Phaeochromocytoma

Meet the patient

A 38-year-old woman is sent to the medical admissions unit by her GP for "panic attacks" that now strike three times a week: a thumping headache, drenching sweat, a heart that "tries to leave the chest", and — her husband insists — a face that goes deathly pale, never red. Her blood pressure in the unit is 168/104, but the nurse who clerked her an hour ago wrote down 122/78.[1][5]

Between spells she is tired, dizzy on standing, and has lost four kilograms. She takes no regular medication. The single question that must be answered before anyone prescribes, scans, or anaesthetises her is the question that defines this whole disease: is she alpha-blocked yet? Everything below exists to keep her safe until she is.[1][2]

What phaeochromocytoma actually is — chromaffin, Zellballen, and the rule of 10 that died

A phaeochromocytoma is a vascular tumour of neural-crest-derived chromaffin cells, and its histology is its signature. The cells sit in nested balls — Zellballen, German for "cell balls" — wrapped by a rich capillary network and rimmed by S100-positive sustentacular cells. Tumours in the adrenal medulla are phaeochromocytomas; histologically identical tumours in extra-adrenal sympathetic paraganglia (the organ of Zuckerkandl near the aortic bifurcation, the sympathetic chain, the bladder wall, the thorax) are paragangliomas, and the two are now grouped as PPGL because they share genetics, biochemistry and management.[1][3]

About 80 to 85 percent of catecholamine-producing tumours arise in the adrenal medulla and 15 to 20 percent are extra-adrenal. Sympathetic paragangliomas secrete noradrenaline and produce the classic pressor spells; parasympathetic paragangliomas of the head and neck (carotid body, glomus jugulare, vagal) are usually non-functional and present as a mass, hearing loss or cranial-nerve palsies rather than hypertension.[1][3]

Etymology for viva gold: phaeos is Greek for "dusky", chroma for "colour" — the cells stain dark with chromium salts (the chromaffin reaction), which is how they were first spotted. Zellballen and organ of Zuckerkandl are two German eponyms examiners love; drop either and you sound like you have been to a histology lab.[3]

Forget the rule of 10 for heritability — it is a fossil. The old teaching that roughly 10 percent each are bilateral, malignant, extra-adrenal, familial and paediatric survives as a memory scaffold, but modern genotyping has buried the "familial 10 percent": 30 to 40 percent of all patients carry a germline mutation in RET, VHL, NF1, SDHx, MAX or TMEM127. State the rule, then immediately supersede it — that two-step answer is what earns the mark.[1][3]

How common, who, and where to fish

Phaeochromocytoma is rare, but it hides in places you must always look. The annual incidence is only about 2 to 8 per million, and it accounts for 0.1 to 0.6 percent of all hypertension — but it turns up in 5 to 7 percent of adrenal incidentalomas, which is why every adrenal mass found by chance must be biochemically screened before anyone touches it.[1][5]

Sporadic disease peaks in the 4th to 5th decade with no sex bias; bilateral, multifocal, or paediatric disease should immediately raise the hereditary flag. The Endocrine Society's high-yield screening groups are:[1]

• Paroxysmal or resistant hypertension, especially with the classic triad of headache, sweating and palpitations.
• Any adrenal incidentaloma — screen metanephrines every time, before biopsy or surgery.
• A family history or known carrier status for a susceptibility gene, or a previously resected phaeochromocytoma under surveillance.
• Paradoxical or worsening hypertension on a beta-blocker, hypertension in pregnancy, or pressor collapse on induction of anaesthesia or with contrast.
• Spell-like episodes — anxiety, flushing, tremor, pallor — that do not fit a cleaner diagnosis.[1][3]

Why metanephrines, not catecholamines — the one biochemical insight that runs the whole disease

The tumour leaks metanephrines continuously, even when the patient feels well — and that single fact makes phaeochromocytoma diagnosable. Catecholamine biosynthesis runs a fixed cascade: tyrosine to L-DOPA (via tyrosine hydroxylase, the rate-limiting step) to dopamine, to noradrenaline, and finally to adrenaline by phenylethanolamine N-methyltransferase (PNMT).[1][3]

PNMT is switched on by the high cortisol delivered straight from the adrenal cortex through the portal system — which is why extra-adrenal tumours, denied that cortisol bath, almost always secrete noradrenaline alone, a clean biochemical clue to a paraganglioma. Inside the tumour, catechol-O-methyltransferase (COMT) mops up the excess, converting noradrenaline to normetanephrine and adrenaline to metanephrine, and these metabolites leak steadily into the bloodstream regardless of the episodic surges that produce the spells.[1][3]

Random catecholamines surge and crash with each spell and are easily missed between attacks; metanephrines do not. That is why plasma free metanephrines (sensitivity 96 to 100 percent) and 24-hour urine fractionated metanephrines (slightly less sensitive, more specific) are the first-line tests, and why measuring catecholamines or vanillylmandelic acid (VMA) is a generation behind.[1]

The excess catecholamines act on adrenergic receptors to build the clinical picture: alpha-1 activation causes vasoconstriction (hypertension, pallor, cold extremities); beta-1 activation drives tachycardia and palpitations; beta-2 activation produces tremor and a vasodilatory counter-regulation. Orthostatic hypotension appears paradoxically in chronic disease through volume depletion and impaired baroreflex buffering — its presence in a hypertensive patient is a valuable clue.[1]

The catecholamine storm — how the patient actually looks

Read the spell, not the blood pressure between spells. The clinical hallmark is the paroxysm: an abrupt, dramatic episode lasting minutes to an hour, built around the classic triad of severe throbbing headache, profuse generalised sweating, and a pounding, racing heart, with paroxysmal or sustained hypertension. The single best discriminator at the bedside is the colour of the patient's face — pallor, not flushing, because alpha-1-mediated vasoconstriction shuts the skin.[1][5]

The accompanying features complete the storm: anxiety, terror, a sense of impending doom, tremor, nausea and abdominal pain. Spells are triggered by anything that squeezes the tumour or floods it with catecholamines:[1]

• Straining, bending, micturition, defaecation, abdominal palpation, exertion, anaesthesia and radiological contrast.
• Tyramine-rich foods — cheese, red wine, smoked meats.
• Drugs — tricyclics, MAOIs, decongestants, cocaine, opioids, metoclopramide, glucocorticoids.
• Micturition-triggered spells specifically mean a bladder paraganglioma — ask, because patients rarely volunteer it.[1]

Between spells the patient is often sustained hypertensive, but a valuable clue is orthostatic hypotension — a postural drop in a hypertensive patient points to chronic catecholamine excess with volume depletion. Weight loss, hyperglycaemia or new diabetes, and constipation round out the chronic picture.[1]

The classic trap — the normotensive phaeochromocytoma. A substantial minority — up to 15 to 30 percent — present with no hypertension at all, declaring themselves through catecholamine cardiomyopathy, Takotsubo (apical ballooning), acute heart failure, cardiogenic shock, ventricular arrhythmia, or sudden death, sometimes with normal coronaries. Sustained catecholamine exposure causes coronary vasospasm, microvascular injury, focal myocyte necrosis and interstitial fibrosis. Reaching for a beta-blocker or an ACE inhibitor in that patient without alpha-blockade is how an unopposed-alpha catastrophe begins on top of the cardiomyopathy.[2]

Split the spells — the differential face-off

The decisive discriminator is always biochemistry plus localisation, not the spell itself. The mimics of episodic hypertension split cleanly once you know what to test:[1]

The one-line discriminator beneath: pallor with raised metanephrines is phaeo; flushing with raised 5-HIAA is carcinoid; normal metanephrines with a flush is menopause, anxiety, or a drug.[1]

For the adrenal mass itself, phaeochromocytoma (over 10 HU on unenhanced CT, raised metanephrines) must be separated from a cortical adenoma (lipid-rich, under 10 HU, over 60 percent washout at 10 minutes), a cortisol adenoma (Cushing phenotype, fails to suppress on 1 mg overnight dexamethasone), an aldosteronoma (hypokalaemic hypertension, raised aldosterone-to-renin ratio), myelolipoma (macroscopic fat), metastasis (known primary, often bilateral, non-functional), and adrenocortical carcinoma (over 4 cm, irregular, heterogeneous). Every adrenal incidentaloma therefore earns a triple screen — metanephrines, dexamethasone suppression, aldosterone-renin ratio with potassium corrected.[1]

The bedside round — what to look for, and what not to press

Bedside assessment rarely makes the diagnosis; it finds the syndromic stigmata and the end-organ damage, and it avoids triggering a crisis. Run it in this order:[1]

• Blood pressure both lying and standing — paroxysmal or sustained hypertension with an orthostatic drop over 20/10 mmHg is a strong clue in a hypertensive patient.
• Syndromic stigmata — marfanoid habitus with mucosal neuromas and a thyroid nodule (MEN 2); café-au-lait patches, axillary freckling, cutaneous neurofibromas, Lisch nodules (NF1); retinal and CNS haemangioblastomas, renal cysts or renal cell carcinoma (VHL); multiple paragangliomas, especially with paternal transmission (SDHD).
• Micturition history — headache, sweating and hypertension during or after voiding means a bladder paraganglioma until proven otherwise.
• End-organ assessment — hypertensive retinopathy, heart failure or cardiomyopathy, prior stroke. Examine the abdomen, but never deep-palpate a known mass — you can precipitate a fatal crisis.[1][3]

Biochemistry first, then pictures — the fixed diagnostic ladder

Never localise, never biopsy, never block, until the biochemistry is done. The Endocrine Society pathway runs in a fixed order: plasma free metanephrines or 24-hour urine fractionated metanephrines first, anatomical imaging second, functional imaging and genetics third. The first-line test is plasma free metanephrines (highest sensitivity); add the 24-hour urine collection when plasma is borderline, because its higher specificity settles the equivocal result.[1]

Before drawing blood, stop interfering drugs for at least 48 hours — tricyclic antidepressants, phenoxybenzamine, pseudoephedrine, caffeine, MAOIs, and many antidepressants — and avoid paracetamol for 24 hours because it interferes with the plasma assay. Calcium-channel blockers and alpha-blockers raise levels modestly but rarely need to be withdrawn. For an equivocal result, use the clonidine suppression test: clonidine normally suppresses catecholamine release, so a failure of metanephrines to fall confirms autonomous tumoural production.[1]

Interpretation turns on pre-test probability. The Endocrine Society considers plasma free normetanephrine over 0.8 nmol/L or metanephrine over 0.5 nmol/L highly suggestive, and levels more than four times the upper limit of normal are essentially diagnostic. Because specificity is only 85 to 89 percent, false positives are common — from drugs, severe physiological stress (pain, surgery, myocardial infarction, stroke, obstructive sleep apnoea), and renal impairment. Repeat the test with the patient supine and rested for at least 30 minutes, withdraw interferents, and consider clonidine suppression before chasing a borderline result.[1]

Anatomical localisation is CT or MRI of the abdomen and pelvis with contrast. A phaeochromocytoma is typically over 10 HU on unenhanced CT (often 40 to 50 HU from its vascularity), enhances intensely and heterogeneously, and shows slow washout — under 60 percent absolute washout at 10 minutes — the mirror image of a lipid-rich adenoma. MRI shows high T2 signal, the "light-bulb" sign, though it is not always present.[1]

Functional imaging is reserved, not routine — for extra-adrenal, metastatic, hereditary, large (over 5 cm), biochemistry-radiology mismatch, or recurrent disease. The tracers are chosen to genotype and intent: 123I-MIBG scintigraphy (noradrenaline transporter uptake, the traditional whole-body tracer), 18F-DOPA PET (excellent for SDHx disease), 18F-FDG PET (high uptake in SDHB-mutated and aggressive tumours), and increasingly 68Ga-DOTATATE PET (somatostatin-receptor imaging, the most sensitive tracer for metastatic and SDHx disease).[1][3]

Genetic testing is offered to every patient, because over 30 percent carry a germline mutation. A tiered approach directs the workup: adrenergic, adrenal tumours to RET, NF1, MAX, TMEM127; noradrenergic, extra-adrenal tumours to VHL and SDHx (especially SDHB and SDHD). A mutation changes surveillance, predicts malignancy risk, enables cascade testing of relatives, and informs cortical-sparing surgery.[1][3]

The traps that kill patients — read this twice

Three errors account for the preventable deaths in this disease, and all three are sequence errors — doing the right thing in the wrong order.[1][2]

• Giving a beta-blocker before an alpha-blocker. Beta-blockade removes beta-2-mediated vasodilation while leaving alpha-1-mediated vasoconstriction untouched, producing catastrophic vasoconstriction and a hypertensive crisis. This is the single most dangerous mistake in endocrinology.
• Biopsying an unblocked tumour. Needle manipulation of a phaeochromocytoma can trigger a fatal catecholamine crisis. Screen the biochemistry first in every adrenal incidentaloma; if metanephrines are raised, prepare with alpha-blockade and resect — biopsy is reserved for confirming metastatic disease under blockade, never for diagnosing the primary.
• Missing the normotensive phaeo. A patient in cardiogenic shock or acute heart failure with normal coronaries may have a catecholamine cardiomyopathy, and a beta-blocker given by reflex will precipitate the very crisis you are trying to treat.[1][2]

Catecholamine crisis — the first fifteen minutes

A catecholamine crisis is a hypertensive emergency, and the first drug is an alpha-blocker, never a beta-blocker. It is typically precipitated by anaesthesia induction, tumour handling at surgery, biopsy, contrast, or a beta-blocker, metoclopramide or glucocorticoid given to an unblocked patient — and it may be the first manifestation of the disease. Manage it in a high-dependency or intensive-care setting with invasive arterial monitoring from the start.[1][2]

The resuscitation sequence, in order:[2]

• IV phentolamine — a short-acting, non-selective alpha-blocker, 2.5 to 5 mg IV bolus, repeated or as an infusion (0.1 to 2 mg/min) titrated to blood pressure. This is the first-line vasodilator because it directly reverses the alpha-mediated vasoconstriction driving the crisis.
• Alternatives — a sodium nitroprusside infusion (0.3 to 2 mcg/kg/min), a nicardipine infusion (5 to 15 mg/hour), clevidipine, or urapidil, all titratable.
• Intravenous fluids to restore intravascular volume, plus magnesium sulphate 2 to 4 g IV as an adjunct for both blood pressure and arrhythmia control.
• Never give a beta-blocker alone first. Treat arrhythmia with a short-acting beta-blocker such as esmolol (loading 500 mcg/kg over 1 minute, then 50 to 200 mcg/kg/min) only after alpha-blockade is established.
• For an undiagnosed phaeo precipitated on induction of anaesthesia, recognise it, abort the procedure if possible, give IV phentolamine, fluids and vasopressors as needed, and arrange the definitive workup once stabilised.[2]

ALPHA before BETA — the cardinal rule and the 10-to-14-day runway

The cure is surgery, but the safe road to surgery is alpha-blockade first, always. The goal of preoperative preparation is to convert a patient who could die on the table into one who tolerates the catecholamine swings of induction, tumour handling and tumour-vein clamping. The non-negotiable sequence is: alpha-blockade first, then volume expansion, then a beta-blocker for tachycardia, then surgery.[1]

The endpoints of adequate alpha-blockade are worth memorising as a cluster, because they are how you decide the patient is ready for theatre: a seated blood pressure of about 130/80, a mild orthostatic drop but no syncope, nasal congestion (the clinical sign of complete alpha-blockade), controlled tachycardia under 80, and no spells for a week. Add the beta-blocker only once those are achieved.[1]

Selective alternatives, and the trials behind them. Phenoxybenzamine is the traditional choice because it is non-competitive and irreversible — catecholamines cannot displace it. Selective alpha-1 blockers (doxazosin 2 to 8 mg/day, terazosin 1 to 10 mg/day, prazosin 1 to 5 mg two to three times daily) are competitive and shorter-acting; a large single-centre comparison (Zhu et al, 2022) found comparable intraoperative stability between phenoxybenzamine and doxazosin, with less postoperative hypotension in some selective-blocker groups.[7] A landmark multicentre randomised controlled trial (Buitenwerf et al, 2020), however, questioned whether routine phenoxybenzamine meaningfully improves intraoperative haemodynamic control versus no phenoxybenzamine — a finding that has fuelled debate but has not overturned standard practice, and certainly does not license skipping alpha-blockade of any kind.[4]

Calcium-channel blockers (nicardipine, amlodipine, nifedipine) are used as adjuncts or, in some centres, as sole agents in mild disease. Metyrosine — a tyrosine hydroxylase inhibitor that cuts catecholamine synthesis at the source — is reserved for refractory disease or large tumour burden.[1]

Theatre and the two haemodynamic swings

Laparoscopic adrenalectomy is the standard of care for most tumours, and the anaesthetic plan is built around two predictable swings. Open adrenalectomy is reserved for large tumours (over 6 to 8 cm), locally invasive or clearly malignant disease, or when laparoscopic control is difficult. In bilateral or hereditary disease — especially MEN 2 and VHL — cortical-sparing (partial) adrenalectomy is preferred to preserve cortisol and aldosterone production and avoid lifelong steroid dependence, accepting a slightly higher recurrence risk.[1]

Surgery demands an experienced anaesthetic team and invasive arterial-line monitoring from induction. Two swings bracket tumour devascularisation, and the team prepares for both:[1][2]

• On tumour handling, catecholamine surges cause severe hypertension — treat with boluses of IV phentolamine or magnesium, or a nitroprusside or nicardipine infusion.
• Immediately after the adrenal vein is ligated, the abrupt loss of catecholamine tone on a fully alpha-blockaded, vasodilated patient causes hypotension — treat with IV fluids and noradrenaline or phenylephrine, weaning as vascular tone returns.
• Avoid histamine- or catecholamine-releasing drugs — morphine, atracurium, metoclopramide, droperidol — and prefer fentanyl, remifentanil, propofol, vecuronium or rocuronium.[1][2]

The consultant confession: I have never regretted blocking a patient for an extra two days; I have regretted rushing to theatre twice. The blockade runway is not where this disease kills people — the unblocked induction is.[1]

Post-resection, anticipate the two predictable shifts: hypotension from the loss of catecholamine tone (IV fluids and vasopressors such as noradrenaline or phenylephrine), and hypoglycaemia from the loss of catecholamine-driven hyperglycaemia with residual insulin action (monitor glucose for 24 to 48 hours, treat with dextrose). After bilateral surgery, transient adrenal insufficiency may require glucocorticoid replacement. Most patients are admitted to HDU or ICU for 24 to 48 hours.[2]

The hereditary 30 to 40 percent — know the syndromes cold

Over 30 percent of phaeochromocytomas are hereditary, and the syndrome changes the surveillance, the surgery, and the family. Each susceptibility gene writes a recognisable phenotype, and the biochemistry often points to it before the gene test does:[1]

The biochemistry-to-genotype link is a viva favourite. Adrenergic tumours (secreting adrenaline and metanephrine, typically adrenal and intra-tumoural) point to RET, NF1, MAX and TMEM127; noradrenergic tumours (predominantly noradrenaline and normetanephrine, often extra-adrenal) point to VHL and SDHx. At the molecular level these map onto two transcriptional clusters — a pseudo-hypoxia cluster (VHL, SDHx, EPAS1) that is noradrenergic, extra-adrenal and carries the highest metastatic risk, and a kinase-signalling cluster (RET, NF1, RAS, MAX, TMEM127) that is adrenergic, adrenal and lower-risk; a smaller WNT cluster (MAML3 fusions) is metastatic and mixed.[3]

The one gene to circle in red is SDHB — it carries the highest risk of malignancy and metastasis, up to 35 to 40 percent, and its tumours are typically extra-adrenal. SDHD shows parental imprinting: disease appears only when the mutation is inherited from the father.[3]

Pregnancy, children, and the silent incidentaloma

Phaeochromocytoma in pregnancy is rare and, untreated, lethal — and it mimics pre-eclampsia. The decisive clue is that the hypertension comes in paroxysmal spells rather than the sustained rise of pre-eclampsia, with orthostatic hypotension, which is unusual in pre-eclampsia. Alpha-blockade with phenoxybenzamine is safe in pregnancy; add a beta-blocker cautiously for tachycardia. Plan a multidisciplinary, scheduled caesarean delivery — avoid vaginal pushing, which can trigger a crisis, and avoid catecholamine-releasing oxytocic and anaesthetic agents. Resect at caesarean or soon after.[1][5]

Children more often have bilateral, extra-adrenal and hereditary disease; genetic testing is mandatory and frequently reveals SDHx, VHL or MEN 2, and cortical-sparing surgery is preferred in bilateral disease. Hereditary carriers enter surveillance from childhood, gene-specific in age and modality, and are offered cortical-sparing surgery to preserve adrenal cortical function. Any patient needing non-adrenal surgery with a known or occult phaeo must be blocked first — an undiagnosed tumour is a classic cause of unexplained haemodynamic collapse on induction.[1][2][3]

Malignant and metastatic disease — defined by spread, not by histology

Malignancy in PPGL is defined by the presence of metastases at non-chromaffin sites — bone, lung, liver, or distant lymph nodes — because histology alone cannot reliably predict it. Scoring systems attempt to stratify risk: the GAPP (Grading of Adrenal Phaeochromocytoma and Paraganglioma) score and PASS (Phaeochromocytoma of the Adrenal Gland Scaled Score). Metastatic disease clusters with SDHB mutations and extra-adrenal primary site, and carries a 5-year survival of roughly 50 to 80 percent depending on burden, site and genotype.[1][3]

Management is multidisciplinary and built around reducing catecholamine load and treating spread:[1][6]

• Surgical debulking to reduce catecholamine load and relieve mass effects.
• Radionuclide therapy — 131I-MIBG for MIBG-avid disease, and 177Lu-DOTATATE peptide radioligand therapy for somatostatin-receptor-positive disease.
• Chemotherapy — the CVD regimen (cyclophosphamide, vincristine, dacarbazine) for progressive disease.
• Tyrosine-kinase inhibition with sunitinib, now with randomised evidence, and metyrosine to suppress catecholamine synthesis.[6]

Bladder and head-and-neck paragangliomas — the functional and the silent

Bladder paragangliomas announce themselves at the urinal. The classic presentation is micturition spells — headache, sweating, palpitations and hypertension during or immediately after voiding, sometimes with haematuria — and the tumour is often small enough to need functional imaging to localise.[1][3]

Head-and-neck paragangliomas (carotid body, glomus jugulare, glomus tympanicum, vagal) are usually parasympathetic and non-functional, presenting as a pulsatile neck mass, hearing loss, tinnitus or cranial-nerve palsies rather than hypertension, and are frequently SDHD- or SDHC-related. They are a different clinical beast — the biochemistry is often normal, and the workup leans on imaging and genotype.[1][3]

How phaeo patients come to harm — the preventable list

• A beta-blocker given first, precipitating an unopposed-alpha crisis — the preventable death this disease is famous for.[2]
• An adrenal mass biopsied before metanephrines were checked, triggering a fatal crisis on the table.[1]
• Inadequate preoperative blockade or volume expansion, causing intra-operative haemodynamic instability and post-resection hypotension.[1]
• The diagnosis missed in pregnancy by attributing spells to pre-eclampsia.[5]
• Relying on random catecholamines or VMA instead of metanephrines, or not stopping interfering drugs, producing false positives and negatives.[1]
• Failing to test genetics in a young, bilateral or recurrent patient, and omitting lifelong surveillance after resection — missing a metachronous tumour or metastasis.[3]

Prognosis, surveillance, and the lifelong sentence

A completely resected benign phaeochromocytoma is curative, and the blood pressure usually normalises — but surveillance is forever. Some patients remain hypertensive from chronic vascular remodelling. Lifelong biochemical surveillance is mandatory: plasma metanephrines at 6 weeks postoperatively to confirm biochemical cure, then every 6 to 12 months indefinitely, for local recurrence, metastasis and new primaries — metachronous tumours are common in hereditary disease. Patients with a germline mutation and their relatives enter a surveillance programme from childhood.[1][3]

Malignant or metastatic disease carries a variable but often guarded prognosis, with 5-year survival of roughly 50 to 80 percent. Catecholamine-crisis mortality is high when unrecognised, which is why meticulous preoperative alpha-blockade and a high index of suspicion in any adrenal mass or refractory hypertension are not optional.[1][2][6]

Evidence, controversy, and regional deltas

The Endocrine Society 2014 guideline (Lenders et al) sets the international standard and is the most-cited reference in the field: first-line plasma free metanephrines or 24-hour urine fractionated metanephrines, CT/MRI for localisation, preoperative alpha-blockade, surgical resection, and genetic testing for all. The 2024 scoping review by Saavedra et al consolidates contemporary practice from presentation to management.[1][5]

The live controversy is the choice of preoperative alpha-blockade. Traditional teaching and the Endocrine Society favour non-competitive phenoxybenzamine for its complete, irreversible blockade. The Buitenwerf 2020 multicentre RCT found phenoxybenzamine did not significantly improve intraoperative haemodynamic control versus no phenoxybenzamine — stimulating debate but not yet overturning practice pending larger trials.[4] The Zhu et al 2022 comparison found comparable intraoperative stability between phenoxybenzamine and doxazosin, with less postoperative hypotension in some selective alpha-blocker groups.[7]

For metastatic disease, the FIRSTMAPPP trial (Baudin et al, 2024) is the landmark — the first randomised, placebo-controlled phase 2 trial to show a progression-free survival benefit for sunitinib in progressive metastatic PPGL.[6] The personalised-management framework of Nölting et al (2022) ties genotype to imaging tracer and therapy — 18F-FDG for SDHB, 68Ga-DOTATATE for somatostatin-receptor-positive disease, 18F-DOPA for sporadic and SDHx disease.[3]

Regional practice varies mainly in functional imaging (MIBG versus PET tracers, with European centres using 68Ga-DOTATATE earlier), blockade drug preference (phenoxybenzamine in the UK and much of Europe; doxazosin or calcium-channel blockers in some North American centres), and surveillance intensity. In India and similar resource-limited settings, 24-hour urine fractionated metanephrines and VMA remain widely used because plasma free metanephrine assays are not universally available — but the diagnostic sequence and the alpha-before-beta rule are identical everywhere.[1][3]

The mantra, and the mnemonics

The mantra: ALPHA before BETA — everything else is detail.[1][2]

Ward-round test — three stems, thirty seconds each