Case report: coexistence of pheochromocytoma and bilateral aldosterone-producing adenomas in a 36-year-old woman

A screening for secondary hypertension is important especially in the young patients. Primary aldosteronism has been reported to be more prevalent than previously considered, and accounts for 3–10% of all hypertensive patients.1 In contrast, pheochromocytoma is considered to be rare cause of secondary hypertension. Thus, coexistence of adrenal cortical adenoma and pheochromocytoma seems to be extremely rare. It is well known that plasma renin activity (PRA) is suppressed in patients with primary aldosteronism and patients with pheochromocytoma occasionally show elevated PRA and secondary aldosteronism. Here, we present a rare case of primary aldosteronism without suppressed PRA because of the coexistence of pheochromocytoma. A 36-year-old female was admitted to our hospital for the evaluation of hypertension of 3-year duration and right adrenal mass. On admission, her blood pressure (BP) was 202/120 mm Hg without antihypertensive agents and pulse rate was 80 beats min–1. Orthostatic hypotension was not found. She had no typical symptoms of pheochromocytoma, such as paroxysmal hypertension, headache or hyperhidrosis and she had no family history of pheochromocytoma or primary aldosteronism. Examination of the optic fundi showed grade 1 hypertensive retinopathy. Laboratory studies showed hypokalemia (3.0 mEq l–1). Endocrinological evaluation disclosed an elevated plasma aldosterone concentration (PAC), plasma and urinary catecholamines (Table 1). In contrast, PRA was not suppressed. There were no morphological and functional abnormalities in the thyroid and parathyroid glands, although we have not conducted genetic testing. On the basis of magnetic resonance imaging (MRI), bilateral adrenal adenomas and pheochromocytoma in the right adrenal gland were suspected (Figure 1). 131I-metaiodobenzylguanidine (MIBG) scintigraphy failed to show a hot lesion, while 131I-cholesterol adrenal scintigraphy revealed tracer accumulation in the bilateral adrenal glands. Furosemide administration and standing for 2 h showed idiopathic hyperaldosteronism pattern (PAC 368 → 852 pg ml–1), whereas, the circadian rhythm of cortisol and PAC showed aldosterone-producing adenoma pattern (cortisol 13.0 → 8.3 → 6.4 μg per 100 ml, PAC 398 → 323 → 181 pg ml–1). Adrenal venous sampling confirmed the exaggerated aldosterone secretion from the bilateral adrenal glands and catecholamines secretion in the right adrenal gland (Table 2). A diagnosis of acquired bilateral adrenal cortical adenomas and pheochromocytoma in the right adrenal gland was established. Nifedipine, doxazosin and potassium substitution therapy was started orally and her BP decreased to 130–140/70–80 mm Hg. One month later, the patient underwent laparoscopic right adrenalectomy. The resected adrenal contained two well-circumscribed tumours, whose sizes were 11 and 22 mm in the greatest diameter, respectively. Pathologically, the former, golden–yellowish and composed of lipid-laden clear cells, was diagnosed as an adrenocortical adenoma (Figure 2, black arrow, and Figure 3a). In situ hybridization showing the expression of steroidogenic enzyme messenger RNAs supported that the adenoma cell had actively produced aldosterone. The latter gray–brown tumour was a pheochromocytoma composed of cells with granular and basophilic cytoplasm showing zellballen architecture (Figure 2, white arrow, and Figure 3b). Immunohistochemical studies showed positive for phenylethanolamine-N-methyltransferase, thyrosine hydroxylase and dopamine-β-hydroxylase. Repeat analyses of hormonal and electrolyte parameters 1 week after the surgery were compared with preoperative values. The plasma noradrenaline and adrenaline were normalized (91 and 5 pg ml–1, respectively), while hypokalemia and hyperaldosteronism remained (K 3.0 mEq l–1, PAC 527 pg ml–1) after the surgery. Interestingly, PRA turned to be suppressed (<0.1 ng ml–1 h–1). BP decreased from 140/90 to 130/80 mm Hg and doxazosin was discontinued. During the follow-up period of 2 years, her BP remained 120–130/70–80 mm Hg with the use of nifedipine and spironolactone. Left adrenal cortical adenoma on computed tomography showed no remarkable change. Coexistence of pheochromocytoma and primary aldosteronism is considered to be very rare. As far as we have examined, only two case reports have been published.2, 3 Although simultaneous occurrence of adrenal cortical adenoma and pheochromocytoma has been considered to be accidental, some papers hypothesized a functional relationship between them. Pheochromocytoma occasionally shows an elevation of PRA leading to secondary hyperaldosteronism.2, 4, 5, 6 The mechanism of renin stimulation by catecholamines is considered to be reduction in renal perfusion pressure5 or direct effects of catecholamines, especially norepinephrine, on juxtaglomerular cells.5, 7, 8 In addition, pheochromocytoma on rare occasions secretes some factors, such as an adrenocorticotropin (ACTH)-like substance, aldosterone-stimulating factor, pro-opiomelanocortin derivatives and serotonin.9 These conditions may lead to the pathogenesis of primary aldosteronism because of adrenocortical hyperplasia and adenoma.2, 3, 10 The functional relationship between hyperaldosteronism and pheochromocytoma were suggested in these observations. However, the extreme rarity of the coexistence of these two clinical features is against this hypothesis. In this case, the possibility of extra-adrenal localizations of pheochromocytoma was undeniable because noradrenaline level was dominantly elevated and the MIBG scintigraphy was negative. The sensitivity of MIBG scintigraphy had reported to be 86–92%1, 11, 12 and may show false negative in pheochromocytoma with small size or weak function. In this patient, the finding that noradrenaline and adrenaline concentrations in the right adrenal vein were 60 and 2.8 times higher compared with those in the left adrenal vein along with the MRI findings strongly suggested the presence of pheochromocytoma in the right adrenal gland. The decrease of plasma catecholamines after the surgery and the typical histological features of the resected specimen confirmed the diagnosis. In addition, plasma aldosterone/cortisol ratio in the left adrenal vein was higher than that in the right and PAC did not decrease after right adrenalectomy. Therefore, left adrenal might be major source of aldosterone production. We decided to resect right adrenal gland because of the coexistence of pheochromocytoma. We also speculated that aldosterone secretion in the right adrenal gland was also exaggerated because plasma aldosterone/cortisol ratio in the right adrenal vein was approximately 2.5 times higher compared with that in the lower inferior cava vein. In conclusion, we described a case of hyperaldosteronism because of bilateral adrenal cortical adenoma with coexistence of pheochromocytoma. As residual left adrenal cortical adenoma exists and the recurrence of pheochromocytoma may occur, a careful and long-term follow-up is required. The authors declare no conflict of interest. We greatly appreciate Dr Kazuto Shigematsu at the Department of Pathology, Japanese Red-Cross Nagasaki Atomic Bomb Hospital for performing immunohistochemical and in situ hybridization analyses.