SUN-072 - Asymptomatic Ectopic ACTH-Dependent Cushing Syndrome Secondary to Small Cell Neuroendocrine Carcinoma

Background: ACTH-dependent Cushing syndrome is classically associated with overt clinical features such as proximal muscle weakness, weight gain, and characteristic Cushingoid stigmata. In contrast, ectopic ACTH secretion may present insidiously and be identified primarily through biochemical abnormalities. Recognition of occult hypercortisolism is critical, as delayed diagnosis can lead to severe metabolic complications. In this context, noninvasive dynamic testing may provide diagnostic insight when imaging is nondiagnostic.

Case: A 77-year-old woman with an extensive oncologic history presented with uncontrolled hypertension and severe hypokalemia refractory to supplementation, prompting endocrine evaluation. She denied fatigue, weight gain or muscle weakness and did not exhibit clinical features of Cushing syndrome. Laboratory testing revealed markedly elevated plasma ACTH (229 pg/mL), serum cortisol up to 59.3 µg/dL, and a 24-hour urinary free cortisol exceeding 2,600 µg/24 h. Cortisol failed to suppress following low- and high-dose dexamethasone, confirming ACTH-dependent hypercortisolism. An elevated urinary potassium-to-creatinine ratio supported renal potassium wasting from cortisol-mediated mineralocorticoid excess.

Pituitary MRI showed no adenoma. Despite the absence of clinical features, the degree of biochemical hypercortisolism raised concern for ectopic ACTH secretion. A desmopressin (DDAVP) stimulation test demonstrated no significant rise in ACTH or cortisol, arguing against a pituitary source. Imaging revealed rapidly progressive metastatic disease, and liver biopsy confirmed small cell neuroendocrine carcinoma (synaptophysin-positive, TTF-1–positive, Ki-67 95%), consistent with a pulmonary primary. DOTATATE PET scan showed heterogeneous uptake, highlighting limitations of somatostatin receptor–based imaging in poorly differentiated neuroendocrine tumors. Medical adrenal blockade with osilodrostat and mineralocorticoid receptor antagonism with spironolactone improved electrolyte abnormalities and blood pressure. The patient subsequently initiated systemic chemotherapy with carboplatin and etoposide.

Conclusion: This case illustrates that ectopic ACTH-dependent Cushing syndrome may present without overt clinical features despite severe hypercortisolism, with metabolic derangements as the only initial clue. Lack of ACTH and cortisol response to DDAVP, together with negative pituitary imaging, supported an ectopic source. This case underscores the importance of maintaining a high index of suspicion for occult Cushing syndrome in patients with unexplained hypokalemia and malignancy and supports DDAVP testing as a useful noninvasive adjunct in the evaluation of ACTH-dependent hypercortisolism.

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