The sodium-iodide symporter (NIS) is expressed by papillary (PTC) and follicular (FTC) thyroid carcinoma, and is essential for iodine uptake. We hypothesized that PTC and FTC with detectable NIS immunostaining would be more amenable to radioactive iodine ((131)I) treatment and follow a more benevolent course. To test this, we determined NIS expression by immunohistochemistry in 23 PTC, 9 FTC, and 12 benign thyroid lesions from children and adolescents. NIS expression was determined by two blinded examiners and graded as absent = 0, minimal = 1, moderate = 2, intense = 3, and very intense = 4. NIS was detected in 35% (eight of 23) of PTC, 44% (four of 9) of FTC, 25% (two of eight) of benign tumors, and 100% (four of four) of autoimmune lesions. The intensity of NIS expression was similar in PTC (0.61 +/- 0.24), FTC (0.56 +/- 0.24), and benign tumors (0.50 +/- 0.33) but was more intense in autoimmune lesions (3.0 +/- 0.7, p < 0.005). Distant metastases were found only among PTC with undetectable NIS (two of 15, 13%), and recurrence developed exclusively from PTC and FTC with undetectable NIS (four of 20, 20% versus zero of 12, p = 0.043). The dose of iodine 131 required to achieve remission in the five patients with PTC who had undetectable NIS (213.3 +/- 53 mCi) was greater than that required by patients with similar age and extent of disease for whom NIS expression is unknown (109 +/- 22 mCi, p = 0.06). We conclude that NIS expression is associated with a lower risk of recurrence for PTC and FTC of children and adolescents.

Intense expression of the b7-2 antigen presentation coactivator is an unfavorable prognostic indicator for differentiated thyroid carcinoma of children and adolescents.

Previous observations suggest that an immune response against thyroid carcinoma could be important for long-term survival. We recently found that infiltration of thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival, but the factors that control lymphocytic infiltration and proliferation are largely unknown. We hypothesized that the antigen presentation coactivators (B7-1 and B7-2), which are important in other immune-mediated thyroid diseases, might be important in lymphocytic infiltration of thyroid carcinoma. To test this, we determined B7-1 and B7-2 expression by immunohistochemistry [absent (grade 0) to intense (grade 3)] in 27 papillary (PTC) and 8 follicular (FTC) thyroid carcinomas and 9 benign thyroid lesions. B7-1 and B7-2 were expressed by the majority of PTC and FTC (78% of PTC and 100% of FTC expressed B7-1; 88% of PTC and 88% of FTC expressed B7-2). B7-1 expression was more intense in PTC (1.4 +/- 0.2; P = 0.01) and FTC (2.6 +/- 0.2; P < 0.001) than in benign tumors (0.57 +/- 0.30) or presumably normal adjacent thyroid (0.07 +/- 0.07) and was more intense in carcinoma that contained lymphocytes (1.95 +/- 0.21) than in carcinoma that did not (1.08 +/- 0.26; P = 0.016). B7-2 expression was of similar intensity in benign and malignant tumors (PTC, 1.6 +/- 0.2; FTC, 2.1 +/- 0.4; benign, 1.86 +/- 0.4), but was more intense than in presumably normal adjacent thyroid (0.64 +/- 0.25; P