Residency · Residency · Endocrinology

Adrenal Incidentaloma

Definition and Epidemiology

Definition

An adrenal incidentaloma is defined as an adrenal mass of 1 cm or greater discovered incidentally on imaging performed for non-adrenal indications. This definition explicitly excludes patients with known malignancy undergoing staging or those with known endocrine syndromes being evaluated, as the clinical management and diagnostic probability in these populations differs fundamentally from that of a truly incidental finding.

Prevalence

The prevalence of adrenal incidentalomas reflects the increasing use of cross-sectional imaging in clinical practice. CT scans demonstrate adrenal incidentalomas in 4-5% of abdominal studies, with prevalence increasing with age to as high as 10% in elderly populations. Autopsy series report prevalence rates of 2-9%, depending on the series and patient age. Bilateral adrenal incidentalomas are present in 10-15% of cases, a finding that broadens the differential diagnosis and necessitates additional considerations. The vast majority of adrenal incidentalomas are benign, non-functioning cortical adenomas, accounting for 75-80% of all cases.

Differential Diagnosis by Frequency

The differential diagnosis of adrenal incidentalomas encompasses a spectrum from benign, inconsequential lesions to life-threatening conditions. Adrenal cortical adenoma accounts for 75-80% of cases, most of which are non-functioning, though a subset may produce cortisol, aldosterone, or androgens. Pheochromocytoma, present in 5-7% of incidentalomas, must always be excluded because of the potentially catastrophic consequences of unrecognized disease during interventions. Adrenocortical carcinoma (ACC) constitutes approximately 5% of cases, with risk increasing substantially with larger tumor size, particularly those exceeding 4 cm. Metastatic disease from lung, breast, melanoma, renal cell carcinoma, or lymphoma accounts for 2-5%, with bilateral involvement being common. Myelolipoma, a benign tumor containing fat and hematopoietic tissue, represents 5-7% and is identified by its pathognomonic macroscopic fat content on CT. Less common entities include adrenal cysts, ganglioneuromas, adrenal hemorrhage, granulomatous disease (tuberculosis, histoplasmosis, sarcoidosis), and congenital adrenal hyperplasia presenting as bilateral adrenal hyperplasia.

Imaging Characterization

CT Characteristics

The imaging appearance on CT provides critical information for risk stratification. Unenhanced CT attenuation, measured in Hounsfield Units (HU), is the single most useful imaging parameter. A value of 10 HU or less identifies a lipid-rich adenoma with greater than 98% specificity; these lesions can be confidently classified as benign without further imaging follow-up. Values exceeding 10 HU indicate a lipid-poor lesion that is indeterminate and requires further characterization with contrast washout CT or MRI.

Contrast washout CT adds specificity for lipid-poor lesions. An absolute washout exceeding 60% at 15 minutes indicates an adenoma with sensitivity of 86-88% and specificity of 92-96%. A relative washout exceeding 40% at 15 minutes similarly suggests an adenoma. Low washout values are suspicious for malignancy, pheochromocytoma, or metastasis.

Size is the most important imaging predictor of malignancy. Lesions smaller than 4 cm carry approximately 2% malignancy risk, those between 4 and 6 cm approximately 6%, and those exceeding 6 cm approximately 25%. Other concerning CT features include irregular margins, heterogeneous enhancement, calcification, necrosis, local invasion, and vena cava thrombus.

MRI Characteristics

Chemical shift MRI, using in-phase and out-of-phase sequences, exploits the intracellular lipid content of adenomas. Lipid-rich adenomas demonstrate signal drop on out-of-phase images, quantified by the adrenal-to-spleen signal intensity ratio or signal intensity index (a drop exceeding 16.5% confirms an adenoma). MRI avoids radiation exposure and is particularly useful for characterizing lesions that remain indeterminate on CT. Pheochromocytomas classically appear bright on T2-weighted sequences, though this appearance is variable, and may show restricted diffusion.

FDG-PET/CT

FDG-PET/CT is useful primarily when metastatic disease is suspected in a patient with known extra-adrenal malignancy. An adrenal-to-liver SUV ratio exceeding 1.5-2.0 suggests malignancy or pheochromocytoma, while benign adenomas typically demonstrate FDG uptake at or below the level of the liver. This modality is not routinely recommended for all incidentalomas.

<image>A visual guide to CT characterization of adrenal incidentalomas. Show four CT image panels with annotations: (1) Lipid-rich adenoma: well-defined, homogeneous, ≤10 HU on unenhanced CT, with a green "BENIGN" label. (2) Lipid-poor adenoma: >10 HU unenhanced but >60% absolute washout on delayed contrast CT, shown with contrast-enhanced and delayed images side by side, labeled "LIKELY BENIGN." (3) Myelolipoma: macroscopic fat content (very negative HU, -30 to -100), labeled "BENIGN - pathognomonic fat." (4) Suspicious for ACC or metastasis: large (>4 cm), heterogeneous, irregular margins, low washout, with a red "CONCERNING" label. Include a HU scale bar and size measurements. Below, show a decision matrix: ≤10 HU → benign adenoma (no further imaging); >10 HU → washout CT or chemical shift MRI; large/heterogeneous → surgical evaluation.</image>

Hormonal Evaluation

Mandatory Biochemical Workup for All Adrenal Incidentalomas

Every adrenal incidentaloma, regardless of size or imaging characteristics, requires a systematic biochemical evaluation to exclude hormonal excess and, critically, pheochromocytoma.

1. Pheochromocytoma Screening

Plasma free metanephrines (measuring both metanephrine and normetanephrine) are the most sensitive test for detecting pheochromocytoma. Twenty-four-hour urine fractionated metanephrines and catecholamines serve as an alternative. Exclusion of PPGL before any intervention -- whether biopsy or surgery -- is absolutely essential because manipulation of an unrecognized pheochromocytoma can trigger a lethal catecholamine crisis.

2. Cortisol Excess (Autonomous Cortisol Secretion)

The 1 mg overnight dexamethasone suppression test (DST) is the recommended screening test for cortisol excess. A post-DST cortisol below 1.8 mcg/dL (50 nmol/L) indicates normal suppression and excludes autonomous cortisol secretion. Values between 1.8 and 5.0 mcg/dL define "possible autonomous cortisol secretion" (PACS), formerly termed "subclinical Cushing syndrome." Values exceeding 5.0 mcg/dL define "autonomous cortisol secretion" (ACS), corresponding to overt or near-overt Cushing syndrome. When the DST is abnormal, additional testing should include ACTH (suppressed in adrenal cortisol excess), DHEA-S (suppressed by autonomous cortisol), midnight salivary cortisol, and 24-hour urinary free cortisol. The prevalence of autonomous cortisol secretion ranges from 5-30% depending on the cutoff used, with true clinical Cushing syndrome occurring in approximately 5%.

3. Aldosterone Excess (If Hypertensive or Hypokalemic)

The aldosterone-to-renin ratio (ARR) should be measured in hypertensive patients. An ARR of 30 or greater with a PAC of at least 15 ng/dL is suggestive of primary aldosteronism. This test is not necessary in normotensive, normokalemic patients, although some guidelines recommend universal screening.

4. Sex Steroids and Adrenal Androgens (If Virilization or ACC Suspected)

Measurement of DHEA-S, androstenedione, testosterone (in women), estradiol (in men), and 17-hydroxyprogesterone should be performed when clinical virilization is present or ACC is suspected. Elevated androgens in combination with cortisol excess are highly characteristic of ACC. In cases of bilateral adrenal hyperplasia, 17-hydroxyprogesterone should be checked to exclude congenital adrenal hyperplasia.

Autonomous Cortisol Secretion (ACS) -- Clinical Impact

Terminology Change (ESE/ENSAT 2016)

The 2016 European Society of Endocrinology/ENSAT guidelines replaced the term "subclinical Cushing syndrome" with "autonomous cortisol secretion," divided into possible ACS (PACS) and definite ACS. This terminology change reflects the understanding that cortisol excess exists on a continuum and that patients may develop significant metabolic consequences without manifesting overt Cushingoid features.

Associated Comorbidities of ACS

ACS is associated with type 2 diabetes and metabolic syndrome (odds ratio 1.5-2.5), hypertension (odds ratio 1.5-2.0), osteoporosis and vertebral fractures (odds ratio 2-4, with cortisol excess impairing bone quality disproportionate to BMD), dyslipidemia, increased cardiovascular events in observational studies, and depression with cognitive impairment.

Management of ACS

The management of ACS remains controversial due to the absence of randomized controlled trials comparing surgery with observation for PACS. Adrenalectomy should be considered in young patients with ACS accompanied by metabolic comorbidities (diabetes, hypertension, osteoporosis with fractures) that are potentially attributable to cortisol excess. Medical management of the associated comorbidities is appropriate when surgery is not pursued. When adrenalectomy is performed for ACS, post-operative adrenal insufficiency should be anticipated because the contralateral adrenal is suppressed. Perioperative stress-dose glucocorticoids and a postoperative glucocorticoid taper are required, with recovery potentially taking months.

Management Algorithm

Surgical Indications

Surgery is indicated for functioning tumors producing any degree of hormonal excess requiring treatment (PPGL, overt Cushing syndrome, primary aldosteronism with a unilateral source, ACC). Surgery is also indicated when malignancy is suspected based on imaging characteristics: size exceeding 4 cm (especially greater than 6 cm), irregular margins, heterogeneous appearance, high unenhanced HU with low washout, local invasion, or growth on serial imaging. An important exception is adrenal metastasis from a known extra-adrenal primary malignancy, where biopsy may be preferred over surgery. Interval growth, defined as significant growth exceeding 1 cm or a greater than 20% increase in maximum diameter on serial imaging, also warrants surgical consideration. ACS with attributable comorbidities requires individualized decision-making.

Observation (Non-Surgical)

Benign-appearing, non-functioning adenomas smaller than 4 cm can be observed. The 2016 ESE/ENSAT guidelines provide streamlined follow-up recommendations that are less aggressive than prior guidelines. If the unenhanced CT attenuation is 10 HU or less (clear adenoma), no further imaging follow-up is needed. If imaging is indeterminate (>10 HU but ≤4 cm without concerning features), repeat imaging at 6-12 months is recommended; if stable, no further imaging is needed. For hormonal follow-up, the 1 mg DST should be repeated annually for 2-4 years if the initial DST was normal, or for longer if clinical features change. Earlier guidelines from the 2002 NIH consensus recommended serial imaging for up to 5 years and annual biochemical testing, but current guidelines have adopted a more conservative approach to reduce unnecessary testing.

Adrenal Biopsy

Adrenal biopsy has limited indications. Its validated role is restricted to patients with a known extra-adrenal malignancy who develop a new adrenal mass where the biopsy result would change management, specifically distinguishing metastasis from an incidental adenoma. Pheochromocytoma must be excluded biochemically before biopsy, as the procedure can trigger a catastrophic catecholamine crisis. Biopsy cannot reliably distinguish adrenal cortical adenoma from ACC (histology is unreliable for this distinction). The procedure is CT-guided, with risks including pneumothorax, hemorrhage, and needle-track seeding (a particular concern with ACC).

Bilateral Adrenal Incidentalomas

Bilateral adrenal incidentalomas, present in 10-15% of cases, require a broadened differential diagnosis including bilateral adenomas, bilateral pheochromocytoma (consider MEN2, VHL), bilateral metastases, congenital adrenal hyperplasia, and bilateral macronodular hyperplasia (BMAH/AIMAH). The same biochemical workup applies, with the addition of 17-hydroxyprogesterone to exclude CAH. Genetic syndromes should be considered when bilateral pheochromocytoma is identified.

Adrenocortical Carcinoma (ACC) Considerations

Features Suggesting ACC

Several features raise concern for ACC: size exceeding 4 cm (particularly greater than 6 cm), rapid growth, heterogeneous appearance with high unenhanced HU and low washout, and hormonal activity characterized by mixed cortisol and androgen secretion (60% of ACC are hormonally active). Histologically, the Weiss score, which incorporates 9 criteria including mitotic rate, atypical mitoses, necrosis, venous and capsular invasion, and nuclear grade, predicts malignancy when 3 or more criteria are present. A Ki-67 index above 5% indicates aggressive behavior, and values exceeding 20% portend a very poor prognosis.

ACC Management (Overview)

Surgical resection consists of en bloc resection via an open approach, with care taken to avoid tumor rupture or morcellation. Mitotane, an adrenolytic agent, is used as adjuvant therapy for resected ACC, with the ADIUVO trial suggesting benefit for high-risk ACC with Ki-67 above 10%. Mitotane has a narrow therapeutic window of 14-20 mcg/mL. Chemotherapy for advanced or metastatic ACC uses the EDP-M regimen (etoposide, doxorubicin, cisplatin plus mitotane), which proved superior to streptozocin plus mitotane in the FIRM-ACT trial. Prognosis varies substantially by stage: 5-year survival is 60-80% for Stage I-II, 30-50% for Stage III, and less than 15% for Stage IV.

<image>A comprehensive adrenal incidentaloma management algorithm. Start with "Adrenal mass ≥1 cm discovered incidentally." Step 1: Biochemical evaluation (mandatory for ALL): plasma free metanephrines (rule out PPGL), 1 mg DST (rule out cortisol excess), ARR if hypertensive. Step 2: Imaging characterization: if ≤10 HU → benign adenoma → no further imaging needed; if >10 HU → contrast washout or chemical shift MRI → benign washout pattern → observe; malignant features → surgery. Step 3: Size assessment: <4 cm with benign features → observe with repeat DST annually x 2-4 years; 4-6 cm → consider surgery based on imaging and hormonal status; >6 cm → strong surgical consideration. Decision boxes for: functioning tumor → surgery; ACS with comorbidities → individualized (surgery vs medical management); known primary malignancy → biopsy (after PPGL excluded). Use flowchart with color-coded pathways.</image>

Key Clinical Pearls

• Always exclude pheochromocytoma biochemically BEFORE any intervention on an adrenal incidentaloma (including biopsy and surgery); undiagnosed PPGL manipulation can trigger fatal catecholamine crisis
• Unenhanced CT attenuation ≤10 HU identifies a lipid-rich adrenal adenoma with >98% specificity; these lesions do NOT require further imaging follow-up per current ESE/ENSAT guidelines
• The 1 mg overnight DST is the recommended screening test for autonomous cortisol secretion; post-DST cortisol 1.8-5.0 mcg/dL defines "possible autonomous cortisol secretion" (PACS), which requires clinical correlation with metabolic comorbidities to guide management
• Adrenal biopsy cannot distinguish benign adrenal cortical adenoma from ACC; its only validated role is in patients with known extra-adrenal malignancy where metastasis vs adenoma would change management
• Size remains the most important imaging predictor of malignancy; adrenal masses >4 cm warrant surgical consideration, and >6 cm should be strongly considered for resection regardless of hormonal status
• Bilateral adrenal incidentalomas should prompt consideration of congenital adrenal hyperplasia (17-OHP), bilateral PHEO (genetic syndromes), metastatic disease, and BMAH/AIMAH in addition to standard workup

References

1. Fassnacht M, et al. "Management of Adrenal Incidentalomas: European Society of Endocrinology Clinical Practice Guideline in Collaboration with ENSAT." Eur J Endocrinol. 2016;175(2):G1-G34.
2. Bancos I, et al. "Diagnosis and Management of Adrenal Insufficiency in Patients with Adrenal Incidentalomas." Lancet Diabetes Endocrinol. 2021;9(11):785-793.
3. NIH State-of-the-Science Conference Statement. "Management of the Clinically Inapparent Adrenal Mass (Incidentaloma)." Ann Intern Med. 2003;138(5):424-429.
4. Fassnacht M, et al. "Adrenocortical Carcinoma: A Clinician's Update." Nat Rev Endocrinol. 2011;7(6):323-335.
5. Arlt W, et al. "Surgery vs Observation for Adrenal Incidentaloma with Autonomous Cortisol Secretion." Ann Intern Med. 2022 (emerging data).

Read this lecture as Markdown