Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy of thyroid C-cells characterized by the secretion of several circulating biomarkers, including calcitonin (CT), procalcitonin (PCT), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and pro-gastrin-releasing peptide (proGRP). These analytes substantially contribute to the diagnosis, postoperative monitoring, and prognostic stratification of MTC. Nevertheless, their optimal use remains limited by analytical, pre-analytical, and biological factors that can compromise result reliability and clinical interpretation. Despite improvements in assay technology, significant inter-method variability persists for CT and CA 19-9, while heterophile antibodies, macro-analyte formation, renal dysfunction, and pharmacologic influences may cause spurious or misleading results. Moreover, a lack of harmonized reference intervals and clinical decision thresholds complicates longitudinal follow-up and inter-laboratory comparison. This review systematically addresses current laboratory challenges affecting MTC biomarkers, summarizes the main sources of false-positive or unreliable results, and discusses the complementary diagnostic roles of CT, PCT, and emerging analytes such as ProGRP. Emphasis is placed on standardization needs, verification of analytical performance, and the importance of consistent assay use in patient follow-up. Ultimately, the effective management of MTC biomarkers requires active engagement of clinical chemists and pathologists within multidisciplinary teams to ensure accurate interpretation, resolve analytical ambiguities, and integrate biochemical data into evidence-based therapeutic decision-making.
Giovanella et al. (Thu,) studied this question.