Phaeochromocytoma: The Catecholamine-Secreting Tumour You Must Not Beta-Block First

Introduction

A phaeochromocytoma is a catecholamine-secreting tumour arising from the chromaffin cells of the adrenal medulla. When an identical tumour arises outside the adrenal gland - from the sympathetic paraganglia along the paravertebral and para-aortic chain, or from the organ of Zuckerkandl - it is called a paraganglioma. Both secrete catecholamines (noradrenaline, adrenaline, and sometimes dopamine) and are managed in essentially the same way, so the two are often discussed together.

They are rare, with an incidence of around 2 to 8 per million per year, but are important disproportionate to their frequency: they are a curable cause of hypertension, they can present with life-threatening crises, and missing the diagnosis before surgery or anaesthesia can be fatal.

The rule of 10s - and why it is now out of date

Phaeochromocytoma has traditionally been taught by the "rule of 10s":

• 10% bilateral - more common in familial syndromes
• 10% extra-adrenal (i.e. paraganglioma)
• 10% malignant - better termed metastatic, since malignancy can only be confirmed by finding tumour at a site where chromaffin tissue does not normally occur (e.g. bone, liver, lymph nodes), not by histology alone
• 10% familial

Associated genetic syndromes

Clinical features

The clinical picture reflects intermittent, unpredictable catecholamine release. Symptoms are classically paroxysmal, lasting minutes to an hour, and may be triggered or spontaneous.

• Paroxysmal severe hypertension - the blood pressure may be normal between episodes, particularly in extra-adrenal or noradrenaline-predominant tumours; a minority have sustained hypertension throughout
• Pallor during attacks, rather than flushing - a useful discriminator from carcinoid syndrome, which causes flushing
• Tremor and anxiety - attacks are frequently mistaken for panic attacks or anxiety disorder, which is one of the commonest reasons for delayed diagnosis
• Chest or abdominal pain, nausea and vomiting
• Weight loss despite normal or increased appetite, from the catabolic effect of catecholamine excess
• Postural hypotension between attacks - from chronic volume contraction and down-regulated adrenergic receptors, despite the hypertension during attacks
• Hyperglycaemia - catecholamines inhibit insulin release and promote glycogenolysis
• Constipation - particularly with tumours that co-secrete vasoactive intestinal peptide or other neuropeptides
• A palpable abdominal mass occasionally, in large tumours

Differential diagnosis

• Panic disorder and anxiety states - the commonest misdiagnosis; consider phaeochromocytoma when attacks are accompanied by objectively measured severe hypertension
• Primary hyperthyroidism - tremor, sweating, tachycardia and weight loss overlap, but hypertension and pallor are not typical
• Menopausal flushing - flushing rather than pallor, and blood pressure is usually normal
• Carcinoid syndrome - flushing, diarrhoea and wheeze rather than pallor and severe hypertension
• Hypoglycaemia
• Autonomic dysreflexia in spinal cord injury
• Illicit sympathomimetic drug use - cocaine, amphetamines
• Clonidine withdrawal
• Essential hypertension with anxiety

Investigations

Biochemical confirmation first

Biochemical testing always precedes imaging. Catecholamines themselves are secreted episodically and are unreliable; tumours continuously leak their metabolites - metanephrine and normetanephrine - which are therefore a far more sensitive marker.

Localisation

• CT or MRI of the abdomen and pelvis - performed only after biochemical confirmation, since incidental adrenal lesions are common and biochemically silent ones do not need surgery for this diagnosis. MRI is preferred in children, pregnancy and where iodinated contrast is a concern.
• MIBG (metaiodobenzylguanidine) scintigraphy - a functional scan using a molecule taken up by chromaffin tissue; useful for extra-adrenal disease, multifocal tumours, and to screen for metastases when malignancy is suspected
• Ga-68 DOTATATE PET-CT - increasingly preferred over MIBG for extra-adrenal, metastatic or SDHB-related disease, with higher sensitivity
• Genetic testing - as above, in all confirmed cases

Management

Preoperative medical preparation

Volume and salt loading

Chronic catecholamine excess causes profound vasoconstriction and volume contraction. Once alpha-blockade removes that vasoconstriction, the circulating volume is often inadequate, risking severe hypotension at induction of anaesthesia and after tumour removal. Patients should therefore be advised to liberalise salt and fluid intake in the days before surgery, and are often admitted for intravenous fluid loading immediately preoperatively.

Surgery

• Laparoscopic adrenalectomy is the treatment of choice for most tumours, with open surgery reserved for very large or invasive tumours or where malignancy is strongly suspected
• Anticipate haemodynamic instability: catecholamine surges during tumour handling can cause severe hypertension intraoperatively, and abrupt catecholamine withdrawal once the venous drainage is ligated can cause profound hypotension - invasive arterial monitoring and close anaesthetic input are essential
• Postoperative hypoglycaemia can occur as the suppressive effect of catecholamines on insulin secretion is suddenly removed
• Bilateral disease (e.g. in MEN2 or VHL) may be managed with cortical-sparing adrenalectomy to preserve some adrenocortical function and avoid lifelong steroid replacement, balanced against the risk of local recurrence

Malignant/metastatic disease

• Managed with a combination of surgical debulking, 131I-MIBG therapy where the tumour is MIBG-avid, peptide receptor radionuclide therapy (PRRT) with DOTATATE for somatostatin-receptor-positive disease, and chemotherapy (e.g. cyclophosphamide, vincristine and dacarbazine)
• Metyrosine and alpha/beta-blockade remain important for ongoing symptom and blood pressure control
• Prognosis is more guarded than for benign disease but survival can still be prolonged over many years

Complications

• Hypertensive crisis - with the risk of stroke, myocardial infarction, aortic dissection or acute pulmonary oedema
• Catecholamine-induced cardiomyopathy - which can present as acute heart failure or a Takotsubo-like picture, and typically improves after tumour removal
• Arrhythmias, including life-threatening ventricular arrhythmias during a crisis
• Severe intraoperative haemodynamic instability
• Postoperative hypotension and hypoglycaemia
• Recurrence - local or at a new site, particularly in familial disease
• Metastatic disease - most often to bone, liver, lungs and lymph nodes

Red flags

Prognosis

The great majority of phaeochromocytomas are benign, and surgical removal after adequate alpha-blockade is usually curative, with resolution or major improvement of hypertension in most patients.

Because of the substantial rate of familial disease and the possibility of late recurrence or metachronous tumours, follow-up is lifelong, typically with annual clinical review and biochemical testing (plasma or urinary metanephrines). This is particularly important in confirmed genetic syndromes, where new tumours can develop years after apparently successful surgery.

Metastatic disease carries a more guarded prognosis, though the course can still be prolonged over many years with a combination of surgical, radionuclide and medical therapy. SDHB mutation carriers have the highest risk of metastatic disease and require closer surveillance.