The clinical features of Cushing disease, first described in Cushing’s monograph in 1932, are familiar to virtually everyone in medicine: truncal obesity with reddish purple cutaneous striae over the abdomen and other parts; dryness and pigmentation of the skin and fragility of skin vessels; excessive facial hair and baldness; cyanosis and mottling of the skin of the extremities; osteoporosis and thoracic kyphosis; proximal muscular weakness; hypertension; glycosuria; and a number of psychologic disturbances. Adrenal hyperplasia secondary to a basophil adenoma of the pituitary (pituitary basophilia was Cushing’s term) was the established pathology in Cushing’s cases. It is to this pituitary form of hyperadrenalism that the term Cushing disease has been applied.
The same combination of abnormalities, however, may be associated with chronically increased production of cortisol from a primary adrenal tumor, ectopic production of ACTH by carcinoma of the lung or other carcinomas, and most commonly, with the prolonged administration of glucocorticoids (prednisone, methylprednisolone, or ACTH). For these latter conditions, all but the last being associated with secondary adrenal hyperplasia, the term Cushing syndrome is appropriate. Clinical presentation may vary and some components of the syndrome may be lacking or less conspicuous; diagnosis is then facilitated by measurements of ACTH and cortisol in the blood and urine. Cushing syndrome of ectopic type differs clinically from primary pituitary Cushing disease with respect to its more rapid development and greater degrees of proximal limb weakness, skin pigmentation, hypokalemia, hypertension, and glycosuria. Plasma concentrations of ACTH are usually above 20 pg/mL (at times exceeding 50 pg/mL) in the ectopic type and are not suppressed by dexamethasone. In Orth’s review of 630 cases of Cushing syndrome of endogenous cause, 65 percent were caused by hyperpituitarism (Cushing disease), 12 percent by ectopic production of ACTH, 10 percent by an adrenal adenoma, and 8 percent by adrenal carcinoma.
In Cushing disease, either hyperplasia of pituitary cells or a basophil or chromophobe adenoma produces excessive ACTH, which stimulates the adrenals. Corticotroph (basophil) adenomas are usually microadenomas (<1 cm) and enlarge the sella in only 20 percent of cases. However, it is now appreciated by MRI or high-resolution CT through the sella, that either microor macroadenomas are the cause in approximately 80 percent of cases of Cushing syndrome, higher than in the aforementioned series by Orth. There are only a few cases in which a hypothalamic tumor such as a gangliocytoma has caused Cushing syndrome.