The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology, and practical application of nuclear medicine. SNMMI and EANM members are physicians, technologists, physicists, and scientists specialized in the research and clinical practice of nuclear medicine.
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These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents and are not inflexible rules or requirements of practice. They are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.
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Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine.
The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.
Paediatric brain tumours include a heterogeneous variety of malignancies, which all present specific biological, prognostic, and treatment-related features. Tumours arising within the central nervous system (CNS) are, from the epidemiological point of view, the most frequent solid paediatric malignancy and the second most common after leukaemia. Indeed, they cause up to 27% of all malignancies in children aged 14 and younger and up to 10% of those occurring in adolescents between 15 and 19 years of age. Finally, CNS neoplasm are the main cause of paediatric cancer-related death [1
Paediatric brain gliomas are the most frequent central nervous system tumours in childhood and comprise a heterogeneous collection of neoplasms (including astrocytic and mixed neuronal-glial tumours), which varies from low-grade to highly aggressive malignancies, and can present in a diffusely infiltrating or a more circumscribed growth pattern [3
]. When compared with adult gliomas, paediatric gliomas show divergent mechanisms of tumorigenesis, distinct molecular genetic alterations, and different clinical behaviour. In particular, low-grade paediatric gliomas evolve to their high-grade counterparts infrequently [8
]. Therefore, paediatric gliomas are considered biologically distinct entities [3
]. All these aspects were recently recognized in the 2021 fifth edition of the World Health Organization (WHO) Classification of Tumours of the CNS (CNS5) where diffuse adult-type gliomas were classified separately from those of the paediatric population (“paediatric-type” gliomas) [9
Paediatric low-grade gliomas (pLGG) are defined as grade 1 or 2 malignancies according to the WHO classification. These tumours include many different histological subtypes that can manifest throughout the CNS. The most common entity is pilocytic astrocytoma (a circumscribed astrocytic glioma), whereas paediatric-type diffuse low-grade gliomas and glioneuronal and neuronal tumours compose a notable minority. The most frequent genomic alterations in pLGGs are related to an activation of the mitogen-activated protein kinase (MAPK) pathway [5
]. This alteration can occur in presence of gene rearrangement, due to a tandem duplication at 7q34 determining a fusion between KIAA1549 and BRAF (KIAA1549-BRAF fusion) or by point mutation at the codon 600, which results in an amino acid substitution from valine (V) to glutamic acid (E) (BRAF V600E mutation) [10
]. KIAA1549-BRAF fusion is present in up to 66% of pilocytic astrocytomas and in 15% of all other low-grade gliomas, and it is recognized as a factor associated with a better prognosis [10
]. In addition, a further gene possibly involved in tumorigenesis is the one encoding the isocitrate dehydrogenase (IDH) enzyme, which catalyse the oxidative decarboxylation of isocitrate and therefore has a pivotal role in cell energy production. This gene has been indeed found to be mutated in gliomas [13
]. When compared with adult lower-grade gliomas, IDH mutations are less frequent in the paediatric population particularly in younger children, and malignant progression is extremely rare in paediatric IDH wild-type LGGs [3
Paediatric high-grade gliomas (pHGG), on the other hand, are one of the main causes of cancer-related death in children. These include various WHO grade 3 and 4 entities (some of them newly recognized in the WHO CNS5 under the group of paediatric-type diffuse high-grade gliomas), as well as diffuse midline glioma, H3K27-altered first introduced in the 2016 WHO classification [6
]. The detection of H3K27 alteration, independent of the histological appearance (which could even be that of a low grade diffusely infiltrating lesion), constitutes classification as a WHO grade 4 [6
]. Diffuse midline gliomas (DMG) can arise in any of the central nervous system mid-line structures (e.g. the brain stem, the thalamus, and the spinal cord). The H3K27 alteration is observed in up to 85% of diffuse intrinsic pontine gliomas (DIPG), which are aggressive malignant brainstem DMG for which the median survival is less than 1 year [14
]. Of note, DIPG diagnosis can still be made based on clinical and imaging features alone, without tissue sampling. From the clinical point of view, these tumours manifest with a characteristic triad: multiple cranial neuropathies, long tract signs (hyperreflexia, clonus, increased tone, Babinski reflex), and ataxia. Classic features on MRI are a T1 hypointense and T2 hyperintense diffusely infiltrating lesion arising from and involving ≥ 50% of the pons [14
Despite similar histological characteristics, pHGGs have different molecular features when compared with adult gliomas, both in terms of mutation pattern and in the prognostic implication of those mutations. In particular, approximately 40% of pHGGs are associated with tumour suppressor gene TP53 mutations [15
]. Compared with adults, pHGGs are less likely to bear epidermal growth factor receptor (EGFR) gene amplification and less likely to display mutations in the tumour suppressor PTEN [16
]. Up to one-third of hemispheric pHGGs carry mutations at position 34 (G34R/V) in H3F3A [3
]. Conversely, hotspot mutations in IDH1/2 are rare in older adolescent and represent the lower age spectrum of adult gliomas [3
It is worth noting that familial syndrome might increase the occurrence of CNS paediatric tumours: in fact, 8–19% of these neoplasms is found in patients with genetic predisposition; this figure is significantly lower in adults [19
]. These conditions include tuberous sclerosis, neurofibromatosis, Li-Fraumeni syndrome, rhabdoid tumour predisposition syndrome, von Hippel-Lindau disease, naevoid basal cell carcinoma syndrome, and Turcot’s syndrome [20
Clinical management of paediatric brain gliomas is challenging and requires a multidisciplinary approach in order to devise the best diagnostic and therapeutic strategies in each individual patient. Surgery represents the treatment of choice and can have the most relevant impact on patients’ prognosis. If complete surgical resection is not feasible, biopsy or “debulking” can be considered, and adjuvant therapy with radiotherapy, chemotherapy, or a combination of both may be used. However, for pHGGs, due to possible persistence of microscopic disease, adjuvant therapy is proposed and performed even in case of complete tumour removal. In conclusion, the principal therapeutic approach in paediatric gliomas is represented by surgery in association with chemo- and/or radiotherapy [21
Sensitive and effective non-invasive imaging procedures are especially needed in this “era” of new surgical techniques, radiotherapy planning, and novel systemic treatment. Although conventional MRI is the pivotal imaging procedure in paediatric brain gliomas to determine tumour location, presence of oedema, presence of intratumoural necrosis, cyst formation, haemorrhage, vascularization, mass effect, and contrast enhancement, it has some limitations in distinguishing tumour from tumour mimics and in defining tumour type and grade. Moreover, it does not always allow for precise delineation of tumour margins, distinguish cells in the tumour microenvironment, or inform about the metabolism or state of tumour cells.
Indeed, after treatment, the differentiation between true tumour remnants and treatment-related changes (e.g. “pseudoprogression” or “pseudoresponse”) can be very difficult, specifically when an early response assessment is performed. Pseudoprogression occurs in approximately 21–44% of DIPG [22
] and 7–12% of pHGG cases [23
]; it is a subacute treatment-related reaction (occurring most frequently within the first 3 months after chemoradiotherapy) characterized by a “transient increase in tumour size due to an increase in blood–brain barrier permeability caused by treatment, resulting in increased oedema, or contrast enhancement, or both” [23
Pseudoresponse is a different MRI phenomenon characterized by “radiographical improvement, with overall decreased oedema, or contrast enhancement secondary to the normalisation effect of antiangiogenic agents on the permeability of leaky endothelium, or both, without a change in survival outcome” [23
]. Of note, differently from adult HGG, pseudoresponse is uncommon in pHGG [23
In this setting, although response standard criteria for paediatric gliomas exist [22
], the diffusely infiltrative pattern of pHGGs, often presenting undefined margins and inhomogeneous contrast enhancement, can complicate tumour measurement and response assessment. In this context, MRI contrast enhancement for the estimation of tumour size or growth has limited use. In fact, this parameter reflects the increased permeability of the disrupted blood-tumour barrier to the contrast medium rather than tumour-specific vascularization.
In addition, contrast enhancement can be altered by therapies that influence tumour vascular permeability, such as corticosteroid, antiangiogenic [25
], or immunotherapy agents [26
]. Finally, the real biological activity of gliomas on the first diagnosis is often not correctly estimated by MRI. This limits the usefulness of this imaging procedure in clinical decision-making [27
Multiparametric MRI procedures can overcome some of these constraints being able to reveal additional hemodynamic and metabolic information of brain tumours. The lack of standardization, reproducibility, and comparability of data has reduced their clinical applications. In this context, imaging biomarkers able to provide reliable parameters of tumour biological activity are required to tailor the clinical management of paediatric patients.
In the last two decades, PET imaging has been increasingly used in the paediatric population affected by brain neoplasms, particularly in those suffering from gliomas. Different biological aspects can be studied using different radiopharmaceuticals, with increasing evidence supporting the role of amino acid PET radiopharmaceuticals for use in glioma imaging [28
]. PET imaging of brain tumours with amino acid analogues (namely: L amino acid transport comprising [11
C]MET), O-(2-[18F]fluoroethyl)-L-tyrosine ([18
F]FET) and 3,4-dihydroxy-6-[18
F]DOPA)) has shown clear advantages over [18
F]FDG because of the better contrast between tumour and background uptake. Furthermore, considering that the uptake amino acid radiopharmaceutical does not depend on blood–brain barrier status, but rather on the expression of the amino acid transport system, these radiopharmaceuticals can be taken up in both contrast enhancing and non-enhancing tumour lesions [30
The present practical guidelines/procedure standards highlight, for the first time, the technical aspects of PET image acquisition with [18F]FDG and amino acid PET radiopharmaceuticals in paediatric gliomas imaging.
PET acquisition protocol
The patients should be positioned in the gantry with the head in a dedicated headrest and the arms along the body; the position should be maintained for the duration of the examination. Then, it should be accurately checked that the entire brain is located within the field of view. Once this is done, using flexible head restraints is very helpful to improve the stability of the head. After the rapid CT acquisition, the presence of parents or caregivers during the PET acquisition may be helpful to reassure the children and avoid head movements. Finally, if available, a monitor system for the patients’ condition and movements should be implemented during the entire acquisition.
For PET/CT, a single field of view acquisition should be performed with a low-dose CT component executed only for attenuation correction. In this setting, the CT parameters should be chosen to provide the lowest dose possible.
For PET/MRI, the acquisition protocol depends on the type of technique applied, which can be sequential or simultaneous [91
]. In sequential imaging, the PET and the MRI scanners are positioned in-line with the patient tabletop moving between the two gantries [91
]. Following the advent of semiconductor detectors, including avalanche photodiode or silicon photomultipliers, replacing former photomultiplier tubes, integrated PET/MRI scanners have been implemented which allow for a simultaneous acquisition of both components. The simultaneous PET/MR imaging is to be preferred for the paediatric population, given the significantly reduced scanning time and reduced need for patient sedation or anaesthesia [91
]. Attenuation correction in PET/MRI
systems are based on MRI imaging. Various correction strategies have been implemented and some may lead to systematic errors [94
]. Care should be taken to identify artefacts in the attenuation correction, particularly in bone and lung [95
]. Indeed, as the image quality of newer stand-alone PET/CT and MRI have improved compared to present generation PET/MRI, the scanner choice should be determined by weighting the expected image quality obtained with the discomfort of repeated examinations.
For PET/MRI sequences, axial fluid attenuation inversion recovery (FLAIR), T2-weighted and T1-weighted images, coronal FLAIR and T2-weighted images, and contrast-enhanced (gadolinium chelate, 0.1 mmol/kg) axial, coronal, and sagittal T1-weighted images are performed in addition to those for attenuation correction with a typical total acquisition time of 20–40 min depending on sequence composition and radiopharmaceutical [91
PET acquisition protocol should be adapted to the radiopharmaceutical used. These are briefly summarized in Table 2
Acquisition protocols for [18F]FDG and amino acid PET tracers
20 min (static), immediately after injection (dynamic)
Static and dynamic
10–20 min (static), 40–50 min (dynamic)*
Prior to image interpretation, an adequate quality check of the images (e.g. for movement artefacts) including factors that may affect the semiquantification (i.e. SUV) should be performed (e.g. activity, weight, and height should be correctly reported).
In the case of PET/CT, co-registration with recent MRI images should be always performed (i.e. at least with T1 sequence with contrast medium and T2/FLAIR sequence). Automatic or semiautomatic co-registration is strongly recommended. This allows precise evaluation even of faint uptake areas and easy identification of any brain lesion that needs metabolic characterization without having to adjust the PET display setting from default.
Visual analysis is the “corner stone” for correct interpretation of PET findings. Although SUV should be calculated when needed, its absolute value bears, per se, limited clinical relevance (see below). As the first step, for interpreting static PET images, the brain lesions should be identified, and their uptake should be assessed qualitatively. In the case of a non-negligible uptake (i.e. more intense than white matter), a semi-quantification should be performed by using the contralateral normal brain tissue activity as a reference (i.e. VOI including white and grey matter, measured at the level of the centrum semiovale
]. The target to background ratios (as TBRmean
) should be calculated. Both work for [18
C]MET, and [18
F]FET, but for [18
F]DOPA, the TSR should always be used in addition to TBRs. In the case of anaesthesia or sedation, TBRs can be affected; for example, a reduction in cortical [18
F]FDG uptake can be expected especially in the parietal and occipital regions [99
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