Clinicopathological and Sonographic Characterization of NTRK-Fusion Papillary Thyroid Carcinoma Based on Preoperative Molecular Testing: A Comparative Study with BRAFV600E PTC

Abstract

Background: NTRK fusions are relatively rare in papillary thyroid carcinoma (PTC), and their clinicopathological characteristics, particularly in unselected populations and in comparison with BRAFV600E PTC, have not been systematically elucidated. Methods: In this retrospective study, we analyzed PTC patients who underwent surgery between October 2022 and May 2025. All patients underwent preoperative fine-needle aspiration biopsy and multigene molecular testing. Ultimately, 38 patients with NTRK-fusion PTC and 1196 patients with BRAFV600E PTC were included. A comprehensive analysis of the clinical, ultrasonographic, and pathological features of NTRK-fusion PTC was conducted, with comparison to BRAFV600E PTC. Results: Among the 38 identified NTRK-fusion PTC patients, NTRK3 (81.6%) was the predominant fusion type. Histologically, classical PTC and mixed growth patterns with follicular architecture (34.2% each) were most frequent, followed by the follicular variant (18.4%). NTRK-fusion PTC demonstrated a high rate of lymph node metastasis (LNM) (78.9%). Among preoperative parameters, a tumor diameter >12 mm on ultrasound was associated with increased risk of lateral LNM (OR=5.00, 95% CI: 1.10-22.82; P=0.038). Besides, NTRK1-fusion PTCs demonstrated a significantly higher frequency of bilateral lobe involvement compared to NTRK3-fusion PTCs (57.1% vs. 12.9%, P=0.025). Compared to patients with BRAFV600E PTC, those with isolated NTRK-fusion (n=34) were significantly younger (median age: 35.0 vs 43.0 years), had larger tumors (median diameter: 10.5 vs 7.0 mm), higher rates of LNM (76.5% vs 50.7%), and greater prevalence of co-existing Hashimoto's thyroiditis (61.8% vs 28.3%) and follicular nodular disease (26.5% vs 10.6%) (all P<0.01). Cytopathologically, NTRK-fusion PTC demonstrates a higher proportion of atypia of undetermined significance/ follicular neoplasm compared to BRAFV600E PTC (41.2% vs. 16.1%). Sonographically, isoechogenicity (20.6% vs. 7.9%), microcalcifications (79.4% vs. 58.0%), and a wider-than-tall shape (91.2% vs. 52.5%) were more frequently observed in the NTRK-fusion group (all P<0.05). Conclusions: NTRK-fusion defines a distinct PTC molecular subtype characterized by a high burden of LNM and a spectrum of features linked to follicular growth patterns. These findings facilitate the preoperative identification of this tumor subtype and provide a foundation for individualized risk stratification and tailored management strategies.