Ectopic ACTH Syndrome Research Articles

ACTH Producing Mediastinal Tumor - Multidisciplinary Approach

Abstract Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms. Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value <46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives. Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.

The Dexamethasone-CRH Stimulation Test: A Single-Center Experience

Background: The diagnostic value of adding a Corticotropin Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. We hypothesized that adding CRH to LDDST would provide additional case detection in patients suspected of having Cushing’s disease (CD). Methods: We identified 118 patients who underwent the Dex-CRH test to evaluate ACTH-dependent CS from a prospectively maintained pituitary database over 12 years. Seven patients were excluded (2 lost to follow up, 2 were on Dilantin with no available Dexamethasone (Dex) level, 2 had cyclic CD, and 1 suspected noncompliance with Dex intake). Three patients with ectopic ACTH Syndrome had very high cortisol levels after both LDDST and Dex-CRH tests. The remaining 108 patients are the subjects of this analysis. Patients were instructed to take 8 doses of Dex 0.5 mg PO every 6 hours starting at noon with the last dose of Dex taken at 6 AM. Ovine CRH injection (1 µg/kg, max 100 mcg) was given IV 2 hours afterwards. Cortisol was measured 2 hours after the last Dex dose prior to and 15 minutes after CRH administration. CD diagnosis was made based on positive ACTH staining on pituitary pathology and/or development of hypocortisolism postoperatively. Patients with no Cushing disease (NCD) are the group of patients in whom CD diagnosis could not be confirmed after a minimum follow up of 30 months. Results: Among 108 patients who underwent Dex-CRH test, 66 had CD and 42 had NCD. The female sex ratio, and median (range) for each of age, BMI, and follow-up duration in months were as follows with no statistically significant difference between the two groups: CD: 83%, 40 (15–82), 34 (30–42) and 63 (24–102). NCD: 88%, 40 (20–71), 37 (31–43) and 52 (30–67). Among 66 patients with CD, 5 patients (7.6%) had a cortisol level ≤ 1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of these three patients the LDDST was normal (cortisol post-Dex was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cut-off value of > 1.4 µg/dL at 15 min during Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded from the analysis (n=74), the sensitivity did not change but specificity and accuracy of Dex-CRH test further increased to 97% and 99%, respectively. Conclusion: The CRH test addition to the 2-day LDDST provided additional case detection in 5/66 (7.6%) of patients with CD. It resulted in one additional false-positive case compared to LDDST. Measurement of Dex level provided improved diagnostic accuracy of DEX-CRH test.

Occult Carcinoid Causes Cushing’s Syndrome

Introduction: Lung neuroendocrine tumors (NETs) are a common cause of ectopic ACTH-secretion. Only 3% of NETs cause Cushing’s syndrome1; the majority are small and may be radiographically occult. Additionally, the responses to dexamethasone, metyrapone, and oCRF can be indistinguishable from that observed in pituitary Cushing’s disease2. These challenges lead to misdiagnosis and unnecessary procedures. Case Description: 45-year-old male presented for resection of right-sided pulmonary carcinoid tumor. He was diagnosed with Cushing’s syndrome in 2011 when he experienced uncontrolled hypertension and excessive weight gain with elevations in cortisol and ACTH levels. He underwent transsphenoidal pituitary resection in May 2011 for a possible pituitary microadenoma. Post-operative worsening hypertension, weight gain, and striae led to bilateral adrenalectomy in November 2011, complicated by retroperitoneal hemorrhage and resuscitation-induced pulmonary edema. On chest CT in early 2012, an 8 mm incidental right pulmonary nodule was documented. 8 years later, chest imaging for mild COVID-19 infection again revealed a right-sided pulmonary nodule. He underwent CT-guided biopsy of the nodule in July 2020 with pathology demonstrating carcinoid histology. Right lower lobectomy was performed. Pre-operative ACTH was 1673 pg/mL (normal: 10-60 pg/mL) and post-operative ACTH was 16 pg/mL. The resected tumor stained positive for ACTH, confirming that carcinoid tumor was the source of Cushing’s for the past decade. Conclusion: The diagnosis of ectopic Cushing’s syndrome can be elusive, leading to surgeries with significant morbidity, as seen in our patient. In one retrospective review, 14% of patients with Cushing’s had transsphenoidal resection before they were diagnosed with an ectopic source3. Ectopic Cushing’s syndrome can be a challenging diagnosis to make and a multidisciplinary approach with close collaboration between endocrinologist, radiologist, surgeon and pathologist may increase the diagnosis accuracy. Citations: 1Kamp, K, Alwani, R A, Korpershoek, E, Franssen, G., de Herder, W W, & Feelders, R A. (2016). Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors, European Journal of Endocrinology, 174(3), 271-280. Retrieved Jan 15, 2021, from https://eje.bioscientifica.com/view/journals/eje/174/3/271.xml 2Malchoff CD, Orth DN, Abboud C, Carney JA, Pairolero PC, Carey RM. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. The American Journal of Medicine. 1988;84(4):760-764. doi:10.1016/0002-9343(88)90116-7 3Ioannis Ilias, David J. Torpy, Karel Pacak, Nancy Mullen, Robert A. Wesley, Lynnette K. Nieman,Cushing’s Syndrome Due to Ectopic Corticotropin Secretion: Twenty Years’ Experience at theNational Institutes of Health, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue8, 1 August 2005, Pages 4955–4962, https://doi.org/10.1210/jc.2004-2527

Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)

Cushing Syndrome in the Setting of Chronic Dilated Cardiomyopathy: Can Treatment Improve Chronic Dilated Cardiomyopathy?

Background: Cushing syndrome (CS) is well known to be associated with metabolic syndrome, venous thromboembolism, hypertension, left ventricular hypertrophy, and rarely dilated cardiomyopathy. The pathophysiological effects of hypercortisolism on the myocardium results in cardiomyocyte hypertrophy, myofibrillolysis, myocardial fibrosis, global longitudinal and circumferential strain. Our patient presents an example of CS in the setting of chronic heart failure with reduced ejection fraction, multiple thromboembolic events, and diabetes mellitus in a young adult.Clinical Case: A 34-year male with a past medical history of dilated cardiomyopathy with biventricular failure and left ventricle ejection fraction of 10%, pulmonary embolism, diabetes mellitus, and gout presented with shortness of breath. On physical exam he presented with symptoms of CS: moon facies, supraclavicular fat pads, dorsal fat pads, purple striae of abdominal skin, truncal obesity, ecchymosis, and skin atrophy. Labs showed elevated morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 8.6 mcg/dl, n< 5 mcg/dl), repeat morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 5.7 mcg/dl, n< 5 mcg/dl), and ACTH-concentrations <5 pg/ml. CT-scan was insignificant for adrenal hyperplasia. He was admitted and treated for acute congestive heart failure exacerbation with plans for definitive treatment of CS outpatient with further imaging studies.Conclusion: The occurrence of CS induced heart failure results in increased mortality. There have been numerous accounts of resolution of cardiomyopathy after surgical treatment for CS secondary to adrenal adenoma. Our patient had a 10-year history of chronic dilated cardiomyopathy prior to cushingoid symptoms and confirmatory endocrinological data. The definitive treatment for CS syndrome in our patient would eventually be surgery targeting the source of hypercortisolism, however his cardiovascular risk factors would make him a poor surgical candidate. Severely reduced ejection fraction is a contraindication for generalized anesthesia needed for surgery. When surgery is contraindicated in CS medical management is recommended according to guidelines that target pituitary-directed medical treatments for Cushing’s disease and targeted therapies to treat ectopic ACTH syndrome. To our knowledge there have been few studies that demonstrate the effects of CS treatment on chronic conditions such as dilated cardiomyopathy. Studies have shown that surgical treatment for CS have reversed cardiomyopathy caused by CS but it still remains to be answered whether this same effect is achieved to some degree in chronic dilated cardiomyopathy.

Rapid control of ectopic Cushing's syndrome during the COVID-19 pandemic in a patient with chronic hypokalaemia.

SummaryIn this case report, we describe the management of a patient who was admitted with an ectopic ACTH syndrome during the COVID pandemic with new-onset type 2 diabetes, neutrophilia and unexplained hypokalaemia. These three findings when combined should alert physicians to the potential presence of Cushing’s syndrome (CS). On admission, a quick diagnosis of CS was made based on clinical and biochemical features and the patient was treated urgently using high dose oral metyrapone thus allowing delays in surgery and rapidly improving the patient’s clinical condition. This resulted in the treatment of hyperglycaemia, hypokalaemia and hypertension reducing cardiovascular risk and likely risk for infection. Observing COVID-19 pandemic international guidelines to treat patients with CS has shown to be effective and offers endocrinologists an option to manage these patients adequately in difficult times.Learning pointsThis case report highlights the importance of having a low threshold for suspicion and investigation for Cushing’s syndrome in a patient with neutrophilia and hypokalaemia, recently diagnosed with type 2 diabetes especially in someone with catabolic features of the disease irrespective of losing weight.It also supports the use of alternative methods of approaching the diagnosis and treatment of Cushing’s syndrome during a pandemic as indicated by international protocols designed specifically for managing this condition during Covid-19.

A rare case of ectopic ACTH syndrome caused by primary renal neuroendocrine tumor.

SummaryEctopic adrenocorticotropic hormone (ACTH) secretion is responsible for 5–15% of Cushing’s syndrome (CS). Neuroendocrine tumor (NET) is a common cause of ectopic ACTH syndrome (EAS). However, primary renal NET is exceedingly rare. Fewer than 100 cases have been reported and only a few cases presented with CS. Because of its rarity and lack of long-term follow-up data, clinical manifestations, biological behavior and prognosis are not well understood. Here, we report the case of a 51-year-old man who presented with clinical and laboratory findings compatible with EAS. CT scan revealed a lesion of uncertain nature at the lower pole of the left kidney. Octreotide scan found a filling defect at the lower pole of left kidney. It was difficult to determine if this finding was the true etiology or an incidental finding. Unfortunately, the patient’s clinical status rapidly deteriorated with limited medical treatment. The patient underwent left nephrectomy and left adrenalectomy. Histopathological examination confirmed NET with oncocytic features. Immunohistochemistry staining was positive for ACTH. The patient’s condition gradually improved. Additionally, glucocorticoid replacement was required only 6 months during a gradual recovery of hypothalamic pituitary adrenal axis achieved approximately three years after tumor removal. Although extremely rare, primary renal NET should be considered as a cause of EAS particularly in a patient with rapid clinical deterioration. Thorough investigation, early diagnosis and careful management are crucial to reduce morbidity and mortality.Learning pointsPrimary renal NET is an extremely rare cause of ectopic ACTH syndrome.Ectopic ACTH syndrome has a rapid onset with severe clinical manifestations. In this case, the patient’s condition deteriorated rapidly, resulting from severe hypercortisolism. Resection of the tumor is the most effective treatment.Localization of ectopic ACTH-secreting tumors is very challenging. Multimodality imaging including CT, MRI, octreotide scan, and positron emission tomography plays a crucial role in identifying the tumors. However, each imaging modality has limitations.

Experience of Ectopic Adrenocorticotropin Syndrome: 88 Cases With Identified Causes

ObjectiveEctopic adrenocorticotropic hormone syndrome (EAS) is a rare cause of Cushing's syndrome and diagnosis and management remain challenging. The aim of this study was to present the clinical spectrum of a group of EAS cases in a single center to explore better management strategies. MethodsA retrospective study was conducted to identify 88 confirmed EAS cases at our hospital from 1984 to 2019. The clinical, biochemical, imaging, and pathological features were analyzed. ResultsOf the 88 eligible patients with EAS, 38 (43.2%) cases of pulmonary neuroendocrine tumors (NETs) and a larger number of thymic/mediastinal NETs (29 cases, 33%) were identified. The clinical and biological features of EAS and Cushing's disease overlapped but were more severe in EAS. Inferior petrosal sinus sampling (97.4%) and computed tomography (85.4%) provided the highest positive diagnostic accuracy. Computed tomography is also a useful tool to identify tumors in chest cavity compared with nonchest lesions (91.2% vs 57.1%). Although a greater tumor size (4.54 cm vs 1.44 cm) and higher rate of insuppressible high-dose dexamethasone suppression test (83.3% vs 51.5%) were found in thymic/mediastinum NETs than in pulmonary NETs, the level of hormone production had no difference. ConclusionEAS had more common and severe clinical presentations than Cushing's disease, and multiple imaging approaches are required for reliable diagnosis. A higher proportion of thymic/mediastinal NETs was found in our study. For patients without a certain tumor source, long-term follow-up and further evaluations are needed.

Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review.

Inferior petrosal sinus sampling (IPSS) helps differentiate the source of ACTH-dependent hypercortisolism in patients with inconclusive biochemical testing and imaging, and is considered the gold standard for distinguishing Cushing disease (CD) from ectopic ACTH syndrome. We present a comprehensive approach to interpreting IPSS results by examining several real cases. We performed a comprehensive review of the IPSS literature using PubMed since IPSS was first described in 1977. IPSS cannot be used to confirm the diagnosis of ACTH-dependent Cushing syndrome (CS). It is essential to establish ACTH-dependent hypercortisolism before the procedure. IPSS must be performed by an experienced interventional or neuroradiologist because successful sinus cannulation relies on operator experience. In patients with suspected cyclical CS, it is important to demonstrate the presence of hypercortisolism before IPSS. Concurrent measurement of IPS prolactin levels is useful to confirm adequate IPS venous efflux. This is essential in patients who lack an IPS-to-peripheral (IPS:P) ACTH gradient, suggesting an ectopic source. The prolactin-adjusted IPS:P ACTH ratio can improve differentiation between CD and ectopic ACTH syndrome when there is a lack of proper IPS venous efflux. In patients who have unilateral successful IPS cannulation, a contralateral source cannot be excluded. The value of the intersinus ACTH ratio to predict tumor lateralization may be improved using a prolactin-adjusted ACTH ratio, but this requires further evaluation. A stepwise approach in performing and interpreting IPSS will provide clinicians with the best information from this important but delicate procedure.

Revalidation of inferior petrosal sinus sampling: the latest results from a single-center experience.

Cushing's disease (CD), which manifests as excess cortisol secretion, is caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Such adenomas are occasionally difficult to identify on magnetic resonance imaging (MRI), and thorough endocrinological examination may be required to detect them. Inferior petrosal sinus (IPS) sampling (IPSS) has been the gold standard test for distinguishing CD from ectopic ACTH syndrome (EAS). However, IPSS is an invasive procedure, and proper catheterization is occasionally challenging due to anatomical variations. Thus, there have been ongoing debates regarding the necessity of this procedure. Here, we present our recent IPSS data derived from the analysis of 65 patients who were referred to us for possible CD between April 2018 and December 2020 after undergoing meticulous endocrinological testing. Even with detailed MRI, no obvious lesions were identified in 19 patients. IPSS performed on these 19 individuals identified an IPS-to-peripheral ACTH gradient in 15 of them. The four patients who lacked this gradient were subjected to a classical algorithm using concurrently measured prolactin levels, the results of which were consistent with their ultimately confirmed diagnoses: two true-positive and two true-negative diagnoses. These findings support the validity of the algorithm and demonstrate that the prolactin-adjusted IPS-to-peripheral ACTH ratio can improve the differentiation between CD and EAS. We had no false-negative results, but three patients were false-positive. Consequently, those three patients in which no apparent tumor was clarified during surgery could not have any endocrinological improvement postoperatively.

Hair cortisol and cortisone measurements for the diagnosis of overt and mild Cushing’s syndrome

Hair cortisol (HF) and cortisone (HE) measurements reflect tissular exposure to cortisol over months and are increased in overt Cushing's syndrome (CS). No data is available in mild CS. We compared the diagnostic performance of HF and HE between patients with overt or mild CS. Single centre retrospective study. HF&HE were measured by LC-MS/MS in 48 consecutive adult females with Cushing's disease (CD), ectopic ACTH syndrome, secreting adenomas and carcinomas, and adrenal incidentalomas. All had impaired dexamethasone suppression tests. Overt CS (n = 25) was diagnosed in front of specific symptoms, a mean UFC (>1.5 ULN) and increased midnight serum cortisol or salivary cortisol. Mild CS (n = 23) was diagnosed in patients lacking specific symptoms and displaying at least one additional biological abnormality including mildly increased UFC (≤1.5 ULN), increased midnight serum cortisol or salivary cortisol and suppressed plasma ACTH in patients with adrenal tumours. In this study, 84 healthy subjects and obese patients served as controls. HF and HE showed roughly similar performance in overt CS (92 and 100% sensitivity, 91 and 99% specificity, respectively). HF and HE were lower in mild CS but higher than in controls (P < 0.01). HE was correlated with midnight serum cortisol (P < 0.02) and volume of adrenal incidentalomas (P < 0.04) but not with UFC. HF and HE had 59% and 68% sensitivity, and 79 and 94% specificity, respectively, for the diagnosis of mild CS. Contrary to UFC, both HF and HE were in the range of overt CS in 11/23 patients with mild CS. Patients with mild CS and increased HE required more antihypertensive treatments and showed worser lipid profiles than patients with normal HE. HF and HE measurement performed better in overt than in mild CS but is a useful adjunct to diagnose mild CS and to identify adrenocortical incidentalomas responsible for excessive cortisol exposure.

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients. Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed. EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN. The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas. ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol.

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing’s Syndrome

ObjectiveOvernight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing’s syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing’s disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS). MethodsWe conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required. ResultsPatients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] μg/dL vs 9.9 [5.1-25.0] μg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level. ConclusionThe ON-HDDST had a poor diagnostic value in differentiating CD and EAS.

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.

The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing's Disease.

Cushing’s disease caused due to adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) leads to hypercortisolemia, resulting in increased morbidity and mortality. Autonomous ACTH secretion is attributed to the impaired glucocorticoid negative feedback (glucocorticoid resistance) response. Interestingly, other conditions, such as ectopic ACTH syndrome (EAS) and non-neoplastic hypercortisolemia (NNH, also known as pseudo-Cushing’s syndrome) also exhibit glucocorticoid resistance. Therefore, to differentiate between these conditions, several dynamic tests, including those with desmopressin (DDAVP), corticotrophin-releasing hormone (CRH), and Dex/CRH have been developed. In normal pituitary corticotrophs, ACTH synthesis and secretion are regulated mainly by CRH and glucocorticoids, which are the ACTH secretion-stimulating and -suppressing factors, respectively. These factors regulate ACTH synthesis and secretion through genomic and non-genomic mechanisms. Conversely, glucocorticoid negative feedback is impaired in ACTHomas, which could be due to the overexpression of 11β-HSD2, HSP90, or TR4, or loss of expression of CABLES1 or nuclear BRG1 proteins. Genetic analysis has indicated the involvement of several genes in the etiology of ACTHomas, including USP8, USP48, BRAF, and TP53. However, the association between glucocorticoid resistance and these genes remains unclear. Here, we review the clinical aspects and molecular mechanisms of ACTHomas and compare them to those of other related conditions.

CT signs and parameters of vascularization of pulmonary neuroendocrine tumours and their relationship with the development of ACTH ectopic syndrome

CT signs and parameters of vascularization of pulmonary neuroendocrine tumours and their relationship with the development of ACTH ectopic syndrome

Ectopic ACTH syndrome presenting as pneumocystis pneumonia

Ectopic ACTH syndrome presenting as pneumocystis pneumonia

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report

BackgroundCushing’s syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing’s syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling.Case presentationA 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing’s syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing’s syndrome, including moon face, purple striate and central obesity. The patient’s life quality also improved significantly.ConclusionWe reported a rare case of endogenous Cushing’s syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome.

Corticotropinomas and adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors exhibit differential levels of some microRNAs (miRs) compared to normal tissue. Because miRs can be released from tissues into circulation, they offer promise as novel disease biomarkers.Objective: To evaluate whether miRs are differentially detected in plasma samples of patients with ACTH-dependent Cushing's syndrome (CS).Design: Case-control study.Methods: Morning fasting plasma samples were collected from 41 consecutive patients with confirmed ACTH-dependent CS and 11 healthy subjects and stored at −80°C. Twenty-one miRs previously reported to be differentially expressed in ACTH-secreting tumors vs. healthy tissue samples were quantified in plasma by qPCR.Results: Among enrolled subjects, 28 were confirmed to have Cushing's disease (CD), 13 had ectopic ACTH secretion (EAS) and 11 were healthy controls. We found statistically significant differences in the circulating levels of miR-16-5p [45.04 (95% CI 28.77–61.31) in CD vs. 5.26 (2.65–7.87) in EAS, P < 0.001; q = 0.001], miR-145-5p [0.097 (0.027–0.167) in CD vs. undetectable levels in EAS, P = 0.008; q = 0.087] and differences in miR-7g-5p [1.842 (1.283–2.400) in CD vs. 0.847 (0.187–1.507) in EAS, P = 0.02; q = 0.14]. The area under the receiver-operator (ROC) curve was 0.879 (95% CI 0.770–0.987), p < 0.001, when using miR-16-5p to distinguish between CD and EAS. Circulating levels of miR-16-5p in the healthy control group differed from that of both the CD and EAS groups.Conclusions: Plasma miR levels differ in patients with CD and EAS. In particular, miR-16-5p, miR-145-5p and miR-7g-5p are promising biomarkers for further research to differentiate ACTH-dependent CS.

High accuracy of bilateral and simultaneous petrosal sinus sampling with desmopressin for the differential diagnosis of pediatric ACTH-dependent Cushing's syndrome.

To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing's syndrome (ADCS) METHODS: Retrospective study in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14years (range 9-19years), 53% were males, 18 had Cushing's disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10µg of intravenous desmopressin. The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure. In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.