#377 Adrenal Incidentalomas with Dr. William Young

January 16, 2023 | By Matthew Watto, MD

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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.

Show Segments

• Intro, disclaimer, guest bio
• Case #1 from Kashlak; Definitions
• Discussing adrenal incidentalomas with patients
• Imaging characteristics of adrenal incidentalomas
• Evaluation of hormonal hypersecretion – overview
• Subclinical Cushing’s syndrome
• Pheochromocytoma
• Surgical considerations based on nodule size and imaging phenotype
• Follow-up imaging
• Case#2 from Kashlak 
• Primary hyperaldosteronism – work-up and management
• Bilateral adrenal nodules
• Guest Picks of the Week
• Outro

Adrenal Incidentaloma Pearls

1. The two major questions when evaluating an adrenal incidentaloma are whether the mass is malignant and whether it is functioning (producing hormones.)
2. A non-contrast CT scan allows assessment of the density of the adrenal mass, which provides information about whether the mass is lipid-rich (<10 Hounsfield units) or lipid-poor (>10 Hounsfield units.) Lipid-rich masses are most likely benign adenomas and are highly unlikely to be cancer or pheochromocytomas, while lipid-poor masses may be a primary adrenal malignancy, metastatic cancer, pheochromocytoma, or a lipid-poor benign adenoma.
3. Dr. Young’s expert opinion is that all patients with a lipid-rich mass should receive one follow-up scan at 1 year. Patients with clearly lipid-poor masses (e.g. unenhanced CT attenuation >20 Hounsfield units) should undergo surgical intervention or close monitoring with indefinite follow-up.
4. All patients with adrenal incidentalomas should be screened for subclinical Cushing’s syndrome with ACTH, DHEAS, and cortisol levels. If DHEAS is >100 mcg/dL, this suggests that the patient does not have subclinical Cushing’s and the evaluation can stop, while if DHEAS is <100 mcg/dL, the evaluation should proceed with a 1 mg overnight dexamethasone suppression test. Dr. Young also recommends that all patients with a positive 1 mg overnight dexamethasone suppression test undergo a confirmatory 8 mg overnight dexamethasone suppression test prior to surgical intervention, to avoid false positives.
5. Patients with adrenal incidentalomas with an unenhanced CT attenuation  >10 Hounsfield units should undergo screening for pheochromocytoma with plasma fractionated metanephrines.
6. Patients with adrenal incidentalomas who are hypertensive or hypokalemic should undergo screening for primary hyperaldosteronism with morning aldosterone and renin levels.

Adrenal Incidentaloma – Notes

Definitions / Basics

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.

Imaging 

Forms of Imaging

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.

Imaging Characteristics

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.

Follow-up imaging

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.

Surgical decision-making based on imaging phenotype

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.

Functioning Adrenal Adenomas – Evaluation & Management

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.

Pheochromocytoma

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

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.)

Aldosterone-secreting adenomas

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:

• Dr. Young said the only hard rule for testing is that the blood levels should be drawn in the morning, as aldosterone levels tend to fall throughout the day in patients with aldosterone-producing adenomas.
• Dr. Young generally does not recommend holding blood pressure medications prior to testing, as he feels that this recommendation has been a major barrier to appropriate testing of patients for primary hyperaldosteronism. He notes that the rate of testing for primary hyperaldosteronism is very low (for instance, in a Stanford study of 4,660 patients with resistant hypertension, only ~2% were tested for primary hyperaldosteronism (Jaffe et al 2020), even though guidelines indicate that all patients with resistant hypertension should be tested), and he believes the conversation about holding blood pressure medications prior to testing contributes to this concerning statistic. According to Dr. Young, there is no possibility of causing a false positive test if a cutoff for aldosterone is used (e.g. >10 ng/dL). With regards to false negatives, Dr. Young notes that if a patient truly has primary hyperaldosteronism, it is difficult to make renin rise despite blood pressure medication usage. 

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.

Links

1. Ted Lasso (TV show)
2. Norwegian Wood by Lars Mattson (book)

Goal

Listeners will develop a framework for the work-up and management of a patient with an adrenal incidentaloma.

Learning objectives

After listening to this episode listeners will…  

1. Use imaging characteristics to discern potential etiologies of an adrenal incidentaloma
2. Identify a framework for screening for hormonal hypersecretion in patients with adrenal incidentalomas
3. Describe management considerations for adrenal incidentalomas

Disclosures

Dr. Young reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

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.