- Email: [email protected]
MRI in children
Accepted Manuscript Title: PET/MRI in children Authors: Sergios Gatidis, Benjamin Bender, Matthias Reimold, Jurgen ¨ F. Sch¨afer PII: DOI: Reference:
S0720-048X(17)30022-0 http://dx.doi.org/doi:10.1016/j.ejrad.2017.01.018 EURR 7706
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
16-11-2016 16-1-2017 17-1-2017
Please cite this article as: Gatidis Sergios, Bender Benjamin, Reimold Matthias, Sch¨afer Jurgen ¨ F.PET/MRI in children.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.01.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/MRI in children
Sergios Gatidis MD1, Benjamin Bender MD 2, Matthias Reimold MD 3, Jürgen F. Schäfer MD1
1
University of Tuebingen, Department of Radiology, Diagnostic and Interventional
Radiology 2
University of Tuebingen, Department of Radiology, Diagnostic and Interventional
Neuroradiology 3
University of Tuebingen, Department of Radiology, Nuclear Medicine
Correspondence:
Dr. Sergios Gatidis University of Tuebingen Department of Radiology Hoppe-Seyler-Str. 3, 72076 Tuebingen [email protected]
Highlights:
combined PET/MRI is a versatile diagnostic modality that can be used for numerous oncologic and non-oncologic applications in paediatric medicine
using PET/MRI, diagnostic advantages of PET and MRI can be combined providing additional insight into pathological processes
the combination of PET and MRI may help reduce the number of necessary imaging studies and thereby diagnostic radiation exposure and number of sedations
Abstract During the past decade, combined PET/MRI has been translated from a basic technical concept to a clinical research tool and a clinically applied hybrid imaging modality. Numerous clinical and scientific applications have been proposed for this novel hybrid modality including oncologic, neurologic and cardiovascular imaging. Among these, PET/MRI in children has emerged as a key application, not only due to possible diagnostic advantages but also because of reduced radiation exposure compared to alternative techniques. A variety of clinical indications exists for the use of PET/MR imaging in children mainly in but not limited to the field of paediatric oncology. The purpose of this review article is to discuss possible applications of combined PET/MR in paediatric imaging and to illustrate these by presenting cases from clinical practice.
Keywords: PET/MRI, children, applications
Introduction Paediatric imaging has emerged as a key application of combined PET/MRI. Especially in the context of paediatric oncologic imaging 18F-FDG-PET/MRI has been shown to provide a comprehensive assessment of tumour spread and efficient monitoring of therapeutic courses [1-3]. Besides diagnostic advantages by the combination of functional and highly resolved morphological data sampling, PET/MRI is associated with significantly lower radiation exposure compared to alternative imaging modalities such as CT or PET/CT. Furthermore, a reduction in the total number of required imaging studies has been reported when using PET/MRI which simplifies clinical workflows and reduced the number of necessary sedation in younger children. Compared to whole-body MRI, the addition of PET can improve diagnostic specificity especially in the post-therapeutic situation [1,2,4]. Paediatric oncologic PET/MRI can thus be applied in all clinical situations where whole-body imaging (MR or CT) and PET are indicated. This includes primary staging, therapy monitoring and follow-up imaging of paediatric patients with solid malignancies such as lymphoma, sarcoma, and neuroblastoma [5-9]. Furthermore, PET/MRI is a valuable tool in neurooncology [10] enabling precise imaging of central and peripheral neurogenic malignancies. A specific application in this context is monitoring of patients with Type I neurofibromatosis with the purpose of early detection of malignant transformation [11]. The role of PET/MRI in non-oncologic imaging has not been this clearly defined in children yet. Still, numerous non-oncologic applications of PET/MRI are conceivable mainly targeting inflammatory conditions. 18F-FDG-PET can provide unique information about inflammatory activity [12,13]. The combination with morphologic data from MRI may offer a comprehensive tool for the imaging of disease spread and activity in disorders including chronic inflammatory bowel disease, rheumatoid disorders or chronic infectious disease.
It is important to point out that the availability of combined PET/MRI is still limited. The primary role of PET/MRI in the presence can also be seen in the field of translational imaging research. One application in this context is the evaluation and cross-correlation of novel imaging techniques, specifically of novel PET tracers. The unique possibility of multiparametric imaging in PET/MRI allows for a better understanding of the distribution and biological meaning of tracer accumulations. Using the same multiparametric imaging techniques PET/MRI can also be used to visualize the biological effect of novel therapeutic agents thus possibly contributing to a more efficient translation into clinical use. The purpose of this review article is to discuss the above-mentioned applications of combined PET/MR in paediatric imaging and to illustrate these by presenting cases from clinical practice.
FDG-PET/MRI in Lymphoma FDG-PET is a central element of the diagnostic workup in patients with Hodgkin lymphoma and is mainly used for primary staging and evaluation of treatment response. The choice of appropriate therapeutic schemes with or without irradiation among other factors also depends mainly on response assessment by FDG-PET after initial chemotherapy according to the EuroNet-PHL protocol [8,14-16]. MRI can add additional information in imaging of paediatric lymphoma in cases of low or unknown FDG-avidity of the tumour, in cases of unclear or ambivalent PET findings (e.g. differentiation of brown adipose tissue) as well as for the assessment of tumour- or therapy-associated complications (e.g. osteonecrosis after chemotherapy) [17]. Thus, PET/MRI as a combined modality offers comprehensive imaging in paediatric lymphoma patients. Figure 1 illustrates the application of combined PET/MRI in primary staging and follow-up of patients with Hodgkin Lymphoma.
FDG-PET/MRI in sarcoma MRI plays a central role in the diagnosis and therapy planning of paediatric sarcoma by offering accurate local imaging of the primary tumour and by enabling whole body imaging to assess possible metastatic spread [7,18]. A possible limitation of MRI in this context is the detection of small pulmonary metastasis; thus an additional CT of the thorax is generally recommended in the primary staging of paediatric sarcoma patients [19]. FDG-PET has been shown to allow for an estimation of the metabolic tumour volume of sarcoma thus offering prognostic information [20,21]. The possible diagnostic advantage of combined PET/MR is illustrated in Figure 2.
In addition to its role in primary staging, combined FDG-PET/MRI can provide important diagnostic information on a post therapeutic setting. In this context, MRI alone may show reduced specificity for the discrimination between posttherapeutic changes and possible tumour recurrence [4]. The addition of FDG-PET using combined PET/MRT can give important clinical information and guide patient management as shown in Figure 3.
68Ga-DOTATATE-PET/MRI in neuroendocrine tumours For certain tumour entities, non-FDG PET tracers can provide specific tumour detection enabling precise localization of tumour spread. The prime example for the use of specific PET tracers is imaging of neuroendocrine tumors using Somatostatin receptor (SSR) ligands such as 68Ga-DOTATATE. These tracers specifically bind to SSR on neuroendocrine tumour cells and thus allow for precise assessment of tumour spread [22]. Figure 4 gives an example for the use of 68GaDOTATATE-PET/MRI in a clinical setting.
FDG-PET/MRI in Type I neurofibromatosis Imaging of patients with Type 1 Neurofibromatosis is a particular application for both, PET and MRI. 18F-FDG-PET is used to monitor and detect a possible malignant transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumours. Elevated FDG-uptake is an indicator for a possible malignant transformation although different cut-off value for standardized uptake values (SUV) exist [11,23]. MRI, on the other hand, offers a detailed anatomical depiction of the often widespread tumours and in addition the possibility of further biological characterisation, e.g. using diffusion-weighted imaging (DWI) [24]. The patient example of Figure 5 shows how FDG-PET/MRI can guide patient management in this patient population.
PET/MRI in primary CNS-tumours CNS imaging is one of the most widely implemented applications of MRI. The excellent soft tissue contrast and possibilities of functional imaging allow for a precise characterization of CNS anatomy and pathologies. PET, on the other hand, can add additional information about tumour metabolism [10]. Mainly amino acid tracers such as 18F-FET or 11C-Methionine are used for the purpose of imaging primary CNS tumours [25]. Complementary information from PET and MRI can help in tumour grading and biopsy planning as well as detection of recurrent tumour in a post-therapeutic setting. Figure 6 shows an example of initial tumour characterization using 11C-Methionine PET/MRI.
Non-oncologic applications of FDG-PET/MRI
Besides the numerous applications in paediatric oncology, PET/MRI may also play a role in imaging of non-oncologic diseases. 18F-FDG-PET allows for functional assessment of inflammatory changes and is thus used for the diagnosis and therapy assessment of acute and chronic inflammatory diseases such as fever of unknown origin, chronic inflammatory bowel disease, vasculitis and rheumatoid disease [26]. MRI may add further information by offering detailed information about morphological and functional changes of inflammation such as assessment of perfusion, oedema or wall thickening, etc. [27,28]. Figures 7 and 8 provide examples for possible applications of PET/MRI in inflammatory conditions. A further interesting non-oncologic application is the assessment of structural and functional changes of the brain in epileptic disorders. MRI is the modality-of-choice for the detection of morphological correlates for epileptic foci such as primary CNS tumours or focal cortical dysplasia. Using FDG-PET, the functional extent of epileptic foci can be assessed by depicting areas of asymmetric cortical hypometabolism [29,30] (Figure 9). A possible concern using PET/MRI for non-oncologic purposes is the diagnostic radiation exposure associated with PET. However, recent developments allow for targeted PET imaging with significantly reduced activity by prolonging acquisition time and using state-of the-art PET technology [31,32] (Figure 8).
PET/MRI examination protocols in paediatric oncology Compared to alternative imaging modalities, combined PET/MRI display a higher level of technical complexity. Especially the simultaneous acquisition of PET and MRI demands an efficient planning of the single examination steps in order to limit acquisition time and optimize diagnostic output.
The course of a typical oncologic whole body FDG-PET/MRI examination is shown in Figure 10. Basically, the examination consists of a first part with whole body PET acquisition and simultaneous whole-body MRI followed by MR-only measurements of specific regions of interest. Total acquisition time of such an extensive protocol can extend over 1-1.5 hours. Simultaneous whole body MRI usually consists of T1-weighted gradient-echo sequences for MR-based attenuation corrcection, inversion recovery (STIR) sequences in coronal orientation as well as diffusion-weighted MRI (DWI). Depending on the clinical question and the applied tracer, protocols need to be adapted and optimized.
Considerations In this review article we discussed possible clinical applications of combined PET/MRI in children. We also provided a series of clinical paediatric cases demonstrating the use of combined PET/MRI in children in the daily practice. With this composition of cases, we aimed to illustrate the potential and the possible applications of this still very novel imaging modality. One main advantage of PET/MRI over PET/CT specifically for paediatric applications is the considerable reduction in diagnostic radiation exposure. According to recent study results, a reduction of radiation exposure by about 50 to 80 % is achieved by replacing CT with MRI depending on the CT protocol [1,2,33]. The main technical challenge of PET/MRI compared to PET/CT is MR-based PET attenuation correction. Using the so-called segmentation-based attenuation correction enables overall reliable standardized uptake value (SUV) quantification is PET/MRI with relevant quantification errors around skeletal structures due to the neglection of bone [2]. A solution to this problem is the implementation of atlas-based attenuation correction in paediatric PET/MRI that allows for precise quantification of PET SUVs [34].
As discussed above, numerous oncologic and non-oncologic applications of combined PET/MRI are conceivable. In our experience the combination of highly resolved MRI that is very sensitive and specific PET imaging is promising to increase diagnostic accuracy and confidence. However, more prospective clinical trials are necessary to provide scientific evidence. Especially in paediatric imaging, the completion of such studies is a challenge due to the often limited number of patients and high ethical demands. A multi-centric study approach should thus be encouraged. One possible approach to generate reliable data would be the implementation of paediatric PET/MR imaging registries pooling examinations from different sites and providing the necessary data to answer central clinical questions. Similar approaches have been successful in the past for other imaging applications including cardiac MR imaging. For paediatric oncologic imaging, PET/MRI has already been shown to be a reliable and precise diagnostic tool [1,2]. Future studies should be focused on specific patient groups and clinical questions and investigate non-oncologic applications.
In conclusion, PET/MRI has the potential of being a valuable diagnostic tool for the assessment of oncologic and non-oncologic disorders in children. Further scientific efforts are necessary to establish this novel modality as a routine clinical modality in paediatric imaging.
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Figure captions Figure 1: 15-year-old boy with Hodgkin Lymphoma. This patient presented with B-symptoms and enlarged cervical lymph nodes in an outpatient setting. Biopsy of an enlarged cervical lymph node established the diagnosis of classical Hodgkin lymphoma. Whole body 18F-FDG PET/MR was performed for initial staging. 18F FDG-PET (A.I) and coronal short tau inversion recovery MRI (A.II) show cervical, thoracic and pelvic lymph node involvement. MR Dixon imaging (Fat image B.I) shows that cervical FDG-uptake (B.II) is not located within the fatty tissue and this is not activated brown adipose tissue. MRI revealed additional osseous lesions (C.1, arrow) that were FDG-PET negative (C.II, arrow) but still interpreted as suspicious resulting in a stage IV classification. These bone lesions were diminished after therapy (C.I, C.II) confirming this interpretation.
Figure 2: 17-year-old girl with osteosarcoma of the right humerus. This patient presented with swelling and pain in the left upper arm. A local MRI and consecutive biopsy led to the diagnosis of a chondroblastic osteosarcoma of the left humerus. FDG-PET/MRI was performed to assess the precise local tumour spread and possible distant metastases. Staging with FDG-PET/MRI (A.I) shows the FDG-avid primary tumour of the left upper limb. The metabolic tumour volume as shown by PET is smaller than the tumourrelated morphological changes in MRI (A.II and A.III; morphologic tumour border red line, metabolic tumour border red dotted line). PET/MR after neoadjuvant chemotherapy (B) shows a reduction in size and metabolism. Joint-preserving surgical resection was possible following the initial metabolic extent of the primary tumour.
Figure 3: 8-year-old boy with Ewing-sarcoma of the thoracic spine. This patient was diagnosed with Ewing sarcoma of the thoracic spine (A: pre-therapeutic MRI). After chemotherapy, surgical resection and radiotherapy, a morphologically suspicious focal osseous lesion was detected in MRI (B.I: coronal contrast enhanced T1w TSE; arrow) without focal 18F-FDG-uptake in PET (B.II). In a subsequent follow-up examination, this lesion had declined confirming the diagnosis of posttherapeutic changes rather than local tumour recurrence.
Figure 4: 14-year-old boy with bronchial carcinoid tumour of the right lower lobe. This patient presented with recurrent pulmonary infections of the right lower lobe. Bronchoscopy revealed a bronchial carcinoid tumour of the right lower lobe. Whole body staging was performed by 68Ga-DOTATATE-PET/MRI (Figure 4). 68GA-DOTATATE-PET (A) shows focal tracer uptake of the primary tumour. MRI enables morphological depiction of the tumour (coronal short tau inversion recovery imaging, B.I) as well as functional characterization using diffusion-weighted imaging (Apparent diffusion coefficient map of diffusion weighted imaging, C.I). Follow-up imaging after surgical resection shows a lung lesion of the left lower lobe without tracer uptake, thus correctly interpreted as inflammatory changes without evidence of tumour relapse or metastatic disease.
Figure 5:10-year-old girl with Type 1 Neurofibromatosis. This patient with known Type I neurofibromatosis was monitored using FDG-PET/MRI. MRI shows an enlarged plexiform neurofibroma of the left abdomen (A.I: coronal short tau inversion recovery sequence) with relative restriction of water diffusion (B.I: Apparent diffusion coefficient map of diffusion weighted imaging). 18-F-FDG-PET (A.II and B.II) shows focal FDG-uptake within this lesion. After surgical resection and histopathological confirmation of malignant transformation no residual FDG-avid masses were detectable (C).
Figure 6: 10-year-old boy with Ganglioglioma of the left temporal lobe. This patient presented with recurrent seizures of unknown aetiology. MRI (T2w TSE sequence A.I) shows an asymmetric lesion without contrast enhancement (Contrast-enhanced T1 TSE sequence, A.II). 11C-Methionine PET reveals focal tracer uptake within this lesion (A.III). Biopsy confirms the suspected diagnosis of a low-grade primary brain tumour which is subsequently resected (follow-up after surgical resection, B).
Figure 7: 17-year-old girl with and severe pulmonary manifestations of cystic fibrosis. This patient with referred with the question of the presence of acute pulmonary infection before planned lung transplantation. MRI (transversal T2w TSE sequence, A.I and B.I) shows inflammatory changes but cannot discriminate between chronic and acute inflammation. 18F-FDG-PET (A.II, B.II, C) shows active inflammation of the lower lobes. This PET examination was acquired using an administered tracer activity of only 47 MBq 18F-FDG (1 MBq 18F-FDG per kg bodyweight) over a measurement period of 20 minutes.
Figure 8: 3-year-old boy with Crohn’s-lie disease. This young patient with a genetic immune dysregulation syndrome and known Crohn’s-like disease presented with recurrent fever without a clear clinical correlate. 18F-FDG was performed to screen for possible foci of inflammation and to assess the current state of bowel inflammation 18F-FDG-PET (A) reveals multifocal intestinal inflammation. MRI (B.I contrast-enhanced T1-weithed Flash sequence) shows segmental stenoses and marked contrast enhancement of the intestinal wall (arrow). PET/MRI fusion shown in B.II.
Figure 9: 2-year-old girl with focal cortical dysplasia. This toddler presented with recurring clonic and asymmetric tonic seizures. Combined FDGPET/MRI was performed in order to identify possible epileptogenic foci. Using PET/MRI, this assessment could be performed in a single examination with a single sedation avoiding a second sedation in the case of separated PET and MRI examinations. MRI (T2w TSE sequence, left and middle A.I) shows streaky hyperintensities of the left postcentral gyrus. FDG-PET (right) reveals asymmetric hypometabolism.
Figure 10: Typical protocol of an oncologic whole body FDG-PET/MRI examination. After FDG-administration and uptake time, simultaneous whole-body PET/MRI is performed followed by MR-only measurements of specific regions of interest.
S0720-048X(17)30022-0 http://dx.doi.org/doi:10.1016/j.ejrad.2017.01.018 EURR 7706
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
16-11-2016 16-1-2017 17-1-2017
Please cite this article as: Gatidis Sergios, Bender Benjamin, Reimold Matthias, Sch¨afer Jurgen ¨ F.PET/MRI in children.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.01.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/MRI in children
Sergios Gatidis MD1, Benjamin Bender MD 2, Matthias Reimold MD 3, Jürgen F. Schäfer MD1
1
University of Tuebingen, Department of Radiology, Diagnostic and Interventional
Radiology 2
University of Tuebingen, Department of Radiology, Diagnostic and Interventional
Neuroradiology 3
University of Tuebingen, Department of Radiology, Nuclear Medicine
Correspondence:
Dr. Sergios Gatidis University of Tuebingen Department of Radiology Hoppe-Seyler-Str. 3, 72076 Tuebingen [email protected]
Highlights:
combined PET/MRI is a versatile diagnostic modality that can be used for numerous oncologic and non-oncologic applications in paediatric medicine
using PET/MRI, diagnostic advantages of PET and MRI can be combined providing additional insight into pathological processes
the combination of PET and MRI may help reduce the number of necessary imaging studies and thereby diagnostic radiation exposure and number of sedations
Abstract During the past decade, combined PET/MRI has been translated from a basic technical concept to a clinical research tool and a clinically applied hybrid imaging modality. Numerous clinical and scientific applications have been proposed for this novel hybrid modality including oncologic, neurologic and cardiovascular imaging. Among these, PET/MRI in children has emerged as a key application, not only due to possible diagnostic advantages but also because of reduced radiation exposure compared to alternative techniques. A variety of clinical indications exists for the use of PET/MR imaging in children mainly in but not limited to the field of paediatric oncology. The purpose of this review article is to discuss possible applications of combined PET/MR in paediatric imaging and to illustrate these by presenting cases from clinical practice.
Keywords: PET/MRI, children, applications
Introduction Paediatric imaging has emerged as a key application of combined PET/MRI. Especially in the context of paediatric oncologic imaging 18F-FDG-PET/MRI has been shown to provide a comprehensive assessment of tumour spread and efficient monitoring of therapeutic courses [1-3]. Besides diagnostic advantages by the combination of functional and highly resolved morphological data sampling, PET/MRI is associated with significantly lower radiation exposure compared to alternative imaging modalities such as CT or PET/CT. Furthermore, a reduction in the total number of required imaging studies has been reported when using PET/MRI which simplifies clinical workflows and reduced the number of necessary sedation in younger children. Compared to whole-body MRI, the addition of PET can improve diagnostic specificity especially in the post-therapeutic situation [1,2,4]. Paediatric oncologic PET/MRI can thus be applied in all clinical situations where whole-body imaging (MR or CT) and PET are indicated. This includes primary staging, therapy monitoring and follow-up imaging of paediatric patients with solid malignancies such as lymphoma, sarcoma, and neuroblastoma [5-9]. Furthermore, PET/MRI is a valuable tool in neurooncology [10] enabling precise imaging of central and peripheral neurogenic malignancies. A specific application in this context is monitoring of patients with Type I neurofibromatosis with the purpose of early detection of malignant transformation [11]. The role of PET/MRI in non-oncologic imaging has not been this clearly defined in children yet. Still, numerous non-oncologic applications of PET/MRI are conceivable mainly targeting inflammatory conditions. 18F-FDG-PET can provide unique information about inflammatory activity [12,13]. The combination with morphologic data from MRI may offer a comprehensive tool for the imaging of disease spread and activity in disorders including chronic inflammatory bowel disease, rheumatoid disorders or chronic infectious disease.
It is important to point out that the availability of combined PET/MRI is still limited. The primary role of PET/MRI in the presence can also be seen in the field of translational imaging research. One application in this context is the evaluation and cross-correlation of novel imaging techniques, specifically of novel PET tracers. The unique possibility of multiparametric imaging in PET/MRI allows for a better understanding of the distribution and biological meaning of tracer accumulations. Using the same multiparametric imaging techniques PET/MRI can also be used to visualize the biological effect of novel therapeutic agents thus possibly contributing to a more efficient translation into clinical use. The purpose of this review article is to discuss the above-mentioned applications of combined PET/MR in paediatric imaging and to illustrate these by presenting cases from clinical practice.
FDG-PET/MRI in Lymphoma FDG-PET is a central element of the diagnostic workup in patients with Hodgkin lymphoma and is mainly used for primary staging and evaluation of treatment response. The choice of appropriate therapeutic schemes with or without irradiation among other factors also depends mainly on response assessment by FDG-PET after initial chemotherapy according to the EuroNet-PHL protocol [8,14-16]. MRI can add additional information in imaging of paediatric lymphoma in cases of low or unknown FDG-avidity of the tumour, in cases of unclear or ambivalent PET findings (e.g. differentiation of brown adipose tissue) as well as for the assessment of tumour- or therapy-associated complications (e.g. osteonecrosis after chemotherapy) [17]. Thus, PET/MRI as a combined modality offers comprehensive imaging in paediatric lymphoma patients. Figure 1 illustrates the application of combined PET/MRI in primary staging and follow-up of patients with Hodgkin Lymphoma.
FDG-PET/MRI in sarcoma MRI plays a central role in the diagnosis and therapy planning of paediatric sarcoma by offering accurate local imaging of the primary tumour and by enabling whole body imaging to assess possible metastatic spread [7,18]. A possible limitation of MRI in this context is the detection of small pulmonary metastasis; thus an additional CT of the thorax is generally recommended in the primary staging of paediatric sarcoma patients [19]. FDG-PET has been shown to allow for an estimation of the metabolic tumour volume of sarcoma thus offering prognostic information [20,21]. The possible diagnostic advantage of combined PET/MR is illustrated in Figure 2.
In addition to its role in primary staging, combined FDG-PET/MRI can provide important diagnostic information on a post therapeutic setting. In this context, MRI alone may show reduced specificity for the discrimination between posttherapeutic changes and possible tumour recurrence [4]. The addition of FDG-PET using combined PET/MRT can give important clinical information and guide patient management as shown in Figure 3.
68Ga-DOTATATE-PET/MRI in neuroendocrine tumours For certain tumour entities, non-FDG PET tracers can provide specific tumour detection enabling precise localization of tumour spread. The prime example for the use of specific PET tracers is imaging of neuroendocrine tumors using Somatostatin receptor (SSR) ligands such as 68Ga-DOTATATE. These tracers specifically bind to SSR on neuroendocrine tumour cells and thus allow for precise assessment of tumour spread [22]. Figure 4 gives an example for the use of 68GaDOTATATE-PET/MRI in a clinical setting.
FDG-PET/MRI in Type I neurofibromatosis Imaging of patients with Type 1 Neurofibromatosis is a particular application for both, PET and MRI. 18F-FDG-PET is used to monitor and detect a possible malignant transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumours. Elevated FDG-uptake is an indicator for a possible malignant transformation although different cut-off value for standardized uptake values (SUV) exist [11,23]. MRI, on the other hand, offers a detailed anatomical depiction of the often widespread tumours and in addition the possibility of further biological characterisation, e.g. using diffusion-weighted imaging (DWI) [24]. The patient example of Figure 5 shows how FDG-PET/MRI can guide patient management in this patient population.
PET/MRI in primary CNS-tumours CNS imaging is one of the most widely implemented applications of MRI. The excellent soft tissue contrast and possibilities of functional imaging allow for a precise characterization of CNS anatomy and pathologies. PET, on the other hand, can add additional information about tumour metabolism [10]. Mainly amino acid tracers such as 18F-FET or 11C-Methionine are used for the purpose of imaging primary CNS tumours [25]. Complementary information from PET and MRI can help in tumour grading and biopsy planning as well as detection of recurrent tumour in a post-therapeutic setting. Figure 6 shows an example of initial tumour characterization using 11C-Methionine PET/MRI.
Non-oncologic applications of FDG-PET/MRI
Besides the numerous applications in paediatric oncology, PET/MRI may also play a role in imaging of non-oncologic diseases. 18F-FDG-PET allows for functional assessment of inflammatory changes and is thus used for the diagnosis and therapy assessment of acute and chronic inflammatory diseases such as fever of unknown origin, chronic inflammatory bowel disease, vasculitis and rheumatoid disease [26]. MRI may add further information by offering detailed information about morphological and functional changes of inflammation such as assessment of perfusion, oedema or wall thickening, etc. [27,28]. Figures 7 and 8 provide examples for possible applications of PET/MRI in inflammatory conditions. A further interesting non-oncologic application is the assessment of structural and functional changes of the brain in epileptic disorders. MRI is the modality-of-choice for the detection of morphological correlates for epileptic foci such as primary CNS tumours or focal cortical dysplasia. Using FDG-PET, the functional extent of epileptic foci can be assessed by depicting areas of asymmetric cortical hypometabolism [29,30] (Figure 9). A possible concern using PET/MRI for non-oncologic purposes is the diagnostic radiation exposure associated with PET. However, recent developments allow for targeted PET imaging with significantly reduced activity by prolonging acquisition time and using state-of the-art PET technology [31,32] (Figure 8).
PET/MRI examination protocols in paediatric oncology Compared to alternative imaging modalities, combined PET/MRI display a higher level of technical complexity. Especially the simultaneous acquisition of PET and MRI demands an efficient planning of the single examination steps in order to limit acquisition time and optimize diagnostic output.
The course of a typical oncologic whole body FDG-PET/MRI examination is shown in Figure 10. Basically, the examination consists of a first part with whole body PET acquisition and simultaneous whole-body MRI followed by MR-only measurements of specific regions of interest. Total acquisition time of such an extensive protocol can extend over 1-1.5 hours. Simultaneous whole body MRI usually consists of T1-weighted gradient-echo sequences for MR-based attenuation corrcection, inversion recovery (STIR) sequences in coronal orientation as well as diffusion-weighted MRI (DWI). Depending on the clinical question and the applied tracer, protocols need to be adapted and optimized.
Considerations In this review article we discussed possible clinical applications of combined PET/MRI in children. We also provided a series of clinical paediatric cases demonstrating the use of combined PET/MRI in children in the daily practice. With this composition of cases, we aimed to illustrate the potential and the possible applications of this still very novel imaging modality. One main advantage of PET/MRI over PET/CT specifically for paediatric applications is the considerable reduction in diagnostic radiation exposure. According to recent study results, a reduction of radiation exposure by about 50 to 80 % is achieved by replacing CT with MRI depending on the CT protocol [1,2,33]. The main technical challenge of PET/MRI compared to PET/CT is MR-based PET attenuation correction. Using the so-called segmentation-based attenuation correction enables overall reliable standardized uptake value (SUV) quantification is PET/MRI with relevant quantification errors around skeletal structures due to the neglection of bone [2]. A solution to this problem is the implementation of atlas-based attenuation correction in paediatric PET/MRI that allows for precise quantification of PET SUVs [34].
As discussed above, numerous oncologic and non-oncologic applications of combined PET/MRI are conceivable. In our experience the combination of highly resolved MRI that is very sensitive and specific PET imaging is promising to increase diagnostic accuracy and confidence. However, more prospective clinical trials are necessary to provide scientific evidence. Especially in paediatric imaging, the completion of such studies is a challenge due to the often limited number of patients and high ethical demands. A multi-centric study approach should thus be encouraged. One possible approach to generate reliable data would be the implementation of paediatric PET/MR imaging registries pooling examinations from different sites and providing the necessary data to answer central clinical questions. Similar approaches have been successful in the past for other imaging applications including cardiac MR imaging. For paediatric oncologic imaging, PET/MRI has already been shown to be a reliable and precise diagnostic tool [1,2]. Future studies should be focused on specific patient groups and clinical questions and investigate non-oncologic applications.
In conclusion, PET/MRI has the potential of being a valuable diagnostic tool for the assessment of oncologic and non-oncologic disorders in children. Further scientific efforts are necessary to establish this novel modality as a routine clinical modality in paediatric imaging.
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Figure captions Figure 1: 15-year-old boy with Hodgkin Lymphoma. This patient presented with B-symptoms and enlarged cervical lymph nodes in an outpatient setting. Biopsy of an enlarged cervical lymph node established the diagnosis of classical Hodgkin lymphoma. Whole body 18F-FDG PET/MR was performed for initial staging. 18F FDG-PET (A.I) and coronal short tau inversion recovery MRI (A.II) show cervical, thoracic and pelvic lymph node involvement. MR Dixon imaging (Fat image B.I) shows that cervical FDG-uptake (B.II) is not located within the fatty tissue and this is not activated brown adipose tissue. MRI revealed additional osseous lesions (C.1, arrow) that were FDG-PET negative (C.II, arrow) but still interpreted as suspicious resulting in a stage IV classification. These bone lesions were diminished after therapy (C.I, C.II) confirming this interpretation.
Figure 2: 17-year-old girl with osteosarcoma of the right humerus. This patient presented with swelling and pain in the left upper arm. A local MRI and consecutive biopsy led to the diagnosis of a chondroblastic osteosarcoma of the left humerus. FDG-PET/MRI was performed to assess the precise local tumour spread and possible distant metastases. Staging with FDG-PET/MRI (A.I) shows the FDG-avid primary tumour of the left upper limb. The metabolic tumour volume as shown by PET is smaller than the tumourrelated morphological changes in MRI (A.II and A.III; morphologic tumour border red line, metabolic tumour border red dotted line). PET/MR after neoadjuvant chemotherapy (B) shows a reduction in size and metabolism. Joint-preserving surgical resection was possible following the initial metabolic extent of the primary tumour.
Figure 3: 8-year-old boy with Ewing-sarcoma of the thoracic spine. This patient was diagnosed with Ewing sarcoma of the thoracic spine (A: pre-therapeutic MRI). After chemotherapy, surgical resection and radiotherapy, a morphologically suspicious focal osseous lesion was detected in MRI (B.I: coronal contrast enhanced T1w TSE; arrow) without focal 18F-FDG-uptake in PET (B.II). In a subsequent follow-up examination, this lesion had declined confirming the diagnosis of posttherapeutic changes rather than local tumour recurrence.
Figure 4: 14-year-old boy with bronchial carcinoid tumour of the right lower lobe. This patient presented with recurrent pulmonary infections of the right lower lobe. Bronchoscopy revealed a bronchial carcinoid tumour of the right lower lobe. Whole body staging was performed by 68Ga-DOTATATE-PET/MRI (Figure 4). 68GA-DOTATATE-PET (A) shows focal tracer uptake of the primary tumour. MRI enables morphological depiction of the tumour (coronal short tau inversion recovery imaging, B.I) as well as functional characterization using diffusion-weighted imaging (Apparent diffusion coefficient map of diffusion weighted imaging, C.I). Follow-up imaging after surgical resection shows a lung lesion of the left lower lobe without tracer uptake, thus correctly interpreted as inflammatory changes without evidence of tumour relapse or metastatic disease.
Figure 5:10-year-old girl with Type 1 Neurofibromatosis. This patient with known Type I neurofibromatosis was monitored using FDG-PET/MRI. MRI shows an enlarged plexiform neurofibroma of the left abdomen (A.I: coronal short tau inversion recovery sequence) with relative restriction of water diffusion (B.I: Apparent diffusion coefficient map of diffusion weighted imaging). 18-F-FDG-PET (A.II and B.II) shows focal FDG-uptake within this lesion. After surgical resection and histopathological confirmation of malignant transformation no residual FDG-avid masses were detectable (C).
Figure 6: 10-year-old boy with Ganglioglioma of the left temporal lobe. This patient presented with recurrent seizures of unknown aetiology. MRI (T2w TSE sequence A.I) shows an asymmetric lesion without contrast enhancement (Contrast-enhanced T1 TSE sequence, A.II). 11C-Methionine PET reveals focal tracer uptake within this lesion (A.III). Biopsy confirms the suspected diagnosis of a low-grade primary brain tumour which is subsequently resected (follow-up after surgical resection, B).
Figure 7: 17-year-old girl with and severe pulmonary manifestations of cystic fibrosis. This patient with referred with the question of the presence of acute pulmonary infection before planned lung transplantation. MRI (transversal T2w TSE sequence, A.I and B.I) shows inflammatory changes but cannot discriminate between chronic and acute inflammation. 18F-FDG-PET (A.II, B.II, C) shows active inflammation of the lower lobes. This PET examination was acquired using an administered tracer activity of only 47 MBq 18F-FDG (1 MBq 18F-FDG per kg bodyweight) over a measurement period of 20 minutes.
Figure 8: 3-year-old boy with Crohn’s-lie disease. This young patient with a genetic immune dysregulation syndrome and known Crohn’s-like disease presented with recurrent fever without a clear clinical correlate. 18F-FDG was performed to screen for possible foci of inflammation and to assess the current state of bowel inflammation 18F-FDG-PET (A) reveals multifocal intestinal inflammation. MRI (B.I contrast-enhanced T1-weithed Flash sequence) shows segmental stenoses and marked contrast enhancement of the intestinal wall (arrow). PET/MRI fusion shown in B.II.
Figure 9: 2-year-old girl with focal cortical dysplasia. This toddler presented with recurring clonic and asymmetric tonic seizures. Combined FDGPET/MRI was performed in order to identify possible epileptogenic foci. Using PET/MRI, this assessment could be performed in a single examination with a single sedation avoiding a second sedation in the case of separated PET and MRI examinations. MRI (T2w TSE sequence, left and middle A.I) shows streaky hyperintensities of the left postcentral gyrus. FDG-PET (right) reveals asymmetric hypometabolism.
Figure 10: Typical protocol of an oncologic whole body FDG-PET/MRI examination. After FDG-administration and uptake time, simultaneous whole-body PET/MRI is performed followed by MR-only measurements of specific regions of interest.