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 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.

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Fig. 1: Histologic features of the poorly differentiated thyroid carcinomas.
Fig. 2: Both Case 3 and Case 6 showed poorly differentiated thyroid carcinomas arising in encapsulated follicular variant of papillary thyroid carcinoma.
Fig. 3: RNase IIIb and non-RNase IIIb domain DICER1 somatic mutations.
Fig. 4: One germline mutation involving a cryptic splice site in intron 6 was found in Case 2.


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This work was funded by the CIHR Foundation Grant FDN-148390 to WDF and the National Institutes of Health grant CA181150 to YEN. BR is a Young Investigator from the ALSF and the Mina Neri Foundation for Childhood Cancer.

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Correspondence to Rebecca D. Chernock or Yuri E. Nikiforov.

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YEN owns intellectual property and receives royalties related to ThyroSeq. TJG is a Consultant for Interspace Diagnostics. All other authors have nothing to disclose.

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Chernock, R.D., Rivera, B., Borrelli, N. et al. Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations. Mod Pathol (2020) doi:10.1038/s41379-020-0458-7

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