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Prevalence of endogenous CS is 1/26,000, and CS due to EAS is responsible for 7 to 15% of the cases, with an equal female-to-male ratio.

Clinical features are quite wide ranging. Patients may present like those with CS (truncal and facial obesity and signs of hypercatabolism) and with skin hyperpigmentation like in Cushing disease (CD; see this term), or with skin pigmentation and severe amyotrophy with or without facial fullness or weight gain. Severe hypokalemia, life-threatening infections, psychiatric disorders, osteoporosis and fractures are seen more frequently in CS due to EAS than in CD. Specific signs depend of the causative tumor (paroxystic hypertension in pheochromocytoma, flush or diarrhea in medullary thyroid carcinoma, carcinoid syndrome in metastatic carcinoid tumors; see these terms).

The lung is the primary site of 50% of EAS cases (bronchial endocrine tumor and small cell lung cancer). Other sources include thymic and enteropancreatic endocrine tumors, pheochromocytoma, and medullary thyroid carcinoma (see these terms). EAS is rarely associated with non-endocrine, non-pulmonary tumors. Pheochromocytoma and medullary thyroid carcinoma may be part of genetic conditions such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) disease and neurofibromatosis type 1 (see these terms), and may be associated with specific gene mutations.

The first step of diagnosis should confirm CS (i.e. hypercortisolemic state) based on 1st and 2nd line recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 15-20 pg/mL [3.3-4.4 pmol/L]) from ACTH-independent CS (see this term). In case of doubt, a corticotropin-releasing hormone (CRH) test or even a high-dose dexamethasone suppression test and an adrenal gland computed tomography (CT) may be performed. The third step localizes the site of ACTH over-secretion, non-pituitary (EAS) or pituitary (CD). Diagnosis of CS due to EAS is based on the combination of dynamic hormonal tests (high-dose dexamethasone suppression test, CRH and/or desmopressin stimulation test) to distinguish it from CD, measures of tumour markers, imaging (pituitary magnetic resonance imaging [MRI], thoraco-abdomino-pelvic CT, somatostatin receptor scintigraphy) and bilateral inferior petrosal sinus sampling for ACTH assays.

The differential diagnosis of CS due to EAS is CD.

Antenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases (e.g. MEN 2, VHL disease, etc.).

Suspicion of a genetic disease warrants a specialized multidisciplinary genetic consultation.

The ideal treatment is curative surgery of the underlying tumor. Removal of the tumor may lead to full recovery but the condition may recur. If surgery is not curative due to severe metastatic spread, a multidisciplinary approach includes chemotherapy, radiotherapy, hormone analogues and/or radionuclide treatment to control tumor growth and associated symptoms. If the tumor is unresectable, anticortisolic medication (metyrapone, ketoconazole, mitotane or even etomidate) is recommended. Somatostatin and dopamine agonists have occasionally been used. Bilateral adrenalectomy can resolve hypercortisolism in cases of non operable or non localized secreting tumors or in cases of poor tolerance and inefficacy of medical treatment.

Prognosis and survival depends on tumor histology and staging. Untreated CS can be life-threatening.