Poorly differentiated thyroid carcinoma of childhood and adolescence: A distinct entity characterized by DICER1 mutations

Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of 6 PDTC in patients ≤ 21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole exome sequencing (WES). All tumors had solid, insular or trabecular growth pattern and high mitotic rate, and 5 out of 6 tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in 5 of 6 (83%) tumors, all of which were “hotspot” mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in 5 cases which confirmed all hotspot mutations and detected 2 tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC and other) were detected. On follow-up, available for 5 patients, 3 patients died of disease 8-24 months after diagnosis, whereas 2 were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counselling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.