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S P E C I A L
F E A T U R E
C o m m e n t a r y
Renaissance of 18F-FDG Positron Emission
Tomography in the Imaging of
Pheochromocytoma/Paraganglioma
David Taïeb, Henri J. L. M. Timmers, Barry L. Shulkin, and Karel Pacak
Department of Nuclear Medicine (D.T.), La Timone University Hospital, European Center for Research in
Medical Imaging, Aix-Marseille University, 13005 Marseille, France; Department of Medicine (H.J.L.M.T.),
Section of Endocrinology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands;
Division of Diagnostic Imaging (B.L.S.), Radiological Sciences, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38105; and Program in Reproductive and Adult Endocrinology (K.P.), Eunice
Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, Maryland 20892
T
he synthesis of 2-[18F]-fluoro-2-deoxy-D-glucose
(18F-FDG) was a major scientific discovery after
years of work to develop chemically synthesized fluorosugars. FDG was first synthesized in the Czech Republic
by Pacák and Černý in 1968 (1). Ten years later, FDG was
prepared in a positron-emitting form with the isotope 18F
by Ido et al (2) at the Brookhaven National Laboratory
(Upton, NY) and used for positron emission tomography
(PET) imaging. Clinical PET imaging was introduced as a
diagnostic methodology in the mid-1970s and was soon
considered irreplaceable, especially in the imaging of oncology patients.
Most cancer cells have a voracious appetite for glucose;
thus, they readily take up 18F-FDG and can be easily visualized via PET. This feature is related to several mechanisms in cancer cells, including a shift in cellular metabolism from respiration to glycolysis, despite the presence
of adequate oxygen (aerobic glycolysis). This phenomenon is known as the Warburg effect and is well known to
be present in some pheochromocytoma (PHEO)/paraganglioma (PGL). Nevertheless, the use of PET, particularly
18
F-FDG PET, for localizing PHEO/PGL was delayed until 1999, when the first large study was published (3). The
initial study included PHEO/PGL regardless of their genetic status, leading to somewhat disappointing results. At
the same time, the scientific effort focused on developing
radiopharmaceuticals that would be very specific for localizing PHEO/PGL. This priority was not surprising be-
cause PHEO/PGL are considered nearly ideal for localization by functional imaging. This is based on the fact that
PHEO/PGL cells harbor several important transporters;
the most specific ones are the cell membrane norepinephrine transporter (NET), which mediates cellular reuptake
of norepinephrine/dopamine, and the cytosolic vesicular
monoamine transporters, which sequester cytoplasmic
dopamine into synaptic vesicles. Indeed, the radiopharmaceutical 123I/131I-metaiodobenzylguanidine (123/131IMIBG), which targets the NET and vesicular monoamine
transporters, was initially introduced in 1981 with excellent results in PHEO/PGL (4). Moreover, 131I-MIBG became the best radiotherapeutic option for metastatic
PHEO/PGL, which is still valid today. Well-designed studies have since shown that 123/131I-MIBG scintigraphy is
suboptimal, especially when used to detect metastatic
PHEO/PGL (especially those related to mutations in mitochondrial succinate dehydrogenase subunit B [SDHB])
(5). These and other results accelerated the implementation of 18F-FDG and novel PHEO/PGL-specific radiopharmaceuticals in PET imaging evaluations of these
tumors.
In the early 2000s, [18F]-fluorodihydroxyphenylalanine (18F-FDOPA), which was initially developed to investigate dopaminergic neurotransmission entering cells
via L-type amino acid transporter system 1, was used to
localize PHEO/PGL (6). 18F-FDOPA now shows the best
results in the detection of head and neck paragangliomas
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received January 6, 2014. Accepted April 8, 2014.
First Published Online May 30, 2014
Abbreviations: 18F-FDA, [18F]-fluorodopamine; 18F-FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; 18F-FDOPA, [18F]-fluorodihydroxyphenylalanine; HNPGL, head and neck PGL; 123/
131
I-MIBG, 123I/131I-metaiodobenzylguanidine; NET, norepinephrine transporter; PET, positron emission tomography; PGL, paraganglioma; PHEO, pheochromocytoma; SDHB,
succinate dehydrogenase subunit B.
doi: 10.1210/jc.2014-1048
J Clin Endocrinol Metab, July 2014, 99(7):2337–2339
jcem.endojournals.org
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Taïeb et al
FDG and Pheochromocytoma/Paraganglioma
(HNPGL) and is often used when 123I-MIBG is not available (7). Two other radiopharmaceuticals that target
NET, 11C-hydroxyephedrine and [18F]-fluorodopamine
(18F-FDA), were also used to detect benign and metastatic
PHEO/PGL with greater sensitivity than 123/131I-MIBG
scintigraphy. The very short half-life of 11C, complicated
synthesis of 18F-FDA, and comparable sensitivity to 18FFDG PET have limited their use. Furthermore, 18FFDOPA and 18F-FDA were found to be suboptimal for
evaluating a subset of PHEO/PGL that were first termed
“apparently sporadic.” It was Baysal et al (8) who discovered that mutations in the SDHD subunit play an important role in the pathogenesis of these tumors. Of all the
known genetic mutations, mutations in SDHD are currently the leading cause of hereditary HNPGLs (⬎50%),
followed by SDHB (20 –35%) and SDHC (15%) mutations. SDHB-linked PHEO/PGL syndrome is characterized by a high rate of retroperitoneal PGL, and it is
associated with a higher risk of aggressive behavior, development of metastatic disease, and ultimately death.
18
F-FDA, 18F-FDOPA, and 123I-MIBG were found to be
suboptimal in the localization of these particular tumors.
In contrast, initial large studies from the National Institutes of Health and later from other medical centers demonstrated that 18F-FDG PET is the most sensitive functional imaging tool for detecting and following SDHBrelated PHEO/PGL (9). These studies partially attributed
this finding to the Warburg effect, a very prominent feature of these tumors.
As our knowledge of the genetics of these tumors has
increased, 18F-FDG has been used in a different manner in
these tumors (5, 10). Now we know that genotype alone
is not sufficient to drive a PET radiopharmaceutical-specific imaging phenotype because different tumors in the
same patient exhibit different imaging patterns. This may
be in agreement with recent microarray gene expression
data showing different profiles between SDHD-HNPGLs
and SDHD-thoracoabdominal PGLs. An excellent example is SDHx-related sympathetic PHEO/PGL that often
exhibits a “flip-flop phenomenon”: 18F-FDOPA and 18FFDA-negative/18F-FDG-positive pattern of imaging (9).
Additional new results with 18F-fluoro-L-thymidine PET
have also suggested that a high FDG uptake in these tumors is not well correlated with their proliferation index,
which is usually very low (Pacak, K, unpublished observations). Thus, it is hypothesized that a high 18F-FDG
uptake in these tumors may be explained by SDH dysfunction that leads to stabilization of hypoxia-inducible factor ␣
proteins, thereby resulting in the up-regulation of angiogenesis, glucose transporters, and hexokinase activity.
In conclusion, we predict that the continuing renaissance of 18F-FDG in the evaluation of these tumors will be
J Clin Endocrinol Metab, July 2014, 99(7):2337–2339
further supported by assessing the role of quantification
studies of 18F-FDG uptake in the specific behavioral characteristics of existing and newly discovered hereditary
PHEO/PGL. Additionally, 18F-FDG PET/magnetic resonance imaging using an integrated system with simultaneous acquisition of both techniques holds a new promise
for providing information in the assessment of these tumors at a molecular level and in surgically affected areas
or HNPGL. Furthermore, determining the metabolized
and unmetabolized 18F-FDG fractions in these tumors will
help optimize the use of treatment agents for metastatic
PHEO/PGL. Finally, evaluating how to treat and follow-up metastatic PHEO/PGL with a mismatch between 18F-FDG PET and anatomical studies will be
needed. Due to the worldwide availability of 18F-FDG
PET imaging, this imaging modality will continue to
provide unique and essential information for localizing
and characterizing PHEO/PGL that are biochemically
proven. Nevertheless, different functional imaging
studies using specific radiopharmaceuticals like 123IMIBG, 18F-FDA, or 18F-FDOPA PET may be initially
performed in patients with PHEO. However,18F-FDG
PET is preferred in patients with extra-adrenal sympathetic PGLs, tumor multifocality, and/or SDHx-related
PHEO/PGL in whom this imaging method currently has
the highest sensitivity when compared to other functional imaging modalities.
Acknowledgments
Address all correspondence and requests for reprints to: David
Taïeb, MD, PhD, Department of Nuclear Medicine, La Timone
University Hospital, European Center for Research in Medical
Imaging, Aix-Marseille University, 13005 Marseille, France. Email: [email protected] or Karel Pacak, MD, PhD, DSc,
Chief, Section on Medical Neuroendocrinology, Professor of
Medicine, Program in Reproductive and Adult Endocrinology,
Eunice Kennedy Shriver National Institute of Child Health and
Human Development, National Institutes of Health, Room 1E3140, Building 10, 10 Center Drive, Bethesda, MD 20892–1109.
E-mail: [email protected].
This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child
Health and Development and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
Disclosure Summary: The authors have nothing to disclose.
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