Figure 31.7 Algorithm for testing patients suspected of having Cushing syndrome (CS). Diagnostic criteria that suggest Cushing syndrome are a urinary-free cortisol (UFC) greater than the normal range for the assay, serum cortisol greater than 1.8 μg/dL (50 nmol/L) after 1 mg dexamethasone (1 mg DST), and a late night salivary cortisol greater than 145 ng/dL (4 nmol/L). (Based on recommendations from Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.)
Treatment of ACTH-independent Forms of Cushing Syndrome
Excluding cases that are of iatrogenic or factitious etiology, ACTH-independent forms of Cushing syndrome are adrenal in origin. Adrenal cancers are usually very large by the time Cushing syndrome is manifest. This is because the tumors are relatively inefficient synthesizers of steroid hormones. Tumors are larger than 6 cm in diameter and are easily detectable by computed tomography (CT) scanning or magnetic resonance imaging (MRI). Adrenal cancers often produce steroids other than cortisol. Thus, when Cushing syndrome is accompanied by hirsutism or virilization in women or feminization in men, adrenal cancer should be suspected.
An adrenal tumor that appears large and irregular on radiologic imaging is suggestive of carcinoma. In these cases, a unilateral adrenalectomy through an abdominal exploratory approach is preferable. In most malignant tumors, complete resection is virtually impossible. However, a partial response to postoperative chemotherapy or radiation may be achieved. Most patients with malignancy die within 1 year. When administered immediately after surgery, mitotane (O,P-DDD, an adrenocorticolytic drug) may be of benefit in preventing or delaying recurrent disease (157). Manifestations of Cushing syndrome in these patients are controlled by adrenal enzyme inhibitors.
Adrenal adenomas are smaller than carcinomas and average 3 cm in diameter. These tumors are usually unilateral and infrequently associated with other steroid-mediated syndromes. Micronodular adrenal disease is a disorder of children, adolescents, and young adults. The adrenal glands contain numerous small (>3 mm) nodules, which often are pigmented and secrete sufficient cortisol to suppress pituitary ACTH. This condition can be sporadic or familial.
Surgical removal of a neoplasm is the treatment of choice (158,159). If a unilateral, well-circumscribed adenoma is identified by MRI or CT scanning, the ﬂank approach may be the most convenient. The cure rate following surgical removal of adrenal adenomas approaches 100%. Because normal function of the HPA axis is suppressed by autonomous cortisol production, cortisol replacement follows surgery and is titrated downward over several months, during which recovery of normal adrenal function is monitored.
Treatment of Cushing Disease
The main goals of treatment in ACTH-dependent Cushing syndrome are reversal of clinical features, normalization of biochemical changes with minimal morbidity, and long-term control without recurrence (155).