Distinguishing Cushing's Disease from the Ectopic ACTH Syndrome: Needles in a Haystack or Hiding in Plain Sight?

Overview

Journal J Neuroendocrinol

Specialty Endocrinology

Date 2022 Aug 18

PMID 35980277

Authors

Aimee R Hayes

Ashley B Grossman

Affiliations

Soon will be listed here.

Abstract

In the context of ACTH-dependent Cushing's syndrome, ectopic ACTH secretion from a neuroendocrine tumour is not uncommon, and needs to be carefully differentiated from pituitary-dependent Cushing's syndrome, Cushing's disease, in order to optimise therapy. Some cases may be quite obvious, while in others the diagnosis may be difficult to confirm and the source of ACTH problematic, as many clinical and biochemical tests may overlap with Cushing's disease. Imaging is essential, but needs to be interpreted in the light of both anatomical as well as functional imaging modalities. In this review we summarise some of the main diagnostic problems, and emphasise the multimodal and interdisciplinary nature of the diagnostic pathways.

Citing Articles

Cushing syndrome.

Nieman L, Castinetti F, Newell-Price J, Valassi E, Drouin J, Takahashi Y Nat Rev Dis Primers. 2025; 11(1):4.

PMID: 39848955 DOI: 10.1038/s41572-024-00588-w.

Unusual Presentation of Case of a Lung Carcinoid Tumor With Ectopic Adrenocorticotropic Secretion (EAS) Associated With Acute Weight Gain and Peripheral Edema.

Abouibrahim M, Rahman M, Zafar M, Berliti S, Hacikurt K, Dashora U Cureus. 2024; 16(7):e63619.

PMID: 39092370 PMC: 11290955. DOI: 10.7759/cureus.63619.

The relationship between temporal muscle thickness and disease activity in Cushing's disease.

Ozaydin D, Demir A, Oz A, Birol A, Sulu C, Sahin S J Endocrinol Invest. 2023; 46(11):2411-2420.

PMID: 37704872 DOI: 10.1007/s40618-023-02195-0.

Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation.

Foppiani L, Poeta M, Rutigliani M, Parodi S, Catrambone U, Cavalleri L Endocrinol Diabetes Metab Case Rep. 2023; 2023(2).

PMID: 37162230 PMC: 10266445. DOI: 10.1530/EDM-22-0308.

Distinguishing Cushing's disease from the ectopic ACTH syndrome: Needles in a haystack or hiding in plain sight?.

Hayes A, Grossman A J Neuroendocrinol. 2022; 34(8):e13137.

PMID: 35980277 PMC: 9542389. DOI: 10.1111/jne.13137.

References

Hermus A, Pieters G, Pesman G, Smals A, BENRAAD T, KLOPPENBORG P . The corticotropin-releasing-hormone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome. Lancet. 1986; 2(8506):540-4. DOI: 10.1016/s0140-6736(86)90113-3. View

Wengander S, Trimpou P, Papakokkinou E, Ragnarsson O . The incidence of endogenous Cushing's syndrome in the modern era. Clin Endocrinol (Oxf). 2019; 91(2):263-270. DOI: 10.1111/cen.14014. View

de Bruin C, Hofland L, Nieman L, Van Koetsveld P, Waaijers A, Sprij-Mooij D . Mifepristone effects on tumor somatostatin receptor expression in two patients with Cushing's syndrome due to ectopic adrenocorticotropin secretion. J Clin Endocrinol Metab. 2011; 97(2):455-62. PMC: 3275368. DOI: 10.1210/jc.2011-1264. View

Isidori A, Kaltsas G, Pozza C, Frajese V, Newell-Price J, Reznek R . The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2005; 91(2):371-7. DOI: 10.1210/jc.2005-1542. View

Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz N . Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021; 9(12):847-875. PMC: 8743006. DOI: 10.1016/S2213-8587(21)00235-7. View

LIDDLE G . Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab. 1960; 20:1539-60. DOI: 10.1210/jcem-20-12-1539. View

Davi M, Cosaro E, Piacentini S, Reimondo G, Albiger N, Arnaldi G . Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017; 176(4):453-461. DOI: 10.1530/EJE-16-0809. View

Sharma S, Raff H, Nieman L . Prolactin as a marker of successful catheterization during IPSS in patients with ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab. 2011; 96(12):3687-94. PMC: 3232627. DOI: 10.1210/jc.2011-2149. View

Beuschlein F, Hammer G . Ectopic pro-opiomelanocortin syndrome. Endocrinol Metab Clin North Am. 2002; 31(1):191-234. DOI: 10.1016/s0889-8529(01)00025-1. View

10.

Losa M, Albano L, Bailo M, Barzaghi L, Mortini P . Role of radiosurgery in the treatment of Cushing's disease. J Neuroendocrinol. 2022; 34(8):e13134. DOI: 10.1111/jne.13134. View

11.

Arlt W, Dahia P, Callies F, Nordmeyer J, Allolio B, Grossman A . Ectopic ACTH production by a bronchial carcinoid tumour responsive to desmopressin in vivo and in vitro. Clin Endocrinol (Oxf). 1998; 47(5):623-7. DOI: 10.1046/j.1365-2265.1997.3091129.x. View

12.

Hamblin R, Coulden A, Fountas A, Karavitaki N . The diagnosis and management of Cushing's syndrome in pregnancy. J Neuroendocrinol. 2022; 34(8):e13118. PMC: 9541401. DOI: 10.1111/jne.13118. View

13.

Salehidoost R, Korbonits M . Glucose and lipid metabolism abnormalities in Cushing's syndrome. J Neuroendocrinol. 2022; 34(8):e13143. DOI: 10.1111/jne.13143. View

14.

Valassi E, Santos A, Yaneva M, Toth M, Strasburger C, Chanson P . The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol. 2011; 165(3):383-92. DOI: 10.1530/EJE-11-0272. View

15.

Steffensen C, Bak A, Rubeck K, Jorgensen J . Epidemiology of Cushing's syndrome. Neuroendocrinology. 2010; 92 Suppl 1:1-5. DOI: 10.1159/000314297. View

16.

Limper A, Carpenter P, Scheithauer B, Staats B . The Cushing syndrome induced by bronchial carcinoid tumors. Ann Intern Med. 1992; 117(3):209-14. DOI: 10.7326/0003-4819-117-3-209. View

17.

Arnaldi G, Mancini T, Kola B, Appolloni G, Freddi S, Concettoni C . Cyclical Cushing's syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors. J Clin Endocrinol Metab. 2003; 88(12):5834-40. DOI: 10.1210/jc.2003-030514. View

18.

Findling J, Kehoe M, Raff H . Identification of patients with Cushing's disease with negative pituitary adrenocorticotropin gradients during inferior petrosal sinus sampling: prolactin as an index of pituitary venous effluent. J Clin Endocrinol Metab. 2004; 89(12):6005-9. DOI: 10.1210/jc.2004-1378. View

19.

Oliver R, Davis J, White A . Characterisation of ACTH related peptides in ectopic Cushing's syndrome. Pituitary. 2004; 6(3):119-26. DOI: 10.1023/b:pitu.0000011172.26649.df. View

20.

Kamp K, Alwani R, Korpershoek E, Franssen G, de Herder W, Feelders R . Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. Eur J Endocrinol. 2015; 174(3):271-80. DOI: 10.1530/EJE-15-0968. View