Abstract
Hereditary medullary thyroid cancer (MTC), occurring within multiple endocrine neoplasia 2A syndrome (MEN2A), most often presents in the fourth decade of life but may be detected earlier by biochemical screening in carriers of RET proto-oncogene mutations (1,2). Penetrance of MTC varies in relation to the particular RET proto-oncogene codon affected (3). Pheochromocytoma develops in about 50% of MEN2A families (1), usually after the detection and treatment of MTC. Here, we describe a patient who presented with what appeared to be sporadic pheochromocytoma who was subsequently found to have MEN2A and asymptomatic MTC.
A 55-year-old female Korean immigrant presented with a 2-year history of hypertension, intermittent palpitations, and headache. Urine-fractionated metanephrine excretion was unequivocally raised and computed tomography revealed a 5-cm right adrenal mass. Magnetic resonance imaging was negative for metastasis or extra-adrenal disease. Laparoscopic adrenalectomy was performed and pheochromocytoma was confirmed on histology. The basal serum human calcitonin (hCT) value was mildly elevated at 13 pg/mL (normal female, <5.0 pg/mL). Sequencing of selected exons of the RET proto-oncogene showed that the patient carried a c.2071G>A mutation resulting in an amino acid substitution p.Cys618Phe, which suggested MEN2A. Thyroid examination was normal, as were serum calcium and parathyroid hormone levels. Peak serum hCT level after IV pentagastrin was 135 pg/mL (normal female, <26.2 pg/mL). Thyroid ultrasound scan (USS) revealed a small hypoechoic area in the right thyroid lobe. Total thyroidectomy with bilateral central compartment lymph node dissection was performed. Histology revealed bilateral foci of microscopic MTC arising from a background of C cell hyperplasia, the largest lesion measuring 2 mm in maximum diameter and corresponding to the USS findings. There was no evidence of lymph node involvement in 14 nodes removed. Postoperative basal hCT value was undetectable.
There was no known family history of MEN2A in first-degree relatives. Her 30-year-old son was also mutation positive. He was normotensive with normal plasma metanephrines. His basal and pentagastrin-stimulated hCT, thyroid USS, operative and histological findings, and postoperative basal hCT uniformly showed striking resemblance to that of his mother's.
The finding of similar microscopic MTC in both mother and son, without lymph node spread, indicates the indolent nature of their C cell tumors. These might have been detectable at a young age and, untreated, may have remained dormant throughout their lifespan.
Total thyroidectomy is recommended in MEN2A carriers of codon 618 mutations. These are deemed high risk “B” according to expert recommendations (3). We found pentagastrin testing helpful in reinforcing the indication for surgery and with the extent of surgery—both of our patients had total thyroidectomy with central neck dissection.
Unusually for MEN2A, our proband presented with a symptomatic pheochromocytoma in the sixth decade of life at which time her thyroid tumor was clinically silent. Multifocal micro-MTC was uncovered by further investigation of the raised basal serum calcitonin and knowledge of her RET proto-oncogene mutation. The prevalence of all predisposing germline mutations found in patients presenting with sporadic pheochromocytoma ranges from 7.5% to 27%, whereas RET proto-oncogene mutations are found at a low frequency, ranging from 0% to 5% across four studies (4). Given the likelihood of even lower RET mutation frequency in those over 50 years of age with unilateral sporadic pheochromocytoma, combined with the very high penetrance of MTC in MEN2A by early adulthood when assessed by biochemical screening (2), measurement of basal hCT with modern sensitive assays may best direct RET proto-oncogene testing in this subgroup.
Footnotes
Disclosure Statement
No competing financial interests exist.