Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle <i>via</i> a glucocorticoid-driven positive-feedback mechanism

Abstract

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, whileI-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.

Malignant Pheochromocytomas/Paragangliomas and Ectopic Hormonal Secretion: A Case Series and Review of the Literature

“…A total of 150 cases (Table 3) with ectopic secretion from PCs/PGLs have been reported (data presented in Table 3). ACTH secretion accounted for 33% of all cases (n = 49), whereas CRH, VIP, vasopressin, PTH, renin, aldosterone, insulin or somatostatin, GHRH, and neuropeptide Y secretion have also been described [16,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,…”

“…It is probable that ectopic secretion of bioactive compounds from these tumors is often overloooked or clinical manifestations are masked by the hypersecretion of catecholamines. The most frequent ectopically-secreted hormone is ACTH, mostly reported in benign PCs [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]. Ectopic secretion of hormones or peptides from malignant PCs/PGLs has been reported even more scarcely.…”

Ectopic ACTH-producing neuroendocrine tumor occurring with large recurrent metastatic pheochromocytoma: a case report

“…The pathophysiological characteristics of this exceptional case can be explained by the confirmation of ACTH-producing PCC with glucocorticoid-regulated positive feedback loops [ 6 , 7 ]. A parallel reduction not only in cortisol but also in ACTH and catecholamine levels upon metyrapone treatment (Figs.…”

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome with Recurrent Olfactory Neuroblastoma

“…Following metyrapone administration, the plasma ACTH levels usually increase in patients with pituitary Cushing's disease but decrease in those with ectopic ACTH syndrome (15,16). Cyclic Cushing's syndrome may have influenced the decrease in the ACTH levels, although glucocorticoid-driven positivefeedback regulation in ectopic ACTH syndrome has also been proposed (17).…”