Clinical utility of Circulating Long Non-Coding RNAs in indeterminate thyroid nodules

BACKGROUND: Indeterminate cytology results (Bethesda categories III and IV) from fine-needle aspiration (FNA) create challenges in clinical decision-making. This study evaluated the expression and diagnostic utility of selected long non-coding RNAs (lncRNAs) in cell-free plasma from patients with indeterminate thyroid nodules. DESIGN: Prospective, single-center study. METHODS: Nine candidate long non-coding RNA were selected from a curated disease database. A total of 126 individuals with solitary thyroid nodules were enrolled. RNA was extracted from plasma, FNA, and tissue samples and expression levels were measured using quantitative real-time PCR. In the discovery cohort, patients with benign and malignant nodules confirmed by histopathology, were used to determine optimal cut-off values through receiver operating characteristic analysis. Spearman correlation analyses were performed to assess concordance between plasma and FNA/tissue expression. In the validation phase, significantly altered markers were applied to indeterminate nodules to assess diagnostic performance. RESULTS: In the discovery cohort, PVT1, MALAT1, and BANCR were significantly upregulated in malignant compared with benign nodules (P < 0.0001). Significant positive correlations were observed between plasma and FNA expression for PVT1 (r = 0.7095), MALAT1 (r = 0.5487), and BANCR (r = 0.6792), and between plasma and tissue expression for PVT1 (r = 0.7673), MALAT1 (r = 0.5284), and BANCR (r = 0.6864) (P < 0.0001). In the Bethesda III/IV validation cohort, only PVT1 retained diagnostic utility, with 76% sensitivity, 87.5% specificity, 85% positive predictive value, and 80% negative predictive value, whereas MALAT1 and BANCR did not demonstrate significant diagnostic performance. CONCLUSIONS: Circulating PVT1 expression in plasma may serve as a useful non-invasive biomarker for distinguishing benign from malignant indeterminate thyroid nodules.