How should an incidentally discovered adrenal nodule be evaluated for hormonal activity and malignancy, and what are the recommended management steps?

Evaluation and Management of Incidentally Discovered Adrenal Nodules

All incidentally discovered adrenal nodules ≥1 cm require both comprehensive hormonal screening and radiologic characterization to assess for functional status and malignancy risk, regardless of how benign they appear on initial imaging. 1, 2

Initial Radiologic Assessment

Obtain non-contrast CT as the essential first imaging step to measure Hounsfield Units (HU), which determines whether further workup is needed. 1, 2

Interpretation of Non-Contrast CT:

• If <10 HU and homogeneous/well-circumscribed: This is definitively a benign lipid-rich adenoma—no further imaging characterization needed. 1, 2
• If 10-20 HU: 0.5% risk of adrenocortical carcinoma—proceed to second-line imaging (washout CT or chemical shift MRI). 1
• If >20 HU: 6.3% risk of adrenocortical carcinoma—proceed to second-line imaging and strongly consider surgical consultation. 1, 2

Mandatory Hormonal Screening

Every patient with an adrenal incidentaloma requires screening for autonomous cortisol secretion, regardless of imaging characteristics. 3 Approximately 5% of radiologically benign incidentalomas have subclinical hormone production requiring treatment. 4

Required Tests for All Patients:

• 1 mg overnight dexamethasone suppression test (give 1 mg at 11 PM, measure serum cortisol at 8 AM): This is the preferred initial screening test for autonomous cortisol secretion. 3
  • Cortisol ≤50 nmol/L: Excludes hypersecretion
  • Cortisol 51-138 nmol/L: Possible autonomous secretion
  • Cortisol >138 nmol/L: Evidence of hypersecretion 3

Conditional Hormonal Testing:

• Screen for pheochromocytoma with plasma free metanephrines or 24-hour urinary metanephrines if:

  • Mass measures ≥10 HU on non-contrast CT, OR
  • Patient has headaches, palpitations, sweating, or anxiety attacks 2, 3

• Check aldosterone-to-renin ratio only if:

  • Patient has hypertension and/or hypokalemia
  • Ratio >20 ng/dL per ng/mL/hr indicates hyperaldosteronism 2, 3

• Measure serum androgens (DHEA-S, testosterone, androstenedione) only if:

  • Clinical signs of virilization present, OR
  • Adrenocortical carcinoma suspected based on imaging 2, 3

Size-Based Management Algorithm

Masses <3 cm:

• Most are benign; extensive workup not justified in patients without cancer history. 1, 2
• If <10 HU, homogeneous, and non-functional: No further imaging follow-up required. 3, 4

Masses 3-4 cm:

• If <10 HU and non-functional: Repeat imaging at 6-12 months. 3, 4
• If ≥10 HU or indeterminate: Consider repeat imaging at 3-6 months versus surgical consultation. 4

Masses 4-5 cm:

• If <10 HU and non-functional: Repeat imaging at 6-12 months. 3, 4
• If ≥10 HU, inhomogeneous, or functional: Surgical consultation recommended. 1

Masses >5 cm:

• Should be removed due to higher malignancy risk, particularly when HU >20 (6.3% risk of adrenocortical carcinoma). 1, 2

Indications for Surgery

Adrenalectomy is indicated for: 1, 3

• All pheochromocytomas (regardless of size)
• Aldosterone-secreting adenomas causing primary aldosteronism
• Cortisol-secreting masses with clinically apparent Cushing's syndrome
• Masses >4 cm with inhomogeneous appearance or >20 HU
• Any mass growing >5 mm/year (after repeating functional workup)
• Suspected adrenocortical carcinoma based on imaging characteristics

Use minimally invasive surgery when feasible, except for large adrenocortical carcinomas or locally advanced tumors requiring open approach. 4

Follow-Up Protocol for Non-Operated Masses

For masses with benign characteristics (<10 HU, <4 cm, non-functional):

• No further imaging or hormonal testing required. 3, 4

For masses ≥4 cm that are radiologically benign:

• Repeat unenhanced CT at 6-12 months. 3, 4
• If growth >5 mm/year: Repeat functional workup and consider adrenalectomy. 3, 4

For indeterminate masses:

• Repeat imaging at 3-6 months. 4
• If growth 3-5 mm/year: Continue surveillance. 3
• If growth >5 mm/year: Repeat functional workup and surgical consultation. 3, 4

Multidisciplinary Review Triggers

Maintain a low threshold for involving endocrinology, surgery, and radiology when: 1, 2

• Imaging not consistent with benign lesion
• Evidence of hormone hypersecretion found
• Tumor grows significantly during follow-up (>5 mm/year)
• Adrenal surgery being considered

Special Populations Requiring Expedited Evaluation

• Young adults (<40 years), children, and pregnant patients: Adrenal lesions more likely malignant in these populations; use low-dose CT or chemical shift MRI to minimize radiation. 4
• Patients with known extra-adrenal malignancy: 25-72% of adrenal masses are metastatic depending on primary tumor type (especially bronchogenic carcinoma, renal carcinoma, melanoma). 1, 4

Bilateral Adrenal Incidentalomas

• Characterize each lesion separately using the same protocol as unilateral masses. 3, 4
• Measure serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia. 3, 4
• Assess for adrenal insufficiency if bilateral infiltrative disease, metastases, or hemorrhage suspected. 4

Critical Pitfalls to Avoid

Do NOT perform adrenal biopsy routinely—it is rarely indicated and carries risks including tumor seeding in adrenocortical carcinoma and potential hypertensive crisis if undiagnosed pheochromocytoma is present. 2, 4 Biopsy should only be considered when diagnosis of metastatic disease from extra-adrenal malignancy would change management. 3

Do NOT skip hormonal evaluation even for radiologically benign-appearing lesions, as approximately 5% harbor subclinical hormone production requiring treatment. 4

Do NOT perform unnecessary repeated imaging for confirmed benign masses (<10 HU, <4 cm, non-functional), as this increases radiation exposure, patient anxiety, and healthcare costs without clinical benefit. 2, 3