Is it time to give up calcitonin stimulation in C-cell disease or truly unravel its potential?

Background: Calcitonin (Ctn) is a highly specific and sensitive marker for c-cell disease (CCD). In the era of precision medicine, preoperative differentiation between c-cell hyperplasia (CCH) and medullary thyroid cancer (MTC) facilitates a tailored surgical approach, avoiding over- or undertreatment. Method: 451 patients with CCH or intrathyroidal MTC (TxN0M0), treated at two tertiary care centers between 01/2006 and 07/2025 were analyzed from a prospective database. Two correlating Ctn assays were employed for the biochemical diagnosis. All patients achieved postoperative biochemical cure. Gender- and assay-dependent basal and stimulated cut-off Ctn values as well as stimulated values after 2 and 5 minutes and carcinoembryonic antigen values (CEA) were analyzed and correlated with postoperative findings. The cohort was stratified by RET status. Results: In the overall cohort, basal calcitonin (bCtn) showed the best diagnostic accuracy for preoperative discrimination of CCD and MTC. Stimulated calcitonin (sCtn) provided additional diagnostic benefit in male patients by achieving the highest positive predictive value (PPV) und specificity with a slightly lower area under curve (AUC) compared with bCtn (0.80 versus 0.81). In females with hereditary disease, sCtn showed the highest overall performance with an AUC, PPV and specificity of 0.83, 85% and 87%. CEA cut-offs and calcitonin peak timing did not add diagnostic value. Conclusion: Combined preoperative assessment of basal and stimulated calcitonin testing may provide guidance in individual therapeutic decision-making to preoperatively stratify c-cell disease and tailor the therapeutic approach, helping to prevent over- or undertreatment. This appears to be particularly relevant in male patients in general and for females with hereditary CCD.