Endocrine Abstracts

Introduction: Medullary thyroid cancer (MTC) is a thyroid neuroendocrine tumor with a genetic basis and average biological aggressiveness, with a 5-year survival rate of around 90%. However, the presence of calcitonin (CT) biomarker along with genetic beckground could further improve these data, by earlier diagnosis and proper surgical management of genetically predisposed patients.

Patients and Methods: To set specific thresholds for basal CT and calcium-stimulated CT for predicting thyroid malignancy, we included two groups: 74 women with elevated basal CT (>9.82 pg/ml) and 31 women with normal basal CT. After the calcium test, the histopathology of those submitted to surgery was correlated with basal and stimulated calcitonin. The best cut-offs for distinguishing female patients with medullary thyroid carcinoma or C-Cell-hyperplasia from other thyroid disorders are: 12.9 pg/ml, respectively 285.25 pg/ml . For the genetic approach, RET testing for germline mutations was performed in 74 subjects, (58 complete gene analyses and 16 targeted analyses), 72 of whom were diagnosed with MTC. Among all subjects submitted to germline RET analysis, 16/74 (21.6%) were clinically affected by a hereditary disease at diagnosis and 58/74 (78.3%) were presumed to have sporadic MTC. We identified a germline RET variant in a total of 24/74 (32.4%) cases; from these, 16/16 (100%) had a positive family history, while only 8/58(13.8%) were initially considered sporadic cases. We identified five different RET pathogenic variants. When classified in ATA risk categories, two mutations were of high-risk level (12/24, 50% cases) and three mutations of moderate risk level (12/24, 50% cases). The most common RET proto-oncogene alteration was Cys634 in 11/24 (45.8%) cases. All known pathology results of patients with a positive germline mutation and 5/37 with known wild-type RET patients had multifocal disease. Out of 50 cases tested negative for germline RET mutation, eight cases with advanced, metastatic MTC underwent RET somatic testing. From 6/8(75%) cases, a somatic RET mutation was found, 5/6 (83.3%) having Met918Thr mutation, and one case with Cys634Arg mutation. Among patients with known cancer staging, 7/24(29.1%) of those with a germline RET mutation and 20/50 (40%) of wild-type RET patients had locally advanced disease (T>1). We observed a more aggressive disease in patients with a somatic RET mutation, with metastatic disease, requiring systemic treatment with tyrosine kinase inhibitors, vandetanib, or cabozantinib.

Conclusions: Mutational screening is mandatory in all patients with MTC and crucial in selecting targeted treatment with TKI inhibitors and predicting responsiveness to therapy.