Multinodular Goiter Progression Toward Malignancy in a Case of DICER1 Syndrome

Abstract

Objectives: Multinodular goiter (MNG) and welldifferentiated thyroid carcinoma (WDTC) are emerging phenotypes of DICER1 syndrome. Methods: Histologic and molecular fndings of botryoidtype embryonal rhabdomyosarcoma (bERMS) and thyroid nodules from a 12-year-old DICER1 mutation carrier (p.Arg1060Ilefs∗7) were investigated, providing interesting clues for understanding thyroid carcinogenesis. Results: The patient had bERMS at age 7 years. The thyroid was enlarged and multinodular (61 g). Histologically, some nodules were classifed as adenomatous and others as tumors with "intermediate" nuclei. One displayed vascular invasion and was classifed as WDTC not otherwise specifed (NOS). Somatic DICER1 mutations were identifed in bERMS, two tumors with "intermediate" nuclei and WDTC. No somatic DICER1 mutations were found in adenomatous nodules. No molecular alterations were detected in BRAF600, NRAS61, HRAS12/61, KRAS12/61, TERT promoter, RET/PTC1, RET/PTC3, and PAX8/PPARγ. Conclusions: The fndings obtained from this single case support the assumption that DICER1 syndrome-related WDTC NOS may develop on a background of MNG, via a stepwise process, involving DICER1 somatic mutations and additional molecular events, distinct from the classic pathways of papillary/follicular carcinoma.