Phaeochromocytoma and paraganglioma

Published by the practice of Charalambos Charalambous, MD, ChM, General Surgeon, German Medical Institute, Limassol, Cyprus. Last updated: 19 September 2026.

Phaeochromocytoma is a tumour of the adrenal medulla that produces catecholamines — adrenaline and noradrenaline. Paraganglioma is the same tumour arising outside the adrenal gland, from the paraganglia of the sympathetic or parasympathetic nervous system. Together they are uncommon, but they matter out of proportion to their frequency for three reasons: they cause a potentially curable form of hypertension; they can kill suddenly through a hypertensive crisis, particularly if operated on unprepared; and a remarkably high proportion — around a third to forty per cent — are caused by an inherited genetic mutation, which means the diagnosis has implications for the whole family.

The old teaching that these are "the ten per cent tumour" — ten per cent bilateral, extra-adrenal, malignant and familial — is now known to be wrong on the familial figure by a wide margin, and the hereditary proportion is far higher.

How they form

Both tumours arise from chromaffin cells, which derive from the neural crest and are specialised to synthesise, store and release catecholamines. In the adrenal medulla these cells are exposed to very high local concentrations of cortisol draining from the cortex, which induces the enzyme PNMT and allows conversion of noradrenaline to adrenaline. Outside the adrenal, that cortisol exposure is absent — which is why extra-adrenal paragangliomas typically secrete noradrenaline but not adrenaline, a useful biochemical clue to location.

Tumour cells store catecholamines in vesicles and release them episodically and unpredictably, independent of normal neural control. The paroxysmal nature of the symptoms follows directly from this.

Within the tumour, catecholamines are continuously metabolised by catechol-O-methyltransferase into metanephrines, which leak steadily into the circulation. This is the single most important fact for diagnosis: because metanephrine production is continuous whereas catecholamine release is episodic, measuring metanephrines is far more reliable than measuring catecholamines, and a normal metanephrine level effectively excludes the diagnosis even between attacks.

The genetics — and why they matter

Germline mutations are found in a large minority, and the specific gene predicts behaviour, so testing is recommended in every patient, not only those with a family history. The genes fall into clusters:

• Pseudohypoxia cluster — SDHA/B/C/D, SDHAF2, VHL, FH, EPAS1. These impair cellular oxygen sensing, stabilising HIF and driving tumour growth. SDHB mutation carries a high risk of metastatic disease and of extra-adrenal, often abdominal, tumours — identifying it changes surveillance fundamentally. VHL mutation occurs within von Hippel-Lindau disease, alongside renal cell carcinoma, haemangioblastoma and pancreatic lesions.
• Kinase signalling cluster — RET (multiple endocrine neoplasia type 2, with medullary thyroid carcinoma and hyperparathyroidism), NF1 (neurofibromatosis type 1), TMEM127, MAX. These tend to produce adrenal, adrenaline-secreting, benign tumours.

All phaeochromocytomas and paragangliomas are now regarded as having malignant potential. There is no histological feature that reliably distinguishes benign from malignant; malignancy is defined by the presence of metastases in sites where chromaffin tissue is not normally found.

Symptoms

The classical triad — episodic headache, sweating and palpitations — in a hypertensive patient is highly suggestive, though all three are present in only a minority.

• Hypertension — sustained in about half, paroxysmal in about a third, and absent in the remainder
• Paroxysms — typically lasting minutes to an hour, with headache, sweating, palpitations, pallor (not flushing, which is a useful distinguishing point), tremor, anxiety and a sense of impending doom
• triggers — exertion, bending, abdominal pressure, micturition (with bladder paragangliomas), certain foods and drugs
• postural hypotension, from chronic volume depletion — the combination of hypertension with postural drops is characteristic
• weight loss, glucose intolerance, constipation
• Cardiomyopathy — catecholamine-induced, including takotsubo-like presentations; occasionally the presenting problem
• Crisis — severe hypertension, arrhythmia, pulmonary oedema, stroke, myocardial infarction, multi-organ failure. May be precipitated by anaesthesia, surgery, biopsy, contrast media, certain drugs (beta-blockers given alone, metoclopramide, tricyclic antidepressants), or abdominal palpation of the tumour.
• Head and neck paragangliomas are usually non-secreting and present as a painless neck mass, pulsatile tinnitus, hearing loss or cranial nerve palsy

Who should be tested

• paroxysmal symptoms of the kind described
• resistant or early-onset hypertension
• any adrenal incidentaloma — without exception, before any biopsy or surgery
• a hypertensive response during anaesthesia or a procedure
• a known syndromic mutation or a family history
• unexplained cardiomyopathy

How the diagnosis is made

• Plasma free metanephrines or 24-hour urinary fractionated metanephrines — the first-line test. Plasma samples should be taken supine after twenty to thirty minutes' rest, as upright sampling raises levels and generates false positives. Several drugs interfere, notably tricyclic antidepressants, and should be withdrawn where possible. A normal result effectively excludes the diagnosis. Levels above three times the upper limit are essentially diagnostic; intermediate elevations may require a clonidine suppression test.
• CT or MRI of the abdomen — for localisation, once the diagnosis is biochemically established. MRI is preferred for extra-adrenal and head and neck disease and in children and pregnancy.
• Functional imaging — Ga-68 DOTATATE PET-CT is now the most sensitive modality, particularly for extra-adrenal, multifocal and metastatic disease, and has largely superseded MIBG scintigraphy for staging, though MIBG retains a role in selecting patients for radionuclide therapy.
• Genetic testing — recommended in all patients, with counselling.

Biopsy is contraindicated. Needling a phaeochromocytoma can precipitate a hypertensive crisis and is never required for diagnosis, which is biochemical.

Treatment

Preoperative preparation — the part that saves lives

This is not a formality. Before the advent of routine blockade, operative mortality was high; with proper preparation it is now low. Preparation takes two to four weeks and should never be curtailed for convenience.

• Alpha-blockade first — phenoxybenzamine (non-selective, irreversible) or doxazosin (selective, shorter-acting, fewer side effects). The dose is increased until blood pressure is controlled and mild postural hypotension and nasal stuffiness appear, which indicate adequate blockade.
• Liberal salt and fluid intake — essential, to re-expand the chronically contracted plasma volume. Omitting this is a common reason for severe hypotension after tumour removal.
• Beta-blockade only afterwards, and only if tachycardia requires it. Giving a beta-blocker before alpha-blockade is dangerous: blocking the vasodilatory beta-2 receptors leaves alpha-mediated vasoconstriction unopposed and can precipitate a hypertensive crisis and pulmonary oedema. This is one of the classical and still-occurring errors in this condition.
• Calcium channel blockers may be added.

Surgery

Laparoscopic adrenalectomy is the standard approach, with minimal tumour handling and early ligation of the adrenal vein to limit catecholamine surges. Open surgery is preferred for large tumours, invasive disease and suspected malignancy. Cortical-sparing adrenalectomy is important in hereditary bilateral disease, preserving enough cortex to avoid lifelong steroid dependence.

The operation requires an experienced anaesthetist with invasive monitoring, prepared for both hypertensive surges during tumour manipulation and profound hypotension immediately after the venous drainage is divided, when the circulating catecholamines disappear within minutes from a vasodilated, volume-depleted patient.

Hypoglycaemia may follow removal, as suppressed insulin secretion rebounds, and blood glucose is monitored.

Metastatic disease

Managed with surgical debulking, radionuclide therapy (¹³¹I-MIBG or ¹⁷⁷Lu-DOTATATE), chemotherapy (cyclophosphamide, vincristine and dacarbazine), targeted agents including sunitinib and the HIF-2α inhibitor belzutifan, external beam radiotherapy and ablation, alongside continued alpha-blockade to control symptoms.

Recovery

After laparoscopic adrenalectomy, hospital stay is typically two to three nights. Blood pressure medication is usually stopped, and blood pressure and glucose monitored closely in the first days. Hypertension resolves completely in many patients and improves in most of the rest; long-standing hypertension is less likely to normalise. Metanephrines are rechecked at two to six weeks to confirm cure.

Follow-up

Lifelong annual biochemical surveillance is recommended for all patients, because recurrence and metachronous tumours occur even after apparently complete removal, and because malignancy cannot be excluded histologically. Patients with germline mutations, particularly SDHB, require more intensive imaging surveillance, and their relatives should be offered genetic testing and screening — which is frequently the most valuable outcome of the whole episode.

When to seek an opinion

Episodic headache, sweating and palpitations with hypertension; resistant or early-onset hypertension; any adrenal mass (test before biopsy or surgery); an unexplained severe blood pressure surge during a procedure; or a family history of phaeochromocytoma, paraganglioma, medullary thyroid cancer or von Hippel-Lindau disease.

Common questions

What causes the attacks?

The tumour stores adrenaline-like hormones and releases them in bursts, independently of normal control. When a burst occurs you get a surge of blood pressure with headache, sweating, palpitations and a feeling of alarm, lasting minutes to an hour. Between attacks you may feel entirely well, which is why the condition is often not suspected.

My symptoms come and go. Will a blood test taken between attacks be useful?

Yes — and this is an important point. The test measures the breakdown products of the hormones, which the tumour produces continuously even when it is not releasing bursts. A normal result effectively rules the condition out, whether or not you are having symptoms at the time.

Why can't the lump simply be biopsied?

Because putting a needle into this kind of tumour can trigger a massive release of hormone and a dangerous surge in blood pressure. It is also unnecessary — the diagnosis is made by blood or urine tests, not by examining tissue.

Why do I have to take tablets for several weeks before the operation?

Because handling the tumour during surgery releases a surge of hormone, and without preparation this can cause a life-threatening rise in blood pressure. The tablets block the receptors those hormones act on, and the extra salt and fluid restore the blood volume, which has been chronically reduced. This preparation transformed the safety of the operation and should not be shortened.

Why was I told not to take a beta-blocker?

Because beta-blockers given before the other type of blockade can make things considerably worse — they remove the blood vessel-widening effect of the hormone while leaving the narrowing effect unopposed, which can precipitate a crisis. A beta-blocker may be added later, once the first drug is established, if your heart rate needs it.

Should my family be tested?

Very likely yes. A much higher proportion of these tumours than was once believed — around a third or more — are caused by an inherited gene change, and genetic testing is now recommended for everyone diagnosed, regardless of family history. If a mutation is found, relatives can be tested and those who carry it can be monitored, which often means future tumours are found early and small.

Is it cancer?

Most do not spread, but there is no way to tell from the tissue itself which ones will, so all are now regarded as having some potential to do so. That is why follow-up with a yearly blood test is lifelong even after apparently complete removal. Certain gene mutations, particularly one called SDHB, carry a higher risk, which is another reason genetic testing matters.

Will my blood pressure return to normal?

In many people, completely. In others it improves but some medication is still needed, particularly if the blood pressure has been high for many years and the blood vessels have changed. Your tablets will be reviewed carefully in the days after surgery, because continuing them all unchanged can cause the pressure to drop too far.

Related conditions

Other conditions of the adrenal glands covered on this site:

• Adrenal incidentaloma
• Primary aldosteronism (Conn's syndrome)
• Cushing's syndrome
• Adrenocortical carcinoma
• Adrenal metastases

This page provides general information and does not replace an individual medical consultation. Phaeochromocytoma requires specialist endocrine and surgical management with appropriate preoperative preparation.