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
802 drug discovery papers about Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
802 drug discovery papers about Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-30 | Diabetes mellitus masking an ectopic Cushing syndrome in a young male: a case report
Ectopic adrenocorticotropic hormone (ACTH) secretion is a rare but important cause of Cushing syndrome, often associated with neuroendocrine tumors such as bronchial or gastrointestinal carcinoids. Its presentation can be subtle or atypical, delaying diagnosis and increasing morbidity. Herein this case report presents a 24-year-old male presenting with uncontrolled diabetes mellitus, polyuria, and weight loss (13 kg over 6 months). He exhibited proximal muscle weakness, broad purple striae, and extensive hyperpigmentation. Laboratory evaluation revealed markedly elevated 8 am serum cortisol 82 mcg/dl, midnight awake cortisol 211 mcg/dl, overnight dexamethasone suppression test (27.32 mcg/dl), plasma ACTH 320 pg/ml, and a non-suppressed (<50%) high-dose dexamethasone suppression test (16 mcg/dl). High-resolution computed tomography (HRCT) chest demonstrated multiple pulmonary nodules. Ga-68 DOTANOC PET-CT imaging revealed somatostatin receptor expression in bilateral lung nodules. Endobronchial biopsy confirmed atypical carcinoid tumor, Ki-67 index 4%. This case highlights the diagnostic complexity of ectopic ACTH syndrome, particularly in young adults presenting with rapidly worsening diabetes. The presence of significant pigmentation, proximal myopathy, and metabolic derangements were key clinical clues. Atypical carcinoid tumors exhibit intermediate biological behavior and require a multidisciplinary management approach including surgical resection, somatostatin analog therapy, and cortisol-lowering strategies. Ectopic ACTH syndrome should be considered in young patients with severe metabolic abnormalities, rapid weight loss, and hyperpigmentation. Early recognition and appropriate work-up can prevent complications and improve outcomes.
2025-03-29 | Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice.
Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response. We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed. Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery. This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.
2025-01-30 | Performance of Vasopressin Stimulated Bilateral Inferior Petrosal Sinus Sampling in Corticotropin Dependent Cushing's Syndrome with Negative or Equivocal 3 Tesla Contrast Enhanced Magnetic Resonance Imaging of Pituitary.
Corticotropin releasing hormone (CRH)-stimulated bilateral inferior petrosal sinus sampling (BIPSS) is the most accurate procedure in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) with a sensitivity of 88-100% and a specificity of 67-100%. However, CRH is not available globally currently. We undertook this study of BIPSS using lysine vasopressin (LVP) as an agent to stimulate the release of ACTH from corticotrophs. Our objective was to assess the accuracy of LVP-stimulated BIPSS in differentiating Cushing's disease (CD) from ectopic ACTH syndrome (EAS) with negative or equivocal 3T contrast-enhanced MRI (CEMRI). Seventeen patients with clinically and biochemically confirmed ACTH-dependent CS with equivocal or negative CEMRI pituitary underwent BIPSS using LVP as a stimulating agent. Of seventeen patients who underwent BIPSS, nine patients had a raised central-to-peripheral ACTH ratio and were classified as having CD that was confirmed on histopathology following transsphenoidal sinus surgery. Remaining eight patients, who did not show a raised central-to-peripheral ACTH ratio, were classified to have EAS. All patients with EAS underwent contrast-enhanced computerised tomography of the neck, chest, and abdomen and/or Gallium 68 DOTANOC positron emission tomography/computerised tomography. Seven out of eight patients demonstrated solitary pulmonary nodule in the lung (bronchial carcinoid), and one patient had a mass in the thymus (thymic carcinoid). BIPSS using LVP confirmed the source of ACTH excess correctly in all the patients with ACTH-dependent CS without the loss of specificity.
2024-05-01 | #1704792 Octreotide Use in a Critically Ill Patient with Ectopic ACTH Secretion
Ectopic ACTH secretion is a rare cause of hypercortisolism primarily treated with surgical resection. Octreotide, a somatostatin analogue, is used in the medical management of Cushing Disease. Though it is considered a potential therapy for ectopic ACTH secretion, data supporting its use is lacking. In this case, we describe the successful reduction in serum cortisol with subcutaneous octreotide in a patient with an ACTH-secreting pulmonary carcinoid tumor.
2024-04-04 | The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage.
The ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation. We compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation. The ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively. With the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.
small molecules
2026-09-24 | Management of ectopic Cushing syndrome in medullary thyroid carcinoma: from case reports to systematic literature review.
Ectopic Cushing's syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism. We conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from "C. I. Parhon" National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset. The systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12-84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment. ECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.
2026-09-22 | Conversion therapy followed by curative resection in a patient with ACTH-secreting pancreatic neuroendocrine tumor G3: a case report
Background Pancreatic neuroendocrine tumors (pNETs) with ectopic adrenocorticotropic hormone (ACTH) production are uncommon, highly aggressive, and carry a dismal prognosis. Early nonspecific symptoms often delay diagnosis, and treatment strategies remain controversial. For patients with locally advanced pNETs, conversion therapy has only rarely been reported and remains a sparingly applied strategy. Case presentation A 37-year-old woman presented with a six-month history of progressive swelling in both lower extremities and her face. Further workup confirmed ACTH-dependent Cushing syndrome. CT and MRI identified a 5.7 × 2.8 cm lesion in the pancreatic body/tail that invaded the left adrenal gland and splenic vessels, accompanied by retroperitoneal lymph node spread. Biopsy results indicated a G3 pNET. Given the borderline resectable status due to local advancement, she received conversion therapy comprising a long-acting somatostatin analogue followed by CapTem chemotherapy. After three months of neoadjuvant treatment, imaging showed modest primary tumor shrinkage and marked reduction of lymph node size, reflecting successful downstaging. Subsequently, she underwent distal pancreatectomy with splenectomy, left adrenalectomy, and lymph node dissection, achieving R0 resection. Final pathology confirmed a G3 pNET (Ki-67 30%–40%) with positive SSTR2 and ACTH immunostaining. Although the patient eventually experienced disease progression and succumbed to COVID-19 infection 37 months after initial diagnosis, this case illustrates that conversion therapy can render an initially borderline resectable high-grade pNET amenable to curative resection. Conclusion This report underscores the aggressive trajectory of ACTH-secreting pNET G3 and suggests the potential utility of conversion therapy. Further studies are needed to validate this approach.
2026-09-22 | Ectopic Cushing's syndrome. A metastatic hepatic neuroendocrine tumour: case report and literature review.
This report describes a rare instance of an adrenocorticotropic hormone (ACTH)-secreting metastatic hepatic neuroendocrine tumour (MHNET) exhibiting as an ectopic Cushing's syndrome. A 41-year-old woman with a history of supraglottic neuroendocrine tumour presented with rapid weight gain, severe hypokalemia, and hypercortisolism. Pituitary imaging was unremarkable. However, the DOTATATE PET/CT showed a large liver lesion. Initiating etomidate infusion caused a rapid drop in cortisol, leading to severe vasoplegic and septic shock, which delayed the surgery. The patient required intensive care stabilization pre-operatively and treatment with osilodrostat, which was then followed by surgical management: left lateral hepatectomy and gastric wedge resection. ACTH levels markedly decreased postoperatively, reflecting successful management. This emphasizes that careful medical management and multidisciplinary collaboration are essential in treating severe, potentially life-threatening ectopic hypercortisolism.
2026-09-03 | Metyrapone in the Management of Severe Hypercortisolism Secondary to Ectopic Cushing's Syndrome.
Ectopic Cushing's syndrome (ECS) is a rare but important cause of ACTH-dependent Cushing's syndrome. Metyrapone, a steroidogenesis inhibitor targeting 11-β hydroxylase, has shown effectiveness in controlling hypercortisolism. However, little is known about the practical aspects of its initiation, use, and effectiveness in ECS. We present three cases of severe hypercortisolism secondary to ECS managed with metyrapone and report our experience. Case 1: a 56-year-old male with high-grade neuroendocrine carcinoma. Case 2: a 67-year-old man with a history of stage IIB non-small cell lung cancer (NSCLC) with metastatic neuroendocrine carcinoma. Case 3: a 64-year-old man with metastatic prostate cancer. Biochemical control was achieved with rapid titration of low doses of daily metyrapone in all three cases. Based on our experience, we recommend an initial dose of 1000-1500 mg of metyrapone daily, in divided doses, with physiologic glucocorticoid replacement to mitigate the risk of adrenal insufficiency. Despite improvements in cortisol levels and stabilization of metabolic derangements, all three patients ultimately transitioned to comfort-focused care. Given the rarity, heterogeneity, and aggressiveness of this condition, rapid diagnosis and standardized pharmacologic approach are difficult to achieve. More data are needed to guide optimal therapy selection, dosing, and titration in ECS.
2026-08-13 | Ectopic ACTH-dependent Cushing syndrome in 3 hospitalized patients: lessons learned from management with osilodrostat.
Severe Cushing syndrome (CS) is a rare diagnosis with high mortality, which limits the ability of endocrinologists to gain experience delivering care. Here we describe our experience treating 3 cases of ectopic ACTH-dependent CS presenting in a single year. The initial diagnosis of each case was made during hospitalization resulting from complications of CS, implicating severe disease and delayed diagnosis. Our experience suggests that rapid initiation and titration of osilodrostat effectively treats hypercortisolism and improves outcomes.
oligonucleotides
2023-01-05 | Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice.
It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND. These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.
2022-03-22 | KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
2021-11-04 | Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.
Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.
2015-09-30 | Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature.
OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27(Kip1), CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.
2013-05-08 | Alterations in Polyadenylation and Its Implications for Endocrine Disease
Polyadenylation is the process in which the pre-mRNA is cleaved at the poly(A) site and a poly(A) tail is added - a process necessary for normal mRNA formation. Genes with multiple poly(A) sites can undergo alternative polyadenylation (APA), producing distinct mRNA isoforms with different 3' untranslated regions (3' UTRs) and in some cases different coding regions. Two thirds of all human genes undergo APA. The efficiency of the polyadenylation process regulates gene expression and APA plays an important part in post-transcriptional regulation, as the 3' UTR contains various cis-elements associated with post-transcriptional regulation, such as target sites for micro-RNAs and RNA-binding proteins. Implications of alterations in polyadenylation for endocrine disease: Alterations in polyadenylation have been found to be causative of neonatal diabetes and IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) and to be associated with type I and II diabetes, pre-eclampsia, fragile X-associated premature ovarian insufficiency, ectopic Cushing syndrome, and many cancer diseases, including several types of endocrine tumor diseases.Recent developments in high-throughput sequencing have made it possible to characterize polyadenylation genome-wide. Antisense elements inhibiting or enhancing specific poly(A) site usage can induce desired alterations in polyadenylation, and thus hold the promise of new therapeutic approaches.This review gives a detailed description of alterations in polyadenylation in endocrine disease, an overview of the current literature on polyadenylation and summarizes the clinical implications of the current state of research in this field.
antibodies
2026-08-01 | OC9.2 - ECE_1670 - Single-cell transcriptomic profiling reveals divergent endocrine, immune, and angiogenic programs between ACTH/CRH-secreting and non-secreting pheochromocytomas
Abstract Background Ectopic ACTH and/or CRH-secreting pheochromocytomas are rare catecholamine-secreting tumors originating from adrenal medulla, which could also secrete ectopic adrenocorticotropic hormone (ACTH) and corticotrophin-releasing hormone (CRH), mimicking Cushing syndrome and complicating the diagnosis clinically. The extremely low incidence limits the comprehensive understanding and management for specific individuals accompanied with this kind of tumor. Furthermore, mechanisms of tumorigenesis and ectopic ACTH secretion in pheochromocytomas are unknown. Studying this rare type of tumor will help tailor therapies to the specifically molecular and metabolic characteristics of pheochromocytomas. Methods and Materials Fresh tumor and peritumoral specimens were collected from three ACTH + &CRH+ pheochromocytoma patients and three ACTH-&CRH- pheochromocytoma patients, and then were digested and sent to construct single-cell library as well as sequencing. Subsequent analysis and immunohistochemical staining were conducted to explore the difference of ACTH + &CRH+ pheochromocytomas from the ACTH-&CRH- ones and normal tissues. Results We constructed the linear trajectory of 2 types of pheochromocytomas. The cluster of intermediate cells that differentiated into mature ACTH + &CRH+ pheochromocytomas showing high expression of CEBPB, and the immunohistochemical staining revealed that CEBPB was higher in ACTH + &CRH+ ones. Besides, Higher expression of POMC and PNMT was observed in ACTH + &CRH+ pheochromocytomas compared with ACTH-&CRH- ones, being in accordance with the clinical information that three ACTH + &CRH+ pheochromocytoma patients had relatively higher catecholamine levels. T cells in ACTH + &CRH+ pheochromocytomas were activated by signals, like HLA-B, promoting their cytotoxic functions, while T cells in ACTH-&CRH- ones were subject to inhibitory signals, especially from M2 macrophages. What's more, a population of endothelial cells marked by SELE was identified in ACTH + &CRH+ pheochromocytomas, showing strong interaction with CD8+ T cells and facilitating lymphocyte infiltration, particularly the GZMK⁺IL7R⁺ T cells. While ACTH-&CRH- pheochromocytomas were enriched in glycolysis and HIF signaling pathways, and characterized by lacking T cell infiltration, with macrophages being the dominant immune cells. Conclusions CEBPB plays a significant role in the fate transition of pheochromocytomas and may drive ACTH secretion. In addition, ACTH + &CRH+ pheochromocytomas are considerated as relatively immunologically “hot” tumors but poor in angiogenesis. In contrast, ACTH-&CRH- pheochromocytomas lack immune infiltration while exhibiting extensive angiogenesis. Immunotherapies may be effective for the former, and the latter may benefit from anti-angiogenic therapies.
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.
2025-12-30 | Clinicopathologic Characteristics, Treatment Outcomes, and Survival in Thymic Neuroendocrine Neoplasms (t-NEN): A 25-Year Single-Center Experience.
Background/Objectives: Thymic neuroendocrine neoplasms (t-NENs) are rare, biologically aggressive malignancies of the anterior mediastinum. Due to their low incidence, clinical evidence remains limited, and treatment recommendations are primarily based on expert opinion and extrapolation from other neuroendocrine tumors. This study aimed to analyze the clinicopathological features, treatment patterns, and survival outcomes of patients with t-NENs treated at a single comprehensive cancer center over 25 years. Methods: A retrospective review was performed on 19 adult patients diagnosed with t-NENs between 2000 and 2024. Data on demographics, histology, treatment intent, modalities used, and outcomes were collected. Survival analyses-of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS)-were conducted using the Kaplan-Meier method. Results: The median age was 52 years; 63% of patients were male. Atypical carcinoid was the most common histologic subtype (52.6%), followed by large cell neuroendocrine carcinoma (31.6%). Paraneoplastic syndromes, including Cushing's syndrome, were observed in 26.3% of cases. Radical surgery was performed for 8 patients, but R0 resection was achieved in only 25% of them. Postoperative radiotherapy and chemotherapy were used for 36.8% and 15.8% of patients, respectively. Disease recurrence occurred in 44.4% of curatively treated patients. The median OS for the entire cohort was 127 months; patients treated with curative intent had a significantly longer OS (170 months) compared to those after palliative treatment (33 months). Median PFS in the palliative group was 11 months. Conclusions: t-NENs are aggressive tumors with high risk of recurrence and limited systemic treatment efficacy. Complete surgical resection remains the cornerstone of curative therapy. However, the overall prognosis remains poor, emphasizing the need for novel therapeutic strategies and prospective multicenter studies.
2025-05-28 | ScRNA-seq profiles to identify HES1 associated with ACTH-secreting tumors and the distinct microenvironment between ACTH+/CRH+ and ACTH-/CRH- pheochromocytomas.
e16604 Background: Ectopic ACTH and/or CRH-secreting pheochromocytomas are rare catecholamine-secreting tumors originating from adrenal medulla, which could also secrete ectopic adrenocorticotropic hormone (ACTH) and corticotrophin-releasing hormone (CRH), mimicking Cushing syndrome and complicating the diagnosis clinically. The extremely low incidence limits the comprehensive understanding and management for specific individuals accompanied with this kind of tumor. Furthermore, mechanisms of tumorigenesis and ectopic ACTH secretion in pheochromocytomas are unknown. Studying this rare type of tumor will help tailor therapies to the specifically molecular and metabolic characteristics of pheochromocytomas. Methods: Fresh tumor and peritumoral specimens were collected from three ACTH+&CRH+ pheochromocytoma patients and three ACTH-&CRH- pheochromocytoma patients, and then were digested and sent to construct single-cell library as well as sequencing. Subsequent analysis and immunohistochemical staining were conducted to explore the difference of ACTH+&CRH+ pheochromocytomas from the ACTH-&CRH- ones and normal tissues. Results: We constructed the linear trajectory of 2 types of pheochromocytomas. The cluster of intermediate cells that differentiated into mature ACTH+&CRH+ pheochromocytomas showing high expression of HES1, and the immunohistochemical staining revealed that HES1 was higher in ACTH+&CRH+ ones. Besides, Higher expression of POMC and PNMT was observed in ACTH+&CRH+ pheochromocytomas compared with ACTH-&CRH- ones, being in accordance with the clinical information that three ACTH+&CRH+ pheochromocytoma patients had relatively higher catecholamine levels. T cells in ACTH+&CRH+ pheochromocytomas were activated by signals, like HLA-B, promoting their cytotoxic functions, while T cells in ACTH-&CRH- ones were subject to inhibitory signals, especially from M2 macrophages. What's more, a population of endothelial cells marked by SELE was identified in ACTH+&CRH+ pheochromocytomas, showing strong interaction with CD8+ T cells and facilitating lymphocyte infiltration, particularly the GZMK⁺IL7R⁺ T cells. While ACTH-&CRH- pheochromocytomas were enriched in glycolysis and HIF signaling pathways, and characterized by lacking T cell infiltration, with macrophages being the dominant immune cells. Conclusions: HES1 plays a significant role in the fate transition of pheochromocytomas and may drive ACTH secretion. In addition, ACTH+&CRH+ pheochromocytomas are considerated as relatively immunologically“hot”tumors but poor in angiogenesis. In contrast, ACTH-&CRH- pheochromocytomas lack immune infiltration while exhibiting extensive angiogenesis. Immunotherapies may be effective for the former, and the latter may benefit from anti-angiogenic therapies.
2024-12-20 | Immunochemotherapy for small cell lung cancer with paraneoplastic Cushing syndrome: A case report and literature review.
Paraneoplastic Cushing syndrome (PCS) is an adverse prognostic factor for small cell lung cancer (SCLC) patients. Retrospective studies have shown that the median survival of SCLC complicated with PCS was <7 months. No immunochemotherapy has been recorded in the treatment of SCLC with PCS. Previous preclinical and clinical studies have suggested glucocorticoid exposure may affect the efficacy of immunotherapy. A 60-year-old man was admitted for his irritability and palpitation. During hospitalization, a chest computed tomography scan revealed a lobar soft tissue shadow in his left lower lung. He was diagnosed as limited-stage SCLC (T2bN1M0 IIB) with PCS, ultimately. The patient received 4 courses of immunochemotherapy of etoposide plus platinum with durvalumab and 1 adjuvant radiotherapy alone in 2022 for his limited-stage SCLC, and underwent 5 courses of immunochemotherapy of irinotecan plus platinum with serplulimab in 2023 for his extensive-stage SCLC. The patient achieved a long survival of 20 months. The case preliminarily demonstrated the efficacy of immunochemotherapy in the management of SCLC complicated with PCS. The regime of serplulimab with irinotecan-based chemotherapy also indicated its satisfactory efficacy as a second-line treatment for extensive-stage SCLC. Furthermore, the case has highlighted that the management of hypercortisolism, the improvement of myelosuppression, and the prophylaxis against infection were 3 hinges for the continuation of immunochemotherapy and the holistic management of SCLC with PCS.
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2026-02-12 | Primary bilateral macronodular adrenal hyperplasia presenting as resistant hypertension with bilateral adrenal masses: a case report.
Bilateral adrenal incidentalomas are uncommon and may be associated with autonomous cortisol secretions. One important etiology is primary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome, which may present without typical Cushingoid features. We describe a patient with ACTH-independent Cushing's syndrome due to bilateral adrenal hyperplasia, who achieved clinical improvement after unilateral adrenalectomy. This case highlights the role of unilateral adrenalectomy as a functional treatment option in PBMAH. A 59-year-old man presented with resistant hypertension, bilateral leg edema, and proximal muscle weakness, without typical Cushingoid features. Biochemical evaluation confirmed autonomous cortisol secretion, and computed tomography revealed multiple bilateral adrenal masses. Adrenal venous sampling (AVS) demonstrated left-sided dominant cortisol production, leading to laparoscopic left adrenalectomy. Histopathology confirmed macronodular adrenal hyperplasia, and the patient experienced postoperative improvement in both hypertension and glycemic control. PBMAH often presents as bilateral adrenal enlargement with cortisol excess, and AVS plays a role in determining functional lateralization in selected patients. Because adrenal size strongly correlates with cortisol secretion, imaging and AVS together help refine surgical decision making. While unilateral adrenalectomy offers favorable outcomes, recurrence rates vary widely, highlighting the need for continued surveillance. For patients with ACTH-independent Cushing's syndrome and bilateral adrenal masses, AVS-guided unilateral adrenalectomy provides a targeted treatment strategy that controls cortisol excess while reducing the risk of permanent adrenal insufficiency.
2025-04-17 | Hypokalaemia and hypercortisolaemia at diagnosis are negative prognostic factors: a retrospective analysis of the medical management of ectopic Cushing syndrome
Background Ectopic Cushing syndrome (ECS), related to neuroendocrine neoplasms (NENs), is a rare condition with high morbidity and mortality. We hypothesised that both the severity of hypercortisolaemia and hypokalaemia correlates with prognosis. Materials and methods Fifty-five patients with ECS (37 females), with a mean age of 54 ± 14 (standard deviation) years were identified in our database for further analysis of clinical parameters, biochemical data, symptomatic treatment and outcome. Results Twenty-eight patients had bronchial, 16 pancreatic, 4 thymic and 1 a rectal NEN. In six patients, the primary tumour was unknown. The proliferation index, Ki-67, was ≤20% in 31 patients and hypokalaemia correlated negatively with Ki-67 ( P = 0.043). Severe hypokalaemia at diagnosis (<2.5 mmol/l) was found in 50% of the patients. Hypokalaemia and high doses of potassium substitution were associated with shorter overall survival ( P = 0.009 and P = 0.019, respectively). However, only severe hypercortisolaemia remained an independent negative factor for survival in multivariate analysis ( P = 0.042). Potassium substitution was required in 87% of patients and the dose was positively correlated to baseline hormone levels including urinary free cortisol ( P < 0.001), s-cortisol ( P < 0.001) and adrenocortical hormone (ACTH) ( P = 0.016). Steroidogenesis inhibitors (SIs) were used as initial treatment in 46 patients to improve symptoms. However, within 1 month, 17 proceeded to bilateral adrenalectomy and 3 died. Conclusions We conclude that only hypercortisolaemia was independently prognostic for shorter survival. Furthermore, we suggest that hypercortisolaemia, especially in combination with severe hypokalaemia (<2.5 mmol/l), indicates an acute life-threatening situation. For these patients, immediate actions should be considered to reduce cortisol levels and bilateral adrenalectomy should be discussed upfront.
2018-04-09 | Adrenal Surgery for Cushing’s Syndrome
Recent advances in the molecular pathogenesis and the natural history of Cushing's syndrome have improved the understanding of the management of this disease. The long-term efficacy of several cortisol-lowering medical treatments is currently under evaluation. However, adrenalectomy is a safe option for the treatment of patients affected by Cushing's syndrome. Unilateral adrenalectomy is the gold standard for treatment of adrenocortical adenomas associated with hypercortisolism. Bilateral adrenalectomy has been widely used in the past as definitive treatment of bilateral macronodular hyperplasia and persistent or recurrent Cushing's disease. The indication and the potential applications of this technique have been recently critically analyzed.
2005-05-17 | Cushing's syndrome: adrenalectomy and long-term results.
The objective of this study was to assess the preoperative symptoms, intra- and postoperative complications and follow-up in patients after uni- or bilateral adrenalectomy due to Cushing's syndrome (CS), independent of etiology. Clinical charts of 42 patients (5 with ACTH-dependent, 37 with ACTH-independent CS) were reviewed, and follow-up data were obtained from re-examination of the patients. The symptoms most frequently seen were hypertension, changes of the skin and obesity. Eight bilateral and 36 unilateral adrenalectomies were carried out without any intraoperative complications. Postoperative complications occurred in 5 patients, 1 patient died on the fourth postoperative day. After a mean duration of 4.6 years 28 of 41 patients could be re-examined, 5 patients had died. One patient showed recurrence 4.3 years after unilateral adrenalectomy due to nodular hyperplasia, contralateral adrenalectomy again revealed nodular hyperplasia. Early diagnosis is essential in order to decrease the rate of pre-, intra- and postoperative complications. Endoscopic approach should be taken in a specialized center due to poor patient's condition. Recurrent disease on the contralateral side may represent bilateral adrenal hyperplasia with sequential tumor formation, demonstrating the importance of extensive preoperative biochemical and imaging testing and close follow-up.
2002-04-26 | Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion.
The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form. 7B2 null mice express no PC2 activity and release large quantities of uncleaved ACTH, resulting in a lethal endocrine condition that resembles pituitary Cushing's (Westphal, C. H., Muller, L., Zhou, A., Bonner-Weir, S., Schambelan, M., Steiner, D. F., Lindberg, I. & Leder, P. (1999) Cell 96, 689). Here, we have compared the 7B2 and PC2 null mouse models to determine why the 7B2 null, but not the PC2 null, exhibits a lethal disease state. Both 7B2 and PC2 nulls contained highly elevated pituitary adrenocorticotropic hormone (ACTH); the neurointermediate lobe content of ACTH in 7B2 nulls was 13-fold higher than in WT mice; that of the PC2 null was 65-fold higher. However, circulating ACTH levels were much higher in the 7B2 null than in the PC2 null. Because hypothalamic inhibitory dopaminergic control represents the major influence on intermediate lobe proopiomelanocortin-derived peptide secretion, dopamine levels were measured, and they revealed that 7B2 null pituitaries contained only one-fourth of WT pituitary dopamine. Adrenalectomized 7B2 null animals survived past the usual time of death at 5 weeks; a month after adrenalectomy, they exhibited normal levels of pituitary dopamine, circulating ACTH, and corticosterone. Elevated corticosterone, therefore, seems to play a central role in the lethal phenotype of the 7B2 null, whereas a 7B2-mediated dopaminergic deficiency state may be involved in the actual ACTH hypersecretion phenomenon. Interestingly, adrenalectomized 7B2 nulls also developed unexpectedly severe obesity.
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2025-10-30 | Diabetes mellitus masking an ectopic Cushing syndrome in a young male: a case report
Ectopic adrenocorticotropic hormone (ACTH) secretion is a rare but important cause of Cushing syndrome, often associated with neuroendocrine tumors such as bronchial or gastrointestinal carcinoids. Its presentation can be subtle or atypical, delaying diagnosis and increasing morbidity. Herein this case report presents a 24-year-old male presenting with uncontrolled diabetes mellitus, polyuria, and weight loss (13 kg over 6 months). He exhibited proximal muscle weakness, broad purple striae, and extensive hyperpigmentation. Laboratory evaluation revealed markedly elevated 8 am serum cortisol 82 mcg/dl, midnight awake cortisol 211 mcg/dl, overnight dexamethasone suppression test (27.32 mcg/dl), plasma ACTH 320 pg/ml, and a non-suppressed (<50%) high-dose dexamethasone suppression test (16 mcg/dl). High-resolution computed tomography (HRCT) chest demonstrated multiple pulmonary nodules. Ga-68 DOTANOC PET-CT imaging revealed somatostatin receptor expression in bilateral lung nodules. Endobronchial biopsy confirmed atypical carcinoid tumor, Ki-67 index 4%. This case highlights the diagnostic complexity of ectopic ACTH syndrome, particularly in young adults presenting with rapidly worsening diabetes. The presence of significant pigmentation, proximal myopathy, and metabolic derangements were key clinical clues. Atypical carcinoid tumors exhibit intermediate biological behavior and require a multidisciplinary management approach including surgical resection, somatostatin analog therapy, and cortisol-lowering strategies. Ectopic ACTH syndrome should be considered in young patients with severe metabolic abnormalities, rapid weight loss, and hyperpigmentation. Early recognition and appropriate work-up can prevent complications and improve outcomes.
2025-03-29 | Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice.
Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response. We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed. Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery. This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.
2025-01-30 | Performance of Vasopressin Stimulated Bilateral Inferior Petrosal Sinus Sampling in Corticotropin Dependent Cushing's Syndrome with Negative or Equivocal 3 Tesla Contrast Enhanced Magnetic Resonance Imaging of Pituitary.
Corticotropin releasing hormone (CRH)-stimulated bilateral inferior petrosal sinus sampling (BIPSS) is the most accurate procedure in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) with a sensitivity of 88-100% and a specificity of 67-100%. However, CRH is not available globally currently. We undertook this study of BIPSS using lysine vasopressin (LVP) as an agent to stimulate the release of ACTH from corticotrophs. Our objective was to assess the accuracy of LVP-stimulated BIPSS in differentiating Cushing's disease (CD) from ectopic ACTH syndrome (EAS) with negative or equivocal 3T contrast-enhanced MRI (CEMRI). Seventeen patients with clinically and biochemically confirmed ACTH-dependent CS with equivocal or negative CEMRI pituitary underwent BIPSS using LVP as a stimulating agent. Of seventeen patients who underwent BIPSS, nine patients had a raised central-to-peripheral ACTH ratio and were classified as having CD that was confirmed on histopathology following transsphenoidal sinus surgery. Remaining eight patients, who did not show a raised central-to-peripheral ACTH ratio, were classified to have EAS. All patients with EAS underwent contrast-enhanced computerised tomography of the neck, chest, and abdomen and/or Gallium 68 DOTANOC positron emission tomography/computerised tomography. Seven out of eight patients demonstrated solitary pulmonary nodule in the lung (bronchial carcinoid), and one patient had a mass in the thymus (thymic carcinoid). BIPSS using LVP confirmed the source of ACTH excess correctly in all the patients with ACTH-dependent CS without the loss of specificity.
2024-05-01 | #1704792 Octreotide Use in a Critically Ill Patient with Ectopic ACTH Secretion
Ectopic ACTH secretion is a rare cause of hypercortisolism primarily treated with surgical resection. Octreotide, a somatostatin analogue, is used in the medical management of Cushing Disease. Though it is considered a potential therapy for ectopic ACTH secretion, data supporting its use is lacking. In this case, we describe the successful reduction in serum cortisol with subcutaneous octreotide in a patient with an ACTH-secreting pulmonary carcinoid tumor.
2024-04-04 | The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage.
The ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation. We compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation. The ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively. With the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.
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2026-09-24 | Management of ectopic Cushing syndrome in medullary thyroid carcinoma: from case reports to systematic literature review.
Ectopic Cushing's syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism. We conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from "C. I. Parhon" National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset. The systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12-84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment. ECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.
2026-09-22 | Conversion therapy followed by curative resection in a patient with ACTH-secreting pancreatic neuroendocrine tumor G3: a case report
Background Pancreatic neuroendocrine tumors (pNETs) with ectopic adrenocorticotropic hormone (ACTH) production are uncommon, highly aggressive, and carry a dismal prognosis. Early nonspecific symptoms often delay diagnosis, and treatment strategies remain controversial. For patients with locally advanced pNETs, conversion therapy has only rarely been reported and remains a sparingly applied strategy. Case presentation A 37-year-old woman presented with a six-month history of progressive swelling in both lower extremities and her face. Further workup confirmed ACTH-dependent Cushing syndrome. CT and MRI identified a 5.7 × 2.8 cm lesion in the pancreatic body/tail that invaded the left adrenal gland and splenic vessels, accompanied by retroperitoneal lymph node spread. Biopsy results indicated a G3 pNET. Given the borderline resectable status due to local advancement, she received conversion therapy comprising a long-acting somatostatin analogue followed by CapTem chemotherapy. After three months of neoadjuvant treatment, imaging showed modest primary tumor shrinkage and marked reduction of lymph node size, reflecting successful downstaging. Subsequently, she underwent distal pancreatectomy with splenectomy, left adrenalectomy, and lymph node dissection, achieving R0 resection. Final pathology confirmed a G3 pNET (Ki-67 30%–40%) with positive SSTR2 and ACTH immunostaining. Although the patient eventually experienced disease progression and succumbed to COVID-19 infection 37 months after initial diagnosis, this case illustrates that conversion therapy can render an initially borderline resectable high-grade pNET amenable to curative resection. Conclusion This report underscores the aggressive trajectory of ACTH-secreting pNET G3 and suggests the potential utility of conversion therapy. Further studies are needed to validate this approach.
2026-09-22 | Ectopic Cushing's syndrome. A metastatic hepatic neuroendocrine tumour: case report and literature review.
This report describes a rare instance of an adrenocorticotropic hormone (ACTH)-secreting metastatic hepatic neuroendocrine tumour (MHNET) exhibiting as an ectopic Cushing's syndrome. A 41-year-old woman with a history of supraglottic neuroendocrine tumour presented with rapid weight gain, severe hypokalemia, and hypercortisolism. Pituitary imaging was unremarkable. However, the DOTATATE PET/CT showed a large liver lesion. Initiating etomidate infusion caused a rapid drop in cortisol, leading to severe vasoplegic and septic shock, which delayed the surgery. The patient required intensive care stabilization pre-operatively and treatment with osilodrostat, which was then followed by surgical management: left lateral hepatectomy and gastric wedge resection. ACTH levels markedly decreased postoperatively, reflecting successful management. This emphasizes that careful medical management and multidisciplinary collaboration are essential in treating severe, potentially life-threatening ectopic hypercortisolism.
2026-09-03 | Metyrapone in the Management of Severe Hypercortisolism Secondary to Ectopic Cushing's Syndrome.
Ectopic Cushing's syndrome (ECS) is a rare but important cause of ACTH-dependent Cushing's syndrome. Metyrapone, a steroidogenesis inhibitor targeting 11-β hydroxylase, has shown effectiveness in controlling hypercortisolism. However, little is known about the practical aspects of its initiation, use, and effectiveness in ECS. We present three cases of severe hypercortisolism secondary to ECS managed with metyrapone and report our experience. Case 1: a 56-year-old male with high-grade neuroendocrine carcinoma. Case 2: a 67-year-old man with a history of stage IIB non-small cell lung cancer (NSCLC) with metastatic neuroendocrine carcinoma. Case 3: a 64-year-old man with metastatic prostate cancer. Biochemical control was achieved with rapid titration of low doses of daily metyrapone in all three cases. Based on our experience, we recommend an initial dose of 1000-1500 mg of metyrapone daily, in divided doses, with physiologic glucocorticoid replacement to mitigate the risk of adrenal insufficiency. Despite improvements in cortisol levels and stabilization of metabolic derangements, all three patients ultimately transitioned to comfort-focused care. Given the rarity, heterogeneity, and aggressiveness of this condition, rapid diagnosis and standardized pharmacologic approach are difficult to achieve. More data are needed to guide optimal therapy selection, dosing, and titration in ECS.
2026-08-13 | Ectopic ACTH-dependent Cushing syndrome in 3 hospitalized patients: lessons learned from management with osilodrostat.
Severe Cushing syndrome (CS) is a rare diagnosis with high mortality, which limits the ability of endocrinologists to gain experience delivering care. Here we describe our experience treating 3 cases of ectopic ACTH-dependent CS presenting in a single year. The initial diagnosis of each case was made during hospitalization resulting from complications of CS, implicating severe disease and delayed diagnosis. Our experience suggests that rapid initiation and titration of osilodrostat effectively treats hypercortisolism and improves outcomes.
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2023-01-05 | Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice.
It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND. These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.
2022-03-22 | KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
2021-11-04 | Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.
Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.
2015-09-30 | Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature.
OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27(Kip1), CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.
2013-05-08 | Alterations in Polyadenylation and Its Implications for Endocrine Disease
Polyadenylation is the process in which the pre-mRNA is cleaved at the poly(A) site and a poly(A) tail is added - a process necessary for normal mRNA formation. Genes with multiple poly(A) sites can undergo alternative polyadenylation (APA), producing distinct mRNA isoforms with different 3' untranslated regions (3' UTRs) and in some cases different coding regions. Two thirds of all human genes undergo APA. The efficiency of the polyadenylation process regulates gene expression and APA plays an important part in post-transcriptional regulation, as the 3' UTR contains various cis-elements associated with post-transcriptional regulation, such as target sites for micro-RNAs and RNA-binding proteins. Implications of alterations in polyadenylation for endocrine disease: Alterations in polyadenylation have been found to be causative of neonatal diabetes and IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) and to be associated with type I and II diabetes, pre-eclampsia, fragile X-associated premature ovarian insufficiency, ectopic Cushing syndrome, and many cancer diseases, including several types of endocrine tumor diseases.Recent developments in high-throughput sequencing have made it possible to characterize polyadenylation genome-wide. Antisense elements inhibiting or enhancing specific poly(A) site usage can induce desired alterations in polyadenylation, and thus hold the promise of new therapeutic approaches.This review gives a detailed description of alterations in polyadenylation in endocrine disease, an overview of the current literature on polyadenylation and summarizes the clinical implications of the current state of research in this field.
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2026-08-01 | OC9.2 - ECE_1670 - Single-cell transcriptomic profiling reveals divergent endocrine, immune, and angiogenic programs between ACTH/CRH-secreting and non-secreting pheochromocytomas
Abstract Background Ectopic ACTH and/or CRH-secreting pheochromocytomas are rare catecholamine-secreting tumors originating from adrenal medulla, which could also secrete ectopic adrenocorticotropic hormone (ACTH) and corticotrophin-releasing hormone (CRH), mimicking Cushing syndrome and complicating the diagnosis clinically. The extremely low incidence limits the comprehensive understanding and management for specific individuals accompanied with this kind of tumor. Furthermore, mechanisms of tumorigenesis and ectopic ACTH secretion in pheochromocytomas are unknown. Studying this rare type of tumor will help tailor therapies to the specifically molecular and metabolic characteristics of pheochromocytomas. Methods and Materials Fresh tumor and peritumoral specimens were collected from three ACTH + &CRH+ pheochromocytoma patients and three ACTH-&CRH- pheochromocytoma patients, and then were digested and sent to construct single-cell library as well as sequencing. Subsequent analysis and immunohistochemical staining were conducted to explore the difference of ACTH + &CRH+ pheochromocytomas from the ACTH-&CRH- ones and normal tissues. Results We constructed the linear trajectory of 2 types of pheochromocytomas. The cluster of intermediate cells that differentiated into mature ACTH + &CRH+ pheochromocytomas showing high expression of CEBPB, and the immunohistochemical staining revealed that CEBPB was higher in ACTH + &CRH+ ones. Besides, Higher expression of POMC and PNMT was observed in ACTH + &CRH+ pheochromocytomas compared with ACTH-&CRH- ones, being in accordance with the clinical information that three ACTH + &CRH+ pheochromocytoma patients had relatively higher catecholamine levels. T cells in ACTH + &CRH+ pheochromocytomas were activated by signals, like HLA-B, promoting their cytotoxic functions, while T cells in ACTH-&CRH- ones were subject to inhibitory signals, especially from M2 macrophages. What's more, a population of endothelial cells marked by SELE was identified in ACTH + &CRH+ pheochromocytomas, showing strong interaction with CD8+ T cells and facilitating lymphocyte infiltration, particularly the GZMK⁺IL7R⁺ T cells. While ACTH-&CRH- pheochromocytomas were enriched in glycolysis and HIF signaling pathways, and characterized by lacking T cell infiltration, with macrophages being the dominant immune cells. Conclusions CEBPB plays a significant role in the fate transition of pheochromocytomas and may drive ACTH secretion. In addition, ACTH + &CRH+ pheochromocytomas are considerated as relatively immunologically “hot” tumors but poor in angiogenesis. In contrast, ACTH-&CRH- pheochromocytomas lack immune infiltration while exhibiting extensive angiogenesis. Immunotherapies may be effective for the former, and the latter may benefit from anti-angiogenic therapies.
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.
2025-12-30 | Clinicopathologic Characteristics, Treatment Outcomes, and Survival in Thymic Neuroendocrine Neoplasms (t-NEN): A 25-Year Single-Center Experience.
Background/Objectives: Thymic neuroendocrine neoplasms (t-NENs) are rare, biologically aggressive malignancies of the anterior mediastinum. Due to their low incidence, clinical evidence remains limited, and treatment recommendations are primarily based on expert opinion and extrapolation from other neuroendocrine tumors. This study aimed to analyze the clinicopathological features, treatment patterns, and survival outcomes of patients with t-NENs treated at a single comprehensive cancer center over 25 years. Methods: A retrospective review was performed on 19 adult patients diagnosed with t-NENs between 2000 and 2024. Data on demographics, histology, treatment intent, modalities used, and outcomes were collected. Survival analyses-of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS)-were conducted using the Kaplan-Meier method. Results: The median age was 52 years; 63% of patients were male. Atypical carcinoid was the most common histologic subtype (52.6%), followed by large cell neuroendocrine carcinoma (31.6%). Paraneoplastic syndromes, including Cushing's syndrome, were observed in 26.3% of cases. Radical surgery was performed for 8 patients, but R0 resection was achieved in only 25% of them. Postoperative radiotherapy and chemotherapy were used for 36.8% and 15.8% of patients, respectively. Disease recurrence occurred in 44.4% of curatively treated patients. The median OS for the entire cohort was 127 months; patients treated with curative intent had a significantly longer OS (170 months) compared to those after palliative treatment (33 months). Median PFS in the palliative group was 11 months. Conclusions: t-NENs are aggressive tumors with high risk of recurrence and limited systemic treatment efficacy. Complete surgical resection remains the cornerstone of curative therapy. However, the overall prognosis remains poor, emphasizing the need for novel therapeutic strategies and prospective multicenter studies.
2025-05-28 | ScRNA-seq profiles to identify HES1 associated with ACTH-secreting tumors and the distinct microenvironment between ACTH+/CRH+ and ACTH-/CRH- pheochromocytomas.
e16604 Background: Ectopic ACTH and/or CRH-secreting pheochromocytomas are rare catecholamine-secreting tumors originating from adrenal medulla, which could also secrete ectopic adrenocorticotropic hormone (ACTH) and corticotrophin-releasing hormone (CRH), mimicking Cushing syndrome and complicating the diagnosis clinically. The extremely low incidence limits the comprehensive understanding and management for specific individuals accompanied with this kind of tumor. Furthermore, mechanisms of tumorigenesis and ectopic ACTH secretion in pheochromocytomas are unknown. Studying this rare type of tumor will help tailor therapies to the specifically molecular and metabolic characteristics of pheochromocytomas. Methods: Fresh tumor and peritumoral specimens were collected from three ACTH+&CRH+ pheochromocytoma patients and three ACTH-&CRH- pheochromocytoma patients, and then were digested and sent to construct single-cell library as well as sequencing. Subsequent analysis and immunohistochemical staining were conducted to explore the difference of ACTH+&CRH+ pheochromocytomas from the ACTH-&CRH- ones and normal tissues. Results: We constructed the linear trajectory of 2 types of pheochromocytomas. The cluster of intermediate cells that differentiated into mature ACTH+&CRH+ pheochromocytomas showing high expression of HES1, and the immunohistochemical staining revealed that HES1 was higher in ACTH+&CRH+ ones. Besides, Higher expression of POMC and PNMT was observed in ACTH+&CRH+ pheochromocytomas compared with ACTH-&CRH- ones, being in accordance with the clinical information that three ACTH+&CRH+ pheochromocytoma patients had relatively higher catecholamine levels. T cells in ACTH+&CRH+ pheochromocytomas were activated by signals, like HLA-B, promoting their cytotoxic functions, while T cells in ACTH-&CRH- ones were subject to inhibitory signals, especially from M2 macrophages. What's more, a population of endothelial cells marked by SELE was identified in ACTH+&CRH+ pheochromocytomas, showing strong interaction with CD8+ T cells and facilitating lymphocyte infiltration, particularly the GZMK⁺IL7R⁺ T cells. While ACTH-&CRH- pheochromocytomas were enriched in glycolysis and HIF signaling pathways, and characterized by lacking T cell infiltration, with macrophages being the dominant immune cells. Conclusions: HES1 plays a significant role in the fate transition of pheochromocytomas and may drive ACTH secretion. In addition, ACTH+&CRH+ pheochromocytomas are considerated as relatively immunologically“hot”tumors but poor in angiogenesis. In contrast, ACTH-&CRH- pheochromocytomas lack immune infiltration while exhibiting extensive angiogenesis. Immunotherapies may be effective for the former, and the latter may benefit from anti-angiogenic therapies.
2024-12-20 | Immunochemotherapy for small cell lung cancer with paraneoplastic Cushing syndrome: A case report and literature review.
Paraneoplastic Cushing syndrome (PCS) is an adverse prognostic factor for small cell lung cancer (SCLC) patients. Retrospective studies have shown that the median survival of SCLC complicated with PCS was <7 months. No immunochemotherapy has been recorded in the treatment of SCLC with PCS. Previous preclinical and clinical studies have suggested glucocorticoid exposure may affect the efficacy of immunotherapy. A 60-year-old man was admitted for his irritability and palpitation. During hospitalization, a chest computed tomography scan revealed a lobar soft tissue shadow in his left lower lung. He was diagnosed as limited-stage SCLC (T2bN1M0 IIB) with PCS, ultimately. The patient received 4 courses of immunochemotherapy of etoposide plus platinum with durvalumab and 1 adjuvant radiotherapy alone in 2022 for his limited-stage SCLC, and underwent 5 courses of immunochemotherapy of irinotecan plus platinum with serplulimab in 2023 for his extensive-stage SCLC. The patient achieved a long survival of 20 months. The case preliminarily demonstrated the efficacy of immunochemotherapy in the management of SCLC complicated with PCS. The regime of serplulimab with irinotecan-based chemotherapy also indicated its satisfactory efficacy as a second-line treatment for extensive-stage SCLC. Furthermore, the case has highlighted that the management of hypercortisolism, the improvement of myelosuppression, and the prophylaxis against infection were 3 hinges for the continuation of immunochemotherapy and the holistic management of SCLC with PCS.
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2026-02-12 | Primary bilateral macronodular adrenal hyperplasia presenting as resistant hypertension with bilateral adrenal masses: a case report.
Bilateral adrenal incidentalomas are uncommon and may be associated with autonomous cortisol secretions. One important etiology is primary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome, which may present without typical Cushingoid features. We describe a patient with ACTH-independent Cushing's syndrome due to bilateral adrenal hyperplasia, who achieved clinical improvement after unilateral adrenalectomy. This case highlights the role of unilateral adrenalectomy as a functional treatment option in PBMAH. A 59-year-old man presented with resistant hypertension, bilateral leg edema, and proximal muscle weakness, without typical Cushingoid features. Biochemical evaluation confirmed autonomous cortisol secretion, and computed tomography revealed multiple bilateral adrenal masses. Adrenal venous sampling (AVS) demonstrated left-sided dominant cortisol production, leading to laparoscopic left adrenalectomy. Histopathology confirmed macronodular adrenal hyperplasia, and the patient experienced postoperative improvement in both hypertension and glycemic control. PBMAH often presents as bilateral adrenal enlargement with cortisol excess, and AVS plays a role in determining functional lateralization in selected patients. Because adrenal size strongly correlates with cortisol secretion, imaging and AVS together help refine surgical decision making. While unilateral adrenalectomy offers favorable outcomes, recurrence rates vary widely, highlighting the need for continued surveillance. For patients with ACTH-independent Cushing's syndrome and bilateral adrenal masses, AVS-guided unilateral adrenalectomy provides a targeted treatment strategy that controls cortisol excess while reducing the risk of permanent adrenal insufficiency.
2025-04-17 | Hypokalaemia and hypercortisolaemia at diagnosis are negative prognostic factors: a retrospective analysis of the medical management of ectopic Cushing syndrome
Background Ectopic Cushing syndrome (ECS), related to neuroendocrine neoplasms (NENs), is a rare condition with high morbidity and mortality. We hypothesised that both the severity of hypercortisolaemia and hypokalaemia correlates with prognosis. Materials and methods Fifty-five patients with ECS (37 females), with a mean age of 54 ± 14 (standard deviation) years were identified in our database for further analysis of clinical parameters, biochemical data, symptomatic treatment and outcome. Results Twenty-eight patients had bronchial, 16 pancreatic, 4 thymic and 1 a rectal NEN. In six patients, the primary tumour was unknown. The proliferation index, Ki-67, was ≤20% in 31 patients and hypokalaemia correlated negatively with Ki-67 ( P = 0.043). Severe hypokalaemia at diagnosis (<2.5 mmol/l) was found in 50% of the patients. Hypokalaemia and high doses of potassium substitution were associated with shorter overall survival ( P = 0.009 and P = 0.019, respectively). However, only severe hypercortisolaemia remained an independent negative factor for survival in multivariate analysis ( P = 0.042). Potassium substitution was required in 87% of patients and the dose was positively correlated to baseline hormone levels including urinary free cortisol ( P < 0.001), s-cortisol ( P < 0.001) and adrenocortical hormone (ACTH) ( P = 0.016). Steroidogenesis inhibitors (SIs) were used as initial treatment in 46 patients to improve symptoms. However, within 1 month, 17 proceeded to bilateral adrenalectomy and 3 died. Conclusions We conclude that only hypercortisolaemia was independently prognostic for shorter survival. Furthermore, we suggest that hypercortisolaemia, especially in combination with severe hypokalaemia (<2.5 mmol/l), indicates an acute life-threatening situation. For these patients, immediate actions should be considered to reduce cortisol levels and bilateral adrenalectomy should be discussed upfront.
2018-04-09 | Adrenal Surgery for Cushing’s Syndrome
Recent advances in the molecular pathogenesis and the natural history of Cushing's syndrome have improved the understanding of the management of this disease. The long-term efficacy of several cortisol-lowering medical treatments is currently under evaluation. However, adrenalectomy is a safe option for the treatment of patients affected by Cushing's syndrome. Unilateral adrenalectomy is the gold standard for treatment of adrenocortical adenomas associated with hypercortisolism. Bilateral adrenalectomy has been widely used in the past as definitive treatment of bilateral macronodular hyperplasia and persistent or recurrent Cushing's disease. The indication and the potential applications of this technique have been recently critically analyzed.
2005-05-17 | Cushing's syndrome: adrenalectomy and long-term results.
The objective of this study was to assess the preoperative symptoms, intra- and postoperative complications and follow-up in patients after uni- or bilateral adrenalectomy due to Cushing's syndrome (CS), independent of etiology. Clinical charts of 42 patients (5 with ACTH-dependent, 37 with ACTH-independent CS) were reviewed, and follow-up data were obtained from re-examination of the patients. The symptoms most frequently seen were hypertension, changes of the skin and obesity. Eight bilateral and 36 unilateral adrenalectomies were carried out without any intraoperative complications. Postoperative complications occurred in 5 patients, 1 patient died on the fourth postoperative day. After a mean duration of 4.6 years 28 of 41 patients could be re-examined, 5 patients had died. One patient showed recurrence 4.3 years after unilateral adrenalectomy due to nodular hyperplasia, contralateral adrenalectomy again revealed nodular hyperplasia. Early diagnosis is essential in order to decrease the rate of pre-, intra- and postoperative complications. Endoscopic approach should be taken in a specialized center due to poor patient's condition. Recurrent disease on the contralateral side may represent bilateral adrenal hyperplasia with sequential tumor formation, demonstrating the importance of extensive preoperative biochemical and imaging testing and close follow-up.
2002-04-26 | Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion.
The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form. 7B2 null mice express no PC2 activity and release large quantities of uncleaved ACTH, resulting in a lethal endocrine condition that resembles pituitary Cushing's (Westphal, C. H., Muller, L., Zhou, A., Bonner-Weir, S., Schambelan, M., Steiner, D. F., Lindberg, I. & Leder, P. (1999) Cell 96, 689). Here, we have compared the 7B2 and PC2 null mouse models to determine why the 7B2 null, but not the PC2 null, exhibits a lethal disease state. Both 7B2 and PC2 nulls contained highly elevated pituitary adrenocorticotropic hormone (ACTH); the neurointermediate lobe content of ACTH in 7B2 nulls was 13-fold higher than in WT mice; that of the PC2 null was 65-fold higher. However, circulating ACTH levels were much higher in the 7B2 null than in the PC2 null. Because hypothalamic inhibitory dopaminergic control represents the major influence on intermediate lobe proopiomelanocortin-derived peptide secretion, dopamine levels were measured, and they revealed that 7B2 null pituitaries contained only one-fourth of WT pituitary dopamine. Adrenalectomized 7B2 null animals survived past the usual time of death at 5 weeks; a month after adrenalectomy, they exhibited normal levels of pituitary dopamine, circulating ACTH, and corticosterone. Elevated corticosterone, therefore, seems to play a central role in the lethal phenotype of the 7B2 null, whereas a 7B2-mediated dopaminergic deficiency state may be involved in the actual ACTH hypersecretion phenomenon. Interestingly, adrenalectomized 7B2 nulls also developed unexpectedly severe obesity.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Mifepristone | small molecules | FDA | HRA Pharma |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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