Endocrine Abstracts

Background: Multiple endocrine neoplasia type 2 associated medullary thyroid carcinoma (MTC) is driven by a strong genotype-phenotype correlation, the risk of aggressiveness being defined by the germline RET pathogenic variant (American Thyroid Association (ATA) guidelines). Based on this classification, the germline c.2370G>C, p.Leu790Phe (L790F) RET variant is considered to be of moderate risk of aggressive MTC, while the germline c.2753T>C, p.Met918Thr (M918T) RET variant presents the highest risk. In non-hereditary MTC, the somatic RET M918T mutation is also the main driver mutation of tumorigenesis and correlates with a worse outcome.

Patient findings: A 35-year-old woman presented with highly suspicious right thyroid nodule. Preoperative calcitonin and Carcino-embryonic antigen (CEA) were 2300 pg/ml and 21 ng/ml, respectively. Total thyroidectomy with neck dissection revealed a pT3N1b MTC. Genetic screening identified a moderate risk ATA germline RET-mutation (RET L790F). As the patient rapidly developed lung and bone metastases, a genetic screening was performed on the MTC: a somatic RET-mutation (RET M918T) was identified explaining the rapidly aggressive phenotype presented by the patient. At last follow-up, six years after surgery, calcitonin and CEA were 6566 pg/ml and 84.2 pg/ml, respectively. Imaging investigations showed a persistent metastatic disease with cervical-mediastinal nodes, lung and bones metastasis. The patient showed no other manifestation belonging to the MEN2 spectrum. Her family member were screened for the germline variant and all carriers had normal calcitonin and neck ultrasound.

Discussion: We report the case of a double germline and somatic RET pathogenic variants, leading to a more aggressive profile than what the germline genetic screening was suggesting. Most of the studies reporting the natural history of MTC associated with RET L790F variant are in favor of an indolent disease. A large French multicentric study involving 77 patients with RET L790F germline mutation reported no distant metastases. Lymph node invasion was reported in 10/55 (18.2%) operated patients, with an early age of 32 years. After a 89-month follow-up, most of both index and screened patients were cured. On the other hand, several studies reported that patients with somatic RET-mutated MTC (mainly RET M918T) have a more advanced stage at diagnosis and experienced a worse outcome. The identification of additional somatic RET variant in addition to preexisting mutation in patients with hereditary MTC have been rarely reported and may promote tumorigenesis in vivo. Thus, this situation emphasizes the need to think differently when genotype and phenotype don’t match in MEN2 related MTC.