Catherine Dinauer

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.

Extensive surgery improves recurrence-free survival for children and young patients with class I papillary thyroid carcinoma.

BACKGROUND Children with papillary thyroid cancer (PTC) rarely die of their disease, but are at high risk for recurrence, particularly with multifocal tumors (which occur in 42% of children with PTC). It is not clear if more extensive surgery, with an increased risk of complications, lessens the risk for recurrence. The authors hypothesized that patients with disease presumed to be confined to the thyroid gland (class I PTC) could have multifocal disease, involving the contralateral lobe, of which the surgeon is unaware. Treatment with less than subtotal thyroidectomy might be associated with a higher risk of recurrence. METHODS The charts of 37 patients with Class I PTC diagnosed at < or =21 years of age between 1953 and 1996 were reviewed. The incidence of surgical complications and the risk of recurrence based on the extent of initial surgery ([1] lobectomy with or without isthmusectomy, [2] subtotal, or [3] total thyroidectomy) and adjunctive therapy with thyroid hormone or radioactive iodine (RAI) were examined. RESULTS Eight patients had recurrent PTC. Patients treated with lobectomy with or without isthmusectomy were more likely to have recurrence than patients treated with subtotal or total thyroidectomy (Odds ratio, 8.7; 95% CI 1.4 to 54). Although the incidence of complications was statistically similar among the 3 surgical groups, 3 patients, all treated with more extensive surgery, had permanent hypoparathyroidism. There were too few patients to determine whether treatment with thyroid hormone or RAI offered additional benefit. CONCLUSIONS In children with Class I PTC, more extensive surgery is associated with a lower risk of recurrence. This finding must be weighed against the risk of complications when determining the optimal treatment for individual patients.

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 (131I) 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.

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

An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children.

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.

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.

The Pediatric Thyroid Nodule and Papillary Thyroid Cancer Management

Pediatric thyroid cancer is a rare disease with an excellent prognosis. Compared with adults, epithelial-derived differentiated thyroid cancer (DTC), which includes papillary (PTC), 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 tenfold 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. Reflecting 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 long-term follow-up, since disease can recur decades after initial 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.

Lymph node ratio predicts recurrence in pediatric papillary thyroid cancer

BACKGROUND Regional lymph node (LN) metastasis at the time of presentation plays a significant role in predicting recurrence in patients with papillary thyroid cancer (PTC). Multiple studies in the adult population have demonstrated that the lymph node ratio (LNR) in both the central and lateral neck can improve the accuracy of recurrence prediction, but this ratio has not been studied in the pediatric population. In this study, we sought to investigate the LNR in the central and lateral compartments as a prognostic predictor for recurrence in pediatric patients with PTC. METHODS A retrospective analysis of pediatric patients (≤21 years old) at a single institution between 2002 and 2014 who underwent total thyroidectomy with prophylactic central neck dissection (TTpCND) with at least 3 sampled nodes or total thyroidectomy with unilateral modified radical neck dissection (TTMRND) with at least 10 sampled nodes, and on whom at least 24 months of follow up data were available was performed. The LNR was defined as the ratio of metastatic LNs to total number of investigated LNs. Recurrence after TTpCND and TTMRND was examined separately as a function of LNR, using the value of 0.45 as a cutoff. RESULTS Forty-eight patients met inclusion criteria. Thirty-two underwent TTpCND, and sixteen underwent TTMRND. Median age at time of operation was 17 years (range 6-20), and median duration of follow-up was 53.5 months (range 24-183). In the TTpCND, LNR ranged from 0 to 1.0. There were two recurrences among the eight patients (25%) undergoing TTpCND in patients with LNRs >0.45 and a single recurrence among the 24 patients (4.2%) undergoing TTpCND with an LNR ≤0.45. In the TTMRND, LNR ranged from 0.1 to 1.0. There were 3 recurrences in 12 patients with LNR ≤0.45 (30.8%%) and 4 recurrences in 4 patients with LNR >0.45 (100%) (p = 0.03). CONCLUSIONS Although limited by small sample size, LNR may be a useful predictor to stratify the likelihood of recurrence in pediatric patients undergoing TTpCND or TTMRND for pathologic N1a or N1b PTC. TYPE OF STUDY Prognosis study / retrospective case series. LEVEL OF EVIDENCE Level IV.