PURPOSE: Traditional methods, fine-needle aspiration cytology (FNAC) and washout thyroglobulin (Tg), do not always provide sufficient accuracy for diagnosing lymph node (LN) metastasis in thyroid cancer. This study aimed to validate the diagnostic performance of washout cytokeratin fragment 21-1 (CYFRA 21-1) as a complementary biomarker for diagnosing metastatic LNs in thyroid cancer and to explore its relationship with molecular analysis and distant metastasis. PATIENTS AND METHODS: In this retrospective cohort study involving 230 LNs in 224 patients with PTC, FNAC, washout Tg, and CYFRA 21-1 levels were measured in suspicious LNs. The final LN outcomes were confirmed by surgical histology. RESULTS: Among the 230 LNs, 145 (63.0%) were benign and 85 (37.0%) were metastatic. The optimal cut-off value for washout CYFRA 21-1 was established at 1.12 ng/mL (Area under curve AUC, 0.959
95% confidence interval CI, 0.936-0.982) with sensitivity of 93.4% and specificity of 97.8%. The cut-off value for washout Tg was 12.61 ng/mL (AUC 0.832, 95% CI, 0.772-0.892). The diagnostic performance of CYFRA 21-1 remained consistent across the preoperative (1.14 ng/mL) and postoperative assessment (1.10 ng/mL). The combination of FNAC and washout CYFRA 21-1 showed high sensitivity (93.1%), specificity (95.6%), negative predictive value (95.3%), and diagnostic accuracy (94.6%) than FNAC with washout Tg. Washout CYFRA 21-1 level was associated with TERT mutations (odds ratio, OR 3.35, P<
0.001), LN metastasis (OR 5.43, P=0.019), and distant metastasis (OR 4.27, P =0.019). CONCLUSIONS: Incorporating washout CYFRA 21-1 into the diagnostic process improves the accuracy of metastatic LN detection in thyroid cancer.