Malignancy

PhaeochromocytomaEASILY MISSED?

BMJ 20 February 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

A 51 year old woman presented with a few months’ history of

episodic anxiety associated with sweating, flushing, and
palpitations. The symptoms were thought to be menopausal but
they were not relieved by oestrogen hormone replacement
therapy. She also had a history of hypertension that was
increasingly difficult to control, despite treatment with three
antihypertensive agents. Her general practitioner, concerned
about a possible phaeochromocytoma, referred her to an
endocrinologist. Further investigation showed markedly raised
urine metanephrines and a right adrenal mass on computed
tomography, consistent with a diagnosis of right adrenal
phaeochromocytoma.


What is a phaeochromocytoma?
A phaeochromocytoma is a catecholamine producing tumour arising from the chromaffin cells of the adrenal medulla (85% of cases) or extra-adrenal paraganglia. Although it may be malignant, symptoms usually result from the excess secretion of catecholamines.

Why is phaeochromocytoma missed?

Phaeochromocytomas are uncommon in secondary care and rare in primary care. The symptoms and signs of a
phaeochromocytoma, which vary greatly, are often non-specific and similar to those of many common conditions, such as anxiety.

The so called classic symptoms of aphaeochromocytoma, such as paroxysmal headache, palpitations,
and sweating, are often absent. Hypertension may not be present in 10-20% of cases. As a result, diagnosis is often delayed, with an average interval of three years between the initial symptoms and diagnosis, and many cases are diagnosed only at autopsy.

Why does this matter?

Although we estimate from prevalence data3 that an average full time general practitioner will have only about a 50% chance of seeing a new case of phaeochromocytoma in their career, it
is important not to miss the diagnosis. Unrecognised and
untreated phaeochromocytoma has high morbidity and mortality through cardiovascular complications of catecholamine excess and untreated malignancy.

A hypertensive crisis can be precipitated if a patient with unrecognised phaeochromocytoma is treated with β blocking medication (without α blockade,leading to unopposed α receptor mediated vasoconstriction) or
undergoes surgery (which can trigger catecholamine release).
Additionally, symptoms of phaeochromocytoma are often debilitating and lead to poor quality of life. The condition can be treated effectively with α blocking medication followed by surgery.

About 10% of phaeochromocytomas are malignant,

and early diagnosis and treatment may reduce the risk of metastasis. Furthermore, phaeochromocytoma can be associated with genetic disorders, such as multiple endocrine neoplasia type 2—familial phaeochromocytoma and medullary thyroid
carcinoma with primary hyperparathyroidism (type 2a) or mucosal neuromas and Marfanoid habitus (type 2b). Therefore the diagnosis can also assist investigation and early identification of phaeochromocytoma and related conditions in family members.


How is phaeochromocytoma diagnosed?
Clinical
The most common clinical features of phaeochromocytoma
include hypertension (80-90% of cases), palpitations (60%), headaches (50%), sweating (50%), pallor (40%), and psychological symptoms such as anxiety or panic (35%). The combination of episodic headache, sweating, and palpitations has been reported to have high specificity (>90%) for phaeochromocytoma.

Other less common features include

weight loss, lethargy, tremors, nausea, dyspnoea, vertigo, flushing, orthostatic hypotension, and hyperglycaemia. Patients infrequently present with a hypertensive crisis, shock, or cardiovascular emergencies such as myocardial infarction or
arrhythmia. Symptoms of phaeochromocytoma are episodic in about 65% of cases, typically lasting from minutes to an hour.
Hypertension is sustained in 50-60% of cases but may be episodic (30%) or absent, even on repeated testing (10-20%), making diagnosis potentially difficult.

The (NICE) in England and Wales currently recommends that general practitioners refer for investigation if they suspect a phaeochromocytoma in a patient
with hypertension, and it suggests that labile or postural
hypotension, headaches, palpitations, pallor, and excess sweating are possible symptoms. Worsening of symptoms after introduction of a β blocker and labile blood pressure during surgery should also raise the suspicion of phaeochromocytoma.

Screening of asymptomatic patients with hypertension is not recommended owing to the high false positive rates of currently available tests. On the other hand, consider investigations even in the absence of hypertension if symptoms suggest phaeochromocytoma.

About 25% cases of phaeochromocytoma are currently diagnosed in asymptomatic patients after the incidental finding of an adrenal mass on imaging performed for unrelated reasons
(adrenal incidentaloma). Undertake biochemical screening for phaeochromocytoma in all cases of adrenal incidentaloma.
Screening of asymptomatic patients with a genetic predisposition to phaeochromocytoma (such as multiple endocrine neoplasia type 2) is also indicated.

Investigations

When phaeochromocytoma is clinically suspected, investigate further by confirming the presence of excess catecholamine secretion. Measurement of catecholamines in a 24 hour urine collection has traditionally been used; however, this method
has largely been replaced by measurement of metanephrines (metabolites of catecholamines) either in a 24 hour urine collection or in plasma, both of which have better diagnostic sensitivity.


Although urine collection can often be performed
in primary care (unlike plasma measurement, which requires sample refrigeration or rapid processing), most general practitioners would refer for specialist advice. We recommend referral of any patient where there is high suspicion of phaeochromocytoma.

The sensitivity of metanephrine measurement to detect phaeochromocytoma is 97% for urinary levels and 99% for plasma levels compared with 86% for urinary catecholamines, among symptomatic patients, those with a previous or family history of phaeochromocytoma, or those with an incidental
adrenal mass.

Likewise, the specificities for urinary and plasma metanephrines are 93% and 89%, respectively, compared with 88% for urinary catecholamines. False positive results are common, owing to the relative infrequency of phaeochromocytoma in those tested and to the presence of other medical conditions (such as obstructive sleep apnoea) and medications (such as tricyclic antidepressants, phenoxybenzamine, clozapine, calcium channel blockers, and β blockers) that can cause elevation of metanephrines.

Furthermore, severe physical and psychological stress (for example, major surgery, myocardial infarction, severe pain, panic attacks) could increase catecholamine secretion, leading to false positive results. Concentrations of metanephrines that are over four times normal levels are associated with very high probability of phaeochromocytoma; however, lower raised concentrations will require further biochemical assessment, which may include repeat testing after withdrawal of implicated medication.

By contrast with the now infrequently used

measurement of urine vanillyl mandelic acid, dietary restrictions are not needed when performing these investigations.
When a phaeochromocytoma has been confirmed biochemically, imaging methods such as computed tomography, magnetic resonance imaging, or meta-iodobenzylguanidine radioisotope scanning are used to locate the primary lesion and screen for metastases.

How is phaeochromocytoma managed?

A phaeochromocytoma is treated with α receptor blocking medication followed by surgery. However, because the tumour can recur even after apparently successful surgery for benign disease, lifelong follow-up is needed. Genetic testing should
be considered, particularly in patients under the age of 50 years, in patients with multiple or malignant phaeochromocytoma, and in those with a positive family history.

How common is phaeochromocytoma?

• The prevalence of phaeochromocytoma in hypertensive patients attending general medical outpatient clinics is 0.1-0.6%
• Autopsy studies have shown a prevalence of 0.05%, but many of these cases had not been diagnosed in life.


Key points
• Common symptoms of phaeochromocytoma include episodic palpitations, headaches, sweating, and psychological symptoms such
as anxiety or panic
• Hypertension is present in 80-90% of cases but may be episodic
• Symptoms of phaeochromocytoma are variable and non-specific, leading to frequent long delays between onset and diagnosis
• The recommended initial investigation for a suspected phaeochromocytoma is measurement of metanephrines (a metabolite of mcatecholamines) in 24 hour urine collection or in plasma.