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Published online before print June 20, 2007, 10.1148/radiol.2442060898
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(Radiology 2007;244:557-565.)
© RSNA, 2007

Nuclear Medicine

Solitary Brain Lesions Enhancing at MR Imaging: Evaluation with Fluorine 18–Fluorocholine PET1

Sandi A. Kwee, MD, Jehoon P. Ko, MD, Caroline S. Jiang, MS, Michael R. Watters, MD, and Marc N. Coel, MD

1 From the Hamamatsu/Queen's PET Imaging Center (S.A.K., J.P.K., M.N.C.), Honolulu, Hawaii; and The Queen's Medical Center (C.S.J.) and Department of Medicine (S.A.K., M.R.W.), University of Hawaii John A. Burns School of Medicine, 1301 Punchbowl St, Honolulu, HI 96813. Received May 23, 2006; revision requested July 24; revision received August 14; accepted September 18; final version accepted November 20. Supported by the Queen Emma Research Foundation. Address correspondence to S.A.K. (e-mail: skwee{at}queens.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To prospectively determine whether differences between benign and malignant brain lesions can be depicted with fluorine 18 (18F) fluorocholine positron emission tomography (PET).

Materials and Methods: Thirty consecutive patients (14 women, 16 men; age range, 26–79 years) with solitary brain lesions that were enhanced at magnetic resonance (MR) imaging underwent whole-brain 18F-fluorocholine PET after giving informed consent in this institutional review board–approved, HIPAA-compliant study. Histopathologic diagnoses were made in 24 cases (13 high-grade gliomas, eight metastases to the brain, and three benign lesions). In six cases, benign lesions were diagnosed on the basis of longitudinal follow-up MR findings. The maximum standardized uptake value (SUVmax) for lesion and peritumoral regions was measured on PET images, and a lesion-to–normal tissue uptake ratio (LNR) was calculated. Differences were assessed with one-way analysis of variance, Fisher exact, and Student t tests.

Results: Differences in SUVmax between high-grade gliomas (1.89 ± 0.78 [mean ± standard deviation]), metastases (4.11 ± 1.68), and benign lesions (0.59 ± 0.31) were significant (P < .0001). LNRs also differed significantly (5.15 ± 2.51, 10.91 ± 2.14, and 1.28 ± 0.32, respectively; P < .0001). These differences were also significant at pairwise analysis. The peritumoral LNR exceeded 2.0 in seven high-grade gliomas and no metastases (P = .02). In 14 radiation-treated patients, the lesions classified as benign demonstrated significantly less uptake compared with the recurrent tumors (SUVmax: 0.72 ± 0.38 vs 2.27 ± 1.24, P < .01; LNR: 1.36 ± 0.43 vs 5.88 ± 3.66, P < .01).

Conclusion: High-grade gliomas, metastases, and benign lesions can be distinguished on the basis of measured fluorocholine uptake. Increased peritumoral fluorocholine uptake is a distinguishing characteristic of high-grade gliomas.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
The etiology of a solitary brain mass can be difficult to ascertain with conventional imaging. Benign lesions, such as those caused by tumefactive demyelination, can exhibit many features that are characteristic of malignancy at magnetic resonance (MR) imaging (1–3). Furthermore, different malignant masses such as solitary metastases to the brain (hereafter brain metastases) and high-grade gliomas can demonstrate identical MR imaging characteristics despite having pathologic differences. For example, peritumoral high signal intensity on T2-weighted MR images can be seen in both these entities. In metastases, these changes are attributable to vasogenic edema. In high-grade gliomas, however, they can signify neoplastic infiltration (4). Because benign lesions, metastases, and high-grade glial tumors can generate similar findings at MR imaging, it is worthwhile to investigate other methods of distinguishing solitary enhancing brain lesions.

Proton MR spectroscopy has been used to identify increased choline metabolite levels in both primary glial tumors and metastatic brain tumors (5–7). These changes are believed to reflect the increases in choline phospholipid metabolism that result from increased cell membrane turnover and cellular proliferation. Choline metabolism in vivo can also be assessed by using positron emission tomography (PET) with carbon 11 (11C) choline (8–10). However, the clinical usefulness of this radioactive tracer is limited by the short decay half-life (20 minutes) of 11C. This limitation has been overcome by labeling choline with fluorine 18 (18F), which has a half-life of 110 minutes. Because of the shorter positron range of 18F, use of this tracer, as compared with use of 11C, also yields higher-spatial-resolution PET images. Several 18F-labeled choline derivatives have been preliminarily studied in brain tumors and other malignancies (3,10,11). In particular, fluorocholine has been shown to be a specific substrate for choline kinase, an enzyme commonly overexpressed in malignant lesions (11,12). Phosphorylation with choline kinase results in intracellular trapping of fluorocholine to allow PET visualization of lesions with increased choline metabolism. Thus, the purpose of our study was to prospectively determine whether differences between benign and malignant brain lesions can be depicted with 18F-fluorocholine PET.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Patients
This Health Insurance Portability and Accountability Act–compliant study was conducted after approval from the institutional review board of The Queen's Medical Center was obtained. All patients gave written informed consent. Thirty patients (14 women, 16 men; age range, 26–79 years; mean age, 54 years) with solitary enhancing brain lesions that were discovered at MR imaging between May 2003 and April 2006 were prospectively recruited. Patient eligibility for this study was based on systematic review of the MR findings by one of two radiologists (M.N.C. or J.P.K., 18 and 19 years MR imaging experience, respectively) to confirm the presence of a solitary intracranial mass lesion with contrast enhancement and edema on T1- and T2-weighted images, respectively. Twelve patients had no history of malignancy, four had a history of extracranial malignancy, and 14 had a changing brain lesion after surgery and radiation treatment for a previous brain tumor (10 gliomas, four metastases). Clinical and histopathologic data were obtained (S.A.K.) from the patients' medical records and our institutional oncology data registry. For 24 patients, a final diagnosis of benign or malignant lesion was made at histopathologic examination after biopsy or surgical resection. For the remaining six patients, the classification of a benign lesion was determined clinically on the basis of findings at subsequent brain MR imaging performed 6–27 months later. In these patients, MR image interpretation (M.N.C.) revealed neither new lesions nor increased maximal diameter of the existing lesion on T1- or T2-weighted images.

MR Imaging
MR imaging was performed with a 1.5-T MR unit (Magnetom Symphony; Siemens, Erlangen, Germany) equipped with a standard head coil. Imaging included T2-weighted fast spin-echo (4000/90 [repetition time msec/echo time msec], 256 x 224 matrix, 5-mm section thickness), fluid-attenuated inversion-recovery (9000/108/1000 [repetition time msec/echo time msec/inversion time msec], 256 x 224 matrix, 5-mm section thickness), diffusion-weighted (4000/137, 128 x 128 matrix, 5-mm section thickness), and T1-weighted unenhanced and gadopentetate dimeglumine–enhanced (Magnevist; Schering, Berlin, Germany) spin-echo (525/17, 256 x 224 matrix, 5-mm section thickness) transverse sequences. MR imaging preceded PET; the median time between examinations was 4 days (range, 1–18 days) for patients with new brain lesions and 18 days (range, 3–51 days) for patients with previously treated tumors.

Synthesis of 18F-Fluorocholine
Fluorine 18–fluorocholine was synthesized by means of fluorination of ditosylmethane with 18F, followed by alkylation of fluorotosylmethane with dimethylethanolamine. An automated synthesis procedure was performed in our laboratory by using a chemical process control unit (model CPCU; CTI/Siemens, Knoxville, Tenn) in a U.S. Food and Drug Administration investigational new drug protocol (13). No radiochemical impurities were detectable in the final product.

PET Imaging
PET was performed by using a Hamamatsu SHR-22000 PET instrument (Hamamatsu Photonics, Hamamatsu-City, Japan). For 18F-fluorocholine injection, an 18- or 20-gauge intravenous catheter was inserted into the antecubital region. Imaging was performed with the patient in the supine position by using a head holder. Fasting was not required before imaging. Transmission scanning was performed for 7 minutes by using two germanium 68 rod sources. Emission scanning was performed for 15 minutes, beginning 5–10 minutes after the intravenous administration of 3.3–4.0 Mbq of 18F-fluorocholine per kilogram of body weight. Attenuation correction was applied to the emission data by using the transmission data. Images were reconstructed by using an ordered-subsets expectation maximization algorithm with three iterations and eight subsets and then a 6.0-mm postprocessing Gaussian filter. The voxel size of the reconstructed images was approximately 4 mm and isotropic, and the matrix size was 128 x 128.

Image Analysis
Software-based (HERMES; Hermes Medical Solutions, Battle Ground, Wash) image registration was performed to automatically align the corresponding MR and PET images. The MR images were resampled to a 256 x 256 matrix before registration. The coregistered images were visually inspected (M.N.C. or J.P.K.) for alignment of the orbits, choroid plexus, pituitary gland, and salivary glands. These structures are apparent on both 18F-fluorocholine PET and MR images. A standardized uptake value (SUV), defined as the measured voxel activity divided by the injected radioactivity normalized to body weight, was used to quantify uptake. A lesion region of interest (ROI) was first drawn by hand to outline the areas of contrast enhancement on each T1-weighted image depicting the lesion. Because of coregistration, each ROI could then be applied to the corresponding PET image, with the size and shape of the ROI still conformed to the size and shape of the lesion that was enhancing on the MR image. The maximum SUV (SUVmax) of each ROI was derived from the PET images, and the lesion SUVmax was determined by using the highest SUVmax of all regions. SUVmax measurements were used because they are reproducible and independent of small differences in ROI shape. ROI analysis was performed by two readers (M.N.C., S.A.K., 8 and 6 years PET experience, respectively) independently. The readers were not blinded to the patients' clinical histories or available histopathologic results.

The mean SUV of the normal white matter was measured by drawing a standardized 2-cm-diameter circular ROI in a contralateral region of normal-appearing white matter on the transverse PET image depicting the tumor ROI with the highest uptake. At visual inspection, seven malignant tumors were noted to have increased uptake beyond the lesion ROI. To further investigate this phenomenon, for the 21 lesions diagnosed as malignant, a peritumoral ROI encompassing the area of increased signal intensity surrounding or adjacent to the lesion ROI on the T2-weighted MR image was also assessed by measuring the SUVmax. For our study, the term peritumoral was used while still recognizing the possibility of malignant involvement in this region. Lesion-to–normal tissue uptake ratios (LNRs) for lesion and peritumoral regions were calculated by dividing the corresponding SUVmax by the mean SUV of the normal white matter. Increased peritumoral uptake was deemed to be present if the peritumoral LNR exceeded 2.0. At visual inspection, this value corresponded to a conspicuous degree of uptake. At all PET examinations, concordant SUV measurements were obtained by the two independent readers (M.N.C., S.A.K.).

Statistical Analyses
To determine the sample size, a power analysis was performed by using data from five subjects (two with benign tumors, two with high-grade gliomas, and one with brain metastasis) that were obtained in a pilot study. The sample size was calculated on the basis of the mean difference in LNR between the benign and malignant lesions. Estimated mean LNRs and standard deviations for the benign and malignant tumor groups were 1.15 ± 0.14 and 6.64 ± 4.20, respectively. The minimum number of patients needed per group (n) was determined as follows: n = [({sigma}12 + {sigma}22)·(Z{alpha}/2 + Zß)2]/{delta}2, where {alpha} = .05 (Z{alpha}/2 = 1.96), ß = .10 for 90% power (Zß = 1.28), {delta} = µ2 – µ1 = 5.49, Z is the critical value obtained from the standard normal distribution, {sigma} is the standard deviation, and µ is the mean. With these assumptions, a minimum of seven subjects per group was required.

The Student t test was used to assess differences in LNR and SUVmax between patients with benign and those with malignant lesions. After significant differences were observed between the benign and malignant lesions, one-way analysis of variance was performed to compare LNR and SUVmax measurements between benign lesions, high-grade gliomas, and metastases. When significant differences were observed across the three groups, post hoc pairwise Student t tests were performed to assess differences between group pairs. The Bonferroni method was used to account for multiple comparisons. The Fisher exact test was used to investigate whether the proportion of PET examinations demonstrating increased peritumoral uptake was significantly different between patients with high-grade gliomas and those with metastases. Finally, a subset analysis involving radiation-treated patients was performed by using Student t tests to compare uptake values between recurrent malignant tumors and benign radiation-induced lesions. Statistical analyses were performed by using SAS, version 9, software (2004 release; SAS Institute, Cary, NC). All tests were two sided, and P < .05 indicated significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Lesion Classification
The presence of 13 primary malignancies—all high-grade gliomas—and eight brain metastases was confirmed at histopathologic analysis (Table 1). In four of the eight patients with brain metastases, the histopathologic findings were compatible with the patient's known primary malignancy (ovarian carcinoma, non–small cell lung cancer, lymphoma, and salivary gland carcinoma). The remaining four patients with brain metastases had no previous history of cancer. In two of these four patients, biopsy specimens from both the brain and a pulmonary lesion revealed non–small cell lung cancer (Fig 1). No additional sites of malignancy were discovered in the remaining two patients.


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  		Table 1. Patient Characteristics

 

Figure 1A
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  		Figure 1a: Transverse images of brain metastasis from lung cancer. (a) T2-weighted MR image (4000/90) shows vasogenic edema in the right parietal lobe. (b) Contrast material–enhanced T1-weighted MR image (525/17) shows enhancement of the tumor (arrow). (c) PET image shows increased fluorocholine uptake corresponding to the area of enhancement in b (lesion SUVmax, 5.60; LNR, 14.36) but not to the high-signal-intensity area in a (peritumoral SUVmax, 0.44; LNR, 1.13).

 

Figure 1B
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  		Figure 1b: Transverse images of brain metastasis from lung cancer. (a) T2-weighted MR image (4000/90) shows vasogenic edema in the right parietal lobe. (b) Contrast material–enhanced T1-weighted MR image (525/17) shows enhancement of the tumor (arrow). (c) PET image shows increased fluorocholine uptake corresponding to the area of enhancement in b (lesion SUVmax, 5.60; LNR, 14.36) but not to the high-signal-intensity area in a (peritumoral SUVmax, 0.44; LNR, 1.13).

 

Figure 1C
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  		Figure 1c: Transverse images of brain metastasis from lung cancer. (a) T2-weighted MR image (4000/90) shows vasogenic edema in the right parietal lobe. (b) Contrast material–enhanced T1-weighted MR image (525/17) shows enhancement of the tumor (arrow). (c) PET image shows increased fluorocholine uptake corresponding to the area of enhancement in b (lesion SUVmax, 5.60; LNR, 14.36) but not to the high-signal-intensity area in a (peritumoral SUVmax, 0.44; LNR, 1.13).

 
Nine brain lesions were classified as benign at histopathologic analysis (n = 3) or MR follow-up (n = 6). Demyelinating disease was diagnosed in three patients after tissue biopsy revealed demyelination without malignant cells (Fig 2). In one patient, who did not undergo biopsy, the diagnosis of demyelinating disease was based on a clinical response to antiinflammatory medications and lesion regression seen at 1-year follow-up MR imaging. In five patients with new brain lesions discovered after the completion of radiation therapy, serial MR imaging failed to demonstrate new lesions or increased size of the existing lesion. These radiographically stable lesions were classified as benign and were attributed to radiation necrosis.


Figure 2A
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  		Figure 2a: Transverse images of progressive leukoencephalopathy. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows increased signal intensity (arrow) in the left caudate nucleus and left lentiform nucleus. (b) Gadolinium-enhanced T1-weighted MR image (525/17) shows multiple, corresponding small areas of enhancement. (c) PET image shows no areas of substantially increased fluorocholine uptake (lesion SUVmax, 0.54; LNR, 1.08). A diagnosis of benign lesion was confirmed after biopsy revealed demyelination with viral inclusion bodies due to JC polyoma virus.

 

Figure 2B
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  		Figure 2b: Transverse images of progressive leukoencephalopathy. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows increased signal intensity (arrow) in the left caudate nucleus and left lentiform nucleus. (b) Gadolinium-enhanced T1-weighted MR image (525/17) shows multiple, corresponding small areas of enhancement. (c) PET image shows no areas of substantially increased fluorocholine uptake (lesion SUVmax, 0.54; LNR, 1.08). A diagnosis of benign lesion was confirmed after biopsy revealed demyelination with viral inclusion bodies due to JC polyoma virus.

 

Figure 2C
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  		Figure 2c: Transverse images of progressive leukoencephalopathy. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows increased signal intensity (arrow) in the left caudate nucleus and left lentiform nucleus. (b) Gadolinium-enhanced T1-weighted MR image (525/17) shows multiple, corresponding small areas of enhancement. (c) PET image shows no areas of substantially increased fluorocholine uptake (lesion SUVmax, 0.54; LNR, 1.08). A diagnosis of benign lesion was confirmed after biopsy revealed demyelination with viral inclusion bodies due to JC polyoma virus.

 
Lesion Uptake Measurements
Differences in SUVmax (mean ± standard deviation, 0.59 ± 0.31 vs 2.74 ± 1.60; P < .0001) and LNR (1.28 ± 0.32 vs 7.35 ± 3.69, P < .0001) between benign and malignant tumors were significant. Subsequent analysis of variance revealed significant differences in lesion SUVmax (P < .0001) and LNR (P < .0001) between benign lesions, high-grade gliomas, and brain metastases (Figs 3, 4). At post hoc pairwise analysis (benign lesions vs gliomas, benign lesions vs metastases, and gliomas vs metastases), differences were also significant (Bonferroni adjusted P < .05). On average, brain metastases demonstrated the highest uptake; benign lesions, the lowest uptake; and high-grade gliomas, intermediate uptake (Table 2).


Figure 3
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  		Figure 3: Graph illustrates SUVmax measurements for benign intracranial masses, high-grade gliomas, and metastatic brain tumors. The white line in the box is the median; the top and bottom portions of the box are the 75th and 25th percentiles, respectively; dotted lines are drawn to the largest and smallest nonoutlying values; and the black lines are the outlying values.

 

Figure 4
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  		Figure 4: Graph illustrates LNRs for benign intracranial masses, high-grade gliomas, and metastatic brain tumors. The white line in the box is the median; the top and bottom portions of the box are the 75th and 25th percentiles, respectively; dotted lines are drawn to the largest and smallest nonoutlying values; and the black lines are the outlying values.

 

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  		Table 2. SUVmax for High-Grade Gliomas, Metastases, and Benign Lesions

 
Peritumoral Uptake
A significantly higher proportion of patients with high-grade gliomas than patients with brain metastases had increased peritumoral uptake: Seven patients (five with grade IV, two with grade III) had high-grade gliomas, and none had metastatic tumors (Fisher exact P = .02) (Fig 5). Of the tumors with increased peritumoral uptake, five were newly diagnosed and two were recurrent. In two cases, high-grade gliomas were diagnosed with stereotactic biopsy of the peritumoral region.


Figure 5A
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  		Figure 5a: Transverse images of high-grade glioma with biopsy-confirmed peritumoral invasion. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows a region of increased signal intensity in the left parietal lobe extending across the splenium of the corpus callosum. (b) Contrast-enhanced T1-weighted MR image (525/17) shows ring enhancement of the left parietal mass. The occipital skull defect was caused by previous nondiagnostic biopsy of the tumor. (c) PET image shows increased uptake (tumor SUVmax, 2.40; LNR, 5.22) corresponding to the region of ring enhancement, with increased peritumoral uptake extending anteriorly and contralaterally (peritumoral SUVmax, 1.53; LNR, 3.33). Subsequent peritumoral biopsy was required to determine the diagnosis of glioblastoma multiforme.

 

Figure 5B
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  		Figure 5b: Transverse images of high-grade glioma with biopsy-confirmed peritumoral invasion. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows a region of increased signal intensity in the left parietal lobe extending across the splenium of the corpus callosum. (b) Contrast-enhanced T1-weighted MR image (525/17) shows ring enhancement of the left parietal mass. The occipital skull defect was caused by previous nondiagnostic biopsy of the tumor. (c) PET image shows increased uptake (tumor SUVmax, 2.40; LNR, 5.22) corresponding to the region of ring enhancement, with increased peritumoral uptake extending anteriorly and contralaterally (peritumoral SUVmax, 1.53; LNR, 3.33). Subsequent peritumoral biopsy was required to determine the diagnosis of glioblastoma multiforme.

 

Figure 5C
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  		Figure 5c: Transverse images of high-grade glioma with biopsy-confirmed peritumoral invasion. (a) Fluid-attenuated inversion-recovery MR image (9000/108/1000) shows a region of increased signal intensity in the left parietal lobe extending across the splenium of the corpus callosum. (b) Contrast-enhanced T1-weighted MR image (525/17) shows ring enhancement of the left parietal mass. The occipital skull defect was caused by previous nondiagnostic biopsy of the tumor. (c) PET image shows increased uptake (tumor SUVmax, 2.40; LNR, 5.22) corresponding to the region of ring enhancement, with increased peritumoral uptake extending anteriorly and contralaterally (peritumoral SUVmax, 1.53; LNR, 3.33). Subsequent peritumoral biopsy was required to determine the diagnosis of glioblastoma multiforme.

 
Brain Tumor Uptake after Radiation Therapy
In the patients who had undergone radiation treatment (10 for high-grade glioma, four for brain metastasis), SUVmax and LNR measurements differed significantly between the recurrent tumors (n = 9) and the lesions attributed to radiation necrosis (n = 5) (Table 3). In all nine patients with recurrent tumors (seven high-grade gliomas, two brain metastases), the diagnosis was determined histopathologically.


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  		Table 3. SUVmax Determined according to Diagnosis in Patients with Possible Brain Tumor Recurrence

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
With use of an 18F-labeled derivative of choline to assess tissue choline metabolism with PET, it was possible to differentiate between benign lesions, metastatic tumors, and high-grade glial tumors. In our study, malignant brain tumors exhibited significantly higher fluorocholine uptake than did benign lesions. Furthermore, brain metastases exhibited significantly higher fluorocholine uptake than did high-grade gliomas. In a study involving the use of 11C-choline PET, metastatic tumors also exhibited higher uptake than did primary tumors, but the difference in mean uptake between high-grade gliomas and metastases was not significant statistically (8).

In contrast, studies involving MR spectroscopy have revealed choline metabolite levels in high-grade glial tumors to be higher than or similar to those in metastases (14–16). These findings suggest that the tissue concentrations of choline metabolites measured at MR spectroscopy may not always correspond to the intracellular transport and phosphorylation rates of choline substrates measured at fluorocholine PET. It has been shown that a lesion exhibiting high choline metabolite levels at MR spectroscopy may have little uptake of fluorocholine (3). Further research is needed to reconcile MR spectroscopy and fluorocholine PET findings and determine the potential complementary value of these techniques as adjuncts for tumor diagnosis. Because differences in choline metabolism between primary and metastatic brain tumors may have clinical implications, further study to elucidate the pathophysiologic basis of these differences and determine their relevance to diagnosis and treatment is also warranted.

In addition to demonstrating lower fluorocholine uptake, the high-grade gliomas in our study had a characteristic that was not observed with brain metastases. Specifically, increased peritumoral uptake was observed only at PET examination of the high-grade gliomas. A study involving 11C-choline PET similarly revealed increased uptake by high-grade gliomas in regions beyond the areas of pathologic enhancement at MR imaging (17). A plausible explanation for this finding is pathologic infiltration of peritumoral white matter tracts by malignant cells, which is known to occur with high-grade gliomas (18). In addition, compared with low-grade gliomas and meningiomas, high-grade gliomas have been observed to have lower fractional anisotropy ratios at the periphery on diffusion-tensor MR images, providing further imaging evidence of peritumoral infiltration (19,20). Peritumoral examinations performed with other MR imaging techniques have also revealed differences in metabolite concentrations, blood volumes, and apparent diffusion coefficients between high-grade gliomas and brain metastases (14,16). Because of the clinical importance of occult tumor infiltration, PET and MR imaging techniques for assessing the peritumoral region deserve further evaluation.

With fluorocholine PET, it was possible to detect recurrent tumors in patients who had previously undergone intracranial radiation treatment. Ionizing radiation can cause reactive changes in normal brain tissue that may manifest as a mass lesion accompanied by edema and contrast enhancement. Consequently, it is difficult to distinguish radiation therapy–induced changes from recurrent tumors with MR imaging. In our study, biopsy-confirmed recurrent tumors were distinguishable owing to their increased fluorocholine uptake, which can be attributed to tumor repopulation. However, because it was not possible to routinely confirm radiation necrosis at biopsy, an argument can be made that some patients who are judged to have radiation necrosis may in fact have residual malignant disease that may eventually lead to symptomatic recurrence. In response to this argument, we note our observation that none of the lesions with low fluorocholine uptake in our study had increased in size at 1-year (median) follow-up. Thus, low uptake appears to at least imply a favorable prognosis in this group of patients. Histopathologic confirmation in a future study may be necessary to substantiate the accuracy of fluorocholine PET for distinguishing recurrent brain tumors from radiation necrosis.

It remains conceivable that an increase in fluorocholine uptake could occur with inflammation and consequently cause a false-positive fluorocholine PET result. Models of tissue inflammation caused by infection and acute radiation injury have revealed measurable increases in the uptake of fluorocholine by macrophages (21,22). Correspondingly, the benign lesions in our study demonstrated a slight increase in fluorocholine uptake. However, this increase was significantly lower than that observed in the biopsy-proved malignant tumors. Experimentally, blood-brain barrier disruption in the absence of inflammation (as modeled by using cryolesions) has not been shown to cause substantially increased fluorocholine uptake (22). The lack of an observed correspondence between MR contrast enhancement and fluorocholine uptake in our study corroborates this experimental observation. Further in vivo study of inflammatory (or infectious) brain lesions with fluorocholine PET is necessary to determine the specificity of fluorocholine uptake in the diagnosis of malignant brain tumors.

Fluorocholine PET potentially yields information about tumor proliferation and extent and thus may have value in radiation treatment planning. The treatment of glioblastoma multiforme with radiation dose escalation based on 18F-fluorodeoxyglucose (FDG) PET findings was explored by Douglas et al (23). Although FDG PET–based radiation dose augmentation did not result in improved survival in their study, tumor volume estimates based on PET findings did appear to independently help predict survival and time to tumor progression in another study (24). However, tumor visualization with FDG is limited by the high physiologic uptake of this compound by normal neocortical cells. In contrast, the fluorocholine uptake by normal cerebral gray and white matter tissue is considerably lower than that by malignant tumors. Further study is needed to determine whether tumor and peritumoral volumes can be more precisely defined with fluorocholine PET than with FDG PET.

A limitation of this study was the analysis of the PET images without blinding to the clinical data. However, because we did not rely on subjective interpretations in the analysis, the lack of blinding may not have resulted in substantial interpretation bias. Another limitation was the absence of a wider variety of brain lesions. For example, low-grade gliomas were not studied. Therefore, we could not address whether fluorocholine PET can help distinguish low-grade gliomas from benign lesions or high-grade gliomas. Furthermore, a limited variety of metastases were studied, so it is possible that metastases of different histopathologic origins can exhibit different degrees of fluorocholine uptake. Finally, MR follow-up rather than biopsy was used to classify some lesions as benign after radiation therapy. The prognostic value of fluorocholine PET in the posttreatment setting needs to be further substantiated in a longitudinal study in which survival is measured as an outcome.

In conclusion, as a surrogate method of measuring tissue choline metabolism, fluorocholine PET may aid in the differentiation of benign brain lesions, brain metastases, and high-grade gliomas. It may also aid in the identification of areas of brain tumor recurrence after radiation therapy. The finding of increased peritumoral uptake at fluorocholine PET may help distinguish high-grade gliomas from other intracranial lesions.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   ACKNOWLEDGMENTS
 
The authors thank The Queen's Medical Center oncology data registry for assistance in data collection and Cora Speck, MS, for assistance in manuscript preparation.


   FOOTNOTES
 

Abbreviations: LNR = lesion-to–normal tissue uptake ratio • ROI = region of interest • SUV = standardized uptake value • SUVmax = maximum SUV

Authors stated no financial relationship to disclose.

The findings and conclusions expressed in this article do not necessarily represent the views of The Queen's Medical Center.

Author contributions: Guarantors of integrity of entire study, S.A.K., C.S.J., M.N.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, S.A.K., J.P.K., M.R.W., M.N.C.; clinical studies, S.A.K., J.P.K., M.R.W., M.N.C.; statistical analysis, S.A.K., C.S.J.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

  1. Enzinger C, Strasser-Fuchs S, Ropele S, Kapeller P, Kleinert R, Fazekas F. Tumefactive demyelinating lesions: conventional and advanced magnetic resonance imaging. Mult Scler 2005;11(2):135–139.[Abstract/Free Full Text]
  2. Law M, Meltzer DE, Cha S. Spectroscopic magnetic resonance imaging of a tumefactive demyelinating lesion. Neuroradiology 2002;44(12):986–989.[CrossRef][Medline]
  3. Kwee SA, Coel MN, Lim J, Ko JP. Combined use of F-18 fluorocholine positron emission tomography and magnetic resonance spectroscopy for brain tumor evaluation. J Neuroimaging 2004;14(3):285–289.[CrossRef][Medline]
  4. Kelly PJ, Daumas-Duport C, Scheithauer BW, Kall BA, Kispert DB. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc 1987;62(6):450–459.[Medline]
  5. Sijens PE, Knopp MV, Brunetti A, et al. 1H MR spectroscopy in patients with metastatic brain tumors: a multicenter study. Magn Reson Med 1995;33(6):818–826.[Medline]
  6. Fulham MJ, Bizzi A, Dietz MJ, et al. Mapping of brain tumor metabolites with proton MR spectroscopic imaging: clinical relevance. Radiology 1992;185(3):675–686.[Abstract/Free Full Text]
  7. Alger JR, Frank JA, Bizzi A, et al. Metabolism of human gliomas: assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET. Radiology 1990;177(3):633–641.[Abstract/Free Full Text]
  8. Shinoura N, Nishijima M, Hara T, et al. Brain tumors: detection with C-11 choline PET. Radiology 1997;202(2):497–503.[Abstract/Free Full Text]
  9. Hara T, Kosaka N, Shinoura N, Kondo T. PET imaging of brain tumor with [methyl-11C]choline. J Nucl Med 1997;38(6):842–847.[Abstract/Free Full Text]
  10. Hara T, Kondo T, Kosaka N. Use of 18F-choline and 11C-choline as contrast agents in positron emission tomography imaging-guided stereotactic biopsy sampling of gliomas. J Neurosurg 2003;99(3):474–479.[Medline]
  11. DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers. J Nucl Med 2001;42(12):1805–1814.[Abstract/Free Full Text]
  12. Ramirez de Molina A, Rodriguez-Gonzalez A, Gutierrez R, et al. Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun 2002;296(3):580–583.[CrossRef][Medline]
  13. Lim J, Dorman E, Cabral C. Automated production of [18F]FECh and [18F]FCH: preparation and use of [18F]fluoroalkane sulfonates and fluoroalkylation agents [abstr]. J Label Comput Radiopharm 2003;46(S1):S46.[CrossRef]
  14. Law M, Cha S, Knopp EA, Johnson G, Arnett J, Litt AW. High-grade gliomas and solitary metastases: differentiation by using perfusion and proton spectroscopic MR imaging. Radiology 2002;222(3):715–721.[Abstract/Free Full Text]
  15. Moller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002;44(5):371–381.[CrossRef][Medline]
  16. Chiang IC, Kuo YT, Lu CY, et al. Distinction between high-grade gliomas and solitary metastases using peritumoral 3-T magnetic resonance spectroscopy, diffusion, and perfusion imagings. Neuroradiology 2004;46(8):619–627.[Medline]
  17. Ohtani T, Kurihara H, Ishiuchi S, et al. Brain tumour imaging with carbon-11 choline: comparison with FDG PET and gadolinium-enhanced MR imaging. Eur J Nucl Med 2001;28(11):1664–1670.[CrossRef][Medline]
  18. Burtscher IM, Skagerberg G, Geijer B, Englund E, Stahlberg F, Holtas S. Proton MR spectroscopy and preoperative diagnostic accuracy: an evaluation of intracranial mass lesions characterized by stereotactic biopsy findings. AJNR Am J Neuroradiol 2000;21(1):84–93.[Abstract/Free Full Text]
  19. Goebell E, Paustenbach S, Vaeterlein O, et al. Low-grade and anaplastic gliomas: differences in architecture evaluated with diffusion-tensor MR imaging. Radiology 2006;239(1):217–222.[Abstract/Free Full Text]
  20. Provenzale JM, McGraw P, Mhatre P, Guo AC, Delong D. Peritumoral brain regions in gliomas and meningiomas: investigation with isotropic diffusion-weighted MR imaging and diffusion-tensor MR imaging. Radiology 2004;232(2):451–460.[Abstract/Free Full Text]
  21. Wyss MT, Weber B, Honer M, et al. 18F-choline in experimental soft tissue infection assessed with autoradiography and high-resolution PET. Eur J Nucl Med Mol Imaging 2004;31(3):312–316.[CrossRef][Medline]
  22. Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl Med 2004;45(11):1931–1938.[Abstract/Free Full Text]
  23. Douglas JG, Stelzer KJ, Mankoff DA, et al. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2006;64(3):886–891.[CrossRef][Medline]
  24. Tralins KS, Douglas JG, Stelzer KJ, et al. Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic information and possible role in definition of target volumes in radiation dose escalation. J Nucl Med 2002;43(12):1667–1673.[Abstract/Free Full Text]




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