What is the diagnostic approach for adrenal gland tumors?

Diagnostic Approach for Adrenal Gland Tumors

All patients with suspected adrenal tumors require immediate unenhanced CT imaging combined with comprehensive hormonal screening before any intervention, as this dual approach is mandatory to identify both malignant lesions and hormone-secreting tumors that require specific perioperative management. 1, 2

Initial Clinical Assessment

When evaluating a patient with a suspected adrenal tumor, focus your history and physical examination on:

• Signs of cortisol excess: central obesity, facial plethora, proximal muscle weakness, wide purple striae, easy bruising 1
• Signs of aldosterone excess: hypertension, muscle weakness, polyuria (from hypokalemia) 1
• Signs of catecholamine excess: episodic headaches, palpitations, diaphoresis (especially "cold sweat"), pallor, tremor 1, 3
• Signs of androgen excess: virilization, hirsutism, acne, menstrual irregularities 1
• History of extra-adrenal malignancy: which raises suspicion for metastatic disease 1
• Family history: of pheochromocytoma, MEN2, VHL, NF1, or paraganglioma syndromes 3

The classic triad of headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity for pheochromocytoma and should trigger immediate biochemical testing. 3

Mandatory Hormonal Evaluation

All patients must undergo complete hormonal screening regardless of imaging appearance, as radiological characteristics cannot reliably predict hormone secretion status. 2, 4

Required Tests for Every Patient:

• Cortisol screening: 1 mg overnight dexamethasone suppression test (preferred method) 1, 2, 4, 5
• Plasma ACTH levels 2, 4
• Aldosterone-to-renin ratio if hypertension and/or hypokalemia present 1, 2, 4
• Serum potassium 4

Catecholamine Screening Protocol:

Screen for pheochromocytoma with plasma free metanephrines or 24-hour urinary fractionated metanephrines in all patients with:

• Adrenal masses >10 HU on non-contrast CT 1, 2
• Any symptoms of catecholamine excess 1, 2
• Unequivocal adenomas (<10 HU) without symptoms can skip this testing 1

Plasma free metanephrines are the preferred test (sensitivity 96-100%, specificity 89-98%) and should ideally be collected from an indwelling venous catheter after 30 minutes supine rest to minimize false positives. 3 However, you may bypass this ideal collection method for initial screening, but marginally elevated results must be repeated under proper conditions. 3

Additional Hormone Testing When Indicated:

• Androgen excess panel (DHEA-S, 17-OH-progesterone, androstenedione, 17-beta-estradiol) when clinical virilization present or adrenocortical carcinoma suspected 1, 2, 4
• Plasma methoxytyramine when available, as elevated levels indicate higher malignancy risk in pheochromocytoma 3

Imaging Evaluation Algorithm

First-Line Imaging:

Unenhanced (non-contrast) CT of the abdomen is mandatory as the initial imaging study for all adrenal masses. 1, 2

Interpretation of Hounsfield Units (HU):

• **<10 HU**: Strongly suggests benign adenoma; no further imaging needed unless size >4 cm or growth on follow-up 1, 2
• >10 HU: Requires second-line imaging with either contrast-enhanced washout CT or chemical-shift MRI 1, 2

Concurrent chest CT is required to evaluate for metastatic disease, particularly for suspected adrenocortical carcinoma or pheochromocytoma. 1, 2

Second-Line Imaging (for indeterminate masses with HU >10):

• Contrast-enhanced washout CT (10-15 minute delayed imaging) 1
• Chemical-shift MRI (opposed-phase imaging showing signal intensity loss suggests benign adenoma) 1

Functional Imaging Indications:

FDG-PET is indicated for:

• Radiologically indeterminate lesions after second-line imaging 2
• Suspected adrenocortical carcinoma 1, 2
• Established pheochromocytoma with high-risk features 2

Additional functional imaging for pheochromocytoma/paraganglioma:

• MIBG scintigraphy, DOTA-TATE-PET, or FDOPA-PET when any of these high-risk features are present: 1, 2, 3
  • Tumor size ≥5 cm
  • Extra-adrenal paraganglioma
  • SDHB germline mutation
  • Plasma methoxytyramine >3-fold above upper limit

Critical Diagnostic Pitfalls

Never Perform Biopsy Before Excluding Pheochromocytoma:

Adrenal mass biopsy is contraindicated until pheochromocytoma is biochemically excluded, as biopsy of an undiagnosed pheochromocytoma can trigger fatal hypertensive crisis. 1, 2, 4, 3

Limited indications for biopsy (only after excluding pheochromocytoma):

• History of extra-adrenal malignancy to prove/exclude adrenal metastasis 1
• When tumor sequencing is desired for treatment planning 1

Avoid Contrast-Enhanced CT Until Pheochromocytoma Excluded:

Use MRI preferentially over contrast-enhanced CT when pheochromocytoma is suspected, as IV contrast can precipitate hypertensive crisis. 3

Do Not Skip Hormonal Testing Based on Imaging:

Even "benign-appearing" tumors (<10 HU) require cortisol screening, as subtle autonomous cortisol secretion impacts surgical decision-making and perioperative management. 2, 4

Interpretation of Metanephrine Results

When plasma free metanephrines or urinary fractionated metanephrines are elevated:

• ≥4 times upper limit of normal: Proceed immediately to imaging to localize pheochromocytoma/paraganglioma 3
• 2-4 times upper limit: Repeat testing in 2 months; consider genetic testing for hereditary syndromes 3
• Marginally elevated (1-2 times upper limit): Repeat in 6 months under ideal collection conditions or perform clonidine suppression test 3

Clonidine suppression test has 100% specificity and 96% sensitivity for pheochromocytoma and should be used for equivocal results with strong clinical suspicion. 3

If plasma testing is equivocal (<4-fold elevation), obtain 24-hour urine collection for fractionated metanephrines and catecholamines. 3

Multidisciplinary Review Triggers

Obtain multidisciplinary review by endocrinologists, surgeons, and radiologists when: 1

• Imaging not consistent with benign lesion
• Evidence of hormone hypersecretion
• Tumor has grown significantly during follow-up
• Adrenal surgery is being considered

Special Considerations for Specific Tumor Types

Suspected Adrenocortical Carcinoma:

• Imaging characteristics: Inhomogeneous appearance, irregular margins, irregular enhancement, local invasion, or IVC extension 1
• Additional imaging: Consider bone scintigraphy and FDG-PET 1, 2
• Pathology: Requires experienced pathologist using Weiss score (≥3 suggests malignancy); Ki-67 labeling index helpful for prognosis 1

Confirmed Pheochromocytoma:

• Extend imaging to chest and neck if abdominal imaging negative but biochemistry positive 2, 3
• Genetic testing recommended: 30-35% are hereditary (MEN2, VHL, NF1, SDHx mutations) 3
• SDHB mutations: Associated with higher malignancy risk requiring intensive lifelong surveillance 1, 3
• All patients require long-term follow-up due to malignancy risk, particularly with SDHB mutations, extra-adrenal location, or size >5 cm 3

Head/Neck Paragangliomas:

• MRI with angiography sequences is first-line imaging (sensitivity 88.7%, specificity 93.7%) 3
• Up to 30% produce dopamine indicated by elevated plasma methoxytyramine 3
• Whole-body PET with radiolabeled somatostatin analogs preferred for SDHD-related tumors 3