Adrenal Incidentaloma

• Present in up to 10% of adults on imaging studies, and ~2-4% in autopsy studies (10-15% bilateral at autopsy) ^[2][3]
• Incidence on CT: 0.5–4.5% — this rises with age ^[1]
• Prevalence increases markedly with age:
  • < 30 years: ~1%
  • 50–60 years: ~3-4%
  • > 70 years: ~7-10%
• With the explosion of cross-sectional imaging (CT scans for trauma, staging, abdominal pain, etc.), adrenal incidentalomas are discovered with increasing frequency — a modern "epidemic" of incidental findings.

• Slight female preponderance for non-functioning adenomas
• No clear ethnic predisposition, though studies from Hong Kong and East Asia report similar prevalence figures to Western data
• In Hong Kong, the high utilisation of CT for cancer staging and health screening means adrenal incidentalomas are commonly encountered in clinical practice

• Most are asymptomatic — the mass is usually found during imaging for an unrelated condition ^[2][3]
• Non-functioning adenoma accounts for ~85% of cases ^[2][3]
• The probability of malignancy depends heavily on patient context:
  • In patients without known extra-adrenal malignancy: primary adrenal carcinoma is rare (~2-5%)
  • In patients with known extra-adrenal malignancy (e.g., lung, breast, melanoma, renal): up to 50-75% of adrenal masses may be metastases

• The adrenal glands are paired retroperitoneal organs sitting on the superomedial aspect of each kidney
• Right adrenal: pyramidal/triangular shape, sits posterior to the IVC and right lobe of liver, above the right kidney
• Left adrenal: semilunar/crescent shape, sits medial to the upper pole of left kidney, posterior to the pancreatic tail and splenic vessels
• Each gland weighs ~4-6 g and measures ~3 × 5 cm
• Blood supply: superior (from inferior phrenic artery), middle (from aorta), inferior (from renal artery) adrenal arteries
• Venous drainage: right adrenal vein → IVC directly (short, ~1 cm — important for adrenal vein sampling and surgery); left adrenal vein → left renal vein

The adrenal gland has two embryologically distinct regions:

Adrenal Cortex (mesoderm-derived, ~90% of gland mass):

Mnemonic for layers (superficial → deep): GFR (like the renal GFR) = Glomerulosa, Fasciculata, Reticularis Mnemonic for hormones: Salt, Sugar, Sex (from outside in)

Adrenal Medulla (neural crest-derived):

• Composed of chromaffin cells — modified postganglionic sympathetic neurons
• Secretes catecholamines: mainly adrenaline (epinephrine, ~80%) and noradrenaline (norepinephrine, ~20%)
• Catecholamine synthesis pathway: Tyrosine → DOPA → Dopamine → Norepinephrine → (via PNMT, a cortisol-induced enzyme) → Epinephrine ^[1]
• Catecholamine metabolism: Norepinephrine → Normetanephrine; Epinephrine → Metanephrine (via COMT = catechol-O-methyltransferase) — these metanephrines are measured in screening for phaeochromocytoma

• Cortical tumours → may secrete cortisol (Cushing's), aldosterone (Conn's), or androgens
• Medullary tumours → may secrete catecholamines (phaeochromocytoma)
• Non-functioning tumours → no hormone excess; still need assessment for malignancy
• Metastases → usually non-functional but can rarely destroy enough gland to cause adrenal insufficiency

Benign:

• Non-functional ~90%: adenoma (most common), cyst, haematoma/haemorrhage, haemangioma, myelolipoma, ganglioneuroma ^[1]
• Functional: subclinical Cushing's syndrome (~6%), phaeochromocytoma (~5%), Conn's syndrome (~1%) ^[1]

Malignant:

• Primary: adrenocortical carcinoma (ACC), malignant phaeochromocytoma ^[1]
• Secondary (more common than primary malignancy): metastases from lung, breast, melanoma, RCC, lymphoma ^[1]

• Why no overt Cushing's? The cortisol excess is mild and chronic — insufficient to produce florid clinical features but enough to contribute to metabolic syndrome and cardiovascular morbidity over years.

• Why postural hypotension in a hypertensive tumour? Chronic catecholamine excess causes: (1) volume contraction from pressure natriuresis, (2) downregulation of adrenergic receptors, and (3) desensitisation of baroreceptors. When the patient stands, the reflex compensatory mechanisms are blunted → orthostatic drop.

Most adrenal incidentalomas are asymptomatic — that's the definition (found incidentally). However, a thorough history and examination must be performed to detect subtle signs of hormone excess or malignancy that may have been previously overlooked.

History taking for adrenal incidentaloma should cover: ^[1]

1. History of hypertension (all functional tumours), diabetes (Cushing's)
2. S/S of Cushing's syndrome: weight gain, striae
3. Triad of phaeochromocytoma: episodic headache, sweating, palpitations
4. FHx / Hx of endocrine tumours (MEN)
5. Drug history (exogenous steroids, herbal medicines)
6. Symptoms of androgen excess (women)
7. Symptoms suggesting malignancy (weight loss, known cancer history)

Physical examination should include: ^[1]

1. BP, H'stix (blood glucose)
2. Cushingoid features: moon face, buffalo hump, proximal muscle wasting, central obesity, striae, hirsutism, easy bruising
3. Abdominal mass
4. Thyroid mass
5. Skin examination (NF1 stigmata, pigmentation)
6. Postural blood pressure

• ONDST (Overnight 1 mg Dexamethasone Suppression Test): Give 1 mg dexamethasone at 11 pm, measure serum cortisol at 8 am next morning. Normal response: cortisol < 50 nmol/L (1.8 µg/dL). Failure to suppress = autonomous cortisol secretion. This is the most sensitive screening test for Cushing's.

  • If cortisol > 50 nmol/L but < 138 nmol/L → "possible autonomous cortisol secretion"
  • If cortisol > 138 nmol/L (5 µg/dL) → "autonomous cortisol secretion"
  • Per 2016 ESE/ENSAT guidelines (still current in 2025-2026)

• 24h urine fractionated metanephrines and/or plasma free metanephrines: Should be performed on ALL adrenal incidentalomas before any invasive procedure (including biopsy). Metanephrines are the metabolites of catecholamines and are produced continuously by chromaffin tumour cells (not just during paroxysms), making them more sensitive than measuring catecholamines themselves.

  • Plasma free metanephrines have the highest sensitivity (~96-99%) — best to rule out phaeochromocytoma

• ARR (Aldosterone:Renin Ratio): Only needed if the patient has hypertension and/or hypokalaemia. Elevated ratio suggests autonomous aldosterone secretion.

  • Multiple drugs interfere (beta-blockers, ACEi, ARBs, spironolactone, diuretics) — ideally withdraw interfering medications 2-4 weeks before testing

• Androgen profile (DHEA-S, testosterone): Only if clinical features of virilisation in women or if ACC is suspected (mixed secretion)

Radiological features of malignancy on CT/MRI: ^[2][3]

1. Size: 90% malignant tumours > 4 cm in diameter
2. Configuration: homogeneous, smooth border → more likely benign
3. Lipid content: adenomas usually lipid-rich → fat attenuation ( < 10 HU) on CT
4. Enhancement: malignant tumours tend to retain contrast

Biopsy: ^[2][3]

• Rarely indicated
• Usually only reserved for confirmation of adrenal metastasis (in patients with known extra-adrenal malignancy)
• NOT for primary adrenal tumours — because:
  1. Histology is NOT useful in differentiating benign from malignant adrenal cortical tumours (they look similar)
  2. Risk of hypertensive crisis if phaeochromocytoma
  3. Risk of tumour seeding

For suspected phaeochromocytoma or metastatic disease: ^[8]

• MIBG scan (123I or 131I-MIBG): MIBG = meta-iodobenzylguanidine, an analogue of norepinephrine → taken up by norepinephrine-secreting cells (chromaffin cells). Sensitivity 85%, specificity 95% for phaeochromocytoma. ^[8]
  • CT/MRI is more accurate for primary tumours but MIBG is more sensitive for extra-adrenal and metastatic disease ^[8]
• PET/CT tracers: 18F-FDG (for aggressive/malignant tumours), 68Ga-DOTATATE (for somatostatin receptor-expressing neuroendocrine tumours), 18F-DOPA (for paragangliomas)
• SPECT tracers: 123I/131I-MIBG, In-111 octreotide ^[8]

• Patient with no cancer history: non-functioning adenoma is overwhelmingly most likely (~85%). But you MUST still screen for function and assess imaging characteristics.
• Patient with known malignancy: the probability of metastasis jumps to 50-75%, but ~25-50% are still benign adenomas — so imaging characterisation is still essential before assuming metastasis.
• Young patient with hypertension: think phaeochromocytoma, Conn's syndrome, or RAS.
• Woman with rapid virilisation: think ACC or androgen-secreting adenoma.
• Patient with genetic syndrome (NF1, MEN2, VHL): phaeochromocytoma is high on the list.

This is the most powerful tool for narrowing the DDx non-invasively:

Screening tests for functional tumours: ONDST + spot ARR + 24h urine metanephrines ^[1]

This comes up when phaeochromocytoma is suspected but you need to consider mimics ^[8]:

When the incidentaloma is found in the workup for resistant hypertension, the differential for the hypertension itself includes ^[5][7]:

This subset is particularly important because it narrows the differential significantly:

The single most useful initial discriminator is the Hounsfield Unit (HU) attenuation on unenhanced CT. Why? Because it directly reflects the tissue composition of the mass.

Why does this work from first principles?

• Adrenal cortical adenomas are packed with intracellular lipid droplets (cholesterol esters — the raw material for steroidogenesis). Lipid is low-density → low CT attenuation.
• Malignant tumours (ACC, metastases) and phaeochromocytomas have cellular, vascular, necrotic tissue with minimal intracellular lipid → higher attenuation.
• Myelolipomas contain macroscopic mature fat → very low attenuation (even negative HU values).

Key CT imaging criteria for characterisation: ^[2][3]

If unenhanced attenuation is > 10 HU (the mass is "lipid-poor" and therefore indeterminate), a CT washout protocol is performed. This is a three-phase CT:

1. Unenhanced phase (baseline attenuation)
2. Enhanced phase (~60-90 seconds post-contrast)
3. Delayed phase (~15 minutes post-contrast)

Then calculate:

Absolute percentage washout (APW):

Relative percentage washout (RPW) (used if no unenhanced scan available):

Why does washout work? Adenomas have well-organised, fenestrated capillary beds → contrast enters and exits quickly (rapid washout). Malignant tumours have chaotic, leaky neovascularisation → contrast pools in the interstitium and is slow to wash out. Phaeochromocytomas are also highly vascular with slow washout.

If CT washout is equivocal or unavailable, chemical-shift MRI (also called in-phase/opposed-phase MRI) can detect intracellular lipid:

• Principle: Water and fat protons precess at slightly different frequencies. At specific echo times, their signals are either in-phase (additive) or opposed-phase (cancel out). If a voxel contains both water and fat (as in a lipid-rich adenoma), the signal drops on opposed-phase images.
• Finding: Signal intensity index (SII) > 16.5% drop on opposed-phase = adenoma
• Advantage: No radiation, no contrast needed; good for pregnancy or contrast allergy
• Limitation: Cannot detect macroscopic fat (myelolipoma is better characterised on CT); phaeochromocytomas and metastases do NOT show signal drop (no intracellular lipid)

Screening tests for functional tumours: ONDST + spot ARR + 24h urine metanephrines ^[1]

Let's go through each in detail.

24h urine fractionated metanephrines is the most commonly used screening test ^[1][8][9].

Precautions before testing: ^[8][9]

• Stop drugs affecting catecholamine secretion: TCAs, levodopa, α-agonists, amphetamines, methyldopa, labetalol, sotalol ^[8][9]
• Avoid dietary intake of caffeine, chocolate, bananas before urine collection ^[9]
• Urine specimen should be kept refrigerated during collection ^[9]
• Blood should be drawn supine for plasma metanephrines (30 min rest) to reduce false positives from sympathetic activation

Why metanephrines rather than catecholamines? Catecholamines are released episodically (paroxysmal), so a random sample may miss the peak. Metanephrines are produced continuously within the chromaffin tumour cells by COMT (catechol-O-methyltransferase) — they are always elevated if a tumour is present, regardless of paroxysms. This gives metanephrines much higher sensitivity.

Confirmatory test: Clonidine suppression test ^[1]

• Principle: Clonidine is a central α₂-agonist → suppresses sympathetic outflow → lowers plasma catecholamines/metanephrines in normal individuals. In phaeochromocytoma, catecholamine production is autonomous (not centrally regulated) → NO suppression.
• Procedure: Baseline plasma catecholamines/normetanephrine → 300 µg clonidine PO → repeat at 3 hours
• Positive (phaeochromocytoma): Failure to suppress normetanephrine by > 40% or levels remain above upper limit of normal

Only performed if patient has hypertension and/or unexplained hypokalaemia ^[1][2][5]

Plasma Aldosterone:Renin Ratio (ARR): ^[1][5]

• Principle: In primary hyperaldosteronism, aldosterone is autonomously elevated while renin is suppressed (because volume expansion from Na⁺ retention suppresses the RAAS feedback loop). A high ratio reflects this disconnect.
• Interpretation: Elevated ARR (varies by assay; general guide: aldosterone > 15 ng/dL AND ARR > 30 in conventional units) → proceed to confirmatory testing
• Drug interference: Many antihypertensives interfere — ideally withdraw beta-blockers, ACEi, ARBs, spironolactone, diuretics for 2-4 weeks before testing (use verapamil or doxazosin as "safe" alternatives during washout)

RFT for hypokalaemia: ^[1]

• Classic finding but only present in ~9-37% of cases in modern series
• If present, supports diagnosis but absence does not exclude it

Confirmatory test: Salt loading test / Saline suppression test ^[1][13]

• Procedure: 0.9% NaCl IV (500 mL/h) for 4h in sitting/recumbent position ^[13]
• Monitor BP/P and watch for signs of fluid overload ^[13]
• Measure renin + aldosterone post-salt loading
• Normal: suppression of renin and aldosterone
• Primary hyperaldosteronism: failure or inadequate suppression ^[13]

Subtype differentiation: Adenoma vs. Bilateral Idiopathic Adrenal Hyperplasia (BIAH) — crucial because management differs completely ^[6][11][13]:

Adrenal venous sampling (AVS): ^[7][13]

• Performed from the femoral vein ^[7]
• Gold standard for lateralisation in primary hyperaldosteronism
• Technically demanding (especially right adrenal vein which drains directly into IVC — short and difficult to cannulate)
• Measures aldosterone:cortisol ratio from each adrenal vein and compares to peripheral blood
• A lateralisation ratio > 4:1 indicates a unilateral source (adenoma) → suitable for adrenalectomy

Androgen profile (DHEA-S, testosterone, androstenedione): only if virilisation present in women or if ACC suspected ^[2][3]

• DHEA-S is the most useful marker — it is almost exclusively adrenal in origin
• Very high DHEA-S ( > 700 µg/dL) in combination with a large adrenal mass is highly suspicious for ACC
• Mixed cortisol + androgen elevation is a hallmark of ACC

Only relevant if:

• Bilateral adrenal masses are found (risk of bilateral destruction → insufficiency)
• History of bilateral adrenal metastases, TB, haemorrhage, or infiltrative disease

Tests for adrenal insufficiency: ^[15][16]

• Basal plasma ACTH + cortisol: Primary insufficiency → ↑ACTH + ↓cortisol; Secondary → ↓ACTH + ↓cortisol
• Short Synacthen Test (SST): 250 µg synacthen IV/IM bolus → serum cortisol at 0, 30, 60 min ^[15][16]
  • Peak cortisol > 550 nmol/L = normal
  • < 400 nmol/L = abnormal (adrenal insufficiency)
  • 400-550 nmol/L = borderline → may need insulin tolerance test

Clinical indications: ^[10]

• Diagnosis of phaeochromocytoma, neuroblastoma, or other APUD cell tumours
• Staging and follow-up
• Detection of metastasis and recurrent disease
• Plan for MIBG therapy

Principle: ^[10]

• MIBG (meta-iodobenzylguanidine) is an analogue of norepinephrine
• Reuptake into norepinephrine-secreting cells (sympathetic nerve endings, adrenal medullary cells)
• Radiopharmaceutical: 131I-MIBG or 123I-MIBG

Performance for phaeochromocytoma: ^[10]

• Sensitivity 85%, specificity 95%
• CT/MRI more accurate in primary tumours but MIBG more sensitive for extra-adrenal tumours ^[10]

Physiological distribution: ^[10]

• Liver and spleen, myocardium, salivary glands and thyroid, normal adrenals, nasal mucosa, bladder, colon
• Thyroid blockade should be used (e.g., Lugol's iodine) to prevent thyroid damage from radioiodine ^[10]

Radiopharmaceuticals used: ^[10]

• SPECT tracers: 123I or 131I-MIBG, In-111 octreotide
• PET/CT tracers: 18F-FDA, 18F-DOPA, 11C-epinephrine, 18F-FDG, 68Ga-DOTATATE

This is the most critical pre-operative preparation because failure to do it properly can cause intraoperative death from hypertensive crisis, arrhythmia, or cardiovascular collapse.

Medical therapy: pre-operative prevention of crisis by combined α/β-blockade ^[8][9][17]

The sequence matters — it is exam gold:

α-blocker should be given 10-14 days before operation for adequate blockade to normalize BP and expand the contracted blood volume ^[9]

β-blocker should be given 2-3 days before operation after adequate α-blockade has been achieved to relieve the tachycardia caused by α-blocker ^[9]

Why does this sequence work from first principles?

BP targets: < 120/80 when seated and SBP > 90 mmHg on standing ^[9]

Side effects of α-blockers: ^[9]

• Postural hypotension (expected — shows adequate blockade)
• Palpitations (reflex tachycardia) → reason for subsequent β-blockade
• Flushing, nasal congestion

Alternative agents: ^[8]

• Calcium channel blockers (dipine class, e.g. nifedipine, amlodipine): alternative if α-blockers poorly tolerated
• Metyrosine (α-methyltyrosine): inhibits tyrosine hydroxylase → ↓catecholamine synthesis at source. Used as adjunct in refractory cases.

Adequate α-blockade is indicated by postural BP drop ^[8] — if the patient's standing SBP drops by > 10 mmHg compared to sitting, α-blockade is adequate.

Postoperative monitoring: ^[8]

• BP and HR closely (ICU level for 24-48h)
• H'stix (blood glucose) — rebound hypoglycaemia can occur because catecholamines normally drive glycogenolysis and gluconeogenesis; when the source is removed, insulin action is unopposed → hypoglycaemia
• Watch for hypotension (see above)

When removing a cortisol-secreting adrenal adenoma, the contralateral adrenal gland has been chronically suppressed by negative feedback (low ACTH from pituitary because the adenoma was producing cortisol autonomously). After removal of the adenoma, the remaining adrenal cannot immediately ramp up cortisol production → the patient is effectively adrenally insufficient post-operatively.

Pre-operative and peri-operative cautions: ^[1][17][18]

Steroid cover protocol (typical): ^[8]

• 50-100 mg IV hydrocortisone on-call to theatre
• Post-op: rapid taper over 3 days to maintenance 15-25 mg/day PO hydrocortisone
• Continue maintenance and taper gradually (over months to ~1 year) guided by morning cortisol and SST recovery

Medical therapy for pre-operative control of hypercortisolism (if severe or surgery delayed) ^[18]:

• Metyrapone: first-line — CYP11B1 (11β-hydroxylase) inhibitor → ↓cortisol synthesis; short-acting, effective within 2h
• Ketoconazole: azole antifungal that inhibits cortisol and androgen synthesis; S/E: hepatotoxicity, ↓androgen (gynecomastia)
• Mitotane: cytotoxic to adrenal cortex → "medical adrenalectomy"; used as adjuvant for ACC (see below)
• Block-and-replace strategy: total cortisol ablation with drugs + replacement hydrocortisone (used when cortisol production is highly variable) ^[18]

Management depends on subtype: ^[1][6][11]

Post-operative management after adrenalectomy for Conn's: ^[11]

• Monitor K⁺ for rebound hyperK due to contralateral adrenal suppression (the remaining adrenal gland has been suppressed by volume expansion → temporarily ↓aldosterone → K⁺ retention)
• Monitor aldosterone for test of cure
• Continue treatment of hypertension — HTN can remain in 40-65% due to ?irreversible damage to systemic microcirculation (especially hypertensive nephrosclerosis) ^[11]

Medical therapy agents: ^[11]

• Aldosterone antagonist (1st line): spironolactone (S/E gynecomastia, menstrual irregularity), eplerenone (more expensive but fewer anti-androgenic S/Es)
• K⁺-sparing diuretics (2nd line): amiloride, triamterene — less preferred as they do not counteract the deleterious cardiovascular effects of aldosterone excess ^[11] (aldosterone directly causes myocardial fibrosis and vascular remodelling independent of BP)

• If androgen excess is confirmed and the mass is large → highly suspicious for adrenocortical carcinoma
• Surgery: open adrenalectomy ± en-bloc resection of kidney/spleen (if invaded) ^[19]
• Adjuvant mitotane for at least 2 years ^[19] — mitotane is directly cytotoxic to adrenal cortical tissue (disrupts mitochondrial membranes in adrenocortical cells) and also disrupts cortisol synthesis
  • Mitotane induces CYP3A4 → rapid metabolism of glucocorticoids ^[19] → patients on mitotane need high-dose glucocorticoid replacement (typically 40-60 mg hydrocortisone/day or equivalent dexamethasone, which is less affected by CYP3A4)
• FNA biopsy is NOT indicated for ACC ^[19]: cannot differentiate benign from malignant cortical lesions, risk of tumour seeding
• Chemotherapy for refractory disease ^[19] — typically EDP-M (etoposide, doxorubicin, cisplatin + mitotane)

• Management is guided by the primary cancer and overall staging
• If the adrenal is the only site of metastasis and the primary is controlled → adrenalectomy (metastasectomy) may be considered for improved survival (especially in lung cancer, RCC)
• If widespread metastatic disease → systemic therapy directed at primary cancer
• If bilateral metastases causing adrenal insufficiency → glucocorticoid and mineralocorticoid replacement

• Histologically and biochemically indistinguishable from benign disease; defined by metastasis ^[19]
• Management: ^[19]
  • Surgical excision (tumour debulking) to control catecholamine excess
  • Symptomatic relief: α-blockers
  • Mitotane: adjuvant/palliative treatment
  • 131I-MIBG therapy: targeted radionuclide therapy for MIBG-avid metastatic disease
  • Chemotherapy (CVD regimen): cyclophosphamide, vincristine, dacarbazine for progressive disease
• Prognosis: 5-year survival 95% for benign, 40% for malignant ^[8]