eanm guidelines for radionuclide imaging of...

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EANM/SNMMI 2019 guidelines for radionuclide imaging of pheochromocytoma and 1

paraganglioma 2

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David Taïeb1, Rodney J Hicks2, Elif Hindié3, Benjamin A. Guillet4, Anca Avram5, Pietro 4

Ghedini6, Henri J. Timmers7, Aaron T Scott8, Saeed Elojeimy9, Domenico Rubello10, Irène J 5

Virgolini11, Stefano Fanti6, Sona Balogova12,13, Neeta Pandit-Taskar14, Karel Pacak15 6

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1. Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-8

Marseille Univ, France. 9

2. Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, 10

Australia. 11

3. Department of Nuclear Medicine, Bordeaux University Hospitals, Hôpital Haut-12

Lévêque, Pessac, France. 13

4. Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-14

Marseille Univ, France. 15

5. Nuclear Medicine/Radiology, University of Michigan, Ann Arbor, USA 16

6. Nuclear Medicine Unit, Medicina Nucleare Metropolitana, University Hospital 17

S.Orsola-Malpighi, Bologna. 18

7. Department of Endocrinology, Radboud University Nijmegen Medical Centre, 19

Nijmegen, The Netherlands. 20

8. John Hopkins hospital, Baltimore, USA. 21

9. Department of Radiology, University of New Mexico, Albuquerque, NM. 22

10. Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics, 23

Clinical Laboratory, Microbiology, Pathology, Trasfusional Medicine, Santa Maria 24

della Misericordia Hospital, Rovigo, Italy. 25

11. Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 26

6020, Innsbruck, Austria. 27

12. Department of nuclear medicine, Comenius University and St.Elisabeth oncology 28

institute, Heydukova 10, 81250 Bratislava, Slovakia. 29

13. Department of Nuclear Medicine, Hôpital Tenon Assistance Publique-Hôpitaux de 30

Paris and Sorbonne University, Paris, France. 31

14. Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan 32

Kettering Cancer Center, New York, USA. 33

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15. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National 1

Institutes of Child Health and Human Development, National Institutes of Health, 2

Bethesda MD, USA. 3

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Correspondence: Prof David Taïeb, M.D., Ph.D. 6

Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-7

Marseille Univ, France: +33-4-91-38-55-58, Fax: +33-4-91-38-47-69, david.taieb@ap-8

hm.fr 9

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Running title: Imaging of pheochromocytoma and paraganglioma 11

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Keywords: Guidelines, radionuclide imaging, paraganglioma, pheochromocytoma, 13

radionuclide therapy, PET, SPECT, somatostatin analogs, nuclear, gene, hypoxia, hereditary 14

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mailto:[email protected]

mailto:[email protected]

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Abbreviations 1

2

PPGL = pheochromocytoma and paraganglioma, HNPGL = head and neck paraganglioma; 3

RET = rearranged during transfection proto-oncogene ; VHL= von Hippel-Lindau ; SDH = 4

succinate dehydrogenase; SDHA, -B, -C, -D, = succinate dehydrogenase subunits A, B, C, 5

and D; SDHx = succinate dehydrogenase subunits; NF1 = neurofibromin 1; MAX = myc-6

associated factor X; EGLN2/PHD1 = egl-9 family hypoxia-inducible factor 2; 7

EGLN1/PHD2= egl-9 family hypoxia inducible factor 1; TMEM127 = transmembrane 8

protein 127; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 9

2α, FH= fumarate hydratase, SSAs = somatostatin analogues; MIBG = 10

metaiodobenzyguianidine; RCC = renal cell carcinoma; GIST = gastroinstestinal stromal 11

tumor; MTC = medullary thyroid carcinoma ; WHO = World Health Organization ; MEN = 12

multiple endocrine neoplasia; BAT = brown adipose tissue ; NPV = negative predictive 13

value; PPV = positive predictive value; NE = norepinephrine; EPI = epinephrine; DA = 14

dopamine; NET = neuroendocrine tumor; GI = gastrointestinal; SRS = somatostatin receptor 15

scintigraphy ; COMT = catechol-O-methyltransferase; AADC = aromatic L-amino acid 16

decarboxylase. 17

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Abstract 1

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There are diverse radionuclide imaging techniques available for the diagnosis, staging 3

and follow-up of pheochromocytoma and paraganglioma (PPGL). Beyond their ability to 4

detect and localize disease, these imaging approaches variably characterize these tumors at 5

cellular and molecular levels and can guide therapy. In particular, the excellent results 6

obtained with gallium-68(68Ga)-labelled somatostatin receptor analogs (SSAs) in recent years 7

have simplified the imaging approach that can also be used for selecting patients for peptide 8

receptor radionuclide therapy (PRRT) as a potential alternative or complement to the 9

traditional theranostic approach with iodine-123(123I)- or iodine-131(131I)-labelled meta-iodo-10

benzyl-guanidine (MIBG). Genomic characterization of subgroups with differing risks of 11

developing lesions and of subsequent metastatic spread are refining the use of molecular 12

imaging for surveillance of patients in combination with catecholamine assays. 13

The purpose of the present guidelines is to assist nuclear medicine practitioners in selecting, 14

performing, interpreting, and reporting the results of the currently available SPECT and PET 15

imaging procedures. Guidelines from related fields and relevant literature have been taken 16

into consideration in consultation with leading experts involved in the management of PPGL 17

patients. The information provided should be taken in the context of local laws and 18

regulations as well as availability of various radiopharmaceuticals. 19

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Purpose 21

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The purpose of these guidelines is to assist nuclear medicine practitioners in: 23

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1. Understanding the role and challenges of radionuclide imaging of PPGL. 25

2. Providing practical information for performing different imaging procedures for these 26

tumors. 27

3. Providing an algorithm for selecting the most appropriate imaging procedure in 28

specific clinical situations. 29

30

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Background information and definitions 1

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Tumor origin and location 3

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Pheochromocytoma (PHEO) and paraganglioma (PGL) belong to the same family of 5

neural crest-derived neoplasms (also called PPGL). PPGLs occur with a frequency of up to 6

1:500 in patients with hypertension and up to 1:1000 in unselected post-mortem studies [1]. 7

They are widely distributed from the skull base to the pelvis but almost uniquely develop in 8

close relationship with the sympathetic and parasympathetic divisions of the autonomic 9

nervous system. The sympathetic axis includes the adrenal medulla and chromaffin cells 10

located in posterior mediastinum (in the periaortic regions), or the retroperitoneum, while the 11

parasympathetic paraganglia are mainly located in the head and neck region and 12

anterior/middle mediastinum. Based on the classification published in 2004 by the World 13

Health Organization (WHO), the term pheochromocytoma should be reserved solely for 14

adrenal PGL [2]. The term PGL is used to describe extradrenal tumors, regardless of their 15

location (sympathetic or parasympathetic). 16

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Clinical presentation 18

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PHEO accounts for about 4% of adrenal incidentalomas. However, since their 20

prevalence is higher in autopsy series, there is probably underdiagnosis during life. PHEO 21

usually causes symptoms of catecholamine oversecretion (e.g., sustained or paroxysmal 22

elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor, and 23

apprehension or anxiety). By contrast, head and neck PGLs are often incidentally discovered 24

on imaging studies or are revealed by symptoms and signs of compression or infiltration of 25

adjacent structures (e.g., hearing loss, tinnitus, dysphagia, cranial nerve palsies). 26

27

Spectrum of hereditary syndromes 28

29

Around 5-10% of solitary PHEOs are hereditary, whereas the presence of multiple 30

PHEOs or the combination of a PHEO with synchronous or metachronous extra-adrenal PGL 31

are related to currently known germline/somatic mutations in more of 70% of cases. These are 32

now recognized to be caused by at least 16 susceptibility genes [3]. 33

Most important correlations between the gene(s) involved and a specific tumor 34

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anatomical predispostion have been found as described below: 1

1: PHEO: RET, VHL, SDHx, NF1, MAX, TMEM127,and EPAS1/HIF2A . 2

2: Sympathetic-PGLs: SDHx, VHL, RET, PHD1/2 and EPAS1/HIF2A (somatic 3

mutation). 4

3: Head and neck PGL (HNPGL): SDHx. 5

Major predictors for hereditary PPGL include a family history of PPGL, characteristic 6

syndromic presentation, young age at diagnosis, a previous personal history of PPGL, 7

multifocality, unusual location (e.g. heart, urinary bladder), and/or tumor recurrence, 8

particularly in the adrenal gland and a combined elevation of normetanephrine and 3-9

methoxytyramine [4, 5]. Renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), 10

pituitary adenoma and, rarely, pulmonary chondroma, neuroblastoma and neuroendocrine 11

neoplasms (carcinoids) can also be related to SDHx mutations [6-8]. Other manifestations can 12

also be suggestive of certain gene mutations. For example, prior medullary thyroid cancer 13

(MTC) for RET, café-au-lait spots/neurofibromas for NF1, renal cell carcinoma 14

(RCC)/hemangioblastomas/pancreatic tumors for VHL, congenital polycythemia and 15

duodenal somatostatinoma for EPAS1/HIF2A, and RCC/leiomyomas for FH (Table 1). 16

17

Furthermore, PPGL with an underlying SDHB mutation are associated with a higher 18

risk of aggressive behavior leading ultimately to death, particularly due to the development of 19

metastatic disease. The risk of malignancy in SDHB mutation-associated tumors has been 20

estimated to range from 31% to 71%. In addition to impacting the distribution of disease, the 21

genomically-distinct subgroups of PPGLs have different patterns of catecholamine secretion 22

and the expression of cell membrane receptors and transporters, which impact their imaging 23

phenotype, particularly the uptake of catecholamines or their precursors [9]. 24

Clinical indications for nuclear imaging 25

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Confirmation of diagnosis of PPGL 27

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The diagnosis of PHEO is often based on the presence of high levels of plasma or 29

urinary metanephrines and methoxytyramine in combination with suspicious characteristic 30

clinical features. Some specific radiologic features of anatomic imaging (CT/MRI) may also 31

be suggestive of the diagnosis [10]. Typically, a PHEO demonstrates avid enhancement but 32

can have a heterogeneous appareance due to cystic, necrotic, or fibrotic regions within the 33

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lesion. In cases of a non-secreting adrenal mass, the high specificity of functional imaging 1

may sometimes contribute to its diagnosis. 2

In the presence of a retroperitonal, extra-adrenal non-renal mass, it is important to 3

differentiate a PGL from other tumors or lymph node involvement including metastases. 4

Although specific functional imaging is very helpful to distinguish PGL from other tumors, it 5

is usually not done before biochemical results are available. 6

In head and neck locations, there are also many differential diagnoses such as lymph 7

node metastasis, neurogenic tumors (e.g. schwannoma, neurofibroma, ganglioneuroma), 8

jugular meningioma, internal jugular vein thrombosis, internal carotid artery aneurysm, 9

hemangioma and vascular malposition. 10

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Staging at initial presentation of PPGL 12

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Generally, PPGLs are benign and progress slowly. Metastatic rates vary from less than 14

1% to more than 70%, depending on tumor location, size, biochemical phenotype and, 15

particularly, genetic background. Functional imaging is probably not necessary in the 16

preoperative work-up of patients meeting the following criteria: > 40 yrs, absence of a family 17

history, small (less than 3.0 cm), no multiplicity, adrenergic biochemical phenotype (uniquely 18

pointing towards a tumor in the adrenal gland only) and negative genetic testing. Since the 19

genetic status is often not available before surgery, the presence of multifocal or metastatic 20

disease, substantial locoregional extension, or extremely high methoxytyramine levels calls 21

for nuclear imaging, which is very useful in this regard since it may point towards SDHx 22

mutation. HNPGLs require a specific approach and although metastatic disease is rare, 23

locoregional extension and multifocality are common and often warrant the use of functional 24

imaging modalities as well as detailed anatomical correlation with arterial and venous phase 25

CT or MRI. Early treatment is crucial since most of these tumors become difficult to resect if 26

they are large or involve the skull base. 27

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Restaging and follow-up 29

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Nuclear imaging may be used for restaging following completion of treatment of 31

aggressive tumors or as follow-up of non-secretory and asymptomatic lesions. It can also 32

localize occult tumor sites in cases of positive biochemical results, suspicion of disease 33

recurrence or to clarify equivocal findings on anatomic imaging. PPGLs associated with 34

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adverse pathological features, and/or large tumors, elevated methoxytyramine/dopamine 1

and/or the presence of specific germline/somatic mutations should alert a clinician to carry 2

out extended and prolonged (often lifelong) monitoring. In HNPGL, anatomical identification 3

of tumor remnants or recurrences can be difficult after treatment due to postoperative or 4

radiation-induced morphological changes (e.g., fibrosis, edema, necrosis, or presence of 5

surgical material). Conversely, nuclear imaging using specific radiopharmaceuticals is only 6

minimally influenced by the post-treatment sequelae and therefore, enables accurate diagnosis 7

of tumor recurrences that could be missed by structural imaging [11]. Nuclear imaging can 8

also be helpful in assessing responses to therapies in metastatic or in inoperable PPGL. 9

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Selection for targeted molecular radiotherapy 11

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Recently, the success of PRRT with 177Lu Lu-DOTATATE (oxodotreotide) or other 13

90Y or 177Lu radiolabeled somatostatin analogs in patients with inoperable/metastatic GEP 14

NET has given a great impetus toward the use of PRRT for inoperable/metastatic PPGL. 15

Nuclear imaging (PET or SPECT) gives valuable information when planning targeted 16

radionuclide therapy with radiolabeled 131IMIBG or PRRT with 177LuLu-DOTATATE or 17

other related agents [12]. Besides confirming uptake in lesions, it also helps in personalized 18

dosimetric evaluation of at-risk organs and tumor target. 19

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Radiotherapy planning 21

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Nowadays, integration of multi-modality imaging into radiotherapy planning has 23

brought greater precision to the delivery of radiation. Molecular imaging can complement 24

MRI in difficult situations (especially in the evaluation of venous extension from large 25

jugular PGL or tumor reccurences in the surgical bed) and, therefore, could lead to a more 26

accurate definition of biological target volumes, thereby potentially decreasing the likelihood 27

of complications within surrounding normal tissues. This is particularly true for stereotactic 28

radiosurgery, which enables highly elevated biological effective dose delivery to the tumor. 29

Useful Clinical information for optimal Imaging and interpretation 30

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A nuclear medicine physician should obtain the following information whenever possible: 32

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1. Personal history of PPGL and/or other tumors. 1

2. Personal history of surgery, chemotherapy, and radiotherapy (including timing and 2

frequency). 3

3. Known genetic mutation or documented family history of PPGL. 4

4. Results of PPGL-related laboratory tests (metanephrines, methoxytyramine, 5

calcitonin, chromogranin A). 6

5. Results of previous anatomic and functional imaging modalities (including baseline 7

and nadir on-treatment imaging for the assessment of tumor response(s)). 8

6. Drugs (e.g. proton pump inhibitors, histamine type-2 receptor antagonists) or 9

conditions (gastric disorders, impaired kidney function, chronic heart failure, 10

hypertension, rheumatoid arthritis, inflammatory bowel disease, non-neuroendocrine 11

neoplasms) that may interfere with the accuracy of procedures and measurements 12

(particularly for chromogranin A). 13

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General considerations for image acquisition and interpretation: 15

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1. PPGL have different preferential sites of origin that must be known. The integration of 17

functional and anatomical imaging on hybrid SPECT/CT or PET/CT devices is 18

strongly preferred. 19

2. Images are usually acquired from the top of the skull (for a large jugular PGL) to the 20

pelvis. In case of suspicion of recurrent or metastatic disease, whole-body images are 21

needed. 22

3. Malignancy is defined only by the presence of metastases at sites where chromaffin 23

cells are normally absent (according to current 2017 WHO Classification of Tumours 24

of Endocrine Organs, this includes only bones and lymph nodes). 25

4. The presence of retroperitoneal PGL or multifocal tumors increases the chance of 26

hereditary syndrome and requires extensive search for additional PPGL and any other 27

syndromic lesions (e.g., most commonly GIST, RCC, pancreatic tumor, 28

hemangioblastoma, medullary thyroid carcinoma, pituitary adenoma, neuroblastoma, 29

somatostatinoma, and/or pancreatic tumor). 30

5. All non-physiologic and suspicious foci of tracer uptake must be described since PGL 31

may arise in various atypical locations (e.g., orbital, intrathyroidal, hypoglossal, 32

cardiac, pericardial, gallbladder, urinary bladder, liver, cauda equina). 33

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6. Metastases from PPGL are often small and numerous and could be difficult to 1

precisely localize on co-registered CT images of combined SPECT/CT and PET/CT 2

(unenhanced procedure, thick anatomical sections, or positional shift between CT and 3

PET images). 4

5

General points to consider while reporting: 6

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1. The clinical setting and the clinical question that is raised. 8

2. Details of patient preparation, including concomitant drugs that were withheld. 9

3. The procedure: radiopharmaceutical, activity administered, acquisition protocol, CT 10

parameters in case of hybrid imaging and patient exposure, including the 11

radiopharmaceutical dose and the CT parameters of radiation exposure (volume 12

computed Tomography Dose Index/CTDIVOL, Dose-Lengh Product/DLP). 13

4. The positive findings and interpretation for each anatomical region (i.e., head and 14

neck, chest, abdomen and pelvis, bone/bone marrow). 15

5. Comparative data analysis with other imaging studies or previous nuclear imaging. 16

6. Conclusion: The report should present findings in terms of their consistency with a 17

particular diagnosis followed by a listing of study limitations. When conclusive 18

evidence requires additional diagnostic functional or morphologic examinations or an 19

adequate follow-up, this request should be included in the report as could suitability 20

for radionuclide therapy in the case of metastatic disease. Where a hereditary 21

syndrome is suggested, the implications for genetic testing could be raised. 22

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123I-Iobenguane/123I-Metaiodobenzylguanidine scintigraphy 1

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Radiopharmaceutical 3

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MIBG is commercially available labeled with 123I or 131I. 123IMIBG scintigraphy is highly 5

preferable to 131IMIBG scintigraphy because (a) it provides higher-quality images (the 159 6

keV emission of 123I is better adapted to detection with conventional gamma cameras); (b) the 7

lower radiation burden of 123I allows a higher permissible administered activity, resulting in a 8

higher count rate; (c) SPECT can more feasibly be performed with 123I; (d) less time elapses 9

between injection and imaging with 123IMIBG scintigraphy (24 hours) than with 10

131IMIBG scintigraphy (48–72 hours). Nevertheless, ]IMIBG might not be available to 11

every nuclear medicine facility. Although 131IMIBG can be used in such circumstances, it is 12

not recommended because of low sensitivity and unfavourable dosimetry. 13

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Mechanism of cellular uptake 15

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MIBG, an iodinated analog of guanidine, is structurally similar to NE. Guanidine analogues 17

share the same transport pathway as norepinephrine via the cell membrane NE transporter 18

(NET) system. A non-specific uptake has also been reported for MIBG uptake in PPGL 19

tissues [13, 14]. In the cytoplasmic compartment, MIBG is stored in the neurosecretory 20

granules via vesicular monoamine transporters 1 and 2 (VMAT 1, 2) [15]. MIBG specifically 21

concentrates in tissues expressing catecholamine-secreting tumors, allowing specific detection 22

of other neuroendocrine tumors and, to some degree, in the normal adrenal medulla. 23

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Pharmacokinetics 25

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After IV administration, MIBG concentrates in liver (33%), lungs (3%), heart (0.8%), spleen 27

(0.6%) and salivary glands (0.4%) [16]. In the vascular compartment, the small amount of the 28

remaining MIBG concentrates in platelets through the serotonin (5HT) transporter. Tracer 29

uptake in the normal adrenal glands is weak; the normal adrenals can be faintly visible, 30

especially using 123IMIBG. The majority of MIBG [16] is excreted unaltered by the kidneys 31

(60-90% of the injected dose is eliminated via urine within 4 days from the day of its 32

administration; 50% within 24h), fecal elimination is minor (<2% up to day 4). In PPGL 33

12

patients, uptake in heart and liver is lowered by approximately 40%, most likely as a 1

consequence of competition with circulating catecholamines [17]. 2

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Synthesis and quality control 4

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MIBG labeled with 123I or 131I is currently commercially available in a “ready to use” 6

formulation that conforms to the European/US Pharmacopeia. The labeled product is 7

available in a sterile solution for intravenous use. The solution is colorless or slightly yellow, 8

contains 0.15-0.5 mg/ml of MIBG, is stable 60 h after synthesis and can be diluted in sterile 9

water or saline. The activity of MIBG should be measured in a calibrated ionization chamber, 10

and radiochemical purity can be evaluated using thin-layer chromatography (TLC). 11

12

Drug interactions 13

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Many drugs modify the uptake and storage of MIBG and may interfere with MIBG 15

scintigraphy [18]. It should be underlined that most of the therapeutic pharmaceuticals 16

introduced in the last 25 years and in common use today have never been tested for effect on 17

MIBG uptake [19, 20]. Reported interfering agents include opioids, tricyclic or other 18

antidepressants, sympathomimetics, antipsychotics and antihypertensive agents [21-23]. 19

Labetalol, for example, has been reported to cause false negative scans and should be stopped 20

more than 10 days prior to MIBG administration if a patient’s clinical status allows that [24, 21

25]. A single oral dose of amytriptiline, a tricyclic antidepressant, significantly enhanced 22

cardiac MIBG washout and compete on the NET with catecholamines resulting in less 23

accumulation of MIBG in PPGL [26]. Post-therapy MIBG scintigraphy failed to detect the 24

vast majority of metastatic PPGL lesions in a polytoxicomanic patient in whom the diagnostic 25

scan was positive [27]. Nifedipine, on the other hand, can cause prolonged retention of MIBG 26

in PPGL [28]. Calcium antagonists are usually listed as medications that interfere with MIBG 27

uptake, but a definitive proof is lacking and probably it is not necessary to withdraw them 28

[19]. Very high serum catecholamines levels may be associated with a lower MIBG 29

accumulation [29-32]. To date, many of these interactions are suspected according to in 30

vitro/preclinical observations or only expected according to their pharmacological properties 31

and thus should be interpreted with caution. Furthermore, mechanisms involved in MIBG 32

uptake or retention may differ between models. For example, specific uptake of MIBG is 33

mediated by 5HT transporters in platelets and by NET in PPGL. 34

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1

Side effects 2

• Rare adverse events (tachycardia, pallor, vomiting, abdominal pain) can be minimized 3

by slow injection. 4

• No adverse allergic reactions is expected, although a single case has been reported 5

with 131IMIBG [33]. 6

7

Recommended activity 8

9

131IMIBG: 40-80 MBq (adult), 123IMIBG: 200-400 MBq (adult). Radioactive activity 10

administered to children should be calculated on the basis of a reference dose for an adult, 11

scaled to body weight (for 123IMIBG : 5.2 MBq/kg with a minimum of 37 MBq and a 12

maximum of 370 MBq for the North American consensus guidelines and a maximum of 400 13

MBq for the EANM paediatric dosage card) ; for 123IMIBG : 35-78 MBq [23]. 14

15

Administration 16

17

Intravenous injection. Slow injection is recommended (over at least 1 minute). 18

19

Radiation dosimetry 20

21

The effective dose is 0.013 mSv/MBq for 123IMIBG and 0.14 mSv/MBq for 131IMIBG in 22

adult and is 0.037 mSv/MBq for 123IMIBG and 0.43 mSv/MBq for 131IMIBG in children 23

(5 years) [34]. There is an increased radiation dose from CT in SPECT/CT protocols, the 24

value being dependent on parameter scan. 25

26

Pregnancy 27

28

The use of radiopharmaceuticals is generally contraindicated in pregnancy. However, if 29

clinically necessary, a decision to perform imaging should be based on the benefits against the 30

possible harm to fetus from the procedure in case of pregnancy, whether known or suspected. 31

Proper institutional and local guidelines should be followed in relation to radiation effects. 32

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Breast feeding 1

2

Breast feeding should be discontinued for at least 3 days after scintigraphy using 123IMIBG 3

non-contaminated by 124I or 125I. Breast feeding should be stopped completely when using 4

131IMIBG. 5

6

Renal insufficiency 7

8

Reduced plasma clearance of 123IMIBG occurs in patients with renal insufficiency and is not 9

cleared by dialysis [35]. Therefore, reduced administered activity by 50% should be 10

considered and possible delayed imaging is recommended. 11

12

Patient preparation 13

14

• Thyroid blockade (130 mg/day of potassium iodine; equivalent to 100 mg of iodine) 15

started one day before tracer injection and continued 7-10 days for 131IMIBG [36], 16

but use of this agent for diagnostic imaging is strongly discouraged. Potassium 17

perchlorate may be substituted for Lugol’s iodine in iodine-allergic patients and 18

started 4 hours before tracer injection and continued for 2 days (400-600 mg/day). 19

• Discontinuation of drugs interfering with MIBG uptake and retention (as mentioned in 20

prior section). All have to be withheld for 1–3 days, except for labetalol, which should 21

be discontinued 10 days prior, and antipsychotics, for which the withdrawal period 22

should be about 3-4 weeks. Regarding antipsychotic medications, it can be dangerous 23

to stop these medications, despite their potential effects on MIBG uptake. Therefore, 24

this should only be performed based on a very careful consultation with the patient’s 25

psychiatric care team. 26

• Decision to discontinue other medication should be weighed with the clinical setting 27

and in very good coordination with the managing clinician. 28

29

Image acquisition and reconstruction 30

31

123IMIBG scans should be obtained approximately 24 hours after tracer injection. 32

• Imaging parameters 33

15

Anterior and posterior planar static images of the head and neck (+ right and left lateral 1

oblique views), thorax, abdomen and pelvis are obtained for 10-15 minutes per image (or 2

about 500 kcounts) (using a 256 × 256 matrix, with a large-field-of-view camera, a low-3

energy collimator, and with a 20% window centered at the 159 keV photopeak). Whole-body 4

images can be an alternative to planar views and include anterior and posterior acquisitions 5

into 1024 x 512 word or 1024 x 256 word matrix for a minimum of 30 min (speed 6 cm/min 6

max) [37]. 7

Many centers prefer medium energy collimators because they reduce scatter and septal 8

penetration yields of high energy photons that are part of the 123I decay scheme. However, 9

longer acquisition times required with medium-energy collimators. 10

SPECT (SPECT/CT) over the anatomical regions showing pathological tracer uptake on 11

planar images often complete the image session and can replace lateral oblique planar images 12

of the head and neck region. The SPECT images are performed for a 360° orbit (128 × 128 13

word matrix, 6-degree angle steps, 30-45s per stop). Co-registered CT images (100-130kV, 14

mAs modulation recommended) from SPECT/CT cameras enable attenuation and facilitate 15

precise localization of any focus of increased of tracer. 16

17

• Reconstruction 18

19

Iterative SPECT reconstruction or other validated reconstruction protocols that accurately 20

visualize lesions can be adapted to the clinical setting. CT-based attenuation correction 21

(CTAC) is used for SPECT/CT. 22

23

Imaging interpretation 24

25

• Visual analysis 26

Physiological distribution: Normal uptake of 123IMIBG is observed in myocardium, salivary 27

glands, lacrimal glands, thyroid gland, liver, lungs, adrenal glands (slight uptake can be seen 28

in up to 80% of cases), bowel and uterine uptake during menstrual period. 123IMIBG uptake 29

in the adrenal glands is considered normal if mild (less or equal to liver uptake), symmetric 30

and when the glands are not enlarged on CT. Large intestinal activity may also be visible, 31

especially at later imaging times. Brown adipose tissue (BAT) uptake should be considered as 32

a normal distribution of MIBG. Although this may be more common in children compared to 33

16

adults, BAT can also be enhanced in the presence of PPGL and can potentially mask head and 1

neck and adrenal lesions. Beta adrenoceptor blockade can reduce this finding. However, the 2

use of beta adrenoceptor blockade alone is contraindicated in PPGL patients. 3

4

Pathological uptake: As normal adrenal uptake is faint, distinctly increased uptake or 5

asymmetric adrenal uptake in presence of enlarged gland should be considered to reflect 6

potential pathology until proven otherwise. Extra-adrenal sites of uptake that are focal and 7

cannot be explained by normal physiological distribution are considered abnormal. 8

SPECT/CT is helpful for better localization of abnormal uptake and is generally 9

recommended 10

11

12

• Quantification 13

Quantification of uptake is not routinely utilized as the methodology is not fully clinically 14

established. Quantitative SPECT/CT has been developed to provide dosimetry for therapeutic 15

radionuclides including 177Lu [38, 39] but should not be used in routine clinical practice 16

unless it has been properly validated [40]. 17

18

Common pitfalls 19

20

• False positives 21

CT-based attenuation correction often leads to enhanced physiological visualization of the 22

adrenal medulla and may therefore induce false-positive interpretation unless the 23

interpretation priniciples detailed above are followed and adapted to allow moderate uptake as 24

a normal finding. In MEN-2 patients, 123IMIBG scintigraphy is of limited value for 25

discriminating physiological uptake from diffuse adrenal medullary hyperplasia or PHEO. 26

False-positive cases have also been related to tracer uptake by other neuroendocrine lesions 27

(carcinoid tumor, medullary thyroid carcinoma, Merkel cell carcinoma, ganglioneuroma). 28

Rarely, MIBG uptake has been reported in adrenocortical adenomas or carcinomas, 29

retroperitoneal angiomyolipomas and hemangiomas. SPECT/CT may avoid misleading 30

accumulations in the liver (inhomogeneous uptake, hepatic hemangioma, hepatocellular 31

carcinoma), in the renal parenchyma (diffuse for renal artery stenosis, focal for acute 32

pyelonephritis) or in the urinary tract (hydronephrosis, renal cysts), atelectasis, pneumonia, 33

17

vascular malformations, accessory spleen, adrenal abscess, foregut duplication cysts, 1

hemorrhagic cysts, ovarian torsion, chronic inflammatory foci [23]. 2

3

• False negatives 4

HNPGL, SDHx-related PPGLs, small lesions, large PHEO with cystic degeneration, necrosis, 5

or hemorrhage, poorly-differentiated tumors (low expression of VMAT-1) are more prone to 6

yield false-negative results [41-45]. False negative results may also result from interfering 7

medications (drug-interference). 8

9

Diagnostic accuracy 10

11

123IMIBG scintigraphy has a sensitivity ranging from 83–100% and a high specificity (95–12

100%) for PHEO. Studies, which have included high numbers of extra-adrenal, multiple, or 13

hereditary PGLs, found reduced sensitivity of 123IMIBG scintigraphy (52-75%) [41-44]. 14

123IMIBG scintigraphy may be suboptimal in cases with special genotypic features such as 15

SDHB-related PPGLs [45-47]. In patients with metastatic disease, 123IMIBG scintigraphy 16

may lead to a significant underestimation of the extent of disease with potential to 17

inappropriately guide management. The sensitivity of 123I-MIBG scintigraphy is overall low 18

in HNPGLs (from 18 to 50%). However, importantly, 123IMIBG scintigraphy can be used to 19

select potential candidates for 131IMIBG therapy. 20

21

22

Indium-111(111In)-Pentetreotide scintigraphy 23

24


26

111InIn-DTPA-pentetreotide (OctreoScan) is a 111InIn(DTPA)]0 conjugate of octreotide, a 27

long-acting somatostatin analog. 28

29

Mechanism of uptake 30

31

111InIn-DTPA-pentetreotide specifically binds to somatostatin (SST) receptors expressed on 32

18

cell membranes, especially subtypes 2 and 5. SSTR are expressed on many cells of 1

neuroendocrine origin, and therefore tumours derived from those cell types. 2

3

Pharmacokinetics 4

5

111InIn-DTPA-pentetreotide is cleared from the blood, primarily through the kidneys (50% 6

of the injected dose is recovered in the urine by 6 h, 85% within 24 h). Some of the tracer is, 7

however, retained in tubular cells. Hepatobiliary excretion and spleen trapping are 8

respectively 2% and 2.5 % of the administered dose. However, the bowel is often visualized 9

on delayed imaging and the gallbladder can also contain activity and cause diagnostic 10

uncertainty unless carefully correlated with anatomical imaging. Pituitary and thyroid can also 11

be visualized [48, 49]. 12

13


15

111InIn-DTPA-pentetreotide is commercially available (Octreoscan®, Covidien) and supplied 16

as a monodose kit for radiolabeling. The kit contains two sterile vials containing lyophilized 17

pentetreotide (10 µg) and 111InIndium Chloride (122 MBq/1.1mL at ART). 18

The radiopharmaceutical is prepared by adding the desired activity of 111In-chloride into the 19

vial containing pentetreotide at room temperature. The preparation should be used within 6 20

hours and can be diluted in sterile saline (2-3 mL). 21

The preparation of the 111InIn-DTPA-pentetreotide is stable for 6 hours, and should not be 22

used if radiochemical purity is less than 98%. The pH of the solution ranges between 3.8 and 23

4.3. 24

Thin layer chromatography can be used to check radiochemical purity as follows: solid phase 25

ITLC, mobile-phase 0.1N sodium citrate adjusted with HCl to pH 5, Rf: 111In-pentetreotide 26

0.0, unbound 111In 1.0. 27

28

Drug interactions and side effects 29

30

It has been proposed to temporarily interrupt somatostatin analogue therapy to avoid possible 31

somatostatin receptor blockade, but this is not universally applicable. 32

33

19


2

185–222 MBq in adults and 5 3 MBq/kg in children [50]. 3

4

Administration 5

6

Slow (1-2 minute) intravenous infusion. 7

8


10

The effective dose is about 0.054 mSv/MBq in adults and 0.16 mSv/MBq in children (5 11

years) [51]. There is an increased radiation dose from CT in SPECT/CT protocols, the value 12

being dependent on a parameter scan. 13

14

Renal failure 15

16

For patients with significant renal failure, high blood pool activity may hamper visualization 17

of uptake foci. After haemodialysis, an interpretable scintigram can be obtained. 18

19

Pregnancy 20

Generally use of radiopharmaceuticals is contraindicated in pregnancy. Clinical decision to 21

use, should consider the benefits against the possible harm of carrying out the procedure in 22

case of pregnancy, whether known or suspected. 23

24

Breast feeding 25

26

It is not necessary to discontinue breast-feeding after diagnostic use of 111InIn-DTPA-27

pentetreotide. However, close contact with infants should be restricted during the first 2 days 28

after administration. 29

30


32

• Somatostatin analogs are rarely used in the treatment of PPGLs. Short-acting 33

somatostatin analogs may be discontinued for 24 h before 111InIn-DTPA-34

20

pentetreotide administration, while long-acting preparations are preferably stopped 4–1

6 weeks before the study, and patients should be switched to short-acting 2

formulations, if necessary [50, 52]. 3

• Laxatives are advised, especially when the abdomen is the area of interest. It is of note 4

that this is a controversial when SPECT-CT is planned due to less difficulties for 5

avoiding potential pitfalls due to physiological bowel activity. 6

• To reduce radiation exposure, patients should be well hydrated before and for at least 7

1 day after injection. 8

9

Image acquisition 10

11

• Timing of imaging 12

Scans are obtained 4 hours and 24 hours after tracer injection. 13

14

• Imaging field 15

- Acquisitions are performed using two energy peaks at 171 and 245 keV and large-16

field-of-view medium-energy collimators. 17

- Anterior and posterior planar views of the head & neck (+ right and left lateral oblique 18

views) and thorax, abdomen and pelvis are acquired at 4 hours and 24 hours (512 x 19

512 or 256 x 256 word matrix and are obtained for a 10-15 minutes per view (or about 20

300 kcounts for the head and neck and 500 kcounts for the rest of the body) [49, 50]. 21

- Whole-body imaging can be used instead of planar views. For whole-body images: 22

anterior and posterior images are acquired into 1024 x 512 word or 1024 x 256 word 23

matrix for a minimum of 30 min (speed 6 cm/min max). 24

25

- SPECT over the anatomical regions showing pathological tracer uptake on planar 26

images are clearly helpful. The SPECT images are performed for a 360° orbit (128 × 27

128 word matrix, 6-degree angle steps, 30-45s per stop). Co-registered CT images 28

(100-130 kV, mAs modulation recommended) from SPECT/CT cameras enable 29

attenuation and facilitate precise localization of any focus of increased tracer. 30

SPECT/CT images are particularly useful over the abdomen. If only one SPECT 31

acquisition is obtained, acquisition at 24 hour is preferred because of higher target-to-32

background ratio. 33

34

21

• Optional images 1

- Acquisitions (SPECT and/or planar views) may be repeated at 48 hours for 2

clarification of equivocal abdominal findings. 3

4

Reconstruction 5

6

Iterative SPECT reconstruction or other validated reconstruction protocols that accurately 7

visualize lesions can be adapted to the clinical setting. CT-based attenuation correction 8

(CTAC) for SPECT/CT. 9

10

Image analysis 11

12


Physiological distribution: Uptake is seen in spleen, kidney, liver, bowel (visible on the 24-14

hour images), and the gallbladder if fasting. Normal adrenal glands can also be faintly visible. 15

Other sites with faint uptake are the pituitary gland and the thyroid (increased diffuse uptake 16

in case of thyroiditis). 17

18

Pathological uptake: Accumulation of radioactivity at an abnormal site is considered to 19

represent somatostatin receptor binding especially if it is present on the scintigrams on the 20

two standard imaging time points. 21

22


The optimal time interval to quantify tumors is at 24 hr post-injection or later. Tumor uptake 24

can be scored according to Krenning as follows: 0 = no uptake; 1 = very low/equivocal 25

uptake; 2 = clear, but faint uptake (less than or equal to liver uptake); 3 = moderate uptake 26

(higher than liver uptake); 4 = intense uptake (equal to or greater than that in the spleen). This 27

scoring is mainly used in selecting candidates for PRRT. A modified Krenning score has also 28

been used for SPECT using the same reference tissues but is not necessarily equivalent, 29

especially for small lesions in the liver that may be Krenning 2 on planar imaging but visible 30

above hepatic parenchyma on SPECT and therefore, modified Krenning score 3. 31

32

Pitfalls 33

34

22


Renal parapelvic cysts, accessory splenic tissue or abdominal hernia. False positive cases may 2

be related to tracer uptake by other neuroendocrine lesions or other SST2-expressing tumors 3

(thyroid or breast disease are the most frequent causes of false-positives foci) [50]. Since 4

SST2 is overexpressed in activated lymphocytes and macrophages, FP images may also be 5

related to granulomatous and inflammatory diseases. 6

7


Small HNPGLs, abdominal PGLs. 9

10


12

Considering parasympathetic HNPGLs, several studies have demonstrated the superiority of 13

111InIn-DTPA-pentetreotide scintigraphy compared to 131I/123IMIBG scintigraphy, with 14

sensitivities of 89-100% and 18-50%, respectively [53-58]. However, its sensitivity needs to 15

be revised in patients with hereditary syndromes because some additional lesions can be at the 16

millimeter range and not detectable by conventional scintigraphy [59]. 17

The sensitivity of 111InIn-DTPA-pentetreotide is inferior to that of 123IMIBG scintigraphy 18

in abdominal and metastatic PPGL (except those related to SDHx mutations), even though it 19

can provide additional information in some patients with rapidly progressing metastatic PPGL 20

[41, 60-62]. 111InIn-DTPA-pentetreotide may also detect other syndromic lesions (e.g., 21

neuroendocrine pancreatic tumor, medullary thyroid carcinoma, neuroblastoma, or pituitary 22

tumors). Both single photon agents have been shown to have inferior diagnostic performance 23

compared to the PET/CT techniques described below. 24

25

PET imaging with 68Ga-conjugated somatostatin analogs 26

27

Radiopharmaceuticals 28

29

Imaging somatostatin receptors with PET tracers has been obtained with 3 different DOTA-30

coupled somatostatin agonists (SSTa), Tyr3-octreotide (DOTATOC, edotreotide), Tyr3-31

octreotate (DOTATATE, oxodotreotide), and Nal3-octreotide (DOTANOC). All of them are 32

radiolabeled with 68Ga elutate (68GaGa-SSTa) obtained from 68Ge/68Ga generators eluate. 33

23

68Ge/68Ga generators, GalliaPharm® (Eckert Zeigler) and Galli Eo® (IRE ELIT) have 1

received marketing authorization worldwilde. DOTATATE and DOTATOC were recently 2

approved by respectively US Food and Drug Adminsitration (FDA) and European Medicines 3

Agency (EMA). 4

Due to the short half-life of 68Ga (68 min), 68GaGa-SSTa are synthesized exclusively less 5

than 4 h before patient administration on the day of examination. According to each country's 6

regulations, 68GaGa-SSTa manufacturing can either be centralized and the agent be shipped 7

to Nuclear Medicine Departments, or the agent can by synthesized in local radiopharmacies 8

meeting good radiopharmaceutical practices (GMP). 9

10


12

68GaGa-SSTa target the somatostatin receptor subtype 2 (SST2), which is the most 13

commonly over-expressed receptor in PPGLs, and is internalized into the cells. SST1 is also 14

strongly expressed in some PGLs, while other receptor subtypes are only slightly expressed or 15

are entirely missing. The low expression of SST5 observed in PGLs constitutes a major 16

difference with some endocrine tumors of the gastrointestinal tract. DOTATOC (Tyr3-17

octreotide), DOTATATE (Tyr3-octreotate), and DOTANOC (Nal3-octreotide) have excellent 18

affinity for SSTR2 (IC50: 2.5 nM; 0.2 nM; and 1.9 nM respectively). DOTANOC also binds 19

specifically to SSTR3, SSTR4 and SSTR5. DOTATOC also binds to SSTR5 (although with 20

lower affinity than DOTANOC) [63-65]. 21

22

Tracer binding and retention depends on density of somatostatin receptors (SSTR) on the cell 23

surface and, the degree of internalization of the ligand/receptor complex. Recently, SSTR 24

antagonists such as 68GaGa-NODAGA-JR11 [66] have been developed, and are still under 25

evaluation. SST antagonists should decrease DOTA-peptide washout and increase target 26

residence time, despite the lack of internalization, as these remain radiopharmaceuticals 27

remain anchored within the cell membrane. 68Ga radiolabeled antagonists can also be applied 28

as a theranostic agents [66]. 29

30

31

Pharmacokinetics 32

33

24

After IV administration, SSTa concentrate to all SSTR2-expressing organs: pituitary, thyroid, 1

spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. There is no uptake in 2

the cerebral cortex or in the heart is reached in 60 to 120 minutes [67]. DOTA peptides 3

showed a bi-exponential blood half-life (2 and 50 min), and are mainly excreted by the kidney 4

(40 to 75% of the injected dose respectively at 3 and 24 h after injection). Less than 2% of the 5

injected dose is excreted in the feces up to 48 h and no radiolabeled metabolites have been 6

reported during the first 4 h. 7

8


10

Currently, two 68Ge/68Ga generators and DOTATOC and DOTATATE have marketing 11

authorization. 68Ga can be harvested daily through 68Ge/68Ga generators elution for several 12

months. 13

DOTATOC and DOTATATE are available as commercial kits for radiolabeling. 14

Radiolabelling is 68Ga is robust (radiochemical purity >95%), requires between 20 and 30 15

minutes, and procedure can be performed manually or by mean of automatic devices. 16

Briefly, the labeling procedure is divided into different steps and performed using suitable 17

shielding to reduce radiation exposure. 18

- 68Ga chloride elution: 68Ge/68Ga generators are eluted with hydrochloric acid solution 19

(0.1-1N). 20

- DOTA-peptide radiolabeling: A defined volume of 68Ga elution chloride and pH 21

adjuster buffer are successively added in aseptic conditions and mixture is heated (95°C, 7-8 22

min) according to manufacturer recommendations. 23

- Purification: if required based on generator characteristics, a purification step can be 24

performed using an accessory cartridge to reduce the amount of 68Ge to lower than 0.001%. 25

Radionuclidic identity is then mandatory and tested by half-life measurements, gamma-ray 26

spectral analysis and determination of any long-lived radionuclidic contaminant 24 hours after 27

EOS . 28

- Quality controls: Appearance, pH and radiochemical purity must be assessed before 29

injection using validated methods (i.e., Thin Layer Chromatography or HPLC). 30

25

Radiochemical purity of 68GaGa-DOTATATE and 68GaGa-DOTATOC must be higher 1

than 92% and 95 %, respectively. Ongoing routine samples are tested periodically for sterility. 2

3


5

Somatostatin analogues may affect the tracer accumulation in organ, and in tumour sites [68]. 6

7


9

• The activity administered is 2 MBq/kg (100 to 200 MBq). 10

• The amount of administred SSTa should not exceed 40 mcg. 11

12

Administration 13

14

Slow (1-2 minuten0 intravenous infusion. 15

16


18

The effective dose from radiopharmaceutical is approximately 0.021 mSv/MBq in adult [69]. 19

There is an increased radiation dose from CT in SPECT/CT protocols, the value being 20

dependent on a parameter scan. 21

22

Pregnancy 23

24

Clinical decision is necessary to consider the benefits against the possible harm of carrying 25

out any procedure in case of pregnancy, whether known or suspected. See 18FF-FDG PET 26

section. 27

28

Breast feeding 29

30

Breast feeding should be discontinued for 12 h after injection. 31

32

26


2

No need for fasting before injection. It has been recommended to discontinue octreotide 3

therapy (1 day for short lived molecules and 3-4 weeks for long-acting analogues). To date, 4

this issue is still not definitively clarified. 5

6

Image acquisition 7

8

Scans are usually obtained from 45 to 90 minutes after tracer injection from base of skull to 9

mid-thighs (or over the whole-body depending on the clinical setting). Although, there is no 10

generally accepted acquisition time in the literature, generally 3 minutes per bed position is 11

adequate. However, acquisition times per bed position should be increased in obese patients, 12

if low activity is available or imaging is delayed beyond 90 minutes to minimize the risk of a 13

low statistical quality scan. 14

15

Image reconstruction 16

17

Data acquired in the 3D or 2D mode. Iterative reconstruction algorithms represent the current 18

standard for clinical routine. Point spread function alogrithms may enhance detection of small 19

lesions but tend to increase apparent intensity of uptake in such structures [70]. This may 20

impact interpretation of uptake in the adrenals. CT-based attenuation correction (CTAC). 21

22

Image analysis 23

24


26

Physiological distribution: Intense accumulation of radioactivity is seen in the spleen (and 27

accessory splenic tissue if present), kidneys, adrenals, salivary glands and pituitary. 28

Accumulation in the liver is usually less intense than that noted in the spleen. The thyroid can 29

be faintly visible. Additionally, variable tracer uptake is frequently found in the pancreas 30

particularly in the uncinate process due to the high density in pancreatic polypeptide (PP) 31

cells [71]. Prostate gland and breast glandular tissue may show diffuse low-grade uptake of 32

68GaGa-DOTA-conjugated peptides. 33

34

27


2

SUV is an easy and useful parameter for tumour characterization, if images are acquired and 3

processed in a standardized manner. It should be ensured that the PET/CT system is calibrated 4

for 68Ga half-life. 5

6

Pitfalls 7

8


10

PET could be falsely positive in metastatic lymph nodes due to various cancers, 11

meningiomas, inflammatory processes, pituitary gland, and some rare conditions such as 12

fibrous dysplasia [72, 73]. Focal pancreatic accumulation in the uncinate process may mimic 13

a pancreatic NET. 14

15


There has been no sufficient data to draw any firm conclusions. FN findings mainly occur in 17

PHEO. As for other PET radiopharmaceuticals, the urinary bladder may mask intra- or 18

perivesical PGL. Diuretics can be used in selected cases to to circumvent this drawback. 19

20


22

The use of 68GaGa-DOTA-SSA in the context of primary PHEOs has been less studied that 23

other PET radiopharmaceutcals, but has shown excellent results in localizing these tumors 24

when they are metastatic or extra-adrenal [73-78]. 68GaGa-DOTA-SSA is more sensitive 25

than 123/131I-MIBG scintigraphy. In a recent systematic review and meta-analysis, the pooled 26

detection rate of 68GaGa-DOTA-SSA PET/CT was 93% (95% confidence interval [CI] 91-27

95%), which was significantly higher than that of fluorine-18FDOPA (18FFDOPA) 28

PET/CT (80% [95% CI 69-88%]), 18F-FDG PET/CT (74% [95% CI 46-91%]), and 123/131II-29

MIBG scintigraphy (38% [95% CI 20-59%], P < 0.001 for all) [79]. Although interesting, this 30

meta-analysis is hampered by mixing PPGLs of various origin, the low number of PHEOs, 31

and the comparison limited to lesion-based analysis. 32

28

Head-to-head comparison between 68GaGa-DOTA-SSA and 18FFDOPA PET/CT has been 1

performed in only 4 studies: one retrospective study from Innsbruck Medical University 2

(68GaGa-DOTATOC in 20 patients with unknown genetic background) [80], 2 prospective 3

studies from the NIH (68GaGa-DOTATATE in 17 and 20 patients) [81-83], and one 4

prospective study from La Timone University Hospital (68GaGa-DOTATATE in 30 5

patients) [72]. In these studies, 68GaGa-DOTA-SSA PET/CT detected more PPGLs than 6

18F-FDOPA PET/CT, regardless of the genotype [84], as well as compared to 18FFDG 7

PET/CT in SDHx, metastatic, and head and neck PPGLs. In a recent study from the Royal 8

North Shore Hospital in Australia, 68GaGa-DOTATATE PET/CT had a sensitivity of 84% 9

for PHEO (21/24) and 100% (7/7) for PGL [85]. The elevated clinical value of 68GaGa-10

DOTA-SSA was also observed in the pediatric population [86]. EPAS1 (HIF2A) mutations 11

remain an exception among susceptibility genes since they lead to PPGLs that concentrate 12

less 68GaGa-labeled-SSA in contrast to SDHx-related PPGLs [87]. This mechanism for this 13

phenotype is currently largely unexplained. Overall, based on these data it is suggestive that 14

68GaGa-DOTA-SSA PET/CT is the most sensitive tool in the detection of HNPGLs, 15

especially SDHD-related tumors, which may be very small in size and/or fail to sufficiently 16

concentrate 18FFDOPA. 68GaGa-DOTA-SSA PET/CT might be inferior to 18FFDOPA 17

PET/CT in the detection PHEOs. 18

19

18FFDOPA PET 20

21


23

L-18F6fluoroDOPA 24

25

In many countries, 18Ffluorodihydroxyphenylalaniane (18FFDOPA) is commercially 26

available as a sterile mono- or multi-dose solution for intravenous use. The solution is 27

colorless or pale yellow. In US, 18FFDOPA is not approved and, therefore, it is used in the 28

setting of clinical trials (e.g. National Institutes of Health, Maryland). 29

30


32

29

PPGL can take-up and decarboxylate amino acids such as DOPA. This property depends on 1

the activity of the L-aromatic amino acid decarboxylase (AADC). DOPA, the precursor of all 2

endogenous catecholamines, is taken up through LAT transporters (mainly LAT1). 3

18FFDOPA is converted into 18FFDA by AADC and is stored in neurosecretory vesicles. 4

5

Pharmacokinetics 6

7

After IV administration, 18FFDOPA is specifically trapped by neuroendocrine tissue and 8

follows the metabolic pathways of L-DOPA. Plasma 18FFDOPA is metabolized by COMT 9

and AADC. 18FFDOPA is quickly converted into 18Ffluorodopamine in the proximal renal 10

tubule and other target tissues and eliminated in the urine (50% within 1 h and the rest within 11

12 h). 12

PPGL take up 18FFDOPA very quickly. Preferably, the acquisition for static clinical PET 13

imaging of PPGL with 18FFDOPA can start at 20 minutes post-injection for maximum 14

uptake in tumors. Afterward, a very slight decrease of the tumor SUV starts, which still 15

amounts to 80% of the maximum value after 132 minutes [88]. Some authors use 16

premedication with carbidopa (an AADC inhibitor) to improve bioavailability of the tracer 17

and to decrease physiological uptake by the pancreas [89]. 18

19


21

Before 2016 18FFDOPA was only avalaible through eletrophylic synthesis that requires up 22

to 4 hrs and suffers from low robustness, a low yield of labeling, between 11 and 25% [90, 23

91] and low stability. Expedited by dilution in an acid solution, eletrophylically produced 24

18FFDOPA needs to be extemporaneously neutralized using bicarbonate buffer kit supplied 25

by the manufacturer pH just before the administration. pH determination needs to be 26

performed and should be kept between 4.0 and 5.0. 27

In 2016, a nucleophilic method was validated and significantly improved the radiolabeling 28

robustness with an increased radiolabeling yield and a ready to use radiopharmaceutical with 29

a stability of 12 hours. 30

These two formulations seem to be equivalent, and no additional quality control is needed. 31

Striatum uptake of 18FFDOPA suggests integrity of the labeled molecule and can be used as 32

internal control. 33

30

1


3

Local pain during injection has been reported for 18FFDOPA produced by electrophylic 4

synthesis (due to acidic pH). 5

6

Haloperidol and reserpine have been reported to, respectively, increase and decrease striatal 7

18FFDOPA retention [92, 93]. There is no report of drug interaction in PPGLs. 8

9


11

2-4 Mbq/Kg. 12

13

Administration 14

15

Intravenous. 16

17


19

The effective dose in adults is 0.025 mSv/MBq [51]. There is an increased radiation dose 20

from CT in PET/CT protocols, the value being dependent on a parameter scan. 21

22

Pregnancy 23

24


out any procedure in case of pregnancy known or suspected. See 18FFDG PET section. 26

27

28

Breast feeding 29

30

Breast feeding should be discontinued for 12 h after treatment. 31

32


31

1

Patients should fast for 3-4 h as other amino acids can competitively inhibit 18FFDOPA 2

influx. The administration of 200 mg of carbidopa 1 hr prior 18FFDOPA injection has been 3

reported to increase tumor uptake but its use is not recommended in the setting of PPGL [89]. 4

5

Image acquisition 6

7

• Timing of imaging and image fields : 8

Scans are usually obtained from 30 to 60 minutes after tracer injection from base of skull to 9

mid-thighs (or over the whole-body depending on the clinical setting). 10

11

• Optional images 12

- Early acquisition (10 min after tracer injection) centred over the abdomen may be obtained 13

to overcome difficulties in localizing abdominal PGL located near the hepatobiliary system 14

due to physiological tracer elimination. 15

- Early acquisition centered over the neck (from 10 to 20 minutes) may also be performed in 16

MEN-2 patients with residual hypercalcitoninemia [94]. Medullary thyroid carcinoma lesions 17

often show rapid washout and are better visualized on these early images [95]. 18

19


21


standard for clinical routine. CT-based attenuation correction (CTAC). 23

24

Image analysis 25

26


Physiological distribution: the striatum, kidneys, pancreas, liver, gallbladder, biliary tract and 28

duodenum. Adrenal glands can be visible with variable uptake intensity. 29

Pathological uptake: any non-physiological extra-adrenal focal uptake or asymmetrical 30

adrenal uptake with concordant enlarged gland or adrenal uptake more intense than liver with 31

concordant enlarged gland. 32

33

32


Various PET-derived quantitative indices were found to be correlated with tumor secretion 2

[44]. 3

4

Pitfalls 5

6


False positive cases may be related to tracer uptake by other neuroendocrine tumors including 8

prolactinomas [96] or other tumor types in very rare situations [97]. Rarely, uptake may be 9

due to unspecific inflammation (pneumonia, post-operative changes), since high levels of 10

amino acid transport have also been found in macrophages. 11

12


SDHx-related PPGLs, mainly those arising from the sympathetic paraganglionic system. 14

15


17

In a meta-analysis of 11 studies (275 patients), the pooled sensitivity and specificity on a per 18

lesion-based analysis of 18FFDOPA PET/CT) in detecting PPGLs were 79% (95% CI 76–19

81%) and 95% (95% CI 84–99%), respectively [98]. The most significant factors influencing 20

visualization of 18FFDOPA-avid foci are tumor location and genetic status. 18FFDOPA 21

PET/CT is not an MIBG scintigraphy with higher sensitivity but a new specific radiotracer 22

with its own advantages and limitations [44, 47, 99-104]. 23

A special advantage of 18FFDOPA PET/CT over 123IMIBG scintigraphy or other 24

specific PET tracers stem from its limited uptake by normal adrenal glands [105]. This is 25

particularly helpful in hereditary PHEO which can be very small in size (e.g., MAX and RET 26

mutations) [106]. 18FFDOPA PET/CT may also detect residual medullary thyroid carcinoma 27

lesions and other syndromic tumors such as pancreatic neuroendocrine tumors that may occur 28

in VHL patients (especially after carbidopa premedication to decrease the background 29

activity). Several studies show that 18FFDOPA PET/CT is an excellent first-line imaging 30

tool in HNPGLs with a sensitivity >90% [43, 44, 103, 107-111]. This is due to the high 31

avidity of HNPGLs for 18FFDOPA and the absence of physiological uptake in the adjacent 32

structures (excellent signal-to-noise uptake ratio). The specificity of 18FFDOPA is also very 33

33

high. Its sensitivity also approaches 100% in sporadic PHEOs, but can be lower in SDHB/D-1

related PPGLs [43, 44, 59, 98, 103]. In VHL-patients, 18FFDOPA PET/CT may detect 2

pancreatic neuroendocrine tumors [112]. In metastatic disease, 18FFDOPA PET/CT 3

demonstrated better performance in SDHB negative patients than in SDHB positive patients 4

(sensitivity 93% in carriers without SDHB mutations vs 20% in patients with SDHB 5

mutations) [44, 100, 103, 113]. Recent studies have shown lower sensitivity compared to 6

68GaGa-DOTA-SSA in sporadic HNPGLs and metastatic PPGLs. By contrast, 18F-FDOPA 7

PET/CT is highly sensitive in VHL, EPAS1 (HIF2A), and FH PPGLs [114]. 8

9

18FFDG PET 10

11


13

18FFDG is commercially available in a “ready to use” formula and conditioned in a sterile 14

mono- or multi-dose solution for intravenous use. 15

16


18

18FFDG is taken up by tumour cells via glucose membrane transporters and phosphorylated 19

by hexokinase into 18FFDG-6P. 18FFDG-6P does not follow further enzymatic pathways 20

and accumulates proportionally to the glycolytic cellular rate. It is remarkable that PPGL 21

underlying SDHx mutation are more avid for 18FFDG than other subtypes. This is mainly 22

due to the accumulation of succinate which could acts as an oncometabolite and both induces 23

metabolic reprogramming (pseudoypoxia) [115-120] and activates surrounding stromal tissue 24

[121, 122]. Other PPGL have variable uptake. 25

26

Pharmacokinetics 27

28

After IV administration, 18FFDG is rapidly cleared from the blood, concentrates in brain 29

(8%), heart wall (4%), lung (3%), spleen (0.3%) and liver (5%). There is also high uptake in 30

brain. The majority of the 18FFDG is excreted unaltered by the kidneys (20% of the injected 31

dose is recovered in the urine within 2 h) [51]. 32

34

1


3

18FFDG is commercially available or is prepared « in-house » in a “ready to use” form and 4

conforms to the European and US pharmacopeia. 5

6


8

Blood glucose level is measured before administering 18FFDG and thereby should detect 9

any drug interaction on glucose metabolism. Chemotherapy may change 18FFDG tumour 10

uptake by altering cellular metabolism. The timing of restaging with PET depends on the 11

therapy (from 2 to 5 weeks after end of chemotherapy in cases of metastatic tumours). 12

13


15

2-5 MBq/kg. 16

17

Administration 18

19

Intravenous 20

21


23

The effective dose equivalent is 0.019 mSv/MBq [51]. There is an increased radiation dose 24

from CT in PET/CT protocols, the value being dependent on a parameter scan. 25

26

Pregnancy 27

28


out any procedure in case of pregnancy known or suspected. The International Commission 30

on Radiological Protection (ICRP) reports that for an adult patient the administration of 259 31

MBq of 18FFDG results in an absorbed radiation dose of 4.7 mGy to the nongravid uterus 32

(i.e. 0.018 mGy/MBq) [123]. Direct measurements of 18FFDG uptake in a case study 33

35

suggested somewhat higher doses than are currently provided in standard models [124]. A 1

pregnancy test may help with the decision, provided the 10 day post ovulation blackout is 2

understood. In the event of doubt and in the absence of an emergency, the 10 day rule should 3

be adopted. In Europe, national guidelines may apply. 4

5

Breast feeding 6

7

Breast feeding should be discontinued for 12 h after imaging 8

9


11

Patients must fast for at least 6 h, prior to 18FFDG injection. PHEO patients with secondary 12

diabetes (about 35% of cases) require specific instructions for glucose control. During 13

18FFDG injection and the subsequent uptake phase, patients should remain seated or 14

recumbent, kept warm, in a darkened and quiet room. The use of any premedication for 15

reducing brown adipose tissue uptake is contraindicated in the setting of elevated 16

catecholamine levels due to the associated high risk of hypertensive crisis and 17

tachyarrhythmia. 18

19

Image acquisition 20

21

• Timing of imaging 22

Scans are usually obtained at 60 minutes (45 to 90 min) post-injection. 23

24

• Imaging field 25

From base of skull to mid-thighs (or whole-body imaging, depending on the clinical setting). 26

27


29


standard for clinical routine. CT-based attenuation correction (CTAC). 31

32

Image analysis 33

36

1


Physiological distribution: brain cortex, salivary glands, lympathic tissue of the Waldeyer’s 3

ring, muscles, brown fat, myocardium, mediastinum, liver, kidneys and bladder, 4

gastrointestinal tract, testis, uterus and ovaries (before menopause). Physiologic 18FFDG 5

uptake in BAT occurs predominantly in the younger age group. In patients with PHEO, there 6

is a frequent increase of BAT uptake due to brown adipocyte cell stimulation by 7

norepinephrine. The level of physiological 18FFDG uptake in normal adrenal glands is low 8

even after contralateral adrenalectomy for PHEO but contrasts with the enhanced uptake 9

observed after adrenalectomy for cancer of the adrenal cortex [125, 126]. 10

11

Pathological uptake: any non-physiological extraadrenal focal uptake or adrenal uptake more 12

intense than liver and with concordant enlarged gland. 13

14


Various quantitative indices can be described. Highly elevated uptake values are observed in 16

SDHx-related PPGL. 17

18

19

Pitfalls 20

21


In absence of biochemical information, several potential diagnoses should be considered in 23

cases of highly-avid adrenal masses (especially in the presence of adrenal to liver SUVmax 24

ratio>2): adrenocortical carcinoma (ACC), primary lymphoma, metastasis, myelolipoma 25

(uptake by the myeloid tissue component of the mass) and oncocytoma [127]. When masses 26

are moderately avid for 18FFDG, other etiologies should be considered: adrenal cortex 27

adenoma, ganglioneuroma, metastasis (small lesions or from cancer with lower malignant 28

potential, sarcoma), hematoma and adrenocortical hyperplasia. Extra-adrenal uptake can be 29

due to inflammatory and neoplastic processes. 30

31


33

37

Non-avid sporadic PHEOs and retroperitoneal extraadrenal PGLs, MEN2-related PHEO, 1

HNPGL. 2

3


5

18FFDG PET positivity is a frequent feature of PPGL. Some features are suggestive of 6

PHEO such as well-limited tumor without vena cava involvement, unilateral adrenal 7

involvement, decreased uptake in the central area evidencing parenchymal degeneration (eg., 8

cystic, hematoma) and presence of calcifications on unenhanced CT. Uptake may be widely 9

variable between PHEOs. Sensitivity and NPV are very high (80-100%) but the PPV is lower 10

due to lack of specificity of 18FFDG. 18FFDG PET/CT is mainly influenced by genetic 11

status of patients [125, 128, 129]. In cases of MEN-2 related PHEO, 18FFDG PET/CT is 12

40% sensitive. 18FFDG PET/CT may also detect other syndromic lesions (e.g., GIST, RCC, 13

pancreatic tumor, medullary thyroid carcinoma, or pituitary tumor) [130]. 18FFDG PET/CT 14

is also more frequently contributive in metastatic disease with SDHB mutations and might be 15

suboptimal in other patients (sensitivity per lesion 83% in SDHB positive vs 62% in SDHB 16

negative cases). 17

18

Other Tracers 19

20

technetium-99mTc-hydrazinonicotinamide-Tyr(3)-octreotide (99mTcTc-TOC) is 21

increasingly gaining acceptance as a new radiopharmaceutical for diagnosis of somatostatin 22

receptor-expressing tumours [131, 132]. 18F-fluorodopamine 18FFDA) has been developed 23

at the National Institutes of Health in Bethesda, MD and is currently used as an experimental 24

tracer at the NIH only. 18FFDA is captured by tumor cells via the NE transporter system and 25

stored in intracellular vesicles. 18FFDA PET/CT seems to be a very promising tool in the 26

management of PGLs associated with the sympathetic system [41, 42, 133, 134]. 27

11Chydroxyephedrine (11CHED) has also been evaluated, but its synthesis is complex and 28

the short half-life of 11C is a major drawback for its routine clinical use [135-139]. MIBG 29

analogues for PET imaging have been used in few studies, but to our knowledge, no clinical 30

studies have yet been reported [140-142]. The influence of some new drugs (histone 31

deacetylase inhibitors) on tracer uptake is also subjet to investigations [143]. 32

33

38

SPECT versus PET imaging protocols 1

2

123IMIBG and 111InIn-pentetreotide scintigraphy are well-established nuclear 3

imaging techniques in the staging and restaging of PPGL. SPECT/CT has now become more 4

widely available and has the advantage of sequential acquisition of both morphological and 5

functional data, thus increasing diagnostic confidence in image interpretation, disease 6

localization tovether with enhanced sensitivity. However, these conventional techniques are 7

associated with some practical constraints including long imaging times and relatively 8

prolonged uptake times prior to imaging, as well as GI tract artifacts requiring bowel 9

cleansing, thyroid blockage or need for withdrawal of certain medications that can interfere 10

with interpretation. The somewhat low resolution of conventional SPECT imaging might also 11

limit the ability to detect small lesions. Additionally, SPECT does not easily provide a 12

quantifiable estimate of tumour uptake, although this is being increasingly addressed by 13

quantitative SPECT/CT. Thus, the use of PET imaging has been growing rapidly in the 14

imaging of PPGL, paralleled by great efforts towards the development of new highly sensitive 15

tracers with high affinity for cell membrane transporters and receptors. 18FFDG is the most 16

accessible tracer and plays an important role in the evaluation of SDHx-related PPGL [125, 17

128]. 18FFDOPA is also approved in certain countries, but is not FDA-approved in the US. 18

It is, nevertheless, a sensitive tool in evaluating sporadic and perhaps some metastatic PPGLs. 19

Other tracers, such as 18FFDA or (11Cmeta-hydroxyephedrine (11CHED) which are very 20

specific for chromaffin/ganglionic cells but are presently available at only a few centres and 21

not FDA-approved. 11CHED is limited in use due to the short half-life of 11C. 68GaGa-22

DOTATATE, which is FDA-approved or 68GaGa-DOTATOC, which is EMA-approved for 23

evaluating GEP NETs, as well as other 68GaGa-conjugated SSTAs are currently used in 24

many centres as first imaging tools for PPGL, regardless of the patient genotype [81, 144] 25

(Table 2). 26

27

28

39

Recommendations for clinical practice 1

2

Successful PPGL management requires an interdisciplinary team approach. Precise 3

identification of clinical context and genetic status of patients enable a personalized use of 4

functional imaging modalities [3, 125, 145-147] (Table 3). It is expected that the early 5

detection of PPGL with modern PET imaging will very soon lead to the best staging of these 6

tumors thus minimizing complications related to mass effect and hormonal excess, facilitating 7

the most appropriate curative treatment options and reducing the risk of metastatic spread. 8

9

Apparently sporadic non-metastatic PHEO 10

11

123IMIBG scintigraphy is less sensitive as 18FFDOPA PET/CT and superior to 12

111InIn-pentetreotide in localizing non-metastatic sporadic PHEO. However, 123IMIBG 13

scintigraphy or 18FDOPA PET/CT appear sufficient to confirm the diagnosis of large 14

sporadic PHEO even in rare cases of non-hypersecreting PHEO. 18FFDOPA PET/CT 15

imaging has less practical contraints than 123IMIBG scintigraphy and has no drug 16

interactions, which can be limiting for PHEO detection. 18FFDG can provide with 17

genotypic information which is tightly linked to their tumor behavior (i.e., SDHB). 18

19

20

HNPGL 21

22

18FFDOPA and 68GaGa-DOTA-SSAs appear to be the most sensitive PET 23

radiopharmaceuticals in sporadic cases. In SDHx-patients, 68GaGa-DOTA-SSA PET/CT can 24

reveal very small tumors, which can be missed by 18FFDOPA PET/CT. In the absence of 25

18FFDOPA or 68GaGa-DOTA-SSA PET/CT, SRS may be used as an alternative approach, 26

considering the limitations given by spatial resolution of SPECT. 18FFDG PET has high 27

sensitivity in the setting of SDHx-related HNPGLs and can complement 18FFDOPA 28

PET/CT for detecting additional thoracic/abdominal PGLs. 29

30

Retroperitoneal extraadrenal non-metastatic PGL 31

32

40

In the case of a retroperitonal extra-adrenal non-renal mass, imaging should enable 1

differentiation of PGL from neurogenic tumors, lymph node diseases, or mesenchymal 2

tumors. Therefore, the specificity of functional imaging provides an important contribution. 3

Once the diagnosis of PGL has been established, multiplicity of extra-adrenal localizations 4

should be considered. To this purpose, 18F-FDOPA and 68GaGa-DOTA-SSAs are more 5

specific than 18FFDG and can show more lesions than 18FFDG. Therefore, at present, 6

68GaGa-DOTA-SSA PET/CT is probably the preferred imaging modality, especially in the 7

patients who harbor SDHx mutations. 8

9

Metastatic PPGL 10

11

18FFDOPA shows very good results in detecting metastatic lesions in patients with sporadic 12

PPGL. However, its sensitivity decreased in presence of SDHx mutations. 68GaDOTA-SSA 13

has shown better results that 18FFDOPA, regardless of the genetic background and therefore 14

is is becoming the imaging modality of choice for metastatic PPGL. It can also determine if a 15

patient is likely to benefit from PRRT. 18FFDOPA PET/CT may be the second-line imaging 16

modality in the absence of SDHB mutations, or when genetic status is unknown. 18F-FDG 17

PET/CT is the second line imaging modality of choice for SDHB-related metastatic PPGLs. 18

123IMIBG may lead to significant underestimation of metastatic disease with potential to 19

inappropriately guide management. 123IMIBG and 18FFDOPA images do not completely 20

overlap. Furthermore, 123IMIBG is a theranostic radiopharmaceutical and can be used to 21

determine if a patient is eligible for 131IMIBG therapy. The clinical benefit obtained with 22

high-specific-activity MIBG (Azedra®) in patients with metastatic and/or recurrent and/or 23

unresectable PPGL gives a new impetus toward of MIBG scan for in vivo detection of the cell 24

membrane norepinephrine transporter system. This medication has recently received FDA 25

approval. Although not widely available, the PET-equivalent, 124IMIBG would have 26

significant advantages in terms of spatial resolution and quantitative capability for prospective 27

dosimetry. 28

29

30

VHL and RET (MEN2)-related PPGL 31

32

Limited data is available from the literature with respect to imaging studies in VHL and RET 33

41

patients. Many of RET patients do not need any specific functional imaging since the tumours 1

are almost always confined to the adrenal gland with very low risk of malignancy. For VHL, 2

nuclear imaging enables detection of adrenal and extra-adrenal PGL. 123IMIBG scintigraphy 3

can be used in the detection of these tumours, but sensitivity and specificity are suboptimal. 4

The absence of high 18F-FDOPA uptake by healthy adrenal glands is an interesting feature in 5

the diagnosis, staging and restaging of VHL/RET-related PHEO. 18FFDG PET is also not 6

sufficiently sensitive in this clinical setting. In both disorders, if possible, subtotal 7

adrenalectomy (cortical-sparing surgery) is the treatment of choice [148-150]. Therefore, 8

follow-up should not be delayed beyond the scheduled time for cortical-sparing surgery and 9

18FFDOPA PET/CT together with MRI can help in preoperative mapping PHEO within both 10

adrenals and guide the suregons towards the most appropriate (feasible) approach. 11

12

Screening of SDHx-mutation carriers 13

14

The transmission of disease is also different across PPGL syndromes. Regarding SDHD 15

and SDHB, although both are autosomal dominant diseases, they have different disease 16

penetrance. Transmission of SDHD-related PPGL is modulated by maternal imprinting (i.e., 17

the disease almost always occurs only when the mutations are inherited from the father). 18

SDHD-related mutations (paternally inherited) have very high overall penetrance (>80%), in 19

contrast to SDHB ones that have an estimated penetrance of only 20-40% [151-154]. A lower 20

SDHD disease penetrance may be observed in studies that included low severity mutations 21

[155]. 22

The optimal follow-up algorithm has not yet been validated in non-proband SDHx-23

PPGL but most likely requires a more frequent and complete imaging work-up than for their 24

sporadic counterparts. The aim is to detect tumors at early stages of development, thereby 25

minimizing tumor extension and new cranial nerve impairment for SDHD [156], facilitating 26

curative treatment, and potentially reducing the occurrence of metastases, especially in more 27

aggressive genotypes. At initial staging, the use of PET imaging should provide an adequate 28

sensitivity and specificity at whole body scale with limited radiation exposure and very low, if 29

any, risks (2-2.5 mSv for radiopharmaceutical, 1-3 mSv for CT). Based on clinical studies, 30

68GaGa-DOTA-SSAs PET should be prioritized if available over 18FFDOPA PET, 31

although its indication has not been specifically studied in this setting non-proband SDHx 32

42

cases. In absence of PPGL, follow-up should include annual biochemical screening, and MRI 1

at regular time intervals [157]. 2

3

43

Legends 1 2 Table 1. Characteristics of the various hereditary PPGL 3 4

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-2 Frequent 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-1 Possible family history of NF-1

Often unilateral Very rare EPI Very low Peripheral nerve sheath tumors, optic gliomaa

MAX

PHEO Young adult Frequent 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

Adult Very rarely family history of PPGL

Rare Moderate (retroperitoneum or head and neck)

NE and/or DA

Moderate GIST, RCC

SDHB

PHEO/PGL Adult Possible family history of PPGL

Often unilateral Frequent (retroperitoneum)

NE and/or DA

High GISTc, pituitary adenoma, RCC

SDHD

PHEO/PGL Adult Frequent family history of HNPGL

Uni- or bilateral Frequent (head and neck)

NE and/or DA

Moderate GISTc, pituitary adenoma, RCC

44

SDHC PHEO/PGL Adult

Rarely family history of PHEO/PGL

Rare Frequent (mediastinum)

NE Low/Moderate GISTc, RCC

HIF2A polycythemia (often at birth or early in childhood)

Adolescent-young adult females Absence of family history of PPGL

Very rare Expected (retroperitoneum)

NE High Somatostatinomas

1 aNF-1 is characterized by the presence of multiple neurofibromas, café-au-lait spots, Lisch nodules of the iris and other rare disorders. 2 3 bNon-KIT/PDGFRA gastrointestinal stromal tumors (GISTs) may be caused by mutations in the SDHB, SDHC and SDHD genes and be 4 associated with PGL in the Carney-Stratakis syndrome. 5 6 cVon Hippel-Lindau disease is an autosomal dominant disorder, which also predisposes to renal tumors and clear cell carcinoma, pancreatic 7 serous cystadenomas, pancreatic neuroendocrine tumours, testicular tumors, hemangioblastoma of the eye and central nervous system. 8 9 dHIF2A-related PHEOs/PGL are associated with the presence of duodenal somatostatinoma and retinal abnormalities (Pacak-Zhuang syndrome) 10 11 EPI: epinephrine, NE: norepinephrine, DA: dopamine. 12

45

1

Table 2. PPGL radiopharmaceuticals 2 3

Tracer Molecular target Retention

123IMIBG, 18FFDA or 11CHED Norepinephrine transporter

Neurosecretory vesicles

18FFDOPA Neutral amino acid transporter System L

(LATs)

Decarboxylation (AADC) and retention in neurosecretory

vesicles as 18FFDA

68GaGa-SSA

Somatostatin receptors Internalization (agonists)

18FFDG Glucose transporters (GLUTs)

Phosphorylation (hexokinase)

4

46

Table 3. Clinical algorithm for nuclear imaging investigations of PPGL 1 2 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/MAX

18FFDOPA 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

3 4 Based on the above considerations, the following algorithm can be proposed based on clinical 5 situations. This algorithm should be adapted to the practical situation in each institution, and 6 should evolve with time. 7 8 9

47

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