What are the 2024 European guidelines for working up adrenal nodules?

2024 European Guidelines for Adrenal Nodule Work-Up

Initial Imaging Assessment

All adrenal incidentalomas require dedicated adrenal imaging with non-contrast CT as the first-line modality to characterize the lesion and assess malignancy risk. 1

• Homogeneous lesions with ≤10 Hounsfield Units (HU) on unenhanced CT are definitively benign and require no additional imaging regardless of size. 1
• Lesions with HU 11-20 carry intermediate risk (0.5% malignancy rate), while those >20 HU have 6.3% malignancy risk. 2
• For indeterminate masses (>10 HU on non-contrast CT), proceed to second-line imaging with either washout CT or chemical-shift MRI. 2, 1
• Lesions >4 cm that are inhomogeneous or have HU >20 carry sufficiently high malignancy risk that surgery is usually the management of choice. 1

Important caveat: Recent data shows that 48% of pathologically benign lesions can be accurately identified using ≤20 HU threshold, but size >4 cm alone has poor specificity (57%) for malignancy, as 63% of metastatic lesions and 14% of adrenocortical carcinomas present at <4 cm. 3

Mandatory Hormonal Evaluation

Every patient with an adrenal incidentaloma ≥1 cm requires comprehensive biochemical screening for hormone excess, regardless of imaging characteristics or symptoms. 1

Cortisol Screening (Universal)

• Perform 1 mg overnight dexamethasone suppression test (1 mg at 11 PM, measure serum cortisol at 8 AM) in all patients. 1
• Interpretation thresholds:
  • ≤50 nmol/L (≤1.8 µg/dL): Excludes autonomous cortisol secretion 1
  • 51-138 nmol/L (1.9-5.0 µg/dL): Possible autonomous cortisol secretion 1

  • 138 nmol/L (>5.0 µg/dL): Confirms "mild autonomous cortisol secretion" (MACS) 1

Pheochromocytoma Screening (Selective)

• Do NOT screen patients with unequivocal adrenocortical adenomas (HU <10) who lack signs/symptoms of adrenergic excess. 2
• DO screen if the mass has >10 HU on non-contrast CT OR if symptoms present (episodic hypertension, headaches, palpitations, diaphoresis, anxiety, tremor, pallor). 2, 1
• Use plasma free metanephrines or 24-hour urinary fractionated metanephrines. 1

Aldosterone Screening (Selective)

• Screen only patients with hypertension and/or hypokalemia using aldosterone-to-renin ratio. 2, 1
• Ratio >20 ng/dL per ng/mL/hr has excellent sensitivity/specificity for primary aldosteronism. 4
• Critical step: Perform adrenal vein sampling before offering adrenalectomy in confirmed primary aldosteronism. 2

Androgen Screening (Selective)

• Measure DHEA-S, 17-OH-progesterone, androstenedione, testosterone, and 17-beta-estradiol only when: 2
  • Suspected adrenocortical carcinoma (based on imaging features)
  • Clinical signs of virilization (hirsutism, deepening voice, clitoromegaly in women)
  • Clinical signs of feminization (gynecomastia, testicular atrophy in men)

Multidisciplinary Team Involvement

Discuss all cases in a multidisciplinary expert meeting (endocrinology, surgery, radiology) when: 1

• Imaging is not consistent with a benign lesion (inhomogeneous, >20 HU, >4 cm)
• Evidence of hormone hypersecretion exists
• Tumor has grown >5 mm/year during surveillance
• Adrenal surgery is being considered

Surgical Indications

Surgery is indicated for: 1

• All lesions >4 cm with inhomogeneous appearance or HU >20
• Clinically apparent Cushing's syndrome from cortisol-secreting adenomas
• Confirmed aldosterone-secreting adenomas (after adrenal vein sampling)
• All pheochromocytomas
• Growth >5 mm/year during surveillance (after repeating functional work-up) 2

Surgery should be considered in patients with MACS (cortisol >138 nmol/L post-dexamethasone) who have cortisol-related comorbidities (hypertension, type 2 diabetes, osteoporosis, obesity) that are difficult to control medically. 1

Surgery is NOT indicated for: 1

• Asymptomatic, nonfunctioning unilateral masses with obvious benign features (HU ≤10, homogeneous, <4 cm)
• Myelolipomas and other masses containing macroscopic fat

Follow-Up Protocol for Non-Operated Patients

For radiologically benign lesions (≤10 HU, homogeneous): 1

• If <4 cm and nonfunctioning: No further imaging or hormonal testing required 2
• If ≥4 cm and nonfunctioning: Repeat imaging in 6-12 months 2

For indeterminate masses not meeting surgical criteria: 2

• Repeat imaging to assess growth
• If growth <3 mm/year: No further follow-up needed
• If growth 3-5 mm/year: Continue surveillance
• If growth >5 mm/year: Repeat functional work-up and consider surgery

All patients with MACS require screening and treatment of cortisol-related comorbidities (hypertension, diabetes, dyslipidemia, osteoporosis) regardless of surgical decision. 1

Special Considerations

Bilateral Adrenal Incidentalomas

• Characterize each lesion separately following the same protocol as unilateral masses. 2
• Measure serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia. 2, 5

Adrenal Biopsy

• Do NOT perform routinely for adrenal incidentaloma work-up. 2, 1
• Consider only when diagnosis of metastatic disease from extra-adrenal malignancy would change management. 2
• Never biopsy without first excluding pheochromocytoma (can precipitate hypertensive crisis). 5

Medication Interference

• Hold interfering medications before testing when possible: 4
  • Beta-blockers, ACE inhibitors, ARBs affect aldosterone/renin ratio
  • Tricyclic antidepressants, decongestants affect metanephrine testing
  • Estrogen, rifampin affect cortisol testing

Critical Pitfalls to Avoid

• Do not rely on size >4 cm alone to determine malignancy—many malignancies present smaller, and imaging characteristics (HU, homogeneity) are more discriminatory. 3
• Do not skip cortisol screening even in small, benign-appearing lesions—MACS is common (affects most patients with post-dexamethasone cortisol >50 nmol/L) and increases morbidity/mortality. 1
• Do not screen for pheochromocytoma in confirmed adenomas (HU <10) without symptoms—this wastes resources and increases false positives. 2
• Do not proceed to adrenalectomy for primary aldosteronism without adrenal vein sampling—lateralization is essential. 2