Pheochromocytomas and paragangliomas are chromaffin cell tumors of neural crest origin that arise from the adrenal medulla or extra-adrenal sympathetic paraganglia, respectively, and are frequently catecholamine secreting.¹ These tumors are usually benign and can occur as a single entity or as part of various hereditary tumor syndromes. Genetically, pheochromocytomas and paragangliomas are heterogeneous, with at least one-third of cases resulting from germline but not somatic mutations in 1 of several independent genes: RET, VHL, NF1, and succinate dehydrogenase (SDH) subunit B, C, and D genes.^2-5 More recently, other candidate susceptibility genes have also been reported, including KIF1Bβ,^6,7EgIN1/PHD2,⁸SDHAF2,^9,10 and SDHA,¹¹ although these findings remain restricted to 1 or 2 occurrences of the reported mutations. Despite this broad spectrum of susceptibility genes, the molecular basis for the majority of pheochromocytomas and paragangliomas, including most of the sporadic and rare familial cases, remains unknown. These observations support the existence of additional pheochromocytoma susceptibility genes, which may account for some of the genetically undefined cases.^12,13

Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice. Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test. A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied. bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test. Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.