Evolving trends in pediatric thyroid nodules and cancer management

Sabitha Sasidharan Pillai; Juliana Austin; Trevor E. Angell

doi:10.6065/apem.2550420.210

Ann Pediatr Endocrinol Metab > Volume 31(3); 2026 > Article

Pillai, Austin, and Angell: Evolving trends in pediatric thyroid nodules and cancer management

Review Article

Annals of Pediatric Endocrinology & Metabolism 2026;31(3): 149-159.

Published online: June 30, 2026

DOI: https://doi.org/10.6065/apem.2550420.210

Evolving trends in pediatric thyroid nodules and cancer management

Sabitha Sasidharan Pillai¹

, Juliana Austin¹

, Trevor E. Angell²

¹Center for Endocrinology, Diabetes & Metabolism, Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

²Division of Endocrinology and Diabetes, Keck School of Medicine of USC, Los Angeles, CA, USA

Address for correspondence: Trevor E. Angell Division of Endocrinology and Diabetes, Keck School of Medicine of USC, 2020 Zonal Avenue, IRD 635, Los Angeles, CA 90089, USA Email: trevor.angell@med.usc.edu

Received October 23, 2025 Revised November 12, 2025 Accepted December 3, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Differentiated thyroid cancer (DTC) is the most common form of pediatric thyroid cancer, yet its management has been largely based on evidence from adults. Recent advances in science and clinical studies of pediatric DTC, particularly in papillary thyroid carcinoma, the predominant subtype, now form the basis of emerging paradigms and revised guidelines. The potential of malignancy in thyroid nodules, as defined by current ultrasound risk stratification systems, has been evaluated in pediatric patients, enabling evidence-based indication for fine-needle aspiration biopsy. Observational studies comparing the effect of different interventions on prognosis, complications, and quality of life, challenge traditional surgical approaches in favor of potentially less extensive initial resection. Recognition of distinct underlying oncogenic drivers has not only paved the way for discoveries in the biology of pediatric thyroid cancer but has also advanced the era of targeted systemic therapy for progressive and metastatic pediatric DTC. Certain genome alterations, particularly oncogenic gene fusions that are more common in pediatric DTC, can now be targeted with small-molecule inhibitors, offering more effective therapy for metastatic disease with fewer and less severe adverse effects. This review offers an evidence-based summary of these data and the evolving trends in the diagnosis and management of pediatric DTC.

Keywords: Pediatric, Thyroid nodule, Thyroid cancer, Radioactive iodine, Thyroidectomy, Ultrasound, Fine-needle aspiration, Cytology, Molecular testing

Highlights

· This review examines current management and emerging concepts in pediatric thyroid nodules and thyroid cancer, emphasizing evidence-based, individualized care and recent developments shaping clinical practice. The evaluation of thyroid nodules is increasingly informed by cancer risk assessed by ultrasound features, cytology and molecular testing, while evolving concepts in thyroid cancer treatment span from surgery and radioactive iodine use to novel targeted therapies for advanced or metastatic disease.

Introduction

Pediatric thyroid cancer is rare, with an incidence of 11.4 cases per 1 million individuals 19 years of age and younger [1]. It accounts for approximately 2% of cancers from birth to 14 years, while the incidence of thyroid cancer is higher in children 15–19 years of age (31.3 cases per 1 million people), representing 12% of all cancers for this group [2]. The incidence of pediatric thyroid cancer has spiked in the last decade, with increases of up to 9.5% per year in the United States, probably due to an increased incidental detection of small nodules by diagnostic imaging [3]. Differentiated thyroid cancer (DTC) is the most common form of pediatric thyroid cancer. Of these, 90% or more are papillary thyroid carcinoma (PTC), the rest being follicular thyroid carcinoma (FTC). While other forms of thyroid cancer may rarely occur, this review will focus on topics related to DTC.

Pediatric DTC differs notably from the adult disease in clinical presentation, molecular alterations, pathological findings, and outcomes, leading to the development of distinct guidelines for its management [4,5]. Pediatric DTC is characterized by higher rates of RET (rearranged in transformation)/PTC gene rearrangements and lower BRAF (V-raf murine sarcoma viral oncogene homolog B) or RAS (rat sarcoma) point variants. Although pediatric DTC generally has more aggressive pathologic findings, its prognosis is more favorable, with higher progression-free survival and lower cause-specific mortality compared to adult DTC [5,6].

Historically, the diagnosis and management of pediatric thyroid cancer have been guided largely by extrapolating evidence from the literature on adult thyroid cancer. Yet, the management of children with DTC presents distinct challenges. Morbidity and mortality are often secondary to the long-term effects of treatment rather than the disease itself. In recent years, new data have emerged specifically for pediatric DTC that help provide new perspectives and strategies for management, and inform new guidelines, including those under development by the American Thyroid Association (ATA). Here, we concentrate on the evolving trends in the management of pediatric DTC, with particular emphasis on the accuracy of ultrasound and fine-needle aspiration (FNA), molecular testing of pathologic specimens, extent of initial surgical resection, and targeted systemic therapies. In doing so, we hope to provide the reader with an up-to-date, evidence-based review.

Thyroid nodule evaluation

The 2015 ATA Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer recommend evaluating thyroid nodules with FNA biopsy based on size, ultrasound characteristics, and clinical risk factors [5,7]. FNA biopsy is generally performed for pediatric thyroid nodules ≥1 cm in size, as well as those <1 cm that have suspicious clinical characteristics (e.g., history of radiation therapy, familial DTC, or hereditary tumor syndromes associated with DTC) or concerning sonographic features. Thyroid FNA cytology is described using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) (Table 1). Surgery is favored for most thyroid nodules with nonbenign cytology, given that the underlying risk of malignancy (RoM) is higher in pediatric patients (22%–25%) compared to adults (5%–10%) [5,7]. A multimodal approach, now including clinical assessment, imaging, cytopathology, and, increasingly, molecular analysis, is crucial for selecting whether patients should undergo either observation or surgery.

1. Ultrasound risk stratification

The use of sonographic features for thyroid nodule evaluation in adult patients has become increasingly nuanced and has led to formalized ultrasound risk stratification systems (US-RSSs), such as the Korean Thyroid Imaging Reporting & Data System (K-TIRADS) [8], the ATA ultrasound risk stratification system [9], American College of Radiology (ACR)-TIRADS [10], and others. Sonographic features most associated with malignancy and regularly included in these systems are solid composition, hypoechogenicity, taller-than-wide shape, irregular/invasive margins, nonshadowing echogenic foci and macrocalcifications, and suspicious-appearing cervical lymph nodes. These features perform better for the identification of PTC compared to FTC [11]. US-RSSs place thyroid nodules into categories with designated malignancy risks and size criteria at which FNA biopsy is recommended. This has been shown to reduce the number of unnecessary FNA biopsies for benign nodules [12].

Ultrasound risk assessment and the use of US-RSSs have increasingly been studied in pediatric populations, confirming several sonographic features as predictive of malignancy. Creo et al. [13] evaluated 145 nodules in 112 children without germline risk syndromes or history of radiation exposure who had a mean age ± standard deviation of 15.5±3.2 years. Using univariate analysis, they reported that malignancy was significantly associated with >75% solid, hypoechogenicity, presence of calcifications, irregular margins, increased blood flow, or the presence of suspicious lymph nodes. A study of 236 pediatric thyroid nodules found that while all suspicious sonographic features were associated with malignancy, hypoechogenicity and extrathyroidal extension remained statistically significant in multivariable analysis [14]. In a study by Richman et al., [15] nodule size and suspicious sonographic features were associated with malignancy, while clinical features related to patient age (11 years cutoff) and sex were not.

Numerous studies have investigated the application of US-RSSs to pediatric patients, the majority of which have assessed ACR-TIRADS [16-19]. In ACR-TIRADS, the likelihood of malignancy increases as the risk categories increase from TR1 to TR5. One study of 404 thyroid nodules in patients ≤18 years of age observed higher malignancy risks by ACR-TIRADS category when compared to the estimated RoM in adults for the same categories [16]. Notably, 17 of 77 cancers (22.1%) would have been overlooked during the initial assessment based on adult criteria for recommending FNA. An analysis of pediatric thyroid nodules using K-TIRADS found that diagnostic performance was improved by modifying the FNA criteria to use smaller size cutoffs [17]. A 2021 systematic review and meta-analysis assessing the diagnostic performance of US-RSSs for pediatric thyroid nodules reported pooled RoMs for ACR-TIRADS of 5.5%, 6.0%, 11.0%, 20.7%, and 59.3% for TR1, TR2, TR3, TR4, and TR5, respectively, and pooled RoMs for ATA US-RSS of 7.5% for very low, 12.2% for low, 34.2% for intermediate, and 55.4% for high suspicion [18].

Current data indicate that sonographic phenotype may improve the risk stratification of thyroid nodules with cytology that is atypia of undetermined significance (AUS, Bethesda III), but not follicular neoplasm (FN, Bethesda IV) [8,18-20]. Richman et al. [21] retrospectively assessed 87 nodules ≥1 cm in patients under 19 years old with an FNA of Bethesda III-V. Although no sonographic feature or ACR-TIRADS category had a negative predictive value low enough to avoid surgery, irregular margins (positive predictive value [PPV] 100%) or TIRADS 5 category (PPV 80%) indicated a higher risk, and could influence the decision to perform total thyroidectomy over lobectomy.

Finally, potential differences may occur in the interpretation of ultrasound findings in pediatric patients compared to adults. In a case series and review of literature, Frates et al. [22] showed that intrathyroidal thymic tissue in pediatric patients may appear as a solid, hypoechoic, well-marginated nodule with multiple focal internal nonshadowing echogenicities, which would be considered suspicious for malignancy (SM) if seen in an adult patient.

2. FNA cytology

The assessment for thyroid cancer with FNA biopsy for thyroid nodules that meet criteria after ultrasound (US) risk stratification should be assessed using TBSRTC. The first edition of TBSRTC was published in 2010 and proposed 6 standardized categories. It was updated in 2017 [10], incorporating the reclassification of some indolent thyroid neoplasms as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [11]. The 3rd edition of TBSRTC was published in 2023 and contained revisions that again sought to clarify terminology and improve the risk prediction (Table 1). The 3rd edition also updated category names to improve clarity and align with other terminology, such as the 2022 World Health Organization Classification of Thyroid Neoplasms (5th edition) [17]. The 2023 categories are: (1) nondiagnostic (ND), (2) benign, (3) AUS, (4) FN, (5) SM, and (6) malignant. Several studies report a higher RoM for aspirates categorized as AUS because of nuclear (cytologic) atypia compared to other causes, such as architectural or oncocytic atypia [18-21]. TBSRTC 2023 now includes separate average RoMs and expected ranges for the pediatric population (Table 1).

Similar to findings for US-based risk stratification, recent data comparing cytologic results have generally found higher RoMs for each TBSRTC category in pediatric patients than those reported for adults. One of the largest studies, which included 1,217 thyroid nodules in pediatric patients from 7 institutions in 5 Asian countries, found an overall RoM (encompassing both resected and unresected nodules) of 2.5%, 1.8%, 14.8%, 28.6%, 91.7%, 82%, for ND, Benign, AUS, FN, SM, and malignant, respectively, and these RoMs were notably higher than those estimated for adult patients from a previous meta-analysis [23,24]. Cherella et al. [25] performed a retrospective analysis comparing 430 pediatric thyroid nodules and 13,415 adult thyroid nodules, all of which had been evaluated by the same cytopathologists. The overall RoM was higher in pediatric patients (19%) compared to adults (12%) (P=0.0002) with statistically significant differences observed in the categories of ND (11% vs. 4%, P=0.03), Benign (0.7% vs. 1%, P=0.001), AUS (44% vs. 22%, P=0.004), and FN (71% vs. 28%, P=0.001), but not SM (73% vs. 68%, P=0.82) or malignant (97% vs. 95%, P=1.0). Lower resection rates in adult patients may lead to an underestimation of malignancy risk compared to pediatric patients, and there is relatively high variability in the RoM within each Bethesda category across pediatric studies [24-28]. Nevertheless, current data indicate that pediatric thyroid nodules carry a higher malignancy risk in both US risk and cytologic criteria, suggesting that adult-based recommendations may need modification to allow more stringent evaluation of nodules and reduce the chance of missed malignancy in pediatric patients.

3. Molecular diagnostics

Our expanding knowledge on the molecular underpinnings of thyroid tumors has revolutionized the approach to their diagnosis, management, prognosis, and surveillance [2,29-33]. Several studies have now investigated the role of molecular analysis in the management of pediatric thyroid neoplasia [34-52]. Landmark data from The Cancer Genome Atlas (TCGA) project for thyroid cancer in 2014 involved predominantly adult participants with PTC. It was observed that PTC is usually driven by mutually exclusive point alterations in BRAF (60% of tumors) or RAS (13% of tumors), or by oncogenic fusions, most commonly between RET and either CCEC6 (RET-PTC1) or NCOA4 (RET-PTC3) (5.3% of tumors). TCGA described the BRAF-RAS score and defined tumors into 2 categories: BRAF-like or RAS-like. Subsequently, a study from Canada observed that, unlike the categorization of adult PTC, gene expression in pediatric PTC (pPTC) was discernible from that in adults, and described 3 clusters of distinct gene expression related to thyroid differentiation and mitogen-activated protein kinase (MAPK) signaling [37].

Approximately 60%–80% of pPTC have been found to have at least one genetic alteration. A 3-tiered classification that incorporates the predominance of fusions found in pPTC in addition to RAS and BRAF has been proposed [38,47,53]. Kinase fusions (e.g., RET fusions or NTRK fusions) occur with an increased frequency (50%) in sporadic pPTC compared to adult PTC (15%), especially in children with a history of radiation exposure [47,48,50,51,53-57]. Less common fusions seen in pPTC involve NTRK3, ALK, NTRK1, BRAF, and MET [37,47,54]. Given that current data on oncogenic drivers of pPTC derived from small cohorts are from diverse demographic, geographic, and environmental circumstances that evaluated single genes or small multi-gene panels, there is a relatively wide range of frequencies for reported molecular alterations (Table 2) [42,58-60].

Even with the same gene alteration, the clinical presentation of pPTC is different than that in adult PTC. Fusion oncogenes are associated with more invasive disease, lateral neck and lung metastases, and heightened risk for persistent disease in children with PTC. This differs from adult PTC, where aggressive behavior and loss of radioactive iodine (RAI) avidity are more strongly associated with BRAFV600E compared to gene fusions [34,47,49,52,54]. The prevalence of BRAFV600E in pPTC ranges from 0%–20% and is less commonly associated with invasive disease, though some develop lateral neck and lung metastases [61,62]. The reason for differing behavior between pPTC and adult PTC with the same oncogenic driver is not clear. Larger and more comprehensive studies may yield a deeper understanding of the molecular changes and their potential contribution to the observed clinical presentations.

Molecular testing for pathogenic alterations in DNA or gene expression has refined the preoperative RoM in adult patients with indeterminate cytology thyroid nodules (i.e., AUS or FN), predominantly to reduce the need for thyroidectomy [29-31,38,41,45,46,63,64]. Although the 2015 ATA guidelines for pediatric patients recommend lobectomy plus isthmectomy for children with indeterminate thyroid nodules because of the higher RoM (28% for AUS and 50% for FN) [5,65], more recent data suggest that molecular testing may be used as an adjunct to refine preoperative RoM and modify treatment in pediatric patients.

Current molecular testing, using next-generation sequencing (NGS) to detect genetic alterations in children with indeterminate thyroid nodules, can detect oncogenic drivers associated with low risk (RAS, DICER1, PTEN), intermediate risk (BRAFV600E), or high risk (fusions involving RET, NTRK3, BRAF, and ALK) for invasive disease. Indeterminate nodules harboring oncogenes with low risk for invasive behavior usually do not have lymph node metastasis and can be managed with lobectomy. However, a complete thyroidectomy may be necessary if there are adverse histopathology findings, including >2 foci of vascular invasion, more aggressive histologic features (such as solid, trabecular, or insular growth patterns), a mitotic index of ≥3 per 10 high-power fields, necrosis, or convoluted nuclei [2,66]. Indeterminate nodules with rare genetic alternations associated with no or minimal risk for invasive disease (TSHR, THADA, GNAS) can be monitored without surgical intervention in the absence of autonomous function or invasive behavior. Gene expression classifier tools have not yet been validated in the pediatric population [50,67]. Testing that combines oncogene assessment by NGS and expression analysis of selected microRNA (miRNA) may also offer improved preoperative RoM assessment for indeterminate nodules in pediatric patients [68,69]. A recent study, which assessed the use of combined oncogene and miRNA analysis of FNA cytopathology in a pediatric cohort of 37 patients with a mean age of 13.9 years, observed that identification of a strong oncogenic driver or positive miRNA result had 90.5% sensitivity and 88.9% specificity, respectively, in predicting malignant versus benign pathology [69].

Total thyroidectomy versus lobectomy

The 2015 ATA guidelines recommended more aggressive initial management for children with PTC compared to adults with PTC [5]. Thyroid surgery should be performed by a high-volume thyroid surgeon, defined as a surgeon who performs at least 30 cervical endocrine procedures annually within the age group of the patient undergoing surgery, to reduce the risk of permanent operative complications to below 1%–3% [5]. Total thyroidectomy is thought to be associated with increased disease-free survival in pediatric patients, who are more likely to have bilateral and multifocal disease and locoregional metastasis at diagnosis [4]. In a study of 215 children aged 3–20 years with PTC managed between 1940 and 2008, a lower recurrence risk was observed in children who had total thyroidectomy compared to those who had lobectomy during a follow-up of 40 years (6% vs. 30%) [5,70].

Low-risk DTC is defined as disease confined to the thyroid gland, or with only incidentally detected, minimal, and microscopic disease in the central neck lymph nodes. Pediatric patients with extensive extrathyroidal invasion or metastases are at higher risk for persistent regional or distant disease, supporting further postoperative staging with thyroid simulating hormone-stimulated thyroglobulin and diagnostic 123I scan to identify those who would likely benefit from RAI treatment. Therapeutic 131I is suggested for iodine-avid persistent locoregional or distant nodal disease that is not amenable to surgery or iodine-avid distant metastases [5].

Shifting management strategies toward less extensive surgery for low-risk DTC among adults has inspired efforts to identify potential pediatric subgroups who might be adequately treated with lobectomy rather than total thyroidectomy [3]. Children with DTC have higher surgical complications from thyroidectomy and lower disease-specific mortality compared to adults, highlighting the specific risks and benefits associated with the extent of surgery in children [3,71,72]. Recent evidence suggests that children with unifocal tumors and no lymph node metastases may have a low risk of bilateral disease, making lobectomy a reasonable consideration for these patients [73-75]. Moreover, other studies do not indicate that multifocality is a predictor of tumor recurrence or contralateral lobe PTC and suggest lobectomy as an effective treatment modality for patients with microscopic multifocal disease [76,77].

Lobectomy is probably sufficient for NIFTP and in those with minimally invasive FTC, which is defined as FTC with microscopic or no capsular invasion and/or vascular invasion that is <4 vessels in or adjacent to the tumor capsule [5,78,79]. A study that evaluated 153 children ≤18 years of age with no evidence of lymph node metastasis or extrathyroidal extension preoperatively found that the disease-free survival rate was similar between those who underwent lobectomy compared to total thyroidectomy during the median 15 years of follow-up [80]. However, prophylactic neck dissection, including lateral neck dissection, was performed in two-thirds of patients, including those who underwent lobectomy, limiting the generalization of these results to current practice. Out of 89 patients in the low-risk category, 64 had prophylactic modified neck dissection, including central and lateral neck dissection, and none had lymph node involvement [80]. It is important to highlight that another study assessing health-related quality of life in children with low-risk PTC observed increased psychological burden with poor emotional and mood responses in those who had total thyroidectomy compared to lobectomy [81].

Oncogene targeted systemic therapy

Dysregulated activation of the MAPK pathway is one of the most common oncogenic processes in thyroid cancer. This can occur via pathogenic alteration throughout the signaling chain (Fig. 1). Alterations occur as pathogenic point variants or rearrangements, most commonly involving RAS, BRAF, RET, NTRK, DICER1, PAX8/PPARγ, and PTEN (phosphatase and tensin homolog) [82-84]. Many of these genetic alterations lead to gain-of-function kinase activity, resulting in activation of the MAPK, as well as the PI3K-AKT-mTOR, pathways [82,83,85-87]. Pathogenic RAS alterations result in constitutive activation of the RAS protein, preferentially activating the PI3K-AKT-mTOR pathway rather than the MAPK pathway [84,85]. The point alteration in the BRAF gene that yields the BRAFV600E kinase results in a constitutively active protein without appropriate feedback inhibition stimulus from RAS. RET is not usually expressed in thyroid follicular cells, but RET/PTC rearrangements, resulting from the fusion of the tyrosine kinase domain of RET to the 5' portion of different genes that are constitutively expressed in thyroid follicular cells, result in ligand-independent constitutive activation of tyrosine kinase. The NTRK genes encode transmembrane receptor proteins that regulate cellular functions through the MAPK, PI3K/AKT, and phospholipase C-gamma pathways. NTRK fusions result in the constitutive activation of these pathways, promoting tumorigenesis and progression [66].

This enhanced knowledge of the key molecular regulators of oncogenesis in DTC has led to the development of tyrosine kinase inhibitors (TKIs) targeting these aberrant proteins. TKIs used in the clinical treatment of advanced DTC include multikinase inhibitors (e.g., lenvatinib, sorafenib, vandetinib, and cabozantinib) and highly specific inhibitors of relevant targets, including selpercatinib and pralsetinib (RET fusions), larotrectinib and entrectinib (NTRK fusions), crizotinib (ALK and MET fusions), the combination BRAF/MEK inhibitor dabrafenib/trametinib, and vemurafenib (BRAFV600E) [30,35,37,87-94].

In addition to direct effects on reduced tumor size and progression, selective fusion-directed therapy increases sodium iodide symporter (NIS) expression and may restore RAI avidity and increase the effectiveness of RAI treatment in patients with advanced disease that are not amenable to surgery or with low iodine avidity [43,95]. Available data also imply that oncogene-specific targeted therapies are effective as neoadjuvant therapy before surgery, inducing tumor regression in pediatric patients with extensive thyroid cancer invading the trachea, esophagus, vascular, or neural structures [36].

The development of side effects or tumor resistance is among the limitations of targeted therapy. Commonly observed side effects of TKIs include hepatic impairment, gastrointestinal events (diarrhea, nausea, vomiting, and rarely pancreatic atrophy), hypertension, decreased left ventricular function, proteinuria, hand-foot syndrome, and fatigue. Side effects usually develop in about 2–3 weeks of drug initiation, affecting patient adherence to the treatment. Early detection and adequate management of side effects are crucial to minimize toxicities and ensure the continuation of therapy to maximize the effectiveness of treatment.

Conclusions

Pediatric DTC is characterized by more aggressive disease with lymph node involvement, extrathyroidal extension, and pulmonary metastasis at diagnosis, but more favorable progression-free survival and cause-specific mortality compared to adult DTC. A more refined understanding of the RoM based on ultrasound appearance and FNA cytology are improving the initial diagnostic assessment of thyroid nodules, and the application of molecular testing is revolutionizing not only diagnostic approaches but also therapeutic options for patients with metastatic, radioiodine-refractory disease.

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contribution

Conceptualization: SSP, JA, TEA; Data curation: SSP; Project administration: TEA; Visualization: TEA; Writing - original draft: SSP, JA, TEA; Writing - review & editing: SSP, JA, TEA;

Fig. 1.

Molecular pathway and potential targets in pediatric thyroid cancer. Receptor tyrosine kinases (RTKs) of the surface of thyroid cancer cells bind growth factors that influence cellular actions. In DTC, pathogenic fusion rearrangements in several key RTK, including RET, NTRK, and ALK, lead to constitutive activation and augmented activation of RAS. Activated RAS binds to and recruits RAF proteins, which are serine/threonine kinases (mainly BRAF in thyroid follicular cells). Pathogenic alterations in RAS or BRAF, typically point variants, lead to constitutive activity of these proteins. From RAS or aberrant function, activated BRAF phosphorylates and activates mitogen-activated protein kinase/extracellularsignal-regulated kinase (MEK), which in turn phosphorylates ERK. Activated ERK enters the nucleus and influences transcription of genes governed by this MAPK pathway, leading to oncogenic cell differentiation, proliferation, and survival. Activated RAS also activates the PI3K-AKT-mTOR pathway, which is inhibited by PTEN function. Nonspecific multikinase inhibitor therapies with activity against other RTKs, such as VEGFR, FGFR, PDGFR, and c-MET, block receptor activation and downstream signaling that supports various protumoral changes, including growth, vascularization, and immune microenvironment. MKIs, multikinase inhibitors; DTC, differentiated thyroid carcinoma, RET, rearranged during transfection, NTRK, neurotrophic receptor tyrosine kinase, ALK, anaplastic lymphoma kinase, RAS, rat sarcoma, BRAF, v-raf murine sarcoma viral oncogene homolog B, ERK, extracellular-signal-regulated kinase, MAPK, mitogen-activated protein kinase, PI3K-AKT-mTOR, phosphatidylinositol 3'-kinase - Protein Kinase B - mammalian target of rapamysin, PTEN, phosphatase and tensin homolog, VEGFR, vascular endothelial growth factor receptor, FGFR, fibroblast growth factor receptor, PDGFR, platelet derived growth factor receptor, c-MET, mesenchymal-epithelial transition. Created in BioRender (2025) https://BioRender.com/0i6a2u9.

Table 1.

Previous and 2023 versions of Bethesda System for Reporting Thyroid Cytopathology Diagnostic Category (BSRTC)

2017 BSRTC		2023 BSRTC
2017 BSRTC			Adult		Pediatric
Diagnostic category	RoM (NIFTP malignant/NIFTP not malignant)	Diagnostic category	Mean (range)/mean RoM if NIFTP not malignant	Usual management	Mean (range) for RoM	Usual management
Nondiagnostic/unsatisfactory (I)	5%–10%/5%–10%	Nondiagnostic (I)	13% (5%–20%)/12%	Repeat FNA with ultrasound guidance	14% (0%–33%)	Repeat FNA with ultrasound guidance
Benign (II)	0%–3 %/0%–3%	Benign (II)	4% (2%–7%)/2%	Clinical and US follow-up	6% (0%–27%)	Clinical and ultrasound follow-up
Atypia/follicular lesion of undetermined significance (III)	~10%–30%/6%–18%	Atypia undetermined significance (III)	22% (13%–30%)/16%	Repeat FNA, MT, diagnostic lobectomy, or surveillance	28% (11%–54%)	Repeat FNA or surgical resection
Follicular neoplasm/Suspicious for follicular neoplasm (IV)a	25%–40%/10%–40%	Follicular neoplasm (IV)^*	30% (23%–34%)/23%	MT, diagnostic lobectomy	50% (28%–100%)	Surgical resection
Suspicious of malignancy (V)	50%–75%/45%–60%	Suspicious of malignancy (V)	74% (67%–83%)/65%	MT, lobectomy or near–total thyroidectomy	81% (40%–100%)	Surgical resection
Malignant (VI)	97%–99%/94%–96%	Malignant (VI)	97% (97%–100%)/94%	Lobectomy or near–total thyroidectomy	98% (86%–100%)	Surgical resection

RoM, risk of malignancy; NIFTP, noninvasive follicular neoplasm with papillary-like nuclear features; FNA, fine-needle aspiration; MT, molecular testing.

^* Including follicular neoplasm with oncocytic features.

Table 2.

Reported frequencies of molecular alterations in pediatric differentiated thyroid cancer

Variable	Paulson et al. 2019 (range) [58]	Rangel-Pozzo et al. 2020 [42]	Guleria et al. 2022 [59]	Colli et al. 2025 [60]
Papillary thyroid cancer
BRAF mutation	25%–30% (0%–63%)	0%–63% (0%–70% post irradiation)	0%–63% (0%–70% post irradiation)	0%–63%
BRAF fusion	10% (0%–18%)	0%–19% (0%–11% post irradiation)	0%–20% (0%–11% post irradiation)	0%–19%
RET fusion	25%–30% (14%–55%) (45% (14%–87%)–post irradiation)	0–37% (0–77% post irradiation)	22%–65% (33%–77% post irradiation	0%–57%
NTRK fusion	10% (0%–26%)	0%–18% (1.4%–14.5% post irradiation)	0%–20% (1%–15% post irradiation)	0%–18%
ALK fusion	5% (0%–21%)	0%–6.5% (1.4%–7% post irradiation)	0%–6% (0%–7% post irradiation)	0%–6.5%
PAX8-PPARγ fusion	<5% (0%–9%)	0%–9% (4% post irradiation)	0%–9% (4% post irradiation)
MET fusion	-	-	-	1%
RAS mutation	<5% (0%–18%)	0%–7% (0%–9% post irradiation)	<10%	-
TERT promoter mutation	-	0%–4%	0%–27%	-
DICER 1 mutation	10%	-	7.6%	-
Follicular thyroid cancer
RAS mutation	10%–15% (0%–20%)	-	0%–50%	-
PAX8-PPARγ fusion	<5% (0%–20%)	-	0%–20%	-
PTEN mutation	-	-	<2% (25%–carriers of PTEN mutation)	-
DICER 1 mutation	-	-	25%–53%	-

BRAF, V-raf murine sarcoma viral oncogene homolog B; RET, rearranged in transformation; NTRK, neurotrophic tyrosine kinase; ALK, anaplastic lymphoma kinase; PAX8-PPARγ, PAired box 8 and peroxisome proliferator-activated receptor gamma; MET, mesenchymal-epithelial transition; RAS, rat sarcoma; TERT, telomerase reverse transcriptase.

References

1. Qian ZJ, Jin MC, Meister KD, Megwalu UC. Pediatric thyroid cancer incidence and mortality trends in the United States, 1973-2013. JAMA Otolaryngol Head Neck Surg 2019;145:617-23.

2. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10-45.

3. Cherella CE, Wassner AJ. Pediatric thyroid cancer: recent developments. Best Pract Res Clin Endocrinol Metab 2023;37:101715.

4. Lebbink CA, Links TP, Czarniecka A, Dias RP, Elisei R, Izatt L, et al. 2022 European Thyroid Association guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. Eur Thyroid J 2022;11:e220146.

5. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid 2015;25:716-59.

6. Lebbink CA, Dekker BL, Bocca G, Braat AJ, Derikx JPM, Dierselhuis MP, et al. New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands. Eur J Endocrinol 2020;183:P11-8.

7. Krane JF. Improving risk assessment in indeterminate pediatric thyroid FNA biopsies. Cancer Cytopathol 2022;130:326-27.

8. Yang W, Fananapazir G, LaRoy J, Wilson M, Campbell MJ. Can the American Thyroid Association, K-TIRADS, and ACR-TIRADS ultrasound classification systems be used to predict malignancy in Bethesda category IV nodules? Endocr Pract 2020;26:945-52.

9. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.

10. Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, et al. ACR thyroid imaging, reporting and data system (TI-RADS): white paper of the ACR TI-RADS committee. J Am Coll Radiol 2017;14:587-95.

11. Trimboli P, Castellana M, Piccardo A, Romanelli F, Grani G, Giovanella L, et al. The ultrasound risk stratification systems for thyroid nodule have been evaluated against papillary carcinoma. A meta-analysis. Rev Endocr Metab Disord 2021;22:453-60.

12. Kim PH, Suh CH, Baek JH, Chung SR, Choi YJ, Lee JH. Diagnostic performance of four ultrasound risk stratification systems: a systematic review and meta-analysis. Thyroid 2020;30:1159-68.

13. Creo A, Alahdab F, Al Nofal A, Thomas K, Kolbe A, Pittock ST. Ultrasonography and the American thyroid association ultrasound-based risk stratification tool: Utility in pediatric and adolescent thyroid nodules. Horm Res Paediatr 2018;90:93-101.

14. Gannon AW, Langer JE, Bellah R, Ratcliffe S, Pizza J, Mostoufi-Moab S, et al. Diagnostic accuracy of ultrasound with color flow Doppler in children with thyroid nodules. J Clin Endocrinol Metab 2018;103:1958-65.

15. Richman DM, Benson CB, Doubilet PM, Peters HE, Huang SA, Asch E, et al. Thyroid nodules in pediatric patients: Sonographic characteristics and likelihood of cancer. Radiology 2018;288:591-9.

16. Richman DM, Benson CB, Doubilet PM, Wassner AJ, Asch E, Cherella CE, et al. Assessment of American college of radiology thyroid imaging reporting and data system (TI-RADS) for pediatric thyroid nodules. Radiology 2020;294:415-20.

17. Lee SB, Cho YJ, Lee S, Choi YH, Cheon JE, Kim WS. Korean Society of Thyroid Radiology guidelines for the management of pediatric thyroid nodules: suitability and risk factors. Thyroid 2021;31:1472-80.

18. Marina M, Zatelli MC, Goldoni M, Del Rio P, Corcione L, Martorana D, et al. Combination of ultrasound and molecular testing in malignancy risk estimate of Bethesda category IV thyroid nodules: results from a single-institution prospective study. J Endocrinol Invest 2021;44:2635-43.

19. Ahmadi S, Herbst R, Oyekunle T, Jiang X', Strickland K, Roman S, et al. Using the ATA and ACR TI-RADS sonographic classifications as adjunctive predictors of malignancy for indeterminate thyroid nodules. Endocr Pract 2019;25:908-17.

20. Barbosa TL, Junior COM, Graf H, Cavalvanti T, Trippia MA, da Silveira Ugino RT, et al. ACR TI-RADS and ATA US scores are helpful for the management of thyroid nodules with indeterminate cytology. BMC Endocr Disord 2019;19:112.

21. Richman DM, Cherella CE, Smith JR, Modi BP, Zendejas B, Frates MC, et al. Clinical utility of sonographic features in indeterminate pediatric thyroid nodules. Eur J Endocrinol 2021;184:657-65.

22. Frates MC, Benson CB, Dorfman DM, Cibas ES, Huang SA. Ectopic intrathyroidal thymic tissue mimicking thyroid nodules in children. J Ultrasound Med 2018;37:783-91.

23. Vuong HG, Ngo HT, Bychkov A, Jung CK, Vu TH, Lu KB, et al. Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: a systematic review and meta-analysis. Cancer Cytopathol 2020;128:238-49.

24. Vuong HG, Suzuki A, Na HY, Tuyen PV, Khuy DM, Nguyen HC, et al. Application of the Bethesda System for reporting thyroid cytopathology in the pediatric population. Am J Clin Pathol 2021;155:680-9.

25. Cherella CE, Angell TE, Richman DM, Frates MC, Benson CB, Moore FD, et al. Differences in thyroid nodule cytology and malignancy risk between children and adults. Thyroid 2019;29:1097-104.

26. Bose S, Walts AE. Thyroid fine needle aspirate: a post-Bethesda update. Adv Anat Pathol 2012;19:160-9.

27. Buryk MA, Simons JP, Picarsic J, Monaco SE, Ozolek JA, Joyce J, et al. Can malignant thyroid nodules be distinguished from benign thyroid nodules in children and adolescents by clinical characteristics? A review of 89 pediatric patients with thyroid nodules. Thyroid 2015;25:392-400.

28. Lale SA, Morgenstern NN, Chiara S, Wasserman P. Fine needle aspiration of thyroid nodules in the pediatric population: a 12-year cyto-histological correlation experience at north shore-long island jewish health system. Diagn Cytopathol 2015;43:598-604.

29. Ghanem M, Levy Y, Mazeh H. Preoperative diagnosis of benign thyroid nodules with intermediate cytology. Gland Surg 2012;1:89-91.

30. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94:2092-8.

31. Moses W, Weng J, Sansano I, Peng M, Khanafshar E, Ljung BM, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg 2010;34:2589-94.

32. Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, et al. Impact of the multi-gene thyroseq next-generation sequencing assay on cancer diagnosis in thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology. Thyroid 2015;25:1217-23.

33. Stack BC, Twining C, Rastatter J, Angelos P, Baloch Z, Diercks G, et al. Consensus statement by the American Association of Clinical Endocrinology (AACE) and the American Head and Neck Society Endocrine Surgery Section (AHNS-ES) on pediatric benign and malignant thyroid surgery. Head Neck 2021;43:1027-42.

34. Giles Şenyürek Y, İşcan Y, Sormaz İC, Poyrazoğlu Ş, Tunca F. The role of American Thyroid Association pediatric thyroid cancer risk stratification and BRAFV600E mutation in predicting the response to treatment in papillary thyroid cancer patients ≤18 years old. J Clin Res Pediatr Endocrinol 2022;14:196-206.

35. Vanden Borre P, Schrock AB, Anderson PM, Morris JC, Heilmann AM, Holmes O, et al. Pediatric, adolescent, and young adult thyroid carcinoma harbors frequent and diverse targetable genomic alterations, including kinase fusions. Oncologist 2017;22:255-63.

36. Kazahaya K, Prickett KK, Paulson VA, Dahl JP, Manning SC, Rudzinski ER, et al. Targeted oncogene therapy before surgery in pediatric patients with advanced invasive thyroid cancer at initial presentation: Is it time for a paradigm shift? JAMA Otolaryngol Head Neck Surg 2020;146:748-53.

37. Stosic A, Fuligni F, Anderson ND, Davidson S, de Borja R, Acker M, et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Res 2021;81:5625-37.

38. Ricarte-Filho JC, Franco AT. The evolving genomic landscape of pediatric papillary thyroid cancer. Curr Opin Endocr Metab Res 2023;33:100483.

39. van der Tuin K, Ruano D, Knijnenburg J, van der Luijt RB, Morreau H, Links TP, et al. Clinically relevant germline variants in children with nonmedullary thyroid cancer. J Clin Endocrinol Metab 2024;109:e2214-21.

40. Pekova B, Dvorakova S, Sykorova V, Vacinova G, Vaclavikova E, Moravcova J, et al. Somatic genetic alterations in a large cohort of pediatric thyroid nodules. Endocr Connect 2019;8:796-805.

41. Baran JA, Halada S, Bauer AJ, Ricarte-Filho JC, Isaza A, Surrey LF, et al. Indeterminate thyroid fine-needle aspirations in pediatrics: exploring clinicopathologic features and utility of molecular profiling. Horm Res Paediatr 2022;95:430-41.

42. Rangel-Pozzo A, Sisdelli L, Cordioli MIV, Vaisman F, Caria P, Mai S, et al. Genetic landscape of papillary thyroid carcinoma and nuclear architecture: an overview comparing pediatric and adult populations. Cancers (Basel) 2020;12:3146.

43. Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, et al. NTRK and RET fusion–directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest 2021;131:e144847.

44. Potter SL, Reuther J, Chandramohan R, Gandhi I, Hollingsworth F, Sayeed H, et al. Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma. Pediatr Blood Cancer 2021;68:e28741.

45. Spaulding SL, Maayah M, Dinauer CA, Prasad M, Darbinyan A, Morotti R, et al. Molecular genetics augment cytopathologic evaluation and surgical planning of pediatric thyroid nodules. J Pediatr Surg 2024;59:975-80.

46. Wang Y, Wang H, Tan G, Wu X, Wang B, Tan Z, et al. Application value of multi-gene mutation detection in the clinical management of pediatric papillary thyroid carcinoma: a preliminary exploration. Front Endocrinol (Lausanne) 2024;15:1405142.

47. Franco AT, Ricarte-Filho JC, Isaza A, Jones Z, Jain N, Mostoufi-Moab S, et al. Fusion oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers. J Clin Oncol 2022;40:1081-90.

48. Newfield RS, Jiang W, Sugganth DX, Hantash FM, Lee E, Newbury RO. Mutational analysis using next generation sequencing in pediatric thyroid cancer reveals BRAF and fusion oncogenes are common. Int J Pediatr Otorhinolaryngol 2022;157:111121.

49. Macerola E, Proietti A, Poma AM, Ugolini C, Torregrossa L, Vignali P, et al. Molecular alterations in relation to histopathological characteristics in a large series of pediatric papillary thyroid carcinoma from a single institution. Cancers (Basel) 2021;13.

50. Seminati D, Ceola S, Pincelli AI, Leni D, Gatti A, Garancini M, et al. The complex cyto-molecular landscape of thyroid nodules in pediatrics. Cancers (Basel) 2023;15:3123.

51. Gallant JN, Chen SC, Ortega CA, Rohde SL, Belcher RH, Netterville JL, et al. Evaluation of the molecular landscape of pediatric thyroid nodules and use of a multigene genomic classifier in children. JAMA Oncol 2022;8:1323-7.

52. Mostoufi-Moab S, Labourier E, Sullivan L, LiVolsi V, Li Y, Xiao R, et al. Molecular testing for oncogenic gene alterations in pediatric thyroid lesions. Thyroid 2018;28:60-7.

53. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014;159:676-90.

54. Pekova B, Sykorova V, Dvorakova S, Vaclavikova E, Moravcova J, Katra R, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid 2020;30:1771-80.

55. Cordioli MI, Moraes L, Bastos AU, Besson P, Alves MT, Delcelo R, et al. Fusion oncogenes are the main genetic events found in sporadic papillary thyroid carcinomas from children. Thyroid 2017;27:182-8.

56. Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde C, Voza F, Knauf JA, et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest 2013;123:4935-44.

57. Monaco SE, Pantanowitz L, Khalbuss WE, Benkovich VA, Ozolek J, Nikiforova MN, et al. Cytomorphological and molecular genetic findings in pediatric thyroid fine-needle aspiration. Cancer Cytopathol 2012;120:342-50.

58. Paulson VA, Rudzinski ER, Hawkins DS. Thyroid cancer in the pediatric population. Genes (Basel) 2019;10:723.

59. Guleria P, Srinivasan R, Rana C, Agarwal S. Molecular landscape of pediatric thyroid cancer: a review. Diagnostics (Basel) 2022;12:3136.

60. Colli SL, Boycho ME, Papendieck P, Mangone FM, Chiesa A, García Lombardi M, et al. Prevalent genetic alterations in pediatric thyroid carcinoma: Insights from an Argentinean study. PLoS One 2025;20:e0323271.

61. Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF, Hunt JP. BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. Laryngoscope 2014;124:E389-93.

62. Henke LE, Perkins SM, Pfeifer JD, Ma C, Chen Y, DeWees T, et al. BRAF V600E mutational status in pediatric thyroid cancer. Pediatr Blood Cancer 2014;61:1168-72.

63. Buryk MA, Monaco SE, Witchel SF, Mehta DK, Gurtunca N, Nikiforov YE, et al. Preoperative cytology with molecular analysis to help guide surgery for pediatric thyroid nodules. Int J Pediatr Otorhinolaryngol 2013;77:1697-700.

64. Rossi ED, Larocca LM, Pantanowitz L. Ancillary molecular testing of indeterminate thyroid nodules. Cancer Cytopathol 2018;126 Suppl 8:654-71.

65. Ali SZ, Baloch ZW, Cochand-Priollet B, Schmitt FC, Vielh P, VanderLaan PA. The 2023 Bethesda System for reporting thyroid cytopathology. Thyroid 2023;33:1039-44.

66. Vanderniet JA, Fuentes-Bolanos NA, Cho YH, Tucker KM, Anazodo A, Bauer AJ, et al. Paediatric thyroid carcinoma: the genetic revolution and its implications for therapy and outcomes. Cancers (Basel) 2025;17:1549.

67. Bauer AJ. Thyroid nodules in children and adolescents. Curr Opin Endocrinol Diabetes Obes 2019;26:266-74.

68. Franco AT, Labourier E, Ablordeppey KK, Surrey LF, Mostoufi-Moab S, Isaza A, et al. miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing. Pediatr Blood Cancer 2020;67:e28276.

69. Aekka A, Arva NC, Ren HZ, Raval M, Rastatter J, Finkelstein S, et al. Multiplatform molecular testing as an adjunct to fine needle aspiration in the evaluation of pediatric thyroid nodules. J Clin Endocrinol Metab 2025;110:e3738-44.

70. Hay ID, Gonzalez-Losada T, Reinalda MS, Honetschlager JA, Richards ML, Thompson GB. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg 2010;34:1192-202.

71. Sosa JA, Tuggle CT, Wang TS, Thomas DC, Boudourakis L, Rivkees S, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93:3058-65.

72. Francis GL. Trends in lobectomy for pediatric thyroid cancer. Clin Thyroidol 2022;34:347-50.

73. Banik GL, Shindo ML, Kraimer KL, Manzione KL, Reddy A, Kazahaya K, et al. Prevalence and risk factors for multifocality in pediatric thyroid cancer. JAMA Otolaryngol Head Neck Surg 2021;147:1100-6.

74. Sudoko CK, Jenks CM, Bauer AJ, Isaza A, Mostoufi-Moab S, Surrey LF, et al. Thyroid lobectomy for T1 papillary thyroid carcinoma in pediatric patients. JAMA Otolaryngol Head Neck Surg 2021;147:943-50.

75. Cherella CE, Richman DM, Liu E, Frates MC, Modi BP, Zendejas B, et al. Predictors of bilateral disease in pediatric differentiated thyroid cancer. J Clin Endocrinol Metab 2021;106:e4242-50.

76. Chen J, Huang N, Ji Q, Wang Y, Zhu Y, Li D. Multifocal papillary thyroid cancer in children and adolescents: 12-year experience in a single center. Gland Surg 2019;8:507-15.

77. Scholfield DW, Lopez J, Eagan A, Antal Z, Tuttle RM, Ghossein R, et al. Is multifocality a predictor of poor outcome in childhood and adolescent papillary thyroid carcinoma? J Clin Endocrinol Metab 2023;108:3135-44.

78. Dionigi G, Kraimps JL, Schmid KW, Hermann M, Sheu-Grabellus SY, De Wailly P, et al. Minimally invasive follicular thyroid cancer (MIFTC)--a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg 2014;399:165-84.

79. Nikiforov YE, Baloch ZW, Hodak SP, Giordano TJ, Lloyd RV, Seethala RR, et al. Change in diagnostic criteria for noninvasive follicular thyroid neoplasm with papillarylike nuclear features. JAMA Oncol 2018;4:1125-6.

80. Sugino K, Nagahama M, Kitagawa W, Ohkuwa K, Uruno T, Matsuzu K, et al. Risk stratification of pediatric patients with differentiated thyroid cancer: Is total thyroidectomy necessary for patients at any risk? Thyroid 2020;30:548-56.

81. Su Y, Wang F, Chen S, Yao X. Effects of different surgical approaches on health-related quality of life in pediatric and adolescent patients with papillary thyroid carcinoma. Discov Oncol 2024;15:55.

82. Franco AT, Ricarte-Filho JC, Laetsch TW, Bauer AJ. Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer. J Clin Invest 2021;131:e152696.

83. Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol 2008;21 Suppl 2:S37-43.

84. Armstrong MJ, Yang H, Yip L, Ohori NP, McCoy KL, Stang MT, et al. PAX8/PPARγ rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. Thyroid 2014;24:1369-74.

85. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol 2002;13:3-16.

86. Mitsutake N, Saenko V. Molecular pathogenesis of pediatric thyroid carcinoma. J Radiat Res 2021;62:i71-7.

87. Puliafito I, Esposito F, Prestifilippo A, Marchisotta S, Sciacca D, Vitale MP, et al. Target therapy in thyroid cancer: current challenge in clinical use of tyrosine kinase inhibitors and management of side effects. Front Endocrinol (Lausanne) 2022;13:860671.

88. Colanta A, Lin O, Tafe L, Ghossein R, Nafa K, Mitchell T, et al. BRAF mutation analysis of fine-needle aspiration biopsies of papillary thyroid carcinoma: impact on diagnosis and prognosis. Acta Cytol 2011;55:563-9.

89. Ferraz C. Molecular testing for thyroid nodules: Where are we now? Rev Endocr Metab Disord 2024;25:149-59.

90. Donner JR, DeNardo B, Topor LS. Long-term treatment of pediatric metastatic papillary thyroid cancer with lenvatinib. JCEM Case Rep 2024;2:luad175.

91. Mahajan P, Dawrant J, Kheradpour A, Quintanilla NM, Lopez ME, Orth RC, et al. Response to lenvatinib in children with papillary thyroid carcinoma. Thyroid 2018;28:1450-4.

92. Higuchi Y, Motoki T, Ishida H, Kanamitsu K, Washio K, Oyama T, et al. Sorafenib treatment for papillary thyroid carcinoma with diffuse lung metastases in a child with autism spectrum disorder: a case report. BMC Cancer 2017;17:775.

93. Iyer P, Mayer JL, Ewig JM. Response to sorafenib in a pediatric patient with papillary thyroid carcinoma with diffuse nodular pulmonary disease requiring mechanical ventilation. Thyroid 2014;24:169-74.

94. Pérot G, Soubeyran I, Ribeiro A, Bonhomme B, Savagner F, Boutet-Bouzamondo N, et al. Identification of a recurrent STRN/ALK fusion in thyroid carcinomas. PLoS One 2014;9:e87170.

95. Nikitski AV, Condello V, Divakaran SS, Nikiforov YE. Inhibition of ALK-Signaling overcomes STRN-ALK-induced downregulation of the sodium iodine symporter and restores radioiodine uptake in thyroid cells. Thyroid 2023;33:464-73.