Cushings Syndrome

David Bailey Wilson and Richard A. Prinz Introduction Definition

In 1932, Harvey W. Cushing defined a syndrome he called "pituitary basophilism." Muscular weakness, truncal obesity, abdominal striae, diabetes and hypertension characterized this clinical complex. Today, the condition resulting from chronic glucocorticoid excess due to any source is known as "Cushing's syndrome," as opposed to the pituitary-derived "Cushing's disease."

Statistics

Cushing's syndrome is a rare disorder, with a prevalence of 10 patients per million population per year. It can be classified into ACTH (corticotropin)-dependent and ACTH-independent disease. Eighty percent of patients have ACTH-depen-dent disease, with a pituitary (70%) or ectopic (10%) source of the excess ACTH. Either of these conditions results in adrenal cortical hyperplasia of the zona reticularis and fasciculata. The resulting cortisol hyperproduction leads to the clinical manifestations of the syndrome. Pituitary tumors are more common in women than men, and often occur in the second and third decades of life. Ectopic ACTH syndrome may occur with a number of different tumors, and usually is rapidly progressive. Ectopic ACTH production is more common in men than in women, and typically occurs in the fourth and fifth decades of life.

Twenty percent of patients have ACTH-independent disease. This is due to an adrenal source of excess cortisol, either an adenoma (10%), or carcinoma (10%). ACTH production is suppressed by the autonomous production of cortisol in these patients. ACTH-independent Cushing's syndrome occurs more commonly in women, who are typically aged 20-40.

Diagnosis

Clinical Suspicion

A high index of suspicion is necessary to make the diagnosis of Cushing's syndrome early in its course. A constellation of symptoms and signs are recognized. These include a characteristic round facies, proximal muscle weakness, truncal obesity, buffalo hump, thin skin, hirsutism, easy bruisability, purple striae, depression, osteoporosis, hypertension, and glucose intolerance (Table 18.1).

Table 18.1. Clinical symptoms of Cushing's disease

Round facies

Proximal muscle weakness

Truncal obesity

Buffalo hump

Thin skin

Hirsutism

Easy bruisability

Purple abdominal striae

Depression

Osteoporosis

Hypertension

Glucose intolerance

ConfirmatoryTests

A 24-hour urine collection for free cortisol is the most common screening test. Low dose dexamethasone suppression test follows (either as 1 mg po before bedtime or as 0.5 mg po q6" for 48 hours). An elevated 24 hour urine free cortisol level or a failure to suppress plasma cortisol by dexamethasone suggests Cushing's syndrome with 95% accuracy.

ACTHLeveJ

The next step is to distinguish between ACTH-dependent and independent disease. Immunoradiometric assays (ACTH-IRMA) can consistently and reliably detect suppressed levels of ACTH, with an ACTH-independent adrenal source of cortisol. This is an improvement over older radioimmunoassays which could not always distinguish ACTH from nonsuppressed precursor molecules, and gave falsely elevated results.

Localizing

ACTH-Dependent

Having distinguished between ACTH-dependent and independent disease, localization of the tumor is possible. Clinically, patients with a pituitary source of ACTH tend to have a long-standing history of slowly developing symptoms and signs. In contrast, most ectopic sources of ACTH have a rapidly progressive course.

High dose dexamethasone suppression testing (HDDMS) is a noninvasive method to distinguish pituitary from ectopic sources of excess corticotropin. Dexamethasone is given as either 2 mg po q6" for 48 or as 8 mg po before bed. Suppression of 24 hour urine free cortisol or plasma cortisol by more than 50% is consistent with pituitary disease. This is because of the pituitary's partial sensitivity to feedback suppression by the exogenous steroid. Sensitivity and specificity of this test range from 80-90%. Because the test's accuracy is less than the pretest probability of having pituitary disease, some authors advocate stricter criteria for a positive test. Suppression of 24 hour urine free cortisol by > 90%, and 17-hydroxy-corticosteroid secretion by > 64%, gives HDDMS 100% specificity.1 Magnetic resonance imaging is most commonly used to identify suspected pituitary disease. Scanning before and after gadolinium enhancement allows identification of some microadenomata (<10 mm.) as well as any local invasion or compression of the adjacent structures. If the diagnosis is still in doubt, simultaneous sampling of the inferior petrosal sinuses should be performed. Invasive and expensive, inferior petrosal sinus sampling requires specialized interventional radiology techniques. In this procedure, the left and right petrosal sinuses are individually cannulated, most commonly via a femoral vein approach. Blood samples are drawn before and after an infusion of corticotropin releasing hormone (CRH). Using CRH stimulation, IPSS can identify and lateral-ize a pituitary source of excess ACTH with nearly 100% accuracy.

ACTH-Independent

For ACTH-independent Cushing's syndrome, radiographic imaging is used to distinguish unilateral from bilateral adrenal pathology. Computed tomography is the standard modality for gaining anatomic information. Thin sections through the adrenals (3-5 mm) will reveal a unilateral adenoma (80%), carcinoma (10%), or bilateral symmetric or asymmetric pathology (10%). Carcinomas tend to be larger (> 5 cm), inhomogeneous, with an irregular border. Distinguishing adenoma from carcinoma in large tumors can be aided by magnetic resonance imaging. Carcinomas appear brighter than the liver on T2 weighted images.

Iodocholesterol scintiscanning with the radiolabeled cholesterol analog NP-59 is a noninvasive test of adrenal function. Taken up by active adrenal tissue, this isotope is not metabolized. Hyperfunctioning lesions as small as 1-2 cm can then be visualized because of the high concentration of isotope. Undifferentiated carcinomas do not show activity. Although NP-59 requires several days to complete and can be variable in its uptake and reliability, it is useful in distinguishing between unilateral and bilateral disease (Fig. 18.1).

Treatment

Medical Therapy

Pharmacological blockade of cortisol synthesis is possible. Metyrapone, an 11-beta hydroxylase inhibitor, can be used preoperatively in severe cases of Cushing's syndrome. It is also used along with ketoconazole and aminoglutethamide to reduce the cortisol synthesis in metastatic disease. Mitotane can be used in metastatic or unresectable disease. Its onset of action is slow, requiring several weeks to control symptoms. Remission occurs in 80% of patients, but relapse follows cessation of therapy. Octreotide, a synthetic somatostatin analogue, has been shown to reduce ACTH production and thereby cortisol levels. It can be used either preoperatively to decrease the risk of operation, or more long term with unresectable tumors in patients with ectopic ACTH syndrome.2

Patients with Cushing's syndrome are typically at increased risk for perioperative complications. They are obese, have glucose intolerance, and are more susceptible to infections. Perioperative antibiotics are indicated. Glucocorticoid supplementation

Buffalo Hump And Diabetes
Fig. 18.1. Diagnostic workup

is necessary perioperatively as well. Usually hydrocortisone 100 mg is given IM or IV preoperatively and q6 hours postoperatively until oral supplements are tolerated. With a unilateral cortisol producing adenoma, the contralateral gland's function is usually suppressed. This varies in duration, but recovery of the hypothalamic-pitu-itary-adrenal axis usually requires at least two to twelve months. After bilateral adrena-lectomy, glucocorticoid and adrenocorticoid supplements are required for life.

Operative Therapy

The optimal treatment of Cushing' s syndrome is surgical resection of the source. This is true for both ACTH-dependent and independent disease.

Pituitary

Corticotroph adenomas are found in approximately 80% of patients with Cushing's disease. Most are monoclonal, and surrounded by suppressed normal pituitary tissue. Some patients have separate corticotroph hyperplasia, either with or without an adenoma. No conclusive evidence has been found, however, of hypotha-lamic or other central nervous system source of excessive stimuli of corticotropin release. Transsphenoidal resection of an adenoma or hyperplastic corticotropic tissue is standard treatment. Patients with a microadenoma confined to the sella have the highest likelihood of cure. Up to 88% will have a long-term remission. An undetect-able postoperative corticotropin level suggests a cure. Incomplete removal of a tumor, or subtotal resection of a diffusely hyperplastic gland leads to a fall in ACTH and cortisol levels to nearly normal levels, and clinical improvement Feedback regulation of the pituitary remains abnormal, though, and ACTH secretion often increases with time necessitating further treatment.

Repeat surgery on the pituitary can be performed. After successful resection of a recurrent or persistent adenoma, remission rates in the range of 70-75% can occur. Diabetes insipidus, cerebrospinal fluid rhinorrhea, low-grade meningitis, hypothy-roidism, and hypogonadism are the more common complications. Radiation therapy with adjunctive adrenolytic drugs is also an important second- line therapy. Doses in the range of 45-54 Gy are used. The timing of repeat surgery or radiation therapy is usually based on symptom return, am plasma cortisol levels, 24" urine free cortisol, and low dose dexamethasone suppression testing.

Bilateral adrenalectomy provides definitive treatment for ACTH-dependent pituitary disease refractory to the above therapies. Beside the need for life-long glu-cocorticoid and mineralocorticoid supplementation, Nelson's syndrome occurs in approximately 5-25% of patients with Cushing's Disease treated with bilateral adrenalectomy. Defined by hyperpigmentation, elevated ACTH levels, and an aggressively expanding pituitary tumor, Nelson's syndrome is due to the absence of cortisol feedback inhibition on the pituitary. Prophylactic pituitary irradiation has reduced this occurrence by 50%. Controversy remains over the use of radiation therapy on glands that have been treated with surgical resection.

Ectopic A CTH Syndrome

Certain nonpituitary neoplasms may produce biologically active ACTH, among other hormones. This accounts for 10-30% of patients with Cushing's syndrome from all causes. A majority of these tumors will be found in the chest. Small cell lung carcinoma is the most common lesion, accounting for fifty percent of the patients. Another 10% are from thymic carcinomas and carcinoids. Bronchial adenomas and carcinoids cause approximately 5%. Pancreatic tumors, including carcinoids and islet cell carcinomas, are the source in 10% of cases. Pheochromocytoma, neuro-blastoma, ganglioma and paraganglioma account for 5%, as does medullary carcinoma of the thyroid. Anecdotal reports show ACTH activity in a variety of common and uncommon neoplasms. Virtually all nonmesodermal neoplasms have been reported to synthesize this hormone.3 Although most of these tumors express a glucocorticoid receptor, transcription of the proopiomelanocortin gene and secretion of ACTH are not subject to feedback inhibition by cortisol. Bronchial carcinoids may be an exception, with some susceptibility to high-dose dexamethasone suppression. These slow growing tumors often produce Cushing's syndrome long before they can be found clinically. A relatively recent advance in making this difficult diagnosis utilizes the finding that ectopic corticotropin-producing tumors often express somatostatin receptors while pituitary and adrenal adenomas do not. This can be exploited for localization by using labeled octreotide scintigraphy (octreoscan). This modality is 80% successful in localizing these tumors.

Adrenal

For patients with an adenoma, adrenalectomy is curative. The recommended approach is based on the tumor's size and malignantcy potential, the patient's body habitus and the surgeon's experience. Tumors less than 5 cm can be resected through a flank or posterior approach. By avoiding the peritoneal cavity, paralytic ileus and the risk of future adhesions are avoided. Larger tumors should be approached transabdominally or with a thoracoabdominal approach. These approaches allow for en bloc resection of adjacent organs in the case of locally invasive carcinomas.

Worldwide, the incidence of adrenal carcinoma is 2/1,000,000. Two thirds of these tumors secrete excess steroid hormones, and Cushing's syndrome is the most common resultant clinical entity. They also can secrete multiple other hormones. One clinical finding that suggests the presence of a carcinoma is virilization or defeminization. The tumors are often large (> 6 cm) with necrosis, calcification, and local invasion. At the time of diagnosis, 33% are confined to the gland, while 38% have distant metastases. The most common targets are lungs (70%), liver (40%), lymph nodes (40-70%), and bone (30%). The remainder are locally invasive. Surgical debulking with adjuvant mitotane therapy offers the best chance for remission. Still, median survival from the onset of symptoms is only 4 years and 5 year survival is 10%.

Bilateral adrenalectomy can be performed with either an anterior or a bilateral posterior approach. For patients who have persistent or recurrent disease after transsphenoidal pituitary resections, or occult or unresectable ectopic tumors, bilateral adrenalectomy can result in substantial symptomatic improvement.5 Primary adrenal hyperplasia is also an indication for bilateral adrenalectomy.

Five to ten percent of patients with Cushing's syndrome will have bilateral adrenal nodules on high-resolution CT scans. The nodules range in size from 0.5-7 cm. These are believed to be an end response to long-standing ACTH stimulation in which the nodules become ACTH-independent. Biochemical and radiological test results are mixed or inconsistent since there may be findings of both ACTH dependence and independence. Treatment depends upon identifying an ACTH producing tumor, either orthotopic or ectopic. Successful resection results in both clinical cure and involution of the nodules. Bilateral adrenalectomy is necessary if the ACTH-producing tumor cannot be identified and resected.

Primary pigmented nodular adrenal dysplasia (PPNAD) is a rare ACTH-inde-pendent bilateral disease consisting of small darkly pigmented adrenal nodules. The disease can be sporadic or familial and is thought to be autoimmune in origin. Subtle adrenal enlargement and nodularity is inconsistently seen on preoperative CT scans. Bilateral adrenalectomy is curative. Twenty percent of these patients will have Carney's complex, which is an autosomal dominant disease of multiorgan tumors. The complex includes cardiac myxomas, testicular tumors, pigmented skin lesions, cutaneous myxomas, breast myxoid fibroadenomas, pituitary adenomas and other myxoid and fibrous tumors.

Advances

Laparoscopic Adrenalectomy

Tumors up to 6-8 cm in diameter can be removed laparoscopically. The technique was first reported in 1992 by Gagner et al and has since been reported widely.5 Advantages to this approach include shorter hospital stay, shorter convalescence, and decreased postoperative narcotic requirements. In Cushing's syndrome, another potential advantage includes fewer infectious and wound complications.6

Referenres

1. Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 1994; 23(3):511-537. This article provides a detailed summary of the diagnostic steps for Cushings syndrome.

2. Woodhouse NJ, Dagogo-Jack S, Ahmed M et al. Acute and long- term effects of octreotide in patients with ACTH- dependent Cushing's syndrome. Am J Med 1993; 95(3):305-8. This study reports a clinical response to octreotide in some patients with ectopic disease. It was used prior to detection of the ACTH source, and as treatment of metastatic disease.

3. Odell WD. Ectopic ACTH secretion: A misnomer. Endocrinol Metab Clin North Am 1991; 20(2):371-379. This is an interesting summary of the diagnosis and treatment ofA CTH-secreting nonpituitary tumors. The authors propose that some carcinomas convert the normal ACTH precursors found in all tissues to biologically active ACTH, producing Cushing's syndrome.

4. Zeiger MA, Fraker DL, Pass HI et al. Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy. Surgery 1993; 114:1138-43. The group at NIH reviewed the long term symptomatic improvement in patients who underwent bilateral adrenalectomy for failed pituitary resections, occult or metastatic ectopic tumors and bilateral adrenal hyperplasia.

5. Gagner M, Lacroix A, Prinz RA et al. Early experience with laparoscopic approach for adrenalectomy. Surgery 1993; 114:1120-5. The lateral decubitus transabdominal laparoscopic approach is described in detail.

6. Staren ED, Prinz RA. Adrenalectomy in the era of laparoscopy. Surgery 1996; 120:706-11. In this retrospective review of open and laparoscopic adrenalectomies over a three year period the indications for various approaches are reviewed. A laparoscopic approach is feasible in 60% of patients with surgically correctable adrenal disease.

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