SUN-022 - Expecting the Unexpected: Cushing'S Disease with Extreme Adrenocorticotropic Hormone Elevation and Pituitary Apoplexy

Introduction:
Cushing's disease (CD) typically develops insidiously and is most often caused by pituitary microadenomas < 6 mm. In contrast, ectopic Cushing’s syndrome (ECS) usually presents rapidly and with more significant hypercortisolemia, ACTH levels >250 pg/mL, and 24-hour urinary free cortisol (24hr UFC) >10x the upper normal. Pituitary apoplexy in CD is rare (3.8%) and may result in hypocortisolemia in 3.8% of cases, potentially obscuring the diagnosis. Biochemical confirmation before transsphenoidal surgery is critical, as up to 40% of patients with ECS harbor incidental pituitary lesions. We report a rare case of CD from a macroadenoma with extreme ACTH elevation in the setting of apoplexy and absent Cushingoid features, highlighting diagnostic challenges when urgent surgery precedes full evaluation.

Case Presentation:
A 57-year-old male with resistant hypertension and prediabetes presented with new onset of severe unremitting headache of 5 days. MRI demonstrated a 1.9-cm sellar mass with stalk thickening and deviation. He had no cushingoid or acromegalic features and denied weight gain, striae, or visual symptoms. Labs revealed AM cortisol 90 µg/dL and ACTH 640 pg/mL (repeat 298 pg/mL) despite dexamethasone 10 mg the prior day, 24hr UFC >4,450 ug/24 hr along with central hypothyroidism, hypogonadotropic hypogonadism, and low prolactin.
Given marked ACTH elevation and imaging findings, the differential included CD, ECS, and infiltrative hypophysitis. Despite recommendations for completing biochemical confirmation with IPSS, the patient elected for urgent transsphenoidal resection.
Pathology confirmed a corticotroph adenoma with pituitary apoplexy. Post-operatively, cortisol fell to 21.9 µg/dL (POD1) and 5.8 µg/dL (POD2), with ACTH decreasing to 36.9 and 21.2 pg/mL respectively. He was started on hydrocortisone and levothyroxine. MRI showed no residual tumor but persistent stalk deviation. He developed chronic hypopituitarism without diabetes insipidus. One month later, he developed an aortic dissection requiring pericardial window and a deep vein thrombosis. He remains in biochemical remission.

Discussion:
This case highlights a diagnostically challenging and atypical presentation of CD. ACTH-secreting macroadenomas are uncommon, and ACTH levels >250 pg/mL are more typical of ECS. Although lesion size supported pituitary origin, stalk thickening and extreme ACTH elevation warranted concern for ectopic or infiltrative etiologies. Although pathology confirmed CD and his clinical achievement of remission with adrenal insufficiency retrospectively confirmed the diagnosis, this outcome was not predictable preoperatively. This case underscores the importance of comprehensive biochemical confirmation prior to surgery when feasible and the need for astute clinical judgment that anticipates atypical and unexpected presentations.

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