Cushing syndrome due to ectopic ACTH secretion (ORPHA:99889)
A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by the secretion of ACTH by non-pituitary neuroendocrine tumors (NETs) of various locations and various degrees of histological differentiation and aggressiveness.
Epidemiology
The annual incidence of Cushing syndrome (CS) due to ectopic ACTH secretion (EAS), is estimated at about 1/1,250,000. The vast majority cases are sporadic and occur in adulthood, with an equal female-to-male ratio.
Clinical description
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), 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 on the causative tumor, its site and extension, and may include paroxystic hypertension in pheochromocytoma, flush or diarrhea in medullary thyroid carcinoma, and carcinoid syndrome in metastatic carcinoid tumors.
Etiology
The tumors responsible for an EAS have a variety of locations and histological types. The lung is the primary site of 40% of EAS cases (bronchial carcinoid and small cell lung cancer). Other tumors derive mainly from the foregut (larynx, thymus, stomach, duodenum and pancreas). Rarely, pheochromocytomas and medullary thyroid carcinoma secrete ACTH in addition to catecholamines and calcitonin, respectively. Some exceptional inherited cases are described, with ACTH-secreting thymic neuroendocrine tumors (NETs), in the context of multiple endocrine neoplasia type 1 (MEN1), medullary thyroid cancers in MEN2 and pancreatic NETs in the Von Hippel-Lindau syndrome.
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL; 4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL; 2.2 pmol/L). Cortisol and ACTH levels can be very high in EAS. The third step localizes the site of ACTH over-secretion, pituitary (CD) or non-pituitary (EAS). Diagnosis is based on dynamic hormonal tests to analyze the corticotropic response that distinguishes CD (with response often partially regulated: ''positive'' tests) from EAS (with response generally unregulated: ''negative'' tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computer tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay. Rare concomitant secretion of corticotropin-releasing hormone (CRH) and ACTH, and exceptional exclusive CRH secretion have been described.
Differential diagnosis
The differential diagnosis of CS due to EAS is CD.
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases (e.g. MEN2, VHL disease, etc.).
Genetic counseling
Suspicion of a genetic disease warrants a specialized genetic consultation. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
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 or possible, a multidisciplinary approach includes chemotherapy, radiotherapy, hormone analogues and/or radionuclide treatment to control tumor growth and associated symptoms. If the tumor is unresectable, or while waiting for the effectiveness of the treatment of the tumor in cases of severe CS, anticortisolic medication and preventive and curative treatment of comorbidities are recommended. 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
Prognosis depends on tumor histology and staging, and on severity of CS. Untreated CS can be life-threatening.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Dr Laurence GUIGNAT | Endo-ERN*


                                * European Reference Network