Ectopic ACTH Syndrome Research Articles

Long-term treatment of acute ectopic ACTH syndrome with Etomidate

Long-term treatment of acute ectopic ACTH syndrome with Etomidate

Ectopic ACTH syndrome presenting with partial loss of conciousness and nonconvulsive status epilepticus in a patient with no signs of Cushing syndrome

Ectopic ACTH syndrome presenting with partial loss of conciousness and nonconvulsive status epilepticus in a patient with no signs of Cushing syndrome

Atypical Presentation of Metastatic Esthesioneuroblastoma with Ectopic ACTH Syndrome After 7 Years

Atypical Presentation of Metastatic Esthesioneuroblastoma with Ectopic ACTH Syndrome After 7 Years

Sphenoid sinus carcinoid tumour causing ectopic ACTH syndrome

A thirty-eight year old patient presented with a gradual increase in weight and Cushingoid facies of two years duration. He also had orbital congestion, with puffy eyelids and corkscrew conjunctival vessels, associated with painful eye movements. An endocrine evaluation revealed raised cortisol and ACTH. Head imaging was performed which showed an enhancing tumour arising from the sphenoid sinus, with osseous erosion of the sphenoid sinus, extending to the nasopharynx, sellar and a small amount extending intracranially. He underwent an endoscopic endonasal resection of the tumour and histology revealed a low-grade carcinoid tumour with ACTH staining. The patient also underwent radiotherapy for the intracranial extension. He is currently in his fourth year of follow-up and imaging has showed a small, stable intracranial remnant. His anterior pituitary hormonal profile remains normal.

Clinical and morphological characteristic of ACTH producing tumors of various localization and the ectopic Cushing’s syndrome

Background: Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is a type hypercorticism caused by ectopic production of ACTH and/or its precursors by neuroendocrine tumors (NET) of various localization, such as lung and thymus carcinoids, less frequently those of pancreas and gastrointestinal tract, medullary thyroid cancer, pheochromocytoma, small cell lung cancer, as well as some other tumor types. The wide spectrum of tumors associated with the ectopic ACTH syndrome (EAS) makes their diagnosis and treatment a complicated issue. Materials and methods : The study was done with surgical and diagnostic biopsy samples from 60 patients who had tumors with EAS, 36 (60%) of them being bronchopulmonary carcinoids, 10 (16.7%) thymus carcinoids, 5 (8.3%) pancreatic NETs, 3 (5%) medullary thyroid cancers, 3 (5%) NETs of unknown primary localization, and NET of appendix, cecum and pheochromocytoma (one case of each, i.e. 1.7%, 1.7%, 1.7%). There were 38 female and 22 male patients (1.72:1), with their mean age of 39 ± 14 years (range, 16 to 77 years). We analyzed their clinical data, as well as the results of morphological and immunohistochemical examination of the tumors. Results : According to the World Health Organization classification (2015), typical carcinoids (TC) of the lung were found in 77.8% (28/36) of the bronchopulmonary tumors. 22.2% (8/36) of the bronchopulmonary tumors and all thymus tumors (100%, n = 10) were classified as atypical carcinoids (ATC). Four pancreatic NETs were classified as Grade 2 (G2), 1 as G3, and NETs of the cecum and appendix as G1 and G2, respectively. At present, 29 (48%) patients are living with no relapse (mean age 39 ± 13.5 years), whereas 22 (37%) of patients developed a relapse (mean age 35 ± 13 years), and 15 (25%) of them died, regardless of the age of the patients The history of the disease was not traced in 4 cases. 5-year relapse-free survival of patients with TC of the lung was 85.7% (24/28), of those with ATC 25% (2/8), with ATC of the thymus and medullary thyroid cancer 0%. Mortality from to TC of the lung for the entire follow-up period was 3.6% (1/28), to ATC 12.5% (1/8), to ATC of the thymus and for medullary thyroid cancer 62.5% and 100%, respectively. The patients with NET of the cecum, appendix and pheochromocytoma are alive without progression for 4, 5 and 6 years, respectively. Therefore, the lowest 5-year survival of patients with EAS was observed in medullary thyroid cancer, pancreatic NET and thymus carcinoids: in 100% (3/3), 75% (3/4), and 57.1% (4/7), respectively. Conclusion: The most unfavorable prognostic factors in the EAS are the localization of tumors in the thymus, pancreas and thyroid gland. This indicates the necessity of a differentiated treatment approaches to patients with this syndrome.

Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome.

Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform. We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors. Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.

Nocardiosis in ectopic ACTH syndrome: A case report and review of 11 cases from the literature.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) associated with nocardiosis is rare, and little information is available regarding its clinical characteristics. In this study, the case of a 35-year-old male patient who showed significant cushingoid features and had a cough with yellow phlegm for 1 month is described. Pulmonary computed tomography (CT) scanning and 18F-fluorodeoxyglucose positron emission tomography combined with CT identified two different lesions in the mediastinum and pulmonary region, respectively. The lesion in the mediastinum was finally diagnosed as an ACTH-secreting mediastinal paraganglioma via biopsy. The sputum culture confirmed pulmonary nocardiosis. The patient was effectively treated with complete tumor resection following the treatment of nocardiosis using trimethoprim-sulfamethoxazole. Following the present case, 11 additional cases of nocardiosis in EAS were identified in the literature and their clinical characteristics were compared and evaluated. It may be concluded that, although Nocardia remains a rare opportunistic infection pathogen in EAS, it is necessary to consider nocardiosis as a diagnosis for patients with pulmonary imaging findings of cavity, consolidation or nodule, particularly when there are brain and extra-pulmonary lesions as well as a poor response to regular treatment.

Frequency of Cushing\u2019s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center

Cushing’s syndrome due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions has occasionally been described. We retrospectively reviewed all 164 cases of Cushing’s syndrome and 77 cases of pheochromocytomas during 10 years. Of all cases with Cushing’s syndrome, only two cases (1.2 %) were due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions (one case of pheochromocytoma and one case of adrenal medullary hyperplasia). Of all pheochromocytomas only the above-mentioned case (1.3 %) also gave rise to an ectopic adrenocorticotropic hormone syndrome. The clinical presentation of adrenocorticotropic hormone-secreting pheochromocytoma and adrenal medullary hyperplasia can be anything from mild to dramatic. These are rare conditions important to bear in mind in the workup of a patient with Cushing’s syndrome or with pheochromocytoma. The identification of ectopic adrenocorticotropic hormone secretion from adrenal medullary lesions can be life-saving.

Carbon dioxide combining power/potassium ratio in etiological diagnosis of Cushing's syndrome

Objective To evaluate carbon dioxide combining power/potassium ratio (CO2CP/K)in etiological diagnosis of Cushing's syndrome. Methods The clinical data 489 patients with pathohistologically confirmed Cushing's syndrome treated in PLA General Hospital between 1993 and 2015 were retrospectively reviewed. Among 489 patients, there were 246 cases of adrenocorticotropic hormone(ACTH) nondependent Cushing's syndrome and 243 cases of ACTH dependent Cushing's syndrome, including 214 cases of Cushing's disease (CD) and 29 cases of ectopic ACTH syndrome (EAS). Receiver operating characteristic(ROC) curve was used to evaluate efficacy of CO2CP/K for etiological diagnosis and the cut-off value and corresponding sensitivity and specificity were analyzed. Results Blood potassium levels were lower in ACTH nondependent group than those in ACTH dependent group[(3.46±0.77) vs.(3.69±0.57)mmol/L, t=3.433, P=0.001]. Bicarbonate, base excess and CO2CP/K (10.0±5.5 vs. 7.6±2.1) were higher in ACTH nondependent group than those in ACTH dependent group (t=-3.612, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and pH value between two groups (P>0.05). Blood potassium [(2.47±0.63) vs.(3.62±0.67)mmol/L] and chlorine levels were lower in EAS group than those in CD group. Bicarbonate, base excess and CO2CP/K (15.6±8.0 vs. 7.8±2.4) were higher in EAS group than those in CD group (t=- 10.145, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and PH value between two groups (P>0.05). Taking 8.95 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of ACTH dependent Cushing's syndrome were 0.34 and 0.85, while taking 9.09 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of EAS were 0.89 and 0.78, respectively. Conclusions The value of CO2CP/K is limited in distinguishing between ACTH dependent and non-ACTH independent Cushing, s syndrome. It may distinguish CD from EAS to some extent, indicating that it might be used as the screening method for etiological diagnosis. Key words: Cushing's syndrome; Hypokalemia; Etiology; Diagnosis; Adrenal gland neoplasms

Pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome

Solitary fibrous tumors occasionally present with hypoglycemia because of the excessive release of insulin-like growth factor II. We report the first case of pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome. An 82-year-old Japanese man presented with lower limb edema, uncontrolled hypertension, hypokalemia, and baseline hypercortisolism. Distal pancreatectomy was performed after the clinical diagnosis of a neuroendocrine tumor with ectopic secretion of adrenocorticotropic hormone. On histological examination, the tumor showed spindle cells in a fascicular arrangement. The diagnosis of the solitary fibrous tumor was confirmed by the identification of the NAB2-STAT6 fusion gene and positive immuno-histochemical staining for STAT6 and CD34. Using quantitative real-time polymerase chain reaction, mRNA that encoded proopiomelanocortin, precursor of adrenocorticotropic hormone, was detected. Proopiomelanocortin production through the demethylation of the promoter region Domain IV was detected. Pancreatic solitary fibrous tumors represent a new cause of ectopic adrenocorticotropic hormone syndrome.

Etiology analysis of 522 hospitalized cases with Cushing syndrome

To summarize the characteristics of the etiology distribution of Cushing syndrome (CS) patients in Chinese PLA general hospital during the past 20 years. All data of CS patients admitted to Chinese PLA General Hospital between 1995 and 2014 were collected. The sex ratio of patients, visiting age, final diagnosis were retrospectively analyzed. From January 1995 to December 2014, 522 patients with CS were admitted, of which, 134 (25.67%) were males and 388(74.33%) were females. The overall mean age was (42±13) years old. 46.36% of the cases were adrenocorticotropic hormone (ACTH) dependent, and ACTH independent CS accounted for 53.64%. At the 41-60 age group, the proportion of ACTH independent CS was higher than that of ACTH independent CS.The proportions of ACTH-independent macronodular adrenal hyperplasia (AIMAH), ectopic ACTH syndrome and adrenal cortical carcinoma were higher in male group than in female group. The number of CS patients was gradually increased during the past 20 years. The proportion of ACTH independent CS was increased (from 32.8% to 60.4%). The proportion of ACTH dependent CS was declined (from 67.2% to 39.6%). The etiology spectrum of CS has changed. There was significant gender-related, age-related difference of etiology distribution in patients with CS.

ACTH Antagonists.

Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.

Ectopic ACTH syndrome caused by hepatic metastases from previously non-functional pancreatic neuroendocrine tumor

Background: Pancreatic neuroendocrine tumors (NETs) are rare; representing less than 10% of all primary pancreatic tumors. The minority of these tumors are functional producing a clinical syndrome according to the hormone secreted. ACTH production by pancreatic NETs is rare and even rarer, it occurs from liver metastasis later in the course of the disease. Case Report: We report a case of a 30-year-old Libyan man who presented with Cushing's syndrome due to ectopic ACTH production from liver metastases of a pancreatic NET. The pancreatic NET was diagnosed 7 years previously when it was considered a nonfunctional at the time of diagnosis; the tumor was resected completely then. In the current presentation there was no evidence of the primary tumor but multiple liver metastases were present. Conclusions: This report highlights the fact that initially non-functional pancreatic NETs may present later with a functional hormonal syndrome either from the primary tumor itself or from its metastatic secondary tumors elsewhere.

Proopiomelanocortin interference in the measurement of adrenocorticotrophic hormone: a United Kingdom National External Quality Assessment Service study.

It is recognized that measurement of ACTH-precursor peptides including proopiomelanocortin (POMC) has clinical utility in identifying the aetiology of Cushing's syndrome. Recent data have also demonstrated cross-reactivity of POMC in ACTH immunoassays used in clinical laboratories. The aim of this study was to assess the cross-reactivity of POMC in the main commercial immunoassays for ACTH and to survey the awareness of laboratory professionals to this potential interference. To assess cross-reactivity, specimens containing ACTH and/or POMC were prepared by the UK National External Quality Assessment Service (UK NEQAS) [Edinburgh]. A separate interpretative exercise was also sent to participating laboratories. Eighty-seven laboratories measured 'total' ACTH (i.e. ACTH and/or POMC) in their assays. Cross-reactivity of POMC varied from a mean of 1·6-4·7% (reflected in a large percentage increase in measured ACTH of up to 261% due to POMC cross-reactivity) depending on the manufacturer. Major differences in the clinical interpretation of test results were observed in returned responses to the interpretative exercise. An appraisal of POMC cross-reactivity in currently available ACTH immunoassays has been achieved. Cross-reactivity was sufficient to detect ACTH precursors at concentrations that could be found in patients with ectopic ACTH syndrome. These data will assist laboratories in interpreting results when assessing the hypothalamic-pituitary-adrenal axis. Endocrinologists and laboratory professionals should be aware of the degree of cross-reactivity in ACTH immunoassay in order to minimize the risk of misinterpretation of results and/or potentially delayed treatment.

ACTH-producing medullary thyroid cancer. Clinical case.

Medullary thyroid cancer with ectopic ACTH production - the disease is extremely rare. The literature describes only a few cases of this disease. Rare ectopic ACTH syndrome caused by medullary thyroid cancer, and the diversity of the clinical picture are responsible for numerous diagnostic errors leading to ineffective treatment. In this regard, we consider it expedient to share our own experience in this area.

A rare case of ectopic ACTH syndrome originated from malignant renal paraganglioma

A rare case of ectopic ACTH syndrome originated from malignant renal paraganglioma

Primary intracranial neuroendocrine tumor with ectopic adrenocorticotropic hormone syndrome: A rare and complicated case report and literature review.

Neuroendocrine tumors (NETs) and ectopic adrenocorticotropic hormone (ACTH) syndrome are frequent in adult patients. However, primary intracranial NETs, exhibiting immunonegativity for ACTH, high serum ACTH level and treated with anterior skull base reconstruction, are rare and complicated. We herein present a case of a primary intracranial NET immunonegative for ACTH, resulting in ectopic ACTH syndrome. A 40-year-old woman presented with intermittent rhinorrhea, rapid weight gain, polydipsia, polyuria, hypertension, dimness, bilateral exophthalmus, diminution of vision in the left eye and pigmentation of the skin of the face and trunk. Computed tomography (CT) and magnetic resonance imaging scans revealed a sizeable enhancing tumor in the anterior cranial fossa, which infiltrated the sphenoid and ethmoid sinuses bilaterally, the left maxillary sinus and the nasal cavity. Abdominal CT scans revealed bilateral adrenal hyperplasia. The biochemical findings included hypokalemia and high glucose, cortisol, plasma ACTH, 24-h urinary free cortisol and testosterone levels. The neoplasm was exposed through a right frontal craniotomy, while anterior skull base reconstruction was performed during surgery. The intracranial surgery achieved gross removal of the tumor; however, part of the tumor remained in the nasal cavity. Histopathological examination of the surgical specimen confirmed the diagnosis of a low-grade small-cell NET, exhibiting immunonegativity for ACTH. A postoperative abdominal CT scan demonstrated bilateral regression of the adrenal gland hyperplasia and the serum ACTH level returned to normal after 16 days. To the best of our knowledge, there are no previous reports of primary intracranial NETs, immunohistochemically negative for ACTH, resulting in ectopic ACTH syndrome.

Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor.

The study was to review the clinical manifestations and laboratory examinations of ectopic adrenocorticotropic hormone (ACTH) syndrome, and to analyze the efficacy of surgical treatment. The clinical data, surgical therapy, and outcome of 23 cases of ectopic ACTH syndrome accompanied by intra-thoracic tumors were reviewed. The tumors were removed from all the patients according to the principles of radical resection. The tumors were confirmed as associated with ectopic ACTH secretion in 19 cases. Hyperglycemia and hypokalemia were recovered, while plasma cortisol, plasma ACTH and 24-hour urinary free cortisol (UFC) levels were significantly reduced after surgery in these 19 cases. Recurrences of the disease were found in six cases during following-up, and five of them died. The thoracic cavity should be a focus in routine examinations of patients with symptoms of Cushing's syndrome (CS), because ectopic ACTH-producing tumors are commonly found in bronchus/lung and mediastinum. Despite the incidence of the pulmonary nodule secondary to opportunistic infection in some cases, surgery is still the first choice if the tumor is localized. The surgical procedure should be performed according to the principles in resection of lung cancer and mediastinal tumor. The surgical efficacy is significant for short-term periods; however, the recurrence of the disease in long-term periods is in great part related to distal metastasis or relapse of the tumor.

Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus: 30-year experience with 16 patients at a single institute in the People's Republic of China.

Background and purposeThymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease.MethodsFrom June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed.ResultsThe median age was 32.5 years (range: 13–47 years), and the median disease duration was 8.5 months (range: 1–150 months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing’s syndrome. Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2 weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41 months (95% CI: 30.3–51.7 months), and the progression-free survival was 28 months (95% CI: 21.6–34.3 months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection.ConclusionTNEC is an extremely aggressive disease that should be considered when treating patients with Cushing’s syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However, additional patients and a longer follow-up will be needed to determine the variables that are predictive of survival and to improve patient prognosis.

Value of desmopressin stimulation test and high dose dexamethasone suppression testin the etiologic diagnosis of ACTH dependent Cushing's syndrome

To investigate the value of desmopressin (DDAVP) stimulation test and high dose dexamethasone suppression test (HDDST) in establishing the cause of ACTH dependent Cushing's syndrome. The clinical data of patients with ACTH dependent Cushing's syndrome at West China Hospital from January 1, 2010 to September 30, 2015 was analyzed. The sensitivity and specificity of DDAVP stimulation test, HDDST, and the diagnostic accordance rate when the two tests were combined, were evaluated based on the diagnostic gold standard. A total of 85 patients with Cushing's disease and 10 patients with ectopic ACTH syndrome were included. The sensitivity and specificity of DDAVP stimulation test were 87% and 5/5, respectively, whereas those of HDDST were 79% and 8/10, respectively. The standard high dose dexamethasone suppression test showed a higher sensitivity than overnight 8 mg dexamethasone suppression test. When the two tests had consistent results, the diagnostic accordance rate was 100%. DDAVP stimulation test and HDDST are both efficient modalities for the diagnosis of Cushing's Disease and ectopic ACTH syndrome. The accuracy of diagnosis can be further improved by combining the two tests.