Investigations for phaeochromocytoma
Two questions, in order
- Two questions, in order:
- 1. Is there excess catecholamine secretion? -> biochemistry
- 2. Where is it, and is it metastatic? -> anatomical then functional imaging
- *Never image first.* An adrenal lesion found before biochemistry cannot be interpreted
Who to test
- Paroxysmal headache + palpitations + diaphoresis (the classic triad, ~90% specific)
- Resistant or paroxysmal hypertension; hypertension <20 or >50y
- Pressor response to anaesthesia, surgery or contrast
- Adrenal incidentaloma (every one)
- Known germline mutation or syndromic family history
- Unexplained cardiomyopathy, hyperglycaemia with weight loss
Epidemiology and heritability
- 0.2-0.6% of hypertensive patients
- ~40% carry a germline mutation - the highest heritability of any tumour
- ~10% metastatic at presentation; higher with SDHB and extra-adrenal disease
Why metanephrines and not catecholamines
- Catecholamines are released episodically -> a normal level between spells proves nothing
- Metanephrines are produced continuously by intratumoural COMT, independent of secretion
- -> metanephrines are the test; plasma/urinary catecholamines are obsolete as a screen
Secretory phenotype predicts biology
| Pattern | Suggests |
|---|---|
| Adrenaline/metanephrine | Adrenal (PNMT needs cortisol - only the adrenal medulla makes adrenaline) |
| Noradrenaline/normetanephrine | Extra-adrenal paraganglioma, or adrenal |
| Dopamine/3-methoxytyramine | Head and neck paraganglioma, SDHB, malignant potential |
Biochemistry - the diagnostic test
A. Biochemistry - the diagnostic test
- Plasma free metanephrines OR 24h urinary fractionated metanephrines
- Plasma: supine, cannulated, rested 30 min - seated sampling is a major source of false positives
- Preparation: no food, caffeine, strenuous exercise or smoking for 8-12 h
- >4x upper reference limit = near-100% probability - proceed straight to imaging
- Normal metanephrines effectively exclude the diagnosis (sensitivity ~97-99%)
- Add 3-methoxytyramine if head/neck paraganglioma or SDHx suspected
### False positives - the commonest reason a phaeo workup goes wrong
- TCAs (biggest offender), SNRIs, MAOIs
- Levodopa, adrenergic agonists (decongestants), amphetamines
- Buspirone, antipsychotics, prochlorperazine, reserpine
- Clonidine or other sympatholytic withdrawal
- Cocaine, heroin, ethanol
- Physiological stress: acute illness, OSA, pain, exercise
- Repeat correctly prepared, off the offending drug, before escalating
Clonidine suppression test - for equivocal results only
B. Clonidine suppression test - for equivocal results only
- Use when metanephrines are elevated but <4x the upper limit
- Clonidine 0.3 mg, plasma normetanephrine at 0 and 3 h
- Failure to suppress to <40% of baseline = phaeochromocytoma (sens ~100%, spec ~96%)
- Clonidine suppresses neurogenic release; autonomous tumour secretion is unaffected
Anatomical imaging - only once biochemistry is positive
C. Anatomical imaging - only once biochemistry is positive
- CT abdomen/pelvis with contrast first line (modern non-ionic contrast does not require alpha blockade)
- MRI preferred in children, pregnancy, skull base/neck paraganglioma, or to avoid radiation in known germline carriers
- Phaeo on CT: unenhanced attenuation >10 HU, often heterogeneous, cystic/haemorrhagic; MRI T2 bright
Functional imaging - for staging, not diagnosis
D. Functional imaging - for staging, not diagnosis
Indicated if tumour >5-10 cm, extra-adrenal, multifocal, known SDHx, or metastatic disease suspected
| Modality | Best for |
|---|---|
| 68Ga-DOTATATE PET/CT | Highest sensitivity - now first choice for metastatic and SDHx-related PPGL, and head/neck paraganglioma |
| 18F-FDG PET/CT | SDHB-related metastatic disease |
| 123I-MIBG | Mainly to confirm avidity before 131I-MIBG therapy |
Genetic testing
E. Genetic testing
- Offer to every patient - not just the young or syndromic
- SDHA/B/C/D/AF2, VHL, RET, NF1, MAX, TMEM127, FH
- SDHB -> highest metastatic risk -> lifelong whole-body surveillance
Histology
- No histological feature reliably predicts malignancy - metastasis at a site where chromaffin tissue does not normally occur is the only definition
- PASS and GAPP scores are prognostic aids only
Before any surgery or procedure
- Alpha blockade first, always - phenoxybenzamine or prazosin, 10-14 days pre-op
- Beta blocker only after alpha blockade is established
- Unopposed alpha stimulation -> hypertensive crisis
- Liberal salt and fluid to re-expand the contracted plasma volume
- Exclude phaeochromocytoma before thyroid or parathyroid surgery in any MEN2 patient
Post-operative
- Metanephrines at 2-6 weeks to confirm biochemical cure
- Annual biochemical surveillance for life - recurrence occurs decades later, and in up to 15%
- Germline carriers: lifelong imaging surveillance schedule by genotype
Hereditary syndromes
- MEN2A / MEN2B (RET) - bilateral adrenal phaeo, rarely metastatic
- VHL - bilateral adrenal, noradrenergic, young
- NF1 - adrenal phaeo in ~1-5%
- SDHB - extra-adrenal, highest metastatic risk, dopaminergic
- SDHD - head and neck paraganglioma, paternal transmission (imprinted)
- Carney triad / Carney-Stratakis dyad - paraganglioma + GIST +/- pulmonary chondroma
Prognosis
- Untreated: hypertensive crisis, takotsubo or catecholamine cardiomyopathy, arrhythmia, stroke, bowel ischaemia, death
- Multisystem crisis can be precipitated by anaesthesia, contrast, surgery, or beta blockade given alone
- 5-year survival >95% for resected localised disease
- Metastatic: median survival highly variable (years to decades); SDHB worst
- Treatment: 131I-MIBG (high specific activity), 177Lu-DOTATATE, sunitinib/cabozantinib, CVD chemotherapy
- ~10-15% recurrence over decades -> surveillance never stops
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