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 six
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 five out of six
tumors showed
tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (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 five cases which confirmed all hotspot mutations and detected two
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 five patients, three patients died of disease 8-24 months after diagnosis, whereas two 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 counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid
tumors with DICER1 mutations reported to date.