Preoperative Co‐Mutation of BRAF V600E and TERT Promoter Predicts Tumor Aggressiveness and Recurrence‐Free Survival in Papillary Thyroid Carcinoma

Background The individual prognostic impacts of BRAF V600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) are established, but the clinical significance of their co‐occurrence, especially when assessed preoperatively, requires further elucidation. Objective To evaluate the clinicopathological features and recurrence risk associated with the combined BRAF V600E /TERT mutation in PTC using preoperative specimens. Methods This retrospective study included 756 PTC patients. Mutations were detected from preoperative fine‐needle aspiration (FNA) samples. Patients were stratified into three groups: double wild‐type (BRAF−/TERT−, n = 121), BRAF‐mutant only (BRAF+/TERT−, n = 606), and both‐mutant (BRAF+/TERT+, n = 27). Clinicopathological comparisons used appropriate statistical tests. Risk factors for extrathyroidal extension (ETE) and high nodal burden (NLNM ≥ 5) were analyzed via univariate and multivariate logistic regression. Recurrence‐free survival (RFS) was assessed by Kaplan–Meier analysis and log‐rank test. Results The BRAF+/TERT+ group exhibited the most aggressive phenotype: older age (mean 55.2 vs. 41.9–42.7 years, p < 0.001), larger tumors (median 20.0 vs. 8.7–9.3 mm, p < 0.001), highest rates of ETE (85.2% vs. 10.7%–14.0%, p < 0.001), and heaviest nodal burden (NLNM ≥ 5: 63.0% vs. 25.4%–31.4%, p < 0.001). In multivariate analysis, the double‐mutant status was the strongest independent risk factor for both ETE (OR = 11.35; p < 0.001) and NLNM ≥ 5 (OR = 8.02; p = 0.044). With a median follow‐up of 27 months, Kaplan–Meier analysis revealed a significantly inferior RFS for the BRAF+/TERT+ group compared to the others (log‐rank p < 0.001). In contrast, the only BRAF‐mutant group exhibited fewer aggressive features, primarily associated with a higher body mass index (BMI) and lower prevalence of Hashimoto's thyroiditis. Conclusion BRAF V600E and TERT promoter co‐mutation, identifiable preoperatively, defines a distinct PTC subtype with a profoundly aggressive clinicopathological profile and a significantly elevated risk of recurrence. This combined molecular signature is a potent preoperative biomarker for stratifying patients into the highest‐risk category, potentially guiding more individualized initial therapeutic strategies.