Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma

Abstract

Abstract Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT). Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n <= 5) and 276.2 ng/mL (n <= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n <= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n <= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n <= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n <= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin <= 2 pg/ml, CEA 26.8 ng/mL, MN < 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C>G (p.Cys634Trp). Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.