An Overview of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropin Secretion
9 affiliations
- 1Department of Endocrinology, Hippokration Hospital, 115 27 Athens, Greece
- 2School of Medicine, PROMISE Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medicinal Specialties, University of Palermo, 90133 Palermo, Italy
- 3Department of Anatomy, Faculty of General Medicine, Ovidius University, 900470 Constanta, Romania
- 4Department and Clinic of Internal Diseases and Metabolic Disorders, Poznan University of Medical Sciences, 61-701 Poznań, Poland
- 5Department of Pharmacoeconomics and Social Pharmacy, Poznan University of Medical Sciences, 61-701 Poznań, Poland
- 6Department of Anatomical Pathology & Clinical Morphology, Mkhitar Heratsi Yerevan State Medical University, Yerevan 0025, Armenia
- 7Isfahan Cardiovascular Research Centre, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan 81465-1148, Iran
- 8RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
- 9RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
Abstract
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.
Related
- First case report of ectopic Cushing's syndrome secondary to synchronous mediastinal neuroendocrine tumors.
- Analysis of biochemical parameters and tumor markers in Cushing’s disease and ectopic adrenocorticotropic hormone syndrome
- Gynecomastia in iatrogenic Cushing syndrome.
- When anorexia nervosa conceals Cushing syndrome: a diagnostic pitfall in hypercortisolemia
- Venous thromboembolism in Cushing syndrome: current evidence and a practical thromboprophylaxis algorithm
BibTeX
@article{ilias2026overview,
title = {{An Overview of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropin Secretion}},
author = {Ioannis Ilias and Viviana Maggio and Sorina Ispas and Karolina Hoffmann and Anna Paczkowska and Ashot Avagimyan and Imran Rashid Rangraze and Adil Farooq Wali and Sirajunisa Talath and Syed Arman Rabbani and Bhoomendra A. Bhongade and Shakta Mani Satyam and Manfredi Rizzo and Mohamed El-Tanani},
journal = {Journal of Clinical Medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15208192},
url = {https://www.mdpi.com/2077-0383/15/20/8192},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - An Overview of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropin Secretion
AU - Ioannis Ilias
AU - Viviana Maggio
AU - Sorina Ispas
AU - Karolina Hoffmann
AU - Anna Paczkowska
AU - Ashot Avagimyan
AU - Imran Rashid Rangraze
AU - Adil Farooq Wali
AU - Sirajunisa Talath
AU - Syed Arman Rabbani
AU - Bhoomendra A. Bhongade
AU - Shakta Mani Satyam
AU - Manfredi Rizzo
AU - Mohamed El-Tanani
PY - 2026
DA - 2026/10/01
JO - Journal of Clinical Medicine
DO - 10.3390/jcm15208192
UR - https://www.mdpi.com/2077-0383/15/20/8192
AB - 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.
SN - 2077-0383
ER -