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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., Competing Interests: Conflicts of interests The authors have no competing interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Children's Oncology Group (COG) Rare Tumor Committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that do not fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes., (© 2023 Wiley Periodicals LLC.)

Differentiated thyroid carcinomas are rare in young children but represent almost 10% of all malignancies diagnosed in older adolescents. Differentiated thyroid carcinoma in children is more likely to demonstrate nodal involvement and is associated with higher recurrence rates than seen in adults. Decisions regarding extent of surgical resection are based on clinical and radiologic features, cytology, and risk assessment. Total thyroidectomy and compartment-based resection of involved lymph node basins form the cornerstone of treatment. The use of molecular genetics to inform treatment strategies and the use of targeted therapies to unresectable progressive disease is evolving., Competing Interests: Disclosure The authors have no relevant commercial or financial conflicts of interest. The work related to this review was unfunded., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Differentiated thyroid carcinomas (DTCs) are rare in young children but represent almost 10% of all malignancies diagnosed in older adolescents., Methods: This article reviews the recent literature describing surgical therapeutic approaches to pediatric DTC, associated complications, and long-term recurrence and survival outcomes., Results: Similar to adult thyroid cancers, pediatric DTCs are more common in females and are associated with thyroid nodules, family history of thyroid cancer, radiation exposure, iodine deficiency, autoimmune thyroid disease, and genetic syndromes. Management of thyroid cancers in children involves ultrasound imaging, fine needle aspiration, and surgical resection with treatment decisions based on clinical and radiological features, cytology and risk assessment., Conclusions: Total thyroidectomy and compartment based resection of clinically involved lymph node basins form the cornerstone of treatment of DTC. There is an evolving literature regarding the use of molecular genetics to inform treatment strategies and the use of targeted therapies to treat iodine refractory and surgically unresectable progressive disease., Type of Study: Summary review., Level of Evidence: This is a review article of previously published Level 1-5 articles that includes expert opinion (Level 5)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Germline and somatic mutations of DICER1 have been identified in various types of neoplastic lesions, with germline DICER1 mutation being linked to autosomal dominant hereditary pleiotropic tumor syndrome (DICER1 syndrome). Patients with DICER1 syndrome are at increased risk of developing thyroid disease, including thyroid cancer. The goal of this study was to identify diagnostic cytologic features in thyroid fine-needle aspiration (FNA) samples from patients with DICER1 mutation., Methods: Cytology cases of thyroid FNA from 7 patients with DICER1 mutation were identified. Clinical, imaging, cytomorphologic, and molecular data were analyzed., Results: Cytologic preparations from reviewed cases showed thyroid lesions of follicular derivation with scant colloid, moderate cellularity, uniform follicular cells with round nuclei and inconspicuous nucleoli arranged in small crowded groups and microfollicles. Follicular neoplasm was diagnosed in 4 cases and follicular lesion of undetermined significance in 3 cases, based on the Bethesda System for Reporting Thyroid Cytopathology. Histopathological analysis of thyroid tissue confirmed neoplastic process in 6 out of 7 cases: follicular carcinoma (FC, 3 cases), papillary thyroid carcinoma (2 cases), poorly differentiated thyroid carcinoma (PDTC, 1 case). Genetic studies identified 3 different somatic variants of DICER1 gene, including transcript consequence c.5428G>T, which was detected in FC and PDTC (and has been described previously in multinodular goiter)., Conclusion: DICER1 mutation in all analyzed patients was identified as a result of thyroid FNA evaluation, emphasizing the critical role of FNA in the screening of patients with thyroid nodules, proper diagnosis of thyroid disease, and monitoring of patients with DICER1 mutation., (© 2020 American Cancer Society.)

Background: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms., Materials and Methods: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence., Results: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07)., Conclusions: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection., Level of Evidence: Prognosis study, level IV, retrospective case series., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis., Methods: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples., Results: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden., Conclusions: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.

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., (© 2016 American Cancer Society.)

The incidence of thyroid cancer, particularly papillary thyroid cancer, is rising at an epidemic rate. The mainstay of treatment of most patients with thyroid cancer is surgery. Considerable controversy exists about the extent of thyroid surgery and lymph node resection in patients with thyroid cancer. Surgical experience in judgment and technique is required to achieve optimal patient outcomes., (Copyright © 2014 Elsevier Inc. All rights reserved.)