Quick Reference
RxDrug of choicePhenoxybenzamine (alpha-blocker) for preoperative pheochromocytoma; spironolactone for primary aldosteronism; laparoscopic adrenalectomy for functioning adenomas.
AltAlternativesDoxazosin or prazosin for pheochromocytoma if phenoxybenzamine unavailable; eplerenone for aldosteronism (fewer antiandrogen effects); ketoconazole or metyrapone for preoperative cortisol control.
⊘AvoidBiopsy of an adrenal mass without prior exclusion of pheochromocytoma (risk of hypertensive crisis).
DxTest of choiceNon-contrast CT with Hounsfield unit measurement (≤10 HU = benign adenoma).
ScKey scoreAdrenal washout protocol: >60% absolute washout at 15 minutes suggests adenoma; Weiss histopathologic score for ACC (mitotic rate, nuclear grade, necrosis).
→When to referSize >4 cm, any hormonal excess, suspicious imaging features (irregular margins, necrosis, rapid growth), or known extra-adrenal malignancy.
Most incidental adrenal nodules are benign and require only initial biochemical and imaging workup with follow-up. The critical steps are to rule out pheochromocytoma and ACC, and to identify functioning adenomas that may benefit from surgery.
An incidental adrenal nodule (incidentaloma) is an adrenal mass discovered on imaging performed for an unrelated indication, found in approximately 5% of abdominal CT scans. The vast majority are benign, non-functioning adenomas, but a systematic approach is essential to exclude hormonal excess (pheochromocytoma, aldosteronoma, subclinical Cushing syndrome) and malignancy (adrenal cortical carcinoma, metastasis). Management hinges on biochemical workup, imaging characterization, and risk stratification by size and growth.
Overview and Recommendations
Background
- •An incidental adrenal nodule is defined as a mass ≥1 cm detected on cross-sectional imaging (CT, MRI, or PET) performed for non-adrenal indications. The prevalence rises with age, from ~1% in patients <30 years to >7% in those >70 years, and is roughly equal in men and women.
- •Most incidentalomas (~80%) are benign, non-functioning adrenocortical adenomas. Other benign entities include myelolipomas, cysts, and ganglioneuromas. Functioning adenomas (subclinical Cushing, aldosteronoma, pheochromocytoma) account for 5-15%, while primary adrenal malignancy (adrenal cortical carcinoma, ACC) is rare (<2%) but carries a poor prognosis if >4 cm.
- •The clinical paradigm is that the majority require no intervention, but missing a pheochromocytoma or ACC can be catastrophic. The 2016 European Society of Endocrinology (ESE) and 2023 American Association of Clinical Endocrinology (AACE) guidelines provide a standardized framework for evaluation and follow-up.
- •Key variants include: non-functioning adenoma (most common), subclinical hypercortisolism (autonomous cortisol secretion without overt Cushing stigmata), primary aldosteronism (often with hypertension ± hypokalemia), pheochromocytoma (catecholamine-secreting), and ACC (large, heterogeneous, often with hormonal excess).
- •The natural history of non-functioning adenomas is benign, with <5% developing hormonal excess or significant growth over 5 years. However, subclinical hypercortisolism is associated with increased cardiovascular risk, diabetes, and osteoporosis, warranting consideration of adrenalectomy in selected patients.
Evaluation
- •Suspect an incidental adrenal nodule whenever a mass is reported on any abdominal imaging (CT, MRI, ultrasound, PET). The first step is to confirm the mass is truly adrenal (not renal, splenic, or pancreatic) and measure its size and imaging characteristics.
- •Ask about symptoms of catecholamine excess: paroxysmal hypertension, palpitations, diaphoresis, headache, or pallor. Also inquire about hypertension, hypokalemia (suggesting aldosteronoma), and features of cortisol excess: weight gain, easy bruising, proximal muscle weakness, osteoporosis, or new-onset diabetes.
- •Examine for signs of Cushing syndrome (moon facies, buffalo hump, abdominal striae, central obesity), virilization (hirsutism, clitoromegaly, male-pattern baldness), and hypertension. Measure blood pressure and check for orthostatic changes.
- •Order biochemical testing in all patients with an adrenal nodule, regardless of size or imaging appearance. First-line tests include: plasma free metanephrines or 24-hour urinary fractionated metanephrines (to rule out pheochromocytoma); 1 mg overnight dexamethasone suppression test (1 mg DST) with serum cortisol measured at 8 AM (to detect autonomous cortisol secretion); and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) for aldosterone-to-renin ratio (ARR) if the patient is hypertensive or hypokalemic.
- •Diagnostic criteria for pheochromocytoma: plasma metanephrines >2-3 times the upper limit of normal (ULN) or urinary metanephrines >2× ULN. For subclinical hypercortisolism: post-1 mg DST cortisol >1.8 mcg/dL (50 nmol/L). For primary aldosteronism: ARR >20 (with PAC in ng/dL and PRA in ng/mL/h) followed by confirmatory testing (saline infusion test or captopril challenge).
- •Imaging characterization is critical. Perform a dedicated adrenal CT with non-contrast and delayed contrast phases. A homogeneous mass with attenuation ≤10 Hounsfield units (HU) on non-contrast CT is diagnostic of a benign lipid-rich adenoma (specificity >95%). If attenuation >10 HU, calculate the absolute or relative contrast washout: >60% absolute washout (or >40% relative) at 15 minutes is typical of adenoma.
- •For indeterminate masses (e.g., >10 HU but with good washout, or atypical features), consider MRI with chemical shift imaging: signal drop on out-of-phase images indicates intracellular lipid (adenoma). Alternatively, adrenal scintigraphy with NP-59 (iodocholesterol) can confirm benignity but is rarely used.
- •Also consider the possibility of metastasis if the patient has a known extra-adrenal malignancy (lung, breast, melanoma, renal cell). In such cases, consider PET-CT or biopsy after ruling out pheochromocytoma. Biopsy is reserved for suspected metastasis or when imaging is inconclusive and pheochromocytoma has been excluded.
- •Size is a key predictor of malignancy: ACC risk increases with diameter >4 cm (sensitivity ~90% for >4 cm). Features suspicious for ACC include irregular margins, necrosis, hemorrhage, calcifications, and rapid growth (>1 cm/year). For masses >4 cm or with suspicious features, consider dedicated adrenal CT or MRI and refer to an endocrine surgeon.
- •Additional workup may include DHEA-S, androstenedione, and testosterone if virilization is present or ACC is suspected. For large masses, consider a 24-hour urine for cortisol, aldosterone, and catecholamines to fully characterize hormonal activity.
Management
- •For a non-functioning, benign-appearing adenoma (≤10 HU on non-contrast CT, <4 cm, no hormonal excess): no treatment is required. Repeat imaging (CT or MRI) at 6-12 months to confirm stability, and repeat biochemical testing (1 mg DST, plasma metanephrines, and ARR if hypertensive) annually for 5 years. If stable after 5 years, follow-up can be discontinued.
- •For a functioning adenoma with subclinical hypercortisolism (post-1 mg DST cortisol >1.8 mcg/dL but <5 mcg/dL, no overt Cushing signs): consider laparoscopic adrenalectomy in younger patients (<65 years), those with poorly controlled diabetes, hypertension, or osteoporosis. If surgery is not performed, monitor with annual biochemical testing and imaging.
- •For overt Cushing syndrome (post-1 mg DST cortisol >5 mcg/dL, elevated 24-hour urinary free cortisol, suppressed ACTH): unilateral laparoscopic adrenalectomy is first-line. Preoperative control of hypercortisolism with ketoconazole (200-400 mg BID) or metyrapone (250-500 mg TID) may be needed to reduce surgical risk.
- •For primary aldosteronism confirmed by adrenal vein sampling (AVS) showing lateralization: unilateral laparoscopic adrenalectomy is curative in ~60% of cases. If AVS is not feasible or shows bilateral disease, treat medically with spironolactone (25-100 mg daily, titrate to blood pressure and potassium) or eplerenone (25-50 mg BID, preferred in men due to fewer antiandrogen side effects).
- •For pheochromocytoma: initiate preoperative alpha-adrenergic blockade at least 7-14 days before surgery. Start phenoxybenzamine 10 mg BID, titrate by 10 mg every 2-3 days to a target blood pressure <130/80 mmHg and heart rate <100 bpm (typical dose 20-40 mg BID). After adequate alpha blockade, add a beta-blocker (e.g., propranolol 20-40 mg TID) to control reflex tachycardia. Do not start beta-blocker before alpha blockade (risk of hypertensive crisis).
- •After adequate preoperative preparation, perform laparoscopic adrenalectomy for pheochromocytoma. Monitor for intraoperative hypertensive crises and postoperative hypotension. Continue alpha-blockade for 24-48 hours post-op, then taper. Check plasma metanephrines 4-6 weeks after surgery to confirm cure.
- •For adrenal cortical carcinoma (ACC): open adrenalectomy is the standard of care (laparoscopic only for small, well-encapsulated tumors). Postoperative mitotane therapy (starting at 1 g daily, titrate to 3-6 g daily to achieve serum levels 14-20 mg/L) is recommended for high-risk patients (stage III, incomplete resection, or Ki-67 >10%). Monitor for adrenal insufficiency (give hydrocortisone 20-30 mg daily) and mitotane side effects (GI, neurologic, hepatic).
- •For metastatic disease to the adrenal: treatment depends on the primary cancer. Biopsy may be needed to confirm histology. Local control with stereotactic body radiotherapy (SBRT) or radiofrequency ablation can be considered for oligometastases.
- •What NOT to do: never biopsy an adrenal mass without first ruling out pheochromocytoma (plasma metanephrines). Biopsy of a pheochromocytoma can precipitate a life-threatening hypertensive crisis. Also, avoid fine-needle aspiration for suspected ACC (risk of seeding and nondiagnostic sample).
- •When to refer: refer to endocrinology for any functioning nodule, size >4 cm, or suspicious imaging features. Refer to endocrine surgery for functioning nodules, size >4 cm, or growth on follow-up. Refer to oncology for confirmed ACC or metastatic disease.
- •Discharge criteria after adrenalectomy: stable blood pressure, no signs of adrenal insufficiency (if bilateral or cortisol-producing tumor, give stress-dose steroids and taper), and adequate pain control. For pheochromocytoma, ensure normotension off alpha-blockers before discharge.
- •Monitoring after adrenalectomy for functioning tumors: check appropriate hormones (metanephrines, aldosterone, cortisol) at 4-6 weeks to confirm cure. For ACC, follow with CT every 3-6 months for 2 years, then annually. For non-functioning adenomas that remain stable, follow-up can be discontinued after 5 years.
Board Review — High Yield
- •Incidentaloma prevalence, ~5% of abdominal CTs; increases with age.
- •Benign adenoma on CT, ≤10 HU on non-contrast CT is diagnostic (lipid-rich).
- •Pheochromocytoma rule-out, Always check plasma or urinary metanephrines before biopsy or surgery.
- •1 mg DST, Cortisol >1.8 mcg/dL indicates autonomous secretion (subclinical Cushing).
- •ARR, Aldosterone-to-renin ratio >20 suggests primary aldosteronism; confirm with saline infusion.
- •Size and ACC risk, >4 cm diameter increases risk of adrenal cortical carcinoma; >6 cm is highly suspicious.
- •Adrenal washout, >60% absolute washout at 15 minutes = adenoma; <60% suggests non-adenoma (pheo, metastasis, ACC).
- •Preoperative alpha blockade, Start phenoxybenzamine 7-14 days before pheochromocytoma surgery; never give beta-blocker first.
- •Biopsy contraindication, Never biopsy an adrenal mass without ruling out pheochromocytoma.
- •Follow-up duration, Non-functioning adenomas: imaging at 6-12 months, then annually for 5 years; if stable, discontinue.