Cushing Syndrome Associated With Ectopic Corticotropin and Corticotropin-Releasing Hormone–Secreting Pheochromocytoma

Most patients with corticotropin (ACTH)-dependent Cushing syndrome (CS) will have an ACTH-secreting pituitary microadenoma. Approximately 15% of patients with ACTH-dependent CS have an ectopic source of ACTH secretion. The most common neoplasms associated with ectopic ACTH secretion are bronchial carcinoid (≈25%), pancreatic neuroendocrine tumor (≈16%), occult and unlocalized tumor (≈16%), small cell lung cancer (≈11%), medullary thyroid carcinoma (≈9%), other neuroendocrine tumors (≈7%), thymic carcinoid (≈5%), and pheochromocytoma (≈3%). The main clues that a patient may have ectopic ACTH-dependent CS include severe CS as evidenced by spontaneous hypokalemia and 24-hour urinary free cortisol (UFC) >1000 mcg, rapid onset of CS (sometimes so rapid that there is not time to develop the typical physical stigmata of CS), previous diagnosis of a neuroendocrine tumor, and male sex. Herein we present a case of ectopic secretion of ACTH and corticotropin-releasing hormone (CRH) from a pheochromocytoma causing severe CS.

Case Report

The patient was a 49-year-old woman who presented with a 1-month history of lower extremity edema, polydipsia, and polyuria. She had a 6-year history of untreated hypertension. She had no recent weight gain. On physical examination her blood pressure was 210/115 mmHg. She appeared cushingoid with a plethoric face, lanugo-type facial hair, central obesity, red abdominal striae, and edema ( Fig. 63.1 ).

INVESTIGATIONS

The laboratory test results are shown in Table 63.1 . Severe hypercortisolism was documented with a 24-hour urinary free cortisol excretion that was more than 100-fold elevated above the upper limit of normal. Although the patient was clearly cushingoid on physical examination, there was a mismatch between the severity of hypercortisolism and the physical stigmata of CS, which was consistent with a short duration of disease. Computed tomography (CT) of the chest and abdomen showed a 4-cm left adrenal mass ( Fig. 63.2 ). The 24-hour urine for total metanephrines and fractionated catecholamines confirmed that the patient had an adrenergic pheochromocytoma (see Table 63.1 ). Adrenal venous sampling confirmed a gradient of both ACTH and CRH from the left adrenal gland ( Box 63.1 ).

TABLE 63.1

Laboratory Tests

Biochemical Test	Result	Repeat Test Result	Reference Range
Sodium, mEq/L	139		135–145
Potassium, mEq/L	3.6		3.6–5.2
Fasting plasma glucose, mg/dL	312		70–100
8 am serum cortisol, mcg/dL	74		7–25
ACTH, pg/mL	550		10–60
CRH, pg/mL	2	11	<34
24-Hour urine:
Free cortisol, mcg	12,454		<108
Total metanephrines, mcg	5.4		<1.3
Norepinephrine, mcg	476		<80
Epinephrine, mcg	1124		<20
Dopamine, mcg	279		<400