Clinical Significance of Thyroid Nodules Below Recommended Biopsy Thresholds: A Real‐World Cytopathologic Analysis
Charalampos Milionis, Aikaterini Michou, Anastasia Lekkou, Sofia Makrydima, Evaggelia Venaki, Ioannis Ilias, Eftychia KoukkouABSTRACT
Background
Thyroid nodules are common in clinical practice, with most being benign despite the increasing incidence of thyroid cancer. The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI‐RADS) is widely used to stratify malignancy risk and guide fine‐needle aspiration (FNA) decisions based on ultrasound features and size thresholds. However, concerns exist that nodules below these thresholds may still harbor clinically significant disease. The present study aimed to evaluate the prevalence of clinically significant cytopathologic findings in thyroid nodules that did not meet ACR TI‐RADS biopsy criteria but underwent FNA, and to investigate the clinical rationale for performing biopsy in these cases. This study was designed to evaluate a selected subgroup of guideline‐discordant biopsies rather than the overall diagnostic performance of the ACR TI‐RADS system.
Methods
This retrospective observational research included 163 thyroid nodules from 163 patients who underwent ultrasound‐guided FNA between 2018 and 2025. All nodules were below ACR TI‐RADS size thresholds for biopsy. Cytology was classified using the Bethesda System. Primary outcome was the prevalence of clinically significant cytology (Bethesda V–VI), and secondary outcomes included expanded clinically relevant cytology (Bethesda III–VI), histopathologic findings, tumor staging, and indications for biopsy. Statistical analysis included descriptive statistics and Fisher's exact test.
Results
Bethesda V–VI and III–VI cytology was identified in 9.8% and 20.2% of nodules, respectively. Malignancy was observed across TI‐RADS categories, including 3.1% of TI‐RADS 3, 17.7% of TI‐RADS 4, and 66.7% of TI‐RADS 5 nodules. Among 23 surgically resected nodules, 20 were confirmed malignant. Most of them were early‐stage tumors, although some exhibited nodal involvement or local advancement. No specific biopsy rationale was significantly associated with malignancy.
Conclusions
Thyroid nodules below ACR TI‐RADS biopsy thresholds may still harbor clinically significant cytopathology. While TI‐RADS remains a useful risk stratification tool, reliance solely on size‐based thresholds may lead to missed malignancies. Selective use of FNA based on clinical judgment and additional risk factors may improve early detection. These findings should be interpreted within the context of a selected cohort of nodules that underwent biopsy despite not meeting ACR TI‐RADS size criteria and should not be construed as an assessment of the overall performance of the ACR TI‐RADS system.