Background
Magnetic resonance imaging with or without gadolinium enhancement is the standard method for the diagnosis of brain tumors, but new imaging methods have also been proposed based on the specific metabolic characteristics of gliomas. Malignant gliomas have increased metabolism caused by anaerobic glycolysis, so that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (
18F-FDG), a glucose analog, is now widely used for the diagnosis of gliomas [
1]. However, the high utilization of glucose by normal gray matter makes identification of other brain tumors difficult on
18F-FDG PET [
2]. Consequently, PET imaging of glucose metabolism is basically unsuitable for the detection of tumors against the background of the normal brain.
Radiolabeled amino acids are well-established tracers for brain tumor imaging with PET. The Response Assessment in Neuro-Oncology working group has recently recommended the use of amino acid PET imaging for brain tumor management in addition to magnetic resonance imaging [
3,
4]. L-[methyl-
11C]methionine (
11C-MET) is the most widely used amino acid PET imaging tracer for gliomas for the preoperative detection, diagnosis of subtypes and grades, differential diagnosis from radiation necrosis, estimation of tumor infiltration, and delineation of the border of tumor removal [
5,
6]. Methyl-
11C-choline, another PET radiotracer, potentially reflects the grade of malignancy [
7]. However, the short half-life (20 min) of
11C requires in-house radiosynthesis and repeated radiolabeling of the tracer for each PET study, resulting in limited use only in PET centers with an in-house cyclotron facility [
7]. Consequently, development of an amino acid tracer using the long half-life of
18F has been desirable to overcome these disadvantages of
11C-labeled agents [
2]. Recently, the
18F-based PET tracers,
O-(2-[
18F]fluoroethyl)-L-tyrosine (
18F-FET) and L-6-[
18F]fluoro-3,4-dihydroxyphenylalnine have been used for the imaging of brain tumors [
8‐
12]. In Europe, the high clinical interest in
18F-FET PET has led to more than 10000 PET scans being performed in some centers [
13].
Previously, we developed L-[3-
18F]-α-methyltyrosine (
18F-FAMT), a new amino acid tracer for PET imaging and demonstrated its potential for detecting neoplasms using experimental tumor models [
14,
15].
18F-FAMT accumulates in tumor cells only via an amino acid transport system, and most of the incorporated
18F-FAMT is not metabolized [
14,
15]. Recently, we have made advances in the clinical utility of
18F-FAMT PET for the investigation of lung cancers, oral and maxillofacial cancers, and other tumors [
16‐
20]. Our preliminary study showed specific accumulation of the tracer in 15 patients with glioma, including 7 cases before treatment [
21]. However, no detailed study has assessed
18F-FAMT PET in a glioma series.
The present study investigated the value of 18F-FAMT uptake for differentiating high-grade glioma (HGG) from low-grade glioma (LGG) and the correlation with the proliferation rate, compared with 18F-FDG as the standard PET tracer.
Discussion
The T/N ratios of both 18F-FAMT and 18F-FDG were significantly higher for HGGs than for LGGs, although the T/N ratios of different tumor grades showed wide overlap. For HGGs, 18F-FAMT uptake beyond a T/N ratio cutoff of 3.37 or 18F-FDG uptake beyond a T/N ratio cutoff of 0.92 had a PPV of 84 or 84%, respectively. The T/N ratios of 18F-FAMT were not correlated with MIB-1 LI in all gliomas. The T/N ratio of 18F-FAMT was significantly higher than that of 18F-FDG in all gliomas and all tumor subtypes.
Radiosynthesis of
18F-FAMT, an amino acid analog with a relatively high chemical yield, was originally developed at our institute [
14], and experimental and clinical investigations have demonstrated that accumulation of
18F-FAMT in tumor cells occurs via an amino acid transport system [
14,
15,
23].
18F-FAMT was predicted to act as a specific radiotracer of brain tumor tissue based on the low uptake by normal brain tissue compared with
18F-FDG and has proven specificity to detect gliomas [
15]. No significant relationship between
18F-FAMT uptake and WHO grade of tumor was found in the first series of 15 glioma cases [
21]. The current study has now demonstrated significantly different
18F-FAMT uptake in gliomas of various histologies and grades compared to
18F-FDG.
Recently,
11C-MET PET has become the most commonly used amino acid imaging modality for gliomas, although use is restricted to PET centers with an in-house cyclotron facility.
11C-MET PET is useful for detecting and delineating gliomas [
5,
6,
25‐
28].
11C-MET uptake shows positive correlation with astrocytoma grade (II/IV and III/IV) [
5,
27]. However, oligodendroglioma, which is a low-grade tumor, may show higher uptake of
11C-MET than diffuse astrocytoma (WHO grade II) [
5].
18F-FAMT tracer was developed on the basis of the known accumulation in brain tumor tissue of L-3-[
123I]iodo-α-methyl tyrosine [
21]. Uptake of L-3-[
123I]iodo-α-methyl tyrosine and of
11C-MET involves almost the same transport mechanism, system L, which is a Na-independent amino acid transport system, in cultured glioma cell lines [
29]. In fact, L-3-[
123I]iodo-α-methyl tyrosine single photon emission computed tomography and
11C-MET PET have equivalent clinical value in the diagnostic evaluation of glioma [
29,
30]. Therefore,
18F-FAMT PET imaging is likely to have similar characteristics to
11C-MET PET imaging for glioma diagnosis. However, the cell transport systems of
18F-FAMT and
11C-MET may be different. L-type amino acid transporter 1 (LAT1) is a major route for the transport of large neutral amino acids, including L-tyrosine, L-leucine, and L-methionine, through the plasma membrane. LAT1 is essential in tumor growth and is widely expressed in primary human cancers as well as gliomas [
31‐
33]. Recent findings have proved that
18F-FAMT is highly selective for LAT1 because of its α-methyl moiety [
34], which suggests that the tumor imaging sensitivity and specificity of
18F-FAMT PET and
11C-MET PET may have subtle differences. Recently, another
18F-labeled amino acid tracer,
18F-FET, has been shown to be useful for PET diagnosis of glioma [
8‐
10,
35].
18F-FET PET has high T/N ratio and better contrast in all gliomas compared to
18F-FDG PET, similar to our findings for
18F-FAMT PET, and is a clinically valuable PET tracer for imaging of gliomas [
8‐
10,
35].
18F-FET was clearly proved to be transported through both LAT1 and LAT2, with less selectivity for LAT1 than
18F-FAMT [
34]. However, a more recent study suggested that trapping of
18F-FET within the cells is caused by the asymmetry of its intra- and extracellular recognition by LAT1 [
36]. Therefore,
18F-FET and
18F-FAMT have similar characteristics as
18F-based brain tumor imaging tracers, but with structural differences and different biological activities. Standard
18F-FET summation image analysis of the 20–40 min time frame revealed mean maximum tumor-to-background ratio (TBR
max) of 2.1 in LGGs and significantly higher TBR
max of 3.3 in HGGs (
p < 0.001) [
37]. ROC analyses revealed a cutoff value of TBR
max 2.7 for the differentiation between LGGs and HGGs in the conventional 20–40 min summation images (sensitivity 66.7%, specificity 77.9%, accuracy 70.4%) [
37]. In our series, ROC analysis for differentiation between HGGs and LGGs yielded an optimal cutoff value of 3.37 for the T/N ratio of
18F-FAMT (sensitivity 81%, specificity 67%, accuracy 76%) The cutoff value is higher than for
18F-FET PET, but the accuracy of
18F-FAMT uptake may be considered equivalent. Further study is required for comparison of the imaging characteristics of
18F-FET PET and
18F-FAMT PET for the diagnosis of glioma.
MIB-1 LI is considered to be an indicator of the simple cell proliferation rate. In contrast, WHO grade is a direct index of the malignancy grade, based on the consideration of various pathological factors, including the presence of necrosis, nuclear polymorphism, microvascular proliferation, mitotic activity, etc. The present investigation found that the T/N ratio of
18F-FAMT PET was not correlated, but the T/N ratio of
18F-FDG PET was correlated with MIB-1 LI in all gliomas. The increase in
18F-FAMT uptake does not necessarily indicate high cell proliferation activity. Comparisons of the T/N ratios of
11C-MET PET and the MIB-1 LI have found a significant correlation in diffuse astrocytoma but not in oligodendroglial tumor [
5,
26,
28]. In our cohort, the ratio of diffuse astrocytoma was small, and the larger ratio of oligodendroglial tumor may have affected our results suggesting the T/N ratio of
18F-FAMT PET was not correlated with MIB-1 LI in all gliomas.
The glucose metabolic rate is highest in the brain parenchyma compared to the other organs of the body. Consequently,
18F-FDG is less effective as a tracer for the diagnostic imaging of brain tumor. Therefore, novel non-
18F-FDG brain tumor radiotracers have been intensively researched in the past decade [
2]. Multiple studies have compared brain tumor imaging with radiolabeled amino acids and
18F-FDG with the general finding that amino acids are more sensitive than
18F-FDG to detect brain tumors [
12,
38‐
47]. Amino acids provide higher tumor-normal brain contrast and are better suited to delineate the tumor extent, to differentiate tumor recurrence from treatment-related changes, and to assess treatment response. Whether
18F-FDG or amino acids is the better choice for grading and prognosis remains controversial [
48]. In our study, the T/N ratios of
18F-FAMT PET and
18F-FDG PET in the ROC analysis were almost equivalent for the differential diagnosis of tumor grade.
18F-FAMT uptake in the normal brain parenchyma was 0.94 (median SUV) in our series, lower than that of
18F-FDG, and almost the same as that of
11C-MET [
27] and
18F-FET [
8].
18F-FAMT PET provided clearer imaging with higher T/N ratio and better contrast in all gliomas compared to
18F-FDG PET. Delineation of tumor extent and definition of the optimal site for biopsy are well-known and important advantages of amino acid PET at initial evaluation of brain tumors [
38‐
40,
45]. In this study, the difference in T/N ratio between
18F-FAMT PET and
18F-FDG PET was significant. We are interested in whether
18F-FAMT PET can provide valuable data for the decisions concerning evaluation of true tumor size, extent of tumor excision range, and identification of the optimal site for biopsy. Further study will be necessary for these investigations.
More reliable grading may be possible with dynamic
18F-FET PET, since this tracer exhibits differences in the time-activity curves of tracer uptake depending on tumor grade [
34]. HGGs are characterized by an early peak around 10–15 min after injection followed by a decrease of
18F-FET uptake. In contrast, LGGs typically exhibit delayed and steadily increasing tracer uptake [
49]. The differential kinetics of tracer uptake in HGGs and LGGs appear to be a special property of
18F-FET because such differences were not observed with
11C-MET or L-6-[
18F]fluoro-3,4-dihydroxyphenylalnine [
11,
50]. Therefore, dynamic study with
18F-labeled tracer may be useful as an indicator of tumor grade. Further dynamic study using
18F-FAMT PET will be necessary in the future.
There were limitations to the present study. This study was based on relatively strict pathological and grading differentiations in astrocytomas and oligodendroglial tumors. Therefore, some pathological categories included a relatively small number of samples. Furthermore, simultaneous
18F-FAMT PET and
18F-FDG PET imaging is the ideal method of comparison. Since both tracers are labeled with fluorine, the tracer half-life requires a suitable interval between these PET studies. In these 38 cases, the interval between
18F-FAMT PET and
18F-FDG PET studies ranged from 1 to 38 days, and the median was 5 days. Recently, accumulation of
18F-FAMT was reported to be strongly correlated with the expression of LAT1 in cancers [
34]. However, correlation of
18F-FAMT transport and LAT1 expression was not examined in this study. A further study will be needed to investigate the mechanism of
18F-FAMT accumulations in gliomas.
18F-FAMT is a new radiotracer for brain tumor imaging. More experience with cases of gliomas or other brain tumors is needed. A comparative study with radiotracers other than
18F-FDG is also needed to clarify the diagnostic utility of
18F-FAMT PET.