Conquer your fear of adrenal incidentalomas! We’re joined by Dr. William Young, who teaches us pearls for evaluating imaging characteristics of adrenal incidentalomas, tips for assessing and managing functioning adenomas, approaches to follow-up and surgical considerations, and more.
Adrenal incidentalomas are adrenal masses found serendipitously on a CT or MRI obtained for a different purpose in a patient without signs or symptoms of adrenal disease (Kebebew, 2021; Young, 2007). The mass also must be of significant size (generally 1 cm or larger) to be certain that it is a definitive mass rather than simply adrenal thickening.
The two major questions when an adrenal incidentaloma is found are: 1) whether the mass is malignant, and 2) whether the mass is hormone-secreting (Kebebew, 2021). 95% of adrenal incidentalomas are non-malignant and 85% are non-functioning (Kebebew, 2021).
Discussing the finding of an adrenal incidentaloma with patients: Adrenal incidentalomas can be anxiety-provoking for patients. Dr. Young says that when talking with patients, he usually reassures patients that the vast majority of adrenal incidentalomas are benign and non-functioning. He also finds it helpful to show patients their adrenal mass on the scan, as it can help provide perspective and reassurance.
According to Dr. Young, the most important imaging test to assess an adrenal incidentaloma is a non-contrast CT. Non-contrast CT scans allow discernment of the density of the adrenal mass, which provides critical information about whether the mass is lipid-poor or lipid-rich (Kebebew, 2021; Young, 2007).
Contrast-enhanced CT scans can provide some useful information – for instance, primary adrenal malignancy, metastatic disease, and pheochromocytomas all tend to be highly vascular and light up significantly with contrast. However, Dr. Young notes that using the degree of contrast wash-out to help differentiate the etiology of an adrenal incidentaloma is actually less useful than once thought (Corwin et al 2022).
MRIs can also be used to determine the lipid content of an adrenal mass, like non-contrast CT scans. According to Dr. Young, usually either non-contrast CT scan or MRI is suggested as a follow-up imaging test if the adrenal incidentaloma was initially picked up on a contrast CT scan, in order to evaluate the mass’ lipid content.
The density of an adrenal incidentaloma, as measured in Hounsfield units (HU) on a non-contrast CT, is critical to assessing its etiology (Kebebew, 2021; Young, 2007). If the unenhanced CT attenuation is <10 HU, this signifies that the mass is lipid-rich, suggesting that the mass is most likely a benign adenoma and the likelihood of malignancy or pheochromocytoma is low. However, if the unenhanced CT attenuation is >10 HU, this indicates that the mass is lipid-poor. Iin this situation, the mass could be either primary adrenal malignancy, metastatic disease, pheochromocytoma, or a lipid-poor benign adenoma.
Other imaging characteristics to consider include the homogeneity of the mass and the smoothness of the borders – a homogeneous incidentaloma with smooth borders is less likely to be malignant.
Bilateral adrenal incidentalomas are rarer and have a much broader differential diagnosis (including underlying congenital adrenal hyperplasia, bilateral myelolipomas, bilateral pheochromocytomas, adrenal lymphomas, or metastatic disease) (Kebebew, 2021; Young, 2007). For a patient with bilateral adrenal incidentalomas, Dr. Young recommends referral to an endocrinologist.
For patients with benign-appearing, lipid-rich masses, Dr. Young’s expert opinion is to obtain one scan 1 year after the initial imaging study to make sure that the mass is not growing and that the initial radiologist’s read was correct. This recommendation differs from that of the European guidelines, which says that benign-appearing lipid-rich masses do not require follow-up imaging (Fassnacht et al 2016). For patients with lipid-poor masses, Dr. Young notes that these patients should either undergo surgery or be monitored closely with indefinite follow-up imaging.
The imaging phenotype of an adrenal incidentaloma is critical to inform surgical decision-making. In addition to indications for adrenalectomy based on whether the adenoma is biochemically functional (discussed in more detail below), concerning imaging characteristics can lead physicians to favor upfront surgery. While size >4 cm is often suggested as a cut-off beyond which surgery should be pursued, Dr. Young emphasizes that size should not be considered in isolation (Iniguez-Ariza et al 2017): for instance, he notes that a 2 cm lipid-poor mass is concerning, while a 5.5 cm lipid-rich mass (despite being over >4 cm) is not concerning.
The three possible types of functioning adrenal adenomas are: pheochromocytoma, aldosterone-secreting adenoma, and cortisol-producing adenomas causing subclinical Cushing’s syndrome. Dr. Young stresses that unless the incidentaloma is indicated by the radiologist to be an adrenal myelolipoma (which is always non-functioning), all other patients with an adrenal incidentaloma should receive some degree of hormonal work-up.
If the unenhanced CT attenuation of the incidentaloma is <10 HU (indicating a lipid-rich mass), Dr. Young’s expert opinion is that it is not necessary to screen for pheochromocytoma, as the likelihood of a false positive is high (Canu et al 2019).
If the density is >10 HU (indicating a lipid-poor mass), Dr. Young indicates that screening for pheochromocytoma should be performed (Canu et al 2019). The most sensitive biochemical test to obtain is plasma fractionated metanephrines. However, Dr. Young stresses that considering the size of the mass is important in interpreting the results, as small pheochromocytomas less than 1.5 cm in diameter may not be detectable biochemically; thus, there needs to be a high degree of suspicion for pheochromocytoma based on imaging phenotype.
Dr. Young notes that the most common way of picking up pheochromocytomas is through work-up of patients with adrenal incidentalomas (rather than the classic presentation of paroxysms of sweating, palpitations, and hypertension): 60% of pheochromocytomas operated on at Mayo Clinic were discovered as adrenal incidentalomas (Gruber et al 2019.)
Subclinical Cushing’s syndrome signifies autonomous cortisol production without overt signs of Cushing’s (e.g. moon facies, supraclavicular fat pads, abdominal striae, etc) (Kebebew, 2021; Young, 2007).
Testing for Subclinical Cushing’s: All patients with an adrenal incidentaloma should be screened for subclinical Cushing’s. Dr. Young recommends first obtaining baseline adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEAS), and cortisol levels. DHEAS secretion is promoted by ACTH, and levels of DHEAS provide information on the level of exposure of the adrenal gland to ACTH (Carafone et al 2021, Dennedy et al 2017). Unlike ACTH, DHEAS has a long half life and levels remain relatively steady, thus is a good biomarker. One pearl that Dr. Young shared is that if the DHEAS is >100 mcg/dL, this suggests that the patient does not have subclinical Cushing’s, and no further evaluation is needed, thus avoiding performance of a 1 mg overnight dexamethasone suppression test. If the DHEAS is not >100 mcg/dL, a 1 mg overnight dexamethasone suppression test should be performed, which is done by giving 1 mg dexamethasone at 11 pm and then obtaining a blood cortisol level the next morning at 8 am. A normal result is suppression of morning cortisol to <1.8 mcg/dL; a cortisol level >1.8 mcg/dL after a 1 mg overnight dexamethasone suppression test is consistent with subclinical Cushing’s.
Dr. Young’s expert opinion is that all patients with a positive 1 mg overnight dexamethasone suppression test should undergo a follow-up 8 mg overnight dexamethasone suppression test to confirm the diagnosis of subclinical Cushing’s before undergoing surgical intervention. This practice helps avoid false positives and prevent unnecessary surgery.
Management of subclinical Cushing’s: Dr. Young stresses that patients with subclinical Cushing’s are constantly being exposed to excess levels of cortisol, which may contribute to worsening hyperlipidemia, hyperglycemia, hypertension, and osteoporosis/osteopenia (Sbardella et al, 2018, Prete et al 2022, Chiodini et al 2009, Morelli et al 2011). Dr. Young also notes that these nodules tend to slowly grow over time, meaning the issue will become progressively worse.
The indications for pursuing surgery for subclinical Cushing’s are controversial, and the field is awaiting robust data. Dr. Young notes that there are several considerations that factor into his decision to intervene. If patients are younger, he may be more aggressive in recommending surgery compared to a patient that is older with lots of comorbidities. Per Dr. Young, patients with subclinical Cushing’s should all receive a DEXA scan to assess bone density, which may push the decision one way or the other. Additionally, Dr. Young notes that the ultimate decision depends on whether there is access to an expert laparoscopic surgeon.
If monitoring is pursued instead of surgery, Dr. Young recommends obtaining repeat labs in 1 year (including repeat cortisol, ACTH, DHEAS, and 8 mg overnight dexamethasone suppression test; Dr Young also suggests the addition of a 24 hour urine cortisol.)
All patients with adrenal incidentalomas who are hypertensive or hypokalemic should be screened for primary hyperaldosteronism with morning aldosterone and renin levels (Fassnacht et al 2016; Kebebew, 2021; Funder et al 2016).
Logistics of testing:
Interpreting aldosterone / renin results: The classic aldosterone / renin findings in a patient with primary aldosteronism are aldosterone > 10 ng/dL and plasma renin <1 ng/mL/hr (or plasma renin concentration less than the lower limit of the reference range.) However, Dr. Young notes that the sensitivity and specificity of this test is not very good (Funder et al 2016). If a patient has a suppressed renin but an aldosterone that does not quite reach the >10 ng/dL threshold (for instance, an aldosterone of 7 ng/dL), he would still be concerned, and would recommend confirmatory testing with a 24 hour urine aldosterone, sodium, and creatinine on a generous high-salt diet. In a patient with low renin, a urine aldosterone >12 mcg in the setting of a urine sodium >200 mEq (i.e. a high urine aldosterone in the setting of volume expansion) is diagnostic of primary hyperaldosteronism.
Treating primary hyperaldosteronism:
Unilateral aldosterone-producing adenomas (~40% of cases) are amenable to surgery (unilateral adrenalectomy), while bilateral adrenal hyperplasia (in which both adrenal glands are producing excess aldosterone, ~60% of cases) should be treated medically with a mineralocorticoid-receptor antagonist (MRA) rather than bilateral adrenalectomy (Funder et al 2016). According to Dr. Young, there is ongoing research on identifying good predictors of whether a patient is more likely to have unilateral or bilateral adrenal disease in order to prioritize / direct which patients should undergo thorough subtype evaluation with adrenal venous sampling.
Mineralocorticoid receptor antagonists (MRAs) include spironolactone (longer-acting, dosed one time per day) and eplerenone (dosed BID.) According to Dr. Young, as patients with primary hyperaldosteronism are treated with MRAs, one indication that the treatment is working is that the renin level will start to rise (since blocking aldosterone prevents sodium reabsorption / volume expansion, thus causing an increase in renin levels.)
Dr. Young emphasizes that when managing patients with primary hyperaldosteronism, physicians should have a low threshold for referral to endocrinology or nephrology.
Listeners will develop a framework for the work-up and management of a patient with an adrenal incidentaloma.
After listening to this episode listeners will…
Dr. Young reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Gandhi MM, Young WF, Williams PN, Watto MF. “#377 Adrenal Incidentalomas with Dr. William Young”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list January 16, 2023.
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