Looking Beyond Diabetes: A Case of Worsening Hyperglycemia as a Manifestation of Ectopic Cushing’s Syndrome Secondary to an Adrenocorticotropic Hormone-Producing Pheochromocytoma

Abstract

A 76-year-old woman presented with worsening fasting hyperglycemia on routine blood sugar measurement, previously well-controlled on Metformin, requiring initiation of insulin. Her medical history included type 2 diabetes mellitus, hypertension, and aortic stenosis. Over the next few weeks, she developed bilateral upper and lower extremity proximal muscle weakness, episodes of confusion, rapid weight loss and increasing lower extremity edema. She did not have typical Cushingoid features of moon facies, easy bruising, centripetal obesity, abdominal striae, dorsocervical fat padding, or hyperpigmentation. Laboratory data revealed severe hypokalemia, elevated cortisol of 138 (3.7–19.4 ug/dL) and ACTH of 368 (6–50 pg/mL) consistent with ACTH-dependent Cushing’s syndrome. She was hospitalized for emergent therapy with etomidate infusion, potassium supplementation, and started on spironolactone. 24-hour urinary analysis demonstrated elevated catecholamines and metanephrines: epinephrine 552 (2–16 mcg/g cr), norepinephrine 1881 (7-5 mcg/g cr), metanephrine 4095 (21–153 mcg/g cr), normetanephrine 3920 (108–524 mcg/g cr).CT abdomen showed 3.8 cm mass in the left adrenal gland with enhancing walls and central hypoattenuation and a normal contralateral adrenal gland. MR brain showed a partial empty sella without any mass. 123I-metaiodobenzylguanidine scintigraphy showed uptake in the left adrenal mass. Once cortisol was reduced to <25 ug/dL, she was transitioned from etomidate to metyrapone; alpha-methyltyrosine and prazosin was also begun. Following left laparoscopic adrenalectomy, ACTH decreased to <5 pg/mL confirming that the pheochromocytoma was the source of ectopic Cushing’s. Gross examination of the mass was notable for a spongy, tan, roughly spherical medullary neoplasm (3 cm in diameter) with a rim of brown and focally yellow adrenal cortex up to 4 mm thick. Marked diffuse adrenal cortical hyperplasia was noted. The tumor showed varied growth patterns, including solid areas and spongy, angioma-like areas with prominent small blood vessels. Immunohistochemical staining was positive for somatostatin receptor 2A, tyrosine hydroxylase and ACTH in tumor cells and negative for T-PIT. She was discharged on replacement hydrocortisone therapy, minimal insulin for diabetes and has shown substantial clinical improvement.Cushing’s syndrome due to ectopic ACTH-producing pheochromocytoma is rare. Worsening hyperglycemia in the presence of hypertension, even without typical clinical findings of Cushing’s, should prompt further hormonal work up. The absence of the transcription factor TPIT, which is a lineage determinant for pituitary corticotrophs, suggests that novel pathways are involved in differentiation of cells that produce ectopic ACTH.