SAT-038 - The Smoking Gun in the Pelvis: Ectopic ACTH Syndrome from A Gynecological Carcinosarcoma

Introduction:
Ectopic ACTH secretion by gynecologic carcinosarcoma is exceedingly rare. Here we report a novel case of ACTH producing gynecological carcinosarcoma with ACTH levels lower than typically seen in ectopic ACTH syndrome (EAS).

Case:
A 64-year-old female was referred to endocrine for management of uncontrolled type 2 diabetes (T2D). She had a rapid decline in health over four months, noted by worsening T2D (HbA1c 6.6% to 10%), progressive weakness, abdominal distension, pedal edema and hypertension. She had a clavicular fracture after falling due to weakness. During hospitalization, she had significant hypokalemia (2.6 mmol/L). Imaging identified an 18.5 cm pelvic mass projecting posterolateral to the uterus, confirmed by biopsy as a high-grade carcinosarcoma. Tumor resection was aborted as the mass was extremely friable and deemed inoperable. PET scan did not show evidence of metastatic disease.
Due to severe hypokalemia and sudden metabolic worsening, hypercortisolism was suspected. Diagnostic workup confirmed ACTH-dependent Cushing’s syndrome: AM cortisol of 48.3 mcg/dL following dexamethasone, an unsuppressed ACTH of 33 pg/mL, and a 24-hour urinary free cortisol (UFC) significantly elevated at 1589 mcg/day. CT imaging noted bilateral adrenal hyperplasia, and pelvic lavage from the tumor site stained positive for ACTH, confirming diagnosis of EAS.
Insulin and steroidogenesis inhibitor ketoconazole was started. After four weeks, UFC normalized to 23 mcg/day, insulin needs decreased and potassium levels stabilized. Concurrently, she started neoadjuvant chemotherapy (carboplatin and paclitaxel). Ketoconazole was discontinued at week five due to QTc prolongation, despite that she remained in biochemical and clinical remission. Eight weeks after stopping ketoconazole, UFC remained normal (29.8 mcg/day) with no clinical stigmata of hypercortisolism. Her chemotherapy likely successfully reduced the tumor burden below the threshold required for ectopic hormone production, effectively curing the paraneoplastic syndrome despite the persistence of the primary malignancy. She underwent surgery of her gynecologic mass and had < 5% of tumor noted on pathology.

Discussion:
Carcinosarcomas are typically aggressive gynecologic malignancies but ACTH production is very rare with only a few cases reported. In our case ACTH levels were not markedly elevated which is typical in EAS. The possibility of assay interference (hook effect) was considered and excluded by serial dilution with no change in ACTH results. This case is remarkable for the rare association of gynecological carcinosarcoma with EAS. It underscores the importance of ACTH immunohistochemistry of the available samples for definitive localization of the ectopic source. It also highlights the necessity of screening for EAS in cancer patients with abrupt metabolic decompensation.

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