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Karel Pacak, Professor of Medicine, MD, PhD, DSc
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Health
Building 10, CRC 1E-3140, MSC 1109
10 Center Drive, Bethesda, MD 20892-1583, United States
Phone: +1 3014024594
Fax: +1 3014024712
Henri J.L.M. Timmers, MD, PhD
Department of Internal Medicine, Division of Endocrinology
Radboud University Medical Centre
PO Box 9101, 6500HB Nijmegen, the Netherlands
Phone: +31 243614599
Fax: +31 243618809
David Taieb, MD, PhD
Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, European Center for Research in Medical Imaging
264 rue Saint-Pierre 13385 Marseille Cedex 5, France
Phone: +33 0491385558
Barry Shulkin, MD
Chief, Nuclear Medicine Division
Department of Radiological Sciences, Division of Nuclear Medicine
St. Jude Children’s Research Hospital
262 Danny Thomas Place, Memphis, TN 38105-3678
Phone: +1 9015953347
Fax: +1 9015953981
Keiichiro Yoshinaga, MD, PhD
Department of Molecular Imaging
Hokkaido University School of Medicine
Kita15 Nishi7, Kita-Ku, Sapporo, Hokkaido, Japan 060-8638.
Tel: +81 117067155
Fax: +81 117067155
Alexander Kroiss, MD
Department of Nuclear Medicine
Innsbruck Medical University
Anichstrasse 35, 6020, Innsbruck, Austria, .
Tel.: +43 5050422651
Fax: +43 05050422659
After establishing a biochemical diagnosis, pheochromocytomas and paragangliomas can be localized using different imaging modalities. Appropriate imaging is critical for:
First line anatomical imaging modalities for pheochromocytoma and paraganglioma imaging include computed tomography (CT) or magnetic resonance imaging (MRI). MRI is a preferred method in children, young adults, pregnant women and in those with cardiac tumors. CT and MRI provide a high sensitivity and allow precise tumor delineation, which is critical for pre-surgical evaluation. The specificity of these techniques is limited, however and often must be coupled with the use of specific functional imaging.
Functional imaging is complimentary to anatomical imaging and provides specific information about the tumor’s functional characteristics. Nuclear medicine scanning techniques include planar scintigrapy, single-photon emission computed tomography (SPECT) and positron emission tomography (PET). These imaging modalities involve the use of radiotracers which are taken up by the tumor cells through the targeting of specific transporter systems or peptide receptors on the cell membrane. The most widely used radiotracers for pheochromocytoma and paraganglioma scintigraphy are [123I]-labeled metaiodobenzylguanidine (123I-MIBG) and 111In-DTPA-pentetreotide scintigraphy. They have long been considered as the ‘gold standard’ modalities. However, novel PET tracers been proven to be very useful for the functional imaging of pheochromocytomas and paragangliomas. These include 6-[18F]-fluorodopamine (18F-FDA), 6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) and 2-[18F]-Fluoro-2-deoxy-D-glucose (18F-FDG).
The performance of the different functional imaging modalities is largely determined by tumor location (adrenal pheochromocytoma and extra-adrenal paraganglioma versus head and neck paraganglioma), benign versus metastatic disease and the underlying hereditary syndrome.
Current recommendations regarding the optimal functional imaging strategy for pheochromocytomas and paragangliomas have been published online by the European Association for Nuclear Medicine. Precise identification of the clinical context and genetic status of patients enables personalized use of functional imaging modalities.
Apparently sporadic nonmetastatic pheochromoctyoma
123I-MIBG is as sensitive as PET imaging (18F -FDOPA PET, 18F-FDA PET, 18F-FDG), and definitely superior to 111In-DTPA-pentetreotide SPECT(/CT) in localizing nonmetastatic sporadic pheochromoctyoma. With its ability for whole-body screening, it can rule out extraadrenal disease and act as a guide for additional CT and MRI investigations. There is no clear advantage of using PET tracers over 123I-MIBG scintigraphy in these patients. Their use should be reserved for MIBG-negative cases, multifocal tumors on 123I-MIBG scintigraphy and/or patients taking drugs that significantly interfere with the accuracy of 123I-MIBG scintigraphy.
Head and neck paraganglioma
18F-FDOPA PET appears to be the most sensitive imaging tool for these tumors in general with a sensitivity approaching 100%. In the absence of 18F-FDOPA, SSTR scintigraphy with 111In-DTPA-pentetreotide SPECT(/CT) acquisition may be used as the first-line evaluation. PET imaging with 68Gaconjugated peptide SST analogues seems to be highly sensitive and deserves to be compared with 18F-FDOPA in clinical trials. 123I-MIBG scintigraphy and 18F-FDA PET are not sufficiently sensitive. 18F-FDG PET has high sensitivity in the setting of SDHx-related head and neck paragangliomas and may help detect additional thoracic/abdominal tumors.
Retroperitoneal extraadrenal nonmetastatic paragangliomas
In patients with a retroperitoneal extraadrenal nonrenal mass, imaging should differentiate a paraganglioma from a neurogenic tumor, lymph node diseases, or a mesenchymal tumour.
Therefore, the specificity of functional imaging provides an important contribution. Once the diagnosis of PGL has been established, the multiplicity of extraadrenal localizations should be considered. 18F-FDOPA PET has higher sensitivity than 123I-MIBG scintigraphy, and is more specific than 18F-FDG PET. Therefore, at present, 18F-FDOPA PET is probably the preferred imaging modality when extra-adrenal parganglioma is suspected. 18F-FDG PET is especially sensitive in the setting of SDHx- and VHL-related sympathetic paragangliomas. 18F-FDA PET has the highest sensitivity and specificity across genetically different paragangliomas, but suffers from its limited availability.
Metastatic pheochromocytoma / paraganglioma
Several studies have demonstrated the limitations of using 123I-MIBG scintigraphy alone in the staging of hereditary and metastatic pheochromocytoma / paraganglioma. The use of 123I-MIBG may lead to significant underestimation of metastatic disease with potentially inappropriate management. 18F-FDG PET is the imaging modality of choice for SDHB-related metastases, whereas 18F-FDOPA PET/CT may be the imaging modality of choice in the absence of SDHB mutations, or when genetic status is unknown. Once it becomes more widely available, 18F-FDA PET might be used as a first-line diagnostic imaging modality in patients with metastatic disease, whatever their genetic status. The main purpose of 123I-MIBG or 111In-DTPA-pentetreotide scintigraphy in a patient with metastases is to determine if internal targeted radiotherapy is an appropriate treatment choice.
Algorithm for imaging investigations in pheochromocytoma and paraganglioma.
Adapted from Taieb D, Timmers HJ, Hindie E, et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2012;39:1977-95
This algorithm should be adapted to the practical situation in each institution. In bold first-line imaging procedures according to accessibility of tracers and clinical approvals in European countries. 18F-FDA and 68Ga-DOTA-SSTa (asterisks) are experimental tracers that should be used in the setting of clinical trials. 18F-FDA PET is currently used at the NIH only. 68Ga-DOTA-SSTa is now accessible in many clinical and research centers in Europe. Abbrviations: PCC=pheochromocytoma, HNP=head and neck paraganglioma, SDH=succinate dehydrogenase, VHL=Von Hippel Lindau, RET=RET proto-oncogene, NF1=neurofibromatosis type 1 (for abbreviations of radiotracers, see previous)