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Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD
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Cite this article as: Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD, Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.07.001 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.
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Title: Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in the Evaluation of Brain Tumors: Current Status and Future Prospects Authors: Nghi Nguyen, MD; Jesse Montagnese, DO; Lisa R. Rogers, DO; Leo Wolansky, MD From the Departments of Radiology (N.N., J.M., L.W.) and Neurology (L.R.), University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106.
Please address correspondence to Leo Wolansky, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106; email: [email protected]
Abstract Various designs of positron emission tomography/magnetic resonance imaging (PET/MRI) systems have been recently introduced into clinical practice, which have overcome technical challenges concerning the fusion of PET and MRI. This review summarizes the literature on the use of PET and MRI as well as addresses the potential benefit and contributions of hybrid PET/MRI in neuro-oncology. Multiple functional parameters derived from this novel technology are appealing as imaging biomarkers because of its noninvasive nature, complementary information and quantitative capability. There is a need for the development of time efficient acquisition protocols that tailor the various clinical indications as well as systematic evaluation in standardized, multi-center clinical trials. There are grounds for cautious optimism that hybrid PET/MRI will become a valuable imaging tool for the detection and characterization of brain tumors as well as for monitoring the response to therapy.
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INTRODUCTION Epidemiology and types of CNS tumors Brain neoplasms can be classified as primary brain tumors and secondary metastatic tumors arising from extracranial malignancies. The latter are encountered more frequently than the former. According to the American Cancer Society, more than 100,000 people die each year due to symptomatic brain metastases while an estimated 12,760 people, among the 20,500 newly-diagnosed primary brain tumors, die [1]. The most common tumors to metastasize to the brain are carcinoma of the breast, lung, colon and kidney, followed by melanoma. Roughly half of brain metastases are single and half are multiple. Although primary brain tumors can occur at any age, there are two age peaks, one in adults between 40 and 70 years, and one in children between 3 and 12 years. Primary brain tumors are rare in adults and account for only 3% of all new cancer cases; however, up to 20% of newly diagnosed cancers in childhood are brain tumors [2]. The most common site for primary brain tumors depends upon patient age. In adults, two thirds of tumors arise in the supratentorial compartment; the opposite is true for pediatric brain tumors, in which two thirds arise in the infratentorial compartment. The World Health Organization provides a classification and grading system of brain tumors that is accepted and in use worldwide [3]. The most common adult primary brain tumors arise from neuroepithelial tissue. The most common of these is astrocytoma, of which there are four grades: grade 1 (pilocytic astrocytoma), grade 2 (diffuse/fibrillary
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astrocytoma), grade 3 (anaplastic astrocytoma), and grade 4 (glioblastoma multiforme). A less common glioma, but one of considerable clinical relevance because of the comparatively improved response to treatment and long term survival as compared with astrocytoma, is the oligodendroglioma, of which there are two grades; grade 2 and grade 3 (anaplastic oligodendroglioma). Other common primary brain tumors in adults include those of the meninges (typically meningioma, of which there are three grades), cranial nerves (e.g. schwannoma), and benign tumors of the sellar region. Less common are tumors of hematopoietic origin (lymphoma) and germ cells. CNS lymphoma may be primary or secondary, with primary CNS lymphoma accounting for 6.6% of all primary brain tumors in adults. The most common pediatric primary brain tumors include medulloblastoma, an embryonal tumor which typically arises in the fourth ventricle, ependymoma, and glioma. The majority of adult and pediatric primary brain tumors require surgery for histological confirmation and for therapeutic debulking. Aside from some low grade tumors, the majority of brain tumors are subsequently treated with radiation therapy and/or chemotherapy.
Technological advancements in functional hybrid imaging Contrast-enhanced MRI is a well-established imaging modality in the clinical and research setting. It has numerous clinical applications and is the gold standard in neuroimaging due to its superb anatomical details [4]. Although much of the information obtained from magnetic resonance imaging (MRI) is morphologic in nature, biochemical
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composition influences even the most fundamental pulse sequences. Furthermore, advanced MRI techniques, such as diffusion-weighted MRI (DWI), MR spectroscopy (MRS) and perfusion MRI (pMRI) provide improved biochemical characterization of tissues; thus, morphologic and functional MRI are complementary allowing both anatomical and molecular imaging capabilities [5]. Besides computed tomography (CT) and MRI, advances in multimodality imaging such as positron-emission-tomography/computed-tomography (PET/CT) have significantly improved patient care, particularly in oncology. Since its introduction in 2000, PET/CT imaging has become widely used and made enormous contribution to the diagnosis, staging, and treatment monitoring in cancer patients [6, 7]. In brain imaging, PET and PET/CT imaging using various radiopharmaceuticals have also proven to be helpful. It is expected that PET/MRI will provide more clinically relevant information than PET or PET/CT in neuroimaging because MRI provides superb soft tissue contrast and functional imaging capabilities. Integrated whole-body PET/MRI systems are now commercially available and expected to change the medical imaging field by providing optimal anatomic-metabolic image information. In 2010, Philips Healthcare installed the first sequential PET/MRI system (Ingenuity TF PET/MRI, Philips Healthcare) at Mount Sinai Medical Center, New York [8]. At our institution, Case Western Reserve University/University Hospitals Case Medical Center in Cleveland, the Ingenuity TF PET/MRI was installed in 2011 and has been used since for both clinical service and research. In this review, we describe our first clinical experience with PET/MRI in neuroimaging and discuss the current status as well as perspectives of integrated PET/MRI.
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Co-registration of PET and MRI images Co-registration (fusion) of brain PET and MRI images is used with increasing frequency to achieve better anatomical localization and characterization of PET lesions. Image fusion of separate PET and MRI data can be carried out with help of various commercial and free software programs. The accuracy of co-registration is high with an error as low as 2 mm in the brain, making co-registration of PET and MRI brain images a viable option in clinical practice [9]. In a retrospective study of 47 patients with brain tumors that were previously treated with stereotactic radiosurgery, the co-registration of PET and MRI data resulted in an increase in sensitivity for tumor recurrence from 65% to 86% while maintaining the specificity at 80% [10]. There are however, a number of limitations. 1) In many cases, the PET examination and MRI examination are performed on different days, so the tumor biology may have changed between the scans, resulting in suboptimal correlation of PET and MRI. 2) Some patients will have the scans performed at different departments that may not share a common picture archiving and communication system (PACS); consequently, the combined interpretation of the two modalities may not be practical. 3) Despite the fact that image fusion software is now available for clinical use, most comprehensive and user-friendly software packages will require a software purchase, which may limit its widespread clinical use overall. 4) Because the PET and MRI images are acquired separately, the imaging protocols of PET and MRI are not optimized for each other, and as a result, simple differences in matrix size, slice thickness, head position, as well as imaging planes may complicate accurate correlation. 5) The interpretation of PET and MRI images may be inconsistent
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because the MRI scan may be read separately without the knowledge of the PET scan and vice versa.
PET/MRI SCANNER DESIGNS Siemens Medical Solutions The industry saw the market niche for integrated PET/MRI, soon after marketing of PET/CT systems was successful. The first integrated PET/MRI system (“BrainPET/MRI”) dedicated for brain imaging was introduced by Siemens Medical Solutions in 2007 [11-13]. The system consists of an MR-compatible PET system that is inserted into a modified whole-body MR scanner with 3 Tesla magnet (Magnetom Trio). Several technical difficulties have been resolved to allow a simultaneous acquisition of PET and MRI. For PET, conventional photomultiplier tubes are replaced by avalanche photodiodes to allow for magnetic field compatibility. Appropriate shielding of PET components located inside the MRI system has been achieved to minimize interference with the radiofrequency and gradient fields of the MRI. In 2010, Siemens introduced the first whole-body PET/MRI (“Biograph mMR”) which allows a simultaneous acquisition of MRI and PET because the two systems are fully integrated within the same gantry. The advantages of this scanner design include the low risk of patient motion affecting image quality and co-registration. Most important benefit however lies in the simultaneous acquisition of PET and MRI, allowing unmatched temporal and spatial correlation between PET and MRI, particularly by means of dynamic imaging and allowing translational neurologic and psychiatric
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research. The setup of the PET scanner inside the MRI system has additional advantage of partial volume correction and motion correction of PET data based on MRI information. Brain imaging using the whole-body PET/MRI results in less favorable spatial resolution compared to the dedicated BrainPET/MRI, but the former has a larger bore and enables imaging of the body.
Philips Healthcare Philips Healthcare has a sequential approach in the PET/MRI design. Their Ingenuity TF PET/MRI system is a hybrid of the Gemini TF PET scanner with time-of-flight technology and the Achieva 3 T MRI scanner that is housed in a single room. The gantry of the two scanners is approximately 4.2 m apart; the scanner table is in the middle between the two scanners and rotates 180° for scanning with MRI vs. PET. Technically, this approach is less challenging to achieve compared to the simultaneous PET/MRI system from Siemens. Although a simultaneous acquisition is not possible with this system design, the PET and MR images are automatically co-registered. The main advantages of the Ingenuity TF PET/MRI lie in the cost saving from the simple scanner design and high image quality of PET using time-of-flight technology as well as the preserved MR image quality due to minimal PET interference with the magnetic field of the MRI [14].
GE Healthcare
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As with Philips Healthcare, GE Healthcare has pursued a sequential but tri-modality system that allows MRI scanning (Discovery MR750w at 3 Tesla) in one room and PET/CT scanning (Discovery PET/CT with time-of-flight technology) in an adjacent room. A two-room setup is required for this scanner system configuration. The patient is transferred between the two scanners on a hover table. The advantage of the sequential design over the simultaneous design lies mainly in reduced cost as well as the flexible use of PET/CT, MRI or both. Other advantages include preserved MRI image quality due to the minimal interference of the PET system with the MRI magnetic field and the robust attenuation correction of PET using CT data instead of MRI information [15].
DIAGNOSTIC VALUE OF SEPARATE MRI AND PET MRI Contrast-enhanced MRI MRI has become the gold standard for non-invasive imaging of brain tumors [4]. It provides great structural details and enables the detection and localization of brain lesions to submillimeter resolution. T2-weighted and Fluid-attenuated inversion-recovery (FLAIR) sequences, based on the fast spin-echo technology are standard in brain imaging because these display high sensitivity to edema, a common denominator of most cerebral pathology, being manifest as hyperintensity. Although highly sensitive [4], FLAIR signal hyperintensity (Fig. 1) is not particularly specific for a brain tumor. Contrast enhancement adds some degree of specificity in the diagnosis of high-grade gliomas
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(grades III and IV). Tumor contrast enhancement is largely due to leakage of gadolinium (Gd) chelate into the interstitium because of blood-brain-barrier (BBB) breakdown, which is usually related to neovascularization and necrosis. Contrast enhancement is also not entirely specific being seen in other malignant tumors, e.g., primary CNS lymphomas and metastases. Furthermore, enhancement can be seen with benign tumors, such as meningiomas, pilocytic astrocytomas and hemangioblastomas as well as many non-neoplastic processes, abscesses, acute demyelination , and subacute infarction. The diagnostic accuracy of conventional MRI in the diagnosis of malignant brain tumor is approximately 86% [16], so surgical biopsy or resection is carried out in most cases to provide histological diagnosis. There are also limitations to histological diagnosis, e.g. sampling errors in surgical biopsies due to tumor heterogeneity, which may result in undergrading of the tumor, or due to tissue sampling at the edge of a lesion, which may be difficult to differentiate a low-grade glioma (Fig. 1A-C) from reactive gliosis. Despite continued progress in imaging, MRI is often not able to detect areas of microscopic tumor infiltration, which frequently renders gliomas incurable.
Diffusion-weighted Imaging (DWI) DWI utilizes the microscopic mobility of water, classic Brownian motion, to detect biologic abnormalities. Parameters such as apparent diffusion coefficient (ADC) derived from DWI are appealing as biomarkers because of the noninvasive nature, not requiring intravenous contrast infusion; but are nevertheless quantitative and rapid, being easily incorporated into the routine MRI examination. Diffusivity is inversely correlated with
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cellularity, with reduced diffusivity (diminished ADC signal) often correlating with higher grade (hypercellular) tumor (Fig. 1), which can aid in staging intracranial neoplasm, particularly glioma. Specifically, the use of ADC histograms has shown promising results in the grading of gliomas particularly when focusing on the lower diffusivity peak, corresponding to the non-necrotic portion of the tumor [17]. Furthermore, ADC has been used to assess brain tumor response to therapy and to predict survival, particularly in patients with high grade gliomas [18]. Insert Fig. 1
Proton MR Spectroscopy (MRS) MRS allows non-invasive measurement of metabolites in brain tumors, with most neoplasms demonstrating increased Choline (Cho) and reduced N-acetylaspartic acid (NAA) and creatine (Cr) – Fig. 2. MRS can help differentiate tumor grade and aid in differentiation of recurrent neoplasm from radiation change. Furthermore, it could be used to guide biopsies and define radiotherapy targets as well as to monitor patients after treatment [19]. However, clinical application is hampered by technical factors, e.g. standardization of data acquisition across different scanning systems and the effect of field strength variations because of voxel measurements in spatially heterogeneous tumors. As a result, MRS may be unreliable for lesions less than 2 cm in diameter or for lesions close to bone, cerebrospinal fluid or fat because of signal contaminations, e.g. base of skull and retro-orbital region. The field heterogeneity is amplified in the patients who have ferromagnetic surgical hardware for craniotomy flap fixation overlying the
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cerebral lesion. In addition, MRS is time consuming and labor intensive, often requiring compromise in terms of lesion coverage, especially using single-voxel technique. Consequently, the measured data may not reflect the biology in other parts of the tumor. This consideration is particularly important in high-grade gliomas, which are heterogeneous due to cystic degeneration and necrosis. In contrast, multi-voxel spectroscopy can provide greater tumor coverage and display regional differences within a tumor, but the signal to noise ratio and associated quality of the spectra are significantly worse than single voxel spectroscopy. Thus, multi-voxel spectroscopy is technically demanding, less reproducible and more difficult for quantitative evaluation [17]. Insert Fig. 2 Perfusion-weighted MRI Perfusion-weighted MRI allows an evaluation and quantification of cerebral hemodynamics. Three technical approaches are being used clinically. The first two of these require IV contrast infusion and are known as dynamic contrast enhanced MRI (DCE-MRI). The first of these is based on T1 relaxation enhancement during serial imaging and is typically referred to as DCE-T1 or by the shortened, deceptively nonspecific name “DCE.” The second technique makes use of the magnetic susceptibility (T2*) effect of the contrast bolus induced tissue heterogeneity. This is referred to as dynamic susceptibility contrast MRI (DSC-MRI). These techniques provide information about tissue perfusion and permeability and are increasingly used in tumor grading, pre-treatment planning as well as assessing therapeutic response,
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particularly in the setting of antiangiogenic therapy [20-22]. The regional cerebral blood volume (rCBV) derived from the DSC data, either as an absolute measure or a ratio with the contralateral “normal’’ white matter have been shown to correlate with microvascular density and with tumor grade in that maximum regional cerebral blood volume (rCBV) values of low-grade gliomas are significantly lower than those of highgrade gliomas (Fig. 3). Recent data also suggests that rCBV is helpful in predicting progression in gliomas, both low-grade gliomas treated conservatively [23] as well as low-grade and high-grade gliomas prior to as well as after surgery [24]. However, there are still significant limitations particularly regarding the lack of specificity. Arterial spin labelling (ASL) is an emerging technique that allows perfusion measurements (rCBF) without the need of contrast agent and is based on flow saturation, the blood being labeled magnetically as part of the imaging sequence [25]. ASL has been shown to have higher rCBF in glioblastoma than grade II and III gliomas; these findings correlate with the higher rCBV derived from DSC-MRI as well [25].
Functional MRI (fMRI) fMRI is another innovative MR technique for measuring brain activity. It works by detecting the changes in blood oxygen levels in response to neural activity and resulting changes in blood flow due to autoregulation (blood-oxygen-level-dependent or BOLD). fMRI can be used to produce activation maps showing which parts of the brain are involved in the particular mental process. The method is most accurate at delineating brain regions associated with motor tasks [26]. BOLD–fMRI is valuable in the
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preoperative planning of brain tumor surgery, especially if the tumor is in close proximity to eloquent functional brain centers.
PET Imaging F-18 FDG PET Molecular imaging with PET has gained significant interest over the years because it has the potential to image a wide range of biochemical processes that are critical for the understanding of pathophysiology of neoplasms, and thereby can play a major role in drug development and monitoring of targeted treatments. Although there are certain advantages for the use of newer radiotracers, F-18 FDG is the most commonly used radiotracer because of its overall acceptable diagnostic accuracy, low cost and widespread availability as well as favorable half-life (110 minutes). FDG-PET is being used in more than 90% of cancers for staging, restaging and assessing therapy response. The goal of FDG PET is to detect increased glucose metabolism in tumors. There is however a high metabolic activity in normal gray matter, mostly reflecting physiological state of neuronal activity. This high FDG uptake in normal brain tissue often limits the delineation of tumor from normal brain metabolic activity. As a result, only 3-6% of low-grade gliomas and 21-47% of high-grade gliomas show increased FDG metabolism [27, 28]. It is therefore highly recommended to interpret FDG PET images in conjunction with anatomical images, such as CT and MRI. Metastases from various extracranial malignancies may have variable FDG uptake [29]. In a retrospective study conducted on 104 neurologically asymptomatic patients for
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initial lung cancer staging, FDG PET/CT detected only 7.7% of brain metastases as opposed to 21.2% with brain MRI [29]. Therefore, FDG PET or PET/CT is usually not recommended to screen for brain metastasis [29]. Standard uptake value (SUV) is a semi-quantitative parameter of metabolic activity and can provide more precise diagnosis than visual interpretation, and the relative change in SUV is very helpful in characterizing treatment response. The use of SUV however has some limitations, particularly if the brain tumor is located in an area of high physiologic brain uptake. As an alternative, activity ratios (SUV ratio) to the contralateral brain or to the adjacent white matter have been used to better characterize the brain lesions. The increased FDG uptake in brain tumors correlates well with the degree of malignancy (Fig. 3, Fig. 6). Di Chiro et al. [30] found in a study of 23 patients that all 10 high-grade (III and IV) gliomas demonstrated high glucose metabolism (7.4 ± 3.5 mg/100g per min) whereas the 13 low-grade gliomas (I and II) showed lower uptake (4.0 ± 1.8 mg/100g per min). Besides tumor grading, FDG PET provides valuable information about prognosis. In studies with high grade gliomas, a high metabolic activity was associated with a mean/median survival time of 5-7 months compared to 19-33 months for those with low metabolic activity [31, 32]. Insert Fig. 3 It is evident that FDG PET has positive clinical value in predicting tumor response and may be used to assess early treatment response and to aid the therapeutic management of brain tumors [33, 34]. The differential diagnosis of post-treatment radiation change and residual or recurrent tumor remains a challenging task in clinical
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practice. The effect of radiation change and necrosis is particularly notable in patients with high-grade tumors treated in “standard of care” combination chemoradiation (Temozolomide). The diagnostic accuracy of FDG PET in differentiating post-radiation change (Fig. 4) from viable tumor (Fig. 2) varies significantly, with a sensitivity of 8186% and a specificity of 40-90% [35]. Insert Fig. 4
Non-FDG PET There is an increasing interest in applying other PET radiotracers to avoid the shortcomings of FDG PET. The integration of novel radiotracers, such as C-11 methionine (MET), and F-18 fluorothymidine (FLT), enables an enhanced evaluation of tumor pathophysiology and metabolism, resulting in improved accuracy for CNS tumor diagnosis and follow-up. The following section will provide an overview of some of the commonly used non-FDG radiotracers in the literature. Based on its favorable half-life of 110 min, F-18 is the most practical isotope for radiolabeling; C-11with a half-life 20 min is being used mainly in clinical research settings where on-site cyclotrons are available. At the time of this writing, FDG is the only radiotracer currently FDA approved for clinical use, although many of them are being studied as Investigational New Drug Applications (INDs). The ability to develop PET tracers for specific molecular targets is potentially important and a large number of them are in development [36]. Besides FDG, the radiolabeled amino acids C-11 Methionine (MET) and F-18 fluoroethyl-tyrosine (FET) are the most commonly used PET tracers for brain tumors. The
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most significant advantage of using radiolabeled amino acids over FDG is the relatively low uptake of amino acids by normal brain tissue. The high uptake in gliomas therefore results in good lesion-to-background ratio so that the tumor can be detected more easily. As the building blocks of proteins, amino acids serve well as a target for molecular imaging. As a component of many metabolic cycles, the metabolism of amino acids is up-regulated in cells with increased proliferative activity, such as in cancer. This makes it attractive for researchers to develop radiotracers labeling PET isotopes with amino acids for tumor imaging. The uptake mechanism for the most commonly used amino acid radiotracers (MET, FET) is mainly explained by the transport via specific amino acid transporters although a small amount of the radiotracer may be further metabolized or incorporated into protein synthesis within the cell [37]. Certain amino acids radiotracers are being used more common than others depending on the ease of biochemical compounding, the availability of an on-site cyclotron and clinical indication as well as cost consideration. MET is the most popular amino acid radiotracer in neurooncology although its use is limited to PET centers with on-site cyclotron. Its popularity is largely due to the relatively simple steps of production. FET is newer than MET and has the advantage of longer half-life (110 min) and wider availability, obviating the need for an on-site cyclotron. FLT is an analog to the nucleoside thymidine and was developed as a PET radiotracer to assess cellular proliferation. The phosphorylated FLT within the cell reflects cell proliferation and correlates strongly with thymidine incorporation into the DNA. The actual incorporation of FLT into the DNA is however low, and the majority of the phosphorylated FLT is trapped in the cytosol [38, 39]. As a biomarker for cell
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proliferation, FLT has the tremendous potential in monitoring and treatment response assessment. This is demonstrated in a study of 19 patients treated with bevacizumab and irinotecan. Comparative studies between MET and FET have shown similar results in gliomas [40, 41]. Because amino acid radiotracers easily diffuse into the brain tissue, a disruption of the BBB is not required for the increased metabolism in brain tumors. Consequently, amino acid radiotracers enable imaging of both low-grade tumors without BBB leakage and high-grade tumors with BBB leakage. The sensitivity and specificity of MET PET and FET PET is in the range of 70-90% each [42, 43]. C-11 Choline is a natural amine that enters the cells and is involved in the synthesis of the cell membrane. Given the increased cell proliferation of tumor cells, there is also increased cell membrane turnover; therefore, choline can serve as a marker for phospholipid synthesis. Comparative studies have shown that C-11 choline is superior to FDG PET in delineating the extent of tumor [39, 44]. The uptake of C-11 choline is reported to be 3-4 times higher in glioblastomas than in normal brain tissue, and the uptake in low-grade tumors remains low and is comparable with the non-neoplastic lesions [45, 46]. Hypoxia in malignant gliomas represents a significant risk for resistance to both radiation and chemotherapy, and is associated with a more aggressive tumor phenotype and worse prognosis. Diagnostic imaging with hypoxia markers such as 18Ffluoromisonidazole (FMISO) enables the quantification of hypoxia in tumors and
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provides valuable information for prognosis, treatment planning and response to therapy [47, 48].
POTENTIAL DIAGNOSTIC VALUE OF HYBRID PET/MRI Functional imaging plays an important role in aiding the clinical management of patients with brain tumors. Multi-parametric imaging with hybrid PET/MRI is now available at some imaging centers, enabling an in-depth studying of pathophysiologic processes at a molecular level. Intuitively, the different functional data derived from multimodal imaging will enhance diagnostic confidence and accuracy. However, the era of PET/MRI has just started, and much more work lies ahead to demonstrate its clinical potential, particularly compared with currently available modalities of MRI and PET/CT as well as co-registration of individual MRI and PET data. To date, the literature on the use of hybrid PET/MRI in neuro-oncology is limited to a few reports [11-13]. These studies were carried out on the dedicated BrainPET/MRI system which is being used in a few imaging centers. It is expected that future PET/MRI applications and investigations will be primarily done using the whole-body PET/MRI systems that are being offered by the three major vendors Siemens, Philips and GE. It will take several more years before a good amount of research data is available on the use of hybrid PET/MRI. Researchers at the University of Tuebingen were the first to report on the use of hybrid PET/MRI in human brain [11, 13]. Using the BrainPET/MRI system, the tumor delineation in the seven patients undergoing MET PET was compatible between
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PET/MRI and PET/CT [13]. They performed Ga-68 DOTATOC PET in eight patients as well for the diagnosis of meningioma. Six of eight patients were found to have comparable lesions between PET/MRI and PET/CT, whereas an additional lesion was suggested in the remaining two patients [13]. This study was however mainly an image quality evaluation, in which the authors shared their initial clinical experience on a simultaneous PET/MRI system, and the clinical indications were wide, ranging from meningiomas, head and neck tumors to astrocytomas. Comprehensive studies evaluating the clinical value of hybrid PET/MRI are under way and the results are to be expected for the coming years. In the following section, the current literature on the use of separate MRI and PET scanning with subsequent image fusion is reviewed and the clinical and research potential of hybrid PET/MRI is discussed.
Tumor grading and prognosis Gliomas may consist of different parts that are heterogeneous in terms of tumor grading. Thus, low- and high-grade areas may be present within the same tumor. Although MRI is the modality of choice to detect intracerebral neoplasms, the inherent heterogeneity of gliomas may not be sufficiently depicted by conventional MRI, particularly in non-enhancing gliomas (Fig. 1A-C). To date, several studies combining single modalities of functional MRI and PET have been reported in the literature [25, 49]. In a prospective study of 61 patients with WHO grade II-IV gliomas, Weber at al. [23] wanted to answer the question whether the use of various functional imaging modalities would lead to similar target areas for biopsy. Using an extensive array of
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functional MRI (Na-23-, MRS, ASL, DCE and DSC, DW) in combination with FDG- and FLT-PET, they found that FLT-PET, DSC-, DW- and DCE-MRI as well as MRS correctly identified all three non-enhancing grade III lesions and showed no significant tumor heterogeneity in all 15 grade II gliomas. Tumor grading correlated well with semiquantitative parameters of tumor vascularity and proliferation. In the majority of the cases (>80%), areas of increased FLT uptake matched with that of choline peak on MRS [25]. Tumors with the same histopathological diagnosis can behave in very different ways. Novel biomarkers of prognosis can aid treatment strategy, moving towards personalized treatments. Functional imaging can serve as noninvasive biomarkers of prognosis, which commonly mirrors the biomarkers found for grading. In a study that included 189 patients with grade II glioma, high rCBV at DSC-MRI predicted a short time to disease progression and poor clinical outcome [24]. In a retrospective study including 187 patients with high-grade gliomas, Majos et al. [50] established that MRS at diagnosis could identify patients with poor prognosis, depending on spectral characteristics such as low myo-inositol levels and high levels of mobile lipids. In a retrospective study, the mean and minimum ADC were found to be significantly lower in patients with progressive, compared with stable, high-grade gliomas at 2 years [18]. Using FET-PET, the combination with MR morphology has been found to be a significant prognostic predictor for patients with newly diagnosed low-grade gliomas [51]. Baseline FET uptake and a circumscribed versus a diffuse growth pattern on MRI were highly significant predictors for patients’ course and outcome. One could envision that multiparametric PET/MRI could enhance our knowledge of both prognostic and predictive
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outcome. Multi-parametric PET/MRI has the potential to evolve into a valuable tool for research, potentially important for the understanding of tumor microenvironment and drug development.
Biopsy guidance Often, brain tumors exhibit different degrees of anaplasia in different tumor parts. Thus, surgical biopsies, especially when taken stereotactically, may miss the most malignant tumor area and therefore underestimate the tumor grade. Although surgical resection is a key intervention in many patients, including adults with low-grade and high-grade gliomas, biopsy is still important in some cases, such as in patients with diffuse tumors and those tumors in which extensive surgery would pose a significant risk to life. In addition to providing noninvasive diagnosis, functional imaging can be used to guide biopsy in large complex lesions in which there is a risk that the tissue obtained may not be representative of the highest grade within the tumor (Fig. 5). Insert Fig. 5 Weber et al. [25] conducted a study of 61 patients using MRS, DWI, ASL, DCE-T1, DSC, 23Na-MRI as well as FLT and FDG PET. These authors showed that target areas for vascularity, cellularity and proliferation were similar among the various functional parameters. In areas without tumor necrosis, there was a good agreement between markers of cell proliferation (increased choline at MRS and FLT uptake at PET) and cellularity (low ADC values, increased FDG uptake) as well as microcirculation and angiogenesis (elevated rCBV and rCBF). Functional MRI also showed similar hot spots
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compared with those observed with PET. Widhalm et al. [49] showed in a study of 32 patients using co-registration of MRS and MET PET that areas of positive MRS and PET for anaplasia overlapped 50% in 18/21 cases and
Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD
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S0037-198X(14)00037-6 http://dx.doi.org/10.1053/j.ro.2014.07.001 YSROE50481
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Seminar in Roentgenology
Cite this article as: Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD, Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.07.001 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.
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Title: Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in the Evaluation of Brain Tumors: Current Status and Future Prospects Authors: Nghi Nguyen, MD; Jesse Montagnese, DO; Lisa R. Rogers, DO; Leo Wolansky, MD From the Departments of Radiology (N.N., J.M., L.W.) and Neurology (L.R.), University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106.
Please address correspondence to Leo Wolansky, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106; email: [email protected]
Abstract Various designs of positron emission tomography/magnetic resonance imaging (PET/MRI) systems have been recently introduced into clinical practice, which have overcome technical challenges concerning the fusion of PET and MRI. This review summarizes the literature on the use of PET and MRI as well as addresses the potential benefit and contributions of hybrid PET/MRI in neuro-oncology. Multiple functional parameters derived from this novel technology are appealing as imaging biomarkers because of its noninvasive nature, complementary information and quantitative capability. There is a need for the development of time efficient acquisition protocols that tailor the various clinical indications as well as systematic evaluation in standardized, multi-center clinical trials. There are grounds for cautious optimism that hybrid PET/MRI will become a valuable imaging tool for the detection and characterization of brain tumors as well as for monitoring the response to therapy.
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INTRODUCTION Epidemiology and types of CNS tumors Brain neoplasms can be classified as primary brain tumors and secondary metastatic tumors arising from extracranial malignancies. The latter are encountered more frequently than the former. According to the American Cancer Society, more than 100,000 people die each year due to symptomatic brain metastases while an estimated 12,760 people, among the 20,500 newly-diagnosed primary brain tumors, die [1]. The most common tumors to metastasize to the brain are carcinoma of the breast, lung, colon and kidney, followed by melanoma. Roughly half of brain metastases are single and half are multiple. Although primary brain tumors can occur at any age, there are two age peaks, one in adults between 40 and 70 years, and one in children between 3 and 12 years. Primary brain tumors are rare in adults and account for only 3% of all new cancer cases; however, up to 20% of newly diagnosed cancers in childhood are brain tumors [2]. The most common site for primary brain tumors depends upon patient age. In adults, two thirds of tumors arise in the supratentorial compartment; the opposite is true for pediatric brain tumors, in which two thirds arise in the infratentorial compartment. The World Health Organization provides a classification and grading system of brain tumors that is accepted and in use worldwide [3]. The most common adult primary brain tumors arise from neuroepithelial tissue. The most common of these is astrocytoma, of which there are four grades: grade 1 (pilocytic astrocytoma), grade 2 (diffuse/fibrillary
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astrocytoma), grade 3 (anaplastic astrocytoma), and grade 4 (glioblastoma multiforme). A less common glioma, but one of considerable clinical relevance because of the comparatively improved response to treatment and long term survival as compared with astrocytoma, is the oligodendroglioma, of which there are two grades; grade 2 and grade 3 (anaplastic oligodendroglioma). Other common primary brain tumors in adults include those of the meninges (typically meningioma, of which there are three grades), cranial nerves (e.g. schwannoma), and benign tumors of the sellar region. Less common are tumors of hematopoietic origin (lymphoma) and germ cells. CNS lymphoma may be primary or secondary, with primary CNS lymphoma accounting for 6.6% of all primary brain tumors in adults. The most common pediatric primary brain tumors include medulloblastoma, an embryonal tumor which typically arises in the fourth ventricle, ependymoma, and glioma. The majority of adult and pediatric primary brain tumors require surgery for histological confirmation and for therapeutic debulking. Aside from some low grade tumors, the majority of brain tumors are subsequently treated with radiation therapy and/or chemotherapy.
Technological advancements in functional hybrid imaging Contrast-enhanced MRI is a well-established imaging modality in the clinical and research setting. It has numerous clinical applications and is the gold standard in neuroimaging due to its superb anatomical details [4]. Although much of the information obtained from magnetic resonance imaging (MRI) is morphologic in nature, biochemical
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composition influences even the most fundamental pulse sequences. Furthermore, advanced MRI techniques, such as diffusion-weighted MRI (DWI), MR spectroscopy (MRS) and perfusion MRI (pMRI) provide improved biochemical characterization of tissues; thus, morphologic and functional MRI are complementary allowing both anatomical and molecular imaging capabilities [5]. Besides computed tomography (CT) and MRI, advances in multimodality imaging such as positron-emission-tomography/computed-tomography (PET/CT) have significantly improved patient care, particularly in oncology. Since its introduction in 2000, PET/CT imaging has become widely used and made enormous contribution to the diagnosis, staging, and treatment monitoring in cancer patients [6, 7]. In brain imaging, PET and PET/CT imaging using various radiopharmaceuticals have also proven to be helpful. It is expected that PET/MRI will provide more clinically relevant information than PET or PET/CT in neuroimaging because MRI provides superb soft tissue contrast and functional imaging capabilities. Integrated whole-body PET/MRI systems are now commercially available and expected to change the medical imaging field by providing optimal anatomic-metabolic image information. In 2010, Philips Healthcare installed the first sequential PET/MRI system (Ingenuity TF PET/MRI, Philips Healthcare) at Mount Sinai Medical Center, New York [8]. At our institution, Case Western Reserve University/University Hospitals Case Medical Center in Cleveland, the Ingenuity TF PET/MRI was installed in 2011 and has been used since for both clinical service and research. In this review, we describe our first clinical experience with PET/MRI in neuroimaging and discuss the current status as well as perspectives of integrated PET/MRI.
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Co-registration of PET and MRI images Co-registration (fusion) of brain PET and MRI images is used with increasing frequency to achieve better anatomical localization and characterization of PET lesions. Image fusion of separate PET and MRI data can be carried out with help of various commercial and free software programs. The accuracy of co-registration is high with an error as low as 2 mm in the brain, making co-registration of PET and MRI brain images a viable option in clinical practice [9]. In a retrospective study of 47 patients with brain tumors that were previously treated with stereotactic radiosurgery, the co-registration of PET and MRI data resulted in an increase in sensitivity for tumor recurrence from 65% to 86% while maintaining the specificity at 80% [10]. There are however, a number of limitations. 1) In many cases, the PET examination and MRI examination are performed on different days, so the tumor biology may have changed between the scans, resulting in suboptimal correlation of PET and MRI. 2) Some patients will have the scans performed at different departments that may not share a common picture archiving and communication system (PACS); consequently, the combined interpretation of the two modalities may not be practical. 3) Despite the fact that image fusion software is now available for clinical use, most comprehensive and user-friendly software packages will require a software purchase, which may limit its widespread clinical use overall. 4) Because the PET and MRI images are acquired separately, the imaging protocols of PET and MRI are not optimized for each other, and as a result, simple differences in matrix size, slice thickness, head position, as well as imaging planes may complicate accurate correlation. 5) The interpretation of PET and MRI images may be inconsistent
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because the MRI scan may be read separately without the knowledge of the PET scan and vice versa.
PET/MRI SCANNER DESIGNS Siemens Medical Solutions The industry saw the market niche for integrated PET/MRI, soon after marketing of PET/CT systems was successful. The first integrated PET/MRI system (“BrainPET/MRI”) dedicated for brain imaging was introduced by Siemens Medical Solutions in 2007 [11-13]. The system consists of an MR-compatible PET system that is inserted into a modified whole-body MR scanner with 3 Tesla magnet (Magnetom Trio). Several technical difficulties have been resolved to allow a simultaneous acquisition of PET and MRI. For PET, conventional photomultiplier tubes are replaced by avalanche photodiodes to allow for magnetic field compatibility. Appropriate shielding of PET components located inside the MRI system has been achieved to minimize interference with the radiofrequency and gradient fields of the MRI. In 2010, Siemens introduced the first whole-body PET/MRI (“Biograph mMR”) which allows a simultaneous acquisition of MRI and PET because the two systems are fully integrated within the same gantry. The advantages of this scanner design include the low risk of patient motion affecting image quality and co-registration. Most important benefit however lies in the simultaneous acquisition of PET and MRI, allowing unmatched temporal and spatial correlation between PET and MRI, particularly by means of dynamic imaging and allowing translational neurologic and psychiatric
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research. The setup of the PET scanner inside the MRI system has additional advantage of partial volume correction and motion correction of PET data based on MRI information. Brain imaging using the whole-body PET/MRI results in less favorable spatial resolution compared to the dedicated BrainPET/MRI, but the former has a larger bore and enables imaging of the body.
Philips Healthcare Philips Healthcare has a sequential approach in the PET/MRI design. Their Ingenuity TF PET/MRI system is a hybrid of the Gemini TF PET scanner with time-of-flight technology and the Achieva 3 T MRI scanner that is housed in a single room. The gantry of the two scanners is approximately 4.2 m apart; the scanner table is in the middle between the two scanners and rotates 180° for scanning with MRI vs. PET. Technically, this approach is less challenging to achieve compared to the simultaneous PET/MRI system from Siemens. Although a simultaneous acquisition is not possible with this system design, the PET and MR images are automatically co-registered. The main advantages of the Ingenuity TF PET/MRI lie in the cost saving from the simple scanner design and high image quality of PET using time-of-flight technology as well as the preserved MR image quality due to minimal PET interference with the magnetic field of the MRI [14].
GE Healthcare
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As with Philips Healthcare, GE Healthcare has pursued a sequential but tri-modality system that allows MRI scanning (Discovery MR750w at 3 Tesla) in one room and PET/CT scanning (Discovery PET/CT with time-of-flight technology) in an adjacent room. A two-room setup is required for this scanner system configuration. The patient is transferred between the two scanners on a hover table. The advantage of the sequential design over the simultaneous design lies mainly in reduced cost as well as the flexible use of PET/CT, MRI or both. Other advantages include preserved MRI image quality due to the minimal interference of the PET system with the MRI magnetic field and the robust attenuation correction of PET using CT data instead of MRI information [15].
DIAGNOSTIC VALUE OF SEPARATE MRI AND PET MRI Contrast-enhanced MRI MRI has become the gold standard for non-invasive imaging of brain tumors [4]. It provides great structural details and enables the detection and localization of brain lesions to submillimeter resolution. T2-weighted and Fluid-attenuated inversion-recovery (FLAIR) sequences, based on the fast spin-echo technology are standard in brain imaging because these display high sensitivity to edema, a common denominator of most cerebral pathology, being manifest as hyperintensity. Although highly sensitive [4], FLAIR signal hyperintensity (Fig. 1) is not particularly specific for a brain tumor. Contrast enhancement adds some degree of specificity in the diagnosis of high-grade gliomas
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(grades III and IV). Tumor contrast enhancement is largely due to leakage of gadolinium (Gd) chelate into the interstitium because of blood-brain-barrier (BBB) breakdown, which is usually related to neovascularization and necrosis. Contrast enhancement is also not entirely specific being seen in other malignant tumors, e.g., primary CNS lymphomas and metastases. Furthermore, enhancement can be seen with benign tumors, such as meningiomas, pilocytic astrocytomas and hemangioblastomas as well as many non-neoplastic processes, abscesses, acute demyelination , and subacute infarction. The diagnostic accuracy of conventional MRI in the diagnosis of malignant brain tumor is approximately 86% [16], so surgical biopsy or resection is carried out in most cases to provide histological diagnosis. There are also limitations to histological diagnosis, e.g. sampling errors in surgical biopsies due to tumor heterogeneity, which may result in undergrading of the tumor, or due to tissue sampling at the edge of a lesion, which may be difficult to differentiate a low-grade glioma (Fig. 1A-C) from reactive gliosis. Despite continued progress in imaging, MRI is often not able to detect areas of microscopic tumor infiltration, which frequently renders gliomas incurable.
Diffusion-weighted Imaging (DWI) DWI utilizes the microscopic mobility of water, classic Brownian motion, to detect biologic abnormalities. Parameters such as apparent diffusion coefficient (ADC) derived from DWI are appealing as biomarkers because of the noninvasive nature, not requiring intravenous contrast infusion; but are nevertheless quantitative and rapid, being easily incorporated into the routine MRI examination. Diffusivity is inversely correlated with
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cellularity, with reduced diffusivity (diminished ADC signal) often correlating with higher grade (hypercellular) tumor (Fig. 1), which can aid in staging intracranial neoplasm, particularly glioma. Specifically, the use of ADC histograms has shown promising results in the grading of gliomas particularly when focusing on the lower diffusivity peak, corresponding to the non-necrotic portion of the tumor [17]. Furthermore, ADC has been used to assess brain tumor response to therapy and to predict survival, particularly in patients with high grade gliomas [18]. Insert Fig. 1
Proton MR Spectroscopy (MRS) MRS allows non-invasive measurement of metabolites in brain tumors, with most neoplasms demonstrating increased Choline (Cho) and reduced N-acetylaspartic acid (NAA) and creatine (Cr) – Fig. 2. MRS can help differentiate tumor grade and aid in differentiation of recurrent neoplasm from radiation change. Furthermore, it could be used to guide biopsies and define radiotherapy targets as well as to monitor patients after treatment [19]. However, clinical application is hampered by technical factors, e.g. standardization of data acquisition across different scanning systems and the effect of field strength variations because of voxel measurements in spatially heterogeneous tumors. As a result, MRS may be unreliable for lesions less than 2 cm in diameter or for lesions close to bone, cerebrospinal fluid or fat because of signal contaminations, e.g. base of skull and retro-orbital region. The field heterogeneity is amplified in the patients who have ferromagnetic surgical hardware for craniotomy flap fixation overlying the
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cerebral lesion. In addition, MRS is time consuming and labor intensive, often requiring compromise in terms of lesion coverage, especially using single-voxel technique. Consequently, the measured data may not reflect the biology in other parts of the tumor. This consideration is particularly important in high-grade gliomas, which are heterogeneous due to cystic degeneration and necrosis. In contrast, multi-voxel spectroscopy can provide greater tumor coverage and display regional differences within a tumor, but the signal to noise ratio and associated quality of the spectra are significantly worse than single voxel spectroscopy. Thus, multi-voxel spectroscopy is technically demanding, less reproducible and more difficult for quantitative evaluation [17]. Insert Fig. 2 Perfusion-weighted MRI Perfusion-weighted MRI allows an evaluation and quantification of cerebral hemodynamics. Three technical approaches are being used clinically. The first two of these require IV contrast infusion and are known as dynamic contrast enhanced MRI (DCE-MRI). The first of these is based on T1 relaxation enhancement during serial imaging and is typically referred to as DCE-T1 or by the shortened, deceptively nonspecific name “DCE.” The second technique makes use of the magnetic susceptibility (T2*) effect of the contrast bolus induced tissue heterogeneity. This is referred to as dynamic susceptibility contrast MRI (DSC-MRI). These techniques provide information about tissue perfusion and permeability and are increasingly used in tumor grading, pre-treatment planning as well as assessing therapeutic response,
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particularly in the setting of antiangiogenic therapy [20-22]. The regional cerebral blood volume (rCBV) derived from the DSC data, either as an absolute measure or a ratio with the contralateral “normal’’ white matter have been shown to correlate with microvascular density and with tumor grade in that maximum regional cerebral blood volume (rCBV) values of low-grade gliomas are significantly lower than those of highgrade gliomas (Fig. 3). Recent data also suggests that rCBV is helpful in predicting progression in gliomas, both low-grade gliomas treated conservatively [23] as well as low-grade and high-grade gliomas prior to as well as after surgery [24]. However, there are still significant limitations particularly regarding the lack of specificity. Arterial spin labelling (ASL) is an emerging technique that allows perfusion measurements (rCBF) without the need of contrast agent and is based on flow saturation, the blood being labeled magnetically as part of the imaging sequence [25]. ASL has been shown to have higher rCBF in glioblastoma than grade II and III gliomas; these findings correlate with the higher rCBV derived from DSC-MRI as well [25].
Functional MRI (fMRI) fMRI is another innovative MR technique for measuring brain activity. It works by detecting the changes in blood oxygen levels in response to neural activity and resulting changes in blood flow due to autoregulation (blood-oxygen-level-dependent or BOLD). fMRI can be used to produce activation maps showing which parts of the brain are involved in the particular mental process. The method is most accurate at delineating brain regions associated with motor tasks [26]. BOLD–fMRI is valuable in the
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preoperative planning of brain tumor surgery, especially if the tumor is in close proximity to eloquent functional brain centers.
PET Imaging F-18 FDG PET Molecular imaging with PET has gained significant interest over the years because it has the potential to image a wide range of biochemical processes that are critical for the understanding of pathophysiology of neoplasms, and thereby can play a major role in drug development and monitoring of targeted treatments. Although there are certain advantages for the use of newer radiotracers, F-18 FDG is the most commonly used radiotracer because of its overall acceptable diagnostic accuracy, low cost and widespread availability as well as favorable half-life (110 minutes). FDG-PET is being used in more than 90% of cancers for staging, restaging and assessing therapy response. The goal of FDG PET is to detect increased glucose metabolism in tumors. There is however a high metabolic activity in normal gray matter, mostly reflecting physiological state of neuronal activity. This high FDG uptake in normal brain tissue often limits the delineation of tumor from normal brain metabolic activity. As a result, only 3-6% of low-grade gliomas and 21-47% of high-grade gliomas show increased FDG metabolism [27, 28]. It is therefore highly recommended to interpret FDG PET images in conjunction with anatomical images, such as CT and MRI. Metastases from various extracranial malignancies may have variable FDG uptake [29]. In a retrospective study conducted on 104 neurologically asymptomatic patients for
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initial lung cancer staging, FDG PET/CT detected only 7.7% of brain metastases as opposed to 21.2% with brain MRI [29]. Therefore, FDG PET or PET/CT is usually not recommended to screen for brain metastasis [29]. Standard uptake value (SUV) is a semi-quantitative parameter of metabolic activity and can provide more precise diagnosis than visual interpretation, and the relative change in SUV is very helpful in characterizing treatment response. The use of SUV however has some limitations, particularly if the brain tumor is located in an area of high physiologic brain uptake. As an alternative, activity ratios (SUV ratio) to the contralateral brain or to the adjacent white matter have been used to better characterize the brain lesions. The increased FDG uptake in brain tumors correlates well with the degree of malignancy (Fig. 3, Fig. 6). Di Chiro et al. [30] found in a study of 23 patients that all 10 high-grade (III and IV) gliomas demonstrated high glucose metabolism (7.4 ± 3.5 mg/100g per min) whereas the 13 low-grade gliomas (I and II) showed lower uptake (4.0 ± 1.8 mg/100g per min). Besides tumor grading, FDG PET provides valuable information about prognosis. In studies with high grade gliomas, a high metabolic activity was associated with a mean/median survival time of 5-7 months compared to 19-33 months for those with low metabolic activity [31, 32]. Insert Fig. 3 It is evident that FDG PET has positive clinical value in predicting tumor response and may be used to assess early treatment response and to aid the therapeutic management of brain tumors [33, 34]. The differential diagnosis of post-treatment radiation change and residual or recurrent tumor remains a challenging task in clinical
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practice. The effect of radiation change and necrosis is particularly notable in patients with high-grade tumors treated in “standard of care” combination chemoradiation (Temozolomide). The diagnostic accuracy of FDG PET in differentiating post-radiation change (Fig. 4) from viable tumor (Fig. 2) varies significantly, with a sensitivity of 8186% and a specificity of 40-90% [35]. Insert Fig. 4
Non-FDG PET There is an increasing interest in applying other PET radiotracers to avoid the shortcomings of FDG PET. The integration of novel radiotracers, such as C-11 methionine (MET), and F-18 fluorothymidine (FLT), enables an enhanced evaluation of tumor pathophysiology and metabolism, resulting in improved accuracy for CNS tumor diagnosis and follow-up. The following section will provide an overview of some of the commonly used non-FDG radiotracers in the literature. Based on its favorable half-life of 110 min, F-18 is the most practical isotope for radiolabeling; C-11with a half-life 20 min is being used mainly in clinical research settings where on-site cyclotrons are available. At the time of this writing, FDG is the only radiotracer currently FDA approved for clinical use, although many of them are being studied as Investigational New Drug Applications (INDs). The ability to develop PET tracers for specific molecular targets is potentially important and a large number of them are in development [36]. Besides FDG, the radiolabeled amino acids C-11 Methionine (MET) and F-18 fluoroethyl-tyrosine (FET) are the most commonly used PET tracers for brain tumors. The
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most significant advantage of using radiolabeled amino acids over FDG is the relatively low uptake of amino acids by normal brain tissue. The high uptake in gliomas therefore results in good lesion-to-background ratio so that the tumor can be detected more easily. As the building blocks of proteins, amino acids serve well as a target for molecular imaging. As a component of many metabolic cycles, the metabolism of amino acids is up-regulated in cells with increased proliferative activity, such as in cancer. This makes it attractive for researchers to develop radiotracers labeling PET isotopes with amino acids for tumor imaging. The uptake mechanism for the most commonly used amino acid radiotracers (MET, FET) is mainly explained by the transport via specific amino acid transporters although a small amount of the radiotracer may be further metabolized or incorporated into protein synthesis within the cell [37]. Certain amino acids radiotracers are being used more common than others depending on the ease of biochemical compounding, the availability of an on-site cyclotron and clinical indication as well as cost consideration. MET is the most popular amino acid radiotracer in neurooncology although its use is limited to PET centers with on-site cyclotron. Its popularity is largely due to the relatively simple steps of production. FET is newer than MET and has the advantage of longer half-life (110 min) and wider availability, obviating the need for an on-site cyclotron. FLT is an analog to the nucleoside thymidine and was developed as a PET radiotracer to assess cellular proliferation. The phosphorylated FLT within the cell reflects cell proliferation and correlates strongly with thymidine incorporation into the DNA. The actual incorporation of FLT into the DNA is however low, and the majority of the phosphorylated FLT is trapped in the cytosol [38, 39]. As a biomarker for cell
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proliferation, FLT has the tremendous potential in monitoring and treatment response assessment. This is demonstrated in a study of 19 patients treated with bevacizumab and irinotecan. Comparative studies between MET and FET have shown similar results in gliomas [40, 41]. Because amino acid radiotracers easily diffuse into the brain tissue, a disruption of the BBB is not required for the increased metabolism in brain tumors. Consequently, amino acid radiotracers enable imaging of both low-grade tumors without BBB leakage and high-grade tumors with BBB leakage. The sensitivity and specificity of MET PET and FET PET is in the range of 70-90% each [42, 43]. C-11 Choline is a natural amine that enters the cells and is involved in the synthesis of the cell membrane. Given the increased cell proliferation of tumor cells, there is also increased cell membrane turnover; therefore, choline can serve as a marker for phospholipid synthesis. Comparative studies have shown that C-11 choline is superior to FDG PET in delineating the extent of tumor [39, 44]. The uptake of C-11 choline is reported to be 3-4 times higher in glioblastomas than in normal brain tissue, and the uptake in low-grade tumors remains low and is comparable with the non-neoplastic lesions [45, 46]. Hypoxia in malignant gliomas represents a significant risk for resistance to both radiation and chemotherapy, and is associated with a more aggressive tumor phenotype and worse prognosis. Diagnostic imaging with hypoxia markers such as 18Ffluoromisonidazole (FMISO) enables the quantification of hypoxia in tumors and
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provides valuable information for prognosis, treatment planning and response to therapy [47, 48].
POTENTIAL DIAGNOSTIC VALUE OF HYBRID PET/MRI Functional imaging plays an important role in aiding the clinical management of patients with brain tumors. Multi-parametric imaging with hybrid PET/MRI is now available at some imaging centers, enabling an in-depth studying of pathophysiologic processes at a molecular level. Intuitively, the different functional data derived from multimodal imaging will enhance diagnostic confidence and accuracy. However, the era of PET/MRI has just started, and much more work lies ahead to demonstrate its clinical potential, particularly compared with currently available modalities of MRI and PET/CT as well as co-registration of individual MRI and PET data. To date, the literature on the use of hybrid PET/MRI in neuro-oncology is limited to a few reports [11-13]. These studies were carried out on the dedicated BrainPET/MRI system which is being used in a few imaging centers. It is expected that future PET/MRI applications and investigations will be primarily done using the whole-body PET/MRI systems that are being offered by the three major vendors Siemens, Philips and GE. It will take several more years before a good amount of research data is available on the use of hybrid PET/MRI. Researchers at the University of Tuebingen were the first to report on the use of hybrid PET/MRI in human brain [11, 13]. Using the BrainPET/MRI system, the tumor delineation in the seven patients undergoing MET PET was compatible between
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PET/MRI and PET/CT [13]. They performed Ga-68 DOTATOC PET in eight patients as well for the diagnosis of meningioma. Six of eight patients were found to have comparable lesions between PET/MRI and PET/CT, whereas an additional lesion was suggested in the remaining two patients [13]. This study was however mainly an image quality evaluation, in which the authors shared their initial clinical experience on a simultaneous PET/MRI system, and the clinical indications were wide, ranging from meningiomas, head and neck tumors to astrocytomas. Comprehensive studies evaluating the clinical value of hybrid PET/MRI are under way and the results are to be expected for the coming years. In the following section, the current literature on the use of separate MRI and PET scanning with subsequent image fusion is reviewed and the clinical and research potential of hybrid PET/MRI is discussed.
Tumor grading and prognosis Gliomas may consist of different parts that are heterogeneous in terms of tumor grading. Thus, low- and high-grade areas may be present within the same tumor. Although MRI is the modality of choice to detect intracerebral neoplasms, the inherent heterogeneity of gliomas may not be sufficiently depicted by conventional MRI, particularly in non-enhancing gliomas (Fig. 1A-C). To date, several studies combining single modalities of functional MRI and PET have been reported in the literature [25, 49]. In a prospective study of 61 patients with WHO grade II-IV gliomas, Weber at al. [23] wanted to answer the question whether the use of various functional imaging modalities would lead to similar target areas for biopsy. Using an extensive array of
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functional MRI (Na-23-, MRS, ASL, DCE and DSC, DW) in combination with FDG- and FLT-PET, they found that FLT-PET, DSC-, DW- and DCE-MRI as well as MRS correctly identified all three non-enhancing grade III lesions and showed no significant tumor heterogeneity in all 15 grade II gliomas. Tumor grading correlated well with semiquantitative parameters of tumor vascularity and proliferation. In the majority of the cases (>80%), areas of increased FLT uptake matched with that of choline peak on MRS [25]. Tumors with the same histopathological diagnosis can behave in very different ways. Novel biomarkers of prognosis can aid treatment strategy, moving towards personalized treatments. Functional imaging can serve as noninvasive biomarkers of prognosis, which commonly mirrors the biomarkers found for grading. In a study that included 189 patients with grade II glioma, high rCBV at DSC-MRI predicted a short time to disease progression and poor clinical outcome [24]. In a retrospective study including 187 patients with high-grade gliomas, Majos et al. [50] established that MRS at diagnosis could identify patients with poor prognosis, depending on spectral characteristics such as low myo-inositol levels and high levels of mobile lipids. In a retrospective study, the mean and minimum ADC were found to be significantly lower in patients with progressive, compared with stable, high-grade gliomas at 2 years [18]. Using FET-PET, the combination with MR morphology has been found to be a significant prognostic predictor for patients with newly diagnosed low-grade gliomas [51]. Baseline FET uptake and a circumscribed versus a diffuse growth pattern on MRI were highly significant predictors for patients’ course and outcome. One could envision that multiparametric PET/MRI could enhance our knowledge of both prognostic and predictive
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outcome. Multi-parametric PET/MRI has the potential to evolve into a valuable tool for research, potentially important for the understanding of tumor microenvironment and drug development.
Biopsy guidance Often, brain tumors exhibit different degrees of anaplasia in different tumor parts. Thus, surgical biopsies, especially when taken stereotactically, may miss the most malignant tumor area and therefore underestimate the tumor grade. Although surgical resection is a key intervention in many patients, including adults with low-grade and high-grade gliomas, biopsy is still important in some cases, such as in patients with diffuse tumors and those tumors in which extensive surgery would pose a significant risk to life. In addition to providing noninvasive diagnosis, functional imaging can be used to guide biopsy in large complex lesions in which there is a risk that the tissue obtained may not be representative of the highest grade within the tumor (Fig. 5). Insert Fig. 5 Weber et al. [25] conducted a study of 61 patients using MRS, DWI, ASL, DCE-T1, DSC, 23Na-MRI as well as FLT and FDG PET. These authors showed that target areas for vascularity, cellularity and proliferation were similar among the various functional parameters. In areas without tumor necrosis, there was a good agreement between markers of cell proliferation (increased choline at MRS and FLT uptake at PET) and cellularity (low ADC values, increased FDG uptake) as well as microcirculation and angiogenesis (elevated rCBV and rCBF). Functional MRI also showed similar hot spots
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compared with those observed with PET. Widhalm et al. [49] showed in a study of 32 patients using co-registration of MRS and MET PET that areas of positive MRS and PET for anaplasia overlapped 50% in 18/21 cases and
