Phaeochromocytoma and paraganglioma

• A phaeochromocytoma is a catecholamine-secreting tumour of the adrenal medulla; a paraganglioma is the same kind of tumour arising from sympathetic or parasympathetic paraganglia outside the adrenal. Together they are called PPGLs.
• Most patients have paroxysmal headaches, sweating, palpitations and labile or sustained blood pressure; only about a quarter have the classic triad of severe headache, sudden palpitations and sweating together. ^[5]
• First biochemical test is plasma free metanephrines or 24-hour urine fractionated metanephrines. Imaging follows only after biochemical confirmation. ^[1]
• Roughly a quarter to two-fifths of cases are associated with an inherited germline variant, so genetic testing is recommended for all patients. ^{[2][5] [3]}
• Treatment is preoperative alpha blockade for 7 to 14 days, then a beta blocker, volume repletion, laparoscopic adrenalectomy, and long-term biochemical follow-up. ^[1][5][6]

By the end of this page you should be able to:

1. Explain what a phaeochromocytoma and a paraganglioma are, where they arise, and how their catecholamine excess produces symptoms.
2. List the main symptoms and signs, the classic triad, and the conditions that can be mistaken for PPGL.
3. Plan the biochemical and imaging work-up, including the thresholds that separate a positive from a negative test.
4. Outline preoperative alpha then beta blockade, volume repletion, and surgical approach.
5. Explain the genetic syndromes, malignancy risk, postoperative follow-up, and surveillance imaging.
6. Describe management of hypertensive crisis and care in pregnancy, children and low-resource settings.

Pheochromocytomas are a subtype of paraganglioma, but clinically the adrenal origin matters: adrenal tumours are usually adrenergic (metanephrine-secreting), whereas extra-adrenal sympathetic tumours are usually noradrenergic (normetanephrine-secreting), and parasympathetic head-and-neck tumours are usually biochemically silent. ^[5]

Classification that guides management:

• By site. Adrenal (phaeochromocytoma, PCC) versus extra-adrenal (paraganglioma, PGL). About 83% are adrenal and 17% extra-adrenal. ^[2]
• By function. Functional (catecholamine-secreting) versus nonfunctional.
• By heredity. Sporadic versus hereditary (germline variant in a susceptibility gene).
• By behaviour. Localised versus metastatic. A PPGL is classified as malignant only when metastases are present; histology alone cannot reliably separate benign from malignant disease. ^[5]
• By molecular cluster. Cluster 1 (pseudohypoxic, often extra-adrenal, high metastatic risk), cluster 2 (kinase signalling, mostly adrenal, lower metastatic risk) and cluster 3 (Wnt signalling). ^[5]

PPGLs are rare but important because they are a curable cause of hypertension and are often missed.

• Reported incidence ranges from about 0.8 per 100,000 per year in a 2023 review to about 5 cases per million person-years in a Japanese guideline, the latter figure thought to reflect increased detection of incidental, small and low-secreting tumours. ^[2][5]
• In the same review, 15% of phaeochromocytomas and up to 50% of abdominal paragangliomas will metastasise; up to 20% of patients present with metastatic disease from the start. ^[5]
• Most patients are diagnosed in the fourth or fifth decade; up to 20% of cases occur in childhood. ^[5]
• The occurrence of PPGL among all people with sustained hypertension is only about 0.05% to 0.1%, so biochemical screening is reserved for suspected, resistant or paradoxical cases rather than all hypertensive patients. ^[5]
• Head-and-neck paragangliomas are different: roughly 99% are nonfunctional and usually grow slowly. ^[5]
• Mortality from large case series has fallen: sufficient preoperative blockade has reduced perioperative mortality to below 3%. ^[2]

Roughly a quarter to two-fifths of all PPGLs are associated with a germline pathogenic variant, and up to about 40% of cases may harbour a somatic mutation in a susceptibility or tumour gene. ^[2][5] Because no single clinical feature reliably separates sporadic from hereditary disease, genetic testing is recommended in every patient. ^[3]

PPGLs arise from chromaffin cells. Their catecholamines (adrenaline, noradrenaline and dopamine) produce the clinical picture through adrenergic receptors:

• Noradrenaline and adrenaline activate alpha-1 receptors, producing vasoconstriction and hypertension.
• Beta-1 receptor activation produces tachycardia and palpitations.
• Secretion is often episodic rather than constant, which explains paroxysmal symptoms and why a patient may be normotensive between spells.
• Pressure natriuresis and reduced plasma volume can produce orthostatic hypotension despite high average blood pressure.
• Catecholamine excess also causes hyperglycaemia, sweating and, in severe cases, cardiovascular collapse.

The amount of catecholamine produced is not related to tumour size, and small tumours can cause severe hypertension.

Symptoms reflect catecholamine excess. ^[2][5]

• Headache, often severe and migraine-like.
• Episodic or sustained hypertension.
• Sweating and palpitations.
• Anxiety, tremor, nausea, weakness, pallor and weight loss.
• Postural hypotension.

The classic triad of severe headache, sudden palpitations and sweating is present in only 24% of patients, but it is highly suggestive when it occurs. ^[5] Catecholamine excess can also lead to a lethal phaeochromocytoma crisis. ^[5] Rarely a PPGL secretes erythropoietin or ACTH, causing polycythaemia or Cushing syndrome. ^[5]

Crises and paroxysms can be provoked by:

• Anaesthesia, surgery and physical manipulation of the tumour.
• Drugs: beta blockers given without prior alpha blockade, metoclopramide, decongestant nasal sprays, amphetamines and other sympathomimetics, clonidine withdrawal, and high-dose glucocorticoids, which can precipitate a hypertensive crisis. ^[2]
• Foods and drinks high in caffeine, tyramine (aged cheese, red wine) and chocolate may affect testing and symptoms. ^[2]

• Tachycardia, tremor, pallor or flushing and sweating.
• Labile or severe hypertension; orthostatic hypotension in some.
• Evidence of end-organ damage: retinopathy, left ventricular hypertrophy, or proteinuria.
• Features of associated syndromes: café-au-lait spots or neurofibromas (NF1), retinal haemangioblastomas (VHL), thyroid nodules or hyperparathyroidism (MEN2).

A spell of headache, sweating and palpitations with high blood pressure has many mimics. The first question is whether a spell is a PPGL at all; the second is whether a catecholamine-secreting tumour is present.

The first test is plasma free metanephrines or 24-hour urine fractionated metanephrines. ^[1]

Metanephrines are produced continuously inside the tumour by catechol-O-methyltransferase, so they are more stable and more sensitive than direct catecholamine measurements, which can be normal in up to 20% of PPGLs because secretion is intermittent. ^[5]

Common thresholds used (adapt to the laboratory's own reference ranges):

• Random urine fractionated metanephrines (corrected for creatinine): over three times the upper limit is positive on screening. ^[2]
• 24-hour urine fractionated metanephrines: over three times the upper limit. ^[2]
• 24-hour urine fractionated catecholamines: over two times the upper limit. ^[2]
• Plasma free fractionated metanephrines: above the upper limit. ^[2]
• Plasma metanephrines, normetanephrines and 3-methoxytyramine exceeding three times the upper normal limit are considered diagnostic. ^[5]

Pre-analytical points: rest the patient supine before sampling, use an indwelling needle in the forearm, avoid exercise, stress and temperature change. Stop or account for drugs that affect catecholamines (metoclopramide, decongestants, amphetamines, buspirone, and others listed in Table 3 of the Japanese guideline), high-dose dexamethasone and caffeine, alcohol, bananas, cheese, chocolate and vanilla-containing foods. ^[2] Interpret results with the clinical picture; many apparent "PPGL" results are false positives.

When a result is borderline, a clonidine suppression test can help. Clonidine 0.15 to 0.3 mg by mouth suppresses noradrenaline in healthy people so that adrenaline and noradrenaline fall below 50% of baseline or below 500 pg per mL; in catecholamine-secreting PPGL they do not fall. ^[2]

Chromogranin A has a clinical sensitivity of about 90% in PPGL and can complement metanephrines in nonfunctional or dopamine-secreting tumours; plasma 3-methoxytyramine is the most useful marker of metastatic disease. ^[5]

Imaging is used to locate the tumour, assess spread and look for metastasis; it follows biochemical confirmation except in emergency or research situations. ^[2]

• CT provides high spatial resolution and is useful for lung, liver and adrenal lesions; it is not disease specific. ^[2]
• MRI offers high contrast resolution and is preferred for head-and-neck paragangliomas, for children and for repeated studies, because it avoids radiation. ^[2]
• 123I-MIBG scintigraphy is highly specific for PPGL and helps find paragangliomas and metastases, although its sensitivity is lower for metastatic and SDHx-related disease. Thyroid blockade is recommended before 123I-MIBG. ^[2]
• 18F-FDG PET is useful for metastatic lesions, particularly in SDHx-related disease. ^[2]
• Functional imaging: 68Ga-DOTATATE PET/CT has the highest detection rate overall (about 93% in a meta-analysis) and is preferred for extra-adrenal and metastatic disease; 18F-FDOPA PET/CT is more effective for phaeochromocytomas and sporadic head-and-neck paragangliomas. ^[5]

All patients should be considered for genetic testing in an accredited laboratory. ^[1][3]

Targeted testing patterns:

• All patients with paraganglioma are tested for SDHx mutations.
• Patients with metastatic disease are tested for SDHB.
• Patients with VHL, RET and NF1 are tested according to clinical features.

In practice, a gene-panel approach is preferred. Germline mutation in SDHB carries the highest metastatic risk; SDHD cases often present as head-and-neck paragangliomas through paternal inheritance (maternal imprinting); VHL-associated tumours are noradrenergic with early onset and frequent bilaterality; MEN2-associated phaeochromocytomas have a penetrance of about 60%. ^[2][5]

• The proportion of hereditary PPGLs with heterozygous germline pathogenic variants is reported at 20% to 40%. ^[2]
• In one Japanese cohort of 370 PPGL probands, the germline pathogenic variant rate was 32.4%, most commonly SDHB (15.4%), SDHD (7.3%) and VHL (4.9%). ^[2]
• About 25% of patients have inherited genetic disorders and 40% of cases may harbour a somatic mutation. ^[5]
• Penetrance: SDHB about 22%, SDHD about 43% by age 60, VHL 15 to 20%, MEN2 about 60%. ^[2]

There is no serum or histological criterion that on its own confirms PPGL; diagnosis combines:

1. Biochemical excess (abnormal plasma or urinary metanephrines, or catecholamine suppression test).
2. Anatomical tumour on CT or MRI in the expected location.
3. Functional imaging uptake when uncertainty remains.

Staging uses the AJCC TNM classification. Head-and-neck paragangliomas are excluded from this staging because of their low metastatic risk. ^[2]

For malignancy risk scores, PASS and GAPP have high negative predictive value (they are useful for ruling malignancy out) but poor positive predictive value; molecular cluster and germline genetics are more informative. ^[5]

Treat as a medical emergency in an intensive care setting, without waiting for the biochemical result:

• Stop precipitating drugs and treat the cause (infection, surgery, drugs).
• Phentolamine intravenously is the first option for rapid control.
• If blood pressure remains too high, add intravenous nicardipine. ^[2]
• Use an arterial line, aggressive but controlled blood-pressure lowering, and volume support.
• Avoid starting a beta blocker before alpha blockade is established.
• Metyrosine, a catecholamine synthesis inhibitor, can be used in severe or refractory cases; its safety data in pregnancy are limited. ^[2]

Every patient with a functional tumour needs preoperative blockade. International guidelines recommend alpha-adrenergic blockade for 7 to 14 days before surgery. ^{[5][6] [1]}

Recommended sequence:

1. Alpha blockade first. Phenoxybenzamine 10 mg twice or three times daily, or selective alpha-1 blockade with doxazosin, starting at 1 to 2 mg daily and titrating up to 16 mg. ^[2][5]
2. Volume repletion. Guidelines differ: the Endocrine Society 2014 recommends a high-sodium diet and fluid intake, the Japanese 2025 guideline recommends a normal-salt diet or saline infusion, and a 2023 review lists volume repletion with a low-salt diet. Choose according to local practice and avoid volume depletion in all cases. ^[1][2][5]
3. Beta blocker only after alpha blockade is adequate. Add atenolol, propranolol or another beta blocker for reflex tachycardia. Do not use labetalol or carvedilol as the sole agent, because their beta blockade can worsen hypertensive control, and labetalol interferes with 131I-MIBG imaging. ^[2]
4. Calcium-channel blockers can be added if blood pressure remains unstable. ^[5]

• Minimally invasive laparoscopic adrenalectomy is appropriate for most phaeochromocytomas. ^[1][5]
• Open resection is preferred for large or invasive tumours, for paragangliomas and where metastasis is suspected. ^[1][5]
• Adrenalectomy should be performed by a high-volume adrenal surgeon (at least 12 adrenalectomies a year; more than 20 is desirable). ^[4]
• Partial (cortical-sparing) adrenalectomy is an option for selected patients, especially with bilateral disease or hereditary PPGL, to avoid lifelong steroid replacement; bilateral cases need individual assessment because of the risk of recurrence. ^[2][5]
• For head-and-neck paragangliomas the approach depends on site and cranial nerve risk; selected jugular and jugulotympanic tumours may be treated with radiotherapy instead of surgery. ^[5]
• Adjacent vein ligation, gentle handling to avoid catecholamine surges and monitoring in the post-anaesthetic period are standard.

• Watch for postoperative hypotension and hypoglycaemia, because catecholamine levels fall abruptly.
• After recovery and completion of perioperative care, confirm biochemical cure with plasma or urinary metanephrines.

Lifelong follow-up is required, because recurrence and new tumours can appear years later. ^[1][3]

• Genetic testing is recommended in all patients; identifying an SDHB or VHL variant changes surveillance intensity. ^[1][3]
• Biochemical testing: plasma free or 24-hour urine fractionated metanephrines every year. ^{[3] [1]}
• Minimum follow-up: at least 10 years for every patient. High-risk patients (young age, genetic disease, large tumour of 5 cm or more, paraganglioma, noradrenergic phenotype) should have lifelong annual follow-up. ^[2][3]
• A cancer-medicine review suggests a practical schedule: biochemical testing every 3 to 12 months in the first year, every 6 to 12 months for the first 3 years, then annually up to 10 years; cluster 1A/B and cluster 3 tumours need MRI from skull base to pelvis every 12 months initially then every 12 to 24 months, whereas cluster 2 tumours need abdominal and pelvic MRI at least every 5 years. ^[5]
• Patients with SDHB-related disease warrant the most intensive surveillance because of a high metastatic rate (35 to 75% in some analyses). ^[2]

Metastatic or unresectable disease is managed with a multidisciplinary team. Treatment options include debulking surgery, 131I-MIBG, peptide receptor radionuclide therapy, chemotherapy (cyclophosphamide, vincristine and dacarbazine) and tyrosine kinase inhibitors; observation is acceptable for slow-growing disease without symptoms. This is beyond the scope of this page and should be in specialist hands.

• Hypertensive crisis, arrhythmia, myocardial infarction, catecholaminergic cardiomyopathy, pulmonary oedema and stroke during uncontrolled secretion. ^[5]
• Severe postoperative hypotension and hypoglycaemia after tumour removal.
• Metastatic spread, mainly to lymph nodes, bone, liver and lungs. ^[5]
• In untreated disease, recurrent paroxysms, orthostatic intolerance and impaired quality of life.

• Metastasis occurs in roughly 10 to 15% of PPGLs overall, with the rate about three times higher in paragangliomas than in phaeochromocytomas. ^[2]
• Clusters 1A and 1B carry the highest metastatic potential (60% of metastatic disease is cluster 1), cluster 2 the lowest (~4%). ^[5]
• 3-Methoxytyramine is the most useful plasma marker for separating localised from metastatic disease and is markedly higher in patients with metastases. ^[5]
• PASS and GAPP have limited positive predictive value and are best used to exclude malignancy. ^[5]
• Five-year survival is excellent for localised disease and much lower with metastatic disease; metastatic disease is usually slowly progressive.

• Diagnose early; tumour removal is recommended before 24 weeks of gestation if feasible, and medical management is continued beyond that until the fetus is viable. ^[2]
• Antihypertensive choice excludes ACE inhibitors, ARBs and direct renin inhibitors; alpha blockade remains the basis of treatment, and nicardipine is used in crisis. ^[2]
• Doxazosin-like alpha blockade and fluid management are adapted by an obstetric-medicine team.

• Up to 20% of PPGLs occur in childhood, and many are hereditary; genetic testing is mandatory in young patients. ^[5]
• MRI rather than CT is preferred for repeated imaging.

• MEN2 and phaeochromocytoma: the phaeochromocytoma is usually treated before thyroid surgery to avoid a catecholamine storm.
• Bilateral phaeochromocytoma is common with VHL and MEN2; partial adrenalectomy may preserve cortisol production.

• Where plasma or urinary metanephrines are unavailable, rely on clinical suspicion, 24-hour urine VMA or catecholamines if available, and blood pressure patterns; treat at least as severe as the clinical picture suggests.
• Where functional imaging is unavailable, use contrast CT or MRI for localisation and chest and pelvic imaging for staging.
• Oral alpha blockade (prazosin, doxazosin) plus volume repletion can be given where phenoxybenzamine is not stocked; phentolamine may not be available for crisis, so alternative intravenous vasodilators must be planned with anaesthetics.
• Refer for laparoscopic adrenalectomy at a centre able to handle catecholamine lability; minimum monitoring still includes an arterial line.
• Establish how genetic testing will be arranged (regional centre or research programme) before discharge.

• Secondary hypertension
• Primary hyperaldosteronism
• Adrenal insufficiency and adrenal crisis
• Multiple endocrine neoplasia (when published)
• Congenital adrenal hyperplasia
• Diabetes mellitus: chronic complications (cardiovascular risk context)