Paediatric Thyroid Carcinoma: The Genetic Revolution and Its Implications for Therapy and Outcomes

Abstract

Background: The understanding of the molecular basis of paediatric thyroid carcinoma has expanded rapidly in the last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, paediatric carcinomas are less commonly associated with point mutations and more commonly with gene fusions, which are characterised by more-invasive disease. Cancer predisposition genes play an important role in a small percentage of tumours, and the family history and the recognition of other syndromic features are key to identifying these patients. Molecular testing platforms for clinical use have been developed and validated in adults, and their use is becoming established in the management of indeterminate thyroid nodules, where they significantly reduce the rates of diagnostic lobectomy. Paediatric data are more limited than adult data, and the role of molecular testing in paediatric thyroid carcinoma management is evolving. Methods: This review describes the current knowledge of molecular alterations in paediatric thyroid carcinomas, evidence supporting molecular testing in clinical practice, and future directions for research. Results and Conclusions: A molecular diagnosis enables the use of molecularly targeted therapies for children and adolescents with advanced or radioiodine-refractory disease. There is also great potential for molecular testing to improve the accuracy of the risk-stratification of paediatric thyroid nodules, reducing surgical intervention and complications without negatively impacting outcomes, and data to support such an approach are emerging.

Keywords: cancer predisposition syndrome; molecularly targeted therapy; thyroid nodule risk-stratification.

Figure 1

The incorporation of pre-operative molecular data across the 3-tiered paediatric risk of invasive behaviour of differentiated thyroid carcinomas to stratify the surgical management of a thyroid nodule. High-grade histologic features include solid, trabecular, or insular growth patterns; a mitotic index of ≥ 3 per 10 high power fields; necrosis; and convoluted nuclei. Reprinted with permission from Ref. [77]. 2025, Oxford University Press. PEF: punctate echogenic foci; TBSRTC: The Bethesda System for Reporting Thyroid Cytopathology; US: ultrasound.