ACTH-dependent Hypercortisolism Research Articles

8282 A Diagnostically Challenging Case of Ectopic ACTH Secreting Pancreatic Neuroendocrine Tumor Presenting with Cushing’s Syndrome

Abstract Disclosure: O.A. Aluko: None. S. Patel: None. S.V. Silparshetty: None. T. Gallagher: None. Introduction: Ectopic ACTH mediated Cushing’s syndrome is an uncommon but treatable condition that poses time constrained diagnostic and therapeutic challenge due to severe morbidity as illustrated by our case below. Clinical case:A 65-year-old male was admitted with profound generalized weakness. He became restricted to wheelchair from being able to hike a trail at Yosemite national park 8 weeks prior. Recent history included hospitalization with uncontrolled diabetes and hypertension, new vertebral compression fractures, AKI, hypokalemia, proximal myopathy, anasarca, upper GI bleed and acute upper extremity DVT. Initial testing there revealed hypercortisolemia, elevated ACTH and a normal pituitary MRI. Further workup at our center revealed elevated 24hr urinary cortisol 2598 (n = 5 - 64 μg/24hr), random cortisol 55 (n= 4.2 -22.4 μg/dL) with elevated ACTH 194 (n= 7.2 - 63.3 pg/mL) consistent with ACTH dependent hypercortisolism. IPSS deferred due to AKI, underlying comorbidities and severe cervical stenosis with myelopathy. ACTH and cortisol remained elevated with an 8mg dexamethasone suppression test suggesting ectopic source ACTH. CT with contrast of chest, abdomen and pelvis showed 5mm right lower lobe lung nodule and bilateral adrenal nodularity. Bronchoscopic FNAC was negative for NET.Ketoconazole 400 mg twice daily was started pending localization of culprit lesion with improvement in 24 hr urinary cortisol to 554μg/24 hr however this was stopped within 4 weeks due to acute transaminasemia. Repeat imaging with Gallium-68 dotatate PET CT showed a 1.8 X 2.4 X 1.7 cm pancreatic mass. He underwent distal pancreatectomy with splenectomy. Pathology confirmed a 2.2cm well differentiated neuroendocrine tumor limited to the pancreas with immunohistochemistry strongly for ACTH and weakly for Gastrin. Postoperatively, patient was given hydrocortisone replacement. ACTH was 14.3 pg/mL and cortisol 6.2μg/dL a few weeks later. His diabetes, hypertension, hypokalemia, transaminasemia and proximal myopathy improved. Discussion:Ectopic ACTH mediated Cushing’s syndrome is responsible for about 5 - 20% of all Cushing’s syndrome cases. Pancreatic neuroendocrine tumor secreting Ectopic ACTH is rarer but can be aggressive. Clinical presentation can be confounding due to secretion of >1 neurohormone i.e ACTH and Gastrin in our patient. Gallium-DOTATATE PET/CT tracer has a very high sensitivity and specificity. Early use of this imaging may prevent comorbidity and mortality as surgical resection of ectopic ACTH secreting neuroendocrine tumor is first line therapy. Other diagnostic principles to consider are that severely elevated ACTH levels correlate only with a pituitary macroadenoma, IPSS is invasive and has relative contraindication in sick patients and Desmopressin stimulation test is not widely available. Presentation: 6/1/2024

8356 Total Hypophysectomy in Cushing’s Disease: Results from a Terciary Center

Abstract Disclosure: M.V. Lopes: None. M.D. Severino: None. J. Rocha: None. C.R. Peixe: None. M.I. Alexandre: None. A. Gomes: None. M.J. Bugalho: None. Introduction: Transsphenoidal surgery (TSS) is the first line treatment for Cushing’s disease (CD), leading to remission in 70-80% of cases. Though selective adenomectomy is the preferred approach, total hypophysectomy may be needed. Objective: To describe 3 CD patients in which total hypophysectomy was performed. Clinical cases 1. A 58-year-old man with a history of type 2 diabetes (T2D) and obesity, was referred to the Endocrinology Clinic due to abdominal purple striae and facial plethora. Laboratory tests suggested ACTH dependent hypercortisolism, with normal serum ACTH, high 24h urinary cortisol and no cortisol suppression in the overnight 1mg dexamethasone suppression test (DST). The CRH test was suggestive of CD but no adenoma was found on pituitary MRI. Inferior petrosal sinus sampling (IPSS) was compatible with CD with right-sided lateralization. Right hypophysectomy was performed but no CD remission was achieved, so the patient underwent total hypophysectomy. Corticotroph hyperplasia was identified in histology. After 9 months of follow-up, he mantains CD remission. 2.A 37-year-old woman was diagnosed with ACTH dependent hypercortisolism after referral to the Endocrinology Clinic for alopecia, amenorrhea, hypertension and hirsutism. Laboratory tests showed severe hypokalemia, high plasma ACTH and 24h urinary cortisol and the MRI showed a right-sided macroadenoma. Nonetheless, considering the clinical severity, an IPSS was performed and definitely excluded an ectopic Cushing’s syndrome (CS) thus confirming the diagnosis of CD with right-sided lateralization. The patient underwent selective TSS, however, for lack of CD remission, total hypophysectomy was performed. Histology revealed an adenocorticotrophic adenoma. Yet, a year later, she maintains persistence of CD, although less severe, and is under treatment with metyrapone. 3.A 58-year-old woman with a history of T2D and class 3 obesity, was evaluated in our Endocrinology Clinic due to obesity. Her physical examination suggested CS, so this hypothesis was investigated. Laboratory tests suggested ACTH dependent hypercortisolism, with normal serum ACTH, elevated 24h urinary cortisol and no cortisol suppression in the overnight 1mg DST. The high dose DST was suggestive of CD but the pituitary MRI didn’t show an adenoma. IPSS was compatible with CD but it was not possible to determine lateralization. So, total hypophysectomy was performed. An adenocorticotrophic adenoma was identified in histology. Postoperative CD remission was achieved and persists 3 months later. Conclusions: These 3 cases highlight the challenge of treating CD and suggest that in certain cases total hypophysectomy may be the treatment of choice to cure or at least improve CD. Although it is associated with more complications than selective TSS, our patients had no complications, only developed panhypopituitarism and diabetes insipidus. Presentation: 6/1/2024

7667 Cushing’s Puzzle: Echinococcal Pituitary Cyst In A Rare Encounter

Abstract Disclosure: E. Sari: None. F. Erenler: None. Introduction: Echinococcus is a rare parasitic infection endemic in the Mediterranean, Middle East, South America and Africa, which can cause cystic disease in several organs. Central nervous system involvement is known to comprise 1-2% of all cystic echinococcal disease. Hereby, we report a case of an opportunistic pituitary echinococcus infection in a patient with hypercortisolism due to adrenocortical adenoma with initial misdiagnosis of Cushing’s disease. Clinical Case: A 40-year-old South American female with poorly controlled T2DM on oral agents and hypertension presented to the ER with abdominal pain and subsequent CT of the abdomen with contrast showed a right adrenal mass measuring up to 2.8 cm. A follow up CT with adrenal protocol confirmed 3.3 cm right adrenal mass, 46 HU in precontrast images with >50% washout. Review of records revealed that a recent MRI brain with contrast was performed for headache evaluation and showed an incidental 5x7x4 mm lesion in the pituitary gland. Endocrinology evaluation revealed 24-hour urine volume 1800 mL, elevated free cortisol levels 277.6 mcg/24hr (RR: 4.0-50.0 mcg/24hr), creatinine of 0.67g/24hr (RR: 0.50-2.15g/24hr). 1 mg dexamethasone suppression test showed AM cortisol of 28.7 mcg/dL. ACTH was elevated at 67 pg/mL (RR: 6-50 pg/mL). FSH, LH, and GH were normal. Presumed diagnosis of ACTH-dependent hypercortisolism was made and she underwent bilateral inferior petrosal sinus sampling with confirmed successful cannulation but this was inconclusive due to low ACTH levels. Follow-up MRI of the pituitary gland showed T1 bright, T2 isointense circumscribed lesion measuring 7x6x3 mm at anterior pituitary gland with a thin rim of peripheral enhancement consistent with cystic features. She underwent transsphenoidal resection of the pituitary lesion and the pathology specimen showed parasites consistent with echinococcosis. Infectious disease was consulted, and the patient started on albendazole. Post-operative laboratory evaluation was notable for persistently elevated AM cortisol, 24-hour urine free cortisol levels, and low ACTH levels, confirming ACTH independent hypercortisolism. She underwent right adrenal nodule resection and pathology was consistent with adrenocortical adenoma. Post-adrenalectomy AM cortisol levels were < 2 mcg/dL, indicating the resolution of hypercortisolism along with substantiating the diagnosis of primary adrenocortical hyperfunction. Conclusion: To the best of our knowledge, this is the first case report of an opportunistic echinococcus infection presenting as a pituitary lesion in the setting of Cushing Syndrome. We would like to highlight the importance of recognizing opportunistic infections, including Echinococcus as a potential etiology in the setting of hypercortisolism, especially for patients from endemic regions. Presentation: 6/2/2024

The Differential Diagnosis between Cushing's Disease and Pseudocushing Syndrome in a Pre-agonic Patient.

The pseudo-Cushing's encompass several disorders that can occur in high-stress situations and that show biochemical features like those of Cushing's syndrome. We present a case with difficult differential diagnosis for overlapping laboratory findings. A 74-year-old man was admitted to our hospital for worsening dyspnoea for a month, 15 kilograms of weight loss in the previous months, asthenia, hypotonia, and muscle hypotrophy. Moreover, due to the onset of acute hypoxic-hypercapnic respiratory failure, the patient was treated with non-invasive ventilation and then admitted to the intensive care unit, for pneumonia and respiratory failure due to Meticillin-sensitive Staphylococcus aureus and Klebsiella Aerogenes. Antibiotic therapy was started. During the treatment in the ICU, the patient underwent endotracheal intubation for the worsening of respiratory function, and inotropic drug therapy was introduced for the development of septic shock. Hormones were tested, showing an ACTH-dependent hypercortisolism. The results of Nugent, Liddle, and the dexamethasone- suppressed CRH stimulation tests suggested a not-neoplastic ACTH-dependent hypercortisolism. The pituitary contrasted magnetic resonance image showed gland hypertrophy, and the abdominal computed tomography ruled out adrenal lesions. Unfortunately, the patient developed a multi-organ failure and died. The autopsy finding confirmed the absence of pituitary and other neuroendocrine tumors and showed bilateral adrenal hypotrophy. Our clinical case described a patient with pseudo-Cushing's syndrome during sepsis and pre-agonist phase, with a difficult differential diagnosis, in which the combination of the low-dose dexamethasone suppression test and the CRH test allowed a conclusive and correct diagnostic orientation.

Machine learning in differential diagnosis of ACTH-dependent hypercortisolism

Machine learning in differential diagnosis of ACTH-dependent hypercortisolism

Ectopic ACTH Syndrome: Possibilities of Modern Diagnostics

The ectopic ACTH syndrome (EAS) is a constellation of clinical signs and symptoms caused by chronic excess production of cortisol by the adrenal glands due to stimulation by adrenocorticotropic hormone (ACTH) of extrapituitary origin. EAS is a rare pathology, it accounts for approximately 20% of all cases of ACTH-dependent hypercortisolism and up to 10% of all causes of endogenous autonomic cortisol production, however, it is often associated with severe hypercortisolism and is a life-threatening condition. The sources of ectopic secretion of ACTH are neuroendocrine tumors (NET), which differ in histological type, malignant potential, clinical course, and also have different, often difficult to detect localization. Early identification of ACTH -producing NET reduces the risk of death of the patient both from severe hypercortisolism and the tumor itself. The paper describes the features of the course of EAS, the possibilities of its diagnosis, and presents an algorithm for EAS diagnosis, created on the basis of the latest achievements of Russian and world medicine.

Machine learning methods in differential diagnosis of ACTH-dependent hypercortisolism

To develop a noninvasive method of differential diagnosis of ACTH-dependent hypercortisolism, as well as to evaluate the effectiveness of an optimal algorithm for predicting the probability of ectopic ACTH syndrome (EAS) obtained using machine learning methods based on the analysis of clinical data. As part of a single-center, one-stage, cohort study, a retrospective prediction of the probability of EAS among patients with ACTH-dependent hypercortisolism was carried out. Patients were randomly stratified into 2 samples: training (80%) and test (20%). Eleven machine learning algorithms were used to develop predictive models: Linear Discriminant Analysis, Logistic Regression, elastic network (GLMNET), Support Vector machine (SVM Radial), k-nearest neighbors (kNN), Naive Bayes, binary decision tree (CART), C5.0 decision tree algorithms, Bagged CART, Random Forest, Gradient Boosting (Stochastic Gradient Boosting, GBM). The study included 223 patients (163 women, 60 men) with ACTH-dependent hypercortisolism, of which 175 patients with Cushing's disease (CD), 48 - with EAS. As a result of preliminary data processing and selection of the most informative signs, the final variables for the classification and prediction of EAS were selected: ACTH level at 08:00 hours, potassium level (the minimum value of potassium in the active stage of the disease), 24-h urinary free cortisol, late-night serum cortisol, late-night salivary cortisol, the largest size of pituitary adenoma according to MRI of the brain. The best predictive ability in a training sample of all trained machine learning models for all three final metrics (ROC-AUC (0.867), sensitivity (90%), specificity (56.4%)) demonstrated a model of gradient boosting (Generalized Boosted Modeling, GBM). In the test sample, the AUC, sensitivity and specificity of the model in predicting EAS were 0.920; 77.8% and 97.1%, respectively. The prognostic model based on machine learning methods makes it possible to differentiate patients with EAS and CD based on basic clinical results and can be used as a primary screening of patients with ACTH-dependent hypercortisolism.

CATALYST: A Phase 4 Study of Hypercortisolism in Patients with Difficult-to-Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies Assessing Prevalence and Treatment with Mifepristone

The prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) may be higher than currently appreciated, particularly in persons who require a greater number of antihyperglycemic agents and/or have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we have designed CATALYST, a prospective phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5–11.5%) despite receiving multiple antihyperglycemic agents. CATALYST is being conducted at about 30 sites in the United States. In Part 1, about 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test (cutoff: serum cortisol >1.8 µg/dL; dexamethasone ≥140 ng/dL). Patients with ACTH-dependent hypercortisolism will be referred out of the study. The primary study endpoint—the prevalence of ACTH-independent hypercortisolism—will be evaluated in Part 1. Patients with ACTH-independent hypercortisolism may advance to Part 2, a prospective, 2:1 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the competitive glucocorticoid receptor antagonist mifepristone. Patients will be randomized (stratified by the presence/absence of adrenal adenomas on CT) and receive treatment for 24 weeks. The mifepristone dose will be 300 mg QD for 4 weeks, then increased to 600 mg QD for 20 weeks based on glycemic efficacy and tolerability (option to increase to mifepristone 900 mg). Secondary endpoints include changes in HbA1c from baseline to 24 weeks and changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life).

Efficacious Primary Pasireotide Therapy in a Case of a Large Invasive Adrenocorticotropin-secreting Pituitary Tumor

Abstract A 41-year-old woman presented with a headache, diplopia, weight gain, moon face, and central obesity. Her plasma adrenocorticotropin (ACTH) level was 25.5 pmol/L (116 pg/mL) (normal range, 1.6-13.9 pmol/L [7.2-63.3 pg/mL]), serum cortisol level was 397.3 nmol/L (14.4 µg/dL) (normal range, 195.1-540.7 nmol/L [7.1-19.6 µg/dL]), and urinary free cortisol was 413.9 nmol/day (150.3 µg/day) (normal range, <221.5 mmol/day [<80.3 µg/day]). ACTH-dependent hypercortisolism was present, with cortisol suppression using a high-dose dexamethasone suppression test. Cushing disease was diagnosed and a contrast-enhanced magnetic resonance imaging scan demonstrated a 36-mm pituitary tumor with right cavernous sinus invasion. Before surgery, 20 mg pasireotide long-acting-release was initiated, and her symptoms rapidly improved. After 1 month, obvious tumor shrinkage was observed, ACTH and cortisol levels decreased, and diplopia resolved; therefore, we continued medical therapy. After 11 months, her ACTH and cortisol levels normalized, and most of the tumor had disappeared. The clinical course in this case suggests that pasireotide may be useful for preoperative treatment and primary medical therapy, at least in some patients with Cushing disease caused by a large tumor predicted to have difficulty achieving remission by surgery.

SAT327 A Curious Case of Immune Checkpoint Inhibitor Induced Hypophysitis with Transient ACTH-dependent Hypercortisolism

Abstract Disclosure: M. Shi: None. F. AlRubaish: None. N. Gupta: None. V. Larouche: None. S. Christopoulos: None. The use of immune checkpoint inhibitors (ICI) has increased exponentially over the last decade as these agents have shown to substantially improve the prognosis in multiple advanced malignancies. Despite these important clinical benefits, ICI are associated with many immune-related adverse events (irAE). Endocrinopathies are the most frequent irAE and include autoimmune thyroid disorders, hypophysitis and primary adrenal insufficiency. These endocrinopathies often require long-term surveillance and hormone supplementation. We report a relatively novel irAE case of transient central hypercortisolism that progressed to hypopituitarism. A 72-year-old woman with metastatic melanoma on combined ICI therapy of nivolumab-ipilimumab developed subclinical hyperthyroidism (TSH <0.02 mU/L [reference range (RR) 0.40-4.50 mU/L]; FT4 20.2 pmol/L [RR 9.0-26.0 pmol/L]) eight weeks following initiation of her immunotherapy. At week 11, she was found to have refractory hypokalemia (initial potassium at presentation 2.3 mmol/L RR 3.5-5.5 mmol/L) and metabolic alkalosis (pH 7.57 [RR 7.35-7.45]; bicarbonate 39 mmol/L [RR 22-31 mmol/L]). Physical exam was unremarkable for Cushingoid features. Subsequent investigations revealed central hypothyroidism (TSH 0.02 mU/L [RR 0.40-4.50 mU/L]; FT4 8.1 pmol/L [RR 9.0-26.0 pmol/L]) and levothyroxine replacement was started. She also had evidence of hypogonadotropic hypogonadism (FSH 4.2 U/L [postmenopausal RR 25.8-143.9 U/L]; LH 1.5 U/L [postmenopausal RR 13.2-45.7U/L]) and central hypercortisolism with a morning cortisol of 1082 nmol/L [RR 172-497 nmol/L] and an ACTH level of 18.3 pmol/L [RR 1.6-13.9 pmol/L]. The low dose dexamethasone suppression test was not suppressed (morning cortisol at 983 nmol/L). She underwent imaging studies of her abdomen and brain which revealed normal adrenal and pituitary glands, respectively. Close pituitary function monitoring during endocrinology follow-up revealed persistent elevation of cortisol and ACTH levels until week 15, then a subsequent decline in both cortisol and ACTH levels for which she started hydrocortisone replacement. Further follow-up blood work revealed morning cortisol levels below 50 nmol/L [RR 172-497 nmol/L] with undetectable ACTH levels from week 16 onwards. The hydrocortisone and levothyroxine replacement were continued, and the patient remained asymptomatic throughout her follow-ups. This case highlights that a transient episode of ACTH dependent hypercortisolism may be an early marker prior to the development of central adrenal insufficiency from ICI-related destructive immune hypophysitis. Furthermore, our report highlights that physicians and other healthcare professionals should remain vigilant in monitoring laboratory progression in these patients, as early recognition facilitated timely management in our patient and prevented complications. Presentation: Saturday, June 17, 2023

FRI183 Phase 4 Study Of Hypercortisolism In Patients With Difficult-to-Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence And Treatment With Mifepristone

FRI183 Phase 4 Study Of Hypercortisolism In Patients With Difficult-to-Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence And Treatment With Mifepristone

SAT320 Cyclic Cushing Syndrome Caused By An ACTH-Producing Pheochromocytoma

Abstract Disclosure: Y.B. Omotosho: None. M.E. Wierman: None. K. Bukhari: None. K. Pacak: None. R. McGlotten: None. L.K. Nieman: None. Background: Although pheochromocytomas (Pheo) predominantly produce catecholamines, they also rarely produce Adrenocorticotropin (ACTH) and present with Cushing syndrome (CS). Cyclic CS is an uncommon presentation of hypercortisolism. We here report a unique case of cyclic ectopic ACTH secretion from a Pheo. Clinical case: A 72-year-old female was referred to the NIH with a five-year history of intermittent episodes of unintentional weight gain, hair loss, skin thinning, striae, tremors, labile emotions, glucose intolerance, and a sense of impending doom, interspersed with anorexia, weight loss, normal glucose levels, headaches, and fatigue. The external evaluation documented ACTH-dependent CS with episodes of hypercortisolism, thought to be occult ectopic ACTH secretion. On admission, blood pressure ranged from 122/75 to 171/78 mmHg, and she had a Cushingoid habitus. The biochemical investigation showed basal ACTH 219 pg/ml (NL 5- 46 pg/ml); serum cortisol of 76.9 mcg/dl after 1mg dexamethasone (Dex) suppression test (NL <1.8 mcg/dl), with Dex level of 903; cortisol increased from 13.3 mcg/dl to 15.5 mcg/dl after 8mg Dex, Dex level 4680 ng/ml; plasma normetanephrine 1.8 nmol/L, (NL < 0.9 nmol/L); metanephrine 0.6 nmol/L (NL <0.5 nmol/L); norepinephrine 1493 pg/mL (NL 70-750 pg/mL); epinephrine 298 pg/mL (NL <111 pg/mL); chromogranin A 1314 ng/mL (NL <93 ng/mL). MRI pituitary was normal and bilateral inferior petrosal sinus sampling did not show a central: peripheral gradient before or after desmopressin administration. CT abdomen showed a right adrenal nodule measuring 2.3 cm x 1.8 cm, with pre-and post-contrast Hounsfield units of 30 and 106, and 54% washout. The adrenal mass showed intense activity on 68Ga-DOTATATE and 18F-DOPA PET/CT scans. The patient underwent a right adrenalectomy; the 2.7 x 2.3 x 1.5 cm mass was a Pheo with immunohistochemical staining for ACTH, chromogranin A, and synaptophysin. Post-operatively, blood pressure normalized, and medications were reduced from preoperative metoprolol, lisinopril, and doxazosin to low-dose metoprolol at discharge. Morning cortisol and ACTH levels were <1 mcg/dl and <5 pg/ml. Physiologic replacement of hydrocortisone (15 mg on awakening and 5 mg in the afternoon) was started and switched to prednisone 5mg daily for ACTH deficiency and convenience. The pituitary-adrenal axis remained suppressed at her 6-month follow-up visit. Conclusion: Cyclic CS poses a diagnostic challenge. Here, desmopressin helped to exclude Cushing's Disease. Although ACTH-producing Pheo is rare, it should be considered in the context of ACTH-dependent hypercortisolism if an adrenal mass is present. Presentation: Saturday, June 17, 2023

FRI371 Serum Androstenedione As An Additive Biomarker In Ectopic Cushing’s Syndrome Evaluation

Abstract Disclosure: S. Zhang: None. J.C. Lo: None. M.G. Jaffe: None. H. Arzumanyan: None. Background: Ectopic Cushing’s syndrome (ECS) results from glucocorticoid excess secondary to ectopic ACTH or CRH producing tumors. Although ECS identification can be challenging when presentation lacks classic Cushing’s features, ectopic ACTH secretion can result in a key constellation of findings that facilitate early clinical recognition. We describe a case of ECS from an ACTH-producing carcinoid tumor of the lung presenting with resistant hypertension, severe hypokalemia, and muscle weakness. In addition to significant hypercortisolism, laboratory findings were notable for high androstenedione levels without concomitant increase in DHEAS and testosterone levels. Case: A 59-year-old female athlete with history of well-controlled hypertension developed difficult to control hypertension, requiring escalation to triple antihypertensive therapy within 3 months. During this time, she had multiple emergency department visits for progressive muscle weakness, hypertension, and persistent hypokalemia despite potassium supplementation. She was hospitalized for further evaluation. Physical examination was notable for bruising, muscle wasting, thin extremities, facial fullness, and disproportionate abdominal adiposity. Workup for Cushing’s syndrome demonstrated ACTH-dependent hypercortisolism and markedly elevated androstenedione 398 ng/dL (normal 20-75 ng/dL) despite normal DHEAS 48 mcg/dL (normal <430 mcg/dL) and total testosterone 11 ng/dL (normal <45 ng/dL) levels. A chest CT identified a 3.8 cm right lower lobe lung mass and transbronchial biopsy confirmed atypical carcinoid tumor. She underwent a right middle and lower lobe bilobectomy with complete tumor resection. Cortisol, androstenedione, and potassium levels rapidly normalized postoperatively, and blood pressure returned to baseline, well-controlled on monotherapy. The patient only required 3 days of hydrocortisone therapy for transient steroid withdrawal symptoms. Conclusions: Our case illustrates a difficult to diagnose uncommon disease presenting with resistant hypertension, hypokalemia and marked androstenedione elevation despite normal DHEAS and testosterone levels. This steroidogenic profile has been reported in other ECS cases and attributed to differential effects of ectopic ACTH production on adrenal androgen biosynthesis (1). Although ECS is rare and the primary lesion can be difficult to identify, disproportionate elevation in androstenedione may prompt recognition of ECS and support early detection and management. Reference: (1) Barbetta L, Dall’Asta C, Re T, Colombo P, Travaglini P, Ambrosi B. Androgen secretion in ectopic ACTH syndrome and in Cushing’s disease: modifications before and after surgery. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2001;33(10):596-601 Presentation: Friday, June 16, 2023

SAT588 Cushing’s Syndrome Due To Ectopic ACTH Secretion From Ovarian Teratomas

Abstract Disclosure: Y. Kang: None. M.S. Gildenberg: None. B.J. Quade: None. R.A. Blair: None. Background: Approximately 9-18% of Cushing’s syndrome (CS) cases are secondary to ectopic ACTH secretion, most commonly from sources in the lung or mediastinum. However, ACTH-producing tumors are rarely found in distant organs, occasionally making the localization and management challenging. Clinical Case: A 32-year-old woman with class 3 obesity, hidradenitis suppurativa, anxiety, and depression experienced atraumatic pelvic and sacral fractures. DXA scan result showed Z-scores of -3.1 in the lumbar spine, -2.6 in the femur neck, and -0.5 in the total hip. She reported a steady weight-gain of 250 lbs over 7 years despite lifestyle modifications and liraglutide. On examination, she had a round face with plethora, acne, violaceous abdominal striae, and dorsocervical fat pad. Laboratory findings revealed elevated midnight salivary cortisol levels of 453 and 424 ng/dL (n: <100 ng/dL), elevated 24-hour urine cortisol levels of 254 and 741 (n: 3.5-45 mcg), and an abnormal 1 mg dexamethasone suppression test (DST) result at 15.1 ug/dL. AM plasma ACTH and cortisol levels were 190 pg/mL and 18.5 ug/dL, suggesting ACTH-dependent hypercortisolism. The plasma cortisol level after an 8 mg DST was unsuppressed at 13.1 ug/dL with a dexamethasone level of 3,380 ng/dL (n: >800 ng/dL). Abdominal CT and MRI scans showed large bilateral adnexal masses measuring up to 13.7 cm on the left and 9.3 cm on the right, with heterogeneous solid and cystic components, consistent with mature cystic ovarian teratomas. DOTATE-PET scan did not show any areas of increased uptake. The patient underwent a laparoscopic right cystectomy and left oophorectomy, with immediate drop in cortisol (1.6 ug/dL) and signs of adrenal insufficiency post-operatively, requiring hydrocortisone replacement. After holding hydrocortisone for 24 hours prior to laboratory assessment one week post-operatively, her ACTH and cortisol were undetectable, reflecting successful source removal. Pathology report showed neuroendocrine tumor with pituitary differentiation with positive ACTH immunohistochemical staining and Ki-67 proliferative index of 22.6% on the left adnexal mass, and a mature cystic teratoma on the right. Conclusion: Although rare, pituitary differentiation of ovarian teratomas should be considered as a possible source of ectopic ACTH secretion in CS patients without obvious sources identified in commonly involved organs. Presentation: Saturday, June 17, 2023

THU647 Patient With Successful Conception During Treatment For Cushing Disease: Case Report

Abstract Disclosure: C. Iweha: None. E.K. Babler: None. M. Castillo: None. Introduction Cushing Disease (CD) is an endocrine disorder that predominantly affects women of childbearing age and is characterized by excess secretion of adrenocorticotropic hormone (ACTH) with hypercortisolism. We report a case of a woman with ACTH-dependent hypercortisolism treated with pasireotide who had a successful pregnancy while on treatment. Clinical Case A 27-year-old woman presented to the initial consult on 9/01/2011 with a 4-year history of ongoing symptoms of hirsutism, diaphoresis, oligomenorrhea, myalgia, and acne. A physical exam revealed an overweight female with mild facial acne and hirsutism. Family history included autoimmune disease in mother (lupus and multiple sclerosis). She was frustrated by the lack of a definitive diagnosis over 4 years; she was anxious and using multiple medications, including anxiolytics and analgesics, without relief of symptoms. Patient did not use alcohol and never smoked. Labs revealed initial morning (AM) cortisol = 26.9 µg/dL (normal range: 5-23 µg/dL) and ACTH = 14 pg/mL (normal: 6-58 pg/mL); 24-hour urinary cortisol was 110.6 µg/24 h (normal:<100 µg/dL) and serum ACTH =8 pg/mL. Low-dose (1 mg) dexamethasone suppression test reduced AM cortisol to 1.7 µg/dL and ACTH of 8 pg/mL. No evidence of adrenal adenoma on abdominal CT or pituitary adenoma on brain MRI, and IPSS confirmed diagnosis. Based on hypercortisolism and normal ACTH level, diagnosis was ACTH-dependent CD. We advised the patient to join a clinical trial for pasireotide, and she began treatment on 1/3/2013. She presented for follow-up on 6/17/2014 and reported improvement of some symptoms on 0.6 mg pasireotide twice daily, the highest dose she could tolerate. She reported experiencing chronic pain; medications included prescription analgesics, muscle relaxants, and anxiolytics. On 6/23/2015, our patient returned for a follow-up when she was 5.5 months pregnant. While on pasireotide, she became pregnant and subsequently left the study and discontinued treatment. She reported recurrence of hirsutism, acne, fatigue, and hyperemesis with discontinuation of pasireotide. Patient returned twice more during pregnancy and had a successful delivery and healthy infant. Clinical Conclusions Successful conception and pregnancy are unusual with CD due to fertility-inhibiting hormonal effects of excess cortisol. Some medications for CD impede pregnancy through their mechanism (eg, mifepristone). Our patient conceiving while on treatment is promising for women with CD. Although her CD symptoms returned when pasireotide was discontinued, she delivered a healthy infant; limited pasireotide data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Our case underscores the potential for successful conception for women with CD when cortisol levels are normalized with treatment that avoids suppressing menstruation. Presentation: Thursday, June 15, 2023

Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome.

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism.

ODP309 Ectopic Cushing's Syndrome: Importance of Methodical Approach to Hide and Seek

Abstract Cushing's syndrome (CS) is associated with high morbidity and fivefold excess mortality. Ectopic ACTH syndrome accounts for 20% of CS cases. It is crucial to identify and localize the source of extrapituitary ACTH secretion because surgical resection of the primary, often malignant, tumor has a high probability of cure with complete remission in 80% of cases. A 72-year-old female was admitted to a community hospital for lateral chest pain after a fall. She endorsed progressive weight gain, new HTN, emotional lability and worsening cognition over the prior 6 months. ACTH and cortisol levels were elevated. MRI brain failed to identify a pituitary lesion. CT chest showed multiple rib fractures and anterior mediastinal mass which was biopsied. While awaiting pathology results, IPS sampling attempted but aborted due to pulmonary edema necessitating ICU care. She was transferred to our institution for planned TSR of suspected pituitary adenoma. Examination showed Cushingoid features. Labs showed hypokalemia, high cortisol and high ACTH. MRI pituitary showed normal sella. MRI spine showed multilevel vertebral compression fractures. CT chest showed interval growth of mediastinal mass. A 1 mg dexamethasone suppression test failed to suppress ACTH and cortisol, confirming ACTH dependent hypercortisolism. A high dose 8 mg dexamethasone test failed to suppress ACTH and cortisol, a 10 mcg DDAVP stimulation test showed a flat response, with ACTH and cortisol levels remaining comparable before and after DDAVP injection. Dynamic testing therefore consistent with ectopic ACTH dependent hypercortisolism. Gallium-68 DOTA-TATE PET Scan demonstrated uptake in mediastinal mass suggestive of somatostatin receptor positive neuroendocrine tumor. Biopsy specimens processed at our institution showed cells positive for epithelial markers Cytokeratin and PAX8. Sample showed neuroendocrine differentiation with positive staining for Chromogranin A, synaptophysin and CD 117. Findings consistent with neuroendocrine thymic neoplasm. The patient was started on oral ketoconazole to control hypercortisolism. Surgical resection of tumor was planned with intent to cure CS. Ultimately, due to proximal myopathy and multiple vertebral fractures her performance status was too poor for safe tumor resection. Unfortunately, she died of complications related to CS while attempting preoperative rehabilitation. This case illustrates the importance of a timely, systematic evaluation for ACTH source in ACTH dependent hypercortisolism. Delay in CS diagnosis and localizing correct ACTH source led to missing the window of fitness for curative surgery. If ACTH is elevated, the most common source is pituitary neoplasia, however ectopic ACTH production must be ruled out. Dynamic testing including high dose dexamethasone suppression test, CRH and DDAVP stimulation tests should be used for preliminary localization of ACTH production. IPS sampling is invasive with greater potential for complications, as in the case of our patient. Therefore, it is only indicated if there are conflicting results from different dynamic tests and imaging studies. Presentation: No date and time listed

PMON94 Collision tumor with Rathke cleft cyst and co existing Cushing's disease

Abstract Introduction - Collision tumors, i.e., co-occurring distinct histopathological lesions are rare. We present a case of a 48-year-old female present with co-existing Rathke cleft cyst (RCC) and pituitary adenoma with Cushing disease. Case - 48-year-old female presented for evaluation of an incidental sellar mass with enlarged pituitary noted on MRI brain. The patient complained of symptoms of mental fogginess, confusion, intermittent dizziness for the last 1 year. The patient had complained of easy bruising with no reported weight gain, change in facial appearance, proximal muscle weakness. MRI brain showed mildly enlarged pituitary measuring 13 mm with RCC.Past medical history was significant for recent-onset Type 2 Diabetes and Hypertension. The examination was unremarkable with no signs of Cushing's syndrome. Lab work showed elevated ACTH of 51 pg/ml (10-48) with AM cortisol level of 14.7 mcg/dl (6- 18.4). IGF-1 levels elevated at 307 ng/ml (77- 220). LH, FSH, FT4, prolactin levels were normal. Given elevated ACTH levels, further testing showed elevated midnight salivary cortisol at 0.22 and 0.239 mcg/dl (0.010-0.090), elevated 24-hour urine cortisol 141 ug/ 24 hrs. (6- 44), absence of suppression with 1 mg dexamethasone with cortisol 12.4 mcg/dl (< 1.8), ACTH 123 pg/ml (10-48) with dexamethasone levels 432 ng/dl (140- 295). Lab work was consistent with ACTH-dependent hypercortisolism. MRI pituitary showed 7.5×7.8 mm RCC.8 mg dexamethasone suppression test and CT chest, abdomen, and pelvis were performed to differentiate between ectopic Cushing's and Cushing's disease. Cortisol levels suppressed greater than 50% after 8 mg dexamethasone from baseline cortisol – 17.7 mcg/dl and ACTH 67 pg/ml to cortisol 3.4 mcg/dl and ACTH – 34 pg/ml with dexamethasone levels of 3120 ng/dl (1600–2850). CT chest abdomen, pelvis showed no evidence of bronchial carcinoid or other potential lesions. With neuroimaging findings and biochemical confirmation of Cushing's disease, the patient underwent transsphenoidal resection. Discussion – The association between RCC and pituitary adenoma was found in 0.5–1.9% cases per literature review1, co-occurrence with ACTH producing pituitary adenoma being rarer. The diagnosis of collision tumors can be challenging as the most common presentation on imaging is a cystic mass. Appropriate biochemical testing is indicated based on clinical presentation, initial laboratory testing, and level of suspicion. Elevated ACTH levels along with diabetes and hypertension led to a diagnosis of Cushing's disease in our patient with the initial presentation of an incidental RCC. The knowledge about collision tumors is important, especially in unusual presentations as in our case. References Sagan KP et al. Cushing's Syndrome in a patient with Rathke's cleft cyst and ACTH cell hyperplasia detected by 11C-Methionine PET Imaging-A Case Presentation. Front Endocrinol (Lausanne). 2020; 11: 460. Published 2020 Jul 22. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Abstract #1179639: Paraneoplastic ACTH-dependent Hypercortisolism and Non-refractory SIADH Associated with Small Cell Lung Cancer

Paraneoplastic endocrine syndromes are often from the remote effects that are not related to the direct invasion or metastasis. Ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) accounts for 10-15% of all Cushing Syndromes. Syndrome of inappropriate antidiuretic hormone (SIADH) is found in up to 10% of small cell lung cancer (SCLC). However, their presentation together is seldomly reported in other case reports. Our main goal is to report the highlights of presentation, diagnosis, treatment and rapid progression of the disease.

Corticotroph pituitary carcinoma with skeletal metastases masquerading as ectopic ACTH syndrome: a long and winding road to diagnosis.

SummaryPituitary carcinoma is a rare type of malignancy and only accounts for 0.1–0.2% of all pituitary tumours. Most pituitary carcinomas are hormonally active and they are mostly represented by corticotroph and lactotroph carcinomas. Corticotroph carcinoma can present as symptomatic Cushing’s disease or can evolve from silent corticotroph adenoma which is not associated with clinical or biochemical evidence of hypercortisolism. We hereby present a case of a bone-metastasized corticotroph pituitary carcinoma masquerading as an ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient with a history of a non-functioning pituitary macro-adenoma. Our patient underwent two transsphenoidal resections of the primary pituitary tumour followed by external beam radiation therapy. Under hydrocortisone substitution therapy she developed ACTH-dependent hypercortisolism without arguments for recurrence on pituitary MRI and without central-to-peripheral ACTH-gradient on inferior petrosal sinus sampling, both suggesting ectopic production. Ultimately, she was diagnosed with an ACTH-secreting vertebral metastasis originating from the primary pituitary tumour. This case report demonstrates the complex pathophysiology of pituitary carcinoma and the long diagnostic work-up. Certain features in pituitary adenoma should raise the suspicion of malignancy.Learning pointsThe diagnosis of pituitary carcinoma can only be made based on documented metastasis, therefore, due to the often long latency period between the detection of the primary tumour and the occurrence of metastasis, the diagnostic work-up most often spans over multiple years.Pituitary carcinoma including corticotroph carcinoma is very rare in contrast to pituitary adenoma and only accounts for 0.1–0.2% of all pituitary tumours.Histopathology in pituitary adenoma should certainly accomplish the following goals: accurate tumour subtyping and assessment of tumoural proliferative potential.Repeated recurrence of pituitary adenoma after surgical resection, a discrepancy between biochemical and radiological findings, resistance to medical and radiation therapy, and silent tumours becoming functional are all hallmarks of pituitary carcinoma.Silent corticotroph adenomas are non-functioning pituitary adenomas that arise from T-PIT lineage adenohypophyseal cells and that can express adrenocorticotropic hormone on immunohistochemistry, but are not associated with biochemical or clinical evidence of hypercortisolism. Silent corticotroph adenomas exhibit a more aggressive clinical behaviour than other non-functioning adenomas.Treatment options for corticotroph carcinoma include primary tumour resection, radiation therapy, medical therapy, and chemotherapy. Sometimes bilateral adrenalectomy is necessary to achieve sufficient control of the cortisol excess.