Progastrin-Releasing Peptide and Procalcitonin as Additional Markers in the Diagnostic Workup for Medullary Thyroid Carcinoma

<b><i>Background:</i></b> Calcitonin (CT), a well-established tumor marker for medullary thyroid carcinoma (MTC), is limited by a high rate of false positives in the diagnostic phase. Potential new markers for MTC are procalcitonin (PCT) and progastrin-releasing peptide (proGRP). Where literature has proven noninferiority for PCT, evidence is lacking for proGRP. Therefore, the present study prospectively evaluated the clinical performance of proGRP and PCT in a multicohort study of patients with MTC compared with other thyroid diseases. <b><i>Methods:</i></b> Adult patients undergoing thyroid surgery for thyroid nodular disease diagnosed in a tertiary center from the Netherlands (discovery cohort) between 2013 and 2025 were prospectively included. Serum samples were collected preoperatively. Diagnostic performance of CT, PCT, proGRP, and carcinoembryonic antigen was calculated separately. A two-step approach, combining different markers, was investigated. Analyses were repeated in a validation cohort from Switzerland. <b><i>Results:</i></b> The discovery and validation cohorts consisted of 335 and 61 patients, respectively. Patients had benign disease (<i>n</i> = 166), other thyroid carcinomas (non-MTC, <i>n</i> = 186), or MTC (<i>n</i> = 44). Median proGRP and PCT levels were significantly higher in MTC compared with benign disease and non-MTC. ProGRP had a low sensitivity (69.2% [CI 48.2-85.7]), while PCT performed similarly to CT (100.0% [CI 89.1-100.0] and 100.0% [CI 88.8-100.0], respectively). The combination of CT and PCT, both in the individual cohorts and when combining the two cohorts, showed the best diagnostic performance with a sensitivity of 100% [CI 91.8-100.0] and negative predictive value of 100% [CI 98.9-100.0] and specificity and positive predictive value of 99.7% [CI 98.4-100.0] and 97.7% [CI 88.0-99.9], respectively. <b><i>Conclusions:</i></b> ProGRP alone or with CT does not have additional value as a diagnostic marker for MTC. A two-step approach combining the use of CT and PCT measurement, in the CT concentration range between 10 and 100 pg/mL, is a promising method to diagnose MTC in patients with thyroid nodules with high diagnostic accuracy.