Cytologic Sub‐Categorization of Bethesda Category IV Nodules Has Significant Clinicopathologic Outcomes

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Abstract
Objective: Fine‐needle aspiration (FNA) is central to evaluation of thyroid nodules, yet risk stratification for follicular neoplasm categorized as Bethesda IV (FN/SFN) remains challenging due to substantial cytologic overlap and evolving diagnostic criteria. This study assesses whether subclassifying FN/SFN cases by nuclear atypia, oncocytic features, together with molecular testing, improves risk of malignancy (ROM) estimation and clinical decision‐making. Methods: This was a retrospective review of thyroid FNAs classified as Bethesda Category IV at our institution from January 2015 to December 2024. FN/SFN cases were subcategorized as FN/SFN, FN/SFN with PTC‐like nuclear features (FN/SFN‐PTC) and oncocytic follicular neoplasm (FN/SFN‐O). Risk of malignancy (ROM) was calculated for each subcategory and correlated with surgical resections when available. Molecular testing results, including mutational analysis and molecular risk, were extracted from Afirma and ThyGeNEXT/ThyraMIR. Chi‐squared analysis was used for statistical analysis with p < 0.05 being significant. Results: Of 13,865 thyroid FNAs, 449 (3.2%) were classified as Bethesda Category IV; 146 had surgical follow‐up (1.1%). FN/SFN‐PTC demonstrated the highest ROM (50.3%) and neoplastic rate (78.1%; p = 0.03). RAS‐like mutations were the most common molecular alteration (27.4%), but were not significantly predictive of malignancy. BRAF‐like alterations were exclusive to FN/SFN‐PTC and all BRAF‐like cases were malignant. FN/SFN‐O showed elevated ROM and neoplastic rate compared with conventional FN. FN/SFN‐O had the highest proportion of mutation‐negative cases (89.4%; p < 0.05); however, 40% of mutation‐negative FN/SFN‐O cases were malignant on surgical resection. Conclusions: Cytologic subcategorization of Bethesda Category IV thyroid FNA specimens provides clinically meaningful and statistically significant risk stratification. PTC‐like nuclear atypia is associated with higher ROMs and neoplastic rates. Oncocytic features show distinct molecular characteristics in which mutation‐negative status does not reliably exclude malignancy, highlighting a diagnostic challenge. Molecular testing complements cytologic subcategorization.

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