Ectopic ACTH: Paraneoplastic Cushing

Ectopic ACTH syndrome is a paraneoplastic condition in which non-pituitary tumors autonomously produce adrenocorticotropic hormone (ACTH) or, less commonly, corticotropin-releasing hormone (CRH), causing ACTH-dependent hypercortisolism. Small cell lung cancer (SCLC) accounts for approximately 50% of ectopic ACTH cases, followed by bronchial carcinoid tumors (10%), thymic carcinoid, pancreatic islet cell tumors, medullary thyroid carcinoma, and pheochromocytoma. The tumor-produced ACTH stimulates bilateral adrenal cortical hyperplasia and excessive cortisol secretion, which overwhelms the normal hypothalamic-pituitary-adrenal (HPA) axis negative feedback mechanism. Unlike pituitary-dependent Cushing disease (where the pituitary adenoma retains partial feedback sensitivity), ectopic ACTH production is autonomous and typically produces very high ACTH and cortisol levels. The rapid onset and severity of hypercortisolism in SCLC-associated ectopic ACTH often produces a distinct clinical picture dominated by hypokalemic metabolic alkalosis (cortisol at very high levels activates mineralocorticoid receptors, causing sodium retention and potassium wasting), proximal myopathy, hyperglycemia, and severe immunosuppression rather than the classic Cushingoid body habitus (which requires months to develop). The clinician must differentiate ectopic ACTH from pituitary Cushing disease using biochemical testing (high-dose dexamethasone suppression test, CRH stimulation test) and inferior petrosal...