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Increased Fluorine-18 2-Fluoro-2-Deoxy-D-Glucose (FDG) Uptake in Childhood CNS Tumors Is Correlated With Malignancy Grade: A Study With FDG Positron Emission Tomography/Magnetic Resonance Imaging Coregistration and Image Fusion

From the Department of Clinical Physiology, Nuclear Medicine, and Positron Emission Tomography; Pediatric Clinic II; Neuroteam, Department of Pathology; and Department of Radiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark

Address reprint requests to Lise Borgwardt, MD, Positron Emission Tomography and Cyclotron Unit, Department of Clinical Physiology, Nuclear Medicine and Positron Emission Tomography, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; e-mail: borgwardtpet{at}rh.dk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited.

PATIENTS AND METHODS: Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H₂¹⁵O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest–based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months).

RESULTS: Four grade 4 tumors had a mean index of 4.27 ± 0.5, four grade 3 tumors had a mean index of 2.47 ± 1.07, 10 grade 2 tumors had a mean index of 1.34 ± 0.73, and eight of 12 grade 1 tumors had a mean index of –0.31 ± 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H₂¹⁵O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases.

CONCLUSION: FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
CNS tumors account for 20% to 25% of all cancers in childhood.¹ Although the prognosis has improved considerably over the last two decades, the overall cure rate today is approximately 60%,² and brain tumors are the leading cause of cancer mortality in children.¹ In addition, the burden of late effects is troublesome.^2,3 The treatment modalities include neurosurgery, chemotherapy, and radiotherapy, and surgical intervention is the mainstay of the diagnostic and therapeutic management of primary brain tumors. Although chemotherapy can be effective,^4,5 its use as chemotherapy before surgery for children with medulloblastoma and other primitive neuroectodermal tumors has been limited⁴ by the lack of the pretherapeutic diagnostic tools to identify the children with potential benefit (ie, malignant tumors).

Surgical intervention is used to establish a histologic diagnosis and to excise the tumor or reduce its volume. Tumors localized centrally, such as those in the hypothalamus, thalamus, or basal ganglia in the dominant hemisphere, tumors in eloquent cortical areas, and tumors that are intrinsic in the brainstem can rarely be totally resected without causing severe neurologic deficits, and even biopsies can be a major risk.

Magnetic resonance imaging (MRI) can delineate the anatomic location and extent of an intracranial neoplasm, but the specificity in grading of malignancy is unsatisfactory.⁶ Positron emission tomography (PET) using the glucose analog tracer fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) adds functional information on the metabolic activity of the CNS tumor. It has been assumed that malignant tumors have a high FDG uptake and benign tumors have a reduced FDG uptake compared with FDG uptake of the average brain.^7-15 However, studies in children have generally been few, small, retrospective, and/or post-therapy,^16-21 and none of these studies combined PET with MRI coregistration and image fusion. Childhood PET studies using the tracer H₂¹⁵O to study cerebral blood flow (CBF) are lacking, but blood flow has been found to be depressed in adult gliomas,²² with the more malignant gliomas tending to have the largest reduction.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients
Nineteen boys and 19 girls with a median age of 8 years (range, 0 to 16 years) with primary CNS tumors were studied with FDG PET before any therapy and after initial MRI diagnosis (Table 1). H₂¹⁵O PET for CBF was performed in 16 patients. The MRIs were all obtained within 1 month before the PET studies.

The 16 patients examined with H₂¹⁵O PET comprised three patients with WHO grade 4 tumor, two patients with WHO grade 3 tumor, and 11 patients with WHO grade 1 tumor.

PET Scanning
PET scanning was performed as previously described.²⁵ In patients who had both CBF and FDG scans performed, the H₂¹⁵O PET²⁶ scan was performed before the FDG²⁷ study.

Dosimetry
The radiation dose administrated was 3 MBq/kg body weight for FDG and 6 MBq/kg for H₂O. The effective dose equivalent is 0.13 mSv/MBq²⁸ for FDG (1-year-old child), thereby resulting in a radiation dose of 3.78 mSv, and 4.38 mSv²⁸ (5-year-old child) and 4.23 mSv²⁸ (10-year-old child), respectively, for FDG. The effective dose equivalent for H₂O is 1.2 mSv/GBq, resulting in an effective dose of 2 mSv (5-year-old child).

Sedation/General Anesthesia
No sedation was given earlier than 30 minutes after FDG tracer injection (ie, right before the scanning procedure). Sedation with rectal choral hydrate 50 mg/kg in a gel-solution was used in four cases, and general anesthesia with thiopental was used in two cases where chloral hydrate was inefficient.

MRI
A structural MRI scan was performed on a 1.5 T Vision scanner (Siemans, Erlangen, Germany), consisting of a T2-weighted and a T1-weighted image followed by a T1-weighted image after intravenous injection of Gd-DTPA contrast (Magnevist 0.2 mL/kg, Shering, Berlin, Germany). If the children were unable to remain motionless during the scan, the MRI scan was performed in general anesthesia.

Image Analysis
Qualitative interpretations of the FDG and the H₂¹⁵O scans were performed from transaxial, coronal, and sagittal slices viewed on a Unix station (GE, Milwaukee, WI). The semiquantitative determination of the FDG scan (ie, the tumor hotspot/brain-index)²⁹ consisted of definition of three 10-mm diameter circular regions-of-interest (ROIs) after coregistration and image fusion to MRI to localize tumor. We selected an ROI in the temporal cortex contralateral to the lesion, a region in the contralateral white matter, and a region containing the tumor hotspot. Average pixel counts were extracted for the gray and white matter regions and the maximum pixel value for the tumor hotspot ROI. Partial volume effects were minimized by placing the borders of the ROIs at least 5 mm from the edge of each structure.

The FDG uptake in contralateral gray and white matter was used as reference for the grading system. As a modification of the visual ranking score suggested earlier,¹⁶ FDG uptake in healthy gray matter was defined as 4, whereas FDG uptake in healthy white matter was defined as 2. These two points were then taken as reference points for a linear function, which then in turn was used to calculate the index value for the tumor hotspot by the equation:

where ROI _tumor, ROI _{white matter}, and ROI _{gray matter} are the above-mentioned ROIs in tumor hotspot, white matter, and gray matter, respectively (Fig 1). For illustrative purposes, the gray matter region in Figure 1 is not placed in the temporal lobe, as described in the Image Analysis section.

View larger version (121K): [in this window] [in a new window]   Fig 1. The tumor hotspot/brain index is significantly positively correlated with the WHO malignancy grading, although the benign hypermetabolic tumors confound the correlation (marked with green, not included in mean for WHO grade 1 tumors).

The interobserver variation on the tumor hotspot/brain index was explored by two observers independently drawing ROIs for the first 18 patients.

Neuropathology
For each of the 30 cases with histology, a neuropathologist (H.L.) characterized the WHO grade of the tumor^23,24 and scored mitotic activity, cell density, proliferation, necrosis, and neovascularity. The number of mitoses per 100 nuclear profiles was counted in hematoxylin and eosin–colored tissue in a field of view of 0.112 mm². The proliferation rates per 100 nuclear profiles were counted in proliferation rate (MIB-1) –colored tissue in a field of view of 0.112 mm². Cell density was measured as number of nuclear profiles per square millimeter. The vascularities were ranked from 0 to 3, with 0 being no increase in vascularity, 1 being minor increase in vascularity (minor glomerulus vessel proliferation), 2 being increased vascularity (glomerulus vessel proliferation), and 3 being neovascularity (glomerulus vessel proliferation with anaplasia). The degree of necrosis was ranked 0 to 3, 0 being no necrosis, 1 being few isolated necroses, 2 being larger areas of necrosis, and 3 being confluent necrosis and/or pseudopalisade tumor cells.

Statistics
The distribution of parameters was expressed as mean ± standard deviation (SD). Spearman's correlation analysis was applied to calculate the relation between parameters. All statistical analyses were performed using SPSS software (SPSS 11.0; SPSS Inc, Chicago, IL). Two-sided P values less than .05 were considered statistically significant.

Ethics
The study was approved by the regional ethical committee (study No. [KF] 01-006/00), and informed consent was obtained from all parents. The study was performed in accordance with the Helsinki Declaration II.

	RESULTS

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Tumor FDG Uptake and Malignancy
The four patients with WHO grade 4 tumors had tumor hotspot/brain indices of 3.60 to 4.80 (mean, 4.27 ± 0.50), the four patients with grade 3 tumors had tumor hotspot/brain indices of 1.8 to 4.0 (mean, 2.47 ± 1.07), and the 10 patients with grade 2 tumors had tumor hotspot/brain indices of 0.50 to 2.55 (mean, 1.34 ± 0.73). The mean tumor hotspot/brain index in this group was 1.04 without the recurring tumors mentioned later in this section (n = 2). Eight of 12 patients with grade 1 tumors had tumor hotspot/brain indices of less than 0.9 (–0.93 to 0.88; mean, –0.31 ± 0.59). The last four of the 12 patients with grade 1 tumors included a patient with a choroid plexus papilloma with a tumor hotspot/brain index of 4.5^16,29,31 and three pilocytic astrocytomas with a tumor hotspot/brain index of 3.3 to 4.3 (mean, 3.8; Table 1).³² The eight patients with no histologic confirmation had a mean index of 1.04 (range, –0.01 to 2.58). Except for the four well-known benign hypermetabolic tumors,^16,31,32 the FDG uptake (ie, tumor hotspot/brain index) was positively correlated with the WHO^23,24 graded tumor malignancy (n = 26; r = 0.89; P < .01; Fig 2). The correlation was slightly decreased when including the eight cases with no histologic confirmation (n = 34; r = 0.72; P < .01) and clearly diminished with the four hypermetabolic benign tumors included (n = 38; r = 0.57; P < .01; Fig 2). Thus all 16 tumors (of the 30 with histologic confirmation) with a tumor hotspot/brain index of less than 1.83 were grade 1 or 2 tumors, and the only two remaining patients with grade 2 tumors who had an index of 2.53 and 2.55, respectively, both developed relapse at 14 and 24 months from time of diagnosis.

View larger version (12K): [in this window] [in a new window]   Fig 2. Digitally performed coregistering and image fusing of positron emission tomography with magnetic resonance imaging increased the specificity in 90% of cases, of tumor location in 23 cases, of tumor extent in 8 cases, and of heterogeneity in 16 cases.

MRI and PET Image Fusion
Digitally performed coregistering and image fusion of PET and MRI were performed in 31 of 38 cases. The remaining seven coregistrations were not done digitally because of lack of compatibility between the MRI scanner system (high-quality MRI done at the referring hospital) and the PET scanner system, but were then done visually. Digitally performed coregistering and image fusing of PET with MRI increased the diagnostic value in 28 of 31 cases, as in the evaluation of tumor location in 23 cases, the delineation of tumor extent in eight cases, and the determination of heterogeneity in 16 cases (Figs. 3 to 5). The three PET scans that did not benefit from digital coregistering were two large, well-delineated, homogenous, benign hypermetabolic tumors and a tumor localized to an anatomic location easy to pinpoint (ie, the pituitary gland).

View larger version (43K): [in this window] [in a new window]   Fig 3. Seven-month-old boy with a tumor in the fossa posterior. Positron emission tomography showed a very hypometabolic tumor with areas of significantly decreased metabolism. After coregistration and image fusion with magnetic resonance imaging, the hypometabolic area was found to be compatible to a central necrosis in a very hypermetabolic tumor.

View larger version (109K): [in this window] [in a new window]   Fig 5. Fluorine-18 2-fluoro-2-deoxy-D-glucose uptake in gray matter 1 is defined as index value No. 4, white matter 2 is defined as No. 2. An individual linear relation is established (3), region of interest (ROI) for the tumor hotspot is evaluated (4), and corresponding uptake class is calculated. arb., arbitrary.

Tumor Blood Flow
The results of CBF in the tumor (regional CBF [rCBF]) determined with H₂¹⁵O PET are shown in Table 1. In these 16 patients, we found no correlation between rCBF and tumor malignancy, nor did we find a correlation between rCBF and the tumor hotspot/brain index.

Histochemical Analyses
Of the five histologic parameters tested, a significant correlation was observed only between the tumor hotspot/brain index and amount of mitoses in the tissue (n = 28; r = 0.45; P = .02). In cases with a mitotic index more than 1%, the lowest tumor hotspot/brain index calculated was 2 (Table 1). A borderline significance was observed between the tumor hotspot/brain index and necrosis (n = 28; r = 0.37; P = .055) and vascular malformation (n = 27; r = 0.35; P = .074), but this could reflect a result of multiple testing, because five parameters have been tested.

	DISCUSSION

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This is the first pediatric study on primary CNS tumors in which FDG PET with MRI coregistration and image fusion has been carried out systematically. When comparing tumor hotspot/brain glucose metabolism index in the different WHO grading groups, we found a positive correlation between FDG uptake and WHO graded malignancy. In addition, the digital PET/MRI coregistration and image fusion improved the information on the tumor location, extent, and heterogeneity in 90% of cases compared with PET alone, whereas visual PET/MRI coregistration only improved the information in three of seven cases.

Only few studies have investigated the usefulness of PET in childhood tumors,^16-21,29 and even fewer studies have investigated the value of PET for preoperative grading. Hoffman et al¹⁶ evaluated the role of FDG PET in posterior fossa brain tumors in 17 pediatric patients and found that in an individual scan, the degree of FDG uptake could not reliably predict histology or predict prognosis, although they found a correlation with the degree of malignancy. Holthoff et al²¹ found FDG PET to be a useful tool to evaluate metabolic activity of brain tumors over time and to assess response to treatment. Both of these studies included patients with primary, residual, and recurrent CNS tumors, and the PET scans were performed before, under, or after oncologic treatment. For the majority of patients in the two studies, this approach may not be ideal for tumor grading, because both radiation and chemotherapy change cerebral glucose use in children.^33,34 Utriainen et al¹⁷ studied 27 primary CNS tumors before therapy and found that FDG and ¹¹C-methionine (amino acid tracer showing the protein synthesis) uptake in pediatric brain tumors is associated with malignancy grade. However, no clear limits between different brain ratios of benign and malignant tumors could be used to differentiate the two and grade CNS tumor malignancy. None of these studies performed PET/MRI coregistration and image fusion, which may explain the better differentiation between benign and malignant primary CNS tumors in the present study. When performing coregistration and image fusion, the PET interpretation typically benefits from the coregistration and image fusion through adjustments of the tumor location from MRI. The group of tumors that typically benefit from PET/MRI coregistration in defining the localization of tumor primarily consist of low metabolic tumors localized in a low metabolic area or high metabolic tumors localized in close relation to high metabolic structures such as basal ganglia, cortex, and so on. Defining tumor extent can be hampered by low metabolic tumors having fibrillary expansions that are not seen on MRI but do affect surrounding tissue that become low metabolic. Similarly, low metabolic tumors may be interpreted as being larger on PET than on MRI because of surrounding edema that reduces the metabolic activity of the nontumor tissue. In heterogeneous tumors, PET might be useful for biopsy guiding combined with MRI by the ability of the fusion to differentiate cystic and necrotic parts of the tumor. The benign hypermetabolic childhood CNS tumors tended to have a more homogeneous FDG uptake in the solid parts of the tumor, compared with malignant tumors that often have a very heterogeneous uptake.

So far, no PET studies using the tracer H₂¹⁵O to study CBF have been published on children with brain tumors. Blood flow has been found to be depressed in adult gliomas, in accordance with their relatively anaerobic energy metabolism.²² However, we found no correlation between perfusion and malignancy of the tumors. The study was hampered, however, by the short half-life of ¹⁵O-labeled water, making studies in children practically quite difficult, and data were visually interpreted, because arterial blood sampling is painful or imaging of the left ventricle would have required extended scanner-time and sedation that in itself affects the CBF.

In the present study, we proposed a semiquantitative method for evaluation of FDG uptake in tumor. Determination of metabolic activity ratios as the ratio of the activity within the brain tumor to various normal structures, such as contralateral white matter or cortex, the basal ganglia, the cerebellum, or even the whole brain, has been proposed as a means of assessing tumor uptake of FDG.^7,8,17,35-39 Currently, there is no consensus about the optimal scheme for pediatric brain tumor evaluation with FDG.⁴⁰ Standardized uptake volume (SUV) and SUV-to-normal brain ratios were found not to be useful in malignancy grading of adult brain tumors.^17,41 The tumor:whole-brain ratio was used,³⁵ but this method includes the diseased part of the brain both in the numerator and the denominator of the ratio, which leads to a systematic error, especially in larger tumors. None of the ratios used so far use information from both white matter and gray matter in only nonaffected tissue, which is the basis of the method proposed here as the tumor hotspot/brain index, allowing the value of the tumor to be normalized to the individual brain. Moreover, it is our experience that it gives the clinicians a useful value, because it can be correlated directly to the value 4, representing gray matter, and the value 2, representing white matter.

The studies of the correlation between FDG uptake and biologic parameters showed considerable overlap between high-grade and low-grade tumors, although we found a significant correlation between tumor hotspot/brain index and mitotic activity. In addition, we did not find a significant correlation between cell density and tumor hotspot/brain index, as has been published previously.⁴² At this point, it is still unresolved whether the limiting process for glucose use and FDG uptake is transport, phosphorylation, or other determinants.

To create a classification system applicable worldwide, the WHO classification of brain tumors assigns a simple numerical grade representing the cellular origin and histology of a tumor as well as the clinical behavior (ie, prognosis). This hampers a high correlation between FDG uptake and histology. Thus it is crucial to recognize benign tumors with known high FDG uptake, such as the juvenile pilocytic astrocytomas, the choroid plexus papilloma,^16,31,32 and the pleomorphic xanthoastrocytoma,^43,44 when interpreting FDG PET. Although by FDG PET/MRI coregistration they may be more clearly identifiable, in some cases they may still be difficult to distinguish from malignant tumors with high FDG uptake.

There is a need for new PET tracers that more specifically identify the benign tumors. Although many amino acids have been radiolabeled to study potential imaging characteristics for PET, they seem more useful for differentiation between neoplastic and nonneoplastic lesions than for tumor grading.^17,19,45,46 Recent studies have shown the potential usefulness of ¹¹C-choline and ¹⁸F-choline in brain tumors,^47,48 and these may be promising in discriminating between benign and malignant brain tumors.^49,50 In addition, assessing DNA synthesis and tumor proliferation imaging with radiolabeled nucleoside analogs⁵¹ seems promising, but uses of these tracer for human brain tumor imaging have not been published yet.

In combination with the new amino acid tracers, the choline analogs or the radiolabeled nucleoside analogs, FDG PET may improve in the differentiation of the benign from the malignant tumors, but this awaits large prospective pediatric studies.

In conclusion, MRI is the method of choice for diagnosis of brain tumors in children. FDG PET of the brain combined with MRI coregistration and image fusion is at this state a supplementary work-up in childhood CNS tumors and might contribute to a higher presurgical level of information on tumor and thereby better treatment of patients. When PET is available, MRI coregistration and image fusion is necessary to obtain maximum information. However, a thorough knowledge of the PET appearance of the benign hypermetabolic tumor is mandatory for the use of PET for malignancy grading.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

View larger version (45K): [in this window] [in a new window]   Fig 4. Twelve-year-old boy with a fourth ventricle tumor with a large cyst in a solid mass. Positron emission tomography showed a slightly deformed right occipital cortex that after coregistration was found to be hypometabolic and compressed by the solid part of a hypermetabolic tumor.

	Acknowledgment

	NOTES

 
Supported by Female Researchers in Joint Action (FREJA; Copenhagen, Denmark) research grant, the Danish National Research Council, and the John and Birthe Meyer Foundation, Copenhagen, Denmark.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted February 10, 2004; accepted February 2, 2005.

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