Never Too Old for Genetics: An Unusually Late Presentation of Medullary Thyroid Cancer in MEN2A

Introduction:
Virtually all germline RET pathogenic variant carriers develop medullary thyroid carcinoma (MTC). If possible, thyroidectomy should be performed prophylactically, before developing MTC. We describe a patient with pheochromocytoma found to have a germline RET p.Cys634Ser pathogenic variant at age sixty years who would be categorized as high risk based on genotype classification described by the American Thyroid Association and would have warranted prophylactic thyroidectomy at a young age.

Case Description:
A 60-year-old man with history of hypothyroidism and osteopenia was found to have an adrenal mass during evaluation for kidney stones. It measured 4.1 x 3.2 x 3.8 cm on CT scan of abdomen and pelvis. MRI with and without gadolinium revealed a 4 cm left adrenal mass with T2 enhancement. Diagnosis of pheochromocytoma was confirmed with elevated levels of plasma free metanephrine and normetanephrine. The adrenal nodule showed avid uptake on PET CT Gallium-68 DOTATATE scan. No uptake was noted on the contralateral adrenal gland or in the neck. Patient underwent left adrenalectomy. Surgical pathology confirmed pheochromocytoma.

Patient also had evidence of primary hyperparathyroidism (pHPT). Germline genetic analysis revealed a RET c.1900T >A(p.Cys634Ser) pathogenic variant confirming the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Calcitonin level was noted to be mildly elevated at 27.8 pg/ml. Subsequently, patient underwent total thyroidectomy, subtotal parathyroidectomy and bilateral central neck dissection. Surgical pathology revealed multifocal MTC, diffuse C-cell hyperplasia, and a foci of papillary thyroid microcarcinoma. Immunohistochemistry for calcitonin revealed diffuse C-cell hyperplasia. Patient was doing well on postoperative follow up and calcitonin level downtrended to <2 pg/ml.

Discussion:
Nearly all patients with MEN2A have either C-cell hyperplasia (CCH) or MTC, approximately 50% have a pheochromocytoma and 20-30% have pHPT. Age-related penetrance of CCH and hMTC is mutation dependent. Peak incidence in index patients is in the third decade of life in MEN2A. Our patient presented in the sixth decade of life. We decided to pursue genetic testing. The DOTATE scan did not show uptake in the neck and the calcitonin was only mildly elevated. However, as there is known complete penetrance of MTC in patients with MEN2A syndrome, patient underwent total thyroidectomy with central neck dissection with results of surgical pathology confirming presence of MTC. This case highlights the importance of considering genetic syndromes even in patients who present at older ages and challenges the classic genotype-phenotype correlation of the RET p.Cys634Ser pathogenic variant and MTC.