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Risk Stratification of Indeterminate Thyroid Nodules (TIR3A vs. TIR3B): Impact of NIFTP Reclassification in a
Pietro De Luca1, Giulia Chiappino2, Luca de Campora3
1Laboratory of Neuromotor Physiology, IRCSS Foundation Santa Lucia, 00179, Rome, Italy.
Background:
Indeterminate thyroid nodules classified as TIR3 according to the SIAPEC-IAP classification represent a heterogeneous group with variable malignancy risk, complicating clinical management. The reclassification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has further influenced risk estimates.
Methods:
We conducted a retrospective single-center study including adult patients who underwent ultrasound-guided fine-needle aspiration cytology followed by thyroid surgery between January 2016 and September 2025. Cytological diagnoses were classified according to the SIAPEC-IAP system and correlated with final histology. Ultrasound risk stratification was performed according to EU-TIRADS criteria. Risk of malignancy (ROM) and cytology-histology concordance were assessed, including the impact of NIFTP reclassification.
Results:
A total of 228 patients were included, with an overall malignancy rate of 27.6%. TIR3A nodules showed a significantly lower ROM than TIR3B (15.6% vs. 48.7%), decreasing to 12.5% and 41.4%, respectively, after exclusion of NIFTP. Cytology-histology agreement was substantial (κ = 0.72). Ultrasound features associated with malignancy included microcalcifications, irregular margins, taller-than-wide shape, and EU-TIRADS ≥4. The BRAF V600E mutation was significantly associated with malignant histology.
Conclusions:
TIR3A and TIR3B nodules exhibit markedly different malignant potential and should not be managed as a homogeneous group. NIFTP significantly modifies malignancy risk estimates and represents an important source of potential overtreatment. Integration of cytological subclassification with ultrasound and molecular findings improves preoperative risk stratification and supports personalized management of indeterminate thyroid nodules.
