What is a pheochromocytoma and where does it arise?
A pheochromocytoma is a rare tumour of the chromaffin cells of the adrenal medulla whose features come from excess catecholamine secretion. Tumours of extra-adrenal chromaffin tissue are called paragangliomas, and the two are studied together as neuroendocrine tumours. Pheochromocytomas account for 80 to 85 per cent of these tumours and sympathetic paragangliomas for 15 to 20 per cent. The 2022 WHO classification uses "pheochromocytoma" specifically for an intra-adrenal paraganglioma.
The medulla is the innermost part of the adrenal gland, surrounded by the cortex. The three cortical zones from outside inward are glomerulosa, fasciculata and reticularis; the medulla lies beneath them and releases catecholamines into the blood like a hormone.
How are catecholamines made, and which one does the tumour secrete?
Catecholamines are made in chromaffin cells in four steps. Tyrosine is converted to DOPA by tyrosine hydroxylase, the rate-limiting step. DOPA decarboxylase converts DOPA to dopamine; dopamine beta-hydroxylase converts dopamine to norepinephrine; and phenylethanolamine N-methyltransferase (PNMT) methylates norepinephrine to epinephrine.
| Step | Enzyme | Product |
|---|---|---|
| Tyrosine → DOPA | Tyrosine hydroxylase (rate-limiting) | DOPA |
| DOPA → dopamine | DOPA decarboxylase | Dopamine |
| Dopamine → norepinephrine | Dopamine beta-hydroxylase | Norepinephrine |
| Norepinephrine → epinephrine | PNMT | Epinephrine |
Tumours generally have a predominant secretory pattern. About half secrete mainly epinephrine with variable norepinephrine; others, including sympathetic paragangliomas, mainly secrete norepinephrine with dopamine as a by-product. Norepinephrine is released continuously, producing persistent hypertension, whereas epinephrine is released in bursts, which can cause tachyarrhythmias. Dopamine production is regarded as an independent predictor of malignancy.
What are the clinical features and triggers?
Hypertension may be paroxysmal, with headache, tachycardia and sweating, or sustained and resistant to several antihypertensives. Resistant hypertension should raise suspicion. Many patients with hereditary syndromes are found by screening and are not hypertensive at diagnosis, and some large tumours present only as an abdominal mass.
- Triggers of severe hypertension: dopamine receptor antagonists, non-selective beta blockers, tricyclic antidepressants, corticosteroids, sympathomimetics and neuromuscular blocking agents.
- Situational triggers: induction of anaesthesia, surgery, intense exertion, trauma, emotional stress and childbirth.
- Laboratory clues: hyperglycaemia, hypercalcaemia and erythrocytosis may be present.
- Differential diagnosis: anxiety disorder, hyperthyroidism, renal artery stenosis, carcinoid syndrome, Cushing syndrome, migraine, pre-eclampsia, drug-induced hypertension.
What is the rule of 10s, and what do current sources say?
The traditional teaching is the "rule of 10s": about 10 per cent extra-adrenal, 10 per cent malignant, 10 per cent bilateral, 10 per cent familial and 10 per cent in children. It still appears in examination options, but several of the figures no longer match current sources, so treat it as a memory aid, not data.
| Traditional "10 per cent" | What current sources state |
|---|---|
| Extra-adrenal | Sympathetic paragangliomas are 15 to 20 per cent of these tumours (pheochromocytoma 80 to 85 per cent). |
| Malignant | StatPearls: about 10 per cent of pheochromocytomas are malignant, about 20 per cent of extra-adrenal paragangliomas. WHO 2022 no longer classifies them as benign or malignant: any lesion can have metastatic potential. |
| Familial | Up to 35 per cent of cases may be linked to germline mutations, well above 10 per cent. |
| Bilateral | Bilateral tumours are most often hereditary (MEN2, VHL); a reliable percentage is not given in the sources used here. |
| Children | Not verified here; younger age at presentation is associated with hereditary syndromes. |
How is a pheochromocytoma diagnosed?
Catecholamines are rapidly inactivated by catechol-O-methyltransferase (COMT) into metanephrine and normetanephrine, which have a longer half-life. These metabolites are therefore better to measure than catecholamines. The Endocrine Society guideline recommends starting with plasma free fractionated metanephrines or urinary fractionated metanephrines. Plasma-free metanephrines are the most reliable test for confirming or excluding the tumour and are more specific than urinary values.
- Sampling: draw plasma metanephrines after the patient has been supine for at least 30 minutes; seated samples raise values and cause false positives. A positive seated result should be repeated supine.
- Interpretation: with a low pre-test probability, false positives outnumber true positives. Reported urinary metanephrine sensitivity is 86 to 97 per cent with specificity 69 to 95 per cent.
- Imaging only after biochemical proof: CT of abdomen and pelvis is the first test; pheochromocytomas appear low-density, and lesions over 3 cm vary in appearance. MRI is an alternative and tumours are hyperintense on T2. FDG-PET is recommended for metastatic disease; 123I-MIBG scan is an alternative, particularly when MIBG radiotherapy is considered.
Which syndromes and genes are linked, and what does histology show?
Up to 35 per cent of cases carry a germline mutation, and over half are sporadic. The best-known hereditary causes follow an autosomal dominant pattern.
| Syndrome | Gene | Other features |
|---|---|---|
| MEN2 | RET | Medullary thyroid cancer, primary hyperparathyroidism, mucocutaneous neuromas, intestinal ganglioneuromas, cutaneous lichen amyloidosis |
| von Hippel-Lindau | VHL | Haemangioblastomas of brain and spine, retinal angiomas, clear cell renal carcinoma, pancreatic neuroendocrine tumours; type 2 carries a higher pheochromocytoma risk than type 1 |
| Neurofibromatosis type 1 | NF1 | Autosomal dominant; one of the three classic familial associations |
| SDH-related | SDHB, SDHD and others | Cluster 1 pseudohypoxia genes |
Histology shows nests of chromaffin cells, the zellballen pattern, with strong chromogranin, synaptophysin and CD56 and focal S100 positivity. No single histological or biochemical feature reliably separates benign from malignant tumours; the PASS score has been used but the WHO neither endorses nor discourages scoring systems.
Why do catecholamines raise blood pressure and heart rate?
Catecholamines act on alpha and beta adrenoceptors. Alpha-adrenoceptors on vascular smooth muscle cause vasoconstriction and hypertension when activated by norepinephrine and epinephrine. Beta-1 receptors in the heart increase rate and contractility through the cyclic AMP pathway; beta-2 receptors in peripheral vessels cause vasodilation. Presynaptic alpha-2 receptors at nerve terminals inhibit further norepinephrine release.
| Receptor | Main effect | Selectivity note |
|---|---|---|
| Alpha-1 | Vasoconstriction | More selective for norepinephrine than epinephrine |
| Alpha-2 | Inhibits norepinephrine release at nerve terminals | Dopamine has affinity for alpha-2 |
| Beta-1 | Cardiac stimulation | Norepinephrine is about 10-fold more selective for beta-1; epinephrine binds beta-1 and beta-2 with similar affinity |
| Beta-2 | Peripheral vasodilation | Activated by epinephrine and norepinephrine |
This receptor map explains the preoperative sequence. Blocking alpha-receptors first removes the dominant vasoconstrictor drive. A beta blocker added alone removes beta-2 mediated vasodilation while the alpha effect is untouched, so blood pressure can rise sharply.
What special situations are asked, such as pregnancy and hereditary screening?
In pregnancy a pheochromocytoma is rare but dangerous, and undiagnosed or untreated tumours carry a significantly higher risk of maternal and fetal complications. A review cited by StatPearls reported maternal or fetal death in 33 of 230 pregnancies (14 per cent) involving pheochromocytoma or paraganglioma. Alpha blockers such as phenoxybenzamine and doxazosin are used during pregnancy, and if surgery is needed the second trimester is considered safer than the first.
- Hereditary screening: once a pathogenic mutation is found, genetic screening of first-degree relatives should be considered.
- Bilateral or young-onset tumour: more likely hereditary, so targeted testing for VHL, MEN2 (RET) and NF1 is recommended.
- Apparently sporadic tumour: in a German study, characteristic mutations were found in 24 per cent of patients with apparently sporadic pheochromocytoma, so testing can still be justified.
- Genetic clusters: cluster 1 (pseudohypoxia: VHL, SDHx, EPAS1), cluster 2 (kinase signalling: NF1, RET, MAX, TMEM127) and cluster 3 (Wnt-altered, somatic).
How is a pheochromocytoma managed — why alpha before beta?
Definitive treatment is surgical resection, usually minimally invasive adrenalectomy for unilateral tumours, with open surgery considered for large or invasive tumours. For bilateral hereditary disease, cortical-sparing adrenalectomy preserves adrenocortical function and reduces the need for lifelong steroid replacement.
| Step | Detail |
|---|---|
| 1. Alpha blockade first | Phenoxybenzamine starting 7 to 14 days before surgery, 10 mg orally twice daily, titrated to a maximum of 1 mg/kg/day; doxazosin (alpha-1 selective) is an acceptable alternative |
| 2. Then beta blockade | Propranolol, atenolol or metoprolol started at least 3 to 4 days after alpha blockade, to control tachycardia |
| 3. Never beta first | Starting a beta blocker without prior alpha blockade can precipitate a hypertensive crisis through unopposed alpha stimulation |
| 4. Other measures | Calcium channel blockers (amlodipine, nifedipine) as alternative or add-on; high-sodium diet a few days after starting alpha blockade to reduce post-operative hypotension |
Perioperative care has four elements: minimal handling and no tumour spillage to prevent a catecholamine surge, early control of the adrenal vein, and effective management of the sudden hypotension after the tumour is removed, when peripheral resistance falls. Metastatic disease may be treated with cytoreductive surgery, chemotherapy (cyclophosphamide, vincristine, dacarbazine or temozolomide) or 131I-MIBG.
What are the common traps in this topic?
- Beta blocker before alpha blocker is the single most tested error.
- Catecholamine excess is tested via metanephrines, which are more reliable than the catecholamines themselves.
- Supine sampling reduces false-positive plasma metanephrines.
- Biochemical confirmation precedes imaging, and CT is the first localising test.
- Rule of 10s is a mnemonic: the familial fraction is up to 35 per cent, and extra-adrenal tumours are 15 to 20 per cent of the group.
- Tyrosine hydroxylase is rate-limiting; PNMT makes epinephrine.
- Triggers: dopamine receptor antagonists, non-selective beta blockers, tricyclic antidepressants, corticosteroids, sympathomimetics and neuromuscular blockers can provoke severe hypertension.