Adrenal Incidentaloma
An adrenal incidentaloma is an adrenal mass >1 cm found incidentally on imaging performed for a non-adrenal indication; evaluation focuses on hormonal function and malignant potential.
Adrenal incidentaloma is defined as an adrenal mass > 1 cm in diameter incidentally found on radiological investigation (CT, MRI, or other imaging) performed for a reason unrelated to suspected adrenal disease [1][2].
Let's break the name down:
- "Adrenal" = relating to the adrenal (Latin: ad- = near, renes = kidney) glands sitting atop each kidney.
- "Incidentaloma" = "incidental" + "-oma" (tumour/mass) — a mass found by accident.
The term is a radiological diagnosis, not a pathological one. It encompasses a heterogeneous group of lesions — the clinical challenge is determining two critical questions:
- Is it functional? (i.e., does it secrete hormones autonomously?)
- Is it malignant? (i.e., does it need surgical removal?)
The Two Big Questions
Every adrenal incidentaloma must be evaluated for hormonal function and malignant potential. This drives the entire diagnostic and management algorithm. "Functional? Malignant potential?" [1]
Epidemiology
- 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
| Risk Factor | Explanation |
|---|---|
| Increasing age | Prevalence of adrenal adenomas rises with age due to cumulative somatic mutations and nodular cortical hyperplasia |
| Obesity / Metabolic syndrome | Associated with subclinical autonomous cortisol secretion (previously called "subclinical Cushing's") |
| Hypertension / Diabetes | Higher detection rate in these populations (both from more frequent imaging AND from functional tumours causing these conditions) |
| Known extra-adrenal malignancy | Lung, breast, melanoma, RCC, lymphoma are the most common cancers to metastasise to the adrenal glands |
| Genetic syndromes | MEN2, VHL, NF-1, Carney complex, Li-Fraumeni, Beckwith-Wiedemann → hereditary adrenal tumours |
| Frequent imaging | Health screening CT, trauma CT, cancer staging → more incidental findings |
Anatomy and Function of the Adrenal Glands
Understanding adrenal incidentalomas requires a solid grasp of adrenal anatomy, because the location within the gland determines the type of tumour and the hormones it may secrete.
- 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
Surgical Anatomy Pearl
The right adrenal vein drains directly into the IVC — this makes right adrenalectomy slightly more dangerous (risk of IVC injury). The left adrenal vein drains into the left renal vein — remember this for adrenal vein sampling in Conn's syndrome and for surgical planning.
The adrenal gland has two embryologically distinct regions:
Adrenal Cortex (mesoderm-derived, ~90% of gland mass):
| Zone | Hormone | Regulator | Mnemonic |
|---|---|---|---|
| Zona Glomerulosa (outermost) | Aldosterone (mineralocorticoid) | Renin-Angiotensin-Aldosterone System (RAAS), K⁺ | Glomerulosa = Go for salt (aldosterone) |
| Zona Fasciculata (middle, thickest) | Cortisol (glucocorticoid) | ACTH (from pituitary, driven by CRH from hypothalamus) | Fasciculata = Fuel (cortisol for metabolism) |
| Zona Reticularis (innermost) | Androgens (DHEA, DHEA-S, androstenedione) | ACTH | Reticularis = Really sexy (androgens) |
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
Why Is PNMT Important?
Phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine to epinephrine and is induced by cortisol. The adrenal medulla is bathed in high-concentration cortisol from the overlying cortex via the portal venous system. This is why adrenal phaeochromocytomas can produce epinephrine, but extra-adrenal paragangliomas (which lack this cortisol-rich environment) typically produce only norepinephrine.
- 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
Aetiology
This is the core of understanding adrenal incidentalomas. The causes span a wide spectrum from completely benign, non-functional lesions to aggressive malignancies.
Detailed Aetiology by Category
- Benign clonal proliferation of adrenocortical cells
- Usually unilateral, < 4 cm, well-circumscribed, homogeneous
- Lipid-rich (intracellular cholesterol and lipid droplets used for steroidogenesis) → characteristically low attenuation on unenhanced CT ( < 10 HU) and rapid contrast washout ( > 50% absolute washout at 15 minutes)
- Pathophysiology: Somatic mutations in various genes (e.g., CTNNB1 for β-catenin, PRKACA for cortisol-secreting ones) drive clonal expansion. Most remain non-functional.
- Autonomous cortisol production without the overt clinical phenotype of Cushing's syndrome
- Modern terminology (per 2016 ESE/ENSAT guidelines and 2023 updates): "autonomous cortisol secretion" (ACS) or "possible ACS" rather than "subclinical Cushing's"
- Important because it is associated with increased cardiovascular risk, metabolic syndrome, osteoporosis, and increased mortality even without overt Cushing's
- Pathophysiology: Cortical adenoma cells express constitutively active ACTH-independent cortisol production → mild cortisol excess → partial suppression of ACTH → contralateral adrenal may atrophy
- Catecholamine-secreting tumour from chromaffin cells of the adrenal medulla
- "Phaeo" (Greek phaios) = dusky/dark, "chromo" = colour, "cytoma" = cell tumour — named because the tumour cells turn dark brown when stained with chromium salts (chromaffin reaction)
Epidemiology — "Rule of 10" (traditional, now considered outdated): [4][5]
- 10% Children
- 10% Familial (MEN2/VHL/NF-1) (up to 24-40%)
- 10% Extra-adrenal (paraganglioma) (up to 15-20%)
- 10% Bilateral
- 10% Malignant (up to 8-36%)
- 10% Not associated with hypertension
- 10% Recurrence
The "traditional rule of 10 is no longer valid" [5] — genetic testing has revealed much higher familial rates (~40%), and malignancy/extra-adrenal rates are also higher than traditionally taught.
Aetiology of phaeochromocytoma: [5][6]
- Sporadic (most common)
- Familial (AD inheritance):
- NF1 (neurofibromatosis type 1)
- MEN2 (RET oncogene): MEN2A (phaeochromocytoma + medullary thyroid carcinoma + parathyroid hyperplasia), MEN2B (phaeochromocytoma + MTC + mucosal neuromas) [4]
- Von Hippel-Lindau disease (retinal and cerebral haemangioblastoma, cystic RCC, phaeochromocytoma) [5]
- Carney triad (GIST + pulmonary chondroma + paragangliomas): succinate dehydrogenase gene mutation [6]
- Paraganglioma syndrome (PGL) types 1-4: H&N paragangliomas [5]
Paraganglioma definition: [6]
- Paraganglioma: tumour arising from chromaffin cells of sympathetic / parasympathetic nervous system
- Sympathetic paraganglioma: usually catecholamine-secreting (i.e., "extra-adrenal phaeochromocytoma"), located along the sympathetic chain
- Parasympathetic paraganglioma: usually non-functional, located in neck / skull base
- Extra-adrenal sites: para-aortic (75%), urinary bladder (10%), thorax (10%), skull base / neck / pelvis (5%) [6]
- The Organ of Zuckerkandl (para-aortic body at the aortic bifurcation) is the most common extra-adrenal site [6]
- Aldosterone-producing adenoma (APA) in the zona glomerulosa
- Causes hypertension + hypokalaemia + metabolic alkalosis
- Pathophysiology: Autonomous aldosterone secretion → Na⁺/H₂O retention → volume expansion → hypertension; K⁺ wasting → hypokalaemia; H⁺ wasting → metabolic alkalosis
- Rare but aggressive malignancy of the adrenal cortex
- Incidence: ~0.7-2 per million per year
- Bimodal age distribution: children < 5 years and adults 40-50 years
- ~60% are functional (cortisol ± androgens most common; pure androgen-secreting or oestrogen-secreting tumours also occur)
- Usually large ( > 4 cm, often > 6 cm) at diagnosis
- Pathophysiology: Associated with TP53 mutations (Li-Fraumeni syndrome), IGF-2 overexpression, Wnt/β-catenin pathway activation, Beckwith-Wiedemann syndrome (11p15 imprinting defect)
- Poor prognosis: 5-year survival ~35-60% overall, < 15% if metastatic
- The adrenal gland is a common site for metastatic disease — the third most common site after lung and liver
- Most common primaries: lung (most common), breast, melanoma, RCC, lymphoma
- In patients with known extra-adrenal malignancy and a new adrenal mass, the probability of metastasis is 50-75%
- Usually non-functional, but bilateral extensive metastases can rarely cause adrenal insufficiency (Addisonian crisis)
- Pathophysiology: Rich arterial blood supply of the adrenal glands + sinusoidal vascular architecture facilitates haematogenous tumour seeding
- Benign tumour composed of mature adipose tissue and haematopoietic elements
- Characteristic appearance: very low (fat) attenuation on CT (often < -30 HU) — essentially diagnostic
- Non-functional, usually incidental
- Only requires surgical intervention if very large ( > 6 cm) or symptomatic (haemorrhage)
- Adrenal cysts: endothelial cysts, pseudocysts, parasitic cysts (echinococcus in endemic areas)
- Adrenal haemorrhage: can occur in trauma, anticoagulation, sepsis (Waterhouse-Friderichsen syndrome in meningococcal sepsis), postoperative, or neonatal stress
- Ganglioneuroma: benign tumour of the sympathetic ganglia, usually non-functional
- Granulomatous disease: TB (important in Hong Kong), histoplasmosis, sarcoidosis — can cause bilateral adrenal enlargement and eventually adrenal insufficiency
- Congenital adrenal hyperplasia: bilateral adrenal hyperplasia in untreated or under-treated CAH
- Amyloidosis: infiltrative, can cause adrenal insufficiency
Hong Kong Context
In Hong Kong, consider TB as an important cause of bilateral adrenal enlargement/calcification. Adrenal TB can present as Addison's disease and is still seen, especially in elderly patients or those from endemic areas. Also, given the high prevalence of hepatocellular carcinoma and lung cancer in Hong Kong, adrenal metastases are commonly encountered.
Pathophysiology of Key Functional Adrenal Incidentalomas
- 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.
Classification of Adrenal Incidentalomas
| Category | Examples | Approximate Frequency |
|---|---|---|
| Non-functional | Adenoma, myelolipoma, cyst, haematoma, ganglioneuroma | ~75-85% |
| Functional | Subclinical Cushing's (5-20%), Phaeochromocytoma (5-7%), Conn's (1-2%), Androgen-secreting (rare) | ~15-25% |
| Category | Examples |
|---|---|
| Benign | Adenoma, myelolipoma, cyst, ganglioneuroma, haematoma |
| Malignant — Primary | Adrenocortical carcinoma, malignant phaeochromocytoma |
| Malignant — Secondary | Metastases (lung, breast, melanoma, RCC, lymphoma) |
| Indeterminate | Lesions with atypical imaging features requiring follow-up or further workup |
| Feature | Likely Benign Adenoma | Suspicious for Malignancy |
|---|---|---|
| Size | < 4 cm | > 4 cm (90% malignant tumours are > 4 cm) [2][3] |
| Configuration | Homogeneous, smooth border [2][3] | Irregular margins, heterogeneous, necrosis, calcification |
| Lipid content (HU) | < 10 HU on unenhanced CT (lipid-rich) [2][3] | > 10 HU (lipid-poor) |
| Contrast washout | Rapid washout (> 50% absolute, > 40% relative at 15 min) | Slow washout (contrast retention) → malignant tumours tend to retain contrast [2][3] |
| Growth | Stable over time | > 1 cm growth → suspicious [2][3] |
Key CT Features for Benign vs. Malignant
A common exam mistake is forgetting the specific HU cut-off. Unenhanced CT attenuation < 10 HU strongly suggests a lipid-rich adenoma (sensitivity ~71%, specificity ~98%). If > 10 HU, contrast washout studies or chemical-shift MRI are needed. Size > 4 cm is the most important size threshold for considering surgical resection. 90% of malignant adrenal tumours are > 4 cm [2][3].
Clinical Features
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.
A. Symptoms
| Symptom | Pathophysiological Basis |
|---|---|
| Weight gain (central) | Cortisol promotes visceral adipogenesis via upregulation of lipoprotein lipase in visceral fat; also causes insulin resistance → hyperinsulinaemia → lipogenesis |
| Proximal muscle weakness | Cortisol causes protein catabolism in skeletal muscle → myopathy |
| Easy bruising | Cortisol inhibits collagen synthesis → thin, fragile capillaries and skin |
| Mood changes, depression, insomnia | Cortisol crosses BBB, affects hippocampal and limbic system glucocorticoid receptors |
| Polyuria, polydipsia | Hyperglycaemia (cortisol → gluconeogenesis + insulin resistance) → osmotic diuresis; also cortisol inhibits ADH |
| Diabetes | Cortisol promotes hepatic gluconeogenesis + peripheral insulin resistance [1] |
| Menstrual irregularity (women) | Cortisol suppresses GnRH pulsatility → ↓LH/FSH |
| Recurrent infections | Cortisol is immunosuppressive (↓T-cell function, ↓inflammatory cytokines) |
| Symptom | Pathophysiological Basis |
|---|---|
| Classic triad: paroxysmal headache + sweating + palpitations [1][5][6] | Headache: sudden hypertension → ↑intracranial arterial pressure. Sweating (perspiration): direct sympathetic activation of eccrine sweat glands. Palpitations: β₁-adrenergic stimulation → ↑HR and ↑contractility |
| Episodic/paroxysmal hypertension [5][6] | Intermittent catecholamine release → α₁-mediated vasoconstriction |
| Anxiety, tremor, panic-like episodes | β-adrenergic stimulation of CNS and peripheral sympathetic system; especially common in adrenaline-producing tumours (adrenaline has greater β₂ effects → tremor, anxiety) [5] |
| Pallor during attacks | α₁-mediated cutaneous vasoconstriction (note: NOT flushing — this is a classic distinguishing feature from carcinoid) [6] |
| Weight loss | Catecholamine-driven hypermetabolism (↑basal metabolic rate, ↑lipolysis, ↑glycogenolysis) |
| Pressor response during procedures or with certain drugs (TCA, IV contrast) or food (cheese) [6] | Tyramine-containing foods, drugs that block noradrenaline reuptake (TCAs), or contrast agents can precipitate massive catecholamine release from tumour |
The "5 P's" of Phaeochromocytoma: Pressure (HT), Pain (headache, chest pain), Palpitation, Perspiration, Pallor (vasoconstriction) [6]
Phaeochromocytoma crisis: APO, ICH — acute pulmonary oedema (from catecholamine-induced cardiomyopathy + afterload) and intracranial haemorrhage (from severe hypertension) [6]
| Symptom | Pathophysiological Basis |
|---|---|
| Hypertension (often resistant) | Aldosterone → Na⁺/H₂O retention → volume expansion |
| Muscle cramps, weakness | Hypokalaemia → impaired muscle cell repolarisation |
| Polyuria, nocturia | Hypokalaemia → nephrogenic diabetes insipidus (impaired renal concentrating ability via downregulation of aquaporin-2) |
| Fatigue | Hypokalaemia → generalised cellular dysfunction |
| Paraesthesias | Hypokalaemia → altered nerve excitability |
| Symptom | Pathophysiological Basis |
|---|---|
| Hirsutism, acne (in women) | Excess adrenal androgens → peripheral conversion to DHT → stimulation of pilosebaceous units |
| Deepening of voice (in women) | Androgen effect on laryngeal cartilage growth |
| Menstrual irregularity | Androgen excess disrupts HPG axis |
| Rapid virilisation | Particularly concerning for adrenocortical carcinoma if acute onset |
| Symptom | Pathophysiological Basis |
|---|---|
| Constitutional symptoms: weight loss, malaise, anorexia, night sweats | Tumour-related cytokine production (TNF-α, IL-6) |
| Abdominal/flank pain or fullness | Large mass causing local compression or capsular stretching |
| Symptoms of primary malignancy | If metastatic disease: cough (lung), breast lump, skin lesion (melanoma), haematuria (RCC) |
History of MEN should be sought: [1][4]
| Syndrome | Gene | Associated Tumours |
|---|---|---|
| MEN1 | MEN1 (encoding menin) | Pancreatic endocrine tumour, Pituitary tumour (prolactinoma), Parathyroid hyperplasia |
| MEN2A | RET | Medullary thyroid carcinoma, Phaeochromocytoma, Parathyroid hyperplasia |
| MEN2B | RET | Medullary thyroid carcinoma, Phaeochromocytoma, Mucosal neuroma / intestinal ganglioneuroma |
B. Signs
| Sign | What It Suggests | Pathophysiological Basis |
|---|---|---|
| Blood pressure — bilateral arms, supine and standing | All functional tumours cause HTN; postural hypotension in phaeochromocytoma | See above |
| H'stix (blood glucose) [1] | Cushing's or phaeochromocytoma | Cortisol → gluconeogenesis; catecholamines → glycogenolysis |
| BMI and body habitus | Central obesity in Cushing's | Cortisol-driven visceral fat deposition |
| Sign | Pathophysiological Basis |
|---|---|
| Moon face [1] | Fat redistribution to face (cortisol-driven visceral/facial adipogenesis) |
| Buffalo hump [1] | Fat deposition in dorsocervical area |
| Central obesity with thin limbs [1] | Visceral fat deposition + peripheral muscle wasting |
| Proximal muscle wasting [1] | Cortisol-induced protein catabolism in type II muscle fibres |
| Purple striae (> 1 cm wide) [1] | Cortisol weakens collagen in dermis → skin thins → subcutaneous blood vessels visible; stretching from obesity further tears weakened skin |
| Hirsutism [1] | Adrenal androgen co-secretion (DHEA-S) |
| Easy bruising, thin skin [1] | Cortisol → ↓collagen and connective tissue → capillary fragility |
| Plethora (facial) | Thinning of facial skin revealing underlying vasculature |
| Supraclavicular fat pads | Additional site of cortisol-driven fat redistribution |
| Hyperpigmentation | Only in ACTH-dependent Cushing's (ACTH shares a precursor — POMC — with MSH) — NOT typical in adrenal Cushing's (ACTH is suppressed) |
Exam Pearl: Pigmentation in Adrenal vs. Pituitary Cushing's
Hyperpigmentation occurs in ACTH-dependent Cushing's (pituitary or ectopic) because ACTH is derived from POMC (pro-opiomelanocortin), which is also cleaved to produce α-MSH. In adrenal Cushing's (adenoma/carcinoma), ACTH is suppressed by negative feedback → NO pigmentation. This is a classic exam discriminator.
| Sign | Pathophysiological Basis |
|---|---|
| Hypertension (sustained or paroxysmal) | Catecholamine-mediated vasoconstriction |
| Postural hypotension [5] | Chronic catecholamine excess → volume depletion + receptor downregulation + impaired baroreflexes |
| Tachycardia | β₁ stimulation |
| Pallor (during spells) | α₁ cutaneous vasoconstriction |
| Tremor | β₂ stimulation |
| Diaphoresis | Sympathetic cholinergic activation of eccrine glands |
| Neurofibromatosis skin stigmata | Association with NF1 (café-au-lait spots, neurofibromas, axillary freckling) [7] |
| Sign | Pathophysiological Basis |
|---|---|
| Hypertension (often severe/resistant) | Volume expansion from Na⁺/H₂O retention |
| Hypokalaemia-related signs: ↓reflexes, muscle weakness, arrhythmias (esp AF) [7] | K⁺ depletion → impaired muscle and cardiac cell repolarisation |
| No oedema (typically) | Aldosterone escape phenomenon: initial Na⁺ retention → volume expansion → ↑ANP + pressure natriuresis → re-establishes Na⁺ balance (but K⁺ wasting continues because it is not subject to this escape) |
| Sign | Pathophysiological Basis |
|---|---|
| Abdominal mass [1] | ACC is often large ( > 6 cm) at presentation |
| Signs of virilisation in women | Androgen-secreting ACC |
| Feminisation in men | Oestrogen-secreting ACC (rare) |
| Mixed Cushingoid + virilisation | ACC often co-secretes cortisol + androgens |
| Cachexia, lymphadenopathy | Advanced/metastatic disease |
| Sign | Syndrome |
|---|---|
| Café-au-lait spots, neurofibromas, axillary freckling | NF1 |
| Thyroid mass [1] | MEN2 (medullary thyroid carcinoma) |
| Retinal haemangioblastoma | VHL |
| Mucosal neuromas (lips, tongue) | MEN2B |
History taking for adrenal incidentaloma should cover: [1]
- History of hypertension (all functional tumours), diabetes (Cushing's)
- S/S of Cushing's syndrome: weight gain, striae
- Triad of phaeochromocytoma: episodic headache, sweating, palpitations
- FHx / Hx of endocrine tumours (MEN)
- Drug history (exogenous steroids, herbal medicines)
- Symptoms of androgen excess (women)
- Symptoms suggesting malignancy (weight loss, known cancer history)
Physical examination should include: [1]
- BP, H'stix (blood glucose)
- Cushingoid features: moon face, buffalo hump, proximal muscle wasting, central obesity, striae, hirsutism, easy bruising
- Abdominal mass
- Thyroid mass
- Skin examination (NF1 stigmata, pigmentation)
- Postural blood pressure
Investigations — Screening for Functional Status
The Triple Screen
Every adrenal incidentaloma > 1 cm that appears benign on imaging should be screened with: ONDST + spot ARR + 24h urine metanephrines [1]. This covers the three most common functional tumours (Cushing's, Conn's, phaeochromocytoma).
| Condition | Screening Test | Confirmatory Test |
|---|---|---|
| Cushing's syndrome | 1 mg ONDST ( > 50 nmol/L abnormal) | Low-dose DST |
| 24h urine free cortisol | ||
| Midnight salivary cortisol | ||
| Conn's syndrome | Aldosterone:Renin Ratio (ARR) | Salt loading test |
| RFT for hypoK | Saline suppression test | |
| Phaeochromocytoma | 24h urine metanephrines | Clonidine suppression test |
-
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)
Critical Safety Rule
Phaeochromocytoma must ALWAYS be excluded BEFORE any surgical intervention or biopsy of an adrenal mass. Biopsy or manipulation of an undiagnosed phaeochromocytoma can precipitate a life-threatening hypertensive crisis. Histology is NOT useful in differentiating benign/malignant adrenal tumours (same appearance). Biopsy may cause precipitation of HTN crisis and tumour seeding if the tumour is a phaeochromocytoma or primary adrenal cancer. [2][3]
Radiological features of malignancy on CT/MRI: [2][3]
- Size: 90% malignant tumours > 4 cm in diameter
- Configuration: homogeneous, smooth border → more likely benign
- Lipid content: adenomas usually lipid-rich → fat attenuation ( < 10 HU) on CT
- Enhancement: malignant tumours tend to retain contrast
- Rarely indicated
- Usually only reserved for confirmation of adrenal metastasis (in patients with known extra-adrenal malignancy)
- NOT for primary adrenal tumours — because:
- Histology is NOT useful in differentiating benign from malignant adrenal cortical tumours (they look similar)
- Risk of hypertensive crisis if phaeochromocytoma
- 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]
High Yield Summary
Definition: Adrenal mass > 1 cm found incidentally on imaging for an unrelated indication.
Two key questions: (1) Is it functional? (2) Is it malignant?
Most common cause: Non-functioning cortical adenoma (~85%).
Functional causes: Subclinical Cushing's (5-20%), phaeochromocytoma (5-7%), Conn's (~1-2%).
Malignant causes: Primary (adrenocortical carcinoma 2-5%), secondary metastases (lung, breast, melanoma, RCC — more common than primary in patients with known cancer).
Triple screen for all incidentalomas > 1 cm: ONDST + plasma/urine metanephrines + ARR (if hypertensive).
CT features of benign adenoma: < 4 cm, homogeneous, smooth border, < 10 HU unenhanced, rapid contrast washout.
CT features suggesting malignancy: > 4 cm, heterogeneous, irregular margins, > 10 HU, slow contrast washout.
Biopsy: Almost never indicated for primary adrenal lesions (cannot distinguish benign from malignant cortical tumours, risk of hypertensive crisis if phaeochromocytoma). Only for confirming metastasis.
Always exclude phaeochromocytoma before surgery or biopsy to avoid hypertensive crisis.
Phaeochromocytoma rule of 10 is outdated — familial rate is up to 40%, malignancy up to 36%.
Surgical indications: Functional tumour, > 4 cm, radiologically suspicious, or growing > 1 cm on follow-up.
Active Recall - Adrenal Incidentaloma (Definition to Clinical Features)
[1] Senior notes: maxim.md (Adrenal incidentaloma section, pp. 432-434) [2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 Adrenal Incidentaloma, p. 68) [3] Senior notes: Ryan Ho Fundamentals.pdf (Section B: Adrenal Incidentaloma, p. 438) [4] Senior notes: felixlai.md (MEN table, pp. 1469-1533) [5] Senior notes: Ryan Ho Endocrine.pdf (Section on Phaeochromocytoma, p. 66) [6] Senior notes: maxim.md (Phaeochromocytoma section, p. 435) [7] Senior notes: Ryan Ho Cardiology.pdf (Secondary hypertension table, p. 178) [8] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Functional imaging for adrenal tumours, pp. 71-72)
Differential Diagnosis of Adrenal Incidentaloma
The differential diagnosis of an adrenal incidentaloma is essentially the differential of "what can this adrenal mass be?" You are not diagnosing a disease from symptoms — you are characterising a mass that was found by accident. The DDx is therefore structured around the two fundamental questions: Is it functional? Is it malignant? [1][2][3]
Think of it systematically by tissue of origin within the adrenal gland, then add extrinsic/non-adrenal mimics.
The adrenal gland has two compartments (cortex and medulla), and masses can also arise from surrounding structures or arrive via the bloodstream. This anatomy-based framework ensures you don't miss anything:
| Category | Diagnosis | Frequency Among Incidentalomas | Key Distinguishing Features | Functional? |
|---|---|---|---|---|
| Cortical — Benign | Non-functioning adenoma | ~85% (most common) [1][2][3] | Lipid-rich → < 10 HU on unenhanced CT, homogeneous, smooth border, < 4 cm, rapid contrast washout ( > 50% absolute at 15 min) [2][3] | No |
| Cortical — Functional | Subclinical Cushing's / Autonomous cortisol secretion | ~5-20% (often underdiagnosed) [1] | ONDST > 50 nmol/L; may have subtle metabolic syndrome, osteoporosis, DM without overt Cushingoid features. ACTH suppressed. Contralateral adrenal may atrophy. [1][4] | Yes — cortisol |
| Cortical — Functional | Conn's syndrome (aldosterone-producing adenoma) | ~1-2% [1] | Resistant HTN + hypokalaemia + metabolic alkalosis; ARR elevated [1][5]; small ( < 2 cm) and lipid-rich. Adrenal venous sampling needed to lateralise before surgery [6][7] | Yes — aldosterone |
| Cortical — Functional | Androgen-secreting adenoma | Rare | Virilisation in women (hirsutism, deepening voice, clitoromegaly); elevated DHEA-S, testosterone | Yes — androgens |
| Cortical — Malignant | Adrenocortical carcinoma (ACC) | ~2-5% [2][3] | Large ( > 4 cm, often > 6 cm), heterogeneous, irregular margins, contrast retention, calcification, necrosis, local invasion (IVC thrombus). ~60% functional (cortisol ± androgens). Mixed cortisol + androgen secretion is a red flag. Rapid virilisation in women highly suspicious. | Often (mixed cortisol + androgens) |
| Medullary | Phaeochromocytoma | ~5-7% [1][2] | Classic triad: paroxysmal headache + sweating + palpitations [1][8][9]; 5 P's: Pressure, Pain, Palpitation, Perspiration, Pallor [8][9]; Postural hypotension despite HTN [8]; CT shows heterogeneous enhancing mass, often > 10 HU, may show cystic/haemorrhagic change ("light bulb" bright on T2 MRI). 24h urine/plasma fractionated metanephrines for screening [1][2]. MIBG scan: sensitivity 85%, specificity 95% [10] | Yes — catecholamines |
| Medullary | Ganglioneuroma | Rare | Benign, well-circumscribed, slow-growing. Non-functional. Homogeneous on CT with gradual enhancement. Usually in younger patients. | No |
| Medullary | Neuroblastoma | Rare (children) | The most common extracranial solid tumour of childhood. Elevated urinary VMA/HVA. Calcification on CT, crosses midline. | Catecholamine metabolites elevated |
| Other adrenal | Myelolipoma | ~5-7% | Very low (fat) attenuation on CT (often < −30 HU) — essentially pathognomonic. Contains mature fat + haematopoietic elements. Non-functional. Only resect if large ( > 6 cm) or symptomatic (haemorrhage). | No |
| Other adrenal | Adrenal cyst / pseudocyst | ~4-5% | Well-defined, thin-walled, fluid-density on CT (0-20 HU), no enhancement of cyst contents. Subtypes: endothelial cyst, pseudocyst, parasitic (echinococcal — consider in endemic regions). | No |
| Other adrenal | Adrenal haemorrhage | Variable | Acute: high attenuation on unenhanced CT ( > 50 HU); chronic: may calcify. History of trauma, anticoagulation, sepsis (Waterhouse-Friderichsen), postoperative, neonatal stress. Can cause adrenal insufficiency if bilateral. | No (but can cause insufficiency) |
| Other adrenal | Granulomatous disease (TB, histoplasmosis, sarcoidosis) | Uncommon but important in HK [2][3] | Bilateral adrenal enlargement, ± calcification (especially old TB). May present as Addison's disease (primary adrenal insufficiency) if enough gland is destroyed. In Hong Kong, TB remains an important cause. | No (but may → insufficiency) |
| Extrinsic | Metastasis | Highly variable; up to 50-75% of adrenal masses in patients with known extra-adrenal malignancy | Most common primaries: lung (most common), breast, melanoma, RCC, lymphoma. Usually > 10 HU, heterogeneous, may be bilateral. Often grows on serial imaging. Biopsy is reserved for confirmation of adrenal metastasis — the main valid indication for adrenal biopsy [2][3]. Usually non-functional but bilateral extensive disease can → adrenal insufficiency. | Usually no |
| Extrinsic | Primary adrenal lymphoma | Very rare | Usually bilateral, large, homogeneous soft-tissue density. Associated with adrenal insufficiency. Consider in elderly with bilateral adrenal masses + B symptoms. | No |
| Extrinsic | Retroperitoneal mass mimicking adrenal | Rare | Upper pole renal mass, pancreatic tail lesion, retroperitoneal sarcoma, or lymphadenopathy can mimic an adrenal mass on imaging. Thin-slice CT or MRI with multiplanar reconstruction can clarify the organ of origin. | N/A |
How to Differentiate: A Logical Approach
The differential diagnosis is narrowed by integrating three streams of information:
- 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:
| Imaging Finding | Favoured Diagnosis | Why |
|---|---|---|
| < 10 HU unenhanced CT | Lipid-rich adenoma [2][3] | Adenomas are packed with intracellular cholesterol/lipid droplets (precursors for steroidogenesis) → low attenuation |
| < −30 HU (macroscopic fat) | Myelolipoma | Contains mature adipose tissue — the only adrenal tumour with macroscopic fat |
| Fluid density (0-20 HU), no enhancement | Adrenal cyst | Simple fluid-filled cavity |
| > 50 HU unenhanced, acute setting | Adrenal haemorrhage | Fresh blood is hyperdense on CT |
| > 10 HU, slow contrast washout | Malignant (ACC or metastasis) or phaeochromocytoma [2][3] | Malignant masses have disordered, leaky vasculature that retains contrast; phaeochromocytomas are also lipid-poor |
| > 4 cm, heterogeneous, irregular | ACC or metastasis [2][3] | 90% of malignant adrenal tumours are > 4 cm [2][3] |
| Bilateral enlargement | Metastases, lymphoma, bilateral cortical hyperplasia, congenital adrenal hyperplasia, granulomatous disease, bilateral phaeochromocytoma (genetic syndrome) | The bilateral pattern immediately narrows the DDx and raises concern for systemic disease |
| "Light bulb" bright on T2-weighted MRI | Phaeochromocytoma (classic but not universal) | High water content and vascularity of chromaffin tumour tissue |
| Calcification | Old granulomatous disease (TB), haemorrhage, ACC, neuroblastoma | Chronic inflammation → dystrophic calcification; ACC and neuroblastoma may have irregular calcification |
Exam Favourite: How to Distinguish Adenoma from Metastasis on CT
This is a very common exam question. The key discriminator is unenhanced CT attenuation:
- < 10 HU = lipid-rich adenoma (specificity ~98%) → safe to follow up
- > 10 HU = indeterminate → perform contrast-enhanced CT with washout study:
- Absolute washout > 50% at 15 min = adenoma (even if lipid-poor)
- Absolute washout < 50% = suspicious for metastasis, ACC, or phaeochromocytoma
- Chemical-shift MRI (in-phase/opposed-phase) can also identify lipid-rich adenomas: signal drop on opposed-phase images indicates intracellular lipid (adenoma). Metastases and phaeochromocytomas do NOT show this signal drop.
Screening tests for functional tumours: ONDST + spot ARR + 24h urine metanephrines [1]
| Test | What It Detects | Result Suggesting Functionality |
|---|---|---|
| 1 mg ONDST [1][4] | Autonomous cortisol secretion | Cortisol > 50 nmol/L (1.8 µg/dL) |
| 24h urine free cortisol [1][4] | Cushing's syndrome | Elevated above upper limit of normal |
| Midnight salivary cortisol [1][4] | Loss of circadian rhythm (Cushing's) | Elevated (loss of nadir) |
| ARR [1][5] | Primary hyperaldosteronism | Elevated ratio (varies by assay; typically aldosterone > 15 ng/dL with renin suppressed) |
| 24h urine fractionated metanephrines [1][8] | Phaeochromocytoma | Elevated metanephrine/normetanephrine (most sensitive screening marker) [8][9] |
| Plasma fractionated metanephrines [8] | Phaeochromocytoma | Sensitivity 96-100%, specificity 85-89% [8] |
| Androgen profile (DHEA-S, testosterone) [2] | Androgen-secreting tumour/ACC | Elevated; particularly important if virilisation present |
Why Screen ALL Incidentalomas for Phaeochromocytoma?
Even if the mass looks benign on CT, phaeochromocytoma must be excluded before any invasive procedure (including biopsy and surgery). An undiagnosed phaeochromocytoma manipulated during biopsy or surgery can cause a fatal hypertensive crisis [2][3]. This is non-negotiable. The screening test (plasma/urine metanephrines) is cheap and non-invasive — there is no excuse to skip it.
Differential Diagnosis of Specific Presentations
Beyond "what is this mass?", certain clinical presentations triggered by the incidentaloma have their own differential:
This comes up when phaeochromocytoma is suspected but you need to consider mimics [8]:
| Condition | Key Differentiating Feature |
|---|---|
| Phaeochromocytoma | Sweating but do NOT flush (pallor instead, due to vasoconstriction) [8] |
| Carcinoid syndrome | Flushing + diarrhoea + wheeze (serotonin + histamine-mediated vasodilation) [8] |
| Thyrotoxicosis | Not usually episodic; warm, moist skin, heat intolerance, weight loss, tremor [8] |
| Oestrogen/testosterone deficiency (e.g. menopause, castration) | Hot flushes, age-appropriate, no hypertension [8] |
| Systemic mastocytosis | Histamine release → flushing, urticaria, pruritus, GI symptoms; elevated serum tryptase [8] |
| Allergy / anaphylaxis | Temporal relationship with allergen exposure [8] |
| Panic disorder / anxiety | Psychiatric history, situational triggers, no hypertension during episodes |
| Medullary thyroid carcinoma | Calcitonin-mediated flushing + diarrhoea; consider if FHx of MEN2 |
Clinical Pearl: Pallor vs. Flushing
A key exam discriminator: phaeochromocytoma causes pallor (α₁-mediated vasoconstriction), whereas carcinoid causes flushing (serotonin/histamine-mediated vasodilation). If the patient says they go pale during attacks — think phaeochromocytoma. If they go red — think carcinoid.
When the incidentaloma is found in the workup for resistant hypertension, the differential for the hypertension itself includes [5][7]:
| Cause | Frequency | Screening | Key Features |
|---|---|---|---|
| Primary aldosteronism (Conn's) | 8-20% [5] | Plasma ARR [1][5] | Resistant HTN, hypokalaemia, alkalosis, muscle cramps, arrhythmias (esp AF with hypoK) [5] |
| Phaeochromocytoma/paraganglioma | 0.1-0.6% [5] | 24h urine fractionated metanephrines, plasma metanephrines [5] | Paroxysmal HTN/crisis, spells of headache + sweating + palpitations + pallor, adrenal incidentaloma, NF stigmata [5] |
| Cushing's syndrome | < 0.1% [5] | 1 mg ONDST [5] | Central obesity, Cushingoid features, proximal myopathy, hyperglycaemia [5] |
| Renal artery stenosis | 5-34% | Renal duplex USG, MRA, CT | Abrupt onset/worsening HTN, flash pulmonary oedema, renal bruit [5] |
| Renal parenchymal disease | 1-2% | Renal USG, urinalysis, biopsy | Haematuria, proteinuria, recurrent UTI, polycystic kidney disease [5] |
| OSA | 25-50% | Polysomnography | Snoring, restless sleep, daytime sleepiness, obesity [5] |
| Coarctation of aorta | 0.1% | Echo, CTA/MRA thorax | Young HTN < 30y, UL > LL BP, radiofemoral delay, continuous murmur [5] |
This subset is particularly important because it narrows the differential significantly:
| Diagnosis | Why Bilateral? |
|---|---|
| Metastases | Haematogenous spread to both glands (lung, breast, melanoma most common) |
| Lymphoma | Systemic disease, bilateral involvement |
| Bilateral adrenal hyperplasia | ACTH-dependent (Cushing's disease, ectopic ACTH) or bilateral idiopathic hyperaldosteronism (BIAH) |
| Congenital adrenal hyperplasia | Enzyme deficiency → ACTH drive → bilateral hyperplasia |
| Granulomatous disease (TB, sarcoid, histoplasmosis) | Bilateral infiltration |
| Bilateral phaeochromocytoma | Strongly suggests genetic syndrome (MEN2, VHL, NF1); sporadic bilateral is very rare |
| Amyloidosis | Bilateral infiltration |
| Bilateral haemorrhage | Anticoagulation, meningococcal sepsis (Waterhouse-Friderichsen), DIC |
| ACTH-independent macronodular adrenal hyperplasia | Rare cause of Cushing's; bilateral large nodules |
Bilateral Adrenal Masses = Think Systemic
If the CT shows bilateral adrenal masses, you should immediately think of systemic processes: metastases, lymphoma, granulomatous disease, bilateral haemorrhage, congenital adrenal hyperplasia, or a genetic phaeochromocytoma syndrome. A solitary unilateral mass is much more likely to be a benign adenoma.
This is a critical sub-differential within primary hyperaldosteronism because management differs completely [6][11]:
| Feature | Aldosterone-Producing Adenoma (APA) | Bilateral Idiopathic Adrenal Hyperplasia (BIAH) |
|---|---|---|
| Laterality | Unilateral [6][11] | Bilateral [6][11] |
| Regulation | ACTH-dependent [6][11] | Angiotensin-dependent [6][11] |
| Biochemical severity | More significant disturbance (very low K, very high Ald) [6][11] | Less significant disturbance [6][11] |
| Postural test | ↓Ald in 70-90% (paradoxical — due to ↓ACTH drive at noon) [6][11] | ↑Ald in 90% (exaggerated response to ↑Ang II in erect posture) [6][11] |
| Adrenal venous sampling | ↑ipsilaterally, ↓contralaterally [11] | ↑bilaterally [11] |
| CT/MRI | Unilateral tumour [11] | Normal or slightly enlarged bilateral [11] |
| Management | Unilateral laparoscopic adrenalectomy (after medical pre-op with spironolactone) [6][11] | Medical treatment: aldosterone antagonist (spironolactone/eplerenone), K-sparing diuretics (amiloride) — bilateral adrenalectomy would cause adrenal crisis [6][11] |
Why does the postural test work? In a normal person, standing up activates the RAAS → aldosterone rises. In an APA, aldosterone production is driven by ACTH (not angiotensin II), so aldosterone paradoxically falls at noon as ACTH follows its circadian decline. In BIAH, aldosterone is angiotensin-sensitive, so it rises exaggeratedly with posture. [6][11]
High Yield Summary — Differential Diagnosis of Adrenal Incidentaloma
Most common cause overall: Non-functioning cortical adenoma (~85%).
Most common functional cause: Subclinical autonomous cortisol secretion (5-20%).
Most common malignant cause in patients WITH known cancer: Metastasis (50-75% of adrenal masses in cancer patients).
Most common malignant cause in patients WITHOUT known cancer: Adrenocortical carcinoma (2-5%).
Key CT discriminators: < 10 HU = adenoma; < −30 HU = myelolipoma; > 10 HU with slow washout = suspicious (ACC, metastasis, phaeochromocytoma).
Size matters: > 4 cm = 90% chance of malignancy among malignant tumours → surgical indication.
Bilateral masses: Think systemic — metastases, lymphoma, granulomatous disease, bilateral hyperplasia, genetic phaeochromocytoma syndrome, haemorrhage.
Phaeochromocytoma: Pallor (NOT flushing), paroxysmal HTN, classic triad of headache + sweating + palpitations.
Conn's adenoma vs. BIAH: Postural test — APA shows paradoxical ↓aldosterone (ACTH-dependent); BIAH shows ↑aldosterone (angiotensin-dependent). Management differs: surgery for APA, medical for BIAH.
Always exclude phaeochromocytoma (metanephrines) before biopsy or surgery.
Biopsy only for suspected metastasis — not for primary adrenal tumours.
Active Recall - Differential Diagnosis of Adrenal Incidentaloma
References
[1] Senior notes: maxim.md (Adrenal incidentaloma section, pp. 432-434) [2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 Adrenal Incidentaloma, p. 68) [3] Senior notes: Ryan Ho Fundamentals.pdf (Section B: Adrenal Incidentaloma, p. 438) [4] Senior notes: Ryan Ho Chemical Path.pdf (Section 4.1 Diagnosis of Cushing Syndrome, p. 29) [5] Senior notes: Ryan Ho Cardiology.pdf (Secondary hypertension table, p. 178) [6] Senior notes: maxim.md (Conn's syndrome section, pp. 434-435) [7] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Interventional radiology — adrenal venous sampling, p. 79) [8] Senior notes: Ryan Ho Endocrine.pdf (Phaeochromocytoma — clinical features and DDx, pp. 66-67) [9] Senior notes: felixlai.md (Phaeochromocytoma clinical manifestation and diagnosis, pp. 1536-1537) [10] Senior notes: Ryan Ho Diagnostic Radiology.pdf (MIBG scan, p. 71) [11] Senior notes: Ryan Ho Endocrine.pdf (Conn's — adenoma vs. hyperplasia, p. 59)
Overarching Principle
Unlike many medical conditions, adrenal incidentaloma does not have a single set of "diagnostic criteria" in the traditional sense (like the Jones criteria for rheumatic fever or the McDonald criteria for MS). Instead, the diagnosis is the radiological finding itself — an adrenal mass > 1 cm found incidentally. The real diagnostic challenge is the characterisation of that mass along two axes:
- Functional status: Does it secrete hormones autonomously?
- Malignant potential: Is it benign, indeterminate, or malignant?
The diagnostic algorithm is therefore a systematic characterisation pathway, not a "rule-in/rule-out" framework. Let's work through this step by step, the way you'd approach it on the ward.
Step 1: Confirm the Finding and Assess Imaging Characteristics
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]
| CT Feature | Finding | Interpretation | Why |
|---|---|---|---|
| Unenhanced attenuation | < 10 HU | Lipid-rich adenoma (sensitivity ~71%, specificity ~98%) [2][3] | Intracellular cholesterol/lipid lowers X-ray attenuation |
| Unenhanced attenuation | < −30 HU | Myelolipoma (pathognomonic) | Macroscopic mature adipose tissue |
| Unenhanced attenuation | > 10 HU | Indeterminate — needs washout study | Could be lipid-poor adenoma, phaeochromocytoma, metastasis, or ACC |
| Unenhanced attenuation | 0–20 HU, no enhancement | Adrenal cyst | Simple fluid |
| Unenhanced attenuation | > 50 HU (acute) | Adrenal haemorrhage | Fresh blood is hyperdense |
| Size | > 4 cm | High suspicion for malignancy [2][3] | 90% of malignant adrenal tumours are > 4 cm [2][3] |
| Configuration | Homogeneous, smooth border | More likely benign [2][3] | Benign tumours grow slowly and concentrically without invading |
| Configuration | Heterogeneous, irregular, necrosis, calcification | Suspicious for malignancy [2][3] | Rapid growth → outstrips blood supply → necrosis; invasion → irregular border |
| Contrast enhancement | Malignant tumours tend to retain contrast [2][3] | Delayed washout = suspicious | Malignant tumours have leaky, disorganised neovascularisation → contrast pools and washes out slowly |
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:
- Unenhanced phase (baseline attenuation)
- Enhanced phase (~60-90 seconds post-contrast)
- Delayed phase (~15 minutes post-contrast)
Then calculate:
Absolute percentage washout (APW):
Relative percentage washout (RPW) (used if no unenhanced scan available):
| Washout | Cut-off | Interpretation |
|---|---|---|
| Absolute washout | > 60% | Adenoma (even lipid-poor) |
| Absolute washout | < 60% | Suspicious (ACC, metastasis, phaeochromocytoma) |
| Relative washout | > 40% | Adenoma |
| Relative washout | < 40% | Suspicious |
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.
Exam Pearl: The Two CT Criteria
For the exam, remember the two key numbers for CT characterisation:
- Unenhanced < 10 HU → adenoma (high specificity)
- Absolute washout > 60% at 15 min → adenoma (even if lipid-poor on unenhanced)
If BOTH criteria are negative (> 10 HU AND < 60% washout), the lesion is indeterminate and requires further workup (MRI, PET/CT, or surgical resection depending on size).
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)
| MRI Feature | Classic Phaeochromocytoma Finding | Why |
|---|---|---|
| T2-weighted | "Light bulb" bright (hyperintense) — classic but not universal (~65%) | High water content, hypervascular, cystic/necrotic areas |
| Chemical shift | No signal drop on opposed-phase | No intracellular lipid |
| Post-gadolinium | Avid heterogeneous enhancement | Highly vascular tumour |
Step 2: Biochemical Screening for Hormonal Function
This is performed in parallel with imaging characterisation. All adrenal incidentalomas > 1 cm should undergo biochemical screening — even those that look radiologically benign — because subtle hormonal excess (particularly autonomous cortisol secretion) has metabolic and cardiovascular consequences that may change management.
Screening tests for functional tumours: ONDST + spot ARR + 24h urine metanephrines [1]
| Condition | Screening Test | Cut-off / Interpretation | Confirmatory Test |
|---|---|---|---|
| Cushing's syndrome | 1 mg ONDST | > 50 nmol/L = abnormal [1][4][12] | Low-dose DST (48h 0.5 mg Q6H) [1] |
| 24h urine free cortisol (UFC) ×2 [4][12] | > Upper limit of normal | ||
| Midnight salivary cortisol ×2 [1][4][12] | Elevated (loss of nadir) | ||
| Conn's syndrome | Aldosterone:Renin Ratio (ARR) [1][5] | Elevated (typically Ald > 15 ng/dL + PRA < 1 ng/mL/h) | Salt loading test / Saline suppression test [1][13] |
| RFT for hypoK [1] | Hypokalaemia | ||
| Phaeochromocytoma | 24h urine fractionated metanephrines [1][9] | > 2× upper limit of normal is highly suggestive | Clonidine suppression test [1] |
| Plasma fractionated metanephrines [8] | Sensitivity 96-100%, specificity 85-89% [8] |
Let's go through each in detail.
A. Screening for Autonomous Cortisol Secretion
This is the first-line screening test for Cushing's syndrome in the incidentaloma setting [1][2][4][12].
- Normal: dexamethasone suppresses ACTH secretion → ↓adrenal cortisol secretion [12]
- Cushing's syndrome: incomplete suppression [12]
Procedure: [12]
- PO 1 mg dexamethasone at 2300h
- Plasma cortisol measured at 0900h the following morning
Interpretation: [12]
- Normal: cortisol suppressed to < 50 nmol/L (1.8 µg/dL)
- > 50 nmol/L but < 138 nmol/L → "possible autonomous cortisol secretion" (per 2016 ESE/ENSAT guidelines)
- > 138 nmol/L (5 µg/dL) → "autonomous cortisol secretion" (high confidence)
- CS: cortisol rarely adequately suppressed [12]
False positives (failed suppression in non-CS): [12]
- Enzyme-inducing drugs (e.g., anti-epileptics, rifampicin) → ↑dexamethasone clearance via CYP3A4 induction
- Women on OCP or pregnancy → ↑corticosteroid-binding globulin (CBG) → total cortisol appears elevated
- Severe depression (30-50%) or systemic illnesses (10-20%) → stress-related HPA activation
- Renal failure on dialysis
- Chronic alcohol abuse ("pseudo-Cushing's")
- Marked obesity
False negatives (suppression despite CS; very rare < 2%): [12]
- Cyclical Cushing's syndrome (cortisol secretion waxes and wanes)
- Slow metabolism of dexamethasone → ↑drug level → excessive suppression
Why 1 mg DST Works
Dexamethasone is a synthetic glucocorticoid that binds glucocorticoid receptors in the hypothalamus and pituitary → suppresses CRH and ACTH secretion → normal adrenals stop producing cortisol overnight. In Cushing's, the feedback loop is broken: either the pituitary is autonomous (Cushing's disease), the ACTH source is ectopic, or the adrenal itself is autonomous → cortisol remains elevated despite dexamethasone. The 1 mg dose is enough to suppress a normal HPA axis but NOT enough to suppress an autonomous one — that's the sweet spot for screening.
| Test | Principle | Key Points |
|---|---|---|
| 24h UFC ×2 [4][12] | Measures total free cortisol excreted over 24h; eliminates pulsatility artefact | Caveat: does not distinguish physiological hypercortisolism (depression, obesity) [13]; problems with under-/over-collection [12] |
| Late-night salivary cortisol ×2 [4][12] | Exploits loss of circadian rhythm in CS; normal nadir occurs at ~midnight | Caveat: not readily available [13]; requires LC-MS for accurate measurement; not suitable for shift workers [12] |
Diagnostic criteria for Cushing's syndrome: ≥2 tests abnormal → diagnostic [1][4][13]
- 1 mg ONDST > 50 nmol/L
- 24h UFC ×3 (some say ×2)
- LDDST / Late-night salivary cortisol ×2 / Late-night plasma cortisol
- OR: 24h UFC > 3-4× ULN (highly specific) [1]
Once Cushing's is confirmed, the next step is to determine whether it is ACTH-dependent or ACTH-independent:
- < 1.1 pmol/L → non-ACTH-dependent CS (adrenal source) [14]
- > 3.3 pmol/L → ACTH-dependent CS (pituitary or ectopic) [14]
For an adrenal incidentaloma with confirmed Cushing's + suppressed ACTH → the diagnosis is adrenal Cushing's (the incidentaloma is the autonomous cortisol-secreting adenoma or carcinoma). No further localisation needed — the mass IS the source.
If ACTH is NOT suppressed (i.e., ACTH-dependent), the incidentaloma may be a coincidental finding, and you need to pursue pituitary/ectopic workup:
Summary of biochemical findings for ACTH-dependent vs. ACTH-independent Cushing's: [8][13][14]
| Cushing's Disease | Ectopic ACTH | Adrenal Adenoma/Carcinoma | Iatrogenic CS | |
|---|---|---|---|---|
| Physiology | Loss of circadian rhythm; HPA axis -ve feedback intact but at ↑set-point | Loss of circadian rhythm; -ve feedback completely lost | Loss of circadian rhythm; monoclonal cortisol-secreting tumour | Exogenous steroids → suppression of HPA axis |
| Cortisol | ↑cortisol | ↑cortisol | ↑cortisol | ↓cortisol (endogenous) |
| LDDST | No suppression | No suppression | No suppression | / |
| ACTH | Normal-high | Usually high (occ normal) | Almost invariably undetectable | Low |
| HDDST | Usually suppressed | Usually no suppression | No suppression | / |
| CRH test | Exaggerated rise | No significant rise above basal | / | / |
| Localisation | Pituitary adenoma on MRI | ACTH-secreting tumour on PET/CT | Adrenal tumour on CT abdomen | +ve drug Hx |
- Usually done before pituitary MRI to avoid picking up a pituitary incidentaloma [8]
- Procedure: 2 mg dexamethasone Q6H for 2 days → measure serum cortisol
- Cushing's disease: ACTH secretion responsive to -ve feedback → ACTH suppressed (< 50% basal)
- Ectopic ACTH: not responsive → ACTH NOT suppressed
CRH stimulation test (if HDDST non-diagnostic): [8][13][14]
- Procedure: 1 µg/kg CRH IV → serial ACTH and cortisol for 2h
- Cushing's disease → exaggerated rise in cortisol (> 20% of baseline) and ACTH (> 50%)
- Ectopic ACTH → no significant rise
24h urine fractionated metanephrines is the most commonly used screening test [1][8][9].
| Test | Sensitivity | Specificity | Notes |
|---|---|---|---|
| 24h urine fractionated metanephrines | ~98% | ~98% [8] | Measures normetanephrine + metanephrine separately; more accurate than total catecholamines or VMA |
| Plasma fractionated metanephrines | 96-100% | 85-89% [8] | Highest sensitivity (best for ruling out); slightly lower specificity → more false positives |
| Urinary VMA | Lower | Lower | Now superseded as less accurate [8] |
| Urinary fractionated catecholamines | Good | Good | Measured alongside metanephrines in many labs |
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]:
| Investigation | Adenoma (APA) | Hyperplasia (BIAH) |
|---|---|---|
| Postural test (9 am supine → 12 nn erect) | ↓Ald in 70-90% (paradoxical: ↓ACTH drive at noon) [11][13] | ↑Ald in 90% (exaggerated response to ↑Ang II in erect posture) [11][13] |
| Adrenal venous sampling [7][11][13] | ↑ipsilaterally, ↓contralaterally | ↑bilaterally |
| CT/MRI [11] | Unilateral tumour | Normal or slightly enlarged |
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
Step 3: Functional Imaging (When Indicated)
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
| Tracer | Best For | Principle |
|---|---|---|
| 18F-FDG | ACC, metastases, aggressive/malignant phaeochromocytoma | Glucose analogue taken up by metabolically active (malignant) cells |
| 68Ga-DOTATATE | Neuroendocrine tumours with somatostatin receptors | Binds somatostatin receptors → identifies well-differentiated NETs |
| 18F-DOPA | Paragangliomas, phaeochromocytoma | Amino acid precursor taken up by catecholamine-producing cells |
Biopsy: rarely indicated [2][3]
- Usually only reserved for confirmation of adrenal metastasis (in patients with known extra-adrenal malignancy and an indeterminate adrenal mass where the result would change management)
- NOT for primary adrenal tumours [2][3]
Why NOT biopsy primary adrenal tumours: [2][3]
- Histology is NOT useful in differentiating benign from malignant adrenal cortical tumours (they look the same microscopically — the Weiss score requires the whole resection specimen)
- Risk of precipitation of HTN crisis if the mass is an undiagnosed phaeochromocytoma
- Risk of tumour seeding along the biopsy tract (especially concerning for ACC)
Contraindications to adrenal biopsy: [7]
- Uncorrected bleeding diathesis (platelet < 50,000/mm³ or INR > 1.5)
- Inaccessible lesion
- Uncooperative or unwilling patient
- Phaeochromocytoma not excluded (must check metanephrines first)
The Biopsy Rule
Never biopsy an adrenal mass until phaeochromocytoma has been biochemically excluded. Never biopsy if the clinical question is "adenoma vs. ACC" — histology cannot answer this reliably on a needle sample. The only valid indication is confirming metastatic disease when this would change the management of the primary cancer.
For masses that are non-functional AND radiologically benign AND < 4 cm:
Imaging follow-up: [1]
- CT abdomen Q6 months for 4 years (some guidelines: repeat at 6-12 months, then annually if stable)
- If any growth > 1 cm → surgical resection [1][2][3]
- If > 0.5 cm growth in 6 months → highly suspicious → consider surgery [1]
Biochemical follow-up: [1]
- Annual biochemical screening (ONDST, metanephrines, ± ARR) for 4 years [1]
- Rationale: Some non-functional adenomas can develop autonomous secretion over time (estimated ~5-20% over 5 years)
After 4 years: If mass has been stable in size and non-functional throughout → low risk of subsequent change → can consider discharge from follow-up (per 2016 ESE/ENSAT guidelines). Some clinicians continue annual biochemistry indefinitely if the mass persists.
| Investigation Category | Specific Test | Purpose | Key Finding |
|---|---|---|---|
| Imaging — Initial | Unenhanced CT attenuation | Characterise tissue composition | < 10 HU = adenoma; < −30 HU = myelolipoma |
| Imaging — Washout | CT washout protocol | Discriminate adenoma from non-adenoma | APW > 60% = adenoma |
| Imaging — MRI | Chemical-shift MRI | Detect intracellular lipid | Signal drop on opposed-phase = adenoma |
| Imaging — MRI | T2-weighted MRI | Characterise phaeochromocytoma | "Light bulb" hyperintensity |
| Biochemistry — Cortisol | 1 mg ONDST | Screen for Cushing's | Cortisol > 50 nmol/L = abnormal |
| Biochemistry — Cortisol | 24h UFC, LNSC | Confirm Cushing's | Elevated |
| Biochemistry — Cortisol | Plasma ACTH | Determine ACTH-dependent vs. independent | < 1.1 pmol/L = adrenal; > 3.3 pmol/L = pituitary/ectopic |
| Biochemistry — Catecholamines | 24h urine fractionated metanephrines | Screen for phaeochromocytoma | Elevated normetanephrine/metanephrine |
| Biochemistry — Catecholamines | Plasma fractionated metanephrines | Screen for phaeochromocytoma | Sensitivity 96-100% |
| Biochemistry — Aldosterone | Plasma ARR | Screen for Conn's (if HTN) | Elevated ratio |
| Biochemistry — Aldosterone | Salt loading / saline suppression | Confirm Conn's | Failure to suppress aldosterone |
| Biochemistry — Androgens | DHEA-S, testosterone | Screen for androgen excess / ACC | Elevated |
| Functional Imaging | 123I/131I-MIBG scan | Localise phaeochromocytoma, extra-adrenal disease | Uptake in tumour; Sens 85%, Spec 95% |
| Functional Imaging | 18F-FDG PET/CT | Detect malignancy, metastases | Avid uptake in aggressive tumours |
| Functional Imaging | 68Ga-DOTATATE PET/CT | NETs, paragangliomas | Uptake at somatostatin receptor-expressing tumours |
| Interventional | Adrenal venous sampling | Lateralise aldosterone source in Conn's | Lateralisation ratio > 4:1 = unilateral |
| Interventional | CT-guided biopsy | Confirm metastasis ONLY | Only if known primary malignancy and result changes management |
| Adrenal insufficiency | Short Synacthen Test | Assess adrenal reserve (bilateral masses) | Peak cortisol > 550 nmol/L = normal |
High Yield Summary — Diagnosis of Adrenal Incidentaloma
Two parallel assessments: (1) Imaging characterisation for malignant potential. (2) Biochemical screening for hormonal function.
CT attenuation is the first branch point: < 10 HU = lipid-rich adenoma (specificity ~98%). > 10 HU = indeterminate → CT washout (APW > 60% = adenoma) or chemical-shift MRI.
Triple biochemical screen for ALL incidentalomas > 1 cm: 1 mg ONDST + plasma/urine metanephrines + ARR (if hypertensive).
ONDST interpretation: Cortisol < 50 nmol/L = normal. 50-138 nmol/L = possible autonomous cortisol secretion. > 138 nmol/L = autonomous cortisol secretion.
Plasma ACTH determines the source of Cushing's: < 1.1 pmol/L = adrenal (non-ACTH-dependent). > 3.3 pmol/L = pituitary or ectopic (ACTH-dependent).
Metanephrines must ALWAYS be checked before biopsy or surgery — undiagnosed phaeochromocytoma can cause fatal crisis.
Biopsy: ONLY for confirming metastasis. NOT for primary adrenal lesions. Histology cannot differentiate benign from malignant adrenal cortical tumours on needle biopsy.
Follow-up for non-operated masses: CT Q6-12 months + annual biochemistry for 4 years. Growth > 1 cm → surgery.
Adrenal venous sampling: Gold standard for lateralising aldosterone source in Conn's syndrome.
Active Recall - Diagnostic Criteria and Algorithm for Adrenal Incidentaloma
[1] Senior notes: maxim.md (Adrenal incidentaloma section, pp. 432-434) [2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 Adrenal Incidentaloma, p. 68) [3] Senior notes: Ryan Ho Fundamentals.pdf (Section B: Adrenal Incidentaloma, p. 438) [4] Senior notes: Ryan Ho Chemical Path.pdf (Section 4.1 Diagnosis of Cushing Syndrome, p. 29) [5] Senior notes: Ryan Ho Cardiology.pdf (Secondary hypertension table, p. 178) [6] Senior notes: maxim.md (Conn's syndrome DDx, pp. 434-435) [7] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Interventional radiology and adrenal venous sampling, p. 79) [8] Senior notes: Ryan Ho Endocrine.pdf (Phaeochromocytoma diagnosis, pp. 66-67) [9] Senior notes: felixlai.md (Phaeochromocytoma diagnosis, pp. 1536-1537) [10] Senior notes: Ryan Ho Diagnostic Radiology.pdf (MIBG scan and functional imaging, pp. 71-72) [11] Senior notes: Ryan Ho Endocrine.pdf (Conn's adenoma vs. hyperplasia, p. 59) [12] Senior notes: Ryan Ho Chemical Path.pdf (1 mg ONDST — procedure and interpretation, p. 30) [13] Senior notes: Ryan Ho Fundamentals.pdf (Cushing's syndrome workup and Conn's subtyping, pp. 434-437) [14] Senior notes: Adrian Lui Pediatrics.pdf (Cushing's syndrome approach and biochemical summary, pp. 286-287) [15] Senior notes: Ryan Ho Endocrine.pdf (Adrenal insufficiency diagnosis and Synacthen test, p. 71) [16] Senior notes: Adrian Lui Pediatrics.pdf (Adrenal insufficiency diagnosis, p. 280)
The management of adrenal incidentaloma flows directly from the two questions we have been asking all along: Is it functional? Is it malignant? The answers determine whether the patient needs surgery, conservative surveillance, or specific medical therapy before surgery. Let's build this from first principles.
Basic principles of endocrine surgery (applicable to all adrenal incidentaloma management) [17]:
- Confirm endocrine diagnosis
- Localization of tumour
- Render patient medically fit
- Establish need to operate
- Surgical tactics
This framework reminds us that endocrine surgery is never "just cut it out" — you need biochemical confirmation, precise localisation, meticulous pre-operative preparation (especially for functional tumours where operative manipulation can trigger life-threatening crises), and a clear rationale for operating.
Surgical removal is indicated if the incidentaloma is unilateral AND any of the following: [1][2][3]
| Indication | Rationale |
|---|---|
| Functioning tumour (Cushing's, phaeochromocytoma, Conn's adenoma, androgen-secreting) [1][2][3] | Autonomous hormone secretion causes ongoing end-organ damage (CVS, metabolic, bone) that will not resolve without removing the source |
| Radiologically suspicious for malignancy [1][2][3] | Features: heterogeneous, irregular borders, contrast retention ( < 60% APW), > 10 HU, calcification, necrosis, local invasion [1] |
| Size > 4 cm [1][2][3] | 90% of malignant adrenal tumours are > 4 cm — the risk-benefit ratio favours resection even if imaging otherwise looks benign |
| Growth > 1 cm on serial imaging [2][3] | Rapid growth is suspicious for malignancy; growing > 0.5 cm over 6 months is also a trigger in some guidelines [1] |
Additional surgical indications: [1][17]
- Adrenal malignancy (ACC, malignant phaeochromocytoma)
- Cushing's disease persistent after transsphenoidal resection (bilateral adrenalectomy as last resort)
Laparoscopic vs. Open Adrenalectomy
Approach: open vs MIS — the choice depends on: [17]
- Size and location
- Pathology of tumour
- Surgical expertise
- Concomitant procedure
| Approach | Indication | Details |
|---|---|---|
| Laparoscopic trans-peritoneal approach [1][17] | Mass < 6 cm, benign-appearing, functional adenoma | Lateral decubitus position, ipsilateral side up [1]. Choices include transabdominal (anterior or lateral) and retroperitoneal (posterior or lateral) [17] |
| Open adrenalectomy [1] | Mass > 6 cm or suspected malignancy (ACC) [1] | Open allows wider exposure for en-bloc resection, vascular control, and lymph node dissection. Choices: anterior transabdominal, lateral extraperitoneal, posterior lumbar [17] |
Nowadays usually prefer MIS approach because of [17]:
- Safety and efficacy
- ↓Hospital stay
- ↓Analgesic requirement
- Hasten return to normal activities
- ↑Overall patient satisfaction
Why open for large or malignant tumours? Adrenocortical carcinoma has a propensity for local invasion (IVC, kidney, liver, diaphragm) and capsular breach during surgery can cause peritoneal seeding. Open surgery provides better control of the vascular pedicle, allows en-bloc resection of invaded structures, and minimises the risk of capsular violation. The 2024 ESE/ENSAT guidelines continue to recommend open surgery for suspected ACC.
Pre-operative Preparation by Functional Type
This is the highest-yield section for exams. Each functional tumour requires specific preparation before the anaesthesia team will agree to proceed. The principle is simple: neutralise the hormone excess before surgery so that operative manipulation does not trigger a crisis.
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]
NEVER Start β-Blocker First!
NEVER start β-blocker first since blockade of peripheral vasodilatory β-adrenergic receptors will lead to vasoconstriction with unopposed α-adrenergic activity (when α-blocker is not started) will further elevate the BP [9]. This is because β₂ receptors in skeletal muscle vasculature mediate vasodilation; blocking them leaves α₁-mediated vasoconstriction completely unopposed → can precipitate a hypertensive crisis. This is a classic exam question.
Why does this sequence work from first principles?
| Step | Drug | Receptor Target | Physiological Effect | Purpose |
|---|---|---|---|---|
| Step 1: α-blockade | Phenoxybenzamine (non-selective, long-acting, irreversible) [8][9] or Doxazosin/Terazosin/Prazosin (selective α₁) | α₁ (and α₂ for phenoxybenzamine) | Blocks catecholamine-mediated vasoconstriction → ↓TPR → ↓BP; allows intravascular volume re-expansion (reverses chronic pressure natriuresis) | Prevent intraoperative hypertensive crisis during tumour manipulation |
| Step 2: β-blockade | Propranolol (non-selective β-blocker) [8][9] | β₁ and β₂ | ↓HR, ↓contractility → controls reflex tachycardia from α-blockade | Prevent tachycardia and arrhythmias; only safe after adequate α-blockade |
| Step 3: Volume expansion | ↑Na ( > 5 g/d) diet and fluid intake [8] | N/A | Reverses catecholamine-induced intravascular volume contraction | Prevent severe postoperative hypotension (once catecholamine source is removed, the patient's α-blocked, volume-depleted circulation can collapse) |
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.
| Pre-op Checklist Item | Target |
|---|---|
| BP sitting | < 120/80 mmHg (or < 130/80 in some protocols) |
| BP standing | SBP > 90 mmHg (no severe postural drop) |
| Heart rate | < 80-100 bpm |
| No ST changes on ECG | Stable |
| Volume status | Euvolaemic (adequate oral fluid/Na intake for 7-14 days) |
Why Postoperative Hypotension Occurs
During surgery, once the phaeochromocytoma is removed, the catecholamine source is abruptly eliminated. The patient has been chronically volume-depleted (from pressure natriuresis) AND α-blocked → profound vasodilation with no catecholamine drive → severe hypotension. This is why pre-operative volume expansion and careful intraoperative fluid management are critical. Post-op, you may need vasopressors (noradrenaline infusion) temporarily.
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]
| Action | Rationale |
|---|---|
| Peri-op steroid cover [1] | Normal HPA axis usually suppressed → risk of adrenal crisis on removal of cortisol source |
| Prophylactic antibiotics [1] | Chronic hypercortisolism → immunosuppression → high risk of infections |
| Prophylactic anticoagulation [1] | Cushing's syndrome → hypercoagulable state (↑factor VIII, ↑VWF, ↑PAI-1) → high risk of VTE |
| Post-op glucocorticoid ± mineralocorticoid supplement [1] | Until HPA axis recovers ~1 year later — taper gradually based on morning cortisol and SST |
| Control HTN, DM, hypokalaemia pre-op [18] | Reduce perioperative cardiovascular risk |
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]
Risk of Nelson's Syndrome
Risk of Nelson's syndrome (8-25% adults, > 50% children) following bilateral adrenalectomy [1][18]. This occurs when both adrenals are removed (e.g., for refractory pituitary-dependent Cushing's disease) → complete loss of cortisol negative feedback → corticotroph pituitary adenoma enlarges aggressively → hyperpigmentation (very high ACTH/MSH), visual field defects, headache. This is why bilateral adrenalectomy is reserved as a last resort and patients need lifelong pituitary MRI surveillance.
Management depends on subtype: [1][6][11]
| Subtype | Management | Pre-op | Why |
|---|---|---|---|
| Aldosterone-producing adenoma (APA) | Laparoscopic adrenalectomy [1][6] | Correct electrolyte imbalance, especially K⁺ [1]; 4 weeks pre-op spironolactone to correct hypoK [6] | Need to replenish total body K⁺ stores before surgery; spironolactone also helps control BP |
| Bilateral idiopathic adrenal hyperplasia (BIAH) | Medical treatment: MRA (spironolactone/eplerenone) ± amiloride [6] | N/A — no surgery | Bilateral adrenalectomy would lead to adrenal crisis — the cure is worse than the disease; medical management controls aldosterone effects without removing essential cortisol-producing tissue [6] |
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]
For incidentalomas that are non-functional, < 4 cm, and radiologically benign:
Conservative management: [1]
- Imaging: CT abdomen Q6 months for 4 years [1]
- Biochemical: annual screening (ONDST, metanephrines, ± ARR) for 4 years [1]
Triggers for converting to surgical management during surveillance: [1][2][3]
- Growth > 0.5 cm in 6 months [1] or > 1 cm on any follow-up [2][3]
- Development of new hormonal function on biochemical screening
- Development of suspicious imaging features (new heterogeneity, loss of smooth borders, contrast retention)
After 4 years of stability → risk of subsequent change is very low → consider discharge (per 2016 ESE/ENSAT guidelines, still current 2025-2026).
Understanding complications requires knowledge of the surgical anatomy and the specific functional tumour being operated on.
General Complications of Adrenalectomy [1][17]
| Timing | Complication | Mechanism / Explanation |
|---|---|---|
| Intra-operative | Haemodynamic instability (phaeochromocytoma) [1][17] | Tumour manipulation → massive catecholamine release → hypertensive crisis, tachyarrhythmia; alternatively, after tumour removal → sudden catecholamine withdrawal → hypotension |
| Intra-operative | Intraoperative haemorrhage: adrenal capsular, IVC [17] | Rich arterial supply + close proximity of right adrenal vein to IVC (short, ~1 cm) → risk of IVC injury especially on right side |
| Intra-operative | Adrenal insufficiency (Conn's, Cushing's) [1] | Contralateral adrenal suppressed by chronic autonomous secretion → cannot produce adequate cortisol/aldosterone immediately → IV hydrocortisone upon removal of adrenal gland [1] |
| Intra-operative | Injury to surroundings: | Anatomical proximity |
| Right adrenalectomy: IVC, right lobe of liver [1] | Right adrenal sits behind IVC and under right hepatic lobe | |
| Left adrenalectomy: pancreatic tail, spleen [1] | Left adrenal sits anterior to left crus, medial to spleen, posterior to pancreatic tail | |
| Intra-operative | Pneumothorax [9][17] | Diaphragmatic injury (adrenal glands sit immediately beneath the diaphragm) |
| Early post-op | Adrenal insufficiency [1] | As above — requires PO hydrocortisone post-op [1] |
| Early post-op | Rebound hypoglycaemia (phaeochromocytoma) [8] | Loss of catecholamine-driven glycogenolysis/gluconeogenesis → unopposed insulin action |
| Early post-op | Hypotension (phaeochromocytoma) [8] | Loss of catecholamine vasoconstriction + volume depletion + residual α-blockade |
| Early post-op | Rebound hyperkalaemia (Conn's) [11] | Contralateral adrenal suppression → temporary ↓aldosterone → K⁺ retention |
| Early post-op | Electrolyte disturbances [17] | Shift in mineralocorticoid/glucocorticoid balance |
| Late | Persistent hypertension [1] | Renal artery injury during surgery [1]; or irreversible hypertensive end-organ damage (nephrosclerosis) |
| Late | Nelson's syndrome (bilateral adrenalectomy only) [1][18] | Loss of cortisol feedback → uninhibited corticotroph growth → enlarging pituitary tumour + hyperpigmentation |
| Late | Lifelong steroid dependence (bilateral adrenalectomy) | No adrenal tissue → no endogenous cortisol or aldosterone → permanent replacement |
Understanding the adrenergic receptor effects clarifies the pre-operative drug rationale [9]:
| Receptor | Location | Effect of Stimulation | Relevance to Phaeochromocytoma |
|---|---|---|---|
| α₁ | Vascular smooth muscle, iris dilator | ↑TPR → vasoconstriction, mydriasis, urinary sphincter closure [9] | Primary driver of hypertension → blocked by phenoxybenzamine/doxazosin |
| α₂ | Pre-synaptic nerve terminals, pancreatic β-cells | ↓insulin release, inhibition of NE release [9] | Pre-synaptic feedback; phenoxybenzamine blocks this too (can paradoxically ↑NE release) |
| β₁ | Heart (SA node, myocardium) | ↑HR, ↑myocardial contractility, ↑lipolysis, ↑renin release [9] | Drives tachycardia and arrhythmia → blocked by propranolol (only AFTER α-blockade) |
| β₂ | Vascular smooth muscle (skeletal muscle), bronchi, liver, uterus | ↓TPR → vasodilation, bronchodilation, ↑glycogenolysis, ↑glucagon release, relax uterine smooth muscle [9] | β₂ in vasculature mediates vasodilation → blocking β₂ BEFORE α₁ → unopposed α₁ vasoconstriction → crisis |
| Diagnosis | Management | Key Pre-op | Key Post-op |
|---|---|---|---|
| Non-functional, < 4 cm, benign | Conservative: CT Q6m + biochemistry Q1y for 4 years [1] | N/A | Growth > 1 cm → surgery |
| Autonomous cortisol secretion | Adrenalectomy [1][2] | Steroid cover, Abx prophylaxis, VTE prophylaxis [1] | Hydrocortisone replacement until HPA recovery (~1 year) [1] |
| Phaeochromocytoma | Adrenalectomy [2][8] | α-blockade 10-14 days → β-blockade 2-3 days → volume expansion [8][9] | Monitor BP, HR, glucose; treat hypotension/hypoglycaemia |
| Conn's adenoma | Laparoscopic adrenalectomy [1][6] | Spironolactone 4 weeks, correct hypoK [6] | Monitor K⁺ (rebound hyperK), continue HTN Rx |
| Conn's — BIAH | Medical: spironolactone/eplerenone ± amiloride [6] | N/A | Lifelong medical management |
| ACC | Open adrenalectomy ± en-bloc resection + adjuvant mitotane ≥ 2 years [19] | Address functional excess if present | High-dose glucocorticoid replacement (mitotane induces CYP3A4) [19] |
| Metastasis | Treat primary; ± metastasectomy if isolated | Depends on primary cancer | Steroid replacement if bilateral adrenal destruction |
| Malignant phaeochromocytoma | Debulking surgery + α-blockers + 131I-MIBG/chemo [19] | As per phaeochromocytoma | Long-term catecholamine monitoring |
High Yield Summary — Management of Adrenal Incidentaloma
Surgical indications: Functional tumour, size > 4 cm, radiologically suspicious for malignancy, or growth > 1 cm on follow-up.
Approach: Laparoscopic for < 6 cm and benign; open for > 6 cm or suspected ACC.
Phaeochromocytoma pre-op: α-blockade FIRST (phenoxybenzamine, 10-14 days) → β-blockade SECOND (propranolol, 2-3 days before) → volume expansion. NEVER β before α.
Cushing's pre-op: Steroid cover, antibiotics, anticoagulation. Post-op hydrocortisone until HPA recovers (~1 year).
Conn's pre-op: Spironolactone for 4 weeks to correct hypokalaemia. Adenoma → surgery. BIAH → medical (do NOT operate bilaterally).
ACC: Open adrenalectomy ± en-bloc resection + adjuvant mitotane ≥ 2 years. Mitotane induces CYP3A4 → need high-dose steroid replacement.
Conservative surveillance: CT Q6-12 months + annual biochemistry for 4 years if non-functional, < 4 cm, benign.
Key complications: Intraoperative HTN crisis (phaeochromocytoma), adrenal insufficiency (Cushing's/Conn's post-op), IVC/organ injury, post-op hypoglycaemia and hypotension (phaeochromocytoma), Nelson's syndrome (bilateral adrenalectomy).
Active Recall - Management of Adrenal Incidentaloma
[1] Senior notes: maxim.md (Adrenal incidentaloma and adrenalectomy sections, pp. 432-434) [2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 Adrenal Incidentaloma, p. 68) [3] Senior notes: Ryan Ho Fundamentals.pdf (Section B: Adrenal Incidentaloma, p. 438) [5] Senior notes: Ryan Ho Cardiology.pdf (Secondary hypertension table, p. 178) [6] Senior notes: maxim.md (Conn's syndrome management, pp. 434-435) [8] Senior notes: Ryan Ho Endocrine.pdf (Phaeochromocytoma management, pp. 66-67) [9] Senior notes: felixlai.md (Phaeochromocytoma treatment and adrenergic receptor table, pp. 1537-1538) [11] Senior notes: Ryan Ho Endocrine.pdf (Conn's adenoma vs. hyperplasia management, p. 59) [17] Senior notes: Ryan Ho Endocrine.pdf (Adrenal surgery — indications, approaches, complications, p. 69) [18] Senior notes: Ryan Ho Endocrine.pdf (Cushing's syndrome management, p. 64) [19] Senior notes: maxim.md (Malignant phaeochromocytoma and adrenocortical carcinoma, p. 438)
Phaeochromocytoma
Phaeochromocytoma is a catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla, causing episodic or sustained hypertension along with the classic triad of headache, sweating, and palpitations.
Adrenocortical Carcinoma
Adrenocortical carcinoma is a rare, aggressive malignant neoplasm arising from the adrenal cortex, often presenting with hormonal excess (particularly cortisol or androgens) and/or a large abdominal mass.