The use of positron emission tomographic (PET) imaging for neurologic imaging is increasing. The authors review the use of PET for the evaluation of brain tumors, including grading tumors, detecting tumor recurrence, localizing the optimum biopsy site, assessing response to therapy, and defining target volumes for radiotherapy. The article also discusses current radiotracers for neuro-PET imaging and the functional information they provide.
is a Professor of Neurology,
is a Professor of Radiology, and
Mr. Mark Muzi
is a Research Scientist, University of Washington School of
Medicine, Seattle, WA.
This article reviews clinical positron emission tomographic
(PET) imaging of brain tumors, chiefly high- and low-grade gliomas,
with emphasis on the use of fluorodeoxyglucose (FDG) for assessing
energy metabolism and the use of [C-11]methionine (MET) for
assessing amino acid transport. Additional tracers that are
potentially applicable in management are briefly discussed.
The current standard noninvasive imaging procedures, computed
tomography (CT) and magnetic resonance imaging (MRI), provide
excellent anatomic precision and sensitivity. Unfortunately,
treatment effects (including surgical trauma,
corticosteroid-induced reduction of edema and contrast enhancement,
and radionecrosis) cannot always be reliably distinguished from
tumor response or recurrence. Because surgical tissue sampling in
the brain carries significant risks, it is imperative to develop
imaging methods that view tumors in their entirety and measure
molecular pathologic processes as they progress over time. Positron
emission tomography and MR spectroscopy add this capability to our
There are several uses for PET: a) Grading tumors and estimating
prognosis; b) Detecting tumor recurrence and distinguishing it from
radionecrosis; c) Localizing the optimum biopsy site; d) Assessing
response to therapy; and e) Defining target volumes for
Energy metabolism: [F-18]fluorodeoxyglucose
Glucose is the main source of energy in brain tumors
; its metabolism begins with transport from the serum to cells and
continues through the process of phosphorylation catalyzed by
hexokinase (HK) (Figure 1). The product, glucose-6-phosphate (G6P),
is the starting compound for glycogen synthesis, for the
Embden-Meyerhof glycolytic pathway leading to lactate (glycolysis)
or pyruvate and entry to the tricarboxylic acid cycle, and for the
Positron emission tomography with FDG is based on the fact that
FDG, similar to glucose, is transported across the blood-brain
barrier (BBB) and cell membranes and then is phosphorylated by HK
to FD-G6-phosphate (FDG6P), which accumlates in tissues at a rate
proportional to the rate of glucose utilization (Figure 1). FDG6P
is not metabolized further along the glucose metabolic pathways but
is slowly dephosphorylated. FDG and glucose differ in their rates
of transport and phosphorylation and respective volumes of
distribution in brain or tumor tissue. As a result, FDG metabolism
is thought to be proportional to but not quantitatively equal to
glucose metabolism in brain tumors.
Grading and prognosis
Di Chiro and coworkers pioneered the application of FDG-PET to
High-grade gliomas contained regions of high FDG uptake and lower
grade gliomas lacked these regions. Patients with grade III or IV
astrocytic gliomas whose ratios of tumor to contralateral normal
brain glucose utilization were greater than 1.4:1 had a median
survival of 5 months, whereas patients whose ratios were less than
1.4:1 showed a median survival of 19 months.
In a similar study, tumor uptake of FDG greater than the cortex was
associated with a median survival of about 10 months.
More recently, Padma et al
reported 331 cases assessed by tumor/reference region ratios: 0 =
no uptake, 1 ≤ normal white matter (WM), 2 normal WM < lesion
< normal cortex, and 3 ≥ normal cortex. In categories 0 and 1
combined, 86% of the tumors were grade I or II by pathology
grading, with a median survival of 2.3 years. In categories II and
III combined, 94% were grade III or IV, with a median survival of
11 months. Figure 2 shows examples with uptake reported as standard
uptake value (SUV) as well as ratios of tumor/white matter (T/WM)
and tumor/cortex (T/C). (Standard uptake value is calculated as
tissue concentration of tracer/dose of injected tracer, usually
normalized to body weight.)
The optimal cutoff levels for distinguishing low- from
high-grade gliomas have been reported as 0.6 for the T/C ratio and
1.5 for the T/WM ratio.
The sensitivity and specificity were 94% and 77%, respectively
(Figure 2). In this study, patients were imaged 35 to 50 minutes
postinjection. However, tumor/ reference region activity ratios
estimated as SUVs steadily increase with time postinjection
(Figures 3 and 4).
Therefore, the cutoff ratios of Delbeke et al
apply only to the imaging times that were used in their report.
On MRI or CT scans, gliomas that appear to be low-grade by
lacking contrast enhancement present several diagnostic and
management problems. Approximately 30% are malignant when
For these cases, FDG-PET may well help estimate grade. This has
been shown to be useful in biopsy-proven low-grade glioma in that
FDG uptake in the tumor greater than white matter signifies a
higher risk for progression and death than uptake equal to or less
than white matter.
Localizing the optimal site for biopsy
There are convincing data that support the practice of selecting
biopsy sites in locations where the uptake of FDG is maximum; this
helps to ensure sampling of the most malignant areas of tumors
Radionecrosis versus recurrence
The sensitivity of FDG-PET for distinguishing recurrence of
glioma from radionecrosis is typically 81% to 86%, although some
reports are up to 100%.
Specificity is problematic in that estimates range from 22% to
100%. In the instructive report by Ricci et al,
there were 31 patients suspected of harboring a recurrence in whom
the pathology was positive in 22 and negative in 9. With the cutoff
of FDG uptake greater than white matter, the sensitivity was 86%
but the specificity was only 22%. With the cutoff greater than
cortex, the sensitivity was 73% and specificity 56% (Figure 6). The
challenge of distinguishing recurrence from radionecrosis at the
outset is beset with the problem that gliomas are ineradicable by
all treatments that spare neurological function. Even though a high
percentage of a given glioma after treatment may be necrotic as
viewed by the pathologist or PET imager, the tumor may harbor
viable cells that later lead to recurrence. Moreover, treated
malignant gliomas wherein FDG-PET scans are hypometabolic
(consistent with radionecrosis) may show, in biopsy or resection
specimens, intact tumor cells that may or may not be capable of
proliferation, energy metabolism, or substrate transport.
Assessing response to therapy
An important question in clinical practice is whether changes in
glucose metabolism are a reliable predictor of the response of
malignant gliomas to therapeutic interventions. Successful RT of a
glioma would be expected to kill tumor cells and cause a reduction
of the metabolic rate of FDG (MRFDG) as reported for
chemohormonotherapy of breast cancer.
Stated as a hypothesis, tumors that respond to treatment show
unchanged or reduced metabolism and, conversely, tumors that do not
respond show increased metabolism. This has been tested in patients
scanned quantitatively with FDG within 2 weeks before RT and/or 1
to 3 weeks after RT.
The results unexpectedly showed that an increase in MRFDG from the
beginning of RT to the end correlated with longer survival while a
decrease was associated with shorter survival (Figure 7).
Similar results, but involving chemotherapy, were reported for
patients with recurrent glioblastoma studied with quantitative
FDG-PET before and after a single cycle of 1,
Following stereotactic radiosurgery (24 to 32 Gy) in a series of
mostly metastatic tumors, Maruyama et al
reported that all of the tumors except 1 showed increased uptake of
FDG compared with levels that preceded the RT. This correlated with
a decrease in the size of the tumors that were seen at later
follow-up with CT or MRI. Therapy might lead to increased
metabolism and relatively better outcome because of increased
transport, infiltration of dead and dying tumor regions with
metabolically active inflammatory elements, energy consumption for
apoptosis, and/or an uncrowding effect as tumor cells die, allowing
more active metabolism in surviving normal elements.
Another way to measure response to therapy is to assess
metabolism at a single time following the intervention and
hypothesize that longer survival correlates with lower metabolism.
In 26 glioma cases from the study cited above, MRFDG measured
shortly after RT did not correlate with survival (Figure 8).
Although no other studies have looked systematically and
quantitatively at the immediate post-RT time to correlate metabolic
rate with outcome, the measurement of the FDG uptake of malignant
gliomas specifically at the time of clinical and/or radiographic
recurrence has been proven to provide a significant predictor of
Gross and coworkers
incorporated FDG-PET results with MRI for delineation of the
3-dimensional 60 Gy treatment volumes for 18 high-grade gliomas.
Their reported median survival of 44 weeks showed no improvement
compared with survival rates reported in other studies. They
concluded that FDG-PET did not add useful information for
conventional treatment planning but suggested that it might prove
useful to define a volume of tumor for a boost dose of RT. Such a
study, in which FDG-PET was used to define the optimal volume for
high-dose boost RT in glioblastoma, was, in fact, under way
Patients received 59.4 Gy in 33 fractions of conventional RT,
followed by an additional 20 Gy in 10 fractions directed at the
FDG-PET-defined volume of hypermetabolism plus a 0.5-cm margin.
Although the median survival for the 40 patients in this trial was
70 weeks, this was not better than that of historical controls. Of
interest, the FDG-avid volumes were predictive of survival and time
to tumor progression in these patients.
This pilot study showed that experimental RT protocols based on PET
imaging are feasible and, in the future, could be designed to
target regions of hypoxia, proliferation, protein synthesis, or
membrane biosynthesis. Other centers are beginning to explore the
incorporation of FDG-PET targeting for a simultaneous integrated
boost in intensity-modulated RT
and for planning radiosurgery target volumes.
These approaches will, of course, need to demonstrate efficacy
before they will be widely applied in clinical practice.
In summary, for prognosis and grading preceding initial
treatment or at recurrence, FDG-PET is clinically useful in that
high uptake signifies more aggressive disease and shorter survival
time. This pertains especially to tumors located in areas that are
too dangerous for surgical sampling. FDG-PET may be used to direct
biopsies to the most metabolically active foci in tumors. For
assessing response with pre- to posttreatment comparisons, the
usefulness of FDG-PET appears to be limited. Also, FDG-PET does not
appear to be useful for assessing response to RT immediately after
the treatment, which is when it would be most helpful to know
whether the treatment succeeded or not.
Amino acid transport and incorporation: [C-11]
The original goal of PET imaging with labeled amino acids was to
assess protein synthesis.
It is now recognized that the dominant process in the uptake of
amino acid tracers is transport via the L system.
Intracellularly, amino acids for protein synthesis come either from
the extracellular pool to which PET tracers contribute or from
intracellular recycling of proteins.
As a result, PET with amino acids does not assess protein synthesis
from endogenous recycling.
Depending on the particular amino acid, additional biochemical
pathways lead in alternate directions for production of nonprotein
biomolecules that cannot be distinguished from protein synthesis
with PET. Therefore, estimating protein synthesis rates with PET
and amino acid tracers is more complicated than quantification of
glucose metabolism with FDG.
Amino acid uptake in normal brain tissue is low relative to FDG
uptake so that the tumor to normal tissue contrast is better with
amino acid imaging. Among several tracers, [C-11] MET has been the
most widely reported. Unfortunately, synthesis of [C-11] MET
requires a cyclotron on site, so it will likely not achieve
widespread use in neuro-oncology. Interest is gaining in
alternative and convenient F-18-containing amino acid tracers.
O-(2-[18F] fluoroethyl)-L-tyrosine (FET) is one such alternative,
but this is not metabolized so that images show transport
Another is [F-18]fluorodopa, which compared favorably with MET in a
recent study (Figure 9).
The uptake of MET in lesions lacking breakdown of the BBB
suggests that there is upregulation of the transport process across
the capillary wall.
The extent of tumor delineated by MET for glioblastoma is larger
than the area defined by gadolinium with MRI but is smaller than
the T2-defined area, although in most cases the MET area extends
partly beyond the T2 volume.
The distribution of methionine through several biosynthetic
processes, including phospholipid synthesis, provides a broad
measure of tumor growth. Proliferating cell nuclear antigen
staining of histology specimens to assess proliferation correlated
with MET uptake in 1 study.
In another study, uptake of MET correlated with microvessel
density, which is consistent with the current understanding that
uptake is predominantly increased transport, a process that
involves both permeability and capillary wall surface area.
However, the same authors did not find an association of MET uptake
with endothelial proliferation of high-grade astrocytomas.
In a report of 50 cases, PET with MET (MET-PET) showed
accumulation in 31 of 32 high-grade gliomas (97% sensitivity) and
11 of 18 low-grade gliomas (61%).
Kracht et al
reported a sensitivity of 87% and a specificity of 89% for
detection of tumor tissue by stereotactic biopsy guided by MET
uptake at a threshold of 1.3 relative to normal brain tissue. The
usefulness of MET-PET for the detection of gliomas that are hypo-
or isometabolic on FDG-PET has been shown by Chung et al.
Eight of 10 le-sions that lacked detectable FDG uptake were
detected by MET-PET. Imaging with MET correctly distinguished
gliomas from nontumoral lesions in 79% of cases when a threshold
ratio of 1.47 was used to compare tumor to contralateral reference
Compared with MET, studies with the nonmetabolized tyrosine
(FET), produce similar results.
For this tracer, the sensitivity and specificity are both 88% for
detecting glioma in cases suspected of having this pathology based
on MR imaging.
However, another group has reported that the capacity of FET to
distinguish tumor tissue from nontumor tissue is limited.
MRI and FET-PET can be used together with neuronavigated biopsies
to improve the diagnostic accuracy of suspected gliomas.
The sensitivity and specificity of MRI alone were 96% and 53%,
respectively, whereas with MRI and FET-PET combined, the results
were 93% and 94%.
Grading and prognosis
In an early study of 22 patients with gliomas, MET uptake was
measured by a ratio of uptake in tumor to uptake in contralateral
healthy brain, and this was correlated with pathology grade.
For grade II gliomas (n = 5) the ratio was 1.0, grade III (n = 5)
1.7, and grade IV (n = 12) 2.3. Despite the small numbers, the
difference between II and III, and II and IV reached significance
but not the difference between III and IV. Another report showed
that tumor-to-mean cortical uptake <2.1 was associated with
survival >5 years, whereas >2.1 was associated with survival
of 8 months.
Interestingly, MET uptake has been found to be greater in grade III
oligodendroglioma than grade III astrocytoma, although the
prognosis is generally better for oligodendroglial than for
In grade II lesions, MET uptake was greater in untreated
oligodendro-glioma than in astrocytoma or oligoastrocytoma.
In contrast to MET, the tracer FET has shown limited usefulness for
distinguishing low- from high-grade gliomas at onset or at
Which tracer-FDG or MET-is a better prognostic marker in glioma
cases? Kim et al
assessed this in 47 patients and claimed that MET is better. They
found that MET uptake--but not FDG uptake--relative to gray matter
correlated with proliferation index assessments. If the uptake
measurements had been relative to contralateral white matter rather
than gray matter, FDG may well have compared better. Many other
studies have confirmed the prognostic value of FDG with which this
study did not agree
even in comparison to MET-PET.
Deoxyribonucleic acid biosynthesis: 2-[C-11]thymidine,
The S-phase fraction in glioblastoma averages about 8%, in
anaplastic astrocytoma 4%, in low-grade glioma 1% to 2%, and in
normal brain at or close to zero.
Consequently, tracers of deoxyribonucleic acid (DNA) synthesis such
as 2-[C-11]thymidine (TdR) or [F-18]3' deoxy-3'-fluorothymidine
(FLT) may provide high contrast between tumor and normal brain in
proportion to the grade and proliferation rate.
However, limited exchange of TdR or FLT across the BBB makes
transport a potentially rate-limiting step in brain tumor imaging.
The metabolic pathways followed by TdR and FLT are illustrated
in Figure 10. Circulating TdR or FLT is taken up and phosphorylated
intracellularly via the salvage pathway. 2-[C-11]thymidine, but not
FLT, becomes incorporated into DNA.
For TdR, the rate-limiting steps are the initial phosphorylation
catalyzed by thymidine kinase-1 (TK1) and the incorporation of
thymidine triphosphate (TTP) into DNA, the latter step being the
one that determines TdR retention in somatic tumors and probably in
brain tumors as well.
In contrast, for FLT, the initial phosphorylation by TK1 is the
rate-limiting step for retention in somatic tumors.
Phosphorylation by TK1 and incorporation into DNA are linked in
and TK1 is upregulated several-fold as cells pass from the G1 phase
to the S phase of the cell cycle.
The production of thymidine mono-phosphate (TMP) via the salvage
route supplements de novo synthesis from intracellular deoxyuridine
such that the rate of uptake of exogenous TdR or FLT is affected by
the relative utilization of the salvage versus de novo pathways.
Tumors wherein the de novo pathway dominates DNA synthesis may be
poorly imaged with PET tracers that are limited to following the
Thymidine labeled with C-11 in either the methyl or 2-position
provided the first PET tracers for imaging cellular proliferation.
Their use has been validated in gliomas, but the necessity for
dynamic imaging, metabolite analysis, and mathematical modeling
prevents their routine use in clinical practice.
[Fluorine-18]3'deoxy-3'-fluorothymidine is a longer-lived and
more convenient alternative that is resistant to degradation,
thereby eliminating the background of labeled metabolites in the
Sloan and coworkers
reported findings in 29 patients with gliomas at presentation or
recurrence and found little FLT uptake in normal brain and greater
levels of uptake the higher the tumor grade. Uptake in areas of
radionecrosis was low. Similar results were recently reported by
Choi et al
in a heterogeneous group of 26 lesions, but it is noteworthy that
they found increased FLT uptake in 1 case each of radionecrosis,
subacute infarction, and multiple sclerosis. Compared with FDG, FLT
was found by another group to be more sensitive for imaging
recurrent high-grade gliomas, proved to be a more powerful
predictor of tumor progression and survival, and correlated better
with Ki-67 estimates of proliferation.
One important common finding in these studies was that tumors
lacking contrast enhancement in MRI images did not have detectable
uptake of FLT.
Mathematical modeling that describes the uptake of FLT is
simpler than that for TdR (Figure 11), since the only plasma
metabolite is the glucuronide (Figure 10). Retention of FLT is
reflected in the flux constant, K
, and transport in K
Flux = K
Quantitative imaging based on this model, arterial blood
sampling, and simple metabolite analysis provide more information
than simple SUV assessment, since transport and flux can be
An example from our preliminary work is illustrated in Figure
The FLT-PET images clearly show an additional dimension to
assessing response to therapy that is achievable by this approach.
In agreement with the above studies, we have been unable to show
any FLT uptake in the absence of breakdown of the BBB in low-grade
gliomas or in regions of high-grade gliomas without BBB breakdown.
In all cases, uptake of FLT has been dominated by transport.
In several types of cancers, low-oxygen- tension levels are
associated with resistance to RT and chemotherapy, persistent tumor
following RT, and subsequent development of local recurrences.
Malignant gliomas often contain regions of hypoxia.
The tracer [F-18]fluoromisonidazole (FMISO), when used with PET,
provides an estimate of the distribution of hypoxia in tumors.
This tracer is sufficiently lipophilic that it diffuses through
cell membranes and is not retained in nonhypoxic tissues, such as
the brain. Liu et al
reported that FMISO was taken up in 14 of 18 brain tumors and
Bruehlmeier et al
found increased uptake in 7 of 7 glioblastomas. Another group
studied 13 newly diagnosed patients prior to surgery and showed a
correlation between FMISO uptake and tumor grade; all high-grade
lesions showed uptake that was frequently heterogenous.
An example shown in Figure 13 shows the heterogenous uptake of
FMISO in a distribution that differs partially from the FDG region
in these coregistered images. These studies show significant
promise for FMISO-PET in gliomas, but research must be extended to
a larger patient population that is examined at additional time
points through the clinical course. Identifying the regional
distribution of hypoxia may improve planning of resections and
allow the targeting of higher doses of RT more precisely to the
Energy metabolism and amino acid transport are important
components of the pathophysiology of brain tumors about which PET
provides information that is clinically useful. Imaging
proliferation with FLT or hypoxia with FMISO is straightforward,
although neither tracer has yet been exploited thoroughly enough to
allow judgment of the potential benefit to the practice of
Measuring membrane biosynthesis with PET and 1-[C-11]acetate or
a choline tracer may yield information about tumor growth as
helpful as DNA synthesis.
New doors are beginning to open in molecular imaging as novel
tracers are being developed for assessing the epidermal growth
factor receptor, angiogenesis, apoptosis, and gene expression.