Oncocytic Plasma proteomic markers in the differential diagnosis of benign and malignant thyroid neoplasms of the Bethesda category IV

BACKGROUND . The Bethesda category IV comprises thyroid nodules of indeterminate malignant potential. As a result, most patients undergo diagnostic surgery that more often confirms a benign lesion. The search for additional preoperative criteria remains relevant. The aim of this study was to assess the diagnostic potential of plasma proteomic markers for the differential diagnosis of benign and malignant thyroid neoplasms within the Bethesda category IV. MATERIALS AND METHODS . This study included 174 patients with Bethesda IV cytology in whom a plasma proteomic profile was obtained and a histological diagnosis was established, comprising 104 benign and 70 malignant lesions. Protein concentrations were estimated by multiple reaction monitoring. RESULTS . The groups were comparable in sex, age, disease duration, thyroid-stimulating hormone level. Patients with malignant lesions had higher concentrations of keratin 19, galectin-3, CD14 differentiation antigen, thrombospondin-1, epidermal growth factor, and filamin-A. The largest areas under the ROC curve were obtained for CD14 differentiation antigen (0.729; 95% CI 0.650–0.808), keratin 19 (0.727; 0.646–0.808), and galectin-3 (0.710; 0.627–0.792). Strong positive correlations were found between keratin 19 and galectin-3 (r=0.82), CD14 differentiation antigen and galectin-3 (r=0.80), and keratin 19 and CD14 differentiation antigen (r=0.78; p < 0.001). CONCLUSION . Several plasma proteins differ between benign and malignant lesions within the Bethesda category IV. Keratin 19, galectin-3, and CD14 differentiation antigen showed the highest, although moderate, differential diagnostic performance. The obtained concentration estimates are semi-quantitative and require quantitative validation before use as clinical thresholds. Taken together, the data indicate that these proteins reflect epithelial proliferative activity rather than a malignancy-specific signal, which limits their standalone diagnostic application.