Clinicopathologic Characteristics of Thyroid Nodules Positive for the THADA-IGF2BP3 Fusion on Preoperative Molecular Analysis

Background: Thyroid adenoma-associated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms. However, the prevalence of this gene fusion and associated phenotypical and clinical features are not well defined. The aim of this study was to characterize thyroid nodules positive for THADA-IGF2BP3 fusions on preoperative molecular analysis, review surgical outcomes, and explore potential impact of the fusion detection on patient management. Methods: Thyroid nodules positive for THADA-IGF2BP3 fusion on ThyroSeq v3 genomic classifier (GC) testing of fine needle aspiration (FNA) (n = 30) samples from November 2017 to August 2019 were identified. Demographic and clinical data were obtained by retrospective chart review; pathology slides were re-examined. Results: Thirty nodules positive for THADA-IGF2BP3 fusion on FNA were identified, representing ∼2% of 1280 nodules that underwent molecular analysis. Of the 27 nodules with available cytology diagnosis data, 22 (81%) were diagnosed as atypia of undetermined significance, 3 (11%) as follicular neoplasm, and 1 (4%) each were benign, and suspicious for malignancy. No additional mutations or gene fusions were identified in any of the nodules. Of the 24 cases with available clinical data, 22 (92%) THADA-IGF2BP3-positive nodules were managed surgically, 14 (64%) by thyroid lobectomy, and 8 (36%) by total thyroidectomy. Of the patients who had initial lobectomy, 3 (21%) had completion surgery. On surgical pathology, 7 (32%) THADA-IGF2BP3-positive nodules were malignant (six encapsulated follicular variant papillary thyroid carcinomas (EFVPTC), one minimally infiltrative FVPTC), 10 (45%) noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 5 (23%) follicular adenomas (FA). THADA-IGF2BP3-positive malignancies were intrathyroidal, without aggressive histology. Nodule size was similar between malignant nodules, NIFTP, and FA (2.6, 2.7, and 2.3 cm, respectively; p = 0.77). On limited follow-up (mean, 18 months) available for six patients with malignant fusion-positive nodule and 4 patients with NIFTP, no tumor recurrences were found. Conclusions: In this series of patients, 77% of THADA-IGF2BP3 fusion-positive thyroid nodules were thyroid tumors requiring surgery, either papillary carcinoma or NIFTP. However, all cancers were low risk, predominantly encapsulated FVPTCs and thus can likely be adequately treated with lobectomy.