An Overview of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropin Secretion

Ectopic Cushing’s syndrome (ECS) causes 10% to 20% of all cases of endogenous hypercortisolism. It is caused by the aberrant secretion of adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) due to the presence of an ectopic tumor. The latter is usually a neuroendocrine (NEN) tumor (mostly thoracic NENs such as bronchial NEN neoplasms, thymic NEN neoplasms, small cell lung carcinoma (SCLC), or pancreatic NEN neoplasms). Clinical presentation is heterogeneous: an aggressive phenotype, typically driven by rapidly growing, poorly differentiated tumors such as small-cell lung carcinoma, manifests with severe symptoms of acute onset, predominant myopathy, resistant arterial hypertension, hypokalemia, and severe hyperpigmentation, usually without the centripetal obesity typical of Cushing’s syndrome; conversely, an indolent phenotype, more often related to well-differentiated neuroendocrine neoplasms such as bronchial carcinoids, may present with the classic centripetal fat distribution, facial plethora, and purple striae also seen in Cushing’s disease, making clinical distinction between the two difficult. The diagnosis of ECS can be cumbersome and time-consuming. Once hypercortisolism is confirmed, the most critical step is to distinguish patients with an ectopic source of ACTH from those with pituitary adenoma. Dynamic endocrine tests such as the high-dose dexamethasone suppression test, CRH stimulation tests, desmopressin tests, and bilateral inferior petrosal sinus sampling (BIPSS) can be helpful in the differential diagnosis. BIPSS is considered the gold standard for distinguishing a pituitary from a non-pituitary source of ACTH: the absence of a central-to-peripheral ACTH gradient supports, but does not by itself localize or confirm, an ectopic source. Tumor localization is achieved by a multimodality imaging protocol, including initial high-resolution computed tomography (CT) scans, followed by functional imaging, mainly Gallium-68-labeled somatostatin receptor positron emission tomography (PET)/CT scans. However, in 10–20% of these patients, the tumors cannot be localized. The treatment of ACTH-dependent hypercortisolism is two-fold: one is to immediately control hypercortisolism to prevent life-threatening complications (opportunistic infections and thromboembolism), and the second is to definitively treat the tumor. Medical treatment with steroidogenesis inhibitors, including metyrapone, ketoconazole, and osilodrostat, or surgical management (bilateral adrenalectomy) can be effective in immediately controlling hypercortisolism. Definitive surgical resection of the tumor is the hoped-for final treatment. The prognosis is variable, depending on the nature of the underlying neoplasm, ranging from excellent in patients with resected bronchial carcinoids to dismal in those with SCLC.