Thyroid Nodules of Uncertain Malignant Potential Non-Conforming to World Health Organization Diagnostic Criteria - Clinicopathologic and Molecular Characterization of 39 Cases.

Thyroid tumors of uncertain malignant potential (UMP) are recognized by the World Health Organization (WHO) as tumors of borderline malignancy, encompassing follicular tumor of uncertain malignant potential (FT-UMP) and well-differentiated tumor of uncertain malignant potential (WDT-UMP). Tumors classified as UMP have questionable capsular invasion (CI) and/or angioinvasion (AI); however, biological uncertainty extends beyond the possibility for invasiveness alone. We conducted a retrospective, single-center study of all thyroid tumors diagnosed as UMP (2005-2025). Upon review of our institutional UMP cohort, we identified 39 tumors that lack questionable CI and/or AI, and therefore, would not meet WHO-defined UMP criteria. This retrospective analytic group of borderline thyroid nodules (BTN) was used to interrogate the overlap between non-invasive follicular-patterned thyroid lesions and worrisome morphologic and/or molecular features. BTN show features of neoplasia (solid growth or microfollicular architecture, papillary thyroid carcinoma (PTC)-like nuclear atypia, oncocytic morphology, conspicuous mitoses, and/or abnormal molecular results) with or without procedural artifacts (mechanically disrupted capsule, squamous metaplasia or ischemic necrosis). BTN were diagnosed in 0.1% of thyroid surgeries; median age 55 years and 1.3:1 female-to-male ratio. Median tumor size was 4 cm. RAS or RAS-like variants were most frequent (25%), followed by gene fusions (10%). Negative molecular testing was identified in 10% of BTN and high-risk gene alterations, including TERT promoter and PIK3CA, were seen in 20%. Most patients underwent hemithyroidectomy (62%), with median follow-up of 2.5 years (range 1-12.5 years), and no recurrences or metastases were documented. Our findings suggest indolent behavior of BTN and support conservative management, such as hemithyroidectomy. Longer-term, multi-institutional studies will refine risk stratification and management strategies, with possible consideration for expanding UMP diagnostic criteria.