Diagnostic Accuracy of Calcitonin, Procalcitonin, proGRP, miR-375 and FNA-Washout Calcitonin for Medullary Thyroid Carcinoma: A Systematic Review and Diagnostic Meta-Analysis.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare but aggressive neuroendocrine thyroid malignancy in which early diagnosis is essential for improving clinical outcomes. Although calcitonin (CT) remains the standard diagnostic biomarker, its interpretation may be limited by false-positive elevations, assay variability, and indeterminate cut-off values. Consequently, alternative biomarkers such as procalcitonin (PCT), circulating microRNA-375 (miR-375), and fine-needle aspiration washout calcitonin (FNA-CT) have gained increasing interest. METHODS: A systematic review and diagnostic meta-analysis were conducted to evaluate the diagnostic performance of circulating and tissue-related biomarkers for MTC. Eligible studies reporting sufficient diagnostic accuracy data were included. Pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves were calculated using a bivariate random-effects model. Methodological quality was assessed using the QUADAS-2 tool. RESULTS: Five diagnostic datasets were included in the quantitative synthesis. The pooled sensitivity and specificity were 0.90 (95% CI: 0.84-0.94) and 0.99 (95% CI: 0.97-0.997), respectively. The pooled LR+ was 84.78, while the pooled LR- was 0.10. The pooled diagnostic odds ratio was 857.30, indicating excellent discriminatory diagnostic performance. SROC analysis demonstrated near-perfect overall diagnostic accuracy with an area under the curve (AUC) of 0.986. Procalcitonin-based approaches showed the most consistent diagnostic performance across studies, while combined CT + PCT strategies achieved the highest overall diagnostic accuracy. Emerging biomarkers such as miR-375 and FNA-CT also demonstrated promising results, although evidence remains limited. CONCLUSIONS: Biomarker-based diagnostic strategies demonstrate excellent diagnostic accuracy for medullary thyroid carcinoma. Among the evaluated biomarkers, procalcitonin-based approaches, particularly combined CT + PCT strategies, showed the most robust and clinically relevant diagnostic performance. These findings support the potential integration of procalcitonin into future diagnostic algorithms for MTC. Further large-scale prospective studies are required to validate diagnostic thresholds and standardize biomarker assessment protocols.