ACTH-dependent Cushing's Syndrome Research Articles

Treatment with osilodrostat in ACTH-independent Cushing's syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Evaluation of the ACTH-CLU index for the differential diagnosis of ACTH-dependent Cushing's syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Should We Use Prolactin Adjustment in Bilateral Inferior Petrosal Sinus Sampling to Diagnose Cushing Disease? A Joint Meta-Analysis of Head-to-Head Diagnostic Tests Accuracy Studies

ObjectivePrevious studies have shown inconsistent results regarding the usefulness of prolactin adjustment in bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS). This meta-analysis compared the diagnostic accuracy of prolactin adjustment versus no adjustment in BIPSS. MethodsThis study searched the PubMed, Embase, Web of Science, Cochrane library, and WanFang databases for published data as of March 2022 on the use of prolactin adjustment in BIPSS to differentially diagnose ACTH-dependent CS. A Bayesian joint bivariate model was used in the head-to-head comparison of the diagnostic accuracy. ResultsThis meta-analysis included a total of 10 studies with 300 patients. The combined sensitivity and specificity for BIPSS without prolactin adjustment were 94.47% (95% CI, 88.67%-98.44%) and 91.14% (95% CI, 57.17%-99.80%), respectively. The combined sensitivity and specificity after prolactin adjustment were 99.97% (95% CI, 99.03%-100.00%) and 80.69% (95% CI, 50.27%-97.82%), respectively. After the prolactin adjustment, the sensitivity of BIPSS to diagnose Cushing disease was improved with a statistically significant difference (difference in sensitivity, 5.39%; 95% CI, 1.37%-11.26%), whereas the decrease in specificity was without a statistically significant difference (difference in specificity, −9.20%; 95% CI, −42.02% to 26.61%). ConclusionThis meta-analysis indicated that prolactin adjustment in BIPSS might help to recognize Cushing disease among patient with ACTH-dependent CS. However, prolactin adjustment may not help identify ectopic ACTH syndrome in BIPSS.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Machine learning models for differential diagnosis of Cushing's disease and ectopic ACTH secretion syndrome.

Using machine learning (ML) to explore the noninvasive differential diagnosis of Cushing's disease (CD) and ectopic corticotropin (ACTH) secretion (EAS) model is the next hot research topic. This study was to develop and evaluate ML models for differentially diagnosing CD and EAS in ACTH-dependent Cushing's syndrome (CS). Two hundred sixty-four CD and forty-seven EAS were randomly divided into training and validation and test datasets. We applied 8 ML algorithms to select the most suitable model. The diagnostic performance of the optimal model and bilateral petrosal sinus sampling (BIPSS) were compared in the same cohort. Eleven adopted variables included age, gender, BMI, duration of disease, morning cortisol, serum ACTH, 24-h UFC, serum potassium, HDDST, LDDST, and MRI. After model selection, the Random Forest (RF) model had the most extraordinary diagnostic performance, with a ROC AUC of 0.976 ± 0.03, a sensitivity of 98.9% ± 4.4%, and a specificity of 87.9% ± 3.0%. The serum potassium, MRI, and serum ACTH were the top three most important features in the RF model. In the validation dataset, the RF model had an AUC of 0.932, a sensitivity of 95.0%, and a specificity of 71.4%. In the complete dataset, the ROC AUC of the RF model was 0.984 (95% CI 0.950-0.993), which was significantly higher than HDDST and LDDST (both p < 0.001). There was no significant statistical difference in the comparison of ROC AUC between the RF model and BIPSS (baseline ROC AUC 0.988 95% CI 0.983-1.000, after stimulation ROC AUC 0.992 95% CI 0.983-1.000). This diagnostic model was shared as an open-access website. A machine learning-based model could be a practical noninvasive approach to distinguishing CD and EAS. The diagnostic performance might be close to BIPSS.

Comparison of the preoperative diagnostic accuracy of BIPSS versus MRI for Cushing disease: a single-centre experience

BackgroundCushing disease (CD) arises due to a pituitary corticotroph adenoma, which is the most common cause of Cushing syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) is a safe method for differentiating CD from ectopic adrenocorticotropic hormone (ACTH)-dependent CS. Enhanced high-resolution magnetic resonance imaging (MRI) can localize tiny pituitary lesions. The aim of this study was to compare the preoperative diagnostic accuracy of BIPSS versus MRI for CD in CS patients. We performed a retrospective study of patients who underwent BIPSS and MRI between 2017 and 2021. Low- and high-dose dexamethasone suppression tests were performed. Blood samples were collected simultaneously from the right and left catheter and femoral vein before and after desmopressin stimulation. MRI images were obtained, and endoscopic endonasal transsphenoidal surgery (EETS) was performed in confirmed CD patients. Dominant sides of ACTH secretion during BIPSS and MRI were compared with surgical findings.ResultsTwenty-nine patients underwent BIPSS and MRI. CD was diagnosed in 28 patients, 27 of whom received EETS. Localizations of microadenomas by MRI and BIPSS agreed with the EETS findings in 96% and 93% of the cases, respectively. BIPSS and EETS were successfully performed on all patients.ConclusionBIPSS was the most accurate method (gold standard) for establishing a preoperative diagnosis of pituitary-dependent CD and was more sensitive than MRI in diagnosing microadenoma. High-resolution MRI with enhancement had an advantage over BIPSS in microadenoma lateralization diagnostics. The combined use of MRI and BIPSS could improve the preoperative diagnosis accuracy in ACTH-dependent CS patients.

Experience in the treatment of patients with ACTH-independent macronodular bilateral adrenal hyperplasia

Aim to determine the optimal tactics for the examination and treatment of patients with macronadular bilateral adrenal hyperplasia.&#x0D; Material and methods. The study included 11 patients with macronodular bilateral adrenal hyperplasia (main group). To compare biochemical parameters, the results of 26 healthy people were studied (control group).&#x0D; Results. The patients with macronodular bilateral adrenal hyperplasia were characterized by deficiency of 11-hydroxylase, 21-hydroxylase, 11-hydroxysteroid dehydrogenase type 2 and increased activity of 5-reductase compared with the control group. The optimal treatment for these patients is unilateral adrenalectomy. A comparative selective blood sampling from the central veins of the adrenals is necessary to select the side of intervention in patients with bilateral macronodular adrenal hyperplasia with ACTH-independent Cushing's syndrome.&#x0D; Conclusion. The first step in the treatment of patients with bilateral macronodular adrenal hyperplasia with ACTH-independent Cushing's syndrome is unilateral adrenalectomy, which reduces the risk of developing adrenal insufficiency and subsequent hormone replacement therapy.

Bilateral macro nodular adrenal hyperplasia causing primary hyperaldosteronism and Cushing syndrome

The coexistence of primary hyperaldosteronism and Cushing's syndrome in the same patient is an uncommon situation. We report the case of a 35-year-old female patient with resistant hypertension since the age of 30 years in whom exploration revealed a combination of primary hyperaldosteronism and ACTH-independent Cushing syndrome in the context of bilateral macro nodular adrenal hyperplasia. G protein-coupled receptors aberrantly expressed in the adrenal cortex appear to have a central role in hormone hypersecretion and cell proliferation in this disease. However, other molecular mechanisms - such as mutations in Gsp or ACTH receptors, and adrenal paracrine hormone secretion may also be involved in this disease. A good understanding of this rare and heterogeneous disease entity has contributed to a more accurate assessment of patients with PBMAH, improving earlier diagnosis and offering new therapeutic and potentially preventive strategies.

Cushing's syndrome, pheochromocytoma, or both?

Abstract Clinical Case A 45-year-old woman presented to the emergency department with weakness and was found to have a Hb level of 68 g/l. She was also tachycardic (pulse 118 x/min) and hypertensive with a BP of 210/108 mmhg. She had a history of ulcerative colitis, menorrhagia and seronegative arthritis for which she had been using 5mg prednisolone daily for several years. The patient had suffered and episode of heart failure 4 years earlier of unknown etiology, during which she was tachycardic, hypertensive and her LVEF was decreased to 35%. In 2016 the patient had undergone an abdominal CT that had shown an incidental finding of a mass in the right adrenal gland, but she did not show up for additional investigations. During the previous year, the patient had developed symptoms of decreased physical fitness, increased weight, livedo reticularis-type skin changes (Figure), agitation, hirsutism and swelling on the neck. Gastroscopy revealed esophageal candidiasis and abdominal CT-scan showed a mass in the right adrenal gland that had increased in size from 2 cm to 3.8 cm compared to the previous CT in 2016 with a density of 21 HU. The patient had clinical Cushing's syndrome, that was confirmed in the lab tests (Table). In addition, lab tests showed an excess production of catecholamines. MRI of the sellar region was performed, that showed a 3×4×3 mm size Rathke's cleft cyst/microadenoma. A CRH stimulation test with inferior petrosal sinus sampling was performed and results were consistent with ectopic ACTH production. The clinical studies were consistent with pheochromocytoma that was also producing ACTH. The patient underwent unilateral adrenalectomy after having been treated with metyrapone and phenoxybenzamine preoperatively. Histopathology was compatible with pheochromcytoma. ACTH staining was negative, but CRH staining was not available. MIB-1 proliferation index was ≤3%. Postoperatively hypercortisolism and catecholamine excess have subsided. The patient has stopped diabetic and antihypertensive medication and she also been cured of the notable livedo reticularis-type skin changes (Figure). Conclusion The clinical presentation of pheochromocytoma in our patient was atypical with coexistence of ACTH-dependent Cushing's syndrome. Furthermore, the patient had a mass in the hypophysis that could have been a potential cause for ACTH-secretion. The clinical and biochemical signs were completely reversed with adrenalectomy, compatible with ectopic Cushing's syndrome due to a pheochromytoma that produced both catecholamines and most probably CRH. In summary pheochromocytomas can rarely also secrete other hormones such as interleukins, calcitonin, ACTH or CRH and this can significantly alter the clinical presentation of both Cushing's syndrome and pheochromocytoma. A recent meta-analysis (Elliott, JCEM 2021) reported 99 published cases of ACTH/CRH-producing pheochromocytomas.

PS-R03-10: CASE REPORT: CUSHING SYNDROME IN A YOUNG MALE

A 27-year-old male without any significant past medical history was advised to visit a hospital for elevated blood pressure, elevated liver enzymes, and dyslipidemia in a workplace health checkup. His body weight had increased by more than 10 kg in the last two years. He presented to our department and underwent laboratory work-up. He had bilateral lower limb pitting edema, hypokalemia, and elevation of low-density lipoprotein. No sign of dysthyroidism, renin-angiotensin-aldosterone system disorder, or increased catecholamine secretion was found. Diet and exercise therapy and calcium channel blocker did not improve his hypertension, and he suffered from lumber vertebral fracture, refractory hypokalemia, and lower leg cellulitis. He was admitted to our department for detailed examination of worsening lower limb edema. On admission, he had striae on his abdomen and legs as well as edema of both lower extremities. The endocrinological data showed high levels of adrenocorticotropic hormone (ACTH) and cortisol. Overnight 1 mg dexamethasone suppression test resulted in a non-suppression response, and his circadian rhythm of cortisol was absent. Urine cortisol level was high. These findings confirmed the diagnosis of ACTH-dependent Cushing syndrome. A contrasted magnetic resonance imaging (MRI) scan demonstrated enlargement of the pituitary gland more than 1 cm in length. Taking into account drug-resistant hypokalemia and vulnerability to infection, he was administered with metyrapone 500 mg per day until he underwent transsphenoidal hypophysectomy. The pathological findings were consistent with that of a pituitary adenoma. Postoperative MRI scan showed remnant lesions which stretch to the bilateral cavernous sinuses and the right middle cranial fossa. Although a decrease in urine cortisol was observed, the absence of a circadian rhythm of cortisol, hypertension, and hypokalemia persisted. He is now treated with somatostatin analog and craniotomy followed by gamma knife surgery is planned. Cushing syndrome should be suspected in cases of early-onset hypertension with symptoms including weight gain, hypokalemia, and bone fracture.

ACTH-Dependent Cushing Syndrome in Metastatic Acinic Cell Carcinoma: A Poor Prognostic Factor

Acinic cell carcinoma (ACC) with high-grade transformation is an aggressive subtype of salivary gland neoplasm. Only a few cases of adrenocorticotropic hormone (ACTH) production in metastatic ACC have been documented. We present a patient case of ACTH-dependent Cushing syndrome (CS) that developed 18 months after surgical resection of ACC. The original tissue sample was found to stain positive for ACTH, and the development of CS coincided with aggressive progression of ACC. Our case highlights the potential significance of ACTH staining in ACC and the development of CS as a signal of dedifferentiation, disease progression, and a poorer prognosis.

PS-BPR01-9: A CASE OF CYCLIC CUSHING'S SYNDROME DIAGNOSED WITH HYPERTENSION AND LEG EDEMA

Background: Cushing's syndrome (CS) is associated with hypertension in approximately 80% of cases, which contributes to the increased mortality risk. Few cases of intermittent hypertension due to cyclic CS(CCS) have been reported. Case presentation: A 66-year-old woman with no specific medical history was referred to our hospital for evaluation of hypertension and leg edema. The Cardiovascular examination showed no abnormality in her cardiac function. Laboratory findings revealed hypokalemia, hyperglycemia, and metabolic alkalosis. She was tentatively initiated on calcium channel blocker (CCB) and insulin therapy. The endocrine examination revealed elevated ACTH and cortisol without circadian variation, which responded to neither the 8 mg dexamethasone suppression test nor CRH stimulation, leading to the diagnosis of ACTH-dependent CS. CT, FDG/PET CT, and Octreotide scan showed no obvious lesion other than bilateral adrenal enlargement. Enhanced MRI showed a normal pituitary gland with neither adenoma nor pituitary stalk deviation/tilt. Since the etiology of CS was not confirmed, metyrapone administration was initiated as symptomatic treatment. Her serum ACTH and cortisol fell rapidly after the initiation of metyrapone, and her blood pressure (BP) and blood glucose levels improved accordingly, even without the use of CCB and insulin. Since both ACTH and cortisol became normalized after discharge, metyrapone was tapered off after 4 months. Furthermore, CT showed normalization of the adrenal enlargement. For the next two months, her ACTH and cortisol remained within the normal limits, and her BP, serum potassium and blood glucose were well controlled. However, she visited our hospital because of re-elevated BP thereafter and was found to have re-elevated ACTH and cortisol with bilateral adrenal enlargement as well as re-decreased serum potassium. Since her BP and serum potassium levels were not controlled well even after she resumed taking metyrapone, the dose of metyrapone was increased, spironolactone was added, and CCB was resumed. Another two months later, her ACTH and cortisol normalized without metyrapone again, and her BP was well-controlled accordingly. This cyclical course of ACTH/cortisol elevation strongly suggested CCS. Conclusion: CCS is a clinical syndrome that exhibits a periodic or irregular increasing pattern in cortisol, which is a rare type of CS. Confirmation of CCS diagnosis is only possible during periods of relapse. In the present case, elevated BP was an indicator of hormonal fluctuations that could be appropriately treated. We report here a case of CCS that was diagnosed because of a good correlation between BP and hormone levels.

Dynamic Testing for Differential Diagnosis of ACTH-Dependent Cushing Syndrome: A Systematic Review and Meta-analysis.

Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.

Relevance of inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome: a case report.

Non-specific signs and symptoms of Cushing's syndrome (CS) can pose a diagnostic challenge. We report the case of a man referred to the service of endocrinology for suspected CS. Hypercortisolism was confirmed on CS screening tests, whereas diagnostic tests confirmed the presence of adrenocorticotropin (ACTH) -dependent CS. The corticotropin-releasing hormone stimulation (CRH) test was performed to determine whether CS hadan endogenous or ectopic origin. Since the CRH and the magnetic resonance imaging (MRI) test were negative, IPSS was performed and suggested that CS was originated in the pituitary glands. Transsphenoidal pituitary resection was carried out. Histopathological analysis confirmed the cortitotrope origin of the tumor. The etiological study and differential diagnosis of CS are complex processes that involve a variety of biochemical and imaging tests. It is important that a sequence of biochemical screening and diagnostic tests is performed, along with studies for establishing the location of the lesion, to determine whether CS has an adrenal, pituitary or ectopic origin. Despite its good diagnostic performance, the results of biochemical tests may not be conclusive, especially in ACTH-dependent CS. In the case reported, the inconclusive results obtained in the CRH test rendered an invasive procedure (IPSS) necessary, which ultimately confirmed diagnosis.

Steroid profiling characteristics in pediatrc adrenal diseases

Adrenocortical adenomas are often followed with steroid hormones hyperproduction, and therefore determination of their concentration plays an important role in the differential diagnosis of adrenal diseases. Steroid profiling by tandem mass spectrometry is one of the main diagnostic methods in steroidogenesis characterization. Currently plasma and urinary steroid profiling is of particular interest in differential diagnosis and subtyping patients with adrenocortical adenomas. Steroid profiling of pediatric patients with adrenal diseases (incidentalomas, ACTH-secreting pituitary adenoma, ACTH-independent Cushing syndrome, premature adrenarche). We conducted a retrospective analysis of steroid profile of 41 pediatric patients with adrenal diseases who were observed between 2005 and 2020 at the Endocrinology Research Centre. All patients were divided into groups due to diagnosis: with ACTH-secreting pituitary adenoma [n=7], ACTH-independent Cushing syndrome (autonomous cortisol secretion by an adrenal adenoma) [n=4], with incidentaloma [n=7] and premature adrenarche [n=23]. In group of patients with ACTH-independent Cushing syndrome identified statistically significant higher levels of 11-deoxycortisol (р=0, 0035) and significant lower levels of 17-hydroxypregnenolone (р=0, 0026) and DHEA (р=0, 0047) compared to other groups. Statistically significant differences in steroid profiles between other groups were not identified. Results of our study steroid profiling can be used as additional differential diagnosis method in patients with adrenocortical adenomas with or without hormonal hyperproduction (ACTH-independent Cushing syndrome and incidentaloma). Further studies are needed to identify steroid markers for subtyping pediatric adrenal diseases.

PMON72 The "RESCUE" Trial: 11beta-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition for ACTH-Dependent Cushing's Syndrome

Abstract Background HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of Cushing's syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition. SPI-62 decreased urinary cortisol metabolites indicating a similar decrease of hepatocellular cortisol in this important target tissue. After a corresponding transient decrease, circulating cortisol homeostasis was restored by ACTH increase which also resulted in a moderate adrenal androgen increase. SPI-62's effects on androgens did not result in adverse effects. Urinary free cortisol was unaffected. The RESCUE trial will assess SPI-62 safety and efficacy in patients with a dysregulated HPA axis, ie., ACTH-dependent Cushing's syndrome. Methods In this randomized, placebo-controlled, crossover, multinational, Phase 2 clinical trial, adult patients (N=26) with ACTH-dependent Cushing's syndrome with active and consistently elevated urinary free cortisol (UFC) will be randomized to receive SPI-62 and placebo for 12 weeks each. A diagnosis of an inadequately treated pituitary adenoma (Cushing's disease) or ectopic ACTH or CRH producing tumor based on established criteria is required. Evidence of Cushing's associated morbidities including at least 2 of A) insulin-resistance/type-2 diabetes mellitus, B) dyslipidemia, C) hypertension, or D) osteopenia is required. Subjects must not have had recent Cushing's surgical, radiation other approved or experimental medical therapies for cortisol excess. Medical conditions or treatments likely to interfere with study assessments or subject safety are also excluded. The primary outcome is pharmacological suppression of the urinary ratio of hepatic 5- and 3-steroid reductase metabolites of cortisol and cortisone (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortisone). Safety is assessed by adverse events, vital signs, ECG, and clinical laboratory analyses including effects on HPA/HPG axis biomarkers. Efficacy is assessed by reduction of Cushing's features and morbidities of hyperglycemia, dyslipidemia, adiposity, hepatic steatosis, hypertension, glaucoma, osteopenia, muscle strength, cognition, sleep, and mood. Assessments include tumor-imaging by MRI, ocular tonometry, timed up-and-go and hand-grip strength tests, dual-energy x-ray absorptiometry, oral glucose tolerance, continuous glucose monitoring, and ambulatory blood pressure monitoring. Results This trial is ongoing; results are pending. Discussion This Phase 2 explores SPI-62 safety, HSD-1 inhibition, effects on HPA/HPG axes, and clinical effects in patients with ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PSAT025 Functional Adrenocortical Oncocytic Neoplasm: A Rare Cause of ACTH Independent Cushing's Syndrome

Abstract Background Adrenal oncocytomas (AOCs) or adrenocortical oncocytic neoplasms (ACONs) are extremely rare tumors of adrenal glands characterized by the presence of oncocytes, which are epithelial cells with eosinophilic cytoplasm. Only about 140 cases have been reported in literature so far. AOCs are more common in females (2.5: 1), more prevalent on the left adrenal gland (3.5: 1), and tumor size ranges from 3 to 17 cm. About two thirds of AOCs are reported to be nonfunctioning, and only less than 6% of functioning are cortisol secreting. The malignant potential of these tumors has been described quite variably in current literature. Based on the most recent systematic literature review, about 35% were found to be benign, 24% malignant, and 41% borderline, based on the Lin Weiss Bisceglia system. The mainstay of treatment is surgical resection. Here we describe a case where biochemical workup and pathology revealed a functional AOC with uncertain malignant potential. Clinical Case A 68 year old female with hypertension was found to have an incidental left 3 cm adrenal nodule on CT abdomen and pelvis during a workup for hematuria. The nodule was biopsied and initially found to be benign. Afterwards, she was referred to endocrinology where biochemical testing was consistent with ACTH-independent Cushing's syndrome. She had three elevated late night salivary cortisol - 0.10 mcg/dL, 0.14 mcg/dL, and 0.19 mcg/dL (≤0. 09 mcg/dL), three abnormal 1 mg dexamethasone suppression tests - 16.4 mcg/dL, 15.1 mcg/dL, and 17.1 mcg/dL (&amp;lt;1.8 mcg/dL), two normal 24 hour urinary cortisol - 22.5 and 31.5 mcg/24h (4-50 mcg/24h), and ACTH &amp;lt;5 pg/mL (6-50 pg/mL). She was then referred to surgery and was treated by laparoscopic adrenalectomy. Surgical pathology showed a 3.5 cm adrenal cortical tumor with oncocytes infiltrating into the periadrenal adipose tissue, with positive staining for synaptophysin and negative for P53. On Ki67 staining, some hot spots were greater than 5%. Therefore, the tumor was characterized as AOC with undetermined malignant potential or a low grade, oncocytic adrenocortical carcinoma. She was evaluated by oncology and radiation oncology, and it was decided to monitor the patient without systemic therapy or adjuvant radiation therapy. A surveillance approach was favored given that the risks of adjacent bowel and kidney toxicity outweighed the benefits of radiation. Conclusion We hereby report a case of AOC with undetermined malignant potential. This case highlights many challenges in the diagnosis, management and long-term surveillance of patients with AOCs, and need for further research. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT044 Management of Severe Cushing's Syndrome in a Patient with Cyclical Ectopic ACTH Production Treated with Osilodrostat.

Abstract Introduction We are presenting a case of severe Cushing's syndrome with multiple complications treated medically with osilodrostat. Clinical Case A 71-year- old female with severe chronic obstructive pulmonary disease was noted to have episodes of hypokalemia, hyperglycemia, and hypertension lasting for several weeks. At the time of presentation to the clinic, she had normal vital signs and no physical exam findings suggestive of hypercortisolism except for mild proximal muscle weakness. Between 2019 and 2021, she had multiple episodes of the presenting symptoms along with elevated morning serum cortisol of 57 to 119 mcg/dl (normal 7-22 mcg/dl), 24-hour urine free cortisol 1343 to 2464 mcg/24 hours (normal 4.5-45 mcg/24 hours), midnight saliva cortisol 509 to 8870 ng/dl (normal &amp;lt;100 ng/dl), and ACTH 105 to 150 pg/ml (normal 5-52 pg/ml). Between episodes labs were normal. A diagnosis of cyclic ACTH-dependent Cushing's syndrome was made. Pituitary MRI was normal, with no evidence of pituitary adenoma. Inferior petrosal sinus sampling was done while cortisol level was elevated, and it showed petrosal sinus to peripheral ACTH ratio of 1.2 following stimulation, a ratio &amp;lt;3.0 suggests ectopic ACTH-dependent Cushing's syndrome. A Ga-65 DOTATATE scan did not localize the tumor. As she was considered a poor surgical candidate for bilateral adrenalectomy, she was started on osilodrostat 10 mg twice daily and hydrocortisone 10 mg twice daily for a block and replace strategy. She was admitted to the hospital 5 days later for increasing fatigue and severe hyperglycemia. Potassium level was 2.2 mmol/L (normal 3.5-5 mmol/L), blood glucose &amp;gt;500 mg/dl, Hemoglobin A1c 8.2%, and random cortisol level was 96 mcg/dl. She was hypertensive and had new acute rib fractures, right lower lobe pulmonary embolism, and deep vein thrombosis. She was given potassium supplements, insulin, anticoagulation, and spironolactone 100 mg bid. The dose of Osilodrostat was increased to 20 mg twice daily. Over 12 days, her cortisol level decreased gradually to 6.3 mcg/dl on the day of discharge. Spironolactone, insulin, and potassium were discontinued and hydrocortisone was prescribed for physiologic replacement. As an outpatient, she continues both osilodrostat and hydrocortisone and is doing quite well. Conclusion Osilodrostat can rapidly and effectively decrease cortisol levels in patients with severe Cushing's syndrome. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT387 An Unusual Case of Sporadic Metastatic Medullary Thyroid Cancer Without a Primary Tumor Presenting with Paraneoplastic Cushing's Syndrome

Abstract Introduction Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and up to 30% of MTCs are hereditary. Only 0.6% of MTCs are associated with a paraneoplastic ACTH-dependent Cushing's syndrome (CS) (PMID: 16029131). Even rarer are MTCs without a primary intra-thyroidal tumor. Here we describe a patient with metastatic MTC without a known primary intrathyroidal tumor presenting with paraneoplastic ACTH-dependent CS. Clinical Case A 47-year-old Ukrainian man was referred to our center for management of metastatic MTC. During evaluation of refractory diarrhea two years earlier, an elevated serum calcitonin (1758 pg/mL, normal: &amp;lt;11.5) led to the diagnosis. Thyroid ultrasound revealed a normal thyroid with bulky cervical lymphadenopathy. Cervical lymph node biopsy revealed metastatic MTC with positive calcitonin, synaptophysin, and chromogranin-A on immunohistochemistry (IHC) and RET protooncogene M918T pathogenic variant on molecular testing. Germline testing for RET pathogenic variants was negative. Prior to referral, the patient was on octreotide to control diarrhea and vandetanib for a few months, but they were discontinued due to financial stress. At our center, patient complained of 4-6 watery bowel movements daily. Physical examination revealed facial plethora, dorsocervical fat pad, central adiposity, wide purple striae, and pustular acne on the chest wall and proximal muscle weakness. Biochemical testing revealed elevated serum calcitonin (158,535 pg/mL, normal: &amp;lt;14.3), carcinoembryonic antigen (3,634 ng/mL, normal: 0.8–6.2), and chromogranin-A (5504 ng/mL, normal&amp;lt;93) levels. Morning serum cortisol (40.4 mcg/dL, normal: 3.7–19.4), and plasma ACTH (116.0 pg/mL, normal: 5.0-46.0) levels were elevated, along with markedly elevated 24-hour urine free cortisol levels (12,460.8 mcg/24-hour, normal: 35-45.0), consistent with ACTH-dependent Cushing's syndrome. Further IHC testing of the tumor biopsy sample revealed mild ACTH positivity. A pituitary MRI was normal. Stool osmolality studies showed a secretory diarrhea pattern. Computed tomography (CT) of neck and torso demonstrated bulky cervical, retroperitoneal, and inguinal lymphadenopathy, and extensive liver metastasis, all of which were strongly avid on an 18-fluorodeoxyglucose positron emission tomography CT scan, but poorly avid on a gallium-68 DOTATATE scan. Sodium fluoride bone scan revealed multiple osseous metastases in the spine, ribs, pelvis, and in the right femoral shaft. An adrenal CT scan revealed bilateral adrenal hyperplasia. The patient was unfortunately not eligible for any ongoing local clinical trials on RET-mutated cancer therapies. After extensive discussion with the patient, a palliative approach was pursued. The cervical lymphadenopathy and right femoral shaft metastasis were treated with external beam radiation. Diarrhea was controlled with loperamide. Cushing's syndrome was initially managed with metyrapone and ketoconazole, followed by bilateral adrenalectomy and hydrocortisone and fludrocortisone replacement. Conclusion Sporadic metastatic MTC can rarely present without an intrathyroidal primary tumor and may originate from ectopic C-cells. Paraneoplastic syndromes such as Cushing's syndrome can be observed in MTC due to ectopic-ACTH production. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON98 High-dose dexamethasone suppression test in ACTH-dependent Cushing's syndrome: Lessons learned on the lack of cortisol suppression

Abstract Background The overnight 8-mg high-dose dexamethasone suppression test (HDDST) has been used to discern Cushing's disease from ectopic ACTH production. However, because of its reported low diagnostic accuracy, its use is limited to the assessment of ACTH-dependent Cushing's disease when combined with a corticotropin releasing hormone (CRH) or a desmopressin stimulation test. We evaluated a patient with Cushing's disease in whom the HDDST failed to identify the pituitary source. We point to limitations in test interpretation and highlight the need of future studies to enhance understanding of the clinical utility of this non-invasive test. Clinical Case A 42-year-old male presented with lower extremity cellulitis and hypertensive emergency. He reported increased abdominal girth, easy bruising, severe back pain and proximal muscle weakness and noted headache and blurred vision. Exam was pertinent for obesity (body mass index 31.5 kg/m2), moon facies, dorso-cervical hump and prominent abdominal striae. Lumbar and thoracic compression fractures were noted on imaging. The elevated 24-hour urinary free cortisol level (198 ug/dL; reference: 10-100 ug/24hr) and lack of suppression on the overnight 1-mg dexamethasone suppression test (morning cortisol 23.7 ug/dL) confirmed Cushing's syndrome; a high ACTH level of 92 pg/dL defined it as ACTH-dependent. The 8-mg HDDST resulted in only a 9.7% reduction of his baseline morning cortisol. The patient was not on any medications that enhanced dexamethasone clearance. Serum dexamethasone levels were measured to aid in test interpretation and, although a level was provided, reference values for the single overnight 8-mg dose of dexamethasone were lacking. A CRH stimulation test was performed and resulted in a 60% increase in ACTH levels from baseline, supporting the diagnosis of Cushing's disease. Additionally, a pituitary MRI revealed a suprasellar 2.5×1.5×1.3 cm mass. Due to ambiguity posed by the HDDST result, despite tumor size, neurosurgery requested inferior petrosal sinus sampling (IPSS). Prior to this procedure, the patient underwent an overnight 16-mg HDDST. While limited information remains on the diagnostic performance of this test, we observed that the baseline morning cortisol decreased by 53.9%. IPSS confirmed the diagnosis of Cushing's disease and pathology identified a corticotroph adenoma. Conclusion The diagnosis of Cushing's disease is complex and recommendations continue to evolve. Th role of the HDDST in combination with another dynamic test remains clinically relevant. It is important that when considering a HDDST, clinicians review medication history to exclude agents that may interfere with dexamethasone metabolism. Our case highlights the need of studies that determine an appropriate reference range for dexamethasone plasma levels after a single 8-mg overnight dose and that evaluate the diagnostic performance of the HDDST in this context. It also brings attention to the need of further elucidating the diagnostic utility of a higher dexamethasone dose in the evaluation of ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.