Assessment of metabolic function
The incidentally-discovered adrenal mass larger than 1 cm requires metabolic evaluation, regardless of its size and imaging characteristics. In fact, more than 10% of these lesions can prove to be metabolically active following an appropriate endocrinologic work-up and thus generally require resection (Table 1).24,29 Testing must rule out hypercortisolemia (Cushing syndrome), hyperaldosteronism (Conn syndrome), and excess catecholamine production (pheochromocytoma).
While Cushing syndrome screening is recommended in all patients given that more than 5% of adrenal masses will hypersecrete cortisol, aldosterone-producing adenomas are exceedingly rare (approximately 1% of cases), and hyperaldosteronism testing is only necessary in patients with hypertension. When diagnosis of adenoma is certain on imaging, pheochromocytoma testing is generally still performed due to reports of isolated pheochromocytomas demonstrating lipid-rich imaging characteristics.16, 30
In all-comers with adrenal incidentaloma, pheochromocytoma is identified in more than 5% of patients; however, these lesions overwhelmingly exhibit lipid-poor imaging characteristics (i.e., greater than 10 HU on non-contrast CT, lack of signal drop-out on MRI, and absence of washout on adrenal protocol CT).
While some practitioners choose to send all patients with adrenal incidentaloma for endocrinologic consultation, initial metabolic screening is not difficult.
Low-dose dexamethasone suppression testing is often the test of choice for initial screening of hypercortisolemia, and this is accomplished by administering 1 mg of dexamethasone at 11 pm on the day prior to testing. A suppressed morning cortisol below 5 mcg/dL largely rules out Cushing syndrome.31 Late-night salivary cortisol testing is an alternative option to the low dose dexamethasone test32, while 24-hour urinary cortisol is felt to not be sensitive enough by some experts.31 Plasma-free metanephrines or 24-hour urinary-fractionated metanephrines are the best initial screening studies to rule out pheochromocytoma.1
Although plasma-free metanephrines may not be as specific as 24-hour urinary testing, the test affords convenience since the same morning blood test can be used to screen for all adrenal hypermetabolic activity.33,34 Generally, plasma-free metanephrines greater than four times the normal value are definitive, whereas lower values represent equivocal results.1
As discussed above, Conn syndrome is exceedingly rare and only patients who exhibit or have a history of hypertension need to be tested. The morning plasma aldosterone level and an aldosterone to renin ratio (ARR) are the tests of choice. Morning aldosterone values greater than 15 ng/mL with a concomitant ARR greater than 30 are strongly suggestive of hyperaldosteronemia.6,24,35-37 Adrenal sex steroids testing is only necessary when adrenocortical carcinoma is strongly suspected, since hypersecretion of adrenal androgens and its derivative can then be harnessed as tumor markers following resection.6,38,39
Initial metabolic screening of adrenal incidentalomas is straightforward, but clinicians must be aware of pitfalls that may produce inaccurate results. A number of medications can interfere with adrenal metabolic interrogation1. The clinician must be attuned to the fact that low-dose dexamethasone suppression testing is affected by oral contraceptives and may yield false-positive results in up to 50% of female patients who use this form of birth control40.
In these patients, late-night salivary cortisol testing or 24-hour urinary cortisol testing should be performed, understanding the limitations of the latter test. Importantly 24-hour urinary testing largely should be limited to patients with normal renal function. To avoid erroneous metanephrine testing, the patient should stop alpha-blockers and tricyclic antidepressants.
Furthermore, caffeine (for 24 hours) and acetaminophen (for at least five days) should be avoided, as these agents can cause false- positive results.41
With regard to testing for Conn syndrome, patients with hypokalemia should undergo potassium repletion, as low potassium levels can cause false-positive results.42 Patients on potassium- sparing diuretics and/or mineralocorticoid receptor blockers must stop the medications for at least six weeks for hyperaldosteronism testing to be meaningful.
Nevertheless, although a small propor- tion of patients on beta-blockers can exhibit false-positive results and some patients on ACE inhibitors may exhibit false-negative findings, most experts do not routinely recommend cessation of these antihypertensive agents during initial metabolic screening. Interestingly, calcium channel blockers generally do not affect the aldosterone-to-renin ratio.42
In summary, testing for hypercortisolemia, hyperaldosteronism, and pheochromocytoma can all be accomplished with the same blood draw. Figure 2 depicts an example of a preprinted prescription that can be used in clinical practice to streamline adrenal incidentaloma testing. The described testing represents preliminary screening for each condition and a referral to an endocrinologist is advised if this testing is positive, since confirmatory studies can be quite nuanced. Notably, all patients with hyperaldosteronism require adrenal venous sampling prior to adrenalectomy.1
Adrenal mass management following initial work-up
As discussed above, re-imaging of adrenal masses is recommended at 6, 12, and 24 months following diagnosis.24 The general recommendation is to repeat metabolic work-up every year for three to four years24; however, only 2% of metabolically silent adrenal lesions will exhibit abnormal endocrinologic activity upon further testing.7
Adrenalectomy is only required in select cases, and should be performed by experienced urologic or general surgical specialists. Resection of even small adrenal masses can be challenging due to the adrenal’s perilous anatomic location. In fact, recent data suggest centra lization of adrenalectomy to high-volume hospitals has occurred over the recent years with perioperative outcomes being superior at these centers.43
Adrenal masses are often incidental, but not always insignificant. Comprehensive evaluation pivots on appropriate radiologic and metabolic interrogation. Given the frequency with which adrenal lesions are encountered in clinical practice and the intimate anatomic/physiologic relationship of the adrenal gland to the kidney, both urologists and nephrologists should be familiar with evaluation of adrenal neoplasia.
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