Mifepristone in the treatment of the ectopic adrenocorticotropic hormone syndrome.

OBJECTIVES: Mifepristone, a glucocorticoid receptor antagonist, can be used to manage hypercortisolism in patients with ectopic adrenocorticotropic hormone syndrome (EAS) when surgical cure is not feasible. Outcomes of EAS patients treated with mifepristone have been limited to reports of isolated cases. We aimed to determine the efficacy and limitations of mifepristone in the treatment of EAS and to compare outcomes with those of patients who underwent bilateral adrenalectomy. METHOD: A retrospective cohort study of EAS patients from the University of Michigan between 1997 and 2017 was conducted. RESULTS: Of the 55 patients with EAS, 16 were treated with mifepristone: eight neuroendocrine tumours, two carcinomas and six occult tumours. Treatment with mifepristone was most commonly prompted by psychosis, uncontrolled glucose and/or hypertension. The median maintenance dose was 600 mg/d. Amelioration of psychosis was observed within 48 hours in 3/3 patients, and the glycaemic control was improved in 14/16 patients. The median duration of treatment was 9 months, and three patients were treated for more than 24 months. The overall survival at 24 months was equivalent between patients with EAS treated with mifepristone vs bilateral adrenalectomy (N = 12) (P = 0.6). CONCLUSIONS: Mifepristone is effective in treating EAS for over 2 years, and survival was not different from that of patients treated with bilateral adrenalectomy. Aggressive concomitant therapy for hypokalaemia and hypertension is necessary.

Cushing's Syndrome With Nocardiosis: A Case Report and a Systematic Review of the Literature.

Objective: To analyze and summarize the clinical characteristics, treatments, and prognosis of Cushing's syndrome (CS) with nocardiosis. Methods: A patient in our hospital and additional 17 patients of CS with nocardiosis in the English literature were included in this study. Clinical characteristics, laboratory data, imaging studies, treatments, and prognosis were evaluated. Results: A 41-year-old man with CS was diagnosed and treated in our hospital. He had co-infections of nocardiosis and aspergillosis. Together with 17 patients of CS with nocardiosis in the English literature, 2 patients (11.1%) were diagnosed as Cushing's disease (CD) while 16 (88.9%) were diagnosed or suspected as ectopic ACTH syndrome (EAS). The average 24hrUFC was 7,587.1 ± 2,772.0 µg/d. The average serum total cortisol and ACTH (8 AM) was 80.2 ± 18.7 µg/dl and 441.8 ± 131.8 pg/ml, respectively. The most common pulmonary radiologic findings in CT scan were cavitary lesions (10/18) and nodules (8/18). Co-infections were found in 33.3% (6/18) patients. The CS patients with co-infections had higher levels of ACTH (671.5 ± 398.2 vs 245.5 ± 217.1 pg/ml, P = 0.047), and 38.9% (7/18) patients survived through the antibiotic therapy and the treatment of CS. Patients with lower level of ACTH (survival vs mortality: 213.1 ± 159.0 vs 554.7 ± 401.0 pg/ml, P = 0.04), no co-infection, underwent CS surgery, and received antibiotic therapy for more than 6 months, had more possibilities to survive. Conclusions: Nocardia infection should be cautioned when a patient of CS presented with abnormal chest radiographs. The mortality risk factors for CS with nocardiosis are high level of ACTH and co-infections. We should endeavor to make early etiological diagnosis, apply long-term sensitive antibiotics and aggressive treatments of CS.

Esthesioneuroblastoma (Olfactory Neuroblastoma) with Ectopic ACTH Syndrome: a multidisciplinary case presentation from the Joan Karnell cancer center of Pennsylvania Hospital.

The case of a patient with recurrent esthesioneuroblastoma complicated by ectopic adrenocorticotropic hormone production is presented, including the workup and management of this uncommon complication of an uncommon disease.

Pneumocystis pneumonia can complicate medical treatment of hypercortisolism even in outpatients with Cushing's disease.

Several cases of Pneumocystosis pneumonia (PCP) have been reported in patients with hypercortisolism, mainly in patients with severe ectopic ACTH syndrome (EAS). We report 2 cases of PCP that did not develop until after starting treatment with metyrapone, one of which occurred in an outpatient with Cushing's disease (CD) without pulmonary symptoms before medical treatment for CD. Patient 1 presented as an outpatient with CD and severe hypercortisolism but nonetheless in good general condition. Treatment with metyrapone was started before pituitary surgery. Patient 2 had EAS due to prostate cancer. Respiratory failure in the two patients occurred 4 days and 30 days, respectively, after the start of metyrapone treatment. In both cases, chest CT showed bilateral interstitial infiltrates, and Pneumocystis jirovecii was found on bronchoalveolar lavage (BAL). A literature review was performed to identify risk factors for PCP in patients with CD: we identified 20 other cases of PCP in patients treated for hypercortisolism, including 16 patients with EAS. Ninety percent of patients had free urinary cortisol greater than 6 times the upper limit of normal (ULN). In conclusion, onset of PCP after initiation of anticortisolic therapy is not limited to patients with EAS, and may occur in CD patients with elevated cortisol levels, even if the patient remains in good general condition and has no pulmonary symptoms before treatment. In such patients, routine prophylactic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) should be considered.

Possible pitfalls in the workup of ectopic ACTH secretion illustrated by four rare cases.

In this case report, we highlight four different cases of ectopic adrenocorticotropic hormone (ACTH) secretion with different pitfalls in the diagnostic workup. Ectopic ACTH secretion (EAS) is an uncommon cause of Cushing's syndrome that accompanies a variety of tumours. It is associated with significant morbidity and mortality. This underlines the importance of early and adequate diagnosis. We will review the causes of EAS and their presentation to increase awareness of this rare and progressive disease.

Advances in the medical treatment of Cushing's syndrome.

Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.

[Ectopic Cushing's syndrome caused by a functioning pancreatic neuroendocrine tumour in a patient with von Hippel-Lindau disease]. / Síndrome de Cushing ectópico, producido por un tumor neuroendocrino pancreático funcionante, en una paciente con enfermedad de von Hippel-Lindau.

We present a 36-year-old woman diagnosed with von Hippel-Lindau disease. A haemangioblastoma of the central nervous system was successfully excised ten years ago and a left nephrectomy had been performed because of clear cell carcinoma. For the last six months, the patient has suffered from amenorrhoea, asthenia, muscular debility and capillary fragility. Physical examination showed hirsutism and bruising. Laboratory findings supported ectopic Cushing's syndrome. A solid pancreatic mass was identified on computed tomography. 111-In-DPTA-pentetreotide scintigraphy demonstrated marked uptake at this location, suggesting a neuroendocrine tumour. Duodenopancreatectomy was performed. After surgery, the cortisol levels returned to normal with complete resolution of the syndrome. This is the first case of Cushing's syndrome caused by an ectopic ACTH-secreting neuroendocrine tumour of the pancreas associated with von Hippel-Lindau disease.

The Ectopic Adrenocorticotropic Hormone Syndrome: Rarely Easy, Always Challenging.

Despite modern imaging techniques, differentiating ectopic adrenocorticotropic hormone (ACTH) syndrome from pituitary-dependent Cushing's syndrome, Cushing's disease, is especially difficult when well-differentiated carcinoids are the source of ACTH secretion, particularly pulmonary carcinoid tumors. ACTH-secreting pulmonary carcinoids, like the corticotroph adenomas causing Cushing's disease, are often small and difficult to detect, and patients present with a gradual onset of the classical signs and symptoms of Cushing's syndrome, indistinguishable from the presentation of Cushing's disease. Hence, the differential diagnosis relies on a combination of clinical assessment, dynamic biochemical tests, inferior petrosal sinus sampling, and multimodal imaging, each with its own caveats and pitfalls.

Ectopic Cushing syndrome: Report of 9 cases. / Síndrome de Cushing ectópico: descripción de 9 casos.

INTRODUCTION: Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years. METHODS: This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015. RESULTS: Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2,840µg/24h and 204pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up. CONCLUSIONS: Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended.

Dopamine receptor expression and function in corticotroph ectopic tumors.

BACKGROUND: Dopamine receptor (DR) expression and dopamine agonist (DA) effectiveness have never been demonstrated in neuroendocrine tumors associated with ectopic ACTH syndrome (EAS). AIM: The aim of the current study was to evaluate DR and particularly D2 subtype expression in neuroendocrine tumors associated with EAS and to evaluate the in vivo effectiveness of the DA cabergoline in the treatment of EAS. PATIENTS AND METHODS: Six ACTH-secreting neuroendocrine tumors, including four lung, one pancreatic, and one thymic carcinoid, were used for the evaluation of D2 expression by immunohistochemistry. DR subtypes and D2 isoforms and number were evaluated by RT-PCR in three cases of persistent EAS after surgery. These patients were treated with cabergoline at the dose of 3.5 mg/wk for 6 months. Clinical parameters, hormonal levels, and tumor size were monitored during the treatment period. RESULTS: At immunohistochemistry, D2 was expressed in five (83.3%) tumors. At RT-PCR, D2 was confirmed in all three cases but at variable numbers, whereas D4 was expressed in two cases. D(2long) was expressed in all three cases, together with D(2short) in one case. A normalization of urinary cortisol levels was found in two patients (66.7%) after 3 months of treatment. However, treatment escape was demonstrated in one of these patients afterward. CONCLUSION: The results of this study demonstrated that DR are expressed in neuroendocrine tumors associated with EAS and that cabergoline treatment could be effective in controlling cortisol excess in a subgroup of patients with EAS. Further studies on a larger number of patients are mandatory to confirm the usefulness of DA in EAS.

Ectopic ACTH syndrome caused by pheochromocytoma: computed tomography-guided percutaneous ethanol injection as an alternative treatment.

Ectopic ACTH secretion represents 8-18% of the cases of endogenous hypercortisolism. Pheochromocytomas correspond to 2-25% of the cases and surgery is the indicated treatment. We describe a case of ACTH-secreting pheochromocytoma treated with percutaneous ethanol injection (PEI) guided by computed tomography (CT). A 71-yr-old man presented with diabetes, severe hypokalemia, weight loss, muscle weakness, and hypertension. Hormonal evaluation revealed elevated levels of urinary cortisol, ACTH, catecholamines, and urinary metanephrines. There was no cortisol or ACTH response to desmopressin stimulation test. Magnetic resonance revealed bilateral adrenal nodules, larger on the left side. The suspected diagnosis was ectopic ACTH syndrome caused by pheochromocytoma. Ketoconazole treatment resulted in reduction of urinary cortisol levels but was followed by severe cholestasis and hepatic dysfunction, preventing surgery; it was substituted by octreotide with reduction of ACTH and cortisol levels, but without improvement of cholestasis. The patient presented cachexia and developed multiple pulmonary abscesses that also prevented surgical treatment, thus he was treated with percutaneous ethanol injection guided by CT of the left adrenal tumor. During the procedure, the patient had an increase in blood pressure controlled by the infusion of sodium nitroprusside followed by hypotension that required infusion of dopamine and volume expansion. Afterwards, he presented hormonal normalization, normal catecholamines levels, and clinical improvement. Histological tissue analysis confirmed pheochromocytoma. We concluded that CT-guided PEI represents an efficient alternative therapy to ectopic ACTH-secreting pheochromocytomas in patients without clinical conditions for surgery.

Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus.

We herein report the case of a 44-year-old man who was diagnosed with pneumocystis pneumonia (PCP) concomitant with ectopic adrenocorticotropic hormone (ACTH) syndrome, which had been caused by a large cell neuroendocrine carcinoma of the thymus. Chest computed tomography revealed ground-glass opacities in the lungs. PCP was diagnosed by a polymerase chain reaction with bronchoalveolar lavage. The levels of cortisol were slowly corrected with an adrenal enzyme inhibitor, and the exacerbation of PCP was successfully avoided. Our case indicates that in addition to prophylaxis, the early diagnosis of PCP and the slow correction of hypercortisolemia should be considered in order to prevent an exacerbation due to the reconstitution of the immune function in patients with ectopic ACTH syndrome.

Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production.

PURPOSE: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Cushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by malignant neoplasms (ECS). PATIENTS AND METHODS: A retrospective chart review was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and for clinical, biochemical, and hormonal responses. RESULTS: There were four women and 11 men with a median age of 59 years (range, 44 to 84). Eleven patients had primary lung cancer (nine small-cell [SCLC], one mixed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one bronchial, one pancreatic); one had hepatocellular carcinoma; and one had medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle weakness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Biochemical abnormalities included hypokalemia (n = 14), metabolic alkalosis (n = 13), and new or worsened diabetes mellitus (n = 10). Patients received ketoconazole in dosages of 400 to 1,200 mg/d titrated by changes in urinary free-cortisol (UFC) levels for a median duration of 26 days (range, 3 to 1,059), and nine also received chemotherapy with ketoconazole. Hypokalemia, metabolic alkalosis, diabetes mellitus, and hypertension improved in the majority of patients. Ten patients had a hormonal response, with seven complete responses (median duration, 25 days; range, 6 to 989). The occurrence of symptomatic hypoadrenalism was definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal control by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154). CONCLUSION: Ketoconazole results in biochemical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For that reason, replacement corticosteroids should be considered for patients with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate control of the syndrome is dependent on successful treatment of the underlying tumor.

Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer.

PURPOSE: This study was undertaken to review the clinical and laboratory features and response to treatment of patients with Cushing's syndrome associated with ectopic corticotropin (adrenocorticotropic hormone; ACTH) production and small-cell lung cancer (SCLC). PATIENTS AND METHODS: We undertook a retrospective chart review of 545 patients with SCLC seen at Toronto General Hospital between 1980 and 1990 and identified 23 patients (4.5%) with Cushing's syndrome and ectopic ACTH production. RESULTS: There were 17 male and six female patients, with a median age of 60 years. The syndrome was diagnosed at the time of initial presentation of SCLC in 13 patients and at relapse in 10 patients. Seven patients had limited disease and 16 had extensive disease at their initial diagnosis of SCLC, but 20 of 23 had extensive disease at the time of diagnosis of Cushing's syndrome. Ten patients had bone marrow involvement. The most frequent physical findings included edema (83%) and proximal myopathy (61%). All patients had elevated plasma and urinary free cortisol levels; 22 had a hypokalemic alkalosis, and 13 had hyperglycemia. Only one patient had a normal ACTH level. The response rate (complete plus partial) to chemotherapy for patients who had the syndrome diagnosed at initial presentation of SCLC was only 46%, and their median survival was only 3.57 months. Only two patients achieved complete normalization of all hormone parameters, and neither experienced hormone relapse at the time of SCLC relapse. Complications of therapy included gastrointestinal (GI) ulceration (six patients), GI bleeding (four), perforation of a duodenal ulcer (one), pneumonia (10), septic shock (three), and fungal infections (five). CONCLUSION: Ectopic ACTH production is associated with a low response to chemotherapy, short survival, and a high rate of complication to therapy.

Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole.

CONTEXT: Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described. OBJECTIVE: To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism. DESIGN: Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN). PATIENTS AND SETTINGS: A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals. INTERVENTION: Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities). MAIN OUTCOME: Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition. RESULTS: After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal. CONCLUSION: Metyrapone-ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.