Unique Molecular Signatures Are Associated with Aggressive Histology in Pediatric Differentiated Thyroid Cancer

Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine-needle aspiration biopsy, reducing the need for diagnostic lobectomy in adult patients with indeterminate nodules (Bethesda class III/IV). However, little is known about genetic alterations in pediatric thyroid carcinoma (TC). Our aim was to analyze MT results of pediatric differentiated TC (DTC) cases to determine associations with histological and clinical features. A retrospective review identified all patients (aged <19 years) diagnosed with DTC from 2001 to 2017 at the University of Pittsburgh Medical Center. Histology was rereviewed to confirm diagnosis and identify tissue for MT using next-generation sequencing (ThyroSeq, version 3, TSv3). Correlation with histological and clinical features was analyzed using regression analysis. Of 71 patients with MT results, 62 (87%) patients had papillary TC. All patients were alive at a median follow-up of 6 years (range 18 days to 18 years). Genetic alterations were identified in 65 (92%) patients. These alterations were grouped as BRAF-like point mutations or fusions (39, 55%), RAS-like mutations or fusions (21, 30%), or copy number alterations (5, 7%). On multiple regression analysis accounting for patient sex and tumor size in patients with papillary TC, increased tumor stage (β: 0.234, p < 0.001), multifocal disease (odds ratio [OR]: 3.60, p = 0.042), and lymph node metastases (OR: 6.13, p = 0.044) were associated with BRAF-like gene fusions. When considering individual mutations, ETV6/NTRK3 fusions were associated with increased tumor stage (β: 2.07, p = 0.023) and BRAF-like point mutations were associated with increased likelihood of surgery for recurrence over time (hazard ratio: 19.5, p = 0.004). Among our cohort of pediatric TC patients who underwent comprehensive MT, >90% had an identifiable genetic alteration. Aggressive features were primarily associated with BRAF-like gene fusions. Preoperative MT results may be useful in guiding the extent of the initial operation in pediatric patients (aged <19 years) with TC.