Uncommon molecular alterations in follicular-derived thyroid carcinoma: A single institution study

Thyroid carcinomas are the most common endocrine malignancy and commonly have alterations in the mitogenactivated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathways in welldifferentiated tumors. Alternative molecular alterations driving thyroid carcinomas have been identified rarely in the literature and are more likely to occur in poorly differentiated or anaplastic cases. In this study, uncommon genetic alterations such as MLH1 , MSH2 , NSD3::NUTM1 , RET::SPECC1L , and G3BP2::FGFR2 were identified in patients with papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and differentiated high-grade thyroid carcinoma. Most of these tumors demonstrated an aggressive biological behavior. Atypical driver mutations in thyroid carcinomas can occur in patients with cancer predisposition syndromes as demonstrated by an NTRK1::TPM3 fusion in a patient with Li Fraumeni syndrome. In these settings of more aggressive disease, molecular testing targeting actionable fusions and mutations is important. As demonstrated in our case cohort, 100% of cases diagnosed as high-grade follicular -derived thyroid carcinoma had a mutation or fusion that is associated with worse prognosis, has a germline syndrome association requiring further work up, or an actionable mutation. This high yield seen in this cohort for molecular testing in patients with high-grade follicular -derived thyroid carcinoma suggests more routine molecular testing in this population would be a beneficial clinical practice.