Phaeochromocytoma

Context

It is important for the emergency physician to consider phaeochromocytoma as part of a differential diagnosis, firstly because an acute crisis can be life threatening and secondly because timely diagnosis can enable complete curative surgical intervention. Autopsy studies have shown that phaeochromocytomas are often missed [1].

Definition

Phaeochromocytomas are rare neuroendocrine tumours that arise from either adrenal medulla or extra adrenal chromaffin tissue.

Incidence and Epidemiology

The spontaneous presentation of phaeochromocytoma is normally between the age of 40 and 50 years, however the hereditary forms often present in younger individuals, including children [2].

About 15% of phaeochromocytomas are extra-adrenal [3]. Surgical treatment can effectively cure phaeochromocytoma in 90% of cases [4].

Phaeochromocytoma is associated with Von Hippel Landau disease, multiple endocrine neoplasia type 2 syndromes and neurofibromatosis type 1 [5].

Basic Science and Pathophysiology

The manifestations of phaeochromocytoma are due mostly to the increased abnormal secretion of catecholamines, principally epinephrine, but also norepinephrine and dopamine.

The relative amounts of catecholamines secreted can differ between tumours and this determines the clinical picture. The catecholamines can also be released episodically.

There are several proposed mechanisms for this including direct pressure, medications and changes in tumour blood flow [6].

The effects of epinephrine and norepinephrine are caused by agonist activity at alpha and beta adrenoceptors and are detailed below [7]:

• Glycogenolysis in liver and skeletal muscle
• Mobilisation of free fatty acids
• Increased serum lactate
• Stimulation of metabolic rate
• Increased force and rate of contraction of the heart
• Both cause vasoconstriction, but epinephrine dilates vessels in skeletal muscle and liver, normally leading to a decrease in overall systemic vascular resistance
• Increase in alertness and evokes feelings of anxiety and fear
• Rise in plasma glucose

Dopamine, when injected, produces renal and mesenteric vascular dilatation. It also has positive inotropic effects and normally leads to an increase in systolic blood pressure.

Clinical features and presentation

The presenting features of phaeochromocytoma are very wide and varied. For this reason it is referred to as the great mimic.

Hypertension is a common presenting feature with systolic blood pressure above 220 mmHg or diastolic pressure above 120 mmHg being generally accepted limiting values. Hypertension is frequently associated with profound tachycardia, pallor and a feeling of anxiety or impending doom [9]. These symptoms are often paroxysmal and can occur many times a month or just once with a single fatal presentation.

Precipitants can include abdominal compression, anaesthesia, opiates, dopamine antagonists, cold medications, radiographic contrast media, catecholamine reuptake inhibitors and childbirth [6,9].

Table 1: Other symptoms and signs [6,8].

Learning Bite

The diagnosis should be considered in any patient presenting with acute hypertension or with a hypertensive crisis but be aware that hypertension can be episodic or absent and consider the diagnosis if there is a syndrome of appropriate clinical features compatible with the diagnosis.

Differential diagnosis of Phaeochromocytoma [6,8]

The differential diagnosis of phaeochromocytoma, as discussed above, is wide and includes the conditions listed below:

Endocrine:

• Hyperthyroidism
• Carcinoid
• Hyperglycaemia
• Medullary thyroid carcinoma
• Mastocytosis
• Menopausal syndrome

Cardiovascular:

• Heart failure
• Arrythmias
• Ischaemic heart disease
• Baroreflex failure
• Renovascular hypertension

Neurological:

• Migraine
• Stroke
• Diencephalic epilepsia
• Meningioma
• Postural orthostatic tachycardia syndrome

Miscellaneous:

• Essential hypertension
• Alcohol withdrawal
• Pre-eclampsia
• Porphyria
• Panic disorder or anxiety
• Factitious disorders
• Drug treatment
• Illegal drug use

Differential diagnosis of a hypertensive crisis

Phaeochromocytoma is a recognised cause of hypertensive crisis; other conditions which may cause a hypertensive crisis are listed below [8]:

• Essential hypertension
• Renovascular hypertension
• Renal parenchymal disease
• Endocrine causes (Phaeochromocytoma, Cushings syndrome, hyperaldosteronism, thyrotoxicosis, hyperparathyroidism, acromegaly, adrenal carcinoma)
• Eclampsia and pre eclampsia
• Vasculitis
• Drugs
• Spinal cord injury
• Coarctation of the aorta

Investigation

Investigation in the ED will be tailored to the patients presenting symptoms and signs and is usually directed at the more common conditions which phaeochromocytoma may mimic.

Investigation will usually include ECG, capillary blood glucose and FBC.

Phaeochromocytoma might mimic these common conditions:

• Acute coronary syndrome
• Subarachnoid haemorrhage
• Gastroenteritis
• Stroke
• Essential hypertension
• Anxiety/panic attacks
• Sepsis
• Drug ingestion (e.g. cocaine)

Specific investigation for phaeochromocytoma is not usually instigated in the ED; appropriate subsequent tests include assay of plasma and urine metanephrines, catecholamines and urine vanillylmandelic acid (VMA).

The most sensitive test is plasma metanephrine assay (99% sensitivity with a specificity of 89%).

Initial imaging is usually CT scan of the abdomen (sensitivity 93-100%); MRI scanning has a similar sensitivity.

Definitive treatment is by surgical resection of the tumour, normally using a laparoscopic approach.

Prior to surgery the acute crisis is treated medically to control the effects of excess catecholamines. This is normally achieved by alpha adrenoceptor blockade.

Phenoxybenzamine is advocated as it blocks adrenoceptors irreversibly and therefore its effect cannot be overcome by increasing catecholamine concentrations. Phentolamine and Doxazosin are alternative alpha antagonists.

Phenoxybenzamine

Phenoxybenzamine is used in the treatment of hypertensive crisis. The main action is vasodilatation by non-competitive antagonism of alpha adrenoceptors.

The dose by intravenous administration is 10-40 mg over one hour. It acts within one hour and its effects last for up to four days. It can be given orally in a dose of 10-60 mg/day in divided doses.

Side effects include hypotension, dizziness, sedation, dry mouth, paralytic ileus and impotence.

Phentolamine

Phentolamine is used in the diagnosis and perioperative management of phaeochromocytoma. It causes vasodilatation, but also has positive inotropic and chronotropic effects. It exerts its effect predominantly by competitive alpha adrenoceptor blockade.

The adult intramuscular dose for control of acute paroxysmal hypertension is 5-10 mg.

Side effects include orthostatic hypotension, dizziness, abdominal discomfort and diarrhoea. Cardiovascular collapse has occurred following treatment of phaeochromocytoma.

Beta adrenoceptor blockade can be instituted to control tachycardia, but this should only be done after adequate alpha blockade, otherwise unopposed alpha activity can lead to worsening hypertension.

Patients may also require additional therapy to treat associated problems such as arrhythmias. Many patients require intravenous fluid as they are relatively fluid depleted. These additional therapies should be tailored on a case by case basis [3,5,6].

Learning Bite

Beta blockade should not be used as sole therapy to control acute hypertension associated with phaeochromocytoma as unopposed alpha activity can lead to further increase in the blood pressure.

If phaeochromocytoma is suspected urgent discussion with an endocrinologist is advised.

Surgical resection is curative in 90% of cases.

• Although the disease is rare and can present in a wide variety of ways, there are several clinical characteristic markers that should alert the clinician to the potential diagnosis
• Autopsy studies have shown that phaeochromocytoma is first diagnosed at post mortem in about 50% of cases. Missing the diagnosis can deprive the patient of curative surgery
• Not all adrenal masses or elevations of catecholamines levels are due to phaeochromocytoma

References

1. Platts JK, Drew PJ, Harvey JN. Death from phaeochromocytoma: lessons from a post-mortem survey. J R Coll Physicians Lond. 1995 Jul-Aug;29(4):299-306.
2. Anderson GH Jr, Blakeman N, Streeten DH. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens. 1994 May;12(5):609-615.
3. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocytoma. J Urol. 1992 Jan;147(1):1-10.
4.  Pacak K, Linehan WM, Eisenhofer G et al. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001 Feb 20;134(4):315-329.
5. Neumann HP, Berger DP, Sigmund G et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993 Nov 18;329(21):1531-8. Erratum in: N Engl J Med 1994 Dec 1;331(22):1535.
6. Ramrakha P, Moore K.  Oxford Handbook of Acute Medicine, Oxford,  2004.

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