Research ArticleCLINICAL INVESTIGATIONS

Spatial Heterogeneity of Low-Grade Gliomas at the Capillary Level: A PET Study on Tumor Blood Flow and Amino Acid Uptake

Matthias T. Wyss, Silvia Hofer, Martin Hefti, Esther Bärtschi, Catrina Uhlmann, Valerie Treyer and Ulrich Roelcke
Journal of Nuclear Medicine July 2007, 48 (7) 1047-1052; DOI: https://doi.org/10.2967/jnumed.106.038489

Abstract

Many low-grade gliomas (World Health Organization grade II) respond to chemotherapy. Cerebral blood flow (CBF) and microvessel density may be critical for drug delivery. We used PET with 18F-fluoro-ethyl-l-tyrosine (FET) to measure the spatial distribution of the amino acid carrier, which is located at the brain capillaries, and 15O-H2O to measure tumor CBF. Methods: Seventeen patients with low-grade glioma were studied. Region-of-interest (ROI) analysis was used to quantify tumor tracer uptake, which was normalized to cerebellar uptake (tumor-to-cerebellum ratio). “Active” tumor was defined as tumor having a radioactivity concentration that was at least 110% of the cerebellar activity. This threshold provided measures of active tumor volume, global and peak tumor CBF, and 18F-FET uptake. Trace ROIs were applied to create voxelwise profiles of CBF and 18F-FET uptake across tumor and brain. Standard MRI sequences were used for spatial correlations. Results: Fourteen of 17 tumors showed increased global CBF and 18F-FET uptake. Active tumor volumes ranged between 3 and 270 cm3 for 18F-FET and between 1 and 41 cm3 for CBF. Global 18F-FET uptake in tumors corresponded to CBF increases (Spearman rank ρ = 0.771, P < 0.01). The volumes of increased CBF and 18F-FET uptake spatially coincided and were also correlated (ρ = 0.944, P < 0.01). Trace ROIs showed that irrespective of increased 18F-FET uptake at the tumor periphery, CBF increases were more confined to the tumor center. Within individual tumors, spatial heterogeneity was present. Particular tumors infiltrating the corpus callosum showed low CBF and 18F-FET uptake in this tumor region. The patterns observed with PET were not reflected on MRI of the tumors, all of which presented as homogeneous non–gadolinium-enhancing lesions. Conclusion: Low-grade gliomas are heterogeneous tumors with regard to the distribution of amino acid uptake and CBF. Both are coupled in the tumor center. At the tumor periphery, where tumor infiltration of surrounding brain occurs, CBF may be low irrespective of increased 18F-FET uptake. An ongoing study is investigating the effect of chemotherapy on these observations.

Most low-grade gliomas affect adults in their third to fifth decades of life. According to the classification of the World Health Organization (WHO), low-grade gliomas (WHO grade II) comprise diffuse astrocytoma, oligodendroglioma, and oligoastrocytoma (1). Although the tumors are considered slowly progressing, an annual increase in tumor size of 4.1 mm has been estimated (2). Surgery is the standard treatment at the time of first presentation. Subsequent radiotherapy remains controversial (3,4). Low-grade gliomas have long been regarded as resistant to chemotherapy; however, several studies published over the last few years showed remarkable responses to regimens such as procarbazine, N-(2-chloroethyl)-N′-cyclo-hexyl-N-nitrosourea, and vincristine or to the alkylating agent temozolomide (5,6). There is evidence that loss of heterozygosity on chromosomes 1p and 19q might be predictive of chemotherapy response, but large, prospective randomized studies on this issue are lacking (6). On the other hand, the effectiveness of chemotherapy depends on adequate delivery of drugs to tumor cells, and this delivery is a function of drug concentration in the blood, blood flow through tumor microvasculature, and the flux of drugs across tumor capillaries. Our study aimed at the in vivo characterization with PET of microvessel distribution and of cerebral blood flow (CBF) in low-grade gliomas. We used 15O-H2O as a standard tracer for CBF measurement. To investigate microvessel distribution, we used 18F-fluoro-ethyl-l-tyrosine (FET) as a tracer for amino acid transport (7). Several PET studies on human brain tumors showed that the uptake of radiolabeled amino acids is governed by increased influx across the blood–brain barrier (8–10). Experimental studies revealed that this influx is mediated by active transendothelial amino acid transport (11,12). Accordingly, the signal measured with 18F-FET PET in tumors reflects the magnitude of amino acid transport and its distribution over tumors.

MATERIALS AND METHODS

Patients

We enrolled 17 patients with either progressive or recurrent supratentorial WHO grade II gliomas. At the time of the first surgery (2–127 mo before the PET study), all tumors were histologically verified WHO grade II gliomas and included 5 fibrillary astrocytomas, 7 oligoastrocytomas, and 5 oligodendrogliomas. Recurrence or progression was defined clinically and on MRI and occurred at a mean of 30 mo (range, 2–127 mo; Table 1) after the first tumor surgery. We included only patients who, at the time of our PET study, did not show any gadolinium enhancement on MRI, because this finding may indicate the presence of a more malignant glioma (WHO grade III or IV). The clinical details are presented in Table 1. PET studies were performed within 2 wk of the MRI studies. Written informed consent was obtained from all patients. The study protocol was approved by the local ethics committee.

View this table:
TABLE 1

Patients Ranked by WHO Grade II Histologic Subgroups According to Global 18F-FET T/Cb Ratio

Image Acquisition and Processing

MRI included standard procedures on a 1.5-T Siemens Magnetom. We obtained digitized pre- and postgadolinium T1- and T2-weighted, proton-density, and fluid-attenuated inversion recovery (FLAIR) sequences (slice thickness, 4.8 mm). Following the methods of recent studies on low-grade gliomas, we used the FLAIR sequences to calculate the tumor volume, because these sequences best delineate between the lesion and adjacent brain (6,13).

PET studies were performed on a whole-body PET/CT scanner (Discovery LS; GE Healthcare) and were acquired in 3-dimensional mode with a 14.6-cm axial field of view and a reconstructed in-plane resolution of 7 mm (voxel size, 0.018 cm3; slice thickness, 4.25 mm). Immediately before the CBF PET study, a low-dose CT scan for attenuation correction was obtained. For the CBF studies, 600–800 MBq of 15O-H2O were administered using an automatic injection device that delivers the bolus over 20 s. After arrival of the bolus in the brain, acquisition of a series of eighteen 10-s frames was initiated. The 15O-H2O PET images were transformed according to a previously described approach yielding absolute CBF values without arterial blood sampling (14). 18F-FET studies were performed subsequent to the CBF studies within the same session. 18F-FET was produced according to the method of Wester et al. (15). For the 18F-FET studies, 140–250 MBq were injected intravenously and tracer accumulation was recorded over 60 min as a series of twelve 5-min frames. To avoid movement of the head during the acquisition, the head was slightly fixed, and PET images were visually assessed for movement artifacts. Attenuation-corrected PET images were reconstructed with standard Fourier rebinning backprojection, including standard calibration factors to receive kBq/mL of tissue and corrections for randoms, scatters, geometry, decay, and dead time. As in other reports (16), our patients showed a plateau phase with a relatively stable tissue radioactivity concentration later than 40 min after intravenous tracer injection. Therefore, our 18F-FET PET data were analyzed on averaged activity images acquired 50–60 min after tracer injection. Dividing these activities by the amount of injected activity per kilogram of body weight yielded standardized uptake values.

Data Analysis

PET data were analyzed with PMOD (17). As a standard procedure in nuclear medicine, tumor uptake values can be normalized to the contralateral normal brain, allowing easy data analysis and reliable interindividual comparisons. However, normalization to contralateral brain depends on the location of the tumor in the brain and may thus infer substantial variation, particularly as 2 tumors in our series crossed the midline. We therefore chose the cerebellum as the reference region because it is a large and homogeneous structure and was distant from the tumor. Regions of interest (ROIs) were first placed over both sides of the cerebellum on 3 subsequent slides. The mean activity of all cerebellar ROIs was used to set the threshold for normalization of tumor tracer uptake (tumor-to-cerebellum [T/Cb] ratio). This thresholding procedure has recently been proposed to provide an observer-independent evaluation, which is particularly important for follow-up PET studies during tumor treatment (18). In a first step, we used thresholds between 100% and 120% of cerebellar activity. Increasing the threshold produced moderate decreases of active tumor volumes and small increases of T/Cb ratios. We finally chose a threshold that gave a volume of active voxels close to what was the “visibly increased” 18F-FET uptake. For our low-grade gliomas, we found this threshold to be 110%. This threshold was also applied for the quantification of CBF. Accordingly, tumor ROIs were placed covering all voxels with activity values above 110% of the mean activity in the cerebellum, thus yielding the active tumor volume for CBF and 18F-FET uptake. The activity in these tumor ROIs was then used for the calculation of global T/Cb ratios (all active voxels) and peak T/Cb ratios (all voxels that were 75% or more of the maximum radioactivity in the tumor ROI). In tumors with inactive tumor volumes (below 110% of the mean activity in the cerebellum), digitized MRI FLAIR images were coregistered with the PET studies to define the placement of tumor ROIs according to the FLAIR lesion volume.

To more precisely investigate the spatial relationship between 18F-FET uptake and CBF, we placed linear trace ROIs that spanned from normal cortex through white matter and tumor and created CBF and 18F-FET profiles across the brain (Fig. 1, yellow line). First, trace ROIs were placed on the 3 adjacent planes that showed the highest tumor tracer uptake. For each of these planes, 3 adjacent parallel trace ROIs were created per plane in the 18F-FET study and were then also used at the same position for the coregistered CBF studies. Depending on the individual tumor location, a single trace ROI consisted of up to 64 voxels (voxel size, 0.018 cm3). At this step, 9 single 18F-FET and CBF profiles per patient were available. Second, the activity of the spatially corresponding voxels derived from these 9 profiles was averaged and yielded a mean trace ROI profile for 18F-FET and CBF activity for each patient. Then, the mean activity for each voxel was normalized to the cerebellum. Accordingly, the data points of these profiles represent voxel averages of T/Cb ratios for CBF and 18F-FET uptake (y-axis) and the distance (mm) across the brain (x-axis).

FIGURE 1. 
FIGURE 1. 

Heterogeneity of 18F-FET uptake and CBF in 3 low-grade gliomas. Corresponding axial slices are presented. Color scale represents T/Cb ratio of 18F-FET and CBF. (A) Oligoastrocytoma shows markedly increased 18F-FET uptake and CBF in right frontoinsular region (patient 11 in Table 1). 18F-FET and CBF peak uptake regions coincide; however, active volume of CBF is smaller than active 18F-FET volume. (B) Reduced 18F-FET uptake and CBF in fibrillary astrocytoma (patient 1). (C) Oligoastrocytoma (patient 12). Anterior tumor part involves corpus callosum and shows substantially reduced CBF and 18F-FET uptake when compared with posterior tumor part. This heterogeneity is not evident from any MRI sequences. Yellow line through posterior part of brain and tumor illustrates positioning of trace ROI (Fig. 4).

Statistics

The Spearman rank test was used to search for correlations between the active tumor volumes of CBF and 18F-FET uptake, between tumor uptake of 18F-FET and tumor CBF, and between these measures and the MRI FLAIR lesion.

RESULTS

The results are summarized in Table 1. Relative to normal brain, we found increased 18F-FET uptake and CBF in 14 of 17 tumors. 18F-FET uptake and CBF were not homogeneously increased across these tumors but rather showed a variable distribution. The peaks of CBF and 18F-FET uptake were spatially colocalized. In 3 tumors, both 18F-FET uptake and CBF were decreased relative to normal brain. The heterogeneity of 18F-FET uptake and CBF within individual tumors and within our group of low-grade gliomas is illustrated in Figure 1.

Tumor tracer uptake was quantified by normalizing the tumor radioactivity concentration to the activity of the cerebellum (uptake ratio). Cerebellar 18F-FET uptake and CBF were calculated as the mean value of both cerebellar hemispheres. Asymmetry between the hemispheres (“crossed cerebellar diaschisis”) was less than 5% for 18F-FET and less than 9% for CBF. For the cerebellum, the 18F-FET standardized uptake value was 1.22 ± 0.32 (mean ± SD). The cerebellar CBF was 36.4 ± 8.6 mL/min/100 mL. At a 110% cutoff of cerebellar tracer uptake, tumor uptake ratios varied between 0.61 and 1.65 for global 18F-FET uptake and between 1.24 and 2.25 for peak 18F-FET uptake. For CBF, these values ranged from 0.45 to 1.50 for the global ratio and from 1.41 to 1.96 for the peak ratio. At lower 18F-FET uptake ratios (global), smaller variations in CBF ratios were observed, whereas for higher 18F-FET uptake ratios (peak), the variation in CBF ratios increased (Fig. 2). Uptake ratios tended to be higher in oligodendroglial tumors than in fibrillary astrocytoma. No correlation between MRI lesion volume and tracer uptake was observed (18F-FET: Spearman rank ρ = 0.023, P = 0.931; CBF: Spearman rank ρ = 0.262, P = 0.309) (Table 1). Over the whole study population, 18F-FET uptake and CBF correlated (Fig. 2): For global uptake ratios, the Spearman rank correlations were ρ = 0.771, P < 0.01 (n = 17). Because of the small number of pairs, the correlation of peak uptake ratios did not reach statistical significance (ρ = 0.571, P = 0.139).

FIGURE 2. 
FIGURE 2. 

Distribution of global (○) and peak (▪) 18F-FET uptake and CBF. Values represent T/Cb ratios.

In most tumors, the volume of increased 18F-FET uptake was smaller than the corresponding tumor volume on MRI FLAIR images. Active tumor volumes of 18F-FET and CBF were colocalized within 1 tumor (Fig. 1); however, the CBF volume was always smaller than the 18F-FET uptake volume. The active tumor volumes ranged from 3 to 270 cm3 for 18F-FET and from 1 to 41 cm3 for CBF. The correlation between active global tumor volumes is presented in Figure 3 (Spearman rank ρ = 0.944, P < 0.01). To address this spatial relationship between intratumoral tracer uptake, we created CBF and 18F-FET profiles across tumor and brain. The positioning of trace ROIs is illustrated for a single patient (patient 12) in Figure 1. The resulting profile of 18F-FET and CBF distribution is exemplified in Figure 4. The presented pattern was observed in all 14 tumors with increased 18F-FET uptake and CBF—that is, the peak coincidence of 18F-FET uptake and CBF. Reflective of our active volume data, the area under the curve in the trace ROIs was smaller for the tumor CBF than for the tumor 18F-FET uptake profiles. Along the profiles, the mean distance between increase of intratumoral 18F-FET uptake and CBF was 6.3 mm (range, 2.2–13.6 mm). At the position where the CBF ratio in tumors started to exceed 1.0, the mean 18F-FET ratio was 1.51 (1.01–2.24).

FIGURE 3. 
FIGURE 3. 

Correlation of global active tumor volumes of 18F-FET and CBF (Spearman rank ρ = 0.944, P < 0.01). Significant correlation is maintained if outlier is excluded from analysis (ρ = 0.885, P < 0.01).

FIGURE 4. 
FIGURE 4. 

Trace ROI analysis in a single patient (patient 12). Pixelwise profiles of 18F-FET uptake (▪) and CBF (⋄) span from normal cortex over white matter and tumor. Vertical dashed lines represent tumor borders on MRI (patient 12; Fig. 1C). Increases of tumor CBF (T/Cb ratio > 1.0) are more confined to tumor center. T/Cb ratio increases in this patient at a ratio of approximately 2.1 of 18F-FET uptake.

DISCUSSION

Our study demonstrated a substantial heterogeneity in CBF and 18F-FET uptake over the whole series of low-grade gliomas that, on MRI, appeared as homogeneous non–gadolinium-enhancing lesions. In many patients, we also observed intratumoral heterogeneity on the PET studies, possibly indicating that subregions of tumors could behave differentially with respect to tumor evolution and treatment response. Knowledge of the individual tumor vasculature is of particular interest with regard to angiogenetic tumor potential and targeted treatment. The total intravascular volume, which comprises all sizes of tumor vessels, can be used as an in vivo marker of angiogenesis and can be studied by following the changes in the MRI signal after administration of gadolinium (19,20). If the point of interest is the distribution of the capillaries themselves, where solutes and drugs are exchanged, markers should exclusively trace mechanisms located at that anatomic level. Such is the case for radiolabeled amino acids that bind to and are transported by the amino acid carriers located in the endothelial cells of the blood–brain barrier (21). In brain tumors of various WHO grades, uptake of 11C-methyl-l-methionine correlates with the microvascular density (MVD) as validated by immunohistochemistry (22). 18F-FET is a nonmetabolized tyrosine analog and behaves similarly to methionine (16). 18F-FET was evaluated for the clinical investigation of gliomas (7,16). We found an 18F-FET uptake ratio of between 0.61 and 1.65 for the whole tumor and peak values of between 1.24 and 2.25. These ratios are in the range of the data presented by Kracht et al. (22). Taking these findings together, our results provide evidence that 18F-FET, like methionine, is a surrogate marker of MVD. To validate this assumption, we initiated a study on 18F-FET PET–guided biopsies and determination of MVD in patients with low-grade gliomas.

In our series, 3 of 17 tumors showed neither increased tyrosine uptake nor increased CBF. In addition, tumor areas contacting or infiltrating the corpus callosum exhibited normal or reduced CBF and 18F-FET uptake, whereas in the same tumor, distant cortical or subcortical areas showed increases of these measures (Fig. 1). Our finding of reduced 18F-FET uptake in some tumors would be in line with immunohistochemical results on microvessel counts in astrocytomas. In particular, low-grade astrocytomas may show MVDs below the level of normal cortex or white matter (23). Studies have shown that microvessels in these tumors are native cerebral vessels co-opted by tumor cells and that the formation of new vessels (“neo-angiogenesis”) and higher vessel densities occur in more malignant tumors (23,24).

Earlier studies on CBF in gliomas reported a similar range for tumors (7–102 mL/100 mL/min) and for normal white matter and cortex (15–59 mL/100 mL/min) (25–27). The magnitude of CBF in these studies did not discriminate between glioma types or WHO grade. Across our series, tumor CBF and 18F-FET uptake correlated (Fig. 2). Our data therefore suggest a coupling between blood flow and microvascular distribution in low-grade gliomas. This coupling is different from known perfusion patterns in more malignant gliomas (WHO grades III and IV), in which, irrespective of the high vascularity, low CBF is considered to be responsible for the formation of hypoxia (28). In addition, we found a significant correlation between active 18F-FET and perfused tumor volumes (Fig. 3). 18F-FET and CBF volumes showed a close spatial coincidence and were independent of lesion size on MRI (Fig. 1). Interestingly, the active CBF volumes were smaller than the corresponding 18F-FET volumes (Table 1), as is explained by the characteristic intratumoral rises in 18F-FET uptake and CBF as presented in the trace ROI analysis (Fig. 4). Our data revealed that CBF increases occurred when uptake of 18F-FET exceeded a certain level (mean ratio, 1.50). Assuming that 18F-FET uptake is related to MVD, our results can be transferred into absolute numbers of tumor MVD by comparison with the data presented by Kracht et al. (22). They reported global 11C-methyl-l-methionine uptake ratios of 1.30 ± 0.20 for astrocytic tumors and 2.30 ± 0.35 for oligodendroglial tumors (WHO grade II)—values that are similar to our 18F-FET uptake values (Table 1). Correlating 11C-methyl-l-methionine uptake and histopathologically proven MVD, an amino acid uptake ratio of 1.50 equals 10 microvessels/0.763 mm2 (22). If we extrapolate a median 18F-FET uptake ratio of 1.50 as calculated from our trace ROIs, an approximate MVD of 13 microvessels/mm2 would result. At this level, CBF starts to increase above the level in normal brain. In view of that fact, we assume that CBF increases follow the formation of new microvessels and therefore represent a subsequent phenomenon.

Intratumoral heterogeneity of tumor CBF and amino acid uptake has been reported in several animal studies. In opposition to our findings, CBF progressively increased from the tumor center to the tumor periphery and to brain surrounding the tumor (29). A corresponding increase in MVD was reported for large tumors of the same tumor model (tumor center, 245/mm2, vs. surrounding brain, 689/mm2) (30). With regard to a cortical or subcortical tumor location, variable amino acid uptake values were found in more “malignant” tumor models (11). In humans, intratumoral variations have not been recognized so far. Overall, we detected in our study no differences in 18F-FET uptake or CBF with regard to cortical or subcortical tumor location. However, we noted intratumoral heterogeneity, particularly in tumor regions infiltrating the corpus callosum. Low CBF and capillary density may initiate the development of a mismatch between metabolic demand and energy supply and may promote hypoxia, possibly making these tumors prone to behaving more aggressively than tumors with the same histopathologic features located outside the corpus callosum (31).

CONCLUSION

Taking our observations together, we found that tumor CBF and amino acid uptake varied substantially in nonenhancing WHO grade II gliomas. This variation was evident within the whole group of tumors and within individual tumors and did not depend on lesion size on MRI. All patients were studied at the time of clinical or radiologic progression, making tumor therapy necessary after initial surgery and observation. Because MVD constitutes a significant independent prognostic factor (32,33), it is tempting to validate whether 18F-FET PET provides a robust means for the in vivo measurement of MVD. Our results in this study led us to initiate a prospective PET study that will address the effect of chemotherapy on regional tumor blood flow and amino acid uptake, with particular emphasis on the tumor-to-brain border zone, because this is the area most critical to tumor cell infiltration of the surrounding brain and to tumor progression and the prognosis of patients with low-grade gliomas.

Acknowledgments

This study was supported by grants from the Swiss Group for Clinical Cancer Research (SAKK) and by Essex Chemie AG, Luzern, Switzerland. We thank Tibor Cservenyak for radiotracer production.

Footnotes

  • COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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  • Received for publication November 29, 2006.
  • Accepted for publication March 20, 2007.
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