Marshall University Joan C. Edwards School of Medicine huntington, United States
Disclosure(s):
Nabila Dawoud, MD: No financial relationships to disclose
Background: Medullary thyroid carcinoma (MTC) accounts for 1–2% of thyroid cancers and is frequently associated with germline RET mutations in Multiple Endocrine Neoplasia type 2 (MEN2). The RET V804M mutation is classified as a low-risk variant with low penetrance for MTC, estimated at approximately 4%. When MTC develops, it typically presents later in life, and current guidelines favor conservative surveillance with serial calcitonin measurements and ultrasound rather than prophylactic thyroidectomy.
Case Presentation: A 63-year-old man with a history of type 2 diabetes mellitus, hypothyroidism, and chronic kidney disease secondary to a congenital left multicystic dysplastic kidney was referred for endocrine evaluation after genetic testing identified a pathogenic RET mutation. Genetic testing was pursued following the detection of multiple polyps on screening colonoscopy and revealed a RET c.2410G >A (p.V804M) mutation. Biochemical evaluation demonstrated persistently elevated serum calcitonin levels (299, 234, and 363 pg/mL) with normal carcinoembryonic antigen levels. Plasma metanephrines and normetanephrines were within normal limits, effectively excluding pheochromocytoma. Parathyroid hormone levels were mildly elevated (60–76 pg/mL) without associated hypercalcemia. Serial thyroid ultrasounds revealed stable subcentimeter nodules, including a 9-mm hypoechoic solid nodule in the left thyroid lobe and a 7-mm hypoechoic nodule in the right lobe. Although these nodules did not meet standard size criteria for biopsy, the patient’s underlying genetic risk and persistently elevated calcitonin levels prompted fine-needle aspiration of the left thyroid nodule, with cytology findings suggestive of medullary thyroid carcinoma. CT of the chest demonstrated multiple bilateral pulmonary nodules measuring 2–6 mm, which were concerning for possible metastatic disease, while CT of the soft tissue neck showed no evidence of metastatic involvement. The patient was subsequently referred to head and neck surgery for further evaluation and management. Notably,. The patient had previously been treated with GLP-1 receptor agonists for several years for type 2 diabetes mellitus; these agents were discontinued following recognition of the RET mutation and calcitonin elevation.
Conclusion: This case highlights that clinically significant medullary thyroid carcinoma can occur in RET V804M mutation carriers despite the low penetrance associated with this variant . Persistent elevation of serum calcitonin prompted diagnostic evaluation beyond standard ultrasound size criteria, leading to early diagnosis despite stable subcentimeter nodules. . Additionally, this case raises the question of whether long-term GLP-1 receptor agonist exposure may influence disease expression in genetically susceptible patients.
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