Pheochromocytoma as the Etiology of Cushing Syndrome Through Paracrine ACTH Signaling

Abstract

\n Introduction: Pheochromocytomas are rare catecholamine-secreting tumors of the adrenal medulla that may also secrete ACTH. There are approximately 100 cases of ACTH-producing pheochromocytomas reported in the peer reviewed literature, and they typically cause Cushing syndrome by significantly raising circulating ACTH levels. We report a pheochromocytoma causing apparent ACTH-independent Cushing syndrome by paracrine action of locally produced ACTH on ipsilateral adrenal cortex. Case: A 64-year-old female was referred for an incidentally discovered left adrenal mass. The mass was 4 cm and 37 Hounsfield units on non-contrast computed tomography, and the right adrenal gland was unremarkable. The patient’s history was notable for three years of resistant hypertension, and examination revealed stigmata of Cushing syndrome including moon facies, scattered bruises, and wide, pink striae. Three measurements of plasma metanephrines ranged from 3- to 4.5-fold elevated, and 24 h urine metanephrines were 5.2-fold elevated. Urine 24 h epinephrine was 2.7-fold elevated. Three 8 AM cortisol measurements on overnight dexamethasone suppression tests were 16.3–17.4 mcg/dL (< 1.8), and 8 AM dexamethasone on one test was 494 ng/dL (140–295). Two midnight salivary cortisol measurements were 0.348 and 0.416 mcg/dL (< 0.112), and 8 AM ACTH levels on two occasions were 6.8 and 7.9 pg/mL (7.2–63.3). After adrenergic blockade, the patient underwent left adrenalectomy. Her tumor stained for synaptophysin and chromogranin consistent with pheochromocytoma, and focal staining for ACTH was also observed. Hyperplasia of the adjacent adrenal cortex was present. Hypertension resolved after adrenalectomy, and the patient developed secondary adrenal insufficiency (8 AM cortisol and ACTH 1.0 mcg/dL [> 15] and 2.9 pg/mL, respectively). Discussion: There are five published reports of pheochromocytoma and subclinical hypercortisolemia due to paracrine ACTH or IL-6 activity on ipsilateral adrenal cortex, but this case is distinguished by the occurrence of overt Cushing syndrome. Our patient had ACTH < 10 pg/mL on two measurements, her pheochromocytoma showed focal staining for ACTH, and hyperplasia of adjacent adrenal cortex was observed. In contrast, median ACTH level was 5-6x above the upper limit of normal in a recent review of 95 cases of pheochromocytomas with Cushing syndrome due to ectopic ACTH secretion. If Cushing syndrome was due to bilateral adrenal hyperplasia independent of the patient’s pheochromocytoma, cortisol excess would not have resolved after unilateral adrenalectomy. Communication between cortical and medullary circulations through venous radicles provides a mechanism for ACTH produced by the patient’s pheochromocytoma to affect the function of adjacent cortex. This case demonstrates a novel mechanism by which ACTH from a pheochromocytoma can cause Cushing syndrome.