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EANM/SNMMI 2019 guidelines for radionuclide imaging of pheochromocytoma and
paraganglioma
David Taïeb1, Rodney J Hicks2, Elif Hindié3, Benjamin A. Guillet4, Anca Avram5, Pietro
Ghedini6, Henri J. Timmers7, Aaron T Scott8, Saeed Elojeimy9, Domenico Rubello10, Irène J
Virgolini11, Stefano Fanti6, Sona Balogova12,13, Neeta Pandit-Taskar14, Karel Pacak15
1. Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-
Marseille Univ, France.
2. Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC,
Australia.
3. Department of Nuclear Medicine, Bordeaux University Hospitals, Hôpital Haut-
Lévêque, Pessac, France.
4. Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-
Marseille Univ, France.
5. Nuclear Medicine/Radiology, University of Michigan, Ann Arbor, USA
6. Nuclear Medicine Unit, Medicina Nucleare Metropolitana, University Hospital
S.Orsola-Malpighi, Bologna.
7. Department of Endocrinology, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands.
8. John Hopkins hospital, Baltimore, USA.
9. Department of Radiology, University of New Mexico, Albuquerque, NM.
10. Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics,
Clinical Laboratory, Microbiology, Pathology, Trasfusional Medicine, Santa Maria
della Misericordia Hospital, Rovigo, Italy.
11. Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35,
6020, Innsbruck, Austria.
12. Department of nuclear medicine, Comenius University and St.Elisabeth oncology
institute, Heydukova 10, 81250 Bratislava, Slovakia.
13. Department of Nuclear Medicine, Hôpital Tenon Assistance Publique-Hôpitaux de
Paris and Sorbonne University, Paris, France.
14. Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan
Kettering Cancer Center, New York, USA.
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15. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National
Institutes of Child Health and Human Development, National Institutes of Health,
Bethesda MD, USA.
Correspondence: Prof David Taïeb, M.D., Ph.D.
Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-
Marseille Univ, France: +33-4-91-38-55-58, Fax: +33-4-91-38-47-69, david.taieb@ap-
hm.fr
Running title: Imaging of pheochromocytoma and paraganglioma
Keywords: Guidelines, radionuclide imaging, paraganglioma, pheochromocytoma,
radionuclide therapy, PET, SPECT, somatostatin analogs, nuclear, gene, hypoxia, hereditary
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Abbreviations
PPGL = pheochromocytoma and paraganglioma, HNPGL = head and neck paraganglioma;
RET = rearranged during transfection proto-oncogene ; VHL= von Hippel-Lindau ; SDH =
succinate dehydrogenase; SDHA, -B, -C, -D, = succinate dehydrogenase subunits A, B, C,
and D; SDHx = succinate dehydrogenase subunits; NF1 = neurofibromin 1; MAX = myc-
associated factor X; EGLN2/PHD1 = egl-9 family hypoxia-inducible factor 2;
EGLN1/PHD2= egl-9 family hypoxia inducible factor 1; TMEM127 = transmembrane
protein 127; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α,
FH= fumarate hydratase, SSAs = somatostatin analogues; MIBG =
metaiodobenzyguianidine; RCC = renal cell carcinoma; GIST = gastroinstestinal stromal
tumor; MTC = medullary thyroid carcinoma ; WHO = World Health Organization ; MEN =
multiple endocrine neoplasia; BAT = brown adipose tissue ; NPV = negative predictive
value; PPV = positive predictive value; NE = norepinephrine; EPI = epinephrine; DA =
dopamine; NET = neuroendocrine tumor; GI = gastrointestinal; SRS = somatostatin receptor
scintigraphy ; COMT = catechol-O-methyltransferase; AADC = aromatic L-amino acid
decarboxylase.
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Abstract
There are diverse radionuclide imaging techniques available for the diagnosis, staging
and follow-up of pheochromocytoma and paraganglioma (PPGL). Beyond their ability to
detect and localize disease, these imaging approaches variably characterize these tumors at
cellular and molecular levels and can guide therapy. In particular, the excellent results
obtained with gallium-68(68Ga)-labelled somatostatin receptor analogs (SSAs) in recent years
have simplified the imaging approach that can also be used for selecting patients for peptide
receptor radionuclide therapy (PRRT) as a potential alternative or complement to the
traditional theranostic approach with iodine-123(123I)- or iodine-131(131I)-labelled meta-iodo-
benzyl-guanidine (MIBG). Genomic characterization of subgroups with differing risks of
developing lesions and of subsequent metastatic spread are refining the use of molecular
imaging for surveillance of patients in combination with catecholamine assays.
The purpose of the present guidelines is to assist nuclear medicine practitioners in selecting,
performing, interpreting, and reporting the results of the currently available SPECT and PET
imaging procedures. Guidelines from related fields and relevant literature have been taken
into consideration in consultation with leading experts involved in the management of PPGL
patients. The information provided should be taken in the context of local laws and
regulations as well as availability of various radiopharmaceuticals.
Purpose
The purpose of these guidelines is to assist nuclear medicine practitioners in:
1. Understanding the role and challenges of radionuclide imaging of PPGL.
2. Providing practical information for performing different imaging procedures for these
tumors.
3. Providing an algorithm for selecting the most appropriate imaging procedure in
specific clinical situations.
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Background information and definitions
Tumor origin and location
Pheochromocytoma (PHEO) and paraganglioma (PGL) belong to the same family of
neural crest-derived neoplasms (also called PPGL). PPGLs occur with a frequency of up to
1:500 in patients with hypertension and up to 1:1000 in unselected post-mortem studies . They
are widely distributed from the skull base to the pelvis but almost uniquely develop in close
relationship with the sympathetic and parasympathetic divisions of the autonomic nervous
system. The sympathetic axis includes the adrenal medulla and chromaffin cells located in
posterior mediastinum (in the periaortic regions), or the retroperitoneum, while the
parasympathetic paraganglia are mainly located in the head and neck region and
anterior/middle mediastinum. Based on the classification published in 2004 by the World
Health Organization (WHO), the term pheochromocytoma should be reserved solely for
adrenal PGL . The term PGL is used to describe extradrenal tumors, regardless of their
location (sympathetic or parasympathetic).
Clinical presentation
PHEO accounts for about 4% of adrenal incidentalomas. However, since their
prevalence is higher in autopsy series, there is probably underdiagnosis during life. PHEO
usually causes symptoms of catecholamine oversecretion (e.g., sustained or paroxysmal
elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor, and
apprehension or anxiety). By contrast, head and neck PGLs are often incidentally discovered
on imaging studies or are revealed by symptoms and signs of compression or infiltration of
adjacent structures (e.g., hearing loss, tinnitus, dysphagia, cranial nerve palsies).
Spectrum of hereditary syndromes
Around 5-10% of solitary PHEOs are hereditary, whereas the presence of multiple
PHEOs or the combination of a PHEO with synchronous or metachronous extra-adrenal PGL
are related to currently known germline/somatic mutations in more of 70% of cases. These are
now recognized to be caused by at least 16 susceptibility genes .
Most important correlations between the gene(s) involved and a specific tumor
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anatomical predispostion have been found as described below:
1: PHEO: RET, VHL, SDHx, NF1, MAX, TMEM127,and EPAS1/HIF2A .
2: Sympathetic-PGLs: SDHx, VHL, RET, PHD1/2 and EPAS1/HIF2A (somatic
mutation).
3: Head and neck PGL (HNPGL): SDHx.
Major predictors for hereditary PPGL include a family history of PPGL, characteristic
syndromic presentation, young age at diagnosis, a previous personal history of PPGL,
multifocality, unusual location (e.g. heart, urinary bladder), and/or tumor recurrence,
particularly in the adrenal gland and a combined elevation of normetanephrine and 3-
methoxytyramine . Renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST),
pituitary adenoma and, rarely, pulmonary chondroma, neuroblastoma and neuroendocrine
neoplasms (carcinoids) can also be related to SDHx mutations . Other manifestations can also
be suggestive of certain gene mutations. For example, prior medullary thyroid cancer (MTC)
for RET, café-au-lait spots/neurofibromas for NF1, renal cell carcinoma
(RCC)/hemangioblastomas/pancreatic tumors for VHL, congenital polycythemia and
duodenal somatostatinoma for EPAS1/HIF2A, and RCC/leiomyomas for FH (Table 1).
Furthermore, PPGL with an underlying SDHB mutation are associated with a higher
risk of aggressive behavior leading ultimately to death, particularly due to the development of
metastatic disease. The risk of malignancy in SDHB mutation-associated tumors has been
estimated to range from 31% to 71%. In addition to impacting the distribution of disease, the
genomically-distinct subgroups of PPGLs have different patterns of catecholamine secretion
and the expression of cell membrane receptors and transporters, which impact their imaging
phenotype, particularly the uptake of catecholamines or their precursors .
Clinical indications for nuclear imaging
Confirmation of diagnosis of PPGL
The diagnosis of PHEO is often based on the presence of high levels of plasma or
urinary metanephrines and methoxytyramine in combination with suspicious characteristic
clinical features. Some specific radiologic features of anatomic imaging (CT/MRI) may also
be suggestive of the diagnosis . Typically, a PHEO demonstrates avid enhancement but can
have a heterogeneous appareance due to cystic, necrotic, or fibrotic regions within the lesion.
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In cases of a non-secreting adrenal mass, the high specificity of functional imaging may
sometimes contribute to its diagnosis.
In the presence of a retroperitonal, extra-adrenal non-renal mass, it is important to
differentiate a PGL from other tumors or lymph node involvement including metastases. A
biopsy is not always contributory and may be contraindicated in the setting of elevated
catecholamine levels due to the the associated high risk of hypertensive crisis and
tachyarrhythmia. Appropriate pharmacological adrenoceptor blockade should be instituted
prior to any biopsy or precedure in such cases. The same safety measures apply to PHEO.
Although specific functional imaging is very helpful to distinguish PGL from other tumors, it
is usually not done before biochemical results are available.
In head and neck locations, there are also many differential diagnoses such as lymph
node metastasis, neurogenic tumors (e.g. schwannoma, neurofibroma, ganglioneuroma),
jugular meningioma, internal jugular vein thrombosis, internal carotid artery aneurysm,
hemangioma and vascular malposition.
Staging at initial presentation of PPGL
Generally, PPGLs are benign and progress slowly. Metastatic rates vary from less than
1% to more than 70%, depending on tumor location, size, biochemical phenotype and,
particularly, genetic background. Functional imaging is probably not necessary in the
preoperative work-up of patients meeting the following criteria: > 40 yrs, absence of a family
history, small (less than 3.0 cm), no multiplicity, adrenergic biochemical phenotype (uniquely
pointing towards a tumor in the adrenal gland only) and negative genetic testing. Since the
genetic status is often not available before surgery, the presence of multifocal or metastatic
disease, substantial locoregional extension, or extremely high methoxytyramine levels calls
for nuclear imaging, which is very useful in this regard since it may point towards SDHx
mutation. HNPGLs require a specific approach and although metastatic disease is rare,
locoregional extension and multifocality are common and often warrant the use of functional
imaging modalities as well as detailed anatomical correlation with arterial and venous phase
CT or MRI. Early treatment is crucial since most of these tumors become difficult to resect if
they are large or involve the skull base.
Restaging and follow-up
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Nuclear imaging may be used for restaging following completion of treatment of
aggressive tumors or as follow-up of non-secretory and asymptomatic lesions. It can also
localize occult tumor sites in cases of positive biochemical results, suspicion of disease
recurrence or to clarify equivocal findings on anatomic imaging. PPGLs associated with
adverse pathological features, and/or large tumors, elevated methoxytyramine/dopamine
and/or the presence of specific germline/somatic mutations should alert a clinician to carry out
extended and prolonged (often lifelong) monitoring. In HNPGL, anatomical identification of
tumor remnants or recurrences can be difficult after treatment due to postoperative or
radiation-induced morphological changes (e.g., fibrosis, edema, necrosis, or presence of
surgical material). Conversely, nuclear imaging using specific radiopharmaceuticals is only
minimally influenced by the post-treatment sequelae and therefore, enables accurate diagnosis
of tumor recurrences that could be missed by structural imaging . Nuclear imaging can also be
helpful in assessing metabolic responses to therapies in metastatic or in inoperable PPGL.
Selection for targeted molecular radiotherapy
Recently, the success of PRRT with 177Lu Lu-DOTATATE (oxodotreotide) or other 90Y or 177Lu radiolabeled somatostatin analogs in patients with inoperable/metastatic GEP
NET has given a great impetus toward the use of PRRT for inoperable/metastatic PPGL.
Nuclear imaging (PET or SPECT) gives valuable information when planning targeted
radionuclide therapy with radiolabeled 131IMIBG or PRRT with 177LuLu-DOTATATE or
other related agents . Besides confirming uptake in lesions, it also helps in personalized
dosimetric evaluation of at-risk organs and tumor target.
Radiotherapy planning
Nowadays, integration of multi-modality imaging into radiotherapy planning has
brought greater precision to the delivery of radiation. Molecular imaging can complement
MRI in difficult situations (especially in the evaluation of venous extension from large
jugular PGL or tumor reccurences in the surgical bed) and, therefore, could lead to a more
accurate definition of biological target volumes, thereby potentially decreasing the likelihood
of complications within surrounding normal tissues. This is particularly true for stereotactic
radiosurgery, which enables highly elevated biological effective dose delivery to the tumor.
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Useful Clinical information for optimal Imaging and interpretation
A nuclear medicine physician should obtain the following information whenever possible:
1. Personal history of PPGL and/or other tumors.
2. Personal history of surgery, chemotherapy, and radiotherapy (including timing and
frequency).
3. Known genetic mutation or documented family history of PPGL.
4. Results of PPGL-related laboratory tests (metanephrines, methoxytyramine,
calcitonin, chromogranin A).
5. Results of previous anatomic and functional imaging modalities (including baseline
and nadir on-treatment imaging for the assessment of tumor response(s)).
6. Drugs (e.g. proton pump inhibitors, histamine type-2 receptor antagonists) or
conditions (gastric disorders, impaired kidney function, chronic heart failure,
hypertension, rheumatoid arthritis, inflammatory bowel disease, non-neuroendocrine
neoplasms) that may interfere with the accuracy of procedures and measurements
(particularly for chromogranin A).
General considerations for image acquisition and interpretation:
1. PPGL have different preferential sites of origin that must be known. The integration of
functional and anatomical imaging on hybrid SPECT/CT or PET/CT devices is
strongly preferred.
2. Images are usually acquired from the top of the skull (for a large jugular PGL) to the
pelvis. In case of suspicion of recurrent or metastatic disease, whole-body images are
needed.
3. Malignancy is defined only by the presence of metastases at sites where chromaffin
cells are normally absent (according to current 2017 WHO Classification of Tumours
of Endocrine Organs, this includes only bones and lymph nodes).
4. The presence of retroperitoneal PGL or multifocal tumors increases the chance of
hereditary syndrome and requires extensive search for additional PPGL and any other
syndromic lesions (e.g., most commonly GIST, RCC, pancreatic tumor,
hemangioblastoma, medullary thyroid carcinoma, pituitary adenoma, neuroblastoma,
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somatostatinoma, and/or pancreatic tumor).
5. All non-physiologic and suspicious foci of tracer uptake must be described since PGL
may arise in various atypical locations (e.g., orbital, intrathyroidal, hypoglossal,
cardiac, pericardial, gallbladder, urinary bladder, liver, cauda equina).
6. Metastases from PPGL are often small and numerous and could be difficult to
precisely localize on co-registered CT images of combined SPECT/CT and PET/CT
(unenhanced procedure, thick anatomical sections, or positional shift between CT and
PET images).
General points to consider while reporting:
1. The clinical setting and the clinical question that is raised.
2. Details of patient preparation, including concomitant drugs that were withheld.
3. The procedure: radiopharmaceutical, activity administered, acquisition protocol, CT
parameters in case of hybrid imaging and patient exposure, including the
radiopharmaceutical dose and the CT parameters of radiation exposure (volume
computed Tomography Dose Index/CTDIVOL, Dose-Lengh Product/DLP).
4. The positive findings and interpretation for each anatomical region (i.e., head and
neck, chest, abdomen and pelvis, bone/bone marrow).
5. Comparative data analysis with other imaging studies or previous nuclear imaging.
6. Conclusion: The report should present findings in terms of their consistency with a
particular diagnosis followed by a listing of study limitations. When conclusive
evidence requires additional diagnostic functional or morphologic examinations or an
adequate follow-up, this request should be included in the report as could suitability
for radionuclide therapy in the case of metastatic disease. Where a hereditary
syndrome is suggested, the implications for genetic testing could be raised.
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123I-Iobenguane/123I-Metaiodobenzylguanidine scintigraphy
Radiopharmaceutical
MIBG is commercially available labeled with 123I or 131I. 123IMIBG scintigraphy is highly
preferable to 131IMIBG scintigraphy because (a) it provides higher-quality images (the 159
keV emission of 123I is better adapted to detection with conventional gamma cameras); (b) the
lower radiation burden of 123I allows a higher permissible administered activity, resulting in a
higher count rate; (c) SPECT can more feasibly be performed with 123I; (d) less time elapses
between injection and imaging with 123IMIBG scintigraphy (24 hours) than with 131IMIBG
scintigraphy (48–72 hours). Nevertheless, ]IMIBG might not be available to every nuclear
medicine facility. Although 131IMIBG can be used in such circumstances, it is not
recommended because of low sensitivity and unfavourable dosimetry.
Mechanism of cellular uptake
MIBG, an iodinated analog of guanidine, is structurally similar to NE. Guanidine analogues
share the same transport pathway as norepinephrine via the cell membrane NE transporter
(NET) system. A non-specific uptake has also been reported for MIBG uptake in PPGL
tissues . In the cytoplasmic compartment, MIBG is stored in the neurosecretory granules via
vesicular monoamine transporters 1 and 2 (VMAT 1, 2) . MIBG specifically concentrates in
tissues expressing catecholamine-secreting tumors, allowing specific detection of other
neuroendocrine tumors and, to some degree, in the normal adrenal medulla.
Pharmacokinetics
After IV administration, MIBG concentrates in liver (33%), lungs (3%), heart (0.8%), spleen
(0.6%) and salivary glands (0.4%) . In the vascular compartment, the small amount of the
remaining MIBG concentrates in platelets through the serotonin (5HT) transporter. Tracer
uptake in the normal adrenal glands is weak; the normal adrenals can be faintly visible,
especially using 123IMIBG. The majority of MIBG is excreted unaltered by the kidneys (60-
90% of the injected dose is eliminated via urine within 4 days from the day of its
administration; 50% within 24h), fecal elimination is minor (<2% up to day 4). In PPGL
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patients, uptake in heart and liver is lowered by approximately 40%, most likely as a
consequence of competition with circulating catecholamines .
Synthesis and quality control
MIBG labeled with 123I or 131I is currently commercially available in a “ready to use”
formulation that conforms to the European/US Pharmacopeia. The labeled product is
available in a sterile solution for intravenous use. The solution is colorless or slightly yellow,
contains 0.15-0.5 mg/ml of MIBG, is stable 60 h after synthesis and can be diluted in sterile
water or saline. The activity of MIBG should be measured in a calibrated ionization chamber,
and radiochemical purity can be evaluated using thin-layer chromatography (TLC).
Drug interactions
Many drugs modify the uptake and storage of MIBG and may interfere with MIBG
scintigraphy . For a review of drugs that may interact or interfere with MIBG uptake, the
reader can refer to some previous reviews and guidelines . It should be underlined that most of
the therapeutic pharmaceuticals introduced in the last 25 years and in common use today have
never been tested for effect on MIBG uptake . Reported interfering agents include opioids,
tricyclic or other antidepressants, sympathomimetics, antipsychotics and antihypertensive
agents . Labetalol, for example, has been reported to cause false negative scans and should be
stopped more than 10 days prior to MIBG administration if a patient’s clinical status allows
that . A single oral dose of amytriptiline, a tricyclic antidepressant, significantly enhanced
cardiac MIBG washout and compete on the NET with catecholamines resulting in less
accumulation of MIBG in PPGL . Post-therapy MIBG scintigraphy failed to detect the vast
majority of metastatic PPGL lesions in a polytoxicomanic patient in whom the diagnostic scan
was positive . Nifedipine, on the other hand, can cause prolonged retention of MIBG in PPGL
. Calcium antagonists are usually listed as medications that interfere with MIBG uptake, but a
definitive proof is lacking and probably it is not necessary to withdraw them . Very high
serum catecholamines levels may be associated with a lower MIBG accumulation . To date,
many of these interactions are suspected according to in vitro/preclinical observations or only
expected according to their pharmacological properties and thus should be interpreted with
caution. Furthermore, mechanisms involved in MIBG uptake or retention may differ between
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models. For example, specific uptake of MIBG is mediated by 5HT transporters in platelets
and by NET in PPGL.
Side effects
Rare adverse events (tachycardia, pallor, vomiting, abdominal pain) can be minimized
by slow injection.
No adverse allergic reactions is expected, although a single case has been reported
with 131IMIBG .
Recommended activity
131IMIBG: 40-80 MBq (adult), 123IMIBG: 200-400 MBq (adult). Radioactive activity
administered to children should be calculated on the basis of a reference dose for an adult,
scaled to body weight according to the schedule proposed by the EANM Committee (for
123IMIBG : 5.2 MBq/kg with a minimum of 37 MBq and a maximum of 370 MBq for the
North American consensus guidelines and a maximum of 400 MBq for the EANM paediatric
dosage card) ; for 123IMIBG : 35-78 MBq .
Administration
Intravenous injection. Slow injection is recommended (over at least 1 minute).
Radiation dosimetry
It can be obtained from the ICRP tables. The effective dose is 0.013 mSv/MBq for 123IMIBG
and 0.14 mSv/MBq for 131IMIBG in adult and is 0.037 mSv/MBq for 123IMIBG and 0.43
mSv/MBq for 131IMIBG in children (5 years) . There is an increased radiation dose from CT
in SPECT/CT protocols, the value being dependent on parameter scan.
Pregnancy
The use of radiopharmaceuticals is generally contraindicated in pregnancy. However, if
clinically necessary, a decision to perform imaging should be based on the benefits against the
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possible harm to fetus from the procedure in case of pregnancy, whether known or suspected.
Proper institutional and local guidelines should be followed in relation to radiation effects.
Breast feeding
Breast feeding should be discontinued for at least 3 days after scintigraphy using 123IMIBG
non-contaminated by 124I or 125I. Breast feeding should be stopped completely when using
131IMIBG.
Renal insufficiency
Reduced plasma clearance of 123IMIBG occurs in patients with renal insufficiency and is not
cleared by dialysis . Therefore, reduced administered activity by 50% should be considered
and possible delayed imaging is recommended.
Patient preparation
Thyroid blockade (130 mg/day of potassium iodine; equivalent to 100 mg of iodine)
started one day before tracer injection and continued for 2 days for 123I-MIBG and 7-
10 days for 131IMIBG , but use of this agent for diagnostic imaging is strongly
discouraged. Potassium perchlorate may be substituted for Lugol’s iodine in iodine-
allergic patients and started 4 hours before tracer injection and continued for 2 days
(400-600 mg/day).
Discontinuation of drugs interfering with MIBG uptake and retention (as mentioned in
prior section). All have to be withheld for 1–3 days, except for labetalol, which should
be discontinued 10 days prior, and antipsychotics, for which the withdrawal period
should be about 3-4 weeks. Regarding antipsychotic medications, it can be dangerous
to stop these medications, despite their potential effects on MIBG uptake. Therefore,
this should only be performed based on a very careful consultation with the patient’s
psychiatric care team.
Decision to discontinue other medication should be weighed with the clinical setting
and in very good coordination with the managing clinician.
Image acquisition and reconstruction
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123IMIBG scans should be obtained approximately 24 hours after tracer injection.
Imaging parameters
Anterior and posterior planar static images of the head and neck (+ right and left lateral
oblique views), thorax, abdomen and pelvis are obtained for 10-15 minutes per image (or
about 500 kcounts) (using a 256 × 256 word matrix, with a large-field-of-view camera, a low-
energy collimator, and with a 20% window centered at the 159 keV photopeak). Whole-body
images can be an alternative to planar views and include anterior and posterior acquisitions
into 1024 x 512 word or 1024 x 256 word matrix for a minimum of 30 min (speed 6 cm/min
max) .
Many centers prefer medium energy collimators because they reduce scatter and septal
penetration yields of high energy photons that are part of the 123I decay scheme. However,
longer acquisition times required with medium-energy collimators.
SPECT (SPECT/CT) over the anatomical regions showing pathological tracer uptake on
planar images often complete the image session and can replace lateral oblique planar images
of the head and neck region. The SPECT images are performed for a 360° orbit (128 × 128
word matrix, 6-degree angle steps, 30-45s per stop). Co-registered CT images (100-130kV,
mAs modulation recommended) from SPECT/CT cameras enable attenuation and facilitate
precise localization of any focus of increased of tracer.
Reconstruction
Iterative SPECT reconstruction or other validated reconstruction protocols that accurately
visualize lesions can be adapted to the clinical setting. CT-based attenuation correction
(CTAC) is used for SPECT/CT.
Imaging interpretation
Visual analysis
Physiological distribution: Normal uptake of 123IMIBG is observed in myocardium, salivary
glands, lacrimal glands, thyroid gland (if inadequate thyroid blockade is performed), liver,
lungs, adrenal glands (slight uptake can be seen in up to 80% of cases), bowel and uterine
uptake during menstrual period. 123IMIBG uptake in the adrenal glands is considered normal
if mild (less or equal to liver uptake), symmetric and when the glands are not enlarged on CT.
Large intestinal activity may also be visible, especially at later imaging times. Brown adipose
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tissue (BAT) uptake should be considered as a normal distribution of MIBG. Although this
may be more common in children compared to adults, BAT can also be enhanced in the
presence of PPGL and can potentially mask head and neck and adrenal lesions. Beta
adrenoceptor blockade can reduce this finding. However, the use of beta adrenoceptor
blockade alone is contraindicated in PPGL patients.
Pathological uptake: As normal adrenal uptake is faint, distinctly increased uptake or
asymmetric adrenal uptake in presence of enlarged gland should be considered to reflect
potential pathology until proven otherwise. Extra-adrenal sites of uptake that are focal and
cannot be explained by normal physiological distribution are considered abnormal.
SPECT/CT is helpful for better localization of abnormal uptake and is generally
recommended
Quantification
Quantification of uptake is not routinely utilized as the methodology is not fully clinically
established. as the methodology is not universalized. Quantitative SPECT/CT has been
developed to provide dosimetry for therapeutic radionuclides including 177Lu but should not
be used in routine clinical practice unless it has been properly validated .
Common pitfalls
False positives
CT-based attenuation correction often leads to enhanced physiological visualization of the
adrenal medulla and may therefore induce false-positive interpretation unless the
interpretation priniciples detailed above are followed and adapted to allow moderate uptake as
a normal finding. In MEN-2 patients, 123IMIBG scintigraphy is of limited value for
discriminating physiological uptake from diffuse adrenal medullary hyperplasia or PHEO.
False-positive cases have also been related to tracer uptake by other neuroendocrine lesions
(carcinoid tumor, medullary thyroid carcinoma, Merkel cell carcinoma, ganglioneuroma).
Rarely, MIBG uptake has been reported in adrenocortical adenomas or carcinomas,
retroperitoneal angiomyolipomas and hemangiomas. SPECT/CT may avoid misleading
accumulations in the liver (inhomogeneous uptake, hepatic hemangioma, hepatocellular
carcinoma), in the renal parenchyma (diffuse for renal artery stenosis, focal for acute
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pyelonephritis) or in the urinary tract (hydronephrosis, renal cysts), atelectasis, pneumonia,
vascular malformations, accessory spleen, adrenal abscess, foregut duplication cysts,
hemorrhagic cysts, ovarian torsion, chronic inflammatory foci .
False negatives
HNPGL, SDHx-related PPGLs, small lesions, large PHEO with cystic degeneration, necrosis,
or hemorrhage, poorly-differentiated tumors (low expression of VMAT-1) are more prone to
yield false-negative results . False negative results may also result from interfering
medications (drug-interference).
Diagnostic accuracy
123IMIBG scintigraphy has a sensitivity ranging from 83–100% and a high specificity (95–
100%) for PHEO. Its specificity decreases in MEN-2-related PHEO. Studies, which have
included high numbers of extra-adrenal, multiple, or hereditary PGLs, found reduced
sensitivity of 123IMIBG scintigraphy (52-75%) . 123IMIBG scintigraphy may be suboptimal
in cases with special genotypic features such as SDHB-related PPGLs . In patients with
metastatic disease, 123IMIBG scintigraphy may lead to a significant underestimation of the
extent of disease with potential to inappropriately guide management. The sensitivity of 123I-
MIBG scintigraphy is overall low in HNPGLs (from 18 to 50%). However, importantly,
123IMIBG scintigraphy can be used to select potential candidates for 131IMIBG therapy.
Indium-111(111In)-Pentetreotide scintigraphy
Radiopharmaceutical
111InIn-DTPA-pentetreotide (OctreoScan) is a 111InIn(DTPA)]0 conjugate of octreotide, a
long-acting somatostatin analog.
Mechanism of uptake
111InIn-DTPA-pentetreotide specifically binds to somatostatin (SST) receptors expressed on
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cell membranes, especially subtypes 2 and 5. SSTR are expressed on many cells of
neuroendocrine origin, and therefore tumours derived from those cell types.
Pharmacokinetics
Twenty-four hours after IV administration, 111InIn-DTPA-pentetreotide is cleared from the
blood, primarily through the kidneys (50% of the injected dose is recovered in the urine by 6
h, 85% within 24 h). Some of the tracer is, however, retained in tubular cells. Hepatobiliary
excretion and spleen trapping are respectively 2% and 2.5 % of the administered dose.
However, the bowel is often visualized on delayed imaging and the gallbladder can also
contain activity and cause diagnostic uncertainty unless carefully correlated with anatomical
imaging. Pituitary and thyroid can also be visualized . Occasionally, the gallbladder can be
visualized and cause diagnostic confusion regarding the possibility of hepatic metastasis but is
easily overcome by SPECT/CT.
Synthesis and quality control
111InIn-DTPA-pentetreotide is commercially available (Octreoscan®, Covidien) and supplied
as a monodose kit for radiolabeling. The kit contains two sterile vials containing lyophilized
pentetreotide (10 µg) and 111InIndium Chloride (122 MBq/1.1mL at ART).
The radiopharmaceutical is prepared by adding the desired activity of 111In-chloride into the
vial containing pentetreotide at room temperature. The preparation should be used within 6
hours and can be diluted in sterile saline (2-3 mL).
The preparation of the 111InIn-DTPA-pentetreotide is stable for 6 hours, and should not be
used if radiochemical purity is less than 98%. The pH of the solution ranges between 3.8 and
4.3.
Thin layer chromatography can be used to check radiochemical purity as follows: solid phase
ITLC, mobile-phase 0.1N sodium citrate adjusted with HCl to pH 5, Rf: 111In-pentetreotide
0.0, unbound 111In 1.0.
Drug interactions and side effects
The amount of pentetreotide injected is about 10 µg and is not expected to have clinically
significant pharmacologic effect.
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It has been proposed to temporarily interrupt somatostatin analogue therapy to avoid possible
somatostatin receptor blockade, but this is not universally applicable. Sometimes, assessment
may be required, when on therapy.
Recommended activity
185–222 MBq (5–6 mCi) in adults and 5 3 MBq/kg (0.14 mCi/kg) in children .
Administration
Slow (1-2 minute) intravenous infusion.
Radiation dosimetry
The effective dose is about 0.054 mSv/MBq in adults and 0.16 mSv/MBq in children (5 years)
. There is an increased radiation dose from CT in SPECT/CT protocols, the value being
dependent on a parameter scan.
Renal failure
For patients with significant renal failure, high blood pool activity may hamper visualization
of uptake foci. After haemodialysis, an interpretable scintigram can be obtained.
Pregnancy
Generally use of radiopharmaceuticals is contraindicated in pregnancy. Clinical decision to
use, should consider the benefits against the possible harm of carrying out the procedure in
case of pregnancy, whether known or suspected.
Breast feeding
Breast feeding should be discontinued for 4 days after injection. It is not necessary to
discontinue breast-feeding after diagnostic use of 111InIn-DTPA-pentetreotide. However,
close contact with infants should be restricted during the first 2 days after administration.
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Patient preparation
Somatostatin analogs are rarely used in the treatment of PPGLs. Short-acting
somatostatin analogs may be discontinued for 24 h before 111InIn-DTPA-
pentetreotide administration, while long-acting preparations are preferably stopped 4–
6 weeks before the study, and patients should be switched to short-acting formulations,
if necessary .
Laxatives are advised, especially when the abdomen is the area of interest. It is of note
that this is a controversial when SPECT-CT is planned due to less difficulties for
avoiding potential pitfalls due to physiological bowel activity.
To reduce radiation exposure, patients should be well hydrated before and for at least
1 day after injection.
Image acquisition
Timing of imaging
Scans are obtained 4 hours and 24 hours after tracer injection.
Imaging field
Acquisitions are performed using two energy peaks at 171 and 245 keV and large-field-of-
view medium-energy collimators.
- Anterior and posterior planar views of the head & neck (+ right and left lateral oblique
views) and thorax, abdomen and pelvis are acquired at 4 hours and 24 hours (512 x
512 or 256 x 256 word matrix and are obtained for a 10-15 minutes per view (or about
300 kcounts for the head and neck and 500 kcounts for the rest of the body) .
- Whole-body imaging can be used instead of planar views. For whole-body images:
anterior and posterior images are acquired into 1024 x 512 word or 1024 x 256 word
matrix for a minimum of 30 min (speed 6 cm/min max).
- SPECT over the anatomical regions showing pathological tracer uptake on planar
images are clearly helpful when available. The SPECT images are performed for a
360° orbit (128 × 128 word matrix, 6-degree angle steps, 30-45s per stop). Co-
registered CT images (100-130 kV, mAs modulation recommended) from SPECT/CT
cameras enable attenuation and facilitate precise localization of any focus of increased
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tracer. SPECT/CT images are particularly useful over the abdomen. If only one
SPECT acquisition is obtained, acquisition at 24 hour is preferred because of higher
target-to-background ratio.
Optional images
- Acquisitions (SPECT and/or planar views) may be repeated at 48 hours for
clarification of equivocal abdominal findings.
Reconstruction
Iterative SPECT reconstruction or other validated reconstruction protocols that accurately
visualize lesions can be adapted to the clinical setting. CT-based attenuation correction
(CTAC) for SPECT/CT.
Image analysis
Visual analysis
Physiological distribution: Uptake is seen in spleen, kidney, liver, bowel (visible on the 24-
hour images), and the gallbladder if fasting. Moderate uptake is often seen over the pituitary
gland and the thyroid. Normal adrenal glands can also be faintly visible. Other sites with faint
uptake are the pituitary gland and the thyroid (increased diffuse uptake in case of thyroiditis).
Pathological uptake: As a rule, and especially in the abdomen, Accumulation of radioactivity
at an abnormal site is considered to represent somatostatin receptor binding especially if it is
present on the scintigrams on the two standard imaging time points.
Quantification
The optimal time interval to quantify tumors is at 24 hr post-injection or later. Tumor uptake
can be scored according to Krenning as follows: 0 = no uptake; 1 = very low/equivocal
uptake; 2 = clear, but faint uptake (less than or equal to liver uptake); 3 = moderate uptake
(higher than liver uptake); 4 = intense uptake (equal to or greater than that in the spleen). This
scoring is mainly used in selecting candidates for PRRT. A modified Krenning score has also
been used for SPECT using the same reference tissues but is not necessarily equivalent,
especially for small lesions in the liver that may be Krenning 2 on planar imaging but visible
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above hepatic parenchyma on SPECT and therefore, modified Krenning score 3.
Pitfalls
False positives
Renal parapelvic cysts, accessory splenic tissue (spenunculi) or abdominal hernia. False
positive cases may be related to tracer uptake by other neuroendocrine lesions or other SST2-
expressing tumors (thyroid or breast disease are the most frequent causes of false-positives
foci) . Since SST2 is overexpressed in activated lymphocytes and macrophages, FP images
may also be related to granulomatous and inflammatory diseases.
False negatives
Small HNPGLs, abdominal PGLs.
Diagnostic accuracy
Considering parasympathetic HNPGLs, several studies have demonstrated the superiority of
111InIn-DTPA-pentetreotide scintigraphy compared to 131I/123IMIBG scintigraphy, with
sensitivities of 89-100% and 18-50%, respectively . However, its sensitivity needs to be
revised in patients with hereditary syndromes because some additional lesions can be at the
millimeter range and not detectable by conventional scintigraphy .
The sensitivity of 111InIn-DTPA-pentetreotide is inferior to that of 123IMIBG scintigraphy in
abdominal and metastatic PPGL (except those related to SDHx mutations), even though it can
provide additional information in some patients with rapidly progressing metastatic PPGL .
111InIn-DTPA-pentetreotide may also detect other syndromic lesions (e.g., neuroendocrine
pancreatic tumor, medullary thyroid carcinoma, neuroblastoma, or pituitary tumors). Both
single photon agents have been shown to have inferior diagnostic performance compared to
the PET/CT techniques described below.
PET imaging with 68Ga-conjugated somatostatin analogs
Radiopharmaceuticals
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Imaging somatostatin receptors with PET tracers has been obtained with 3 different DOTA-
coupled somatostatin agonists (SSTa), Tyr3-octreotide (DOTATOC, edotreotide), Tyr3-
octreotate (DOTATATE, oxodotreotide), and Nal3-octreotide (DOTANOC). All of them are
radiolabeled with 68Ga elutate (68GaGa-SSTa) obtained from 68Ge/68Ga generators eluate. 68Ge/68Ga generators, GalliaPharm® (Eckert Zeigler) and Galli Eo® (IRE ELIT) have received
marketing authorization worldwilde. DOTATATE and DOTATOC were recently approved
by respectively US Food and Drug Adminsitration (FDA) and European Medicines Agency
(EMA).
Due to the short half-life of 68Ga (68 min), 68GaGa-SSTa are synthesized exclusively less
than 4 h before patient administration on the day of examination. According to each country's
regulations, 68GaGa-SSTa manufacturing can either be centralized and the agent be shipped
to Nuclear Medicine Departments, or the agent can by synthesized in local radiopharmacies
meeting good radiopharmaceutical practices (GMP). Nowadays, pharmaceutical grade and
avaibility of 68Ga-SSTa as pharmaceutical kits for radiolabeling reduced drasticly the
complexity of labelling and CQ procedures, must bend for 68Ga based imaging deployment to
clinical practices.
Mechanism of cellular uptake
68GaGa-SSTa target the somatostatin receptor subtype 2 (SST2), which is the most
commonly over-expressed receptor in PPGLs, and is internalized into the cells. SST1 is also
strongly expressed in some PGLs, while other receptor subtypes are only slightly expressed or
are entirely missing. The low expression of SST5 observed in PGLs constitutes a major
difference with some endocrine tumors of the gastrointestinal tract. DOTATOC (Tyr3-
octreotide), DOTATATE (Tyr3-octreotate), and DOTANOC (Nal3-octreotide) have excellent
affinity for SSTR2 (IC50: 2.5 nM; 0.2 nM; and 1.9 nM respectively). DOTANOC also binds
specifically to SSTR3, SSTR4 and SSTR5. DOTATOC also binds to SSTR5 (although with
lower affinity than DOTANOC) .
Tracer binding and retention depends on density of somatostatin receptors (SSTR) on the cell
surface and, the degree of internalization of the ligand/receptor complex. Recently, SSTR
antagonists such as 68GaGa-NODAGA-JR11 have been developed, and are still under
evaluation. SST antagonists should decrease DOTA-peptide washout and increase target
residence time, despite the lack of antagonist/SSTR complexes internalization, as these
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remain radiopharmaceuticals remain anchored within the cell membrane. Preferentially
developped for vectorized 68Ga radiolabeled antagonists could compete with SSTa and can
also be applied as a theranostic agents allowing for dosimetry and personalized medicine.
Pharmacokinetics
After IV administration, SSTa concentrate to all SSTR2-expressing organs: pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. There is no uptake in the cerebral cortex or in the heart is
reached in 60 to 120 minutes . Maximal tumour activity is reached in 60 minutes. DOTA
peptides showed a bi-exponential blood half-life (2 and 50 min), and are mainly excreted by
the kidney (40 to 75% of the injected dose respectively at 3 and 24 h after injection). Less
than 2% of the injected dose is excreted in the feces up to 48 h and no radiolabeled
metabolites have been reported during the first 4 h.
Synthesis and quality control
Currently, two 68Ge/68Ga generators and DOTATOC and DOTATATE have marketing
authorization. 68Ga can be harvested daily through 68Ge/68Ga generators elution and generators
are available for several months.
DOTATOC and DOTATATE are available as commercial kits for radiolabeling.
Radiolabelling is 68Ga is robust (radiochemical purity >95%), requires between 20 and 30
minutes, and procedure can be performed manually or by mean of automatic devices.
Briefly, the labeling procedure is divided into different steps and performed using suitable shielding to reduce radiation exposure.
- 68Ga chloride elution: 68Ge/68Ga generators are eluted with hydrochloric acid solution
(0.1-1N).
- DOTA-peptide radiolabeling: A defined volume of 68Ga elution chloride and pH
adjuster buffer are successively added in aseptic conditions and mixture is heated (95°C, 7-8
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min). Amount of pH adjuster buffer have to be adapted according 68Ga elution chloride
volume according SSTa’s kits according to manufacturer recommendations.
- Purification: if required based on generator characteristics, a purification step can be
performed using an accessory cartridge to reduce the amount of 68Ge to lower
than 0.001%.
- Quality controls: Appearance, pH and radiochemical purity must be assessed before
injection using validated methods (i.e., Thin Layer Chromatography or HPLC).
Radiochemical purity of 68GaGa-DOTATATE and 68GaGa-DOTATOC must be higher
than 92% and 95 %, respectively.
Drug interactions and side effects
Somatostatin analogues may affect the tracer accumulation in organ, and in tumour sites .
Recommended activity
The activity administered is 2 MBq/kg (100 to 200 MBq).
The amount of administred SSTa should not exceed 40 mcg.
Administration
Slow (1-2 minuten0 intravenous infusion.
Radiation dosimetry
The effective dose from radiopharmaceutical is approximately 0.021 mSv/MBq in adult .
There is an increased radiation dose from CT in SPECT/CT protocols, the value being
dependent on a parameter scan.
Pregnancy
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Clinical decision is necessary to consider the benefits against the possible harm of carrying
out any procedure in case of pregnancy, whether known or suspected. See 18FF-FDG PET
section.
Breast feeding
Breast feeding should be discontinued for 12 h after injection.
Patient preparation
No need for fasting before injection. It has been recommended to discontinue octreotide
therapy (1 day for short lived molecules and 3-4 weeks for long-acting analogues). To date,
this issue is still not definitively clarified.
Image acquisition
Scans are usually obtained from 45 to 90 minutes after tracer injection from base of skull to
mid-thighs (or over the whole-body depending on the clinical setting). Although, there is no
generally accepted acquisition time in the literature, generally 3 minutes per bed position is
adequate. However, acquisition times per bed position should be increased in obese patients,
if low activity is available or imaging is delayed beyond 90 minutes to minimize the risk of a
low statistical quality scan.
Image reconstruction
Data acquired in the 3D or 2D mode can be reconstructed directly using a 3D-reconstruction
algorithm or rebinned in 2D data and subsequently be reconstructed with a 2D-reconstruction
algorithm. Iterative reconstruction algorithms represent the current standard for clinical
routine. Point spread function alogrithms may enhance detection of small lesions but tend to
increase apparent intensity of uptake in such structures . This may impact interpretation of
uptake in the adrenals. CT-based attenuation correction (CTAC).
Image analysis
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Visual analysis
Physiological distribution: Intense accumulation of radioactivity is seen in the spleen (and
accessory splenic tissue if present), kidneys, adrenals, salivary glands and pituitary.
Accumulation in the liver is usually less intense than that noted in the spleen. The thyroid can
be faintly visible. Additionally, variable tracer uptake is frequently found in the pancreas
particularly in the uncinate process due to the high density in pancreatic polypeptide (PP)
cells . Prostate gland and breast glandular tissue may show diffuse low-grade uptake of
68GaGa-DOTA-conjugated peptides.
Quantification
SUV is an easy and useful parameter for tumour characterization, if images are acquired and
processed in a standardized manner. It should be ensured that the PET/CT system is calibrated
for 68Ga half-life.
Pitfalls
False positives
PET could be falsely positive in metastatic lymph nodes due to various cancers, meningiomas,
inflammatory processes, pituitary gland, and some rare conditions such as fibrous dysplasia .
In clinical practice, most experienced readers of SSA-based imaging are well aware of these
pitfalls (often significantly less avid than typical sites of disease and other distinguishing
features explained in above reference) and unlikely to make these mistakes.
Focal pancreatic accumulation in the uncinate process may mimic a pancreatic NET.
False negatives
There has been no sufficient data to draw any firm conclusions. FN findings mainly occur in
PHEO. As for other PET radiopharmaceuticals, the urinary bladder may mask intra- or
perivesical PGL. Diuretics can be used in selected cases to to circumvent this drawback.
Diagnostic accuracy
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The use of 68GaGa-DOTA-SSA in the context of primary PHEOs has been less studied that
other PET radiopharmaceutcals, but has shown excellent results in localizing these tumors
when they are metastatic or extra-adrenal . 68GaGa-DOTA-SSA is more sensitive than 123/131I-
MIBG scintigraphy. In a recent systematic review and meta-analysis, the pooled detection rate
of 68GaGa-DOTA-SSA PET/CT was 93% (95% confidence interval [CI] 91-95%), which
was significantly higher than that of fluorine-18FDOPA (18FFDOPA) PET/CT (80% [95%
CI 69-88%]), 18F-FDG PET/CT (74% [95% CI 46-91%]), and 123/131II-MIBG scintigraphy
(38% [95% CI 20-59%], P < 0.001 for all) . Although interesting, this meta-analysis is
hampered by mixing PPGLs of various origin, the low number of PHEOs, and the comparison
limited to lesion-based analysis.
Head-to-head comparison between 68GaGa-DOTA-SSA and 18FFDOPA PET/CT has been
performed in only 4 studies: one retrospective study from Innsbruck Medical University
(68GaGa-DOTATOC in 20 patients with unknown genetic background) , 2 prospective
studies from the NIH (68GaGa-DOTATATE in 17 and 20 patients) , and one prospective
study from La Timone University Hospital (68GaGa-DOTATATE in 30 patients) . In these
studies, 68GaGa-DOTA-SSA PET/CT detected more PPGLs than 18F-FDOPA PET/CT,
regardless of the genotype , as well as compared to 18FFDG PET/CT in SDHx, metastatic,
and head and neck PPGLs. In a recent study from the Royal North Shore Hospital in
Australia, 68GaGa-DOTATATE PET/CT had a sensitivity of 84% for PHEO (21/24) and
100% (7/7) for PGL . The elevated clinical value of 68GaGa-DOTA-SSA was also observed
in the pediatric population . EPAS1 (HIF2A) mutations remain an exception among
susceptibility genes since they lead to PPGLs that concentrate less 68GaGa-labeled-SSA in
contrast to SDHx-related PPGLs . This mechanism for this phenotype is currently largely
unexplained. Overall, based on these data it is suggestive that 68GaGa-DOTA-SSA PET/CT
is the most sensitive tool in the detection of HNPGLs, especially SDHD-related tumors, which
may be very small in size and/or fail to sufficiently concentrate 18FFDOPA. 68GaGa-
DOTA-SSA PET/CT might be inferior to 18FFDOPA PET/CT in the detection PHEOs.
18FFDOPA PET
Radiopharmaceutical
L-18F6fluoroDOPA
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In many countries, 18Ffluorodihydroxyphenylalaniane (18FFDOPA) is commercially
available as a sterile mono- or multi-dose solution for intravenous use. The solution is
colorless or pale yellow. In US, 18FFDOPA is not approved and, therefore, it is used in the
setting of clinical trials (e.g. National Institutes of Health, Maryland).
Mechanism of cellular uptake
PPGL can take-up and decarboxylate amino acids such as DOPA. This property depends on
the activity of the L-aromatic amino acid decarboxylase (AADC). DOPA, the precursor of all
endogenous catecholamines, is taken up through LAT transporters (mainly LAT1).
18FFDOPA is converted into 18FFDA by AADC and is stored in neurosecretory vesicles.
Pharmacokinetics
After IV administration, 18FFDOPA is specifically trapped by neuroendocrine tissue and
follows the metabolic pathways of L-DOPA. Plasma 18FFDOPA is metabolized by COMT
and AADC. 18FFDOPA is quickly converted into 18Ffluorodopamine in the proximal renal
tubule and other target tissues and eliminated in the urine (50% within 1 h and the rest within
12 h).
PPGL take up 18FFDOPA very quickly. Preferably, the acquisition for static clinical PET
imaging of PPGL with 18FFDOPA can start at 20 minutes post-injection for maximum
uptake in tumors. Afterward, a very slight decrease of the tumor SUV starts, which still
amounts to 80% of the maximum value after 132 minutes . Some authors use premedication
with carbidopa (an AADC inhibitor) to improve bioavailability of the tracer and to decrease
physiological uptake by the pancreas .
Synthesis and quality control
Before 2016 18FFDOPA was only avalaible through eletrophylic synthesis that requires up to
4 hrs and suffers from low robustness, a low yield of labeling, between 11 and 25% and low
stability. Expedited by dilution in an acid solution, eletrophylically produced 18FFDOPA
needs to be extemporaneously neutralized using bicarbonate buffer kit supplied by the
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manufacturer pH just before the administration. pH determination needs to be performed and
should be kept between 4.0 and 5.0.
In 2016, a nucleophilic method was validated and significantly improved the radiolabeling
robustness with an increased radiolabeling yield and a ready to use radiopharmaceutical with
a stability of 12 hours.
These two formulations seem to be equivalent, and no additional quality control is needed.
Striatum uptake of 18FFDOPA suggests integrity of the labeled molecule and can be used as
internal control.
Drug interactions and side effects
Local pain during injection has been reported for 18FFDOPA produced by electrophylic
synthesis (due to acidic pH).
Haloperidol and reserpine have been reported to, respectively, increase and decrease striatal
18FFDOPA retention . There is no report of drug interaction in PPGLs.
Recommended activity
2-4 Mbq/Kg.
Administration
Intravenous.
Radiation dosimetry
The effective dose in adults is 0.025 mSv/MBq . There is an increased radiation dose from CT
in PET/CT protocols, the value being dependent on a parameter scan.
Pregnancy
Clinical decision is necessary to consider the benefits against the possible harm of carrying
out any procedure in case of pregnancy known or suspected. See 18FFDG PET section.
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Breast feeding
Breast feeding should be discontinued for 12 h after treatment.
Patient preparation
Patients should fast for 3-4 h as other amino acids can competitively inhibit 18FFDOPA
influx. The administration of 200 mg of carbidopa 1 hr prior 18FFDOPA injection has been
reported to increase tumor uptake but its use is not recommended in the setting of PPGL .
Image acquisition
Timing of imaging and image fields :
Scans are usually obtained from 30 to 60 minutes after tracer injection from base of skull to
mid-thighs (or over the whole-body depending on the clinical setting).
Optional images
- Early acquisition (10 min after tracer injection) centred over the abdomen may be obtained
to overcome difficulties in localizing abdominal PGL located near the hepatobiliary system
due to physiological tracer elimination.
- Early acquisition centered over the neck (from 10 to 20 minutes) may also be performed in
MEN-2 patients with residual hypercalcitoninemia . Medullary thyroid carcinoma lesions
often show rapid washout and are better visualized on these early images .
Image reconstruction
Data acquired in the 3D or 2D mode can be reconstructed directly using a 3D-reconstruction
algorithm or rebinned in 2D data and subsequently be reconstructed with a 2D-reconstruction
algorithm. Iterative reconstruction algorithms represent the current standard for clinical
routine. CT-based attenuation correction (CTAC).
Image analysis
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Visual analysis
Physiological distribution: the striatum, kidneys, pancreas, liver, gallbladder, biliary tract and
duodenum. Adrenal glands can be visible with variable uptake intensity.
Pathological uptake: any non-physiological extra-adrenal focal uptake or asymmetrical
adrenal uptake with concordant enlarged gland or adrenal uptake more intense than liver with
concordant enlarged gland.
Quantification
Various PET-derived quantitative indices were found to be correlated with tumor secretion .
Pitfalls
False positives
False positive cases may be related to tracer uptake by other neuroendocrine tumors including
prolactinomas or other tumor types in very rare situations . Rarely, uptake may be due to
unspecific inflammation (pneumonia, post-operative changes), since high levels of amino acid
transport have also been found in macrophages.
False negatives
SDHx-related PPGLs, mainly those arising from the sympathetic paraganglionic system.
Diagnostic accuracy
In a meta-analysis of 11 studies (275 patients), the pooled sensitivity and specificity on a per
lesion-based analysis of 18FFDOPA PET/CT) in detecting PPGLs were 79% (95% CI 76–
81%) and 95% (95% CI 84–99%), respectively . The most significant factors influencing
visualization of 18FFDOPA-avid foci are tumor location and genetic status. 18FFDOPA
PET/CT is not an MIBG scintigraphy with higher sensitivity but a new specific radiotracer
with its own advantages and limitations . Reported sensivities range from 81-100%.
A special advantage of 18FFDOPA PET/CT over 123IMIBG scintigraphy or other
specific PET tracers stem from its limited uptake by normal adrenal glands . This is
particularly helpful in hereditary PHEO which can be very small in size (e.g., MAX and RET
mutations) . 18FFDOPA PET/CT may also detect residual medullary thyroid carcinoma
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lesions and other syndromic tumors such as pancreatic neuroendocrine tumors that may occur
in VHL patients (especially after carbidopa premedication to decrease the background
activity). Several studies show that 18FFDOPA PET/CT is an excellent first-line imaging tool
in HNPGLs with a sensitivity >90% . This is due to the high avidity of HNPGLs for
18FFDOPA and the absence of physiological uptake in the adjacent structures (excellent
signal-to-noise uptake ratio). The specificity of 18FFDOPA is also very high. Its sensitivity
also approaches 100% in sporadic PHEOs, but can be lower in SDHB/D-related PPGLs . In
VHL-patients, 18FFDOPA PET/CT may detect pancreatic neuroendocrine tumors . In
metastatic disease, 18FFDOPA PET/CT demonstrated better performance in SDHB negative
patients than in SDHB positive patients (sensitivity 93% in carriers without SDHB mutations
vs 20% in patients with SDHB mutations) . Recent studies have shown lower sensitivity
compared to 68GaGa-DOTA-SSA in sporadic HNPGLs and metastatic PPGLs. By contrast,
18F-FDOPA PET/CT is highly sensitive in VHL, EPAS1 (HIF2A), and FH PPGLs .
18FFDG PET
Radiopharmaceutical
18FFDG is commercially available in a “ready to use” formula and conditioned in a sterile
mono- or multi-dose solution for intravenous use.
Mechanism of cellular uptake
18FFDG is taken up by tumour cells via glucose membrane transporters and phosphorylated
by hexokinase into 18FFDG-6P. 18FFDG-6P does not follow further enzymatic pathways
and accumulates proportionally to the glycolytic cellular rate. It is remarkable that PPGL
underlying SDHx mutation are more avid for 18FFDG than other subtypes. This is mainly
due to the accumulation of succinate which could acts as an oncometabolite and both induces
metabolic reprogramming (pseudoypoxia) and activates surrounding stromal tissue . Other
PPGL have variable uptake.
Pharmacokinetics
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After IV administration, 18FFDG is rapidly cleared from the blood, concentrates in brain
(8%), heart wall (4%), lung (3%), spleen (0.3%) and liver (5%). There is also high uptake in
brain. The majority of the 18FFDG is excreted unaltered by the kidneys (20% of the injected
dose is recovered in the urine within 2 h) .
Synthesis and quality control
18FFDG is commercially available or is prepared « in-house » in a “ready to use” form and
conforms to the European and US pharmacopeia.
Drug interactions and side effects
Blood glucose level is measured before administering 18FFDG and thereby should detect any
drug interaction on glucose metabolism. Chemotherapy may change 18FFDG tumour uptake
by altering cellular metabolism. The timing of restaging with PET depends on the therapy
(from 2 to 5 weeks after end of chemotherapy in cases of metastatic tumours).
Recommended activity
2-5 MBq/kg.
Administration
Intravenous
Radiation dosimetry
The effective dose equivalent is 0.019 mSv/MBq . There is an increased radiation dose from
CT in PET/CT protocols, the value being dependent on a parameter scan.
Pregnancy
Clinical decision is necessary to consider the benefits against the possible harm of carrying
out any procedure in case of pregnancy known or suspected. The International Commission
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on Radiological Protection (ICRP) reports that for an adult patient the administration of 259
MBq of 18FFDG results in an absorbed radiation dose of 4.7 mGy to the nongravid uterus
(i.e. 0.018 mGy/MBq) . Direct measurements of 18FFDG uptake in a case study suggested
somewhat higher doses than are currently provided in standard models . A pregnancy test may
help with the decision, provided the 10 day post ovulation blackout is understood. In the event
of doubt and in the absence of an emergency, the 10 day rule should be adopted. In Europe,
national guidelines may apply.
Breast feeding
Breast feeding should be discontinued for 12 h after imaging
Patient preparation
Patients must fast for at least 6 h, prior to 18FFDG injection. PHEO patients with secondary
diabetes (about 35% of cases) require specific instructions for glucose control. During
18FFDG injection and the subsequent uptake phase, patients should remain seated or
recumbent, kept warm, in a darkened and quiet room. The use of any premedication for
reducing brown adipose tissue uptake is contraindicated in the setting of elevated
catecholamine levels due to the associated high risk of hypertensive crisis and
tachyarrhythmia.
Image acquisition
Timing of imaging
Scans are usually obtained at 60 minutes (45 to 90 min) post-injection.
Imaging field
From base of skull to mid-thighs (or whole-body imaging, depending on the clinical setting).
Image reconstruction
Data acquired in the 3D or 2D mode can be reconstructed directly using a 3D-reconstruction
algorithm or rebinned in 2D data and subsequently be reconstructed with a 2D-reconstruction
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algorithm. Iterative reconstruction algorithms represent the current standard for clinical
routine. CT-based attenuation correction (CTAC).
Image analysis
Visual analysis
Physiological distribution: brain cortex, salivary glands, lympathic tissue of the Waldeyer’s
ring, muscles, brown fat, myocardium, mediastinum, liver, kidneys and bladder,
gastrointestinal tract, testis, uterus and ovaries (before menopause). Physiologic 18FFDG
uptake in BAT occurs predominantly in the younger age group. In patients with PHEO, there
is a frequent increase of BAT uptake due to brown adipocyte cell stimulation by
norepinephrine. The level of physiological 18FFDG uptake in normal adrenal glands is low
even after contralateral adrenalectomy for PHEO but contrasts with the enhanced uptake
observed after adrenalectomy for cancer of the adrenal cortex .
Pathological uptake: any non-physiological extraadrenal focal uptake or adrenal uptake more
intense than liver and with concordant enlarged gland.
Quantification
Various quantitative indices can be described. Highly elevated uptake values are observed in
SDHx-related PPGL.
Pitfalls
False positives
In absence of biochemical information, several potential diagnoses should be considered in
cases of highly-avid adrenal masses (especially in the presence of adrenal to liver SUVmax
ratio>2): adrenocortical carcinoma (ACC), primary lymphoma, metastasis, myelolipoma
(uptake by the myeloid tissue component of the mass) and oncocytoma . When masses are
moderately avid for 18FFDG, other etiologies should be considered: adrenal cortex adenoma,
ganglioneuroma, metastasis (small lesions or from cancer with lower malignant potential,
sarcoma), hematoma and adrenocortical hyperplasia. Extra-adrenal uptake can be due to
inflammatory and neoplastic processes.
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False negatives
Non-avid sporadic PHEOs and retroperitoneal extraadrenal PGLs, MEN2-related PHEO,
HNPGL.
Diagnostic accuracy
18FFDG PET positivity is a frequent feature of PPGL. Some features are suggestive of
PHEO such as well-limited tumor without vena cava involvement, unilateral adrenal
involvement, decreased uptake in the central area evidencing parenchymal degeneration (eg.,
cystic, hematoma) and presence of calcifications on unenhanced CT. Uptake may be widely
variable between PHEOs. Sensitivity and NPV are very high (80-100%) but the PPV is lower
due to lack of specificity of 18FFDG. 18FFDG PET/CT is mainly influenced by genetic
status of patients . In cases of MEN-2 related PHEO, 18FFDG PET/CT is 40% sensitive.
18FFDG PET/CT may also detect other syndromic lesions (e.g., GIST, RCC, pancreatic
tumor, medullary thyroid carcinoma, or pituitary tumor) . 18FFDG PET/CT is also more
frequently contributive in metastatic disease with SDHB mutations and might be suboptimal
in other patients (sensitivity per lesion 83% in SDHB positive vs 62% in SDHB negative
cases).
Other Tracers
technetium-99mTc-hydrazinonicotinamide-Tyr(3)-octreotide (99mTcTc-TOC) is
increasingly gaining acceptance as a new radiopharmaceutical for diagnosis of somatostatin
receptor-expressing tumours . 18F-fluorodopamine 18FFDA) has been developed at the
National Institutes of Health in Bethesda, MD and is currently used as an experimental tracer
at the NIH only. 18FFDA is captured by tumor cells via the NE transporter system and stored
in intracellular vesicles. 18FFDA PET/CT seems to be a very promising tool in the
management of PGLs associated with the sympathetic system . 11Chydroxyephedrine
(11CHED) has also been evaluated, but its synthesis is complex and the short half-life of 11C
is a major drawback for its routine clinical use . MIBG analogues for PET imaging have been
used in few studies, but to our knowledge, no clinical studies have yet been reported . The
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influence of some new drugs (histone deacetylase inhibitors) on tracer uptake is also subjet to
investigations .
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SPECT versus PET imaging protocols
123IMIBG and 111InIn-pentetreotide scintigraphy are well-established nuclear imaging
techniques in the staging and restaging of PPGL. SPECT/CT has now become more widely
available and has the advantage of sequential acquisition of both morphological and
functional data, thus increasing diagnostic confidence in image interpretation, disease
localization tovether with enhanced sensitivity. However, these conventional techniques are
associated with some practical constraints including long imaging times and relatively
prolonged uptake times prior to imaging, as well as GI tract artifacts requiring bowel
cleansing, thyroid blockage or need for withdrawal of certain medications that can interfere
with interpretation. The somewhat low resolution of conventional SPECT imaging might also
limit the ability to detect small lesions. Additionally, SPECT does not easily provide a
quantifiable estimate of tumour uptake, although this is being increasingly addressed by
quantitative SPECT/CT. Thus, the use of PET imaging has been growing rapidly in the
imaging of PPGL, paralleled by great efforts towards the development of new highly sensitive
tracers with high affinity for cell membrane transporters and receptors. 18FFDG is the most
accessible tracer and plays an important role in the evaluation of SDHx-related PPGL .
18FFDOPA is also approved in certain countries, but is not FDA-approved in the US. It is,
nevertheless, a sensitive tool in evaluating sporadic and perhaps some metastatic PPGLs.
Other tracers, such as 18FFDA or (11Cmeta-hydroxyephedrine (11CHED) which are very
specific for chromaffin/ganglionic cells but are presently available at only a few centres and
not FDA-approved. 11CHED is limited in use due to the short half-life of 11C. 68GaGa-
DOTATATE, which is FDA-approved or 68GaGa-DOTATOC, which is EMA-approved for
evaluating GEP NETs, as well as other 68GaGa-conjugated SSTAs are currently used in
many centres as first imaging tools for PPGL, regardless of the patient genotype (Table 2).
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Recommendations for clinical practice
Successful PPGL management requires an interdisciplinary team approach. Precise
identification of clinical context and genetic status of patients enable a personalized use of
functional imaging modalities (Table 3). It is expected that the early detection of PPGL with
modern PET imaging will very soon lead to the best staging of these tumors thus minimizing
complications related to mass effect and hormonal excess, facilitating the most appropriate
curative treatment options and reducing the risk of metastatic spread.
Apparently sporadic non-metastatic PHEO
123IMIBG scintigraphy is less sensitive as 18FFDOPA PET/CT and superior to
111InIn-pentetreotide in localizing non-metastatic sporadic PHEO. However, 123IMIBG
scintigraphy or 18FDOPA PET/CT appear sufficient to confirm the diagnosis of large
sporadic PHEO even in rare cases of non-hypersecreting PHEO. 18FFDOPA PET/CT
imaging has less practical contraints than 123IMIBG scintigraphy and has no drug
interactions, which can be limiting for PHEO detection. 18FFDG can provide with genotypic
information which is tightly linked to their tumor behavior (i.e., SDHB).
HNPGL
18FFDOPA and 68GaGa-DOTA-SSAs appear to be the most sensitive PET
radiopharmaceuticals in sporadic cases. In SDHx-patients, 68GaGa-DOTA-SSA PET/CT can
reveal very small tumors, which can be missed by 18FFDOPA PET/CT. In the absence of
18FFDOPA or 68GaGa-DOTA-SSA PET/CT, SRS may be used as an alternative approach,
considering the limitations given by spatial resolution of SPECT. 18FFDG PET has high
sensitivity in the setting of SDHx-related HNPGLs and can complement 18FFDOPA PET/CT
for detecting additional thoracic/abdominal PGLs.
Retroperitoneal extraadrenal non-metastatic PGL
In the case of a retroperitonal extra-adrenal non-renal mass, imaging should enable
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differentiation of PGL from neurogenic tumors, lymph node diseases, or mesenchymal
tumors. Therefore, the specificity of functional imaging provides an important contribution.
Once the diagnosis of PGL has been established, multiplicity of extra-adrenal localizations
should be considered. To this purpose, 18F-FDOPA and 68GaGa-DOTA-SSAs are more
specific than 18FFDG and can show more lesions than 18FFDG. Therefore, at present,
68GaGa-DOTA-SSA PET/CT is probably the preferred imaging modality, especially in the
patients who harbor SDHx mutations.
Metastatic PPGL
18FFDOPA shows very good results in detecting metastatic lesions in patients with sporadic
PPGL. However, its sensitivity decreased in presence of SDHx mutations. 68GaDOTA-SSA
has shown better results that 18FFDOPA, regardless of the genetic background and therefore
is is becoming the imaging modality of choice for metastatic PPGL. It can also determine if a
patient is likely to benefit from PRRT. 18FFDOPA PET/CT may be the second-line imaging
modality in the absence of SDHB mutations, or when genetic status is unknown. 18F-FDG
PET/CT is the second line imaging modality of choice for SDHB-related metastatic PPGLs.
123IMIBG may lead to significant underestimation of metastatic disease with potential to
inappropriately guide management. 123IMIBG and 18FFDOPA images do not completely
overlap. Furthermore, 123IMIBG is a theranostic radiopharmaceutical and can be used to
determine if a patient is eligible for 131IMIBG therapy. The clinical benefit obtained with
high-specific-activity MIBG (Azedra®) in patients with metastatic and/or recurrent and/or
unresectable PPGL gives a new impetus toward of MIBG scan for in vivo detection of the cell
membrane norepinephrine transporter system. This medication has recently received FDA
approval. Although not widely available, the PET-equivalent, 124IMIBG would have
significant advantages in terms of spatial resolution and quantitative capability for prospective
dosimetry.. The main purpose of 123I-MIBG scintigraphy is to determine if a patient is eligible
for 131I-MIBG therapy.
VHL and RET (MEN2)-related PPGL
Limited data is available from the literature with respect to imaging studies in VHL and RET
patients. Many of RET patients do not need any specific functional imaging since the tumours
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are almost always confined to the adrenal gland with very low risk of malignancy. For VHL,
nuclear imaging enables detection of adrenal and extra-adrenal PGL. 123IMIBG scintigraphy
can be used in the detection of these tumours, but sensitivity and specificity are suboptimal.
The absence of high 18F-FDOPA uptake by healthy adrenal glands is an interesting feature in
the diagnosis, staging and restaging of VHL/RET-related PHEO. 18FFDG PET is also not
sufficiently sensitive in this clinical setting. In both disorders, if possible, subtotal
adrenalectomy (cortical-sparing surgery) is the treatment of choice . Therefore, follow-up
should not be delayed beyond the scheduled time for cortical-sparing surgery and
18FFDOPA PET/CT together with MRI can help in preoperative mapping PHEO within both
adrenals and guide the suregons towards the most appropriate (feasible) approach.
Screening of SDHx-mutation carriers
The transmission of disease is also different across PPGL syndromes. Regarding SDHD
and SDHB, although both are autosomal dominant diseases, they have different disease
penetrance. Transmission of SDHD-related PPGL is modulated by maternal imprinting (i.e.,
the disease almost always occurs only when the mutations are inherited from the father).
SDHD-related mutations (paternally inherited) have very high overall penetrance (>80%), in
contrast to SDHB ones that have an estimated penetrance of only 20-40% . A lower SDHD
disease penetrance may be observed in studies that included low severity mutations .
The optimal follow-up algorithm has not yet been validated in non-proband SDHx-
PPGL but most likely requires a more frequent and complete imaging work-up than for their
sporadic counterparts. The aim is to detect tumors at early stages of development, thereby
minimizing tumor extension and new cranial nerve impairment for SDHD , facilitating
curative treatment, and potentially reducing the occurrence of metastases, especially in more
aggressive genotypes. The reduction of radiation exposure as a dogma from CT and/or
radiopharmaceuticals can be counterproductive. At initial staging, the use of PET imaging
should provide an adequate sensitivity and specificity at whole body scale with limited
radiation exposure and very low, if any, risks (2-2.5 mSv for radiopharmaceutical, 1-3 mSv
for CT). Based on clinical studies, 68GaGa-DOTA-SSAs PET should be prioritized if
available over 18FFDOPA PET, although its indication has not been specifically studied in
this setting non-proband SDHx cases. In absence of PPGL, follow-up should include annual
biochemical screening, and MRI at regular time intervals .
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Legends
Table 1. Characteristics of the various hereditary PPGL
First manifestation
Context at presentation (in index cases)
PHEO at presentation
Additional extra-adrenal PGL
Biochemical phenotype
Malignancy risk
Other tumor types
MEN2 MTC Adult Possible phenotypic features of MEN-2Frequent family history of MTC/PHEO
Uni- or bilateral Very rare EPI Very low Parathyroid adenoma/hyperplasia (MEN-2A)
NF1 Neurofibromas Adult Phenotypic feature of NF-1Possible family history of NF-1
Often unilateral Very rare EPI Very low Peripheral nerve sheath tumors, optic gliomaa
MAX PHEO Young adultFrequent family history of PHEO
Bilateral Uncommon EPI and NE Moderate Renal oncocytoma
VHL PHEO/PGL Young adult Frequent family history of PPGL
Uni- or bilateral Moderate(retroperitoneum)
NE Low Multipleb
SDHA PHEO/PGL AdultVery rarely family history of PPGL
Rare Moderate (retroperitoneum or head and neck)
NE and/or DA
Moderate GIST, RCC
SDHB PHEO/PGL AdultPossible family history of PPGL
Often unilateral Frequent(retroperitoneum)
NE and/or DA
High GISTc, pituitary adenoma, RCC
SDHD PHEO/PGL AdultFrequent family history of HNPGL
Uni- or bilateral Frequent(head and neck)
NE and/or DA
Moderate GISTc, pituitary adenoma, RCC
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SDHC PHEO/PGL AdultRarely family history of PHEO/PGL
Rare Frequent(mediastinum)
NE Low/Moderate GISTc, RCC
HIF2A polycythemia(often at birthor earlyin childhood)
Adolescent-young adultfemalesAbsence of family history of PPGL
Very rare Expected(retroperitoneum)
NE High Somatostatinomas
aNF-1 is characterized by the presence of multiple neurofibromas, café-au-lait spots, Lisch nodules of the iris and other rare disorders.
bNon-KIT/PDGFRA gastrointestinal stromal tumors (GISTs) may be caused by mutations in the SDHB, SDHC and SDHD genes and be associated with PGL in the Carney-Stratakis syndrome.
cVon Hippel-Lindau disease is an autosomal dominant disorder, which also predisposes to renal tumors and clear cell carcinoma, pancreatic serous cystadenomas, pancreatic neuroendocrine tumours, testicular tumors, hemangioblastoma of the eye and central nervous system.
dHIF2A-related PHEOs/PGL are associated with the presence of duodenal somatostatinoma and retinal abnormalities (Pacak-Zhuang syndrome)
EPI: epinephrine, NE: norepinephrine, DA: dopamine.
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Table 2. PPGL radiopharmaceuticals
Tracer Molecular target Retention123IMIBG, 18FFDA or 11CHED Norepinephrine
transporterNeurosecretory vesicles
18FFDOPA Neutral amino acid transporter System L
(LATs)
Decarboxylation (AADC)and retention in neurosecretory
vesicles as 18FFDA68GaGa-SSA Somatostatin receptors Internalization (agonists)
18FFDG Glucose transporters (GLUTs)
Phosphorylation (hexokinase)
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Table 3. Clinical algorithm for nuclear imaging investigations of PPGL
1st-choice 2nd-choice 3rd-choice
(If 18F-FDOPA or 68GaGa-
SSA not available)
PHEO (sporadic) 18FFDOPA
or
or 123IMIBG
68GaGa-SSA 18FFDG
Inherited PHEO (except
SDHx) : NF1/RET/VHL/MAX18FFDOPA 123IMIBG or 68GaGa-
SSA
18FFDG
HNPGL (sporadic) 68GaGa-SSA 18FFDOPA 111InIn-SSA /99mTcTc-SSA
Extraadrenal sympathetic
and/or multifocal and/or
metastatic and/or SDHx
mutation
68GaGa-SSA 18FFDG and
18FFDOPA
18FFDG and 123IMIBG or
18FFDG and
111InIn-SSA /99mTcTc-SSA
Based on the above considerations, the following algorithm can be proposed based on clinical situations. This algorithm should be adapted to the practical situation in each institution, and should evolve with time.
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