Endocrinology: phaeochromocytoma
Key point
An update on ‘well-known facts’ about phaeochromocytoma
In adults, phaeochromocytomas were known as the ‘10% tumour’ reflecting approximately:
10% extra-adrenal
10% bilateral/multiple
10% malignant
10% familial.
This no longer holds true with, for example, many more cases now identified with an underlying genetic basis (Table 1). In addition, the prevalence of bilateral tumours is greater than 10% in certain familial syndromes (eg multiple endocrine neoplasia type 2 (MEN-2) and von Hippel–Lindau syndrome (VHL)), while in childhood a higher proportion are extra-adrenal and malignancy is more common.
Key point
Commonly reported symptoms of phaeochromocytoma
headache
sweating
palpitations / forceful heartbeat
anxiety
tremor
nausea and vomiting
chest and abdominal pain / dyspnoea.
Note that the triad of headache, sweating and palpitations is considered to be highly suggestive of a diagnosis of phaeochromocytoma.
Aetiology/pathophysiology
Originating from the chromaffin cells of the sympathetic nervous system, most phaeochromocytomas arise within the adrenal medulla, with a smaller number derived from sympathetic ganglia. They commonly secrete norepinephrine (noradrenaline) and epinephrine (adrenaline), but in some cases significant amounts of dopamine may be released. As with many other endocrine tumours, the diagnosis of malignancy is dependent upon evidence of local infiltration or distant spread, since histological appearances do not reliably distinguish benign from malignant tumours.
Germline mutations in a number of different genes have been found to cause familial phaeochromocytomas (Table 1).
Succinate dehydrogenase (SDH) mutations are a frequent cause of familial phaeochromocytoma and are important as patients with an SDHB mutation typically exhibit more aggressive disease with a high incidence of malignancy (Table 1). They are usually extra-adrenal, mainly occurring as paragangliomas in the head, chest and abdomen. SDHD mutations are maternally imprinted; thus only carriers who have inherited the mutation from the father develop the disease.
Epidemiology
Rare, accounting for 0.1–0.6% of all cases of hypertension in general outpatient clinics. Many remain occult and are only diagnosed at post-mortem.
Clinical presentation
Cases may come to light during the investigation of poorly controlled hypertension, when direct questioning reveals an array of other manifestations of catecholamine excess. These are frequently reported to occur in an episodic or paroxysmal fashion. Occasional cases present with pregnancy-associated hypertension, myocardial infarction, cardiac dysrhythmias or a dilated catecholamine cardiomyopathy. The incidence in normotensive asymptomatic subjects is ‘rising’ due to increased use of high-resolution imaging and screening for phaeochromocytoma in subjects with predisposing genetic mutations. About 5% of all adrenal ‘incidentalomas’ are phaeochromocytomas, with about 25% of all phaeochromocytomas now discovered incidentally during imaging for unrelated disorders.
Physical signs
Features of increased sympathetic activity are often present during a paroxysm, eg tachycardia, sweating, pallor (not flushing). Hypertension may be sustained or episodic and approximately 50% of cases exhibit orthostatic hypotension (the latter reflecting intravascular depletion in response to long-standing hypertension).
Investigations
This should be approached in two stages:
confirm catecholamine excess – through the measurement of their metabolites
localise the tumour.
Confirm catecholamine excess
Urinary metanephrines
Urinary-fractionated metanephrines (ie normetanephrine and metanephrine measured separately) offer a highly sensitive and specific screening test for the detection of phaeochromocytoma and paraganglioma.
Plasma metanephrines
Plasma free metanephrines (normetanephrine and metanephrine) are a convenient (and slightly more sensitive) alternative to 24-hour urinary collections.
3-Methoxytyramine (a metabolite of dopamine, and measured in urine or plasma) is a potential marker of malignancy.
False positives
There are many causes of false positive biochemical screening. These fall into two groups:
true catecholamine excess, due to:
drugs (tricyclic antidepressants, phenoxybenzamine, monoamine oxidase inhibitors, levodopa, alpha-methyldopa, sympathomimetics, calcium channel blockers)
stimulants (eg coffee, nicotine)
anxiety
disease states (eg myocardial infarction (MI), heart failure, cardiogenic shock, obstructive sleep apnoea)
interference with analytical method (different depending on assay but including coffee, labetalol, levodopa, alpha-methyldopa, paracetamol and sympathomimetics).
Most false positive levels are significantly lower than in phaeochromocytoma. Repeat the test having stopped any interfering medication, and consider an alternative screening method.
Clonidine suppression test
Clonidine acts via presynaptic alpha-adrenoreceptors to block catecholamine secretion and can be used to distinguish increased norepinephrine release due to sympathetic activation from autonomous tumoral secretion. Failure to adequately suppress plasma norepinephrine in response to clonidine is highly predictive of phaeochromocytoma (97%), but a normal test result does not exclude phaeochromocytoma (negative predictive value only 75%). Use of plasma normetanephrine increases the positive and negative predictive values to 100 and 96%, respectively.
Localise the tumour
CT/MRI
CTs of the abdomen and pelvis are commonly used (Figs 1 and 2). T2-weighted MRI with gadolinium enhancement has similar sensitivity and specificity to CT. The tumour typically exhibits a distinctive ‘bright white’ signal on T2-weighted images.
Radioiodine-labelled metaiodobenzylguanidine scintigraphy / single-photon emission CT (SPECT)
Metaiodobenzylguanidine (123I-MIBG), which is taken up by chromaffin cells, is useful in localising both adrenal and extra-adrenal tumours (Fig 3) and is the first-line nuclear imaging method. Pretreating with potassium iodide blocks thyroidal uptake.
PET-CT
18F-fluorodeoxyglucose (18F-FDG) PET, 18F-fluorodopa PET and 18F-fluorodopamine PET all offer the higher spatial resolution of PET scanning and may allow detection of smaller lesions not readily visualised with 123I-MIBG. 18F-FDG PET has particular use in malignant disease.
Genetic testing
All patients with a phaeochromocytoma/paraganglioma should be considered for genetic testing, first to allow early diagnosis and treatment of other features of the associated hereditary syndrome; secondly to prompt more stringent, lifelong clinical follow-up, as recurrences are more likely in familial phaeochromocytoma/paraganglioma; and thirdly to prompt appropriate family screening. Presently, cost-effective genetic screening is recommended to those with a positive family history or those under 50 years, especially children. Other clues that should be regarded as an indication for genetic testing include bilateral adrenal or multifocal extra-adrenal disease or the association of phaeochromocytoma with other tumours. The clinical picture may direct genetic testing to one of the suspected genes.
Differential diagnosis
Several conditions may present with features of sympathetic overactivity and thus mimic phaeochromocytoma.
Treatment
Medical therapy
Prior to considering surgical removal, medical treatment must be instituted with the aims of:
ameliorating symptoms
normalising BP
correcting intravascular depletion.
Hazard
Alpha-blockade before beta-blockade
Beta-blockers must not be given to patients with suspected or proven phaeochromocytoma until alpha-blockade has been established, since there is a significant risk of precipitating a life-threatening hypertensive crisis due to unopposed alpha-adrenoceptor activity.
Alpha-blockade
The non-competitive alpha-antagonist phenoxybenzamine is the initial treatment of choice, with escalating dose titration (start with 10 mg twice daily and increase gradually until BP is normalised; most cases require 0.5–2 mg/kg per day in divided doses). The alpha1-antagonist doxazosin provides an alternative for those intolerant of phenoxybenzamine.
Beta-blockade
The non-selective agent propranolol (20–80 mg every 8 hours) is generally preferred, but may not be required in all patients (eg those with a pure noradrenaline-secreting paraganglioma).
Surgical excision
Both traditional and laparoscopic approaches can be used for tumour removal.
Adjunctive therapy for malignant tumours
Options include:
alpha-methylparatyrosine – which ameliorates symptoms through inhibition of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthetic process
radioiodine (131I)-labelled MIBG – although large and repeated doses may be necessary.
Prognosis
Even those with malignant tumours frequently survive for many years. The extent of end-organ damage is often a key factor in determining long-term outcome.
- © Royal College of Physicians 2019. All rights reserved.
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