Review Article Clinics in Pediatrics Published: 23 Sep, 2019

Current Perspectives of Pediatric PET/MRI

Arie Franco* Department of Imaging Sciences, University of Rochester Medical Center, USA

Abstract PET/MRI is a relatively novel integrated modality with the potential to replace PET/CT, specifically in pediatric patients. PET/MRI provides incremental value in interpreting studies with superb soft tissue contrast that spares the risk of radiation. We reviewed the literature and described the current viewpoints, including advantages and disadvantages of this emerging new modality. Keywords: Positron emission ; Magnetic resonance imaging; Pediatric imaging; Oncology imaging

Introduction PET/MRI, similar to PET/CT, is an emerging imaging modality that enables physicians to obtain imaging studies for staging, monitoring and assessing tumor treatments. Although both PET/MRI and PET/CT enable obtaining metabolic information, PET/MRI produces images with a higher soft tissue contrast than PET/CT, an incremental step in formulating a differential diagnosis. PET/MRI, a promising tool in the clinical setting for future applications [1], is complementary to other diagnostic imaging tools in oncological and in neurological applications. The radiation dose of PET/CT is spared, particularly when compared to the attenuation correction with PET/CT. Its ability to perform two studies (PET and MRI) in one setting spares children multiple sedations and associated risks [2]. The first PET/MRI was introduced by Siemens in 2006 (Brain PET, Erlangen, Germany) and was limited to neurological application. This new imaging modality integrates a superb soft-tissue contrast with the highly efficient biological and metabolic sequences of the positron emission tomography. PET/MRI protocols were developed for different types of oncologic applications that decrease the radiation dose [1,3]. Indications and Applications OPEN ACCESS The indications for PET/MRI are similar to the indications for PET/CT. The main benefit and the primary advantage to PET/MRI over PET/CT is the reduced radiation risk to children that *Correspondence: are more sensitive to the increasing risk of radiation. The radiopharmaceutical dose of PET/MRI Arie Franco, Department of Imaging is significantly less than that of PET/CT. Moreover, the anatomic resolving power and the soft- Sciences, University of Rochester tissue contrast are significantly improved by the hybrid PET/MRI imaging [4]. The feasibility of this Medical Center, 601 Elmwood Avenue, newly integrated modality has already proven to be acceptable in a clinical setting without any loss Box 648, Rochester, New York, 14642, of information and with excellent image quality in a short amount of time that is in line with the USA, acceptable time required for PET/CT [4-7]. A child-specific protocol for PET/MR in oncology was E-mail: [email protected]. edu suggested [8], involving whole-body imaging and additional local sequences to visualize a region Received Date: 27 Aug 2019 of primary concern. The oncologic indications of PET/MR include initial assessment of a tumor Accepted Date: 16 Sep 2019 with staging and serial monitoring of treatment. Similar to PET/CT, PET/MRI is a very sound and Published Date: 23 Sep 2019 reliable modality for the detection of hyper metabolic tumor lesions [6]. The main role and the Citation: utility of the new hybrid modality that enables simultaneous data acquisition in clinical and research Franco A. Current Perspectives of applications have yet to be defined. However, it will be best suited in pediatric disease and organ- Pediatric PET/MRI. Clin Pediatri. 2019; specific situations that require patients to undergo repeated imaging and the radiation dose needs to 2: 1016. be kept as low as needed and reasonably achievable [9]. Copyright © 2019 Arie Franco. This is Whole-body MRI is mainly applied in oncology. It enables detection of tumors, monitors an open access article distributed under extension and spread, and evaluates complications. A high diagnostic potential of whole-body the Creative Commons Attribution MRI compared to PET and to plain in the pediatric population was demonstrated License, which permits unrestricted (Figure 1). Potential indications for whole-body MRI include diagnosis and evaluation of malignant use, distribution, and reproduction in and benign tumors, vascular malformations, myopathies, osteonecrosis, and acute and chronic any medium, provided the original work osteomyelitis. It was reported that whole-body MRI can also be used in evaluating virtual autopsy is properly cited. and for assessment of non-accidental trauma. Diffusion-weighted imaging and body-fat mapping

Remedy Publications LLC. 1 2019 | Volume 2 | Article 1016 Arie Franco Clinics in Pediatrics - Pediatric Critical Care has been incorporated with whole-body MRI [10]. PET/MRI is being recognized as very accurate in the staging of soft-tissue sarcomas and osseous malignant tumors. PET/MRI is as accurate as PET/CT with a whole-body imaging staging method. T-staging and N-staging were found to be very accurate and M-staging was found to be very precise in the bone, liver, and brain [11]. Functional MRI may augment the precision in the differentiation of tumor recurrence such as rectal cancer from a scar tissue [12]. FDG PET is useful in the primary staging, in tailoring therapeutic intensity and in the early response assessment in children with the different subtypes of lymphoma and combination with MRI seems to optimize the protocols further [13]. In order to decrease the number of images, the scanning time, and the radiation burden, whole-body MRI should be the primary diagnostic imaging tool in evaluating patients with suspected bone tumors prior to obtaining any additional detailed focal imaging [14]. It was found that 18F-FDG PET/MRI are a primary imaging modality for initial 18 tumor staging (Figure 2). MRI alone is more accurate than F-FDG Figure 1: Fused PET/MRI coronal view of a 16-year old with Hodgkin’s PET and 18F-FDG PET/MRI during initial diagnosis. However, at lymphoma demonstrates increased uptake of 18-F-FDG in the mediastinum, follow-up a superiority of 18F-FDG PET alone was demonstrated [15]. in the right cardiophrenic angle, and in the abdomen. FDG PET and PET/CT are excellent tools that are useful in is very important to avoid misinterpretation of benign lesions or evaluating children with unexplained inflammation and fever of physiologic uptake as malignancies. The use of integrated PET/MRI unknown origin. It is important to depict inflammation in children or integrated PET/CT scanners is associated with artifacts and with that is not trauma related. Inflammation can be accurately localized pitfalls, such as attenuation correction and misregistration artifacts with an integrated PET and CT or with PET and MRI, described as [23]. A dose of 5.18 MBq/kg to 7.4 MBq/kg (0.14 mCi/kg to 0.20 mCi/ very superb tools [16]. These hybrid tools are very useful in evaluating kg) is used for pediatric oncology patients [24]. children with bacterial infections when conventional diagnostic techniques did not yield positive results [17]. The evaluation of DOTATOC (DOTA0-D-Phe1-Tyr3-octreotide) has a high infections with 18F-FDG labelled with white blood cells PET/CT has affinity for somatostatin receptors SSR2 and SSR3 and a low affinity a very precise sensitivity and specificity. It is very accurate in locating for SSR5. DOTATOC can be labeled with 68Ga (Gallium-68), which the site of infection [18]. PET/MRI with its improved soft tissue is generator produced from a parent isotope Germanium-68 and has contrast is a better tool for diagnosing soft tissue infection. a half-life of 68 min. 68Ga-DOTATOC PET has a higher sensitivity for the detection of somatostatin receptors, compared with the MRI allows precise definition of the anatomy in congenital standard somatostatin receptor scintigraphy and the diagnostic cardiac abnormalities without risk of radiation in children. PET has CT, thus 68Ga-DOTATOC PET is a diagnostic imaging tool [25]. quantitative capabilities and can provide a noninvasive assessment of Neuroblastoma, pediatric neuroendocrine tumors, medulloblastoma, coronary flow reserve and of myocardial blood flow. It is accurate in the and supratentorial primitive neuroectodermal tumors are among the detection of coronary atherosclerosis [19]. PET/MRI, a noninvasive pediatric tumors with expression of somatostatin receptors. A 68Ga- diagnostic tool, has the potential for refining the assessment and DOTATOC PET is better than FDG PET in targeting brain tumors. management of patients with congenital cardiac pathology and is a promising technique for evaluations of various brain tumors and Attenuation Correction in PET/MRI neurologic abnormalities such as epilepsy [20]. Attenuation correction in PET/MRI cannot be obtained with Pediatric Use of Radiopharmaceuticals the CT-type attenuation correction technique. This is mostly due to crosstalk between the transmission effect of the CT and the magnetic 18F-FDG- PET is feasible and useful in the study of tumors in field of the MR and due to the limited space of the combined PET children, and may provide unique, clinically important information and MRI gantry. A body surface recognition technique is mostly used [21]. FDG (fluorodeoxyglucose) is a glucose analog labeled fluorine-18, in PET/MRI for attenuation correction. The technique segments four a positron-emitting isotope that is produced by a cyclotron and has classes of voxels with two points, in-phase and out of phase Dixon a half-life of 110 min. Glucose transporters carry 18F-FDG into cells; sequence. With this technique four different segments of voxels are the enzyme hexokinase phosphorylates this radiopharmaceutical that outlined: fat, water, lungs, and air [26-28]. This segmented attenuation remained trapped within the cell. Malignant cells are characterized technique results in SUV changes of approximately 8% for bone by a very high expression of glucose transporters, by a high tumors, 2% for lung tumors, and 4% for neck lesions, when compared glucose metabolic rate, and by highly active hexokinase bound to to the standard method of transmission attenuation correction of CT. mitochondria compared to normal cells. This enables malignant Pelvic bone lesions demonstrated the largest SUV change of 13.1%. A tissue to accumulate 18F-FDG more avidly than normal tissue [22,23]. study demonstrated no difference in study interpretations made by FDG is being trapped not only by malignant cells There are number experienced radiologists with both attenuation techniques [28]. of physiologic variants with normal uptake. Normal physiologic uptake of the FDG is seen in the head and neck, thymus, , liver It is unclear whether this attenuation correction method of and spleen, gastrointestinal and genitourinary system, in the muscles, segmentation into classes of tissues and the assignment of linear bone marrow, and brown adipose tissue. Recognition of these tissues attenuation coefficients to these tissues, adapted for PET/MRI, are with physiologic uptake and of benign lesions with high FDG uptake accurate for pediatric use, as in PET/CT [28]. It was documented

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Figure 3: Coronal HASTE MRI in coronal view (A) and fused PET/MRI (B) of a 11-year-old with Burkitt lymphoma demonstrate a pelvic mass above the bladder. The MR attenuation map (C) demonstrate truncation artifact (arrowheads). Figure 2: 6-year old child with rhabdomyosrcoma originating in the left masticator space. Axial T1-weighted image (A) and PET/MRI fused axial and found that bone and bone marrow lesions were not missed image (B) at the level of the primary lesion. Coronal fused PET/MRI (C and D) demonstrate increased uptake of the FDG in pulmonary metastatic when compared to PET and to MRI separately [4]. CT is known lesions. Magnetic resonance attenuation map is shown in E. to be the reference point for the assessment of lung metastases; however, MRI is becoming an acceptable alternative for evaluation in studies that there is an increase of bone density with increasing of pulmonary abnormalities, mainly for children, in whom radiation age [29] and a decrease in lung density with increasing age [30], should be spared. MRI is more sensitive to for detection findings that may affect SUV measurements with PET/MRI, although of pulmonary nodules and is equally sensitive as CT [4,33]. Lung no difference in the clinical interpretation was documented. MRI metastases with a 5-mm diameter can be evaluated with the aid of susceptibility artifacts decrease the measured attenuation values and triggered T2- weighted turbo-spin-echo sequences [34]. Diffusion- may lead to a decrease of the SUV values of lesions that may not be weighted imaging is an essential sequence to be added to the oncology distinguishable from background [31]. protocols in the region of interest. It has an excellent sensitivity in detecting malignant lesions and in allowing quantification that may PET/MRI attenuation correction techniques are not adapted aid in the assessment of lymphomas [35]. for pediatric use due to variability of the anatomy and the inter- patient and intra-patient variability of the attenuation coefficients. A literature review revealed that the PET/MRI oncology protocols Attenuation maps were created using CT-based attenuation maps to are not significantly different from adult protocols. Immediately overcome these age-related variabilities and to correct the error caused following data acquisition for attenuation correction, MRI is used by omission of osseous tissue. A dedicated pediatric attenuation to acquire more sequences simultaneously with the PET acquisition map, specifically in the bones, reduced interpatient variation error in in the current field of view. For a current bed position, the time of volumes of interest of femur. Intra-patient variability that was higher acquiring data by MRI can extend beyond the PET acquisition time. in the lungs was concluded to improve and be more accurate with a Thus, a study can be delayed [36]. A suggested PET/MRI oncologic patient or a group-specific attenuation map. It was shown that errors protocol includes: Dixon attenuated images, axial or coronal T2 in bone marrow and in femur-adjacent volumes (mean error of -14% single-shot images, diffusion weighted images, fat-saturated images, and -23% respectively) may affect the PET attenuation coefficient and post-contrast images [37]. A suggested PET/MRI protocol for quantification when the bone tissue is ignored [32]. epilepsy includes: Dixon attenuated images, coronal T2 images, axial or coronal fluid attenuated inversion recovery images, sagittal or Pediatric Protocols coronal T1 images, coronal fast 3D gradient echo images, and axial or After attenuation correction data is obtained, additional coronal post contrast images. Gadolinium chelate is not essential for 18 sequences can be obtained per the local protocol. Information on diagnostic evaluation of solid pediatric malignant lesions on F-FDG the clinical potential of pediatric PET/MRI protocols is scarce. A PET/MRI images, except for focal liver lesions [38]. PET/MRI pediatric-specific protocol was recommended, involving a Combining PET to the MR Enterography protocol has the combination of whole-body imaging protocol for determination of potential to improve the evaluation of inflammatory bowel disease. cancer spread with additional local imaging protocol for acquiring A clinical study suggested that 18F-FDG PET/CT can detect the lesion a detailed visualization of the primary tumor [8]. A whole-body of colon, while 68Ga-citrate PET/CT may distinguish between Crohn's pediatric protocol for abdominal imaging may involve a water- disease and ulcerative colitis. Both the lesion of ulcerative colitis and sensitive fast inversion recovery sequence with a T1-weighted Crohn's disease showed moderate to high uptake of 18F-FDG. The gradient echo sequence. These are preferred sequences for a shorter mean of standardized uptake values was 7.83 ± 3.56. The lesion of acquisition time. The sequences for thoracic and for upper abdominal Crohn's disease presented mild uptake of 68Ga-citrate and mean of imaging should be performed with respiratory triggering. Artifacts standardized uptake value was 2.76 ± 0.28. The ulcerative colitis due to diaphragm movements are more effectively eliminated in lesion showed moderate uptake of 68Ga-citrate and the mean of children with the use of a respiratory belt rather than a navigator standardized uptake values was 4.47 ± 1.10 [39]. sequence [4]. Artifacts in PET/MRI The diagnostic usefulness of an integrated 18F-FDG PET/MR in children (specifically lymphoma) was retrospectively analyzed Five main artifacts were reported in PET/MRI:

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• Metallic artifacts are different from that observed in PET/ 8. Hirsch FW, Sattler B, Sorge I, Kurch L, Viehweger A, Ritter L, et al. PET/ CT, where they cause artificially increased uptake. Metallic artifacts MR in children: initial clinical experience in pediatric oncology using an of the PET/MRI underestimate the uptake value in regions that integrated PET/MR scanner. Pediatr Radiol. 2013;43(7):860-75. surrounds metallic implants. 9. Jadvar H, Colletti PM. Competitive advantage of PET/MRI. Eur J Radiol. 2014;83(1):84-94. • Truncation of body parts in the MRI-derived attenuation map and in the body of the MRI image may result due to a smaller 10. Darge K, Jaramillo D, Siegel MJ. Whole-body MRI in children: current field of view of the MRI than field of view of PET (Figure 3). status and future applications. Eur J Radiol. 2008;68(2):289-98. 11. Buchbender C, Heusner TA, Lauenstein TC, Bockisch A, Antoch G. At times lungs may be interpreted as air, resulting in under • Oncologic PET/MRI, part 2: bone tumors, soft-tissue tumors, melanoma, correction of the SUV values. and lymphoma. J Nucl Med. 2012;53(8):1244-52. • The current methods of attenuation correction ignore the 12. Buchbender C, Heusner TA, Lauenstein TC, Bockisch A, Antoch G. cortical bone that results with lower uptake of bone. Oncologic PET/MRI, part 1: tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med. 2012;53(6):928-38. • Misregistration of simultaneous PET/MRI can also be due to differences in respiratory rate. To overcome this artifact 13. Kluge R, Kurch L, Montravers F, Mauz-Körholz C. FDG PET/CT in and to achieve better alignment, it is recommended to acquire the children and adolescents with lymphoma. Pediatr Radiol. 2013;43(4):406- 17. attenuation sequence at the end of expiration [36,40]. 14. Krohmer S, Sorge I, Krausse A, Kluge R, Bierbach U, Marwede D, et al. 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