A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve. Graphical Abstract Open in new tab Download slide

Context Hyperglucagonemia in the absence of glucagonomas is rare. Biallelic inactivating mutations in the glucagon receptor gene (GCGR) cause glucagon cell hyperplasia and neoplasia (GCHN) also termed Mahvash syndrome. Here, we report the first case of GCHN presenting with hypercalcemia and demonstrate a unique relationship between calcium and alpha cell hyperplasia. Case Description A 47 year old man presented with severe PTH independent hypercalcemia, 13.95mg/dl (3.48mmol/L). Imaging and extensive pathology tests yielded no conclusive cause. Glucagon levels over 300x the upper limit of normal were discovered. Sub-total pancreatectomy identified alpha cell hyperplasia and neoplasia with metastatic disease in lymph nodes. Genomic analysis confirmed a homozygous missense variant in GCGR (Asp63Asn). This is a previously described pathologic variant and has a known association with GCHN. Conclusions Inactivating mutations of the glucagon receptor gene lead to non-functional hyperglucagonemia and are associated with GCHN. Homozygous or compound heterozygous GCGR mutations are associated with alpha cell hyperplasia, a known precursor to pancreatic neuroendocrine tumours which can metastasize. Hypercalcemia is an unreported consequence of GCHN with an unclear mechanism.