Society of Diabetic Nephropathy Prevention Journal of Preventive Epidemiology 2476-3934 11 2 2026 07 01 Paraneoplastic hypercortisolism; mechanisms and management of lung cancer–induced ectopic Cushing syndrome e39326 e39326 10.34172/jpe.39326 EN Masoume Bitaraf https://orcid.org/0000-0001-7308-1057 Mohammad Memarian https://orcid.org/0000-0003-4534-3018 Journal Article 10.34172/jpe.39326 2025 12 13 2026 05 14 Paraneoplastic hypercortisolism from lung cancer-induced ectopic Cushing syndrome (ECS) is a critical condition caused by unregulated secretion of adrenocorticotropic hormone (ACTH) from neuroendocrine lung tumors, notably small cell lung cancer (SCLC). SCLC accounts for most ECS cases, due to its aggressive nature, rapid growth, early metastasis, and strong link to tobacco use. Neuroendocrine lung tumors vary from low-grade carcinoids to highly malignant SCLC and large cell neuroendocrine carcinoma, all capable of ectopic ACTH production that stimulates excess cortisol secretion, causing bilateral adrenal hyperplasia. Ectopic Cushing syndrome manifests with rapidly developing severe symptoms such as hypokalemia, metabolic alkalosis, hypertension, hyperglycemia, muscle weakness, facial puffiness, bruising, and hyperpigmentation. Hypokalemia is particularly dangerous. Diagnosis relies on biochemical evidence of elevated ACTH and cortisol with loss of normal cortisol rhythm, complemented by dynamic tests like dexamethasone suppression, though responses can be atypical. Imaging supports tumor localization, with inferior petrosal sinus sampling considered the gold standard to distinguish ectopic ACTH sources. Management involves controlling cortisol excess using steroidogenesis inhibitors and potassium-sparing diuretics, with bilateral adrenalectomy reserved for refractory cases. Simultaneously, treatment targets the underlying malignancy, mainly with chemotherapy (cisplatin/etoposide), radiation, and sometimes surgery in early stages. Despite treatment advances, prognosis remains poor; median survival for extensive SCLC is under 14 months.