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

BACKGROUND: Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine needle aspiration (FNA) 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 in pediatric differentiated TC (DTC) to determine associations with histologic and clinical features.

METHODS: A retrospective review identified all patients (age <19 years) diagnosed with DTC from 2001-2017 at the University of Pittsburgh Medical Center. Histology was re-reviewed to confirm diagnosis and identify tissue for MT using next-generation sequencing (ThyroSeq version 3, TSv3). Correlation with histologic and clinical features was analyzed using regression analysis.

RESULTS: Of 71 patients with MT results, 62 (87%) of patients had papillary TC. All patients were alive at a median follow-up of 6 years (range 18 days-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 (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 undergoing surgery for recurrence over time (HR: 19.5, p=0.004).

CONCLUSIONS: Among our cohort of pediatric TC patients with 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 initial operation in pediatric patients (age<19 years) with TC.