This document discusses brain PET imaging for tumors, including normal brain uptake patterns, radiotracers like FDG and amino acids, factors affecting glioma uptake, and clinical indications for PET/CT and PET/MR imaging in gliomas. It provides details on the various radiotracers, their uses, and examples of images. Key points are that PET is useful for differentiating tumor recurrence from radiation necrosis, tumor grading, delineating edges for surgery/radiation, and provides prognostic information. Amino acids are best for recurrence differentiation while FDG is more advantageous for grading.

1. Tehran University of Medical Sciences
Shariati Hospital
Nuclear Medicine Department
Dr. Mustafa Al-Thabhawee
Brain PET imaging

2. Imaging for Tumors of the Brain
• Introduction.
• Normal pattern of uptake.
• Radiotracers.
 2-Deoxy-2-[18F] Fluoro-D-Glucose ([18F]FDG).
 Amino acid tracers.
 DNA Synthesis.
 Hypoxia Agents.
• Factors affecting uptake of radiopharmaceuticals in gliomas.
• Clinical indications to PET/CT and PET/MR imaging in gliomas.
• PET/MR.
• Key learning points.
• Primary Brain Tumors
 Site of better biopsy.
 Metabolic grading of the tumor.
• Pearls
• Pitfalls.
• The factors that affecting the FDG uptake
• SUV.
• Interpretation criteria

3. It is important that physicians who interpret PET brain scans review a large number
of normal images before interpreting studies in patients with neuropsychiatric
disorders.
There are many histotypes of brain tumors, the most frequent being gliomas, i.e.,
tumors deriving from glia cells. Tumors deriving from neurons, typically the
medulloblastoma, are much less frequent.
In addition to gliomas, malignancies of the central nervous system (CNS) include
meningiomas, primary brain lymphomas, and metastases from tumors outside the
brain. The latter two types of tumors (lymphomas and brain metastases from
primary non-CNS tumors).
Gliomas are classified as high-grade and low-grade gliomas.
• Therapy of gliomas consists in surgery combined to radiotherapy.
Introduction

4. a) The normal brain has high FDG uptake in the gray matter, with a
gray-to-white matter activity ratio ranging from 2:5 to 4:1.
b) The basal ganglia usually have slightly more uptake than the
cortex.
c) The medial temporal cortices typically have less uptake
than the other cortical areas.
d) Mild focal areas of increased activity can be seen normally in the
• Frontal eye fields.
• Posterior cingulate cortex.
• Wernicke's region (posterosuperior temporal lobe).
• Visual cortex.
Normal pattern of uptake

9. Age-related changes
Cortical metabolism decreases with age, particularly in the frontal
lobes. Other areas that can show decreased activity with aging are
the insula. Temporal lobes (lateral), parietal lobes, and anterior and
middle cingulate cortices. The least altered regions during aging are
the primary motor cortices, occipital cortices, precuneus, mesial
temporal lobes, basal ganglia, and cerebellum.

10. Patients with renal failure have decreased
FDG uptake in the cortex and white matter
compared to those with normal renal function.
Renal function

11. There are often minimal asymmetries in uptake between areas in
the left and right hemispheres. Asymmetric uptake should be
interpreted with caution unless:
a) There is a significant difference between the two
sides that correlates with clinical findings.
For example, any level of asymmetry in the
temporal lobes in a patient with epilepsy should be
considered a potential focus for seizure activity.
Quantitatively, a difference of 10 to 15% is often
considered significant but clinical correlation is
paramount.
b) The asymmetry is fairly extensive and seen on
multiple slices.
Symmetry of uptake

12. Comparison with single-photon emission
computed tomography (SPECT)
a) FDG uptake usually correlates with uptake of SPECT perfusion
tracers, except in cases where metabolism and perfusion are
uncoupled (e.g., luxury perfusion post-infarct ).
b) The magnitude of hypometabolism seen on PET is usually greater
than that of hypo-perfusion seen on SPECT.
c) Cerebellar uptake of FDG is variable but in general is less than
seen on SPECT. This differs from brain SPECT images, where
consistently the cerebellum appears more active than other brain
structures.

13. Crossed cerebellar diaschisis
The glucose metabolism in the cerebellar hemisphere
contralateral to a supra-tentorial abnormality (tumor, infarct, or
trauma) is frequently decreased in the acute phase of the disease
and may change over time. This does not indicate cerebellar
pathology.
a) Diaschisis is thought to be related to interruption of the
corticopontocerebellar pathway.
b) Ipsilateral pontine hypometabolism and preservation of
metabolism in the contralateral dentate nucleus have been
reported.

14. Radiotracers

15. Factors affecting uptake
of radiopharmaceuticals in gliomas

17. 2-Deoxy-2-[18F]Fluoro-d-Glucose
([18F]FDG)
[18F]FDG allows measurement of glucose metabolism. [18F] FDG is the most commonly used
tracer for brain tumor imaging. The tracer was described in the 1970’s to study brain
metabolism. In the 1980’s, the tracer was used for brain tumor imaging, since brain tumor
growth implies an increase in glucose consumption.
The 2-deoxyglucose model for quantifying the cerebral metabolic rate for glucose
(CMRglc) was defined by Sokoloff following auto-radiographic experiments in rats and
subsequently adapted for human studies with PET by different authors. [18F]FDG enters
the cell through a carrier-mediated system, and it is phosphorylated within the cytoplasm
by the enzyme hexokinase. Phosphorylated [18F]FDG accumulates into the cytoplasm as a
function of neural activity, it has no other metabolic side pathways, and therefore
[18F]FDG accumulation rate can be easily modeled and quantified. Initially, dynamic
scanning and arterial line-derived input function were adopted for clinical research with
the aim of obtaining absolute quantitative (mg/gram/min) values of CMRglc.
Glucose metabolism is 2–3 times higher in gray matter than in white matter. In conditions
of sensory deprivation and in normal subjects, glucose metabolism is uniform across gray
matter.

18. Amino Acid Tracers
The most frequently used amino acid tracers
are:
1. [11C]methionine.
2. O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET)
3. dihydroxy-6-18F-fluorophenylalanine
(18F-fluorodopa (18F-DOPA)).

19. A 32-year-old woman with anaplastic oligodendroglioma:
(a) [11C]methionine PET image shows slightly elevated [11C]methionine
uptake.
(b) T1-weighted MR image with gadolinium contrast medium shows
no enhancement;

20. (c) fused [11C]methionine PET and MR image.
(d) MR FLAIR image shows a remarkable increase in
the FLAIR signal.
The tumor was partially resected. The patient was
alive at the time of this report 47.4 months after the
operation

21. Combined [18F]FDG (upper row) and [11C]methionine (lower row)
PET studies.
This patient displays tumor recurrence as the primary glioblastoma
grade IV, which is easily detectable with [11C]MET (b) but not on
[18F]FDG (a).

22. This patient is affected by a primary oligo
astrocytoma grade II, which is hot on
[11C]methionine PET (d) and cold on [18F] FDG PET
(c)

23. 18F-FET PET and early postoperative T1-weighted MR.
Early (48–72 h) postoperative post-contrast T1-weighted MR alone and
fused to 18F-FET PET scanning performed 2 weeks later for radiation
treatment planning showing the superiority of PET with 18F-FET over
MR for definition of residual tumor volume after surgery.

24. (a) Residual metabolically active non-enhancing tumor remnant anterior to the resection
cavity identified in the left frontal lobe (red arrow), presumably infiltrating glioblastoma. On
MR, the tumor was evaluated as gross total resected.
(b) This patient was evaluated as partially resected based on a smaller contrast-enhancing
region (blue arrow) in the depth of the resection cavity in the left temporal region. Lack of
metabolic activity on 18F-FET PET, however, suggests reactive changes. Areas of increased 18F-
FET uptake are found in subcortical white matter anterior and posterior to the cavity (red
arrow), presumably infiltrating glioblastoma.

25. Radiolabeled Choline
Radiolabeled choline (either [11C]choline or 18F-fluorocholine) is a phospholipid
precursor. The uptake of the tracer is thought to reflect membrane proliferation,
particularly choline-derived membrane phospholipids. In vivo studies with proton
magnetic resonance spectroscopy have shown increased concentration of choline-
containing phospholipids (i.e., phosphoryl choline and glycerol-phospho-choline) in
brain tumors. In physiological conditions the tracer has no significant uptake in the
brain, and therefore it is suitable for imaging gliomas with high sensitivity. Either
[11C]choline or 18F-fluorocholine is available to most PET centers since the tracer is
successfully used for imaging prostate cancer. This availability facilitated the
application of radiolabeled choline for detection of brain tumors, yielding promising
results. False-positive findings may occur owing to tracer uptake by inflammatory
lesions, in brain metastases, and in meningiomas.
Images are acquired using a static scan 2 min after injection. Image interpretation is
similar to what is described for amino acid tracers.

26. Positive 18F-FDOPA PET/CT and 18F-FDOPA PET/MR images. (a–c) Glioblastoma
multiforme.
The axial FLAIR image (a) shows a lesion in the left insula and temporal lobe
involving the ipsilateral ventral striatum (arrow).
The 18F-FDOPA PET image (b) and fused PET/MR image (c) clearly show asymmetrical
uptake in the ventral striatum, greater on the left, matching the lesion on MRI.

27. The axial FLAIR image (d) shows an extensive infiltrative lesion
involving the left frontal and temporal lobe extending to the genu of
the corpus callosum and to the ipsilateral ventral and dorsal
striatum.
The 18F-FDOPA PET image (e) and fused PET/ MR image (f) show
increased uptake and a modified outline of the left striatum.

28. (g–i) Glioblastoma multiforme.
The axial FLAIR image (g)shows an extensive infiltrative lesion involving
the left temporal-parietal lobe, the ipsilateral thalamus, and the dorsal
striatum (putamen).
The 18F-FDOPA PET image (h) and fused PET/MR image
(i) show increased uptake and a modified outline of the left putamen,
matching the lesion on MRI.

29. Combined 18F-DOPA (upper row) and [18F]FDG (lower row) PET studies. A 27-year-old
man with right frontal grade II oligoastrocytoma treated primarily with surgery and
radiotherapy, presented with clinical suspicion of recurrence.
Trans-axial 18F-DOPA PET (a) and PET/CT
(b) images show tracer accumulation in a right frontal lobe lesion (arrows)
suggestive of recurrence.

30. Transaxial [18F]FDG PET (c) and PET/CT (d) images show no abnormal
focus of tracer uptake and are negative for recurrence.
The patient underwent reoperation and was found to have recurrent
grade III glioma (anaplastic astrocytoma) on histopathology.

31. DNA synthesis is a fundamental step for cell proliferation.
Thymidine is a pyrimidine used for DNA but not for RNA synthesis. Thymidine is incorporated
into DNA through the salvage pathway for pyrimidines.
The amount of DNA synthetized is lower than through the de novo pathway; however, because
of the limited number of compartments involved and modeling assumptions, DNA synthesis
can be more easily quantified. Tracers designed to quantify DNA replication are also named
proliferation tracers.
Initial studies with PET and [11C]thymidine showed rapid metabolism of the compound, which
implied complex corrections of the input function for recirculating radiolabeled metabolites.
Subsequently, 3-deoxy-3-18F-fluorothymidine (18F-FLT, a thymidine analog) was synthetized.
18F-FLT has the advantages of 18F-labeling and of a more favorable metabolism. However, the
BBB limits cellular uptake of 18F-FLT, and kinetic analysis is needed to accurately quantify DNA
synthesis.
However, studies provided conflicting results on the correlation between 18FFLT kinetic
parameters and Ki-67, an index of cellular Replication.
DNA Synthesis

32. Images were traditionally obtained through a two-tissue
Compartment:
1) Four-rate constant kinetic model, which yields parametric images of
the blood-to-tissue transport (K1).
2) Net 18F-FLT transport into the brain (KFLT).
However, very recently it was shown that a late acquisition 1-h post-
injection can be reasonably used in the clinical setting eliminating the
need of the cumbersome kinetic analysis. In physiological conditions,
uptake of the tracer in the brain is negligible, so that images resemble
amino acid images

33. T2-weighted MR, [18F]FDG, and 18F-FLT PET images of a 33-year-old
woman with a grade II astrocytoma.
There is only very subtle decrease in glucose metabolism in the right
anterior cingulus in comparison to the left size and no tumor 18F-FLT
uptake (arrow).

34. The interest in imaging tumor hypoxia is due to the fact that hypoxia is associated
with resistance to radiotherapy and to some chemotherapy regimens and
therefore with tumor progression. Several radiopharmaceuticals have been
evaluated as hypoxia tracers. These tracers include nitroimidazole compounds,
e.g., 18F-fluoromisonidazole (18F-MISO), 18F-azomycin arabinoside (18F-FAZA), and
64Cu-labeled methylthiosemicarbazone (64Cu-ATSM).
The common property of these tracers is that they all are bio-reductive agents and
their tissue binding is dependent on tissue oxygen concentration.
Specifically, as tissue hypoxia increases, trapping also increases. PET studies of
brain tumor hypoxia are mostly limited to the use of 18F-MISO. 18F-MISO freely
crosses the blood brain barrier and rapidly equilibrates within tissues independent
of perfusion. Tracer uptake in glioblastoma multiforme is heterogeneous.
Increased 18F-MISO tumor uptake is generally found in the periphery but not in
the necrotic center of glioblastomas multiforme. The necrotic center is
photopenic.
Hypoxia Agents

36. Sensitivity and specificity for diagnosis of brain gliomas/
glioma recurrence for most common PET tracers
Sensitivity and specificity are both higher than 80% with most tracers
for both indications in most studies, with higher specificity for amino
acid tracers for the differential diagnosis.

37. Indications
to PET/CT or PET/MR

38. Key Learning Points
• There are several indications to PET/CT or PET/ MR for brain tumor
imaging, the most common being the differential diagnosis between
tumor recurrence and radiation necrosis and through the metabolic
characterization of the brain mass, to support the MR-based suspect of
glioma.
• Sensitivity and specificity are both higher than 80% with most tracers
for both indications in most studies, with higher specificity for amino
acid tracers for the differential diagnosis. PET has an increasingly
important role in defining the brain tumor edges before surgery and
radiotherapy, to increase the accuracy of both procedures.
• Many studies have been performed in glioma patients with virtually
any tracer and consistently showed that PET can be successfully used
for any clinical indication and that, therefore, PET should be used in
the work-up of all glioma patients.
• There are some differences among tracers: amino acid tracers are
best for differentiation between tumor recurrence and radiation
necrosis; moreover, they are often used for defining the radiation
therapy plan.

39. • All tracers carry prognostic information.
• [18F]FDG is more advantageous for tumor grading, but it is
increasingly less used nowadays as amino acid tracers find
broader acceptance.
• Hypoxia tracers, proliferation tracers, and radiolabeled
choline are at this moment of second choice PET tracers.
PET/CT is the current state-of-the-art imaging technique for
brain tumors; it is well established and widely available for all
nuclear medicine centers throughout the world.
• PET/MR represents an innovative technique, as it combines
two techniques that are mandatory in the diagnostic process
and avoids exposure to CT-radiation.
• However, PET/MR is less accessible and so far its
clinical use is restricted to academic research
centers.

40. Possible clinical applications include
1. Determining the best biopsy site for optimal grading of the tumor
Despite the overall low degree of FOG uptake in law-grade gliomas, PET may be more useful
for stereotactic biopsy target selection in law-grade gliomas (inhomogeneous gliomas without
contrast enhancement) than in high-grade gliomas3 as contrast enhancement can be used in the
latter case.
2. Metabolic grading of the tumor:
The degree of glucose metabolism correlates with prognosis and outcome in these patients .
This is independent of other prognostic factors. For example. In one study, hypometabolic
low-grade gliomas were associated with a longer average survival compared to hypermetabolic
low-grade gliomas. Ln one report, the accuracy of FDG PET/CT for grading glioma was
superior to that of MRI. In a meta-analysis, l8-F-FET PET was much more accurate than FOG
PET for the brain tumor diagnosis (distinguishing tumoral from non tumoral lesions but both
tracers performed similarly for glioma grading.

41. 3. Evaluation possible transformation
of a low grade glioma to high grade
tumor.
Increased FDG uptake in a previously
diagnosed low-grade lesion is
suggestive of malignant
transformation and associated with
decreased survival.

42. The factors that affecting
the FDG uptake
1. Corticosteroids.
2. Cushing disease.
3. Sedatives and anticonvulsant drugs.
4. Gray matter uptake of FDG.
5. Glucose level.
6. Hyperglycemia.
7. Delayed imaging.

43. SUV may not be as useful in the brain, as it may not
correlate well with regional glucose metabolism. Tumor to
white matter or cortex ratios may be preferable.
SUV max cutoff of 5.7 had a 75% accuracy for detection of
progression, and a normalized SUVmax (ratio of SUV in the
lesion to the SUV in the contralateral normal white matter)
cutoff of 1.9 had an accuracy of 83%.
Glucose-corrected SUVmax>4.3D has also been used to
differentiated recurrent high-grade glioma from post-
treatment change.
Combining MRS (normalized choline/ creatinine ratio) and
PET results (normalized SUVmax.) improves accuracy.
SUV

44. 1. False negatives. Small low-grade neoplasms are often
undetectable on PET. A minority of high grade tumors are also
not appear on PET.
2. False positives:
a) Low grade neoplasms such as pilocytic astrocytoma, pleomorphic
xantboastrocytoma. gangtioglioma, and oligodendroglioma can be
hypermetabolic.
b) Benign lesions such as meningioma , pituitary adenoma and
histiocytosis can be hyper metabolic.
• There is a substantial range of uptake in meningiomas. with some
lesions as high as normal gray matter, while others are hypometabolic.
Glucose consumption in meningiomas may be related to tumor
aggressiveness and probability of recurrence.
c) Seizures at the time of FDG administration can cause false-positive
results due to activated cortex adjacent to the tumor site.
d) Hypermetabolic flare phenomenon may be seen in glioblastoma
treated with chemotherapy if PET is performed 24 hours after the first
dose. This may predict longer survival.
Pitfalls

45. Pituitary adenoma.
(a} Sagittal T1 "Weighted MRI scan demonstrates a
pituitary macro adenoma.
(b) Sagittal PET scan demonstrates intense uptake in this
adenoma

46. Tumor recurrence. (a) Axial MRI scan demonstrates enhancement at the margin of a light parietal
glioma
resection site post-radiation, equivocal for radiation necrosis vs. tumor. (b) Axial PET scan
demonstrates increased uptake
(arrow) in the area of enhancement seen on MRI. consistent with tumor recurrence. Note that it is
important to differentiate this activity from normal gray matter activity decreased ln Intensity
post-radiation. There was no gray matter In this region by MRI correlation. (c) Follow-up axial
MRI done several months after the P£T scan demonstrates
further increased enhancement in this region which show has the exact configuration as the
uptake seen on PET.

48. CNS lymphoma. Axial PET (a) and contrast enhanced MRI (b) in a
patient with diffuse large B-cell lymphoma demonstrated Intense uptake. In the enhancing
frontal lobe mass and decreased uptake in the surrounding edema. Both the intense
uptake in the lesion and the decreased white matter uptake are helpful In differentiating
CNS lymphoma from glioma.

49. Interpretation criteria
a) Visual criteria :
The main criterion for diagnosing recurrence of tumor on PET is relatively
increased uptake compared to the adjacent or contralateral
white matter. The ipsilateral white matter may be less suitable as a reference
because.
• Tumor cells may infiltrate around a focal lesion causing diffuse increased
white matter uptake ipsilaterally.
• Areas of encephalomalacia from prior surgery can cause apparent decreased
white matter uptake. However. this will be apparent when PET and MRl
images are compared. Uptake greater than contralateral gray matter can also
be used as a criterion for a positive.
b) SUV.

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