Evaluation and Management of Adrenal Masses

Sergio Gugisch Moreira, Jr, MD, and Julio M. Pow-Sang, MD


Cancer Control. 2002;9(4) 

In This Article

Evaluation of Adrenal Masses

An adrenal mass is characterized according to functional status, with a medical history, physical examination, and hormonal assessment, and malignant potential, with an assessment of the imaging phenotype and mass size. Most patients diagnosed with adrenal lesions had previous complaints of extra-adrenal origin, such as hepatic and biliary problems, lumbar pain, nephropathy, and abdominal pain that was nonspecific in nature. However, many lesions are associated with subtle symptoms of hormone excess, such as generalized obesity, hypertension, abnormal glucose tolerance, and depression. Also, several inherited syndromes are associated with adrenal gland pathology, such as multiple endocrine neoplasia (MEN) types 1 and 2, von Hippel-Lindau syndrome, neurofibromatosis, Beckwith-Wiedemann syndrome, and congenital adrenal hyperplasia.[4]

The optimal diagnostic approach to a patient with an adrenal mass is not well established. While several different algorithms and methods of determining the optimal treatment of these lesions have been published, most physicians would agree that the evaluation of the patient should start with a careful history and physical examination focusing on signs and symptoms of adrenal hyperfunction and malignancy.

Adrenal Incidentalomas. Abnormalities of endocrine function have been observed in a substantial number of patients with adrenal incidentalomas. Adrenal incidentalomas may retain some hormonal activity, although most are clinically silent. This finding has clinical relevance because endocrine hyperfunction (ie, hypercortisolism, aldosteronism, pheochromocytoma) may be associated with significant morbidity. Measurement of adrenal cortical autonomy is mandatory in all patients with adrenal incidentalomas. Hormonal evaluation includes basal determinations and dynamic tests of cortical and medullary adrenal function.

Hypothalamus-Pituitary-Adrenal Axis. It is important to determine when glucocorticoid secretory autonomy in an adrenal cortical adenoma leads to clinical morbidity. Low adenocorticotropic hormone (ACTH) levels have been reported in approximately 5% to 34% of patients with adrenal incidentalomas, altered circadian cortisol rhythm in 8% to 20%, and elevated urinary-free cortisol in 0% to 21% and serum cortisol in 0% to 12%. Plasma dehydroepiandrosterone sulfate (DHEA-S) concentration may predict the hormonal activity of adrenal incidentalomas and serve as an indicator of hypothalamic-pituitary-adrenal axis suppression.[22] However, in a recent study, the plasma DHEA-S concentration was a poor predictor of hormonal activity.[23] Most centers utilize the overnight 1-mg dexamethasone suppression test. If the cortisol level at 8 AM following dexamethasone given the night before is greater than 5 mg/dL, a formal 2-day, low-or high-dose dexamethasone suppression test is indicated to confirm the autonomy. Some studies suggest a high rate of false-positive results. Until more is learned from the results of long-term follow-up studies, it is reasonable to consider that patients with nonsuppression to both a 1-mg dexamethasone suppression test (8 AM serum cortisol >5 mg/dL) and a formal 2-day, low-or high-dose dexamethasone suppression test (24-hour urinary-free cortisol >20 mg/dL) are candidates for adrenalectomy. Slightly elevated urinary-free cortisol and/or serum cortisol with abnormal rhythm incompletely suppressed by low-dose dexamethasone and decreased ACTH responsiveness to corticotropinreleasing hormone may be observed in clinically silent cortisol hypersecretion.

Baseline serum 17-hydroxyprogesterone is elevated in patients with rare adrenal masses associated with congenital adrenal hyperplasia, whereas adrenal masses have been reported in 82% of those with homozygous 21-hydroxylase defect.[24] Despite extensive experience, there is little consensus regarding selection of the most appropriate and cost-effective tests for endocrine evaluation of adrenal incidentalomas.

Renin Angiotensin Aldosterone Axis. Aldosteronomas have been reported in less than 3% of adrenal incidentalomas. Hypertensive patients with hypokalemic alkalosis should be evaluated by determining plasma renin activity and plasma aldosterone concentration, although essential hypertension may cause hypokalemia. An elevated plasma aldosteronerenin ratio is diagnostic of primary aldosteronism. Other methods, such as posture test and sodium loading have been suggested but are not commonly used in clinical practice. Adrenal vein sampling of aldosterone is the gold standard for localization of aldosterone production; however, it is invasive, labor-intensive, and more challenging.

Adrenal Medulla. Even when clinically silent, pheochromocytomas can be lethal. Autopsy studies have shown that up to 76% of pheochromocytomas are clinically silent and unsuspected before death.[4] However, this lesion should always be suspected to avoid the risk of lethal hypertensive crises, especially during biopsy or surgery. Ninety-nine percent of patients with adrenal pheochromocytomas have increased levels of 24-hour urinary total metanephrines, catecholamines, or both.[25] Most clinicians advocate screening tests with measurements of urinary catecholamines and/or metanephrines in all patients with adrenal incidentalomas. Plasma catecholamine and/or metanephrine determinations are also sensitive and specific tests to detect pheochromocytomas. Less common dynamic tests (eg, glucagon stimulation, clonidine inhibition) may be useful to confirm the diagnosis.

Screening for Other Hormonally Active Processes. Sex hormone-secreting adrenal cortical tumors occur rarely. Patients with these tumors usually have symptoms and do not present with adrenal incidentalomas (except for testosterone-secreting adrenal tumors in men). Routine screening for sex hormone excess in a patient with an adrenal incidentaloma is not warranted.

Nonclassic congenital adrenal hyperplasia can cause unilateral or bilateral adrenal masses, and some investigators have suggested routine corticotropin stimulation testing in all patients with adrenal incidentalomas. This recommendation cannot be supported in view of the relative infrequency of congenital adrenal hyperplasia. Genetic screening and corticotropin stimulation testing should be reserved for patients in whom congenital adrenal hyperplasia is suspected on clinical grounds or for patients who have bilateral adrenal masses.[26]

Diagnostic Algorithm. Several hormonal screening protocols have been suggested, most based on evidence and the experience of the authors. Ross in 1990[27] suggested that a minimal evaluation consisting of screening tests for pheochromocytoma, serum potassium in hypertensive patients, and glucocorticoids or androgens only in the presence of suggestive clinical features may fail to identify those with mild hypercortisolism or congenital adrenal hyperplasia. Favia et al[28] recently suggested that patients with incidentalomas should be tested for (1) baseline plasma cortisol levels, (2) upright plasma aldosterone and plasma renin activity, (3) serum DHEA-S concentration, and (4) 24-hour urinary epinephrine and norepinephrine. For patients with clinical suspicion of hypercortisolism, Barzon and Boscaro[4] recently suggested a protocol for endocrine evaluation of adrenal masses, mainly incidentalomas, in which urinary-free cortisol and ACTH are measured and the 1-mg dexamethasone suppression test is utilized. When hyperaldosteronism is suspected, serum potassium levels and the aldosterone-to-plasma renin ratio should be obtained. Urinary catecholamines and metanephrines are performed to rule out pheochromocytomas.[4] Lenders et al[29] suggested that plasma-free metanephrines provide the best test for excluding or confirming pheochromocytoma. Definitive endocrine evaluation and appropriate management should follow positive results of any screening test. A practical algorithm for metabolic evaluation is suggested in Fig 2.

Suggested algorithm for metabolic evaluation of an adrenal mass.

Abdominal sonography can detect adrenal masses greater than 2 cm in diameter with low costs and risk, although it cannot accurately define lesion size and morphological characteristics. In select cases, abdominal sonography can be used for follow-up, especially for masses in the right adrenal gland. Endoscopic ultrasonography has recently been demonstrated to be more accurate than a transabdominal approach in detection of the left adrenal gland, although it often cannot visualize the right gland.[30] Therefore, routine use of this procedure is limited due to technical difficulty.


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