Adrenal Incidentaloma: A Systematic Approach to Diagnosis and Management

Dr Neeraj Manikath , claude.ai

Abstract

Adrenal incidentalomas are discovered in 4-7% of abdominal imaging studies, with prevalence increasing with age and widespread use of cross-sectional imaging. This comprehensive review provides a structured, evidence-based approach to evaluation and management of these lesions, emphasizing practical clinical decision-making for internists and endocrinologists. We discuss the differential diagnosis, hormonal evaluation, radiological characterization, and management strategies based on current guidelines and recent evidence.

Introduction

The term "adrenal incidentaloma" refers to an adrenal mass ≥1 cm discovered serendipitously on imaging performed for reasons unrelated to adrenal pathology. These lesions present a diagnostic challenge: determining which are functional, malignant, or require intervention among predominantly benign, non-functioning adenomas. The prevalence reaches 10% in elderly populations, making this a common clinical scenario requiring systematic evaluation.

Step 1: Initial Assessment and Risk Stratification

Clinical History: The Foundation

Pearl: Always verify the imaging was truly "incidental." Patients may minimize symptoms of cortisol excess or catecholamine hypersecretion.

Begin with targeted history:

Constitutional symptoms: Weight changes, fatigue, weakness
Cushingoid features: Easy bruising, proximal myopathy, striae, central obesity
Pheochromocytoma symptoms: Paroxysmal headaches, palpitations, diaphoresis (classic triad present in <50%)
Hyperaldosteronism clues: Hypertension, hypokalemia, muscle cramps
Virilization/feminization: Hirsutism, acne, menstrual irregularities

Oyster: Subclinical hypercortisolism may present subtly with poorly controlled diabetes, hypertension, or osteoporosis without classic Cushingoid appearance.

Physical Examination Priorities

Focus on:

Blood pressure (bilateral measurements)
Body habitus and fat distribution
Skin changes (striae, thinning, hyperpigmentation)
Proximal muscle strength
Signs of virilization or feminization

Oncological Context Assessment

Critical Pearl: In patients with known malignancy, 50-75% of adrenal masses are still benign adenomas, not metastases.

Document:

History of malignancy (particularly lung, breast, kidney, melanoma, lymphoma)
Time interval from cancer diagnosis
Other sites of metastatic disease

Step 2: Radiological Characterization

The Unenhanced CT: Your Best Friend

Hack: An unenhanced CT attenuation value <10 Hounsfield Units (HU) has 98% sensitivity and 92% specificity for benign lipid-rich adenoma. This single measurement often obviates further imaging.

Attenuation-Based Classification:

<10 HU: Lipid-rich adenoma (reassuring)
10-20 HU: Indeterminate (requires further evaluation)
>20 HU: Concerning for malignancy or pheochromocytoma

Contrast-Enhanced CT: When Needed

If unenhanced attenuation is >10 HU, perform contrast-enhanced CT with washout protocol:

Absolute percentage washout (APW): APW = [(peak HU - delayed HU) / (peak HU - unenhanced HU)] × 100

Relative percentage washout (RPW): RPW = [(peak HU - delayed HU) / peak HU] × 100

Interpretation Hack:

APW >60% at 10 minutes: benign adenoma
RPW >40% at 10 minutes: benign adenoma
Below these thresholds: consider malignancy

Size Matters: Risk Stratification

<4 cm: 2% malignancy risk
4-6 cm: 6% malignancy risk
>6 cm: 25% malignancy risk

Oyster: Size alone should never dictate management; integrate with imaging characteristics and hormonal function.

MRI: Selected Situations

Consider MRI when:

Contraindication to CT contrast
Young patients (radiation concerns)
Suspected pheochromocytoma (hyperintense on T2)
Pregnancy

Chemical shift imaging: Signal dropout on opposed-phase compared to in-phase imaging indicates lipid-rich adenoma.

Red Flags on Imaging

Irregular margins
Heterogeneous enhancement
Invasion of adjacent structures
Bilateral masses (consider metastases, lymphoma, infection, bilateral hyperplasia)
Calcifications (seen in adrenocortical carcinoma)

Step 3: Hormonal Evaluation - A Systematic Approach

Pearl: ALL incidentalomas require hormonal evaluation regardless of size or imaging characteristics. Functionality determines management more than size.

The Essential Battery: Screen Everyone

1. Autonomous Cortisol Secretion (Previously "Subclinical Cushing's")

Test: 1 mg dexamethasone suppression test (DST)

Administer 1 mg dexamethasone at 11 PM
Measure serum cortisol at 8 AM next morning

Interpretation:

<1.8 μg/dL (50 nmol/L): Normal suppression
1.8-5.0 μg/dL: Possible autonomous secretion
5.0 μg/dL: Autonomous cortisol secretion

Hack: If post-DST cortisol >1.8 μg/dL, add:

24-hour urinary free cortisol
Late-night salivary cortisol (two measurements)
Morning ACTH level (typically suppressed in autonomous secretion)

Oyster: The 2016 European Society of Endocrinology guidelines shifted from "subclinical Cushing's syndrome" to "mild autonomous cortisol secretion" recognizing the spectrum of disease without overt features.

2. Pheochromocytoma Screen

Test: Plasma free metanephrines OR 24-hour urine fractionated metanephrines and catecholamines

Critical Pearl: Screen BEFORE biopsy to prevent hypertensive crisis. One death from undiagnosed pheochromocytoma biopsy negates thousands of negative tests.

Interpretation:

Values <ULN: Excludes pheochromocytoma (99% NPV)
Values >4× ULN: Highly suggestive
Intermediate elevation: Consider medication interference

Medications causing false positives:

Tricyclic antidepressants
Selective serotonin/norepinephrine reuptake inhibitors
Levodopa
Acetaminophen (for some assays)

Hack: If intermediate elevation, repeat after stopping interfering medications for 2 weeks. Consider clonidine suppression test if uncertainty persists.

3. Primary Aldosteronism Screen

Indication: Hypertension OR hypokalemia (spontaneous or diuretic-induced)

Test: Plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio

Optimal conditions:

Morning sample, seated for 5-15 minutes
Maintain normal sodium diet
Ideally off interfering medications (if safe)

Interpretation:

PAC/PRA ratio >20-30 with PAC >15 ng/dL suggests primary aldosteronism
Confirmatory testing required (saline suppression test, captopril challenge)

Oyster: Patients with resistant hypertension and unilateral aldosterone-producing adenoma may achieve cure rates of 50-60% with adrenalectomy, dramatically improving cardiovascular outcomes.

Don't Forget: DHEA-S and 17-Hydroxyprogesterone

When to measure:

Women with virilization
Any mass with features suggestive of adrenocortical carcinoma
Elevated levels suggest malignancy (sensitivity 80-90% for ACC)

Step 4: Integration and Decision-Making

The Decision Matrix

Create a 2×2 framework:

Functional Status:

Non-functioning
Functioning (any hormonal excess)

Malignancy Risk:

Low risk (benign imaging, <4 cm)
High risk (suspicious imaging, >4 cm)

Management Pathways

Scenario 1: Non-Functioning, Low-Risk (<4 cm, <10 HU)

Management: Observation

Repeat imaging at 6-12 months, then annually for 1-2 years
Repeat hormonal evaluation annually for 4 years

Pearl: After 4 years of stability, further surveillance is low-yield. Discharge from follow-up is reasonable.

Rationale: Risk of developing functionality is 3-4% over 5 years; malignant transformation of benign adenoma is exceedingly rare.

Scenario 2: Non-Functioning, Intermediate Risk (>4 cm or indeterminate imaging)

Consider:

Surgical referral if >4 cm
PET-CT if metastatic disease suspected
Biopsy only if differentiating benign from metastatic disease would change systemic therapy AND pheochromocytoma excluded

Hack: For 4-6 cm lesions with benign imaging characteristics, offer individualized approach: surgery vs. close surveillance based on patient age, comorbidities, anxiety level.

Scenario 3: Any Functioning Lesion

Pheochromocytoma:

Surgical resection (laparoscopic adrenalectomy)
Preoperative alpha-blockade (phenoxybenzamine 10-14 days, titrate to mild orthostasis)
Add beta-blockade ONLY after adequate alpha-blockade
Genetic testing (40% hereditary in apparently sporadic cases)

Autonomous Cortisol Secretion:

Post-DST cortisol >5.0 μg/dL: Strong consideration for surgery
- Associated with increased cardiovascular events, vertebral fractures, type 2 diabetes, mortality
Post-DST cortisol 1.8-5.0 μg/dL: Individualized approach
- Assess comorbidities: diabetes control, bone density, cardiovascular risk
- Consider surgery if diabetes, hypertension worsening or osteoporosis present

Pearl: Patients undergoing adrenalectomy for autonomous cortisol secretion require perioperative and postoperative glucocorticoid coverage due to suppressed contralateral gland. Taper over 6-18 months with biochemical monitoring.

Aldosterone-Producing Adenoma:

Adrenal vein sampling to lateralize (if surgical candidate)
Unilateral disease: Consider adrenalectomy
Bilateral disease: Medical management (mineralocorticoid receptor antagonists)

Scenario 4: High Malignancy Suspicion

Immediate surgical referral if:

Imaging characteristics highly suspicious
Size >6 cm
Growth >1 cm/year on surveillance
Elevated DHEA-S, particularly with large size

Adrenocortical Carcinoma Considerations:

Refer to experienced center (outcomes operator-dependent)
En bloc resection essential (avoid tumor spillage)
R0 resection is primary determinant of survival

Step 5: Special Populations and Scenarios

Bilateral Adrenal Masses

Differential Diagnosis:

Metastases (lung, breast, melanoma, lymphoma)
Bilateral adenomas
Congenital adrenal hyperplasia
Infiltrative disease (hemorrhage, infection, lymphoma)
Bilateral pheochromocytomas (suspect genetic syndrome)

Hack: Check morning cortisol and ACTH. If both low-normal, consider adrenal insufficiency from metastatic disease, hemorrhage, or infiltration.

Pregnancy

Approach:

MRI without gadolinium for imaging
Hormonal evaluation essential (pheochromocytoma can be fatal)
Surgery in second trimester if pheochromocytoma confirmed
Defer surgery for other functional lesions until postpartum if possible

Young Patients (<40 years)

Pearl: Malignancy risk higher in younger patients with large lesions. Lower threshold for surgical intervention.

Patients with Known Malignancy

Algorithm:

If isolated adrenal lesion + imaging benign (<10 HU): Likely adenoma, hormonal evaluation, surveillance
If imaging indeterminate: Consider PET-CT
If differentiating would change systemic therapy: Biopsy (after excluding pheochromocytoma)

Oyster: FDG-PET has limited utility for primary adrenal mass characterization (adenomas can be FDG-avid) but useful in cancer patients to detect other metastatic sites.

Pearls Summary: The Top Ten

Unenhanced CT <10 HU: Nearly diagnostic of benign adenoma
Screen everyone for pheochromocytoma: One missed case can be fatal
Post-DST cortisol matters: >1.8 μg/dL warrants further investigation
Size and imaging together: Integration trumps individual features
Biopsy rarely indicated: Risk-benefit favors observation or excision
Genetics in pheochromocytoma: 40% hereditary—refer for testing
Perioperative steroids: Essential after autonomous cortisol secretion resection
Surveillance has endpoints: 4 years for most lesions
Adrenal vein sampling: Required before aldosteronoma surgery
Patient factors matter: Individualize surgery decisions considering age, comorbidities, anxiety

Conclusion

Adrenal incidentalomas require systematic evaluation combining radiological characterization and comprehensive hormonal assessment. The integration of imaging features, size, functionality, and clinical context guides management decisions. Most lesions are benign, non-functioning adenomas requiring limited surveillance. However, identifying the minority that are functional or malignant prevents significant morbidity and mortality. A structured approach ensures appropriate investigation while avoiding unnecessary interventions.

References

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