Can TP53-mutant follicular adenoma be a precursor of anaplastic thyroid carcinoma?

Abstract

Mutations of the\xa0TP53\xa0tumor suppressor gene are highly prevalent in thyroid\xa0anaplastic carcinomas (AC) but are also reported in some well-differentiated cancers and even benign adenomas. The natural history of\xa0TP53-mutant\xa0adenomas, and whether they may represent a precursor for well-differentiated cancer or AC is largely unknown. Similarly, the frequency of\xa0TP53\xa0mutations in thyroid nodules found on routine molecular analysis of\xa0fine-needle aspiration (FNA) samples is not established.\xa0A\xa0database\xa0on 44,510\xa0FNA samples from thyroid nodules with predominantly indeterminate cytology\xa0tested using ThyroSeq v3 was reviewed to identify\xa0TP53-mutant\xa0cases and analyze their genetic profile and available\xa0clinicopathological findings.\xa0Among\xa0260 (0.6%)\xa0selected\xa0thyroid nodules, 36\xa0had\xa0an isolated\xa0TP53\xa0mutation, and 224\xa0carried a combination of\xa0TP53with other genetic alterations. No\xa0significant difference was observed between these groups with respect to patient age, gender, nodule size, and spectrum of\xa0TP53mutations.\xa0Histopathologically,\xa086% of the\xa0resected nodules\xa0with isolated\xa0TP53mutations were benign (mostly adenomas), whereas 82% of nodules carrying\xa0TP53mutations\xa0co-occurring\xa0with other alterations were cancers (P=0.001), including\xa0de-differentiated\xa0AC.\xa0TP53-mutant benign tumors and well-differentiated cancers often had scattered single neoplastic cells with\xa0bizarre\xa0nuclei resembling those comprising AC.\xa0Our\xa0study demonstrates that a small but distinct proportion of thyroid nodules carry a\xa0TP53mutation, either as a single genetic event or in combination with other alterations.\xa0While the latter are mostly cancers prone\xa0to dedifferentiation, there is at least a theoretical possibility that\xa0TP53-mutated adenomas may represent a precursor for such cancers, including AC.