SAT-035 - A Rare Gynecologic Source of Ectopic Cushing'S Syndrome

Background: Ectopic Cushing’s syndrome (CS) is a rare cause of ACTH-dependent Cushing’s. It accounts for less than 10% of cases and is typically caused by neuroendocrine tumors (NETs) most often bronchial NETs or small-cell lung carcinomas. (1) Large-cell neuroendocrine carcinomas (LCNECa) of the endometrium are a rare form of endometrial cancer and there have been no previously described cases of endometrial LCNECa being the source of ectopic CS. (2)

Clinical

Case: A 75-year-old woman with a history of endometrial LCNECa treated with hysterectomy, chemotherapy, and radiation 3 years earlier, presented with acute severe muscle weakness, easy bruising, dyspnea, and marked hypokalemia. Imaging revealed bilateral pulmonary nodules and pleural effusions with cytology confirming metastatic endometrial LCNECa. Laboratory evaluation showed cortisol 91mcg/dL, ACTH 307pg/mL, and 24-hour urinary free cortisol (UFC) 7,593mcg/24hr. After a 1mg and 8mg dexamethasone suppression test, cortisol remained unsuppressed at 98mcg/dL both times. Pituitary MRI demonstrated two small lesions (3mm and 5mm) in the pituitary gland. Ketoconazole therapy reduced UFC to 3806mcg/24hr. She was switched to osilodrostat which, after titration, reduced her UFC level to 51mcg/24hr, but induced adrenal insufficiency. This required inpatient admission for IV steroids, and eventually oral steroid replacement, while continuing osilodrostat under a “block and replace” strategy. Her hospitalization was complicated by multiorgan injury, progressive clinical decline, and uncontrolled pain. Because of this, she transitioned to hospice and died five days later.

Conclusion: This is the first reported case of ectopic Cushing’s syndrome due to metastatic LCNECa of the endometrium. Although small pituitary lesions were present, the severity of her hypercortisolism and marked hypokalemia strongly favored an ectopic source of ACTH secretion. Inferior petrosal sinus sampling was deferred given the patient’s acute illness and the low expected diagnostic utility in this setting. This case highlights the diagnostic complexity, rapid progression, and therapeutic challenges in the treatment of ectopic Cushing’s syndrome.

References:

Ragnarsson O, Juhlin CC, Torpy DJ, Falhammar H. A clinical perspective on ectopic Cushing’s syndrome. Trends in Endocrinology & Metabolism. 2024;35(4):347-360. doi:10.1016/j.tem.2023.12.003

Sato H, Kanai G, Kajiwara H, Itoh J, Osamura RY. Small-cell carcinoma of the endometrium presenting as Cushing's syndrome. Endocr J. 2010;57(1):31-38. doi:10.1507/endocrj.k09e-212

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