THADA-IGF2BP3 gene fusions in thyroid fine needle aspiration is involved in the pathway to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features".

Background: The increased usage and adaptation of molecular testing of thyroid fine needle aspirations (FNA) has expanded the variety and number of gene fusions identified. While the identified number of molecular alterations is increasing, the definitive association between preoperative molecular analysis and phenotype has yet to be established. The aim of this study was to examine Thyroid adenoma-associated (THADA)-IGF2BP3 molecular fusions with FNA categorization, surgical pathology diagnosis, and other molecular alterations detected by ThyroSeq Genomic Classifier testing.

Methods: FNA cytology samples of thyroid nodules from 04/2017 to 01/2023 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) or follicular neoplasm suspicious for follicular neoplasm (FN/SFN; Bethesda IV) with associated ThyroSeqV3 testing were reviewed. Parameters including patient demographics, FNA diagnosis, ThyroSeq V3 results, and surgical pathology follow up were examined.

Results: 87 out of 249 (35%) FNA specimens of thyroid nodules displayed molecular alterations. 64 cases (74%) had a cytology diagnosis of AUS and 23 (26%) had FN. RAS mutation was observed in 48 cases. On surgical follow-up, 17 (35%) cases showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), while 14 (29%) patients had a malignant diagnosis. THADA-IGF2BP3 fusions were seen in 8 cases, all with NIFTP on surgical pathology follow-up (100%).

Conclusions: Analysis of THADA-IGF2BP3 fusion, in our institutional series, shows close association with NIFTP cases. THADA-IGF2BP3 fusion, which seems to be a favorable prognostic indicator in general, may serve as a molecular marker for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).