Diagnosis and Evaluation of Adrenal Mass — Adrenal

Background

An incidental adrenal mass is an adrenal lesion >1 cm discovered on radiologic examination performed for reasons other than to investigate primary adrenal disease. Exclusions to the definition: known malignancy or high suspicion of a malignant process (the mass has a high likelihood of being a metastatic deposit), and clinically overt disease.

Differential Diagnosis

The differential diagnosis of an incidental adrenal mass (10):

Malignant (3): adrenal cortical carcinoma, metastasis, sarcoma.
Benign (7): pheochromocytoma, adenoma (functional vs non-functional), oncocytoma, cyst, myelolipoma, ganglioneuroma, abscess.

About 20% of incidental adrenal masses are found to be potential surgical lesions. (See Campbell's 11th edition, Table 65-15, for characteristics of incidental adrenal masses from a systematic review of published series.)

Workup at a Glance

Per the 2011 CUA guidelines, ALL incidental adrenal masses (excluding myelolipomas, hemorrhages, and cysts) initially require a comprehensive work-up — clinical, radiologic, and hormonal — to distinguish benign from malignant, and non-functioning from hyperfunctioning, tumours.

Labs (3): low-dose dexamethasone suppression test or 24-hour urinary cortisol (rule out hypercortisolism); 24-hour urinary metanephrines and/or catecholamines (rule out pheochromocytoma); and, in hypertensive patients, the aldosterone-to-renin ratio (rule out hyperaldosteronism).
Imaging (1): unenhanced CT; if attenuation ≥ 10 HU, obtain contrast-enhanced CT with adrenal washout.

History and Physical Exam

Most patients are asymptomatic. Screen for signs and symptoms of adrenal hyperfunction:

Hypercortisolism (9): central obesity, moon facies, buffalo hump, facial plethora, menstrual disturbances, hirsutism, proximal muscle weakness, easy bruisability, and abdominal striae. Systemic manifestations include dyslipidemia, insulin resistance, and hypertension.
Hyperaldosteronism: hypertension — classified as elevated (SBP 120–129, DBP <80 mm Hg), stage 1 (SBP 130–139, DBP 80–89 mm Hg), or stage 2 (SBP ≥140, DBP ≥90 mm Hg).
Pheochromocytoma (3): headache, episodic sudden perspiration, tachycardia.
Adrenal sex steroid hypersecretion and adrenal malignancy.

Labs

(See the 2011 CUA Incidental Adrenal Mass Guideline.)

Hypercortisolism — assessed by the overnight low-dose (1 mg) dexamethasone suppression test (sensitivity 85–90%, specificity 95–99%). The 24-hour urine free cortisol (sensitivity 80–98%, specificity 45–98%) may be used for screening, with the 1 mg test used to differentiate Cushing's from subclinical Cushing's syndrome if the 24-hour cortisol is elevated.
Pheochromocytoma — assessed by 24-hour urine metanephrines and catecholamines. Fractionated plasma metanephrines is a newer test that may be more sensitive but less specific, so its use should be reserved for confirmatory testing rather than primary screening. Plasma metanephrine testing may not be widely available outside select centres, so 24-hour urinary metanephrines is suggested for initial screening.
Hyperaldosteronism — assessed in hypertensive patients by the upright plasma aldosterone-to-renin ratio (ARR).
- Pre-testing: mineralocorticoid receptor blockers (e.g. spironolactone) and some diuretics — potassium-sparing (amiloride, triamterene) and potassium-wasting (furosemide, HCTZ, indapamide) — should be discontinued at least 4 weeks before the ARR. If results are non-diagnostic and hypertension can be controlled with relatively non-interfering antihypertensives, withdraw other potentially interfering medications (ACE inhibitors, ARBs, renin inhibitors, dihydropyridine calcium channel antagonists, β-blockers, central α-2 agonists, NSAIDs) for at least 2 weeks before a repeat ARR. Patients should liberalize salt intake leading up to the test for accurate results (acute fluctuations in dietary sodium are reported not to affect ARR accuracy).
- Normokalemia occurs in up to 50% of patients with hyperaldosteronism, although it has traditionally been associated with hypertension and hypokalemia.
Adrenal sex steroid hypersecretion — routine testing of incidentalomas for sex hormones is not currently recommended; hypersecretion by adrenal masses (especially incidentalomas) is exceedingly rare and typically presents with concomitant clinical symptoms (feminization or virilization). Assessed with (2): serum DHEA-S and 24-hour urine 17-ketosteroids.

Confirmatory hormonal testing for all positive screening tests is recommended, to limit false positives and unnecessary surgery.

Imaging

CT — unenhanced CT is the first test. Myelolipoma, cysts, and hemorrhages have distinct features; CT is the most easily interpreted test for intracellular lipid, and adenomas typically contain a greater proportion of intracellular fat than malignant incidentalomas. Attenuation of a region of interest over a mass on unenhanced CT:
- <10 HU — diagnostic for an adrenal adenoma (high intracytoplasmic lipid content); this cutoff has ≈70% sensitivity and 98% specificity. About 30% of adenomas show attenuation >10 HU owing to lower lipid content — these "atypical" or "lipid-poor" adenomas are indistinguishable from non-adenomas on non-contrast density alone.
- >10 HU — obtain contrast-enhanced CT with washout, which has excellent sensitivity and specificity for differentiating adenomas from non-adenomatous incidentalomas. A single-phase enhanced CT is limited, as post-contrast attenuation of adenomas and non-adenomas overlaps considerably.
Phases of an adrenal CT study (3): non-contrast 5-mm images through the adrenal; enhanced (1-minute post-bolus); and 15-minute washout imaging.
Washout indicative of adenoma: absolute percent washout > 60% ([enhanced − delayed] / [enhanced − unenhanced] × 100%), or relative percent washout (RPW) > 40% ([enhanced − delayed] / [enhanced] × 100%). Lipid-poor adenomas wash out identically to lipid-rich adenomas; RCC and HCC metastases may show washout similar to lipid-poor adenomas.
Characteristics of pheochromocytoma and malignant processes (5): size >3 cm, heterogeneous texture, increased vascularity, attenuation >10 HU on unenhanced CT, and decreased contrast washout at 10–15 minutes.
MRI — chemical-shift MRI uses the lipid-rich property of most adenomas to differentiate benign from malignant, but CT with washout is the gold standard and is better than chemical-shift MRI for identifying adenomas.
Ultrasound — a suboptimal modality for detecting and characterizing adrenal lesions.
Functional imaging / PET — limited role for diagnosing pheochromocytoma (most are accurately diagnosed with cross-sectional imaging and metabolic evaluation). 2-[18F] FDG-PET can be useful for detecting metastasis in patients with a history of malignancy, as metabolically active lesions typically show increased FDG uptake versus benign lesions.

Adrenal biopsy

Currently not recommended for the routine work-up of an adrenal incidentaloma. Its role is limited: modern imaging in clinical context affords superb diagnostic capability, adenomas cannot be reliably differentiated from adrenal carcinomas histologically, and biopsy carries risks.
Should be pursued if the diagnosis remains equivocal and the biopsy result will influence management — most useful in patients with primary malignancies that may have recurred in the adrenal gland and whose management will be affected.
Always exclude the possibility of pheochromocytoma before biopsy, to avoid potentially life-threatening hemorrhage and hypertensive crisis.

Management

Two options: adrenalectomy or observation.

Adrenalectomy — indications (11)

Size ≥ 4 cm (except myelolipoma) — most adrenocortical carcinomas are >4 cm, and masses >6 cm should be considered malignant until proven otherwise. Management of 4–6 cm masses is controversial, but in otherwise healthy individuals masses >4 cm should be resected; radiologically benign masses >4 cm may be followed in patients who are not prime surgical candidates. Benign adenoma incidence increases with age, so lesions in younger patients (even <4 cm) warrant greater caution than similar lesions in older patients, whereas >4 cm lesions in older patients with significant comorbidities may be better served by observation.
Size increase > 1 cm on follow-up imaging — current recommendation is to resect, though the incidence of malignancy among these patients is low.
Adrenal hyperfunction — some patients with primary aldosteronism may be managed medically (especially poor surgical candidates). Clinically silent hyperfunction is debated: any lesion exhibiting silent pheochromocytoma (hormonal and radiologic signs without clinical symptoms) should be surgically removed after adequate adrenergic blockade, given the life-threatening complications. Surgery may be elected for younger patients with subclinical Cushing syndrome, or those with new-onset, medically resistant, or deteriorating disease from cortisol excess; the remainder are followed and offered surgery if they develop clinical signs of Cushing's.
Imaging suggestive of malignancy (e.g. lipid-poor, heterogeneous, irregular borders, infiltrating surrounding structures), regardless of size.
Extremely large and/or symptomatic cyst or myelolipoma.
Isolated adrenal metastasis (multidisciplinary decision-making required).
During renal surgery for RCC if the adrenal is abnormal or not visualized because of large renal tumour size, or there is vein thrombus to the level of the adrenal vein.
Failed neurosurgical treatment of Cushing disease, necessitating bilateral adrenalectomy.
Select patients with ectopic ACTH syndrome, requiring bilateral adrenalectomy.
ACTH-independent macronodular adrenal hyperplasia (AIMAH).
Primary pigmented nodular adrenocortical disease (PPNAD).

(The first four are consistent with the CUA Incidental Adrenal Mass Guidelines.)

Observation

Myelolipomas, hemorrhages, and cysts do not necessarily require further evaluation. Non-functioning adenomas (typically <4 cm) and masses not deemed resectable at initial diagnosis should undergo clinical, hormonal, and radiological surveillance. There is no consensus on the proper follow-up methodology.
Surveillance proposed in the 2011 CUA Guidelines:
- Hormonal: annual clinical and hormonal testing for up to 4 years. There is no agreement on the best mechanism and frequency, but it should include the same screening tests used at primary evaluation.
- Radiographic (depends on lesion characteristics ± size): benign-appearing masses — <1 cm: consider no further follow-up or enrolment in a clinical trial; 1–2 cm: first scan at 12 months if the clinical picture warrants; 2–4 cm: first scan at 12 months. Radiologically suspicious lesions not initially removed — any size: first scan at 3–6 months, with further imaging directed by clinical judgment (consider 1–3 assessments within the first 2 years).
Tumours that remain stable on imaging and annual hormonal evaluation may be considered for discharge from follow-up after 4 years.

Self-Test

1. What are the absolute and relative percent washout on CT suggestive of an adrenal adenoma? Absolute percent washout > 60% and relative percent washout > 40%.

2. What is the initial imaging of choice for adrenal adenomas, and what is the gold standard? Initial test: unenhanced CT. Gold standard: contrast-enhanced CT with washout.