Author's Accepted Manuscript

Clinical Applications of Pediatric PET/MRI Sara R. Teixeira MD, Claudia Martinez-Rios MD, Lingzhi Hu PhD, Barbara A. Bangert MD

www.elsevier.com/locate/enganabound

PII: DOI: Reference:

S0037-198X(14)00045-5 http://dx.doi.org/10.1053/j.ro.2014.10.002 YSROE50489

To appear in:

Seminar in Roentgenology

Cite this article as: Sara R. Teixeira MD, Claudia Martinez-Rios MD, Lingzhi Hu PhD, Barbara A. Bangert MD, Clinical Applications of Pediatric PET/MRI, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.10.002 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 galley proof before it is published in its final citable 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.

Clinical applications of pediatric PET/MRI Sara R. Teixeira MD,1, 4,* Claudia Martinez-Rios MD,1,2,* Lingzhi Hu PhD,3 Barbara A. Bangert MD1,2

1

Department of Radiology, University Hospitals Case Medical Center

2

Case Western Reserve University

11100 Euclid Avenue, Cleveland, OH 44106, USA

3

Philips Healthcare Scientist

595 Miner Road, Cleveland, 44143, Ohio

3

Division of Radiology, Ribeirao Preto Medical School, University of Sao Paulo

Av Bandeirantes, 3900 – Ribeirao Preto, SP, Brazil 14049-900

* SRT and CMR contribute equally to this work.

Corresponding author: Barbara A. Bangert, M.D. Email: [email protected] Associate Professor of Radiology and Neurosurgery Case Western Reserve University - University Hospitals Case Medical Center 11100 Euclid Avenue, Cleveland, OH 44106, USA Conflict of interest: There is no conflict of interest

Abstract Introduction Benefits of PET/MRI over PET/CT for the pediatric population a)

Decreased ionizing radiation exposure

b)

Workflow improvement

c)

Imaging related benefits

Challenges of pediatric PET/MRI a)

Pediatric patient challenges

b)

Sedation

c)

Attenuation correction

PET/MRI imaging protocol Clinical applications for PET/MRI in children a)

Lymphoma and leukemia

b)

Neuroblastoma

c)

Bone and soft tissue sarcomas

d)

Brain tumors and epilepsy

Conclusion

Abstract The recent introduction of positron emission tomography/ magnetic resonance imaging (PET/MRI) to the realm of clinical imaging has created an opportunity for improved pediatric patient care, not only from a logistics perspective, simplifying diagnostic workflow in patients requiring multiple studies during their treatment, but also from diagnostic accuracy imaging and radiation exposure standpoints. By combining the metabolic information of positron emission tomography (PET) and the high soft tissue contrast resolution and functional information of magnetic resonance imaging (MRI) in a single examination, diagnostic efficacy is enhanced. By keeping ionizing radiation exposure to a minimum, following the ALARA (as low as reasonable achievable) principle, radiation exposure is reduced. This article will review the particular value of PET/MRI to the pediatric patient population, providing information about clinical protocols and summarizing our own experience with this innovative technique.

Keywords: Positron-emission tomography; Magnetic resonance imaging; Hybrid imaging; PET/MR; Pediatrics; Pediatric oncology

Introduction

PET is a minimally invasive nuclear medicine imaging technique in which a radionuclide labeled with a biologically active molecule is injected into a patient, resulting in images of functional processes within the body, allowing for radiotracer localization and visualization and providing both qualitative and quantitative information of its metabolic behavior. The most common tracer used is a glucose analogue, 2-deoxy-2[18F] fluoro-D-glucose (FDG), the accumulation of which can be measured in the form of standard uptake values (SUV) in PET exams. Many malignant cells are hypermetabolic.

Therefore, various tumors demonstrate increased FDG accumulation on FDG-PET scans. Since the 90’s, FDG-PET has been extensively used for disease staging, assessment of treatment response and follow-up of different oncologic processes and has been used in the evaluation of pediatric brain1 and body2 neoplasms. Quantitative SUV has been found to correlate with the degree of neoplastic malignancy and aggressiveness, leading to changes in the management of patients with lymphoma, brain tumors and sarcomas.1,3 The introduction of combined computed tomography with PET (PET/CT) enabled the co-registration of anatomical and functional images in a single scanning session.4 Compared to PET alone, FDG-PET/CT improves reader confidence and characterization of abnormal FDG uptake in sites of increased tracer activity.5,6 PET/MRI is a new hybrid imaging modality, which brings together the superior soft tissue contrast, high resolution and functional information of magnetic resonance imaging (MRI) with the metabolic capabilities of PET. This article will explore the current potential applications of PET/MRI in the pediatric patient population, delineate clinical protocols and summarize our own experience with this innovative technique.

Benefits of PET/MRI over PET/CT for the pediatric population

a) Decreased ionizing radiation exposure The main benefit of PET/MRI over PET/CT for the pediatric population lies in its reduction of ionizing radiation exposure. The risk for developing a radiation-related cancer can be several times higher for a young child undergoing a CT scan than for an adult undergoing the same scan, due to both an increased age-related sensitivity to the effects of radiation to the longer life span during which the effects of radiation may

become evident.7 Pearce et al8 showed that there is a clear dose-response relationship between radiation dose and incidence of leukemia (excess relative risk per mGy = 0.036) and brain tumors (excess relative risk per mGy = 0.023) in children who had undergone at least one CT at the age < 22 years. Ahmed et al9 found that the median number of procedures in the first five years following diagnosis of a malignancy is 19.2, with ionizing radiation mainly due to CT and nuclear medicine scans. In addition, pediatric PET/CT scans may be limited by discordant findings in the thymus or misregistration of hypermetabolic brown fat. Thus, substitution of the CT component of PET by MRI represents a desirable alternative to PET/CT.

b) Workflow improvement PET/MRI may improve department logistics by reducing overall appointment periods, imaging time and number of sedations, with associated decrease in sedationrelated risks. From a clinical perspective, PET/MRI has the potential to allow treatment initiation following a single dedicated examination.10,11 The acquisition time of a wholebody PET/CT scan is approximately 20 minutes and for PET/MRI, 30 minutes. Although an individual whole-body PET/MRI would last relatively longer, many oncologic patients will currently undergo an additional diagnostic MRI scan, requiring additional scanning time and a second sedation. Such patients also frequently undergo contrast-enhanced CT of the neck chest, abdomen and pelvis. Hirsch et al10 demonstrated that reducing the total number of diagnostic investigations in children following diagnosis of a malignancy would decrease psychological stress and reduce time delay prior to starting treatment. Moreover, they calculated that the effective ionizing radiation dose of PET/MRI to be 20% of that of an equivalent PET/CT,10 underscoring the potential value of PET/MRI for pediatric patients, particularly pediatric oncology patients who will be returning for multiple exams.

c) Imaging related benefits From the imaging perspective, the PET/MRI offers the benefit of including a diagnostic MRI examination, with its improved spatial resolution and superior soft tissue contrast, ultimately combining it with the molecular information from the PET. Additional MRI benefits include its multiparametric including diffusion-weighted imaging (DWI), dynamic contrast enhanced MRI (DCE-MRI) with quantification models and magnetic resonance spectroscopy (MRS) in a single comprehensive examination.12 Although PET/CT data can be fused with magnetic resonance images, hybrid PET/MRI reduces the risk of imaging misalignment due to variance in patient positioning.

Challenges of pediatric PET/MRI

a) Pediatric patient challenges Challenges for pediatric patients undergoing PET/MRI are the same as for MRI or PET alone. However, imaging younger pediatric patients may be particularly challenging, since younger patients may find it difficult to remain motionless for several minutes, cope with noise from MRI scanner, or follow technologist instructions during the exam. Therefore, in order to preserve diagnostic quality and patients’ ability to tolerate the examination, the pediatric PET/MRI protocol must be streamlined and adapted to the individual patient.

b) Sedation Because patient cooperation is essential for a high quality diagnostic MRI scan, sedation may be needed, especially for children younger than 7 years of age. Logistics

for the pediatric sedation unit and appropriate equipment in the room must be planned in advance, in order to maintain a smooth workflow during the examination.

c) Attenuation correction A fundamental step to achieve accurate and reproducible radiotracer quantification in PET imaging is the appropriate attenuation correction of the PET data.13 Attenuation correction for PET/CT systems is not directly applicable to PET/MRI.14 In PET/CT, attenuation measurements acquired from CT, which uses relatively lower energy photons, are used to map the higher energy PET photons through bi-linear conversion. MRI however, does not allow for measurements of tissue electron density and, therefore, there is no direct relation between MRI images and PET attenuation map. MRI signal is mainly determined by the density of hydrogen nuclei rather than tissue electron density, and therefore, it is not possible to directly translate the MRI data into a PET attenuation map.14 In PET/MRI, however, a segmentation approach is usually employed for attenuation correction. Specifically, it first requires an acquisition of MRI image that offers sufficient contrast for automatic segmentation algorithm to detect different tissue type, such as soft-tissue, air, lung, bone and fat et al. Then empirical values of attenuation coefficient for different tissue types are assigned to segmented areas to construct a MR based PET attenuation map.15,16 According to previous published data,17,18 in a series of 40 adult patients population,17 MR attenuation correction (MRAC) using a standard PET/MRI attenuation reconstruction algorithm with an automatic three segment model that accounts for air, lung and soft tissues19 is proved comparable to the CT attenuation correction (CTAC) as the reference standard, yielding similar results in PET quantitation. Differences in SUV values may be seen due to limitations of the segmentation model, which, in many cases, does not account for lung parenchyma or bone.20 A recent study describes consistent PET quantification and

attenuation correction in pediatric PET/MRI using a four segment model which accounts for lung, air, fat and soft tissue. However, underestimation of SUV values was observed in lung and osseous tissues,21 likely reflecting segmentation model limitations. Our experience with pediatric patients using a standard three segment model algorithm has demonstrated high correlation in SUV values between PET/CT and PET/MRI.22 However, we have seen inaccuracies of the MR-based attenuation correction µ-Maps at the level of the lungs and nearby structures, consistent with findings in recent literature.21 Errors in attenuation correction may also be traceable to respiratory motion, MRI-inherent imaging artifacts or other factors exclusive to pediatric patients, especially younger ones, including smaller size, differing body tissue distribution and differing physiology and physiopathology. Additionally, the segmentation algorithms utilized thus far have been based on adult data, which cannot necessarily be extrapolated to pediatric patients. Further work is needed in this area to ensure accurate attenuation correction in pediatric patients.

PET/MRI protocol

Different commercially available solutions for integration of PET and MRI have been developed. One is a fully integrated PET/MRI hybrid system that enables simultaneous PET and MRI data acquisition, developed by Siemens.23 The second solution is the sequential approach, including the tandem design from Philips14 and the tri-modality design from General Electric.24 At our institution, data is acquired using the Philips (Ingenuity TF, Philips Healthcare) hybrid system (Fig. 1). Patients are requested to fast at least 6 hours prior to the study and glucose levels must be evaluated to exclude hyperglycemia. A standard dose of 140 µCi/kg adjusted to body weight is injected intravenously. After injection of

the radionuclide the child is placed for approximately 60 minutes in a cozy room and warm blankets are provided to keep patient as comfortable as possible before imaging. If sedation is needed, the pediatric sedation unit would prepare administration of medications and logistics of sedation before the study. Screening for MRI precautions is performed according to internal protocols. Using a whole-body quadrature body coil (QBC) our PET/MRI protocol starts with the MRI component. Patient is positioned headfirst, arms parallel to the body, with appropriate body positioning and support devices. A whole-body survey is acquired for anatomic localization and planning of the study, followed by a whole-body 3D T1-weighted multi-station spoiled gradient echo sequence providing attenuation correction MR (atMR) images to run a standard automatic three-segment model and, finally, a mDixon sequence for anatomic localization purposes. The table is then rotated 180° and the patient is positioned headfirst with the arms parallel to the body in the PET component of the scanner. A whole-body PET is acquired according to the American College of Radiology practice guidelines25 following reconstruction using the atMR. Additional diagnostic MRI scans may be performed, as needed, following radionuclide injection and either before or after the PET scan. At our institution, we frequently perform additional diagnostic imaging of the neck, chest or abdominopelvic structures using a dedicated coil during the uptake phase, in order to decrease the overall exam time. However, in the case of PET/MRI scans of the brain, we refrain from obtaining additional high resolution MRI of the brain until the PET acquisition is completed. (Table 1) (Fig. 2)

Clinical applications for PET/MRI in children

It is reasonable to consider that PET/MRI may be helpful in a variety of clinical situations in which PET alone or combined PET/CT has already been established. The use of PET/MRI in adult and pediatric patients has been advancing rapidly and its main clinical applications in the pediatric population include evaluation of different malignancies and neurologic processes and also, inflammatory and infectious conditions.10,11

Neoplastic processes Although as the original motivation for radiological imaging, detection and characterization of neoplastic processes is not the sole purpose of imaging. Nowadays, with the advance of the technology, the role of imaging has evolved to the next level, allowing for treatment response monitoring, assessment of tumor dynamics, follow-up surveillance states and detection of residual or recurrent lesions. In children, who are particularly susceptible to ionizing radiation effects, PET/MRI provides a great opportunity to potentially evaluate longitudinal therapy response,13 utilizing less cumulative radiation than would be required with repetitive PET/CT imaging.

Lymphoma and leukemia Lymphoma and leukemia represent fifty percent of all malignancies in childhood. Both conditions share similar origins and may demonstrate comparable imaging features, but need to be evaluated and treated differently.26 Lymphoma accounts for 10 – 15% of all childhood neoplasms,11,26,27 and comprises several pathologic subtypes included in the Hodgkin (HL) and non-Hodgkin (NHL) domains originating from precursors and constituent cells of the immune system. The distribution, demographics and behavior of either HL or NHL differ. HL distributes in a bimodal fashion, accounting the first peak in the 20’s and the second after the 50 years of age, demonstrating higher

incidence in Caucasian adolescent females.26,28 The most common clinical presentation of HL are enlarged lymph nodes in the neck and supraclavicular regions, together with systemic symptomatology including changes in weight, fever and night sweats, known as B symptoms, which have prognostic implications. With current therapeutic approaches, comprised of a combination of chemotherapy and radiation HL treatment yields a high overall event-free survival of over 90%.26,28 Conversely, therapy for NHL, a less prevalent condition, yields a lower survival range of 70% – 85% during a 5-year period.26,28 NHL is more commonly seen in Caucasian boys less than 10 years of age with chest or abdominal masses. NHL also has a greater propensity for disease dissemination at the time of diagnosis, requiring an aggressive chemotherapeutic approach.26 Regardless of the histopathology, accurate staging of lymphoma must be achieved, not only for the prognostic implications, but to provide appropriate and prompt treatment. In the past, Gallium-67 (Ga-67) citrate scintigraphy played an important role in the imaging of lymphoma. PET scans have been proven to be diagnostically superior compared to Ga-67, however.29,30 Current staging systems used for pediatric lymphomas are based on the modified Ann Arbor31 and the St Jude26 classifications for HL and NHL respectively, both based on combined contrast-enhanced CT and FDG-PET/CT. The role of CT in the evaluation and staging of lymphoma based on lymph node size has been extensively used for many years.32 La Fougère et al33 reported a sensitivity of 87.5% and specificity of 85.6% for lymph node involvement assessment. However, CT faces some limitations, especially when evaluating normal size lymph nodes, spleen and bone marrow involvement.32 In children, particularly, the lymph node size criterion is deficient and lymph node enlargement is frequently seen in benign conditions.34 FDGPET has become the preferred imaging modality for lymphoma staging, evaluation of therapeutic response,35-37 assessment for residual lesions and planning for radiation therapy. Montravers et al37 acknowledged its use as a primary approach for staging

childhood lymphoma and suggested its usefulness for treatment response and residual disease evaluation. Regarding bone marrow involvement for staging and treatment response assessment in HL when compared to bone marrow biopsies, FDG-PET demonstrated to be a sensitive and specific method.38 Fusion of PET with CT and/or MRI has shown diagnostic improvement and higher staging accuracy in childhood lymphoma compared to conventional imaging or PET alone.39 FDG-PET/CT has been widely used in the evaluation of lymphomas, yielding high sensitivity in the classic HL and aggressive subtypes of NHL.11,40 Recent studies36,38,41 demonstrated that FDGPET/CT detects bone marrow involvement in the initial staging of pediatric HL with high accuracy, potentially decreasing the need for bone marrow biopsy. The initial staging was modified in 25% – 50% of pediatric patients following evaluation with PET/CT, leading to adaptations in treatment planning.42,43 Similarly, its use for treatment response assessment and long-term follow-up has shown higher sensitivity, specificity and accuracy compared to CT alone.42 (Fig. 3) MRI diagnostic performance compared to FDG-PET/CT for staging lymphoma in children and adolescents, has demonstrated precise depiction for both nodal and extranodal disease using whole-body short time inversion-recovery (STIR) half-Fourier rapid acquisition with relaxation enhancement (RARE).44 In addition, the added value of whole-body DWI in evaluation for treatment response in patients with HL has been studied, complementing the diagnostic information obtained from PET.45 FDG-PET/MRI value for monitoring treatment response in patients with lymphoma has yielded promising results.46 Adams et al47 suggested the use of the hybrid modality is a noninvasive prognostic biomarker for bone marrow assessment in these patients. Hirsch et al10 validated the role of PET/MRI in the evaluation of pediatric lymphoma, describing a synergistic value of the PET and MRI components for initial staging of lymphoma with improvement in the accuracy of the final staging. In one pediatric patient with lymphoma

involvement of the ilium following chemotherapy PET alone was negative, but PET/MRI demonstrated a residual mass. In our experience, PET/MRI has helped differentiating residual lymphadenopathy from areas of activated brown adipose tissue, especially in the supraclavicular and cervical regions by using high resolution MRI sequences, including mDixon (in-phase, out of phase, water and fat categories), and the PET information. (Fig. 4) Leukemia is the third most common malignancy in children48 and is a malignancy classified by cytology, cytogenetic and immunohistochemistry features. Classification of leukemia is based on the World Health Organization guidelines. The most common form is the pre B-cell acute lymphoblastic type (ALL), seen more commonly in boys in the two and three years of age, with a ten-year disease free survival rate ranging from 67% – 78% and 70% – 72% for B-cell precursor and T-cell, respectively.26 Acute myeloid leukemia (AML), a less common malignancy, peaks during the first 2 years of age and then again in the adolescence, with a lower survival rate ranging from 48% to 50% for 5year event free survival rate.48 Different risk factors for leukemia have been described. However, no contributory cause can be found in all cases. Symptomatology in leukemia may be vague with fever, fatigue, anemia, easy bruising and petechial lesions, and up to 50% of children may have bone and joint pain or limping.26 Diagnostic imaging plays an important role, however, there is a poor correlation between the clinical features and imaging findings. X-rays may be the initial approach when symptoms are unspecific. Sinigaglia et al49 described at least one musculoskeletal abnormality seen in up to forty percent of patients with leukemia. Positive bone scintigraphy may be the best initial study to demonstrating leukemic infiltration, with focal or diffuse increase uptake mostly seen in metadiaphysis or diaphysis of long bones, pelvis or spine in symptomatic patients with negative radiologic exams.26 Contrary to imaging in lymphoma, CT is not typically used for staging or follow-up of leukemia, but may be used to evaluate focal

abdominal organ involvement50-52 or thymus infiltration. MRI is the imaging modality of choice to evaluate bone marrow infiltration and other leukemic musculoskeletal changes. However, MRI lacks specificity when the bone marrow is diffusely affected, which may be seen in different hematologic, inflammatory and oncologic conditions.26,53 Nevertheless, familiarity with bone marrow physiology and maturation in children54 may prompt identification of abnormal bone marrow findings, speeding up therapeutic approach. PET also plays a role in the evaluation of AML and extramedullary disease.55 At initial diagnosis forty percent of children with AML have extramedullary disease. An uncommon, but well known, extramedullary manifestation of AML is the granulocytic sarcoma (GS),55-57 a solid FDG avid tumor which tends to appear in the soft tissues of the head and neck regions and the subperiosteum of the lateral orbit wall. Aschoff et al57 described FDG-PET/CT as a more accurate study for lesion detection in patients with GS, and proposed the use of FDG-PET/CT as a diagnostic study with potential treatment monitoring capabilities. PET/MRI in leukemia, as in lymphoma, may be used for initial staging, restaging, follow up, treatment monitoring evaluation and surveillance providing detailed anatomic and molecular information in a single, ALARA-compliant, comprehensive examination.

Neuroblastoma Neuroblastoma, the most common extracranial solid malignancy in children, originates from primitive neural crest cells, most commonly from the adrenal gland, but may originate anywhere within the paravertebral sympathetic chain or presacral region. Neuroblastomas most frequently affect male children under 10 years of age, with more than 80% being boys under five years of age and approximately 35% under 2 years of age.58 Fifty to 70% of patients will present with metastatic disease at the time of diagnosis,59,60 affecting more frequently bone and bone marrow, but it also metastasizes

to liver, lymph nodes and skin. The extent of disease represents a prognostic value; therefore, proper initial staging is critical, proposing directions of the therapeutic approach.11 An appropriate surgical intervention is the treatment of choice in the localized cases, correlating with better local control and overall improved survival. However, despite current therapeutic approaches, the disseminated disease represents a clinical challenge with a cure rate of less than 60%,61 which will require a more aggressive therapeutic scheme. Imaging approach includes plain films, ultrasonography, CT, MRI and radionuclide studies. Mueller et al62 described a neuroblastoma diagnostic approach combining different imaging modalities including [123]Imetaiodobenzylguanidine (MIBG) together with CT, MRI and FDG-PET or PET/CT. A particular characteristic of the neoplastic cells is the expression of a norepinephrine transporter, which allows the use of scintigraphy with MIBG, an analog of guanethidine and norepinephrine, as a highly accurate and specific tumor imaging agent.62-64 More specific positron emission tracers including norepinephrine analogs and sympathetic nervous system tumors tracers are also being studied. However, the current method of choice for neuroblastoma staging, assessment of disseminated disease and evaluation of paraneoplastic syndromes is MIBG scintigraphy. Although the method confers certain limitations, including limited spatial resolution and poor sensitivity when studying small lesions, tumors may also demonstrate reduced uptake following chemotherapy.62 Another limitation of MIBG is its potential for false-negative results, when bone metastases are present, or false-positive results, if physiological distribution of the agent is not known. Time necessary for the exam may be another limitation of the study, since in order to achieve adequate tumor-to-background ratios, at least an 18 to 24 hour waiting period for distribution is required.62 Bone scintigraphy is also considered a valuable method for the detection of skeletal neuroblastoma, especially when MIBG has been negative and bone lesions are suspected.62

FDG-PET imaging may surpass the MIBG limitations described previously. Although FDG uptake may vary from MIBG findings,65 FDG-PET has demonstrated higher sensitivity and specificity detecting neuroblastoma lesions.62 High FDG uptake before chemotherapy is considered an adverse prognostic marker in neuroblastoma metastases,11,66 therefore FDG-PET provides complementary information to a MIBG scan for the initial staging of high-risk neuroblastomas.67 In addition, FDG-PET is considered the primary imaging option defining neuroblastoma involvement in absence of MIBG uptake.11,63 Choi YJ et al65 recently compared FDG-PET versus abdominal CT and bone scintigraphy in the evaluation of neuroblastoma, finding superiority of FDGPET in identifying bone and metastatic lymph nodes.60 Diagnostic CT use in the evaluation of neuroblastomas has decreased and been substituted by MRI mainly due to the radiation implications and relatively poorer image resolution in CT images. MRI provides detailed information about extension of tumor involvement, spinal intracanalicular and vascular encasement required for surgical planning and bone marrow involvement, useful for staging and planning treatment approach. Goo HW et al68 compared whole-body MRI to conventional diagnostic imaging modalities in the evaluation of bone metastasis, and whole-body MRI yielded 99% sensitivity and 94% positive predictive value compared to bone scintigraphy. As a result, PET/CT has become less favored in terms of imaging evaluation of pediatric neuroblastoma. Thus, by merging the imaging advantages of MRI and the metabolic information from PET imaging, FDG-PET/MRI has the potential to provide a more accurate diagnostic examination. PET/MRI may ultimately be further enhanced by potential utilization of different tracers, such as radiolabeled somatostatin analogs in somatostatin-receptor expressed hepatic metastasis and other norepinephrine analogs.11

Bone and soft tissue sarcomas Bone tumors are rare, with an incidence of 0.9 / 100,000 in children between 0 and 19 years of age.69 Osteosarcoma is the most frequent malignant primary bone tumor of childhood, with a higher incidence in adolescence, when it accounts for overall 10% of all pediatric solid tumors.70 Peripheral primitive neuroectodermal tumors of the bone / Ewing sarcoma (ES) are the second in prevalence in the pediatric population71 and, together with osteosarcomas, they account for almost 90% of malignant pediatric bone tumors. While the majority of osteosarcomas are more frequently encountered in the long bones of the legs, ES may occur at a variety of sites, commonly involving the axial skeleton and flat bones, especially the ribs and pelvis. Regardless of the anatomic site and the clinical aggressiveness of the suspected bone tumor, conventional radiographs are usually the first imaging in the diagnostic work-up.70,72 In cases of suspected malignant bone lesions, MRI is the next step and is considered the best modality for local staging.72 CT should be only used in problematic cases to better visualize the periosteal bone formation, cortical destruction or calcifications. For clinical staging, the main factors that are taken into account are tumor burden and the presence of metastases.70 Additional imaging, biopsies of suspected sites or laboratory tests, including alkaline phosphatase and lactate dehydrogenase, may also be used.73,74 To assess bone metastases from osteosarcomas and ES, MRI preferred over CT.72 Twenty to 25% of the patients will have lung metastases at the time of diagnosis; therefore, a chest CT is included in the diagnostic recommendations.72 Functional imaging is required to assess for bone metastases at presentation but is also used for surveillance during and following chemotherapy.72 Although technetium99m-methylene-diphosphonate bone scintigraphy is the most common functional imaging exam used, FDG-PET is recommended for both osteosarcoma and ES at presentation.72 FDG-PET may be used not only for staging but also for therapy

monitoring and detection of recurrence.75 Denecke et al76 showed that FDG-PET using SUVmax ≤ 2.8 may be a useful tool for response assessment in pediatric patients with osteosarcoma, with better results than diagnostic MRI alone. Cheon et al77 showed that decreased metabolic activity assessed by FDG-PET, combined with tumor shrinkage assessed by MRI, is the best predictor of response to chemotherapy. In ES, FDG-PET may predict histologic response of the tumor to preoperative chemotherapy78 and, in addition to whole-body MRI, FDG-PET may detect more bone metastases, potentially impacting therapy regimen and patient outcome.79 London et al80 reported that FDGPET/CT may be able to predict response to neo-adjuvant chemotherapy with higher sensitivity and specificity in evaluating metastases outside the lungs compared to conventional imaging. Therefore, pediatric patients with primary malignant bone tumors may greatly benefit from PET/MRI. The high resolution provided by the MRI component for local/T-staging can be paired with the sensitive metabolic N-staging examination possible with the PET and the whole-body M-staging from the combination of PET/MRI, increasing accuracy of local staging and detection of nodal and distant metastases in a single examination.81 (Fig. 5) Moreover, PET/MRI may help guide biopsies82 and, with the addition of functional MRI sequences such as DWI, may be able to assess therapy response.83 (Fig. 6) Soft tissue sarcomas (STS) are the most common type of extra-cranial solid tumors in the pediatric population,84 with rhabdomyosarcoma (RMS) being the major type. There are two major distinct histologic types of RMS, alveolar and embryonal, which differ in terms of age of onset, propensity to metastasize, primary tumor site and outcome.85 Prognostic factors and risk stratification of STS include pretreatment TNM staging and a surgical/pathologic clinical staging, which are based on extent of residual tumor, lymph node involvement and site of primary tumor.85,86

For initial and, especially, local staging, MRI remains the primary imaging modality in children with STS.87 In assessing response to therapy, conventional imaging alone is less accurate than FDG-PET.88 FDG-PET also added important information in terms of pretreatment whole-body staging of pediatric sarcomas with high sensitivity (88%) for detecting lymph node involvement, significantly impacting therapy decisions for 50% of the patients with RMS,89 although it did not improve T-staging.90 High SUVmax can predict shorter survival91 and FDG-PET can also help in determining a safe surgical margin, in conjunction with MRI.92 In a meta-analysis by Piperkova et al93 for initial staging, response to therapy and re-staging, FDG-PET was more accurate than CT alone (overall accuracy of 94.2% vs 92.2% for CT), but combined PET/CT played a more significant diagnostic role than either PET or CT alone, with an accuracy of 99.4%. A reduction in 35% of the tumor uptake in PET studies following chemotherapy correlated with histopathologic tumor response to early treatment in one study.94 Similar results were reported by others,88 who used FDG-PET to assess response to neoadjuvant chemotherapy in patients with high-grade STS. Apparent diffusion coefficient minimum values derived from DWI were shown to have a linear correlation with STS cellularity and were to be helpful in evaluating early responses to cytotoxic treatment.95 Hybrid modality PET/MRI possesses the potential benefits of both the functional MRI combined with the metabolic information provided by PET.87 Although PET/MRI childhood STS trials require further exploration, simultaneous acquisition of MRI and PET may potentially improve staging, follow-up and treatment response assessment in the evaluation of patients with STS.96,97 (Fig. 7)

Brain tumors Primary brain tumors are the first most common solid malignancy in children, accounting for approximately 20% of all cancers of childhood.69 MRI, which provides

excellent anatomic delineation of intracranial structures, is the main imaging modality used in the diagnosis and follow-up of pediatric brain tumors. However, MRI alone has some limitations in terms of evaluating non-enhancing infiltrative tumors, tumor residue immediately following surgery98 and in distinguishing radiation necrosis from recurrent lesions. Therefore, combined functional and molecular imaging techniques are desirable and may provide noninvasive assessment of tumor biology, improving management of these patients.99 To detect metabolic activity of pediatric brain tumors, FDG-PET was compared to MR spectroscopy imaging (MRSI), which is a functional MRI technique. FDG-PET studies demonstrated inactive lesions that appeared malignant on MRSI in 57% of cases, suggesting a low agreement (42%) between the two techniques.99 In another report, FDG-PET improved diagnostic accuracy in distinguishing tumor recurrence from radiation necrosis, but co-registering it with MRI increased its sensitivity.100 Tracers other than FDG may ultimately be used in the diagnosis and management of pediatric brain tumors. An alternative to FDG-PET is Methyl-[11C]-L-methionine (MET)-PET, which has been shown to distinguish between brain tumors from other brain lesions in children and young adults, with high sensitivity (83%) and specificity (92%).101 However, differentiation between low-grade and high-grade tumors was not possible. MET-PET may also play a complementary role to FDG-PET or MRI in the early postoperative stage. MET-PET demonstrated strong accuracy in delineating tumor from post-operative change compared to MRI.98 Regarding PET/MRI, one small series reported the added value of the hybrid technique for differentiation of surgical sequelae from a residual medulloblastoma.102 Also, PET/MRI was found to be useful in differentiating radiation necrosis from recurrent tumor following radiotherapy during treatment for choroid plexus carcinoma in a pediatric patient.103 Thus, combined PET/MRI may prove to be of significant value in pediatric neuro-oncology patients.11

Epilepsy Epilepsy is a common neurologic disorder, with an estimated incidence of 57 / 100,000 in children and adolescents.104 The majority of patients with seizures respond to first-line treatment with medications but approximately 20% to 25% of patients will develop intractable epilepsy.105 Neurosurgical resection of the epileptogenic focus can potentially improve prognosis in these patients, with excellent outcomes depending on the precise localization of the epileptogenic zone.106 MRI findings are critical in treatment planning. Another tool used for pre-surgical planning in this setting is PET. In epileptic patients with normal MRI exams, FDG-PET has been shown to have high positive predictive value and high rates for localization of epileptogenic focus.107,108 Coregistration of PET with MRI enhances the noninvasive localization improving surgical treatment for cortical dysplasia.109 The same technique may be useful in localizing epileptogenic tubers in patients with tuberous sclerosis.110 Moreover, in the pre-surgical evaluation of epilepsy, PET/MRI has been found to be concordant with the clinical evaluation and electroencephalography in localizing the epileptogenic focus102 and may therefore significantly contribute to accuracy in surgical planning. (Fig. 8) The impact of PET/MRI for pediatric neuroimaging may be increased with the availability of additional sequences such as diffusion tensor imaging, MRI perfusion and MRSI, the use of which has been well established in the diagnosis of a number of neurological disorders. The addition of the functional and metabolic data provided by PET to diagnostic capability of MRI may have a synergistic value.

Conclusion The use of PET/MRI in children is evolving from research and single/small series stage to clinical practice. Standard attenuation correction methods compared to the

reference standard based on adult data thus far have yielded high correlation. However, the use of the same methodology for smaller patients warrants further work. A dedicated pediatric patient algorithm may potentially improve MRAC qualitatively and quantitatively when applied to children. MRI is an imaging tool that not only shows differences between tissues based on morphology and signal intensity, but also may provide molecular and cytoarchitectural information through its functional sequences, such as DWI or MRSI. Moreover, MRI has the additional benefit of lacking of ionizing radiation exposure, a point of particular importance to the pediatric population. Therefore, there is a promising future for hybrid PET/MRI, which combines the metabolic information of PET with the superior diagnostic resolution, soft tissue contrast and functional information of MRI. We believe that the integration of these components in PET/MRI may increase the diagnostic accuracy and follow-up of variable pathologies, staging and re-staging in oncologic patients and serve as an non-invasive biomarker of disease activity, with the added benefit of improved logistics and workflow in the department, while utilizing less ionizing radiation than PET/CT. However, further research is needed on this topic to establish PET/MRI as a standard tool in the management of children with both oncologic and non-oncologic diseases.

References

1.

Hoffman JM, Hanson MW, Friedman HS, et al: FDG-PET in pediatric posterior

fossa brain tumors. J Comput Assist Tomogr 16(1):62-68, 1992 2.

Shulkin BL, Mitchell DS, Ungar DR, et al: Neoplasms in a pediatric population: 2-

[F-18]-fluoro-2-deoxy-D-glucose PET studies. Radiology 194(2):495-500, 1995

3.

Wegner EA, Barrington SF, Kingston JE, et al: The impact of PET scanning on

management of paediatric oncology patients. Eur J Nucl Med Mol Imaging 32(1):23-30, 2005 4.

Beyer T, Townsend DW, Brun T, et al: A combined PET/CT scanner for clinical

oncology. J Nucl Med 41(8):1369-1379, 2000 5.

Yeung HW, Schoder H, Smith A, et al: Clinical value of combined positron

emission tomography/computed tomography imaging in the interpretation of 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography studies in cancer patients. Mol Imaging Biol 7(3):229-235, 2005 6.

Bar-Sever Z, Keidar Z, Ben-Barak A, et al: The incremental value of 18F-FDG

PET/CT in paediatric malignancies. Eur J Nucl Med Mol Imaging 34(5):630-637, 2007 7.

Brenner D, Elliston C, Hall E, et al: Estimated risks of radiation-induced fatal

cancer from pediatric CT. AJR Am J Roentgenol 176(2):289-296, 2001 8.

Pearce MS, Salotti JA, Little MP, et al: Radiation exposure from CT scans in

childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 380(9840):499-505, 2012 9.

Ahmed BA, Connolly BL, Shroff P, et al: Cumulative effective doses from

radiologic procedures for pediatric oncology patients. Pediatrics 126(4):e851-858, 2010 10.

Hirsch FW, Sattler B, Sorge I, et al: PET/MR in children. Initial clinical experience

in paediatric oncology using an integrated PET/MR scanner. Pediatr Radiol 43(7):860875, 2013 11.

Purz S, Sabri O, Viehweger A, et al: Potential Pediatric Applications of PET/MR.

J Nucl Med 55(Supplement 2):32S-39S, 2014 12.

Herzog H, Van Den Hoff J: Combined PET/MR systems: an overview and

comparison of currently available options. Q J Nucl Med Mol Imaging 56(3):247-267, 2012

13.

Quick HH: Integrated PET/MR. J Magn Reson Imaging 39(2):243-258, 2014

14.

Zaidi H, Ojha N, Morich M, et al: Design and performance evaluation of a whole-

body Ingenuity TF PET-MRI system. Phys Med Biol 56(10):3091-3106, 2011 15.

Martinez-Moller A, Souvatzoglou M, Delso G, et al: Tissue classification as a

potential approach for attenuation correction in whole-body PET/MRI: evaluation with PET/CT data. J Nucl Med 50(4):520-526, 2009 16.

Schulz V, Torres-Espallardo I, Renisch S, et al: Automatic, three-segment, MR-

based attenuation correction for whole-body PET/MR data. Eur J Nucl Med Mol Imaging 38(1):138-152, 2011 17.

Kershah S, Partovi S, Traughber BJ, et al: Comparison of standardized uptake

values in normal structures between PET/CT and PET/MRI in an oncology patient population. Mol Imaging Biol 15(6):776-785, 2013 18.

Quick HH, von Gall C, Zeilinger M, et al: Integrated whole-body PET/MR hybrid

imaging: clinical experience. Invest Radiol 48(5):280-289, 2013 19.

Kalemis A, Delattre BM, Heinzer S: Sequential whole-body PET/MR scanner:

concept, clinical use, and optimisation after two years in the clinic. The manufacturer's perspective. Magma 26(1):5-23, 2013 20.

Samarin A, Burger C, Wollenweber SD, et al: PET/MR imaging of bone lesions--

implications for PET quantification from imperfect attenuation correction. Eur J Nucl Med Mol Imaging 39(7):1154-1160, 2012 21.

Schafer JF, Gatidis S, Schmidt H, et al: Simultaneous Whole-Body PET/MR

Imaging in Comparison to PET/CT in Pediatric Oncology: Initial Results. Radiology 131732, 2014 22.

Martinez-Rios C, Sher A, Hu L, et al. Comparison of quantitation of tracer uptake

and radiation dosage between PET/MRI and PET/CT in a pediatric population. The

Society for Pediatric Radiology Annual Meeting. Volume 44. Washington, D.C.: SpringerVerlag GmbH; 2014. 23.

Delso G, Furst S, Jakoby B, et al: Performance measurements of the Siemens

mMR integrated whole-body PET/MR scanner. J Nucl Med 52(12):1914-1922, 2011 24.

The power of flexible choice: PET/CT + MR trimodality imaging.

http://www3.gehealthcare.com/en/Products/Categories/PETCT/PET_CT_and_MR_Trimodality_Imaging#tabs/tab45295910EBED45F5BADC161702 927103: GE Healthcare; 2013. 25.

Rohren EM, Parisi MT, Subramaniam R, et al. ACR-SPR practice guidelines for

performing FDG-PET/CT in oncology. ACR Practice Guidelines: American College of Radiology; 2012. p 1-14. 26.

Averill LW, Acikgoz G, Miller RE, et al: Update on pediatric leukemia and

lymphoma imaging. Semin Ultrasound CT MR 34(6):578-599, 2013 27.

Toma P, Granata C, Rossi A, et al: Multimodality imaging of Hodgkin disease

and non-Hodgkin lymphomas in children. Radiographics 27(5):1335-1354, 2007 28.

Abramson SJ, Price AP: Imaging of pediatric lymphomas. Radiol Clin North Am

46(2):313-338, ix, 2008 29.

Hines-Thomas M, Kaste SC, Hudson MM, et al: Comparison of gallium and PET

scans at diagnosis and follow-up of pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 51(2):198-203, 2008 30.

Mody RJ, Bui C, Hutchinson RJ, et al: Comparison of (18)F Flurodeoxyglucose

PET with Ga-67 scintigraphy and conventional imaging modalities in pediatric lymphoma. Leuk Lymphoma 48(4):699-707, 2007 31.

Lister TA, Crowther D, Sutcliffe SB, et al: Report of a committee convened to

discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7(11):1630-1636, 1989

32.

Vinnicombe SJ, Reznek RH: Computerised tomography in the staging of

Hodgkin's disease and non-Hodgkin's lymphoma. Eur J Nucl Med Mol Imaging 30 Suppl 1(S42-55, 2003 33.

la Fougere C, Hundt W, Brockel N, et al: Value of PET/CT versus PET and CT

performed as separate investigations in patients with Hodgkin's disease and nonHodgkin's lymphoma. Eur J Nucl Med Mol Imaging 33(12):1417-1425, 2006 34.

Kumral A, Olgun N, Uysal KM, et al: Assessment of peripheral

lymphadenopathies: experience at a pediatric hematology-oncology department in Turkey. Pediatr Hematol Oncol 19(4):211-218, 2002 35.

Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's

lymphoma. Pediatr Radiol 34(3):190-198, 2004 36.

Kluge R, Kurch L, Montravers F, et al: FDG PET/CT in children and adolescents

with lymphoma. Pediatr Radiol 43(4):406-417, 2013 37.

Montravers F, McNamara D, Landman-Parker J, et al: [(18)F]FDG in childhood

lymphoma: clinical utility and impact on management. Eur J Nucl Med Mol Imaging 29(9):1155-1165, 2002 38.

Purz S, Mauz-Korholz C, Korholz D, et al: [18F]Fluorodeoxyglucose positron

emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin's lymphoma. J Clin Oncol 29(26):3523-3528, 2011 39.

Furth C, Denecke T, Steffen I, et al: Correlative imaging strategies implementing

CT, MRI, and PET for staging of childhood Hodgkin disease. J Pediatr Hematol Oncol 28(8):501-512, 2006 40.

Gu J, Chan T, Zhang J, et al: Whole-body diffusion-weighted imaging: the added

value to whole-body MRI at initial diagnosis of lymphoma. AJR Am J Roentgenol 197(3):W384-391, 2011

41.

Agrawal K, Mittal BR, Bansal D, et al: Role of F-18 FDG PET/CT in assessing

bone marrow involvement in pediatric Hodgkin's lymphoma. Ann Nucl Med 27(2):146151, 2013 42.

Riad R, Omar W, Kotb M, et al: Role of PET/CT in malignant pediatric lymphoma.

Eur J Nucl Med Mol Imaging 37(2):319-329, 2010 43.

Cheng G, Servaes S, Zhuang H: Value of (18)F-fluoro-2-deoxy-D-glucose

positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma 54(4):737-742, 2013 44.

Punwani S, Taylor SA, Bainbridge A, et al: Pediatric and adolescent lymphoma:

comparison of whole-body STIR half-Fourier RARE MR imaging with an enhanced PET/CT reference for initial staging. Radiology 255(1):182-190, 2010 45.

Punwani S, Taylor SA, Saad ZZ, et al: Diffusion-weighted MRI of lymphoma:

prognostic utility and implications for PET/MRI? Eur J Nucl Med Mol Imaging 40(3):373385, 2013 46.

Platzek I, Beuthien-Baumann B, Langner J, et al: PET/MR for therapy response

evaluation in malignant lymphoma: initial experience. Magma 26(1):49-55, 2013 47.

Adams HJ, Kwee TC, Nievelstein RA: Prognostic implications of imaging-based

bone marrow assessment in lymphoma: 18F-FDG PET, MR imaging, or 18F-FDG PET/MR imaging? J Nucl Med 54(11):2017-2018, 2013 48.

Guillerman RP, Voss SD, Parker BR: Leukemia and lymphoma. Radiol Clin North

Am 49(4):767-797, vii, 2011 49.

Sinigaglia R, Gigante C, Bisinella G, et al: Musculoskeletal manifestations in

pediatric acute leukemia. Journal of pediatric orthopedics 28(1):20-28, 2008

50.

Bach AG, Behrmann C, Holzhausen HJ, et al: Prevalence and patterns of renal

involvement in imaging of malignant lymphoproliferative diseases. Acta Radiol 53(3):343-348, 2012 51.

Bach AG, Behrmann C, Holzhausen HJ, et al: Prevalence and imaging of hepatic

involvement in malignant lymphoproliferative disease. Clin Imaging 36(5):539-546, 2012 52.

Siegel MJ, Chung EM: Wilms' tumor and other pediatric renal masses. Magnetic

resonance imaging clinics of North America 16(3):479-497, vi, 2008 53.

Ruzal-Shapiro C, Berdon WE, Cohen MD, et al: MR imaging of diffuse bone

marrow replacement in pediatric patients with cancer. Radiology 181(2):587-589, 1991 54.

Babyn PS, Ranson M, McCarville ME: Normal bone marrow: signal

characteristics and fatty conversion. Magnetic resonance imaging clinics of North America 6(3):473-495, 1998 55.

Cribe AS, Steenhof M, Marcher CW, et al: Extramedullary disease in patients

with acute myeloid leukemia assessed by 18F-FDG PET. European journal of haematology 90(4):273-278, 2013 56.

Chung EM, Murphey MD, Specht CS, et al: From the Archives of the AFIP.

Pediatric orbit tumors and tumorlike lesions: osseous lesions of the orbit. Radiographics 28(4):1193-1214, 2008 57.

Aschoff P, Hantschel M, Oksuz M, et al: Integrated FDG-PET/CT for detection,

therapy monitoring and follow-up of granulocytic sarcoma. Initial results. Nuklearmedizin 48(5):185-191, 2009 58.

Rha SE, Byun JY, Jung SE, et al: Neurogenic tumors in the abdomen: tumor

types and imaging characteristics. Radiographics 23(1):29-43, 2003 59.

DuBois SG, Matthay KK: Radiolabeled metaiodobenzylguanidine for the

treatment of neuroblastoma. Nuclear medicine and biology 35 Suppl 1(S35-48, 2008

60.

Choi YJ, Hwang HS, Kim HJ, et al: (18)F-FDG PET as a single imaging modality

in pediatric neuroblastoma: comparison with abdomen CT and bone scintigraphy. Ann Nucl Med 28(4):304-313, 2014 61.

Levy D, Aerts I, Michon J, et al: [Childhood cancer: progress but prognosis still

very unequal. Example of Retinoblastoma and high-risk Neuroblastoma]. Bulletin du cancer 101(3):250-257, 2014 62.

Mueller WP, Coppenrath E, Pfluger T: Nuclear medicine and multimodality

imaging of pediatric neuroblastoma. Pediatr Radiol 43(4):418-427, 2013 63.

Jadvar H, Connolly LP, Fahey FH, et al: PET and PET/CT in pediatric oncology.

Semin Nucl Med 37(5):316-331, 2007 64.

Piccardo A, Lopci E, Conte M, et al: PET/CT imaging in neuroblastoma. Q J Nucl

Med Mol Imaging 57(1):29-39, 2013 65.

Melzer HI, Coppenrath E, Schmid I, et al: (1)(2)(3)I-MIBG scintigraphy/SPECT

versus (1)(8)F-FDG PET in paediatric neuroblastoma. Eur J Nucl Med Mol Imaging 38(9):1648-1658, 2011 66.

Shulkin BL, Hutchinson RJ, Castle VP, et al: Neuroblastoma: positron emission

tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose compared with metaiodobenzylguanidine scintigraphy. Radiology 199(3):743-750, 1996 67.

Papathanasiou ND, Gaze MN, Sullivan K, et al: 18F-FDG PET/CT and 123I-

metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52(4):519-525, 2011 68.

Goo HW, Choi SH, Ghim T, et al: Whole-body MRI of paediatric malignant

tumours: comparison with conventional oncological imaging methods. Pediatr Radiol 35(8):766-773, 2005 69.

SEER Cancer Statistics Review 1975-2011. Volume 28: National cancer

Institute. p 14.

70.

Group EESNW: Bone sarcomas: ESMO Clinical Practice Guidelines for

diagnosis, treatment and follow-up. Ann Oncol 23 Suppl 7(vii100-109, 2012 71.

Franchi A: Epidemiology and classification of bone tumors. Clinical cases in

mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases 9(2):92-95, 2012 72.

Meyer JS, Nadel HR, Marina N, et al: Imaging guidelines for children with Ewing

sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51(2):163-170, 2008 73.

Leavey PJ, Collier AB: Ewing sarcoma: prognostic criteria, outcomes and future

treatment. Expert review of anticancer therapy 8(4):617-624, 2008 74.

Bramer JA, van Linge JH, Grimer RJ, et al: Prognostic factors in localized

extremity osteosarcoma: a systematic review. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 35(10):1030-1036, 2009 75.

Grant FD, Drubach LA, Treves ST: 18F-Fluorodeoxyglucose PET and PET/CT in

pediatric musculoskeletal malignancies. PET clinics 5(3):349-361, 2010 76.

Denecke T, Hundsdorfer P, Misch D, et al: Assessment of histological response

of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging 37(10):1842-1853, 2010 77.

Cheon GJ, Kim MS, Lee JA, et al: Prediction model of chemotherapy response in

osteosarcoma by 18F-FDG PET and MRI. J Nucl Med 50(9):1435-1440, 2009 78.

Hawkins DS, Conrad EU, 3rd, Butrynski JE, et al: [F-18]-fluorodeoxy-D-glucose-

positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults. Cancer 115(15):3519-3525, 2009

79.

Furth C, Amthauer H, Denecke T, et al: Impact of whole-body MRI and FDG-PET

on staging and assessment of therapy response in a patient with Ewing sarcoma. Pediatr Blood Cancer 47(5):607-611, 2006 80.

London K, Stege C, Cross S, et al: 18F-FDG PET/CT compared to conventional

imaging modalities in pediatric primary bone tumors. Pediatr Radiol 42(4):418-430, 2012 81.

Buchbender C, Heusner TA, Lauenstein TC, et al: Oncologic PET/MRI, part 2:

bone tumors, soft-tissue tumors, melanoma, and lymphoma. J Nucl Med 53(8):12441252, 2012 82.

Hogendoorn PC, Group EEW, Athanasou N, et al: Bone sarcomas: ESMO

Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21 Suppl 5(v204-213, 2010 83.

Uhl M, Saueressig U, van Buiren M, et al: Osteosarcoma: preliminary results of in

vivo assessment of tumor necrosis after chemotherapy with diffusion- and perfusionweighted magnetic resonance imaging. Invest Radiol 41(8):618-623, 2006 84.

Li J, Thompson TD, Miller JW, et al: Cancer incidence among children and

adolescents in the United States, 2001-2003. Pediatrics 121(6):e1470-1477, 2008 85.

Malempati S, Hawkins DS: Rhabdomyosarcoma: review of the Children's

Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer 59(1):5-10, 2012 86.

Lawrence W, Jr., Anderson JR, Gehan EA, et al: Pretreatment TNM staging of

childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80(6):11651170, 1997 87.

Buchbender C, Heusner TA, Lauenstein TC, et al: Oncologic PET/MRI, part 1:

tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med 53(6):928938, 2012

88.

Evilevitch V, Weber WA, Tap WD, et al: Reduction of glucose metabolic activity

is more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high-grade soft-tissue sarcomas. Clin Cancer Res 14(3):715720, 2008 89.

Volker T, Denecke T, Steffen I, et al: Positron emission tomography for staging of

pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25(34):5435-5441, 2007 90.

Tateishi U, Hosono A, Makimoto A, et al: Comparative study of FDG PET/CT and

conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23(2):155161, 2009 91.

Baum SH, Fruhwald M, Rahbar K, et al: Contribution of PET/CT to prediction of

outcome in children and young adults with rhabdomyosarcoma. J Nucl Med 52(10):1535-1540, 2011 92.

Yokouchi M, Terahara M, Nagano S, et al: Clinical implications of determination

of safe surgical margins by using a combination of CT and 18FDG-positron emission tomography in soft tissue sarcoma. BMC musculoskeletal disorders 12(166, 2011 93.

Piperkova E, Mikhaeil M, Mousavi A, et al: Impact of PET and CT in PET/CT

studies for staging and evaluating treatment response in bone and soft tissue sarcomas. Clin Nucl Med 34(3):146-150, 2009 94.

Benz MR, Czernin J, Allen-Auerbach MS, et al: FDG-PET/CT imaging predicts

histopathologic treatment responses after the initial cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas. Clin Cancer Res 15(8):2856-2863, 2009 95.

Schnapauff D, Zeile M, Niederhagen MB, et al: Diffusion-weighted echo-planar

magnetic resonance imaging for the assessment of tumor cellularity in patients with softtissue sarcomas. J Magn Reson Imaging 29(6):1355-1359, 2009

96.

Partovi S, Kohan A, Rubbert C, et al: Clinical oncologic applications of PET/MRI:

a new horizon. Am J Nucl Med Mol Imaging 4(2):202-212, 2014 97.

Partovi S, Kohan AA, Zipp L, et al: Hybrid PET/MR imaging in two sarcoma

patients - clinical benefits and implications for future trials. International journal of clinical and experimental medicine 7(3):640-648, 2014 98.

Pirotte B, Levivier M, Morelli D, et al: Positron emission tomography for the early

postsurgical evaluation of pediatric brain tumors. Childs Nerv Syst 21(4):294-300, 2005 99.

Hipp SJ, Steffen-Smith EA, Patronas N, et al: Molecular imaging of pediatric

brain tumors: comparison of tumor metabolism using (1)(8)F-FDG-PET and MRSI. J Neurooncol 109(3):521-527, 2012 100.

Chao ST, Suh JH, Raja S, et al: The sensitivity and specificity of FDG PET in

distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery. Int J Cancer 96(3):191-197, 2001 101.

Galldiks N, Kracht LW, Berthold F, et al: [11C]-L-methionine positron emission

tomography in the management of children and young adults with brain tumors. J Neurooncol 96(2):231-239, 2010 102.

Garibotto V, Heinzer S, Vulliemoz S, et al: Clinical applications of hybrid

PET/MRI in neuroimaging. Clin Nucl Med 38(1):e13-18, 2013 103.

Korchi AM, Garibotto V, Ansari M, et al: Pseudoprogression after proton beam

irradiation for a choroid plexus carcinoma in pediatric patient: MRI and PET imaging patterns. Childs Nerv Syst 29(3):509-512, 2013 104.

Hirtz D, Thurman DJ, Gwinn-Hardy K, et al: How common are the "common"

neurologic disorders? Neurology 68(5):326-337, 2007 105.

Stanescu L, Ishak GE, Khanna PC, et al: FDG PET of the brain in pediatric

patients: imaging spectrum with MR imaging correlation. Radiographics 33(5):12791303, 2013

106.

Siegel AM, Jobst BC, Thadani VM, et al: Medically intractable, localization-

related epilepsy with normal MRI: presurgical evaluation and surgical outcome in 43 patients. Epilepsia 42(7):883-888, 2001 107.

Swartz BE, Brown C, Mandelkern MA, et al: The use of 2-deoxy-2-[18F]fluoro-D-

glucose (FDG-PET) positron emission tomography in the routine diagnosis of epilepsy. Mol Imaging Biol 4(3):245-252, 2002 108.

Chugani HT, Shields WD, Shewmon DA, et al: Infantile spasms: I. PET identifies

focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 27(4):406-413, 1990 109.

Salamon N, Kung J, Shaw SJ, et al: FDG-PET/MRI coregistration improves

detection of cortical dysplasia in patients with epilepsy. Neurology 71(20):1594-1601, 2008 110.

Chandra PS, Salamon N, Huang J, et al: FDG-PET/MRI coregistration and

diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia 47(9):1543-1549, 2006

         

Tables Table 1. PET/MRI protocol MRI Whole-body 3D T1w

Whole-body 3D mDixon

Image orientation

Axial

Axial

Read-out encoding direction

Anterior-Posterior

Anterior-Posterior

Field of view (mm)

600

500

Slice thickness (mm)

6

3

Repetition time (ms)

4

3

Echo time (ms)

2.3

1 / 1.9

Number of averages

1

1

Flip angle (°)

10

7

Matrix size

200 x 200

264 x 201

Voxel size (mm)

3x3x6

2x2x3

Time per stack (sec)

16.5

14.4

Stacks thickness (mm)

120

140

Data acquisition time

3 min 18 sec

1 min 55 sec

Overlap (mm)

12

30

Coil

Whole-body Coil

Whole-body Coil

PET Number of bed positions

Average 9.4 ± 1.1

Scan time (sec)/bed

90

Injection dose

140µCi/kg

Reconstruction method

Time of flight list mode

Attenuation Correction method 3-segment model

                   

Figure legends      Figure 1. The hybrid PET/MRI system. The tandem design from Philips has both PET and MRI components built in the same room in a coaxial position (A). The turntable patient handling system (B) reduces patient motion between the components. When sedation is required, the MRI-safe sedation support devices must be placed inside the PET/MRI suite maintaining room logistics.

Figure 2. Illustration of the whole-body FDG-PET/MRI protocol. Whole-body 3D-T1 spoiled gradient-echo sequence (A) is acquired for attenuation correction reconstruction. The MR attenuation correction map (B) is derived from an appropriate three segmentation approach. mDixon (C, water; D, fat; E, in-phase; F, opposed phase) is used for anatomic localization. Coronal FDG-PET (G) and fused FDG-PET/MRI (H). Note the extensive brown fat activation mostly in the supraclavicular and cervical regions in this 16 year-old female with history of osteosarcoma of the left knee status post-resection, knee replacement and chemotherapy.

Figure 3 Eleven year-old boy with history of stage II Hodgkin lymphoma, status postchemotherapy. Left posterior cervical triangle demonstrated asymmetric FDG uptake in the posterior cervical triangle region. Enlarged non FDG-uptaking lymph node was depicted on the right on low dose CT scan from FDG-PET/CT (not shown). Underlying pathology on left could not be discarded. Axial mDixon-water (A), FDG-PET (B), and fused PET image derived from FDG-PET/MRI. mDixon-water (A) demonstrated no

uptake in the right lymph node (circles) and confirmed the presence of activated brown fat in the region of high FDG uptake on the left posterior triangle (arrows).

Figure 4. Extensive activated brown fat in a 9 year-old boy with marginal zone lymphoma. FDGPET/CT (A) for re-staging reported intense tracer activity in the supraclavicular and cervical regions (circles), concerned for underlying hypermetabolic lymph nodes. The child underwent subsequent FDG-PET/MRI showing high radionuclide uptake (dashed arrows in E). Better delineation of regions of brown fat activation discarded underlying lymphadenopathy (arrows in B, C and D) with aid of mDixon (B, fat; C, in-phase; D, water), FDG-PET images (E) and fused PET/MRI images (F).

Figure 5. Nine year-old girl with Ewing sarcoma of the right cubitus status post-surgery. Axial FDG-PET/MRI mDixon-water (A), FDG-PET (B) and fused FDG-PET/MRI images (C) at the level of the axillar region demonstrated FDG uptake of a lymph node on the right (circle). SUV were low indicating probable inflammatory origin, which was confirmed in the follow-up studies (not shown).

Figure 6. 16 year-old girl with newly diagnosed alveolar Ewing sarcoma of the chest wall. Axial FDG-PET/MRI images of the chest demonstrated a well-defined solid mass originated from the chest wall (arrows) with high FDG uptake. (A) mDixon-water, (B) FDG-PET and (C) fused FDG-PET/MRI image.

Figure 7. 11 year-old boy with embryonal rhabdomyosarcoma. There is a soft tissue mass (arrows) in the left parapharyngeal space extending through an enlarged foramen ovale on the left with a small mound of tumor protruding into the middle cranial fossa and involving the left temporal pole (dashed circles). The oval markers are showing a hypermetabolic lesion in and surrounding the medial rectal muscle of the right orbit, consistent with a metastatic lesion, which was better depicted after FDG-PET scan (E). On MRI this lesion appeared as a heterogeneous signal of the muscle on T2-Weighted image (C) with surrounding edema and post-gadolinium enhancement (D). (A), coronal FDG-PET scan; (B), coronal fused PET/MRI; (F), axial fused PET/MRI at the level of the middle cranial fossa and orbits.

Figure 8. Pre-operative evaluation of an eight year-old girl with epilepsy. FDG-PET/MRI helped delineating the epileptogenic zone in the left frontal lobe (*), which showed low FDGuptake. Although the child had other bilateral cortical malformations such as polymicrogyria (arrow), only the left frontal region which showed low uptake of the radionuclide was removed at surgery. The patient experienced interval clinical improvement at short-term follow-up. (A) coronal FDG-PET; (B) fused FDG PET/MRI image; (C – D) T1-weighted contrast-enhanced spoiled gradient-echo MRI.

Fig 1

Fig 2

Fig 3

Fig 4

Fig 5

Fig 6

Fig 7

Fig 8