# Clinicopathological and sonographic characterization of NTRK-fusion papillary thyroid carcinoma based on preoperative molecular testing: a comparative study with BRAFV600E PTC

## TL;DR

This study compares the characteristics of NTRK-fusion and BRAFV600E papillary thyroid carcinomas, highlighting differences in age, tumor size, lymph node metastasis, and ultrasound features.

## Contribution

The study systematically characterizes NTRK-fusion PTC in an unselected population and compares it with BRAFV600E PTC for the first time.

## Key findings

- NTRK-fusion PTC is associated with younger age, larger tumor size, and higher lymph node metastasis rates compared to BRAFV600E PTC.
- NTRK-fusion PTC shows distinct sonographic features like isoechogenicity and microcalcifications more frequently than BRAFV600E PTC.
- NTRK1-fusion PTCs have a higher frequency of bilateral lobe involvement compared to NTRK3-fusion PTCs.

## Abstract

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.

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.

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).

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.