Phaeochromocytoma

A phaeochromocytoma is a rare tumour that secretes catecholamines. It is derived from chromaffin cells, usually in the adrenal medulla but occasionally extra-adrenal phaeochromocytomas or paragangliomas occur.¹ Many but not all authors, define phaeochromocytoma as coming from the adrenal medulla and if the tumour is similar but located elsewhere it is called a paraganglionoma.

The excessive production of catecholamines may cause life-threatening hypertension or cardiac arrhythmias. If the diagnosis is overlooked, the result can be disastrous or fatal but if this rare tumour is diagnosed it is curable.

Up to one third of all symptomatic presentations of phaeochromocytoma or paraganglioma are due to germline mutations in one of six genes defining multiple endocrine neoplasia type 2, von Hippel-Lindau disease, neurofibromatosis type 1 and the paraganglioma syndromes types 1, 3 and 4.²

The name is of Greek etymology. Phios means dusky, chroma means colour and cytoma means tumour. This refers to the colour of tumour cells when stained with chromium salts. 10% of phaeochromocytomas are malignant.

A normal adrenal medulla secretes in response to neural control and produces about 85% adrenaline. These tumours are not innervated and the stimulus for secretion is unknown. They may secrete constantly or intermittently. The familial type tend to produce mostly noradrenaline but the sporadic type produce mostly adrenaline. Dopamine may also be produced.

• They occur in between 0.5 and 2 in 1,000 patients with hypertension but patients may be normotensive or have a labile blood pressure.
• Approximately 15% are malignant, 18% extra-adrenal and 20% familial.³
• In a retrospective study from the Mayo Clinic, the diagnosis was made at autopsy in nearly half the cases.⁴ In 10% the diagnosis is an incidental finding.
• There is no sex difference in incidence nor any particular racial predisposition.
• Diagnosis is usually made between the third and the fifth decades.
• Approximately 10% occur in children.
• In children, 50% are solitary adrenal tumours, 25% are bilateral and 25% are extra-adrenal. They are more likely to be familial than those presenting in adults.⁵

Inherited Forms

• Phaeochromocytomas occur in certain familial syndromes, including:
  • Multiple endocrine neoplasia (MEN) syndrome
  • Neurofibromatosis
  • Von Hippel-Lindau (VHL) syndrome
• It was thought that 10% of cases represent inherited syndromes but this figure may be up to 30%.⁶
• Phaeochromocytomas occur bilaterally in 70% of MEN syndromes.
• Neurofibromatosis has a 1% incidence of phaeochromocytoma.
• The VHL syndrome is associated with phaeochromocytomas, cerebellar haemangioblastomas and renal cell carcinoma.

Symptoms are intermittent and may vary from once a month to several times a day with duration from seconds to hours. With time they tend to get more frequent and more severe.

There are a number of symptoms that may present but the first 4 are in bold as they are almost invariably present:

• Headache
• Profuse sweating
• Palpitations
• Tremor
• Nausea
• Weakness
• Anxiety
• Sense of doom
• Epigastric pain
• Flank pain
• Constipation
• Weight loss

Persons with familial phaeochromocytoma may be asymptomatic.⁷

Again the most important features are in bold:

• Hypertension but it may be paroxysmal in 50%
• Postural hypotension
• Tremor
• Hypertensive retinopathy
• Pallor
• Fever
• Acute hypertension with a tumour that releases predominantly noradrenaline may cause reflex bradycardia

Neurofibromas may be felt and café au lait patches may be seen.

Blood tests

• Blood glucose is often raised.
• Calcium may be elevated.
• Haemoglobin is elevated due to haemoconcentration from reduction in circulating volume.
• Plasma catecholamines and plasma metanephrines (the o-methylated metabolites of catecholamines) have both been used in diagnosis.^8,9

Urine

• 24-hour urine collection is required for creatinine (to assure full 24 hours specimen), total catecholamines, vanillylmandelic acid (VMA) and metanephrines.¹⁰
• The bottle for collection should be dark and acidified and should be kept cold to avoid degradation of the catecholamines.
• Preferably collect urine immediately after a crisis.
• Physical stress and a number of drugs may interfere with the assay and cause false elevation of metanephrines. Drugs include tricyclic antidepressants, alcohol, levodopa, labetalol, sotalol, amfetamines, benzodiazepines and chlorpromazine.
• IVMA has a false positive rate in excess of 15%.One study found that of all urine and blood tests, urine free metanephrines produced the best results.⁸

Imaging

After biochemical confirmation of a tumour, imaging is necessary to locate it.¹¹

• 90% of phaeochromocytomas are in the adrenal glands and 98% within the abdomen.
• Extra-adrenal phaeochromocytomas develop in chromaffin tissue of the sympathetic nervous system and can occur anywhere from the base of the brain to the urinary bladder.
• Common locations for extra-adrenal phaeochromocytomas include close to the origin of the inferior mesenteric artery, bladder wall, heart, mediastinum and carotid and glomus jugulare tumours.

Various techniques may be employed:

• MRI can locate all tumours within the adrenals.
• CT is less sensitive and detects around 85 to 95% of tumours in excess of 1cm in diameter.
• If phaeochromocytoma is confirmed biochemically but CT or MRI do not show a tumour, a scan with metaiodobenzylguanidine (MIBG) labelled with ¹³¹Iodine or ¹²³Iodine may be performed.¹² The molecular structure of MIBG is similar to noradrenaline and concentrates within adrenal or extra-adrenal phaeochromocytomas.
• A somatostatin receptor analog called pentetreotide, labelled with ¹¹¹Indium is less sensitive than MIBG but may be used to detect phaeochromocytomas that do not concentrate MIBG.⁵
• Positron emission tomography (PET) scanning appears promising but is still in fairly early stages of assessment.¹³

The preference for MRI over CT scanning is in contrast to tumours of the adrenal cortex as described in Cushing's syndrome and the adrenal cortex.

Genetic testing

Tumour location and number, age, gender and family history will point to the need for genetic testing. Such testing forms the basis of early diagnosis and follow-up including management of relatives.²

Histology

Histological assessment of tissue removed after surgery using certain criteria (the PASS system) can help to differentiate benign from malignant tumours. A PASS score of <4 is predictive of benign phaeochromocytomas, whereas a score greater than 6 is characteristic of malignant tumours. Such patients should be followed closely for recurrence.¹⁴

Any of the following may precipitate a hypertensive crisis:

• Induction of anaesthesia
• Opiates
• Dopamine antagonists
• Decongestants such as pseudoephedrine
• Drugs that inhibit the reuptake of catecholamines, including tricyclic antidepressants and cocaine
• X-ray contrast media
• Childbirth

If the urine test for total catecholamines, vanillylmandelic acid (VMA) and metanephrines are positive the main differential diagnosis is to decide if is it is part of a familial condition.

• There may be a family history.
• Bilateral tumours suggest MEN.
• There may be features of neurofibromatosis including café au lait spots.
• The von Hippel-Lindau (VHL) syndrome is associated with phaeochromocytomas, cerebellar haemangioblastomas and renal cell carcinoma.

Other considerations include:

• Anxiety disorder
• Carcinoid tumour
• Alcohol withdrawal
• Labile hypertension
• Drug abuse
• Factitious phaeochromocytoma has been described

Associated conditions must be sought and, if found, appropriate management includes genetic counselling.

Surgery can cure the condition but first it must be controlled by medical means:

• Alpha blockade with phenoxybenzamine is started at least 7 to 10 days before operation to allow for expansion of blood volume.
• Only once this is achieved is beta blockade considered. If beta blockade is started too soon, unopposed alpha stimulation can precipitate a hypertensive crisis.
• Calcium channel blockers are also useful.¹⁵
• Complete resection of the tumour is usually possible and surgical mortality rates are less than 2 or 3% with an experienced anaesthetist and surgeon.
• Laparoscopic surgery is being used more often for tumours smaller than 6 cm but, for larger tumours, an open operation is probably safer.¹⁶

After surgery, a 24-hour urine collection for total catecholamines, metanephrines and vanillylmandelic acid (VMA) is required 2 weeks after operation. If results are normal the prognosis is excellent. Make sure that hypertension is controlled or resolved. Check 24 hours urine and BP annually for 5 years.

Sometimes when a patient is being investigated for hypertension, a mass may be found in an adrenal gland. This may represent phaeochromocytoma, glucocorticoid excess or primary aldosteronism. The mass may even be irrelevant and misleading. Such findings are called incidentalomas. If the clinical history or physical examination of a patient with unilateral incidentaloma suggests glucocorticoid, mineralocorticoid, adrenal sex hormone or catecholamine excess, which is confirmed biochemically, the treatment of choice is often adrenalectomy.¹⁷ In one study of 201 patients with incidentalomas, 30% were found to have a phaeochromocytoma.¹⁸

In the rare malignant cases, palliative care may be achieved with radiotherapy and chemotherapy. New emerging therapies, such as the tyrosine kinase inhibitor sunitinib, which rectifies the results of genetic abnormalities, may revolutionise the treatment of malignancy in the future.¹⁹

The 5-year survival rate for non-malignant phaeochromocytoma is over 95% but for malignant phaeochromocytomas it is less than 50%. The risk of malignancy is rather higher when children are affected.²⁰

Most paraganglionomas arise from chromaffin tissue, along the para-aortic sympathetic chain, or within the organs of Zuckerkandl at the origin of the inferior mesenteric artery, the wall of the urinary bladder and the sympathetic chain in the neck or mediastinum. They are usually benign and amenable to surgical resection. Around half are hereditary and so genetic testing should be considered.²¹ They can recur many years after initial presentation, so long-term follow-up is important.¹

Pre-eclampsia is fairly common, whilst phaeochromocytoma is very rare and only a few hundred cases in pregnancy have been reported in the literature.

• If phaeochromocytoma is diagnosed for the first time in pregnancy, there are special concerns with a maternal and fetal mortality rate of 48% and 55% respectively.
• If diagnosis precedes pregnancy, the outcome is vastly better. Alpha-adrenergic blockade with phenoxybenzamine is required as soon as the diagnosis is made.
• If surgery is performed in the first or second trimester, the pregnancy need not be terminated but fetal loss is high.
• In the third trimester, as soon as fetal lung maturity is confirmed, perform lower segment caesarean section (LSCS) followed by surgical removal of the tumour.²²
• Conservative management during pregnancy has been described.²³