pheochromocytoma

CLINICAL PROBLEM SOLVING
Current Approaches and Recommended Algorithm for
the Diagnostic Localization of Pheochromocytoma
IOANNIS ILIAS AND KAREL PACAK
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland 20892-1583
Pheochromocytomas (PHEO) (1–3) are catecholamineproducing
tumors that arise from chromaffin cells. PHEO are
mostly situated within the adrenal medulla, although in
about 9–23% of cases, tumors develop from extraadrenal
chromaffin tissue (adjacent to sympathetic ganglia of the
neck, mediastinum, abdomen, and pelvis) and are often referred
to as paragangliomas (4–6).
PHEO situated in the adrenal gland are identified more
commonly than those in extraadrenal tissues, because clinicians
usually focus on the adrenal gland as a main source of
catecholamine production. Although they usually choose a
proper imaging technique to attempt the localization of
PHEO in the adrenal gland, they are often confused as to
which algorithm to follow and what technique to choose for
the detection of extraadrenal PHEO. Furthermore, physicians
often neglect the facts that up to approximately 25% of
patients with apparent sporadic PHEO may, in fact, be carriers
of germline mutations, indicating hereditary disease
with a predisposition for extraadrenal, often multifocal,
PHEO (7); that in children, multifocal and extraadrenal
PHEO are found in up to 30–43% of cases (6, 8–12); that
malignant PHEO account for up to 26–35% of cases (13–18);
that the prevalence of malignancy in sporadic adrenal PHEO
is 9% (5); and that about 10% of patients with PHEO present
with metastatic disease at the time of their initial work-up
(19). After initial failed surgery, patients with metastatic
PHEO are commonly reevaluated using metaiodobenzylguanidine
(MIBG) scintigraphy, a modality that should actually
be performed before surgery to confirm that a tumor
was indeed a PHEO (5–9% of the population harbor an adrenal
tumor, most commonly a benign adenoma) (20 –22) or
to rule out metastatic disease. These patients are then reoperated
upon, suffering additional surgery-related complications
and substantial financial expenses. Some clinicians consider
the presence of sporadic unilateral small PHEO as
indicative of benign disease. This was concluded in older
studies of series of patients with PHEO (23–25). However,
more recent works from large series of patients with benign
and malignant disease in the United States and Europe do not
support this view; rather, they support the opinion that there
are no absolute clinical, imaging, or laboratory criteria to
predict malignancy and clinical course of PHEO (5, 16, 19,
26–32). Nevertheless, PHEO tumors with a diameter larger
than 5 cm have a higher potential to metastasize, and such
patients should be followed more frequently (33). Consequently,
it seems that ruling out metastatic PHEO before
initial surgery would be useful, because the detection of
other lesions may dramatically affect treatment and
follow-up.
Localization of PHEO should be attempted using at least
two imaging modalities. Anatomical imaging studies [computed
tomography (CT) and magnetic resonance imaging
(MRI)] should be combined with functional (nuclear medicine)
imaging studies for optimal results to locate primary,
recurrent, or metastatic PHEO.
Functional imaging studies (enabled by the presence of the
noradrenergic transporter system on PHEO cells) include
[123I]- or [131I]MIBG scintigraphy, 6-[18F]fluorodopamine
([18F]DA), [18F]dihydroxyphenylalanine ([18F]DOPA),
[11C]hydroxyephedrine, and [11C]epinephrine positron
emission tomography (PET) (34 –38). Chromaffin cells in various
neuroendocrine tissues [such as PHEO, but also medullary
thyroid carcinoma (MTC)] express the plasma membrane
norepinephrine transporter and the intracellular
vesicular monoamine transporter. The norepinephrine transporter
is responsible for the cellular uptake of both MIBG (39)
and [18F]DA (36). We have recently shown that [18F]DA PET
scanning could theoretically represent yet another imaging
modality for the detection of MTCs (40) because MTC cells
often express the norepinephrine transporter and concentrate
MIBG (41).
In most cases, functional imaging modalities are either
able to confirm that a tumor is a PHEO or can lead to further
diagnostic work-up. For example, in a patient with positive
plasma metanephrines and MIBG imaging studies showing
uptake in extraadrenal locations, the possible presence of
Abbreviations: CT, Computed tomography; DA, dopamine; DOPA,
dihydroxyphenylalanine; DTPA, diaminetriaminepentacetate; FDG, fluorodeoxyglucose;
HU, Hounsfield units; MEN 2, multiple endocrine
neoplasia type 2; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance
imaging; MTC, medullary thyroid carcinoma; Octreoscan,
somatostatin receptor scintigraphy with [123I]Tyr3-octreotide or [111In]-
diaminetriaminepentacetate-octreotide; PET, positron emission tomography;
PHEO, pheochromocytoma; SPECT, single photon emission computed
tomography; U/S, ultrasound.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine
community.
0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(2):479–491
Printed in U.S.A. Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-031091
479
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