Ectopic ACTH Secretion Research Articles

12275 Effect Of Osilodrostat On Cardiovascular And Metabolic Manifestations Of Hypercortisolism In Patients With Non-Pituitary Cushing’s Syndrome: Findings From A Retrospective Observational Study (LINC 7)

Abstract Disclosure: N. Scheyer: Other; Self; Recordati Rare Diseases. J. Bertherat: Consulting Fee; Self; Novartis, HRA Pharma, Recordati Rare Diseases. B. Decoudier: Consulting Fee; Self; Recordati Rare Diseases. H. Lasolle: Speaker; Self; Recordati Rare Diseases. H. Lefebvre: Speaker; Self; Recordati Rare Diseases. D. Drui: None. C. Vaillant: None. J. Morera: None. F. Castinetti: Consulting Fee; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. Grant Recipient; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. J. Cristante: Grant Recipient; Self; HRA Pharma, Pfizer, Inc.. N. Chevalier: None. S. Fodil-Cherif: None. A. Antonellini: Employee; Self; Recordati Rare Diseases. W. Agbotounou: Employee; Self; Recordati Rare Diseases. A. Mueller: Employee; Self; Recordati Rare Diseases. A. Tabarin: Consulting Fee; Self; H Lundbeck A/S, Crinetics Pharmaceuticals, HRA Pharma, Recordati Rare Diseases. Introduction: Endogenous Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality because of hypercortisolism. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, is approved for patients (pts) with endogenous CS (EMA) and Cushing’s disease (CD; for whom pituitary surgery is not an option or has not been curative; FDA). The long-term safety and efficacy of osilodrostat has been demonstrated in Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies of CD pts. Here, we investigated the effect of osilodrostat on clinical manifestations of hypercortisolism in a real-world, retrospective, observational study conducted in a heterogeneous patient population with non-pituitary CS (LINC 7; NCT05633953). Methods: Adult pts with non-pituitary CS who initiated osilodrostat prior to EU approval under the French Autorisation Temporaire d’Utilisation scheme and/or, once approved, in routine clinical practice were followed up retrospectively for up to 36 months. The primary endpoint was proportion of pts with mean urinary free cortisol (mUFC) ≤upper limit of normal (ULN) at week (W) 12, based on the modified intention-to-treat (mITT) population (pts with any cortisol measurement at W12 or not collected because of safety reasons). Secondary endpoints included cardiovascular and metabolic parameters, recorded every 4 or 12W, depending on clinical practice. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: 103 pts were enrolled (mean [SD] age: 59.3 years [15.5]; female 61.2% [n=63]; adrenal adenoma [16.5%, n=17/103; mITT: 9.6%, n=5/52], adrenocortical carcinoma [18.4%, n=19/103; mITT: 11.5%, n=6/52], macronodular adrenal hyperplasia [13.6%, n=14/103; mITT: 17.3%, n=9/52], ectopic adrenocorticotropic hormone secretion [51.5%, n=53/103; mITT: 61.5%, n=32/52]). Median (min-max) osilodrostat exposure and dose at baseline was 164.0 days (1-1178) and 5.0 mg/day (1-60), respectively. Median (min-max) osilodrostat dose at W12 and W36 was 6.0 mg/day (0-60) and 10.0 mg/day (0-120), respectively. 23/52 pts (44.2%; 95% CI 30.5-58.7) had mUFC ≤ULN at W12. Mean (95% CI) changes in cardiovascular and metabolic-related parameters from baseline to W12 and W36, respectively, were: systolic blood pressure (−5.7 [−17.9, −6.6] mmHg, n=29 and −6.3 [−19.0, −6.5] mmHg, n=11); diastolic blood pressure (−4.7 [−10.6, −1.1] mmHg, n=29 and −8.2 [−20.7, −4.3] mmHg, n=11); weight (−2.3 [−4.2, −0.4] kg, n=27 and −3.6 [−9.6, −2.5] kg, n=12); body mass index (−0.8 [−1.5, −0.2] kg/m2, n=27 and −1.2 [−3.2, −0.8] kg/m2, n=12). No new safety signals were identified. Conclusions: Findings from this real-world setting show that osilodrostat provides cortisol control alongside improvements in clinical manifestations of hypercortisolism in non-pituitary CS pts, alleviating the disease burden. Presentation: 6/1/2024

12530 Inferior Petrosal Sinus Sampling In Cushing’s Disease

Abstract Disclosure: A. Gondhi: None. S. Antharam: None. I. Moledina: None. Inferior Petrosal Sinus Sampling in Cushing’s Disease Introduction: Cushing's disease (CD) is the most common cause of endogenous Cushing syndrome( CS) caused by ACTH secreting pituitary tumor. MRI is typically used for imaging, but standard MRI may only detect 50% of microadenomas. In these cases, inferior petrosal sinus sampling (IPSS) is the gold standard in detecting pituitary source of ACTH. Case presentation:A 53-year-old man presented with signs and symptoms of CS: fatigue, weight gain, decreased libido, mood swings, new onset prediabetes. Physical examination revealed cushingoid appearance with facial flushing, easy bruising, abdominal purple striae. Initial work up revealed ACTH dependent CS: elevated late night Salivary cortisol 0.39 mcg/dL (<0.09 mcg/dL), 24hr urine free cortisol 192 mcg/24 hour (4 – 50 mcg/24 hour)Non suppressed cortisol 8.1 mcg/dL (<1.8 mcg/dL) after 1mg dexamethasone suppression test8 AM ACTH 56 pg/ml (7.2 – 63 pg/ml), DHEAS 491 mcg/dL (38-318 mcg/dL)Pituitary hormonal work up: normal Prolactin 7.8 ng/mL (2.6-13.1 ng/mL)Low TSH 0.29 ng/ml (0.45-5.3 ng/ml) with normal Free T4 0.76 ng/dl (0.58-1.6 ng/dl)Low Total Testosterone 150 ng/dl (175-781 ng/dl), Low FSH<0.7 mInt units/ml(1.27-19.26 mInt units/ml), Low LH 1 mInt units/ml (1.24- 8.62 mInt units/ml), Normal IGF 180 ng/mL (65-222 ng/mL), A1C 6% (Prediabetes – 5.7-6.4) MRI Brain showed normal pituitary gland. IPSS was performed with DDAVP: +2, +5, +10, +15: Right/ periphery ratio- 31.8, 10.75, 7.6, 5.3. left/periphery ratio- 26.6, 18.8, 8.3, 7.5. All the ratios >=3, which showed clear central to peripheral gradient. and no left or right difference consistent with Cushing's disease. Subsequently, a transsphenoidal pituitary gland resection was performed. Suspicious tissue was excised from both sides during the surgery, showing positive ACTH immunostaining, consistent with pituitary microadenoma. Post-operative labs showed significant improvement with normalization of Cortisol 3.2 mcg/dl, ACTH 45 pg/ml, TSH 3.14 ng/ml, FT4 0.61 ng/dl, FSH 1.7 mInt units/ml, LH 2.4 mInt units/ml, Prolactin 7.1 ng/ml, A1C 5.4 %He was discharged on physiological dose of Hydrocortisone and passed cortisol stimulation test (3.4 mcg/dl ---> 18.1 mcg/dl) Conclusion: Distinguishing between CD and ectopic ACTH secretion is crucial due to the differing treatment options. The most accurate method for differentiation is IPSS, which boasts high sensitivity and specificity compared to other analyses. Despite its invasiveness, IPSS is associated with rare adverse events, making it a valuable tool in clinical practice. Presentation: 6/3/2024

7901 Clinical Challenges Of Paraneoplastic Endocrine Metabolic Syndromes: An Illustrative Example

Abstract Disclosure: S. Shankar: None. S.S. Sundar: None. M.S. Vaishnav: None. K. Thummala: None. L. Lekkala: None. S. Srikanta: None. K. Muniraj: None. T. Deepak: None. R.B. Vijay: None. V. Nath: None. C. Siddlingappa: None. P. Ravikumar: None. M.D. Chitra: None. Introduction: Paraneoplastic endocrine syndromes result from aberrant production by tumors of protein hormones, hormone precursors, or hormone like substances. In patients who are already receiving treatment for cancer, the onset of a paraneoplastic syndrome may be an indication of progression or relapse. Clinical Case: 2021: Age 81 female (hypertension). Carcinoma rectum; S/P surgery, colostomy, chemotherapy and radiotherapy. 2023: Palliative care, due to progressive metastatic (hepatic, pulmonary, bone) malignancy. 2023 Aug: Hospital admission for generalized weakness, not able to walk, severe pain and low-grade fever 10 days. A: Paraneoplastic Hyponatremia: Evaluation: S Sodium= 127, 129, 129, 137, 134 mmol/L (134-145); Spot urine sodium= 65 mmol; S Uric acid= 3.5 mg/dL (4.4-7.6); S Cortisol 8 am= 15.5 (6.7-22.6); T3 total= 0.34 ng/mL (0.97-1.69), T4 total= 6.87 mcg/dL (5.5-11), TSH= 1.87 mIU/mL (0.46-4.68); LH= 0.35 mIU/mL (16-54); FSH= 1.9 mIU/mL (23-116); S calcium= 8.9 mg/dL (8.4-10.2); S Phosphorus= 2.31mg/dL (2.5-4.5) Diagnosis: Possible paraneoplastic ADH secretion/ SIADH; pain/ narcotics-induced hypothalamic ADH secretion. Treatment: Fluid restriction, liberal salt intake, 3% saline; oral sodium bicarbonate and tolvaptan; tapentadol. B: Paraneoplastic Leukemoid reaction: Evaluation: Total leucocyte count= 29960, 36670, 44130, 58450 cells/mm3 (4000-11,000); Differential count: Neutrophils= 85-94%; Lymphocytes= 10-4%; CRP= 93.7, 24.0 mg/dL (<0.3); Procalcitonin= 0.097, 0.083 ng/mL (<0.1); Ruled out significant sepsis; no obvious laboratory or imaging evidence of any infectious or leukemic etiology. Diagnosis: Progressive leucocytosis due to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) secretion from various neoplasms has been reported in literature. Treatment: Empirical antibiotic coverage. C: Paraneoplastic Hypokalemia: Evaluation: S Potassium= 3.3, 3.4, 3.7, 2.9, 3.0 mmol/L (3.5-5.1). Diagnosis: Hypokalemia likely due to (in vivo and in vitro) intracellular potassium uptake by rapidly proliferating leukocytes (and neoplasm- primary and metastatic). (Ectopic ACTH secretion / ruled out). Therapy: IV and oral potassium supplements. D: Paraneoplastic Fever: Cytokines (e.g., tumor necrosis factor and interleukin-1) release from tumor cells or infiltrating mononuclear cells. Clinical Lessons: Endocrine paraneoplastic syndromes can complicate patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread or another “non-existent” clinical entity. They can precede, occur concomitantly or present at later stage of tumour development. Recognition of the diverse clinical manifestations improves clinical outcomes (earlier cancer diagnosis, better quality of life, optimal tumour-directed therapy or decision towards non-aggressive focussed palliative care). Presentation: 6/2/2024

8604 Ectopic Cushing’s Syndrome Associated with a Metastatic Pancreatic Mixed Neuroendocrine Non-neuroendocrine Neoplasm (MiNEN) with Amphicrine Features

Abstract Disclosure: A. DeMarsilis: None. C. Jiang: None. O. Lavrynenko: None. D. Motavalli: None. C. Musurakis: None. Z.H. Taxin: None. E.D. Rosen: Advisory Board Member; Self; Source Bio, Inc.. Consulting Fee; Self; Novartis Pharmaceuticals, Gensaic. M.S. Irwig: None. Background: Ectopic Cushing’s Syndrome (CS) makes up 9-18% of ACTH-dependent CS cases, of which fewer than 15% are attributed to pancreatic neuroendocrine tumors (1). Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare, aggressive carcinomas, often driven by high-grade neuroendocrine components, with a poor prognosis (2). Amphicrine neoplasms contain neuroendocrine and exocrine components in the same cell. Clinical Case: A 34 year-old woman with asthma, hypertension, and depression presented with new onset lower extremity edema, facial hirsutism, mood changes, polyuria and polydipsia. She had an elevated morning serum cortisol of 52 ug/dL (normal < 20) with plasma ACTH 42 pg/mL (normal < 50), 24-hour urine free cortisol of 1003 mcg (normal < 50), K+ of 2.6 mEq/L, and fasting glucose 164 mg/dL. CT showed multiple hepatic lesions, pulmonary nodules, a pancreatic tail lesion, and lymphadenopathy concerning for metastatic disease. Her adrenal glands were thickened bilaterally without nodules. A pituitary MRI was normal. These findings were concerning for ectopic CS. She was admitted due to rapidly developing symptoms. Potassium, insulin, sitagliptin, and prophylactic anticoagulation were started. Spironolactone and ketoconazole were initiated while awaiting biopsy results of liver and pancreas lesions. Osilodrostat was not available and a trial of metyrapone was poorly tolerated. The liver and pancreatic tail lesion biopsy revealed metastatic MiNEN with amphicrine features, of pancreatic origin, with Ki67 proliferation index of 70%. Section staining of pancreas and liver biopsies were negative for ACTH. A Ga-68 Dotatate scan showed minimal uptake, so octreotide was not prescribed. Palliative chemotherapy was planned. Although ketoconazole was titrated to 1600 mg/day, urine free cortisol levels and serum free cortisol levels did not reach target. Cushing disease was considered but not suspected, as ACTH levels remained modest despite a relative decrease in cortisol level. Given significant morbidity from uncontrolled hypercortisolism, and plans for urgent initiation of systemic chemotherapy, after multidisciplinary discussion the patient was treated with a surgical bilateral adrenalectomy. Post-operative morning serum cortisol measured 8.3 ug/dL. After one week, palliative chemotherapy with FOLFIRINOX (oxaliplatin, leucovorin, fluorouracil, and irinotecan) was initiated. She was discharged home on stress dose steroids with plan for taper. Conclusion: Ectopic ACTH secretion is a rare phenomenon, particularly when presenting with a rare case of metastatic pancreatic MiNEN with amphicrine features, associated with significant morbidity. To improve tolerance and survival of further treatment, early surgical bilateral adrenalectomy should be considered.

6419 Cushing’s Syndrome due to Metastatic Pancreatic Neuroendocrine Neoplasm With Incidental Pituitary Microadenoma

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. R. Jain: None. N. El Asmar: None. Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are rare with a reported incidence of 1-2/100,000. While the majority are non-functional, insulinomas and gastrinomas are the most common functional PNENs. Our case of ACTH-producing PNENs is extremely rare. Case presentation: A previously healthy 47-year-old female was hospitalized for worsening dyspnea. Her symptoms included rapid weight gain, skin hyperpigmentation, and lower extremity edema. Her exam was notable for elevated blood pressure of 181/120 mmHg, moon facies, purple abdominal striae, and proximal myopathy. Her lab analysis showed a cortisol level of 42 mcg/dL (6.2-19.4), ACTH of 254 pg/ml (7.2-63), DHEA sulfate of 171 mcg/dl (41-243), HbA1C 7%, K of 3 mmol/l and 24H urine cortisol >2100 mcg/24hrs. A post low-dose DST cortisol level was 42.7 mcg/dl. CT chest demonstrated an ill-defined hypodense lesion in the region of the pancreatic head. MRI abdomen revealed a 3 x 2.3 x 2.3 cm mass in the pancreatic head and many small enhancing lesions within the right lobe of the liver. Adrenal glands appeared normal. Subsequent PET CT scan with GA 68 DOTOTATE showed increased uptake in the pancreatic head mass and in the right hepatic lobe. Her pituitary MRI revealed a right pituitary gland 6 mm hypointense lesion, possibly a microadenoma. A high dose DST resulted in a cortisol level of 80 mcg/dl mostly consistent with ectopic ACTH secretion. EUS-guided biopsy of the pancreatic mass showed a well-differentiated neuroendocrine tumor that stained positive for ACTH, chromogranin, synaptophysin, and CD56. Treatment with Ketoconazole 600mg q6h and Octreotide 50mg q6h was started 3 days before surgery to control acute hypercortisolism as she developed acute psychosis. The patient subsequently underwent a Whipple procedure with successful resection of the pancreatic mass. Post-op, her ACTH levels dropped to 19 pg/ml with a cortisol level of 6 mcg/dl. Final pathology showed a well-differentiated grade 3 neuroendocrine tumor with a KI-67 labeling index greater than 20%. After surgery, the patient received a short course of stress dose hydrocortisone which was tapered off over the following 2 months. The patient is being followed for planning further intervention given the aggressive grade of the tumor and hepatic metastases. Conclusion: Ectopic ACTH-producing PNENs are rare. An accurate and timely diagnosis, while challenging, is key. Patients usually present with rapidly progressing symptoms that could cause life-threatening complications such as thrombosis and sepsis. We demonstrated the importance of utilizing a multidisciplinary team approach and starting cortisol-lowering medications early given the complexity of the disease, requiring rapid intervention and lifelong follow-up. Presentation: 6/3/2024

8104 Rare Case Of Ectopic Cushing’s Syndrome Secondary To Metastatic Parotid Pleomorphic Adenocarcinoma

Abstract Disclosure: B.S. Neutel: None. P. Manroa: None. Background: Pleomorphic adenocarcinoma of the parotid gland is a rare malignancy and ectopic ACTH secretion from these tumors is very rarely described. We report a case of ectopic Cushing’s syndrome (CS) in such a patient and describe the clinical course. Clinical Case: A 69-year-old female with left parotid pleomorphic adenocarcinoma status post surgery and adjuvant radiotherapy presented to her local hospital approximately 7 months after initial treatment with proximal muscle weakness and near-syncope. Workup revealed profound hypokalemia at 1.6 mmol/L (n 3.5-5.3 mmol/L) along with new-onset hypertension (BP 175/110 mm Hg) and hyperglycemia with a HbA1c 6.5 % (n <5.7%), as well as metabolic alkalosis with a bicarbonate level of >40 mmol/L (n 22-32 mmol/L). A CT scan showed multiple liver metastases and a biopsy confirmed metastatic parotid pleomorphic adenocarcinoma. She was then transferred to our comprehensive cancer center for further management. She reported muscle weakness, easy bruising, and facial edema. She denied acne, hirsutism, or abdominal striae. Endocrine workup revealed a random cortisol of 56 mcg/dL (n 3-18 mcg/dL) and ACTH of 378 pg/mL (n 7.2-63.3 pg/mL). Her AM cortisol level remained unsuppressed at 79.2 and 59.4 mcg/dL (n< 1.8 mcg/dL) after 1 mg and 8 mg overnight dexamethasone suppression tests respectively. Late-night salivary cortisol was 7.9 mcg/dL (n <0.112 mcg/dL). An MRI of the sella was negative for any pituitary lesions. After stabilizing her clinical condition and correcting electrolyte abnormalities, she was started on chemotherapy with paclitaxel and carboplatin by the oncologist. Based on clinical suspicion of ectopic CS, ketoconazole was started and titrated upwards with rapid improvement of blood pressure, hypokalemia, and hyperglycemia. She was discharged home and antihypertensives were tapered off. ACTH staining on the liver biopsy was unable to be performed due to paucity of the specimen. A Ga-68-DOTATATE PET CT revealed increased radiotracer uptake in the liver lesion suggestive of SSTR 2 receptor positivity. Despite initial clinical improvement, her disease progressed with widespread liver, lymph node, and osseous metastases within 3 months necessitating escalating doses of ketoconazole, spironolactone, and potassium supplementation. The patient elected to pursue hospice care due to intolerance to chemotherapy and passed away shortly afterward. Conclusion: Although ectopic CS caused by parotid pleomorphic adenocarcinoma is rare, prompt recognition and treatment is necessary because ectopic ACTH production is associated with poor prognosis in these patients. Presentation: 6/3/2024

8233 Cushing Disease Presenting As Severe Persistent Hypokalemia

Abstract Disclosure: G. Palaguachi: None. A. Randhawa: None. M. Sattar: None. G. Mahajan: None. J. Karam: None. Introduction: The clinical presentation of Cushing Disease represents a wide spectrum of clinical and laboratory findings, including electrolyte derangements such as hypokalemia. In this case report, we describe a patient in whom the admission for severe persistent hypokalemia prompted the diagnosis of Cushing Disease. Clinical Case: A 35-year-old woman with history of type 2 diabetes, hypertension, and hyperlipidemia, presented to the Emergency Department with worsening bilateral lower extremities swelling, impairing her ability to walk, found to have severe hypokalemia with K level of 2.8 (3.4-4.8 mmol/L), in additional to right pubic rami fracture, left breast abscess, oral thrush, and severe hyperglycemia with HbA1C of 15.4%. Additional history was relevant for hirsutism, scalp hair thinning, weight gain, and amenorrhea of few months duration. Physical examination was significant for round face, thin scalp hair, oral thrush, facial hirsutism, central obesity, wide abdominal striae, onychomycosis, thin skin with multiple ecchymoses, bilateral lower extremity edema, and thin extremities. Her hypokalemia was resistant to therapy and K level remained in 3.2-3.5 mmol/L range on the third week of admission despite oral and intravenous potassium replacements and spironolactone high dose therapy at 100mg twice a day. Additional laboratory testing showed Cortisol 25.0 (6.70 - 27.60 ug/dL) and normal Aldosterone and renin levels. Given absence of otherwise clear etiology of hypokalemia, and presence of multiple features of Cushing’s syndrome, further inpatient evaluation included 24-hour Urine Free Cortisol level that came back at 2754 (3.5 - 45.0 mcg/24hour), 1 mg Dexamethasone Suppression Test Cortisol of 24.9 (6.70 - 27.60 ug/dL), ACTH of 151.0 (7.2 - 63.3 pg/mL), and 8 mg Dexamethasone Suppression Test Cortisol of 14.2 (6.70 - 27.60 ug/dL). MRI Pituitary showed a pituitary adenoma (0.7 x 0.3 cm) with cavernous sinus involvement. A diagnosis of Cushing disease was made and the patient underwent transsphenoidal surgery on the fourth week of hospital stay with diffuse ACTH staining of the tumor. Postoperatively, cortisol levels were not suppressed suggesting persistent disease, but hypokalemia resolved while on Spironolactone. Conclusion: This patient had several classical features of hypercortisolemia with associated hyperglycemia, recurrent infections, and bone fractures, however the finding that connected the dots and prompted establishing her diagnosis was her severe refractory hypokalemia. Although not a defining feature of Cushing Disease, and usually more pronounced with ectopic ACTH secretion, severe and/or persistent hypokalemia can be part of the presenting symptoms. This case demonstrates the importance of including Cushing Disease as part of the differential diagnosis of persistent hypokalemia in correlation with other clinical signs and diagnostics. Presentation: 6/2/2024

7743 A Case Study of Ectopic Adrenocorticotropic Hormone Secretion from Pancreatic Neuroendocrine Tumor

Abstract Disclosure: K.S. Wei: None. J. Huang: None. Introduction: Pancreatic neuroendocrine tumors (PanNETs) are uncommon cancers that account for less than 2% of pancreatic malignancies. Even rarer are ACTH-producing NETs which may only become symptomatic until after metastasis. This case study examines the distinct presentation and diagnostic complexities associated with ectopic adrenocorticotropic hormone (ACTH) secretion from a PanNET. Clinical Case:A 42 year-old male with hypertension and type 2 diabetes initially presented to the hospital with increased abdominal girth for one month, bilateral lower extremity edema for two weeks, and generalized abdominal pain. He had unremarkable surgical, family, and social histories. Patient was afebrile, normotensive, saturating well on room air, with exam notable for a distended abdomen and 2+ bilateral pitting edema. Admission labs were notable for potassium of 2.4 (ref: 3.5-5.1 mmol/L). MRI abdomen showed hepatomegaly with numerous heterogeneously enhancing masses and an ill-defined pancreatic tail mass with involvement of the spleen. Liver biopsy showed well-differentiated neuroendocrine tumor, grade 2. He was started on octreotide 20mg q4weeks and capecitabine/temozolomide q4weeks. Two months later, the patient was readmitted after presenting with back pain for two days, found to have acute compression fractures of T9-L1 without spinal PET activity. At follow-up visit with endocrinology, he endorsed easy bruising and muscle weakness and had hypertension (161/96 mmHg) with hypokalemia. Random cortisol was 43.7 (ref: 2.5-11.9 mcg/dL). ACTH was 124 (ref: 6-50 pg/mL) despite receiving chemotherapy. 24-hour urine cortisol was 3,049 (ref: 4-50 mcg/24 hrs). He was diagnosed with ectopic Cushing’s disease from ACTH-producing PanNET leading to osteoporosis and fracture of the vertebral bodies. For the ectopic Cushing’s disease, he was started on ketoconazole 200mg BID with plan to start osilodrostat once approved. For the fracture, he is scheduled for Zometa infusion and IR kyphoplasty. Conclusion: This case offers several important clinical insights. In patients with PanNET with Cushingoid exam findings, ACTH-producing PanNET should be high on the differential. Most ACTH NETs are aggressive often with liver metastases, whereby metastatic disease will have already occurred by the time the Cushingoid features develop. The initial severe hypokalemia and hypertension should have prompted investigation for mineralocorticoid excess from hypercortisolism, which may have led to an earlier diagnosis of ectopic ACTH Cushing’s disease, thereby decreasing the possibility of developing vertebral fractures, uncontrolled diabetes and hypertension. Ketoconazole or osilodrostat may be used to treat Cushing’s disease from ACTH NETs. Presentation: 6/1/2024

6409 Successful Treatment Of Severe Ectopic ACTH-dependent Cushing’s Syndrome With Osilodrostat

Abstract Disclosure: K.A. Lee: None. C. Mendes Pessoa: None. W. Huang: Consulting Fee; Self; WH, Honoraria from Consulting and Speaking received from Recordati Rare Disease. Background: Cushing’s syndrome due to ectopic ACTH secretion is rare and may progress rapidly, making treatment very challenging. Previous case reports have described therapeutic options including adrenal steroidogenesis inhibitors, bilateral adrenalectomy (BAL), and adrenal embolization with success. Clinical Case: A 27-year-old woman with metastatic neuroendocrine tumor presented with sudden onset and rapidly progressing symptoms of fatigue, muscle weakness, acne and weight gain within two weeks. Laboratory findings confirmed severe Cushing’s syndrome due to ectopic ACTH secretion: AM cortisol 173.4 µg/dL (5-25), ACTH 1425 pg/mL (7.2-63.3), 24 hour urine cortisol 29,498 mcg/24hr (4-50), DHEA-Sulfate 1314 µg/dL (65 - 380), and testosterone 133 ng/dL (0-100). She was also found to have severe hypokalemia, hypocalcemia and hyperglycemia (despite an HbA1C of 6.2 at 2 weeks before presentation). CT- scan showed diffuse thickening of the bilateral adrenal glands. Due to widely metastatic disease in the peritoneum, BAL was considered non-feasible. The patient was admitted to hospital and initiated on osilodrostat at 20mg twice daily (after correction of hypokalemia) with close monitoring of her electrolytes, cortisol, EKG and steroid withdrawal symptoms. There was a rapid improvement of cortisol levels in response to osilodrostat. During treatment, she developed steroid withdrawal symptoms for which she was started on medium dose hydrocortisone. Bilateral adrenal arterial embolization was attempted but ultimately needed to be converted to right only adrenal gland embolization due to a hypertensive urgency and difficulty with catheterization. Her symptoms of Cushing’s syndrome significantly improved with the treatment. During her hospitalization, her hypokalemia was managed with spironolactone and potassium supplement, hypocalcemia with calcium supplement, and hyperglycemia with basal and bolus insulins. With significant improvement of cortisol levels, her hypocalcemia and hyperglycemia resolved and required no further treatment. Her potassium levels normalized and spironolactone was stopped. She remains on potassium supplement to keep K level at upper half of normal range to avoid long QTc. After discharge, her morning cortisol levels (before morning dose of hydrocortisone) continued to decrease and her osilodrostat dose was gradually tapered to 5mg once daily at night. Hydrocortisone was continued as part of the block-and-replace regimen. Conclusion: This case described a unique sudden onset and rapid progression of ectopic ACTH dependent Cushing’s syndrome and successful utilization of a block-and-replace approach by using the steroidogenesis inhibitor osilodrostat in prompt control of the hypercortisolism and related comorbidities. We also explored the feasibility of adrenal embolization for definitive management in the context of unfeasible BAL. Presentation: 6/2/2024

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

12215 A Rare Cause Of Cushing's Syndrome: Acth-producing Pheochromocytoma

Abstract Disclosure: S. Jimenez Salazar: None. C. Aguilar Londoño: None. N. Aristizabal Henao: None. N. Buitrago Gómez: None. S. Saldarriaga Betancur: None. D.L. Beltran: None. J.L. Torres: None. Background: Cushing's syndrome is a severe endocrine disorder caused by chronic, autonomous, and excessive cortisol secretion. Among all causes, ectopic ACTH production continues to be one of the most challenging diagnoses. Rarely, pheochromocytomas secrete hormones other than catecholamines, including ACTH and CRH. The secretion of these hormones can alter the clinical presentation and make the diagnosis more difficult. Clinical Case: A previously 60-year-old woman with hypertension and no other relevant medical history presented with unintentional weight loss of 16 kg and constipation. Physical examination revealed a moon face, supra-labial and chin facial hair. Laboratory studies demonstrated hypokalemia (potassium 3.02 mEq/L, n: 3.5-5 mEq/L) and newly diagnosed diabetes (HbA1c 8.69%, n <5.7% and fasting glucose 282 mg/dL, n: 70-100 mg/dL), both difficult to control. Considering the clinical and biochemical findings, hypercortisolism was evaluated by measuring 24-hour urinary free cortisol (1853 mcg/24h, n: 4-176 mcg/24h), nocturnal serum cortisol (40.9 mcg/h, n:<7.5 mcg/h), and 1 mg dexamethasone suppression test (43.1 mcg/h, n:<1.8 mcg/h), confirming cortisol excess. ACTH was measured (95 pmol/mL, n: 4.7-48.5 pg/mL) suggesting ACTH-dependent cause, leading to a dynamic test with high doses of dexamethasone (8mg) with suppression greater than 50% and normal pituitary MRI, both compatible with an extrahypophyseal cause. Peripheral imaging evaluation was conducted with cervical-thoracic CT scan and abdominal MRI confirming the presence of a complex adrenal mass. Among adrenal hyperfunction studies, primary hyperaldosteronism was ruled out (Aldosterone 9.8 ng/dL, n: 1-32 ng/dL and Plasma Renin Concentration 1.1 ng/dL, n: 0.16-2.3 ng/dL), and pheochromocytoma was confirmed (Normetanephrines 2725.4 mcg/24h, n: 0-600 mcg/24h and Metanephrines 1550 mcg/24h, n: 0-350 mcg/24h). Considering the described adrenal lesion with biochemical behavior, the possibility of ectopic ACTH production from pheochromocytoma was studied. Therefore, ketoconazole 200mg every 8 hours was initiated for hypercortisolism control and adrenergic blockade protocol as pre-surgical preparation for adrenalectomy. Potassium levels (4.48 mEq/L, n: 3.5-5 mEq/L) and glucose levels (93 mg/dL, n: 70-100 mg/dL) normalized after the procedure. Pathology and immunohistochemistry confirmed the diagnosis of an ACTH-producing pheochromocytoma. Conclusion: Pheochromocytoma is a rare cause of ectopic ACTH secretion where pre-surgical management of catecholamine excess and hypercortisolism is crucial, and adrenalectomy is often curative. Reference: (1) Elliott PF, Berhane T, Ragnarsson O, Falhammar H. Ectopic ACTH- and/or CRH-Producing Pheochromocytomas. J Clin Endocrinol Metab 2021;106:598-608. Presentation: 6/1/2024

6640 Utility of bilateral inferior petrosal sinus sampling for diagnosis and management of Cushing's disease in children ; a case report

Abstract Disclosure: V. leal: None. L. Socha: None. S.S. Awadalla: None. The causes of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) are Cushing's disease (CD) and ectopic ACTH syndrome (EAS). The differential diagnosis of CS and the localization of lesions in CD and EAS are often challenging. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children.A 16-year-old girl was referred for evaluation and treatment of Cushing syndrome she experienced weight gain, secondary amenorrhea, and back pain. 24-hour urinary free cortisol and low-dose dexamethasone suppression tests suggested Cushing syndrome. Adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance reported a microadenoma. To rule ectopic ACTH syndrome, and localize the pituitary tumor, bilateral inferior petrosal sinus sampling (BIPSS) was performed with desmopressin to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to right ACTH-secreting pituitary microadenoma and underwent endoscopic endo-nasal transsphenoidal surgery.In conclusion , BIPSS can be a valuable tool not only for discriminating between pituitary origin and ectopic ACTH-secreting Cushing syndrome, but also for providing precise localization of pituitary adenomas, thereby facilitating appropriate treatment. Presentation: 6/1/2024

12455 Bone Mineral Density Improvement After Resolution Of Endogenous Cushing Syndrome

Abstract Disclosure: C. Plessias: None. N. Charoenngam: None. T. Rittiphairoj: None. T. Suenghataiphorn: None. T. Srikulmontri: None. P. Wattanachayakul: None. M. Kurt: None. Bone Mineral Density Improvement After Resolution of Endogenous Cushing Syndrome: a Meta-analysis and meta-regression Patients with endogenous Cushing syndrome (eCS) are known to have decreased bone mineral density (BMD) and are prone to fragility fractures. Treatment of eCS have been shown in multiple studies to result in improvement in BMD. However, the degree of BMD improvement after resolution of eCS remains inadequately explored due to limited sample sizes in existing studies. Through systematic review, meta-analysis, and meta-regression techniques, we aimed to identify all available evidence to evaluate BMD improvement after resolution of eCS. Potentially eligible studies were identified from the PubMed and EMBASE databases from inception to February 2024, utilizing a search strategy incorporating terms related to "Bone mineral density" and "Cushing syndrome". Eligible studies must include adult or pediatric patients diagnosed with any form of eCS, encompassing Cushing disease (CD), adrenal adenoma, mild autonomous cortisol secretion or ectopic ACTH-secreting tumors, who received treatment resulting in CS resolution. These studies must either present lumbar spine (LS) or femoral neck (FN) BMD measurements in the form of T-score, Z-score or actual BMD values before and after CS resolution, or report mean differences (MD) of BMD, or provide individual BMD data. Point estimates with corresponding standard errors were extracted from each study and combined using the generic inverse variance method. Meta-regression analysis was utilized to explore the impact of time after resolution of eCS on BMD improvement.A total of 5,085 records were identified from the databases. After systematic review, 14 studies, including a total of 386 patients, were deemed eligible for analysis. The meta-analysis demonstrated that resolution of eCS resulted in statistically significantly improvement of LS BMD (pooled MD: Z-score: +0.76, 95%CI 0.50 – 1.02, I2 76%; T-score: +0.87, 95%CI 0.55 – 1.19, I2 78%; actual BMD: +0.092 g/cm2, 95%CI 0.060 – 0.124, I2 74%) and FN BMD (pooled MD: Z-score: +0.54, 95%CI 0.32 – 0.76, I2 75%; T-score: +0.38, 95%CI 0.25 – 0.51, I2 0%; actual BMD: +0.041 g/cm2, 95%CI 0.021 – 0.062, I2 0%). The meta-regression analysis revealed a statistically significant association between follow-up time and improvements in LS T-score BMD (predicted LS T-score improvement = 0.42 + 0.062 × year, p = 0.027) and FN Z-score BMD (predicted FN Z-score improvement = 0.35 + 0.037 × year, p = 0.003), but not with LS Z-score and FN T-score.In summary, our study presents the extent of improvement in LS and FN BMD following the resolution of eCS based on all available data in the literature. These findings have clinical significance as they offer guidance for management of osteoporosis following the resolution of eCS. Presentation: 6/3/2024

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

Cushing syndrome in paediatric population: who and how to screen.

Cushing's syndrome (CS) is characterised by signs and symptoms resulting from excessive and prolonged exposure to exogenous glucocorticoids or endogenous hypercortisolism. In childhood, exogenous CS represents the main cause of CS due to the widespread therapeutic use of glucocorticoids, while endogenous CS is very rare and accounts for about 10% of CS cases. According to the origin of the hypercortisolism, the ACTH-dependent form due to pituitary ACTH-secreting tumours is the most common form of endogenous CS in paediatric age (about 75-80% of cases), following by adrenal causes (about 15-20% of cases) including adenoma, carcinoma (which has a peak of incidence in the first decade), bilateral adrenal hyperplasia or Carney complex, with a different distribution by age. Ectopic ACTH-secreting CS, genetic forms of pituitary adenomas are more uncommon. The insidious onset of hypercortisolism and the absence of salient early signs make the diagnosis of endogenous CS difficult. Facial changes, weight gain with simultaneous growth failure, prepubertal virilisation, or hypogonadism in adolescence represent some of the key features of CS. The diagnostic workup is essentially aimed at confirming hypercortisolism through screening tests whose diagnostic accuracy is not 100% and therefore the combination of more than two tests is mandatory to confirm the diagnosis of CS.

Ectopic Cushing's Syndrome in Pediatric Age

Cushing's syndrome due to ectopic ACTH secretion is a rare clinical condition resulting from a dysregulated ACTH secretion by neuroendocrine tumors. The overall incidence of endogenous Cushing's syndrome is 0.7-2.4 per million people annually, with children accounting for only 10% of new cases each year. When the patient first presented clinically, she was a 17-year-old girl who displayed psychiatric symptoms. Blood tests showed diabetes mellitus and hypokalemia. She had hypertension and vertebral collapses. The hormone assay showed hypercortisolism, and because of this, she began taking metyrapone. The results of the 68Ga-PET/DOTATOC and 18FDG-PET scans were negative. The clinical course was intermittent. After one year, a 68Ga-PET/DOTATOC showed a nodule in the thymic lodge. Despite the thymectomy, the hypercortisolism persisted. A subsequent 68Ga-PET/DOTATOC repeated three months after surgery revealed an uptake corresponding to the thymic lodge. She underwent another surgery, which is finally being resolved. ACTH levels were monitored before, during, and post-surgery. The laboratory provided the ACTH results promptly, and thoracic surgeons waited for hormonal results before concluding the procedure. The adopted strategy permitted us to monitor the surgery outcome. The heterogeneity of ectopic Cushing's syndrome makes diagnosis difficult. 68Ga-PET/DOTATOC proves to be a tracer with good sensitivity and specificity for the identification of ACTH-secreting neuroendocrine lesions. The short half-life of ACTH is found to be a strategy to monitor the complete surgical resection of the neuroendocrine lesion.

#2026 Hypokalemia associated to neuroendocrine carcinoma of the cervix

Abstract Background and Aims Hypokalemia is one of the most common electrolyte disorders seen in clinical practice. Hypokalemia can be caused by decreased intake of potassium, redistribution of potassium (K+) in cells or by excessive gastrointestinal losses or renal losses. In this setting, hypokalemia may also be caused by the paraneoplastic production of ectopic adrenocorticotropic hormone (ACTH) by some tumors. Cancer of the uterine cervix is the fourth common cancer affecting women worldwide and the fourth most common gynecologic cancer in Spain. Neuroendocrine carcinoma of the cervix represents about 2% of all cervical neoplasms. Method We report the case of a 44-year-old Peruvian woman with hypokalemia who was diagnosed with Cushing syndrome secondary to paraneoplastic production of ACTH by neuroendocrine carcinoma of cervix. Results Patient was overweight and affected by uterine myoma and anemia without further investigations. She was admitted to our hospital due to lower back pain, leg swelling and constipation. Blood pressure was normal, chest radiography did not show abnormal findings and ECG showed the U wave. Laboratory tests at admission revealed hypokalemia (2.3 mmol/L), metabolic alkalosis, anemia (hemoglobin 9.5 g/dL), hyperkaliuria (K+ urine/Creatinine urine 70 mmol/g) with an elevated transtubular potassium gradient (TTKG=12) and normal renal function. Laboratory data are presented in Table 1. She developed hypertension in the first day of hospitalization. Renin, aldosterone and cortisol tests was performed. Hypercortisolism was observed and confirmed with 24-hour urinary cortisol excretion. Because of an elevated ACTH (263 pg/mL), pituitary magnetic resonance imaging was performed without lesions. Whole-body computed tomography revealed a cervical mass. PET scan showed pelvic, adrenal, hepatic and local lymphadenopathy activity (see Fig. 1). After the histopathological study, diagnostic of small cell neuroendocrine carcinoma of the cervix was made. Chemotherapy therapy was initiated with cisplatin/etoposide regimen. The patient decide to return to Peru because of the poor prognosis of her illness. At discharge, potassium level was 3 mmol/L despite the treatment with spironolactone, ramipril, losartan and oral potassium chloride (160 mmol). Conclusion Hypokalemia is a common clinical disorder. In some patients it may be caused by an increased mineralocorticoid activity due to ectopic ACTH-secreting tumors. Applying diagnostic algorithms to electrolyte disorders, beyond their simple treatment, can unmask secondary causes and serious diseases.

Diagnostic challenges in cyclic cushing's syndrome: a rare case due to ectopic acth secretion by lung carcinoid

Diagnostic challenges in cyclic cushing's syndrome: a rare case due to ectopic acth secretion by lung carcinoid

Diagnostic approach and clinical outcome. experience of one clinical centre in managing ectopic ACTH secreting syndrome

Diagnostic approach and clinical outcome. experience of one clinical centre in managing ectopic ACTH secreting syndrome

Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing's Syndrome.

Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. Retrospective study. University hospitals. Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation. Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92-.99] in the primary study and .99 [95% CI, .98-1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97-1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3-10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.