CYFRA 21-1 in lymph node fine-needle aspiration washouts: added value in differentiated thyroid cancer

Objectives: Cervical lymph node metastases represent a key challenge in patients with differentiated thyroid carcinoma (DTC). Fine-needle aspiration cytology (FNAC) and thyroglobulin (Tg) measurement in fine-needle washout (FNA-Tg) are widely used but have recognized limitations. Cytokeratin 19 fragment 21-1 measurement in FNA washout (FNA-CYFRA 21-1) has recently emerged as a potential supplementary biomarker. We compared the diagnostic performance of FNAC, FNA-Tg and FNA-CYFRA 21-1 in a series of well characterized DTC patients. Methods: In this observational diagnostic accuracy study, 226 suspicious cervical lymph nodes were assessed by FNAC, FNA-Tg and FNA-CYFRA 21-1. The reference standard was histopathology or a predefined composite clinical follow-up. Receiver operating characteristic (ROC) analysis, logistic regression, and DeLong's test were applied. Results: Of 226 lymph nodes, 87 were metastatic and 139 benign. FNA-CYFRA 21-1 showed near-perfect discrimination (AUC 0.99, 95 % CI 0.99-1.00), followed by FNA-Tg (AUC 0.97, 95 % CI 0.94-0.98). FNAC demonstrated high specificity but lower sensitivity (positivity: 79.3 % in metastatic vs. 3.6 % in benign nodes). In multivariable models, adding washout Tg significantly improved discrimination over FNAC alone (AUC 0.98 vs. 0.91; p=0.0003). A model based solely on FNA-CYFRA 21-1 achieved the highest performance (AUC 0.99), comparable to FNAC combined with FNA-Tg (p=0.09). Diagnostic accuracy remained robust across anti-thyroglobulin antibody strata. Conclusions: FNA-CYFRA 21-1 provides excellent diagnostic accuracy for metastatic cervical lymph nodes in DTC and performs at least comparably to established approaches. Its integration into a multimodal strategy may enhance diagnostic confidence, particularly in cytologically indeterminate or Tg-challenging scenarios.