Testing insulin-like growth factor messenger RNA-binding protein 3 as a surrogate immunohistochemical marker for indeterminate thyroid nodules with THADA fusion in both cytologic and surgical specimens.

BACKGROUND: Thyroid adenoma-associated (THADA) gene fusions are recurrent alterations in thyroid nodules that lead to the overexpression of insulin-like growth factor messenger RNA-binding protein 3 (IMP3). Although IMP3 immunohistochemistry has been studied in thyroid tumors, its utility for detecting THADA fusion-positive thyroid specimens remain unassessed.

METHODS: The authors evaluated IMP3 expression in cytologic and surgical specimens from 20 indeterminate thyroid nodules. Eleven cases harbored THADA fusions, including THADA::IGF2BP3 (n = 9) and THADA::TRA2A (n = 2), whereas nine control cases lacked detectable THADA fusions. Hematoxylin-and-eosin staining and immunohistochemistry for IMP3 and NRAS Q61R were performed on available cell blocks and surgical specimens. Staining was scored based on extent and intensity, with a composite score >2 considered positive.

RESULTS: All nodules with THADA fusions exhibited strong, diffuse, cytoplasmic IMP3 staining in lesional follicular cells, with no staining in adjacent normal thyroid tissue. All control cases were negative for IMP3. NRAS Q61R immunostaining was negative across all cases.

CONCLUSIONS: The current findings in a limited cohort demonstrate that IMP3 is a promising surrogate marker for indeterminate thyroid nodules with THADA fusions in both cytologic and surgical specimens. In addition, IMP3 staining may aid in detecting subtle capsular or vascular invasion.