Circulating Biomarkers in Medullary Thyroid Carcinoma: Assays, Clinical Performance, and Integrated Algorithms

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor arising from parafollicular C-cells, accounting for 2-5% of thyroid cancers. Effective management relies on circulating biomarkers for diagnosis, staging, and post-operative monitoring. Calcitonin (CT) remains the gold standard biomarker, demonstrating high sensitivity and specificity for MTC detection. However, CT measurement faces analytical challenges including pre-analytical degradation, biological confounders, inter-assay variability, and the hook effect. New-generation immunochemilu-minometric assays have significantly improved analytical performance, enabling gender-specific thresholds that reduce false-positive rates while maintaining high diagnostic accuracy. Procalcitonin (ProCT) is a promising complementary or alternative biomarker, offering superior analytical stability and reduced susceptibility to interferences, with particular utility as a rule-out test in patients with indeterminate CT levels. Carcinoembryonic antigen (CEA) serves as a valuable adjunct marker for staging, risk stratification, and post-operative surveillance, with elevated levels indicating more aggressive disease and distant metastases. Doubling time calculations for both CT and CEA provide prognostic information, with doubling times < 6 months correlating with poor survival and >2 years indicating favorable outcomes. Novel biomarkers, including pro-gastrin-releasing peptide (ProGRP) and carbohydrate antigen 19-9 (CA19-9) show promise for monitoring ad-vanced disease and therapy response. This review presents evidence-based algorithms that integrate these biomarkers for optimal management of MTC patients, from initial screening through postoperative follow-up. The rational combination of established and novel biomarkers enhances diagnostic precision while reducing unnecessary interventions, ultimately improving patient outcomes.