Phaeochromocytoma and ACTH‐dependent cushing's syndrome: tumour crf secretion can mimic pituitary cushing's disease

Introduction 10% of corticotrophin (ACTH)-dependent Cushing's syndrome arises from secretion by extra-pituitary tumors, with phaeochromocytoma implicated in a few cases. Ectopic secretion by phaeochromocytoma of corticotropin-releasing hormone (CRF), with secondary corticotroph hyperplasia, is even rarer, with only five cases in the literature hitherto. However, such cases may be classified as “ectopic ACTH” due to incomplete verification. Clinical cases We describe three patients with phaeochromocytoma and ACTH-dependent Cushing's syndrome in whom biochemical cure was achieved following unilateral adrenalectomy. Although unable to access a validated CRF assay within the timeframe for sample storage, we nevertheless inferred CRF secretion in 2/3 cases by tumor-immunostaining (positive for CRF; negative for ACTH), supported in one case by pre-operative inferior petrosal sinus sampling (IPSS) indicative of pituitary ACTH source. Both cases were characterized by rapid post-operative wean off glucocorticoids, presumed to reflect the pituitary stimulatory-effect of CRF outweighing central negative feedback-inhibition by hypercortisolaemia. By contrast, the tumor excised in a third case exhibited positive immunostaining for ACTH -negative for CRF- and post-operative recovery of hypothalamo-pituitary-adrenal axis took significantly longer. Discussion Ectopic CRF production is biochemically indistinguishable from ectopic ACTH secretion, except that IPSS mimics pituitary Cushing's disease and cortisol dynamics may normalize rapidly post-adrenalectomy. CRF secretion can be inferred through tumor-immunohistochemistry, even if no CRF assay is available. Unrecognized phaeochromocytoma ACTH-secretion may underpin some cases of cardiovascular collapse post-adrenalectomy through acute hypocortisolaemia. Despite advances in phaeochromocytoma genetics since previous reports, we were unable to identify somatic DNA defects associated with either ACTH- or CRF secretion. This article is protected by copyright. All rights reserved.