IGF2BP3-Overexpressing Follicular Cell-derived Thyroid Tumors Consist of Low-risk Follicular Patterned Tumors with Frequent HBME-1 Negativity and Distinct Cytomorphologic Features.

Abstract

Thada: IGF2BP3 fusion results in IGF2BP3 (IMP3) overexpression, driving a subset of RAS-like indolent thyroid tumors, typically noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) or minimally invasive encapsulated follicular variant of papillary thyroid carcinoma (miEFVPTC). These also have distinct morphologic features that have yet to be characterized. We assessed 51 cases of surgically resected thyroid nodules with IMP3 positivity or IGF2BP3 overexpression (IMP3+) and compared them to 113 pathologically similar cases without IMP3 positivity (IMP3-) within the same time frame (2014-2025). IMP3+ cases were diagnosed as miEFVPTC (n=36), NIFTP (n=14), with only one follicular adenoma. On comparative morphologic analysis, key features selectively noted in IMP3+ tumors included: low power "pale blue" optical clarity, condensation of cellularity at the nodule periphery, microfollicles interspersed between macrofollicles, perifollicular sclerosis, clear cytoplasm, perinuclear indentation by cytoplasmic vacuoles, "squared-off" nuclei, prominent single nuclear grooves, grade 3 nuclei, and background chronic lymphocytic thyroiditis. Oncocytic cytoplasm and solid/trabecular/insular growth were exclusive to the IMP3- group. Only one of 34 (2.9%) tested cases was weakly HBME-1 positive in the IMP3+ group. A multiple logistic regression model predicting IMP3 status included microfollicles interspersed between macrofollicles, clear cytoplasm, perinuclear indentation by cytoplasmic vacuoles, "squared-off" nuclei, and background chronic lymphocytic thyroiditis (AUC: 0.957, AIC: 63.858, BIC: 81.109). Adding HBME-1 status resulted in a slightly more discriminatory model (AUC: 0.987, AIC: 58.087, BIC: 78.214). No significant difference in disease-free survival was observed between IMP3+ and IMP3- groups (log-rank p = 0.348), although analysis was limited by short follow-up and very few events. In the IMP3+ group (median follow up: 23.3 months), one case recurred 155 months after incomplete excision. IMP3-positive/IGF2BP3-overexpressing thyroid tumors have a RAS-like profile and likely indolent clinical behavior. We demonstrate that they have distinct cytomorphologic features that allow for recognition. The exaggerated overt nuclear features may lead to misclassification as more aggressive subtypes (i.e. conventional). HBME-1 negativity is characteristic and can aid in recognition of IMP3+ tumors.