Abstract
Background: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome caused by inactivating mutations in the RET proto-oncogene. It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and hyperparathyroidism (HPTH). MTC is one of the initial manifestations in 90% of patients. PHEO affects approximately 50% of patients, is almost always benign (98% of cases), usually bilateral and confined to the adrenal glands. HPTH occurs in 20-30% of patients. The clinical presentation, evolution and prognosis of metastatic PHEO associated with RET mutations are not yet well known.
Clinical Case: A previously healthy man was initially diagnosed with hypertension at 24 years of age. Two years later, after recurrent paroxysms of headache, tremors and tachycardia, the patient was suspected of having bilateral PHEO based on laboratory and radiological findings. Bilateral adrenalectomy was performed and the anatomopathological analysis confirmed the suspected diagnosis.
Soon afterward, although the patient was asymptomatic, with urinary metanephrines in the normal range, two possibly metastatic lesions were identified – one in the liver (9 x 8 mm) and one in the left adrenal bed. Some of the patient’s family members were also found to have PHEO and/or MTC, leading to the diagnosis of MEN2A. A RET germline mutation in codon 634 (p.Cys634Phe) of exon 11 was then found in the patient’s family pedigree. At the time, the patient (index case) had no evidence of MTC or HPTH.
Diagnostic 131I-MIBG scintigraphy showed increased uptake in the patient’s liver. The subsequent percutaneous liver biopsy confirmed the presence of metastatic PHEO. Interestingly, no significant 18F-FDG uptake was found on the 18F-FDG-PET/CT scan in the metastatic PHEO sites. For more than 10 years of follow-up with no specific treatment, the metastatic lesions demonstrated slow growth rates; metanephrine levels, although increased (total = 1422 mcg/24h, NR <1000; normetanephrine = 676 mcg/24h, NR <320; and metanephrine = 574 mcg/24h, NR <390), were relatively stable; blood pressure and adrenergic symptoms were under control with a few antihypertensive medications.
At 36 years of age, the calcitonin level was slightly increased (8.6 pg/mL, NR <8.4) and a minuscule thyroid nodule (3 x 3 x 2 mm) was identified on the ultrasound scan. Prophylactic thyroidectomy was performed, with a diagnosis of a 2.5-mm MTC. More recently, an increase in the metanephrine levels was found and treatment with iobenguane 131I may be an option.
Conclusion: Patients with metastatic PHEO caused by mutations in the RET proto-oncogene (MEN2A) may have a long survival time. In such patients, an 18F-FDG-PET/CT scan may exhibit low sensitivity for the diagnosis of metastasis and the onset of PHEO may precede that of MTC by many years.
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