Pitfalls in the diagnosis of phaeochromocytoma
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7440.629 (Published 11 March 2004) Cite this as: BMJ 2004;328:629
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An isolated phenomenal rise in urinary free dopamine excretion should
always be interpreted with caution. The well known interference from anti-
Parkinsonian medication has been documented (1-3). Even the FDA sinemet
data sheet clearly states that: Cases of falsely diagnosed
pheochromocytoma in patients on carbidopa- levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the
plasma and urine levels of catecholamines and their metabolites in
patients on levodopa or carbidopa-levodopa therapy.
There was failure of the laboratory and the clinical team dealing with
this case to recognise this potentially misleading scenario and have
therefore exposed the patient to the risk of an unnecessary adrenalectomy.
Dr. M A Al-Jubouri, FRCPath
1. Collinson PO, Kind PR, Slavin B, Weg MW, Sandler M.
False diagnosis of phaeochromocytoma in patients on Sinemet.
Lancet. 1984 Jun 30;1(8392):1478-9.
2. Quinn N, Carruthers M.
False positive diagnosis of phaeochromocytoma in a patient with
Parkinson's disease receiving levodopa.
J Neurol Neurosurg Psychiatry. 1988 May;51(5):728-9.
3. Jahnel M.
Pseudopheochromocytoma in Parkinson disease and depression.
Psychiatr Prax. 2003 May;30 Suppl 2:S64-5. German.
Competing interests:
None declared
Competing interests: No competing interests
Well i read your article,where you start screening with the dopamie
level in the urine for pheocromcytoma,in a patient who already taking
dopamie precursors. As the main hormones secreted by the adrenal medulla
are epinephrine and nor-epinephrine and to screen for pheochormocytoma we
usually measures the metabolites of these hormones in 24 hrs urine namely
VMA,metnephrine,HVA,and nor-metanephine, if anyof these hormones level in
24 hr urine is high then proceed with the MRI b\c of the incidentolomas
commonly found in the adrenal as you mention in your article.
What i get the idea from your article is that before interpreting any
hormones level we must evaluate its false positiveness and must review
history of drugs the person is taking, if these have done with the pt and
its appropritate levels of hormones were measured pre-operatively then
this patient may be not undergone the unnecessary operation.
As the patient get severe hypertension difficult to control with
medication and specially in the advace age like this patient have one must
exclude the causes of secondary hypertension, you only mention about the
pheochromocytoma, did you evaluate this patient for other causes of
secondary hypertension specially renal artery stenosis.
Competing interests:
None declared
Competing interests: No competing interests
15th March 2004
Dear Editor.
Re: Lesson of the week BMJ 328:629;13th March 2004
May I make some comments. It would appear that no radiologist or
nuclear medicine physician was involved in this article (and possibly none
as reviewer).
The MR image reproduced appears to be an opposed phase T1 weighted image.
Although the in-phase images are not reproduced the adrenal mass shown
appears to be of low signal intensity on the opposed phase image and
would I suspect have been isointense to liver on the inphase image. This
finding in itself is diagnostic of an adrenal adenoma rather than a
phaeochromocytoma.
In addition the MIBG scan clearly shows that the activity thought to
represent and adenoma lies too low for the expected position of the
adrenal and this should have alerted the reporting physician.
Finally and I believe this is the single most important point – any
imaging procedure should be reported with reference to any other imaging
procedures that are available. It is often a failing that nuclear medicine
examinations are reported independently of any other radiological imaging.
While there is some value in having an independent opinion, the most value
to the patient comes from integrating the studies. Had this been done it
would have been clearly rapidly apparent that the uptake seen on the
isotope study was too low to correspond to the lesion seen on the MRI
examination.
I believer the lesson here is that an integrated imaging assessment
(multidisiplinary if necessary) would have avoided the unnecessary
surgery.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
The authors are correct in pointing out that ‘The diagnosis is
excluded by the repeated finding of normal catecholamine’ but less so in
citing dopamine as an example, giving the impression this is the usual
amine raised in phaeochromocytoma. Dopamine-secreting tumours are
exceedingly rare. In phaeochromocytoma the usual biochemical features are
raised urine levels of catecholamines (usually noradrenaline and, less
commonly, adrenaline) and their metabolites (normetadrenaline and
metadrenaline), not raised dopamine level alone. Recently, it has been
recommended that plasma free metadrenaline should be the first line test,
though this, as yet, is not widely available.
The first thing to consider, when faced with such a set of
biochemical results, with raised dopamine and normal catecholamine
excretion, is a dopaminergic drug-related effect. A typical approach is to
advise repeat urine testing, following discontinuation of medication,
rather than first raising the strong possibility of a phaeochromocytoma.
However, the decision for invasive measures in this patient was obviously
made more plausible by the initial finding of an adrenal incidentiloma. It
is unclear why an abdominal ultrasound was utilised during the search for
secondary causes of hypertension, as it would have been simpler to check
urine catecholamine levels first. This would also have been a more logical
approach, and the patient would then have been saved the unnecessary and
expensive investigations that followed. It is, of course, unclear why the
clinical team itself did not first consider a drug related effect. It is
also unclear from the paper whether the initial investigation and
management, as well as subsequent assessment and investigations, were
carried out at the same or another institution.
1. Peaston RT, Weinkove C. Measurement of catecholamine and their
metabolites. Ann Clin Biochem 2004; 41:17-38
2. Lenders, JWM et al. Biochemical diagnosis of phaeochromocytoma, Which
test is best? JAMA 2002; 287:1427-34
3. Eisenhoffer G et al. Biochemical diagnosis of phaeochromocytoma: How to
distinguish true- from false-positive test results. JECM 2003;88:2656-2666
A Waise FRCP, York Hospital, YORK YO31 8HE, UK
Competing interests:
None declared
Competing interests: No competing interests
The interaction of drugs with laboratory tests for phaeocromocytoma
has been previously documented. One phone call to the lab would have saved
unneccessary investigations and costs.
Collinson PO, Kind PRN, Slavin B, Weg W, Sandler M. False diagnosis
of phaeochromocytoma in patients on sinemet. The Lancet, 1984; ii: 1478
- 1479.
Competing interests:
None declared
Competing interests: No competing interests
Zendron et al report their pitfall in diagnosing a phaeochromocytoma
after four separate lines of investigation gave false-positive results
[1]. They claim, in retrospect, that all results should have been
interpreted with a higher degree of scepticism. However, it was the
misinterpretation of the biochemical results that in fact mislead further
investigations.
As urinary tests for increased catecholamine metabolites are cheaper
and more readily available than abdominal imaging, biochemical tests are
used as first-line screening for phaeochromocytoma. Given the infrequency
of phaeochromocytoma, the lack of sensitivity (90%) but high specificity
(98%) of the urine tests, a raised concentration of catecholamines is
unexpected, though when identified is highly suggestive of a
phaeochromocytoma [2, 3, 4]. A positive interpretation of the result leads
to further investigation; furthermore, it provides a premise for the
interpretation of future test results. It is therefore important that the
conditions of the biochemical test, and the interpretation of the results
are correct.
Given the frequency of incidental adrenal lesions, the positive
magnetic resonance and ultrasound images are equivocal, in the absence of
the positive urine test [5]. However, in the presence of increased
catecholamines, these images corroborate with a diagnosis of
phaeochromocytoma.
123I-metaiodobenzylguanidine (mIBG) scintigraphy has a sensitivity of
95% and a specificity approaching 100% [6]. Anatomical abnormalities are
known to cause false-positive mIBG results [7]. Given the positive urine
results, magnetic resonance and ultrasound images, the mIBG scan was
expected to be positive – which it was. Therefore, scepticism of the mIBG
image, that is consistent with all other positive results and itself a
specific test, seems unreasonable.
The interpretation of the initial biochemical tests should received
the greatest amount of scepticism, given the interpretation is normally
negative. Furthermore, clinicians performing and interpreting subsequent
tests should consider that the premise for deeper investigation might be
negative.
References:
[1] Zendron L, Fehrenbach J, Taverna C, Krause M. Pitfalls in the
diagnosis of phaeochromocytoma BMJ. 2004;328:629-630
[2] Kudva YC, Sawka AM. Young WF Jr. Clinical review 164: The
laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic
experience. J Clin Endocrin Metab. 2003;88(10):4533-9.
[3] Hernandez FC, Sanchez M, Alvarez A, Diaz J, Pascual R, Perez M,
Tovar I, Martinez P. A five-year report on experience in the detection of
pheochromocytoma. Clinl Biochem. 2000;33:649-55.
[4] Gardet V, Gatta B, Simonnet G, Tabarin A, Chene G, Ducassou D,
Corcuff JB. Lessons from an unpleasant surprise: a biochemical strategy
for the diagnosis of pheochromocytoma. J Hypertension. 2001;19:1029-35.
[5] Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA,
Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand
HS. Management of the clinically inapparent adrenal mass "incidentaloma").
Ann Intern Med 2003;138:424-9.
[6] Lewington VJ, Clarke SEM. Isotopic evaluation and therapy in
patients with malignant disease. Best Practise & Research: Clinical
Endocrinology and Metabolism. 2000; 15(2):225-239.
[7] Mochizuki T, Murase K, Tauxe WN, Tanada S, Hamamoto K. A
pseudopheochromocytoma? Accumulation of I-123 MIBG in the renal pelvis.
Clin Nucl Med. 1994;19: 1030-1
Competing interests:
None declared
Competing interests: No competing interests
Drug causes should be considered first
EDITOR – The report by Zendon et al highlights the point that drug
causes of raised catecholamines should always be eliminated before
diagnosing a phaeochromocytoma[1]. Besides levodopa a number of other
drugs may cause false positive results either by raising catecholamines or
interfering with assays. These include dihydropyridines, methyldopa,
labetalol, sotalol, tricyclic antidepressants, phenoxybenzamine,
buspirone, phenothiazines, nasal decongestants (phenylpropanolamine) and
terbutaline[2][3]. Recreational drugs like cocaine and amphetamines can
also lead to raised urinary catecholamine excretion. Withdrawal of short-
acting sympathetic antagonists such as clonidine or propanolol can result
in increased sympathetic activity. The isolated elevation of dopamine in
this case should have implicated levodopa. The authors failed to mention
the results of urinary metanephrines, which have a higher specificity for
phaeochromocytoma[4]. Furthermore, pure dopamine secreting tumours are
rare and not usually associated with hypertension[5].
Benjamin AC Fisher
Specialist registrar Rheumatology
Watford General Hospital
Azad Ghuran
Specialist registrar Cardiology
Eastbourne District General Hospital
Kings Rd.
Eastbourne, East Sussex BN21 2UD
Competing interests: None declared
1. Zendron L, Fehrenbach J, Taverna C, Krause M. Pitfalls in the
diagnosis of phaeochromocytoma. BMJ 2004;328:629-30. (13 March)
2. Feldman JM. Falsely elevated urinary excretion of catecholamines
and metanephrines in patients receiving labetalol therapy. J Clin
Pharmacol 1987;27:288-92.
3. Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW,
Keiser HR et al. Biochemical diagnosis of pheochromocytoma: how to
distinguish true- from false-positive test results. J Clin Endocrinol
Metab 2003;88:2656-66.
4. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P
et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA
2002;287:1427-34.
5. Proye C, Fossati P, Wemeau JL, Cecat P, Marmousez TH, Lagache G.
Le pheocromocytome dopamine-secretant. Chirurgie 1984;110:304-8.
Competing interests:
None declared
Competing interests: No competing interests