What are the diagnostic steps for an adrenal nodule?

Diagnostic Evaluation of an Adrenal Nodule

All adrenal nodules ≥1 cm require both hormonal screening and radiologic characterization, regardless of symptoms or imaging appearance. 1, 2

Step 1: Clinical Assessment

Obtain a focused history and physical examination targeting specific manifestations of hormone excess and malignancy 1:

Signs/Symptoms of Cortisol Excess (Cushing's Syndrome)

• Weight gain with central obesity, moon facies, buffalo hump 2
• Purple striae (>1 cm wide), easy bruising, proximal muscle weakness 2
• Hypertension, diabetes, osteoporosis 2

Signs/Symptoms of Aldosterone Excess

• Resistant hypertension, hypokalemia, muscle weakness and cramps 2

Signs/Symptoms of Catecholamine Excess (Pheochromocytoma)

• Episodic hypertension, headaches, palpitations, diaphoresis 2

Signs/Symptoms of Androgen/Estrogen Excess

• Virilization, hirsutism, deepening voice in females 3
• Feminization in males 3

Step 2: Initial Imaging - Non-Contrast CT

Non-contrast CT is the mandatory first-line imaging test 1, 2:

Benign Diagnosis (No Further Imaging Needed)

• Homogeneous, well-circumscribed mass with <10 Hounsfield Units (HU) = lipid-rich adenoma 1, 2
• Risk of malignancy is 0% when HU <10 1

Indeterminate Lesions Requiring Further Characterization

• HU 10-20: 0.5% malignancy risk 1
• HU >20: 6.3% malignancy risk 1
• Proceed to washout CT or chemical-shift MRI for indeterminate masses 2

Important caveat: Recent evidence shows washout CT has limited utility in true incidentalomas without known malignancy, with malignancy prevalence of only 0.3% in nodules <4 cm regardless of washout values 4. However, guidelines still recommend this for indeterminate lesions 2.

Step 3: Hormonal Evaluation (Required for ALL Nodules ≥1 cm)

Universal Screening (All Patients)

1 mg overnight dexamethasone suppression test (give 1 mg at 11 PM, measure serum cortisol at 8 AM) 5, 2:

• Cortisol ≤50 nmol/L (1.8 μg/dL): excludes hypersecretion 5, 2
• Cortisol 51-138 nmol/L (1.9-5.0 μg/dL): possible autonomous secretion 5, 2
• Cortisol >138 nmol/L (>5.0 μg/dL): confirms hypersecretion 5, 2

Conditional Screening Based on Clinical Features

For hypertension and/or hypokalemia:

• Aldosterone-to-renin ratio (ratio >20 ng/dL per ng/mL/hr indicates hyperaldosteronism) 5, 2

For masses ≥10 HU on non-contrast CT OR symptoms of catecholamine excess:

• Plasma free metanephrines OR 24-hour urinary fractionated metanephrines and normetanephrines 1, 5, 2
• Plasma methoxytyramine if available (biomarker for malignancy risk) 1

For suspected adrenocortical carcinoma or virilization:

• DHEAS, testosterone, androstenedione 5
• 17-hydroxyprogesterone if bilateral masses (to exclude congenital adrenal hyperplasia) 5, 3

Critical pitfall: Hold interfering medications before testing when possible—beta-blockers, ACE inhibitors, and ARBs affect aldosterone/renin ratio; tricyclic antidepressants affect metanephrines 5, 3

Step 4: Second-Line Imaging (For Indeterminate Masses)

Washout CT Protocol

• Adenomas show >60% absolute washout or >40% relative washout at 15 minutes 2

Chemical-Shift MRI

• Signal intensity loss on opposed-phase imaging indicates lipid-rich adenoma 2, 6

Advanced Imaging for Suspected Malignancy

For suspected pheochromocytoma/paraganglioma with high metastatic risk (tumor ≥5 cm, extra-adrenal location, SDHB mutation, or methoxytyramine >3× upper limit) 1:

• Functional imaging with [18F]FDG-PET/CT or specific radionuclide imaging 1

For suspected adrenocortical carcinoma:

• Cross-sectional imaging of chest, abdomen, and pelvis to assess for metastases 1
• Look for inhomogeneous appearance, irregular margins, local invasion, or vena cava extension 1

Step 5: Multidisciplinary Review

Engage endocrinology, surgery, and radiology when 1:

• Imaging not consistent with benign lesion
• Evidence of hormone hypersecretion
• Tumor growth >5 mm/year on follow-up 5
• Adrenal surgery being considered

Step 6: Role of Biopsy

Biopsy should NOT be performed routinely 2. Only consider when:

• Diagnosis of metastatic disease from extra-adrenal malignancy would change management 2
• Must exclude pheochromocytoma with biochemical testing BEFORE any biopsy to avoid hypertensive crisis 3

Size-Based Risk Stratification

• <3 cm: Likely benign, but 5% have subclinical hyperfunction 2
• 3-4 cm: Benign if <10 HU; otherwise requires follow-up imaging 2
• ≥4 cm: Higher malignancy risk, especially if >20 HU or inhomogeneous 1, 2
• >6 cm: High risk of malignancy, typically warrants surgical evaluation 7

Note: Masses containing macroscopic fat (myelolipomas) require no further follow-up regardless of size 5