• Phaeochromocytoma is rare in Hong Kong (as globally), but it is an important cause of secondary hypertension that must be excluded in the appropriate clinical context
• Hong Kong has a relatively high prevalence of hypertension (~27% of adults), making the identification of secondary causes clinically relevant
• MEN2 and VHL kindreds have been identified in Hong Kong Chinese families

• The adrenal medulla is derived from neuroectoderm (specifically neural crest cells) ^[3]
• This is the same embryological origin as sympathetic ganglia — which is why extra-adrenal paragangliomas can arise anywhere along the sympathetic chain
• The adrenal cortex, by contrast, is derived from mesoderm

• The adrenal medulla sits in the centre of the adrenal gland, surrounded by the cortex
• It comprises approximately 10% of adrenal gland weight
• Composed almost exclusively of chromaffin cells (named for the chromaffin reaction described above) ^[3]

The adrenal medulla has a dual blood supply ^[3]:

1. Portal blood via corticomedullary sinuses: blood drains from the adrenal cortex through the medulla before exiting

   • This is crucial because cortisol from the cortex bathes the medullary cells at very high local concentrations
   • Cortisol induces phenylethanolamine-N-methyltransferase (PNMT), the enzyme that converts noradrenaline → adrenaline ^[3]
   • This explains why adrenal tumours can produce both noradrenaline AND adrenaline, while extra-adrenal tumours (which lack cortisol exposure) predominantly produce noradrenaline only ^[3]

2. Medullary arteries: direct arterial supply

The biosynthetic pathway in chromaffin cells is almost identical to that in sympathetic neurone terminals, with one additional step ^[3]:

Tyrosine
  ↓ (Tyrosine hydroxylase — rate-limiting step)
DOPA (dihydroxyphenylalanine)
  ↓ (DOPA decarboxylase)
Dopamine
  ↓ (Dopamine β-hydroxylase)
Noradrenaline
  ↓ (Phenylethanolamine-N-methyltransferase / PNMT — ONLY in adrenal medulla, cortisol-dependent)
Adrenaline

This is essential for understanding the biochemical diagnosis:

Two major enzyme systems metabolise catecholamines:

1. Catechol-O-methyltransferase (COMT) — mainly found extra-neuronally in liver and kidneys ^[1][3]

   • Converts catecholamines to their O-methylated derivatives (metanephrines):
     • Adrenaline → metanephrine
     • Noradrenaline → normetanephrine
     • Dopamine → 3-methoxytyramine

2. Monoamine oxidase (MAO) — deamination and oxidation

   • In sympathetic nerve terminals, MAO is the only metabolising enzyme → produces DHPG
   • Eventually, the combined action of COMT + MAO produces vanillylmandelic acid (VMA), which is excreted in urine ^[1][3]

Key point for diagnosis: In the adrenal medullary chromaffin cells themselves, COMT is the dominant enzyme → the major metabolite produced continuously within the tumour is free metanephrine (from adrenaline) and free normetanephrine (from noradrenaline) ^[3]. This continuous production occurs independent of catecholamine release — which is why plasma-free metanephrines have the highest sensitivity for diagnosis.

• Accounts for the majority of cases (60–70%)
• No identifiable genetic cause
• Usually unilateral and adrenal

All are autosomal dominant inheritance:

*The Organ of Zuckerkandl is the largest collection of extra-adrenal chromaffin tissue, located at the aortic bifurcation near the origin of the inferior mesenteric artery. It is the most common site of extra-adrenal phaeochromocytoma (sympathetic paraganglioma).

The tumour consists of chromaffin cells that synthesise, store, and episodically release massive amounts of catecholamines (predominantly noradrenaline, but also adrenaline and dopamine depending on tumour location and enzyme expression).

The clinical manifestations are a direct consequence of α- and β-adrenergic receptor stimulation:

Hypertension — the hallmark:

• α₁ stimulation → arterial vasoconstriction → ↑SVR → ↑BP
• β₁ stimulation → ↑HR + ↑cardiac contractility → ↑CO → ↑BP
• Pattern can be:
  • Sustained hypertension (~50%) — from chronic catecholamine excess
  • Paroxysmal hypertension (~30%) — from episodic catecholamine release
  • Normotensive (~10–20%) — especially dopamine-secreting tumours, or tumours with predominantly adrenaline production (which at low concentrations can cause β₂-mediated vasodilation)

Postural (orthostatic) hypotension — a paradoxical but classic finding ^[2]:

• Chronic catecholamine excess → downregulation of α-adrenergic receptors on blood vessels
• Chronic vasoconstriction → reduced plasma volume (pressure natriuresis + reduced venous capacitance)
• Combined effect: when the patient stands up, the normal baroreceptor-mediated vasoconstriction reflex is blunted → BP drops
• This is why you can see a patient with a BP of 220/120 who becomes orthostatic on standing — this combination should immediately make you think of phaeochromocytoma

Catecholamine surges can be triggered by ^[2]:

• Physical stimulation of the tumour: palpation of the abdomen, exercise, straining, labour/delivery
• Anaesthetic induction: especially without α-blockade
• Certain drugs: tricyclic antidepressants (TCAs), metoclopramide, opioids, glucocorticoids, β-blockers (if given without prior α-blockade — unopposed α stimulation)
• IV contrast (ionic contrast agents)
• Foods: tyramine-rich foods (cheese, wine, fermented foods) — especially relevant if the patient is also on MAO inhibitors
• Procedures: endoscopy, biopsy of the tumour

Phaeochromocytoma crisis ^[2]: Acute, life-threatening catecholamine surge resulting in:

• Acute pulmonary oedema (APO)
• Intracranial haemorrhage (ICH)
• Hypertensive encephalopathy
• Myocardial infarction / arrhythmia
• Multi-organ failure

The WHO 2022 classification has eliminated the terminology of "benign" and "malignant" for PPGLs. Instead:

• All phaeochromocytomas and paragangliomas are now considered to have metastatic potential
• The term "metastatic PPGL" replaces "malignant phaeochromocytoma"
• Metastatic disease is defined by the presence of chromaffin tissue at non-chromaffin sites (e.g. bone, liver, lung, lymph nodes)
• Risk stratification is based on:
  • SDHB mutation → highest risk (up to 30–40% metastatic)
  • Tumour size > 5 cm
  • Extra-adrenal location
  • Dopamine-secreting tumours

• Sporadic (60–70%)
• Hereditary (30–40%): MEN2, VHL, NF1, SDHx, MAX, TMEM127, FH mutations

The mnemonic "5 Ps of Phaeochromocytoma" ^[2]:

• Pressure (hypertension)
• Pain (headache, chest pain)
• Palpitation
• Perspiration (sweating)
• Pallor (vasoconstriction)

A hallmark feature: certain triggers can precipitate catecholamine surges:

• Palpation of the abdomen (tumour manipulation)
• Induction of anaesthesia (intubation, certain agents)
• Certain drugs: TCAs, metoclopramide, IV contrast (ionic), opioids, glucagon, tyramine
• Micturition (if paraganglioma in the bladder wall → paroxysms triggered by bladder distension or voiding)
• Food: tyramine-rich foods (cheese, wine) — especially relevant with MAO inhibitor co-administration

From the ACC/AHA and Endocrine Society guidelines, consider screening for phaeochromocytoma when you see ^[4]:

• Young-onset hypertension (< 30 years) with paroxysmal features
• Treatment-resistant hypertension (especially if previously well-controlled HTN suddenly worsens)
• Paroxysmal hypertension with the classic triad
• Hypertension + orthostatic hypotension (this combination is highly suspicious)
• Adrenal incidentaloma ^[8]
• Family history of PPGL, MEN2, VHL, NF1, SDHx
• Pressor response during procedures, anaesthesia, or specific medications
• Hypertensive crisis precipitated by anaesthesia, surgery, or drugs
• Unexplained dilated cardiomyopathy (catecholamine cardiomyopathy)
• Recurrent panic-like episodes with hypertension and pallor (not flushing) ^[7]

Stop drugs affecting catecholamine secretion before testing ^[3]:

• What it measures: Metanephrine + normetanephrine (O-methylated metabolites of adrenaline and noradrenaline) collected over 24 hours in urine
• Why fractionated?: "Fractionated" means the individual components (metanephrine, normetanephrine, and sometimes 3-methoxytyramine) are measured separately, not as a combined total — this gives better specificity and can help indicate the biochemical phenotype
• Performance: Sensitivity 98%, Specificity 98% ^[3] — this is the best balance of sensitivity and specificity
• Why it works: Chromaffin cells continuously metabolise catecholamines to metanephrines via intracellular COMT. A 24-hour collection integrates this continuous production, smoothing out episodic secretion
• Interpretation: Abnormal if > 2× upper limit of normal ^[2] — at this threshold, specificity is very high and further confirmation is rarely needed
• Advantage: Non-invasive, widely available, excellent combined sensitivity and specificity
• Disadvantage: Requires complete 24-hour collection (inconvenient, potential for under-/over-collection); difficult to interpret in chronic renal failure (impaired urine collection and ↓renal clearance) ^[2]

• What it measures: Free metanephrine + free normetanephrine in plasma (venous blood sample)
• Performance: Sensitivity 96–100%, Specificity 85–89% ^[3]
• Why highest sensitivity?: Chromaffin cells constitutively produce metanephrines via COMT regardless of episodic catecholamine release. Plasma free metanephrines directly reflect this continuous tumour metabolism — so even between paroxysms, levels are elevated
• Sampling conditions: Patient should be supine for > 30 minutes with an indwelling venous catheter (placed > 30 min prior to sampling) to minimise stress-related catecholamine surges ^[2]
• Preferred in: Chronic renal failure (because 24h urine is difficult to interpret) ^[2]; also in patients with high pre-test probability (e.g. known genetic syndromes)
• Disadvantage: Lower specificity than 24h urine → more false positives (especially if sampling conditions are not ideal); not universally available

• Measures adrenaline, noradrenaline, and dopamine directly
• Less sensitive than metanephrines because catecholamine release is episodic — levels may be normal between paroxysms
• Still used as an adjunct in some centres
• Included in some screening panels alongside metanephrines

• The final end-product of catecholamine metabolism
• Now superseded as less accurate ^[3] — lower sensitivity (~64%) and specificity compared to fractionated metanephrines
• Historical test only; not recommended as a first-line screening test

• Direct measurement of circulating noradrenaline, adrenaline, and dopamine
• Very sensitive to sampling conditions (stress, posture, venepuncture itself → false elevation)
• Not recommended as first-line; may be useful as an adjunct

• Principle: Clonidine is a central α₂-agonist that suppresses sympathetic outflow → ↓plasma noradrenaline in healthy individuals and patients with essential hypertension
• In phaeochromocytoma, catecholamine secretion is autonomous (from the tumour), NOT dependent on central sympathetic drive → clonidine fails to suppress plasma noradrenaline/normetanephrine
• Protocol: Measure baseline plasma catecholamines/normetanephrine → give oral clonidine 300 μg → remeasure at 3 hours
• Positive result (suggesting phaeo): Failure of plasma normetanephrine to suppress into the normal range, or < 40% reduction from baseline
• Indication: Borderline biochemistry (metanephrines 1–2× ULN) where diagnosis is uncertain
• Side effect: hypotension and sedation (monitor BP)

• Chromogranin A is a glycoprotein stored in chromaffin granules and co-released with catecholamines
• Useful tumour marker for metastatic disease ^[3] — elevated levels correlate with tumour burden
• Also elevated in other neuroendocrine tumours (carcinoid, neuroblastoma) → not specific
• Caution: elevated by PPIs (proton pump inhibitors), renal failure, chronic atrophic gastritis → stop PPIs before testing

Genetic testing is indicated if ^[3]:

• Other features of genetic syndrome (e.g. medullary thyroid carcinoma → MEN2)
• Family history of phaeochromocytoma
• Presenting age < 50 years old
• Bilateral or multifocal tumours
• Extra-adrenal location (paraganglioma)
• Malignant/metastatic PPGL

Current recommendation: Comprehensive panel testing for RET, VHL, NF1, SDHA/B/C/D, SDHAF2, MAX, TMEM127, FH genes.

CT findings distinguishing phaeo from benign adenoma ^[3][8]:

• Radiopharmaceutical: ¹²³I-MIBG (or ¹³¹I-MIBG)
• Principle: MIBG is an analogue of norepinephrine ^[2][10] → taken up by norepinephrine-secreting cells (chromaffin cells) via the noradrenaline transporter (uptake-1 mechanism) → scintigraphy reveals adrenomedullary images 24–48 hours after injection ^[3]
• Physiological distribution (organs supplied by sympathetic nervous system + excretion routes) ^[10]:
  • Liver and spleen
  • Myocardium
  • Salivary glands and thyroid
  • Normal adrenals
  • Other organs (nasal mucosa, bladder, colon)
• Thyroid blockade should be used as radioiodine in ¹³¹I-MIBG may localise to the thyroid and destroy glandular tissue (e.g. Lugol's solution) ^[10]

• From femoral vein, for Conn's syndrome and phaeochromocytoma ^[10]
• Rarely needed for phaeo (imaging is usually sufficient); more commonly used in primary aldosteronism to lateralise the source
• May be considered in complex/bilateral cases

When an adrenal mass is found incidentally:

• Check CT attenuation: if > 10 HU (lipid-poor), phaeochromocytoma must be excluded biochemically ^[3][8]
• Biopsy is NOT indicated for primary adrenal tumours — especially avoid if phaeochromocytoma is suspected ^[8]
  • Histology is not useful in differentiating benign from malignant primary adrenal tumours
  • Biopsy may precipitate a hypertensive crisis and tumour seeding

For known carriers of susceptibility genes (e.g. MEN2 kindreds):

• Annual screening by plasma/urine metanephrines from 11 years or 16 years of age depending on risk of specific mutation ^[3]
• This is lifelong surveillance because phaeos can develop at any time

• Historically, IV iodinated contrast was considered high-risk for triggering pressor crises in phaeo patients ^[3]
• Modern low-osmolar non-ionic contrast agents are considered safe even without alpha/beta blockade ^[2]
• However, if using ionic or high-osmolar contrast (now rare), alpha-blockade should be established first ^[3]

Why α-blockade first?

The dominant haemodynamic effect of catecholamine excess is α₁-mediated vasoconstriction → ↑SVR → severe hypertension. You must antagonise this before doing anything else.

Adequate α-blockade is indicated by a postural BP drop ^[3] — this tells you that the α₁ receptors are sufficiently blocked such that the normal vasoconstriction on standing is impaired.

Target of pre-operative preparation ^[2]:

• BP < 130/80 mmHg seated (some guidelines say < 140/90)
• HR 60–70 bpm seated
• Postural hypotension present (but SBP standing > 80 mmHg)
• No ST-segment changes on ECG for > 1 week

Why β-blockade?

Once α-blockade is established, the patient often develops reflex tachycardia (because α-blockade → vasodilation → baroreceptor-mediated ↑sympathetic drive → β₁ stimulation → ↑HR). Also, the catecholamine excess itself directly stimulates β₁ receptors. β-blockade controls this.

ALWAYS initiate α-blockade before β-blockade ^[3]. β-blockade alone will cause unopposed α-adrenergic activity → exacerbate HTN ^[3].

Why volume expansion?

Chronic catecholamine excess causes:

1. Pressure natriuresis → chronic sodium and water loss → ↓plasma volume
2. Chronic vasoconstriction → reduced venous capacitance → masked hypovolaemia

Once you establish α-blockade and remove the vasoconstriction, the intravascular compartment "opens up" — if the patient is still volume-depleted, they will become profoundly hypotensive (especially post-operatively when the catecholamine source is removed).

Preop: ↑Na ( > 5 g/day) diet and fluid intake to reverse catecholamine-induced intravascular volume contraction (to prevent post-op hypotension) ^[3]

• Start high-sodium diet on 2nd/3rd day of alpha-blockade ^[2] (not before, because sodium loading before α-blockade could worsen hypertension)
• Liberal oral fluid intake
• Some centres use IV normal saline in the 24–48 hours before surgery

• Metyrosine (α-methyltyrosine) — inhibits catecholamine synthesis ^[3]
  • Mechanism: inhibits tyrosine hydroxylase (the rate-limiting enzyme in catecholamine biosynthesis)
  • Reduces tumour catecholamine stores by 50–80%
  • Used as an add-on when α/β-blockade alone is insufficient for BP/HR control, or in complex cases
  • Side effects: sedation, extrapyramidal symptoms, crystalluria (maintain hydration)
  • Not routinely used; reserved for refractory cases

Required for at least 7–14 days before surgery ^[3]. Some sources recommend 4 weeks of phenoxybenzamine ^[2] — the key is achieving haemodynamic targets, not a fixed duration.

• Biochemically confirmed phaeochromocytoma (any size)
• Functional adrenal tumour regardless of size
• Adrenal incidentaloma meeting resection criteria: functional, suspected malignancy ( > 4 cm, growing > 0.5 cm in 6 months), radiologically suspicious ^[2]

This is where your pre-operative preparation is tested. Even with optimal α/β-blockade, tumour manipulation releases catecholamines.

Potential intra-operative complications ^[2]:

• Hypertensive crisis: during intubation, tumour manipulation → treat with IV phentolamine or nitroprusside
• Hypotension: after tumour ligation/removal (sudden loss of catecholamine drive + residual α-blockade + volume depletion) → treat with IV fluids + vasopressors (noradrenaline/adrenaline)
• Arrhythmias: catecholamine-induced → esmolol, lidocaine
• Injury to surrounding structures ^[2]:
  • Right adrenalectomy: IVC, right lobe of liver
  • Left adrenalectomy: pancreatic tail, spleen

BP targets in hypertensive emergency ^[4]:

• Aim ≤ 25% ↓BP in the first hour
• Then to 160/110 in the next 2–6 hours
• Then cautiously to normal during the next 24–48 hours
• In compelling indications (aortic dissection, phaeo crisis): aim SBP < 140 in the first hour

Additional agents for crisis ^[4]:

Worth noting: the glucagon stimulation test (used for assessment of GH/ACTH reserve) is contraindicated in suspected phaeochromocytoma because glucagon can trigger a hypertensive crisis ^[9]. The mechanism: glucagon stimulates catecholamine release from the adrenal medulla.

• Diagnosed phaeo in pregnancy is a medical emergency — untreated maternal mortality up to 40%
• α-blockade with phenoxybenzamine is the cornerstone (crosses placenta but generally safe)
• β-blockade with propranolol or labetalol added as needed
• Surgical timing: ideally in 2nd trimester (laparoscopic if feasible); if late pregnancy, manage medically and deliver by elective caesarean section with phaeo resection at same or later operation
• Avoid: vaginal delivery (Valsalva manoeuvre can trigger crisis), ergometrine (sympathomimetic)

• Cortical-sparing adrenalectomy preferred to preserve adrenal cortical function
• If bilateral total adrenalectomy required → lifelong glucocorticoid + mineralocorticoid replacement
• Risk of Nelson's syndrome does not apply here (Nelson's is specific to bilateral adrenalectomy for Cushing's disease where the pituitary is the primary driver)
• Annual screening by plasma/urine metanephrines from 11 years or 16 years of age depending on risk of specific mutation ^[3]

• IV iodinated contrast injection may induce a pressor crisis ^[3]
• Consider preparation with complete adrenoceptor blockade, e.g. phenoxybenzamine ^[3]
• However, modern low-osmolar non-ionic contrast is safe even without alpha/beta blockade ^[2]

Phaeochromocytoma crisis: HTN or ↓BP with hyperthermia, altered mentation, multiorgan dysfunction ^[3]

This is the syndrome of catastrophic, uncontrolled catecholamine release leading to:

Triggers for crisis were discussed in the management section: tumour manipulation, anaesthesia, certain drugs (TCAs, β-blockers without α-blockade, metoclopramide, IV contrast), glucagon ^[9].

• 10% recurrence rate ^[2] — this is one of the original "10% rules"
• Recurrence can be local (at the surgical bed) or distant (metastatic)
• Can occur years to decades after initial surgery
• This is why lifelong yearly screening for recurrent, metastatic, or metachronous tumour is mandatory ^[2]
• Screening: urine catecholamines/metanephrines, chromogranin A, imaging ^[2]
• Higher recurrence risk in: large tumours, extra-adrenal location, SDHB mutation, cortical-sparing surgery (~10% local recurrence)

• 8.3–13% malignant: defined not histologically but by local invasion or distal metastases ^[3]
• Histologically and biochemically indistinguishable from benign disease ^[2] — you cannot tell from looking at the tumour under a microscope whether it will metastasise. This is a unique feature of chromaffin tumours
• 3× risk of malignant tumour in females ^[3]
• Metastatic sites: bone (most common), liver, lung, lymph nodes
• Risk factors for malignancy: SDHB mutation (highest risk, 30–40%), extra-adrenal location (paraganglioma), large tumour size ( > 5 cm), dopamine-secreting phenotype
• 5-year survival: 95% for benign, 40% for malignant ^[3]

• In patients with hereditary syndromes (MEN2, VHL, SDHx), new phaeochromocytomas or paragangliomas can develop in previously unaffected chromaffin tissue years after the initial surgery
• This is different from recurrence (which implies tumour at the original site)
• Reinforces the need for lifelong surveillance especially in familial cases

Because phaeochromocytoma is part of several hereditary syndromes, patients may develop complications from the other components of these syndromes: