RARE DISEASE
Cushing syndrome due to ectopic ACTH secretion
Cushing syndrome due to ectopic ACTH secretion
Cushing syndrome due to ectopic ACTH secretion
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Drug discovery
1
drug
With orphan designation
Overview
Cushing syndrome due to ectopic ACTH secretion (EAS) is a rare, ACTH-dependent hypercortisolism caused by neuroendocrine tumors (NETs) outside the pituitary gland. Common sources include bronchial carcinoids (40%) and small cell lung cancer. Diagnosis requires biochemical confirmation of hypercortisolism, elevated ACTH levels (>20 pg/mL), and localization via imaging (CT/MRI) or functional studies (e.g., CRH tests, petrosal sinus sampling). Severe hypokalemia, infections, and metabolic derangements are frequent, necessitating urgent treatment [1][4][6][16].
Therapies
Primary: Surgical resection of ACTH-secreting tumors (curative if localized) [3][18].
Medical: Adrenal enzyme inhibitors (metyrapone, osilodrostat, ketoconazole) or somatostatin analogs to control hypercortisolism [3][8][10].
Adjunctive: Chemotherapy/radiotherapy for malignancies; bilateral adrenalectomy for refractory cases [4][18][20].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
775 drug discovery papers related to Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
775 drug discovery papers related to Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-08 | Ectopic ACTH Production in Medullary Thyroid Carcinoma-A Study of Two Cases.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from thyroid parafollicular C-cells, accounting for 1-2% of all thyroid cancers. An exceedingly rare manifestation of MTC is ectopic adrenocorticotropic hormone (ACTH) production, causing Cushing's syndrome and complicating management. This report presents two cases of MTC with ectopic ACTH production, highlighting diagnostic challenges, therapeutic strategies, and clinical outcomes. A comprehensive literature review on this rare paraneoplastic syndrome is included and supplements the case findings. Case 1 involves a 49-year-old man presenting with abdominal pain, weight loss, and pulmonary nodules, diagnosed with MTC and ectopic ACTH-related Cushing's syndrome. Surgical resection and targeted therapy with selpercatinib improved cortisol levels but were complicated by adverse drug reactions. Case 2 details a 65-year-old woman with severe hypercortisolism and locally advanced MTC. Selpercatinib successfully reduced hormone levels and achieved partial tumor regression. Both cases underscore the critical role of tyrosine kinase inhibitors (TKIs) in controlling tumor progression, and paraneoplastic hormone production is exemplified in both cases, as treatment initiation was followed by a biochemical response with declining levels of ACTH, cortisol, and calcitonin. Ectopic ACTH production in MTC is a rare but clinically significant entity associated with aggressive disease. Early recognition, comprehensive biochemical and imaging evaluations, and a multidisciplinary approach are pivotal for optimal management. The advent of targeted therapies, such as selpercatinib, has transformed the therapeutic landscape, offering improved control of both tumor burden and hormone excess. This report highlights the importance of integrating genomic insights and precision medicine in addressing these complex cases.
2026-06-30 | Dominant T cell receptor clonotypes in adrenocorticotropic hormone-secreting pituitary carcinoma are the highest-frequency clones among CD4+ and CD8+ cells in peripheral blood during effective anti-PD-1 therapy.
Pituitary carcinoma is a rare and highly aggressive tumor. While anti-programmed cell death-1 (PD-1) therapy has shown efficacy in some cases, the factors that predict a favorable response remain largely unclear. To evaluate tumor-infiltrating lymphocytes (TILs) in pituitary carcinoma and to compare T-cell receptor (TCR) clonotypes between the pituitary and peripheral blood. A 34-year-old woman with Lynch syndrome and adrenocorticotropic hormone-secreting pituitary carcinoma with hepatic metastasis received anti-PD-1 therapy, achieving durable disease control exceeding 1 year. Immunohistochemistry was performed on treatment-naïve surgical tumor samples, and TCR repertoire analyses were conducted on both the tumor sample and peripheral blood mononuclear cells collected during effective anti-PD-1 therapy. Treatment-naïve pituitary carcinoma tissues exhibited infiltration of CD4+ and CD8+ T cells. Analysis of the TCR repertoire identified 15 clonotypes with a high frequency (> 1% of sequencing reads) in the tumor; among these, four of the five most prevalent clonotypes were co-detected as dominant clones in peripheral blood after treatment, including the most abundant clones found within the CD4+ and CD8+ T cell populations. Despite control of the primary and hepatic lesions, ovarian metastasis developed, which was associated with reduced CD4+ TILs. The presence of CD4+ and CD8+ TILs may underlie the immunological foundation for PD-1 blockade efficacy in pituitary carcinoma, supported by the detection of tumor-resident TCR clonotypes in peripheral blood during a positive therapeutic response.
2026-06-18 | Ectopic ACTH-producing pheochromocytoma in a patient with an APC gene mutation: A case report.
ACTH-producing pheochromocytomas are rare. Familial adenomatous polyposis (FAP), caused by mutations in the Adenomatous Polyposis Coli (APC) gene, increases the risk of colorectal neoplasia, as well as adrenal lesions. This is the case of a 21-year-old male presenting with a 10cm right adrenal mass and rapidly progressive Cushing's syndrome (CS). Biochemical workup confirmed ACTH-dependent CS and catecholamine excess and a 68Ga-DOTA-NOC PET/CT showed SSR expression limited to the adrenal mass. Methyrapone and alpha/beta blockade were initiated, followed by right adrenalectomy. Histopathology confirmed an ACTH-secreting pheochromocytoma (pheochromocytoma of the adrenal gland scaled score - PASS: 16; grading system for adrenal pheochromocytoma and paraganglioma - GAPP: 8). A truncating germline mutation in the APC gene (c.6189_6190del) was detected, associated with attenuated FAP. This is, to our knowledge, the first case ever reported of an ACTH-producing pheochromocytoma in a patient with an APC gene mutation. This case raises the possibility of a broader phenotypic spectrum in FAP and highlights the importance of vigilance for unusual tumor presentations in hereditary cancer syndromes.
2026-07-08 | Ectopic ACTH Production in Medullary Thyroid Carcinoma-A Study of Two Cases.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from thyroid parafollicular C-cells, accounting for 1-2% of all thyroid cancers. An exceedingly rare manifestation of MTC is ectopic adrenocorticotropic hormone (ACTH) production, causing Cushing's syndrome and complicating management. This report presents two cases of MTC with ectopic ACTH production, highlighting diagnostic challenges, therapeutic strategies, and clinical outcomes. A comprehensive literature review on this rare paraneoplastic syndrome is included and supplements the case findings. Case 1 involves a 49-year-old man presenting with abdominal pain, weight loss, and pulmonary nodules, diagnosed with MTC and ectopic ACTH-related Cushing's syndrome. Surgical resection and targeted therapy with selpercatinib improved cortisol levels but were complicated by adverse drug reactions. Case 2 details a 65-year-old woman with severe hypercortisolism and locally advanced MTC. Selpercatinib successfully reduced hormone levels and achieved partial tumor regression. Both cases underscore the critical role of tyrosine kinase inhibitors (TKIs) in controlling tumor progression, and paraneoplastic hormone production is exemplified in both cases, as treatment initiation was followed by a biochemical response with declining levels of ACTH, cortisol, and calcitonin. Ectopic ACTH production in MTC is a rare but clinically significant entity associated with aggressive disease. Early recognition, comprehensive biochemical and imaging evaluations, and a multidisciplinary approach are pivotal for optimal management. The advent of targeted therapies, such as selpercatinib, has transformed the therapeutic landscape, offering improved control of both tumor burden and hormone excess. This report highlights the importance of integrating genomic insights and precision medicine in addressing these complex cases.
2026-06-30 | Dominant T cell receptor clonotypes in adrenocorticotropic hormone-secreting pituitary carcinoma are the highest-frequency clones among CD4+ and CD8+ cells in peripheral blood during effective anti-PD-1 therapy.
Pituitary carcinoma is a rare and highly aggressive tumor. While anti-programmed cell death-1 (PD-1) therapy has shown efficacy in some cases, the factors that predict a favorable response remain largely unclear. To evaluate tumor-infiltrating lymphocytes (TILs) in pituitary carcinoma and to compare T-cell receptor (TCR) clonotypes between the pituitary and peripheral blood. A 34-year-old woman with Lynch syndrome and adrenocorticotropic hormone-secreting pituitary carcinoma with hepatic metastasis received anti-PD-1 therapy, achieving durable disease control exceeding 1 year. Immunohistochemistry was performed on treatment-naïve surgical tumor samples, and TCR repertoire analyses were conducted on both the tumor sample and peripheral blood mononuclear cells collected during effective anti-PD-1 therapy. Treatment-naïve pituitary carcinoma tissues exhibited infiltration of CD4+ and CD8+ T cells. Analysis of the TCR repertoire identified 15 clonotypes with a high frequency (> 1% of sequencing reads) in the tumor; among these, four of the five most prevalent clonotypes were co-detected as dominant clones in peripheral blood after treatment, including the most abundant clones found within the CD4+ and CD8+ T cell populations. Despite control of the primary and hepatic lesions, ovarian metastasis developed, which was associated with reduced CD4+ TILs. The presence of CD4+ and CD8+ TILs may underlie the immunological foundation for PD-1 blockade efficacy in pituitary carcinoma, supported by the detection of tumor-resident TCR clonotypes in peripheral blood during a positive therapeutic response.
2026-06-18 | Ectopic ACTH-producing pheochromocytoma in a patient with an APC gene mutation: A case report.
ACTH-producing pheochromocytomas are rare. Familial adenomatous polyposis (FAP), caused by mutations in the Adenomatous Polyposis Coli (APC) gene, increases the risk of colorectal neoplasia, as well as adrenal lesions. This is the case of a 21-year-old male presenting with a 10cm right adrenal mass and rapidly progressive Cushing's syndrome (CS). Biochemical workup confirmed ACTH-dependent CS and catecholamine excess and a 68Ga-DOTA-NOC PET/CT showed SSR expression limited to the adrenal mass. Methyrapone and alpha/beta blockade were initiated, followed by right adrenalectomy. Histopathology confirmed an ACTH-secreting pheochromocytoma (pheochromocytoma of the adrenal gland scaled score - PASS: 16; grading system for adrenal pheochromocytoma and paraganglioma - GAPP: 8). A truncating germline mutation in the APC gene (c.6189_6190del) was detected, associated with attenuated FAP. This is, to our knowledge, the first case ever reported of an ACTH-producing pheochromocytoma in a patient with an APC gene mutation. This case raises the possibility of a broader phenotypic spectrum in FAP and highlights the importance of vigilance for unusual tumor presentations in hereditary cancer syndromes.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Cushing syndrome due to ectopic ACTH secretion.
1 orphan drug designation for Cushing syndrome due to ectopic ACTH secretion.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mifepristone | small molecules | FDA | 2005-02-07 | — | HRA Pharma |
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