Calcitonin Thresholds for Prediction of Medullary Thyroid Carcinoma and its Clinical Response in MEN2A Gene Carriers

Purpose In multiple endocrine neoplasia type 2 (MEN2), clinical management of gene carriers (GCs) is still debated, especially in MEN2A. We aimed to evaluate the predictive value of preoperative CTN for medullary thyroid cancer (MTC) diagnosis and excellent response (ER) in MEN2A GCs. Methods Retrospective evaluation from a prospectively maintained database of 106 GCs who underwent surgery and were followed up at an Italian tertiary referral center from 1993 to 2024. Results The most common mutation was RET V804M (36/106, 34.3%), followed by mutations at the 634 codon (17/106, 16.2%). Median age at surgery was 39 years. Eighty-six (81.1%) patients had MTC, while 20 patients (18.9%) had C-cell hyperplasia (CCH) alone. Patients with MTC were older than CCH ones both at RET screening and surgery and showed higher preoperative bCTN and sCTN levels. Values of bCTN > 12.60 ng/L identified MTC patients with a sensitivity of 94.4% and specificity of 74.3%. Incomplete response (IR) was observed in 24/106 (22.9%) patients during a median follow-up of 6.8 years. Patients with IR had higher preoperative bCTN and sCTN levels than patients with ER. bCTN < 28.25 ng/L identified patients with ER with a specificity of 95.5% and sensitivity of 76.8%. In multivariate analysis, bCTN < 28.25 ng/L and the absence of lymph node metastases were independent predictive factors of ER. Conclusion GCs with a preoperative bCTN between 12.6 and 28.3 ng/L have a very high probability of achieving complete biochemical and structural remission after surgery, even when a small intrathyroidal MTC is already present and independently from the RET germline mutation.