Abstract
BACKGROUND: While bilaterality is a frequent characteristic of papillary thyroid carcinoma (PTC), its prognostic implications in the context of BRAF genetic heterogeneity remain undefined. This study investigates the synergistic prognostic value of tumor bilaterality and BRAF mutation status in PTC recurrence risk stratification. METHODS: We retrospectively reviewed 974 consecutive PTC patients who were surgically treated in the First Affiliated Hospital of Zhejiang University School of Medicine. Genomic DNA was extracted from fresh frozen tumor tissues. The BRAF mutation status was confirmed by Sanger sequencing. The cases were analyzed for various histologic and clinical parameters in order to determine the correlation between bilaterality and risk of recurrence in the different BRAF statuses. RESULTS: Overall, bilaterality was associated with larger tumor size, gross extrathyroidal extension (ETE), and lymph node metastasis. Bilateral PTCs had a higher risk for recurrence (9.8% vs. 4.9%, p = 0.014) but did not retain significance after multivariable adjustment. In BRAF-mutant patients, bilaterality was strongly associated with aggressive features such as larger tumor size, gross ETE, and lymph node metastasis and could serve as an independent risk factor for recurrence, corresponding to an HR of 2.23 (95% CI: 1.65,4.76; p = 0.020). BRAF-mutant patients with bilateral tumors also exhibited a high recurrence rate of 10.3%. Notably, this effect was exclusively observed in BRAF-mutant patients. Among these patients, the combination of bilaterality and large tumor size (> 10 mm) identified the highest-risk subgroup, with a disease-free survival (DFS) rate of only 86%. In contrast, these associations were not observed in BRAF wild-type patients, regardless of tumor size or laterality. CONCLUSIONS: The current study provides initial evidence that tumor bilaterality serves as a BRAF genotype-dependent prognostic marker, revealing its synergistic effect with BRAF mutation in predicting PTC recurrence. Its prognostic value is further amplified by large tumor size, with the coexistence of bilaterality and large tumor diameter identifying a distinct high-risk population, exclusively among BRAF-mutant patients. Incorporating BRAF status into the assessment of patients with bilateral PTC, particularly those with larger tumors, may refine postoperative risk stratification and facilitate more tailored surveillance strategies.