Evolving trends in pediatric thyroid nodules and cancer management
Article information
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.
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.
Previous and 2023 versions of Bethesda System for Reporting Thyroid Cytopathology Diagnostic Category (BSRTC)
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].
Reported frequencies of molecular alterations in pediatric differentiated thyroid cancer
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].
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.
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;