Brain tumors Imaging in Nuclear medicine

1. Brain tumors Imaging
Miad Alsulami

3. Learning Objectives
 Overview the types of brain tumors .
 Treatment and outcome of brain tumors .
 Imaging modalities .
 The role of BBB.
 SPECT tracers.
 PET tracers .
 Clinical applications of brain nuclear imaging
.

4. Introduction
 Malignant gliomas and metastatic tumors are the most common brain
tumors.
 In low-grade tumors, neuroimaging is needed to evaluate recurrent
disease and to monitor anaplastic transformation into high-grade
tumors.
 In high-grade and metastatic tumors, the imaging challenge is to
distinguish between recurrent tumor and treatment induced changes
such as radiation necrosis .

5.  The current clinical gold standard, MRI, provides superior structural detail
but poor specificity in identifying viable tumors in brain treated with
surgery, radiation, or chemotherapy.
 Amino acid PET tracers are more sensitive than 18F-FDG in imaging
recurrent tumors and in particular recurrent low-grade tumors.
 They are also promising in differentiating between recurrent tumors and
treatment induced changes.

6. Types of brain tumors

7. Primary brain tumors
 According to WHO ,gliomas are classified in to three different types
 1-astrocytomas,
 2- oligodendrogliomas
 3- mixed oligoastrocytomas
These tumors can be distinguished by their histologic features .
 Grading Of brain tumors :
 Low grades are grades I and II, and high-grade, grades III and IV.
 Grading based on degree of mitosis, microvascular proliferation and
necrosis .

8.  There are 3 subtypes of low-grade gliomas :pilocytic astrocytoma
(grade I), astrocytoma (grade II), oligodendroglioma (grade II).
 High-grade gliomas include anaplastic tumors (astrocytoma , and
oligodendroglioma grade III) and glioblastoma grade IV (most common
glioma)
 Mean age at onset 61 y for glioblastoma and 40 y for anaplastic
astrocytoma.
 Men are more frequently affected than women.
 Low-grade tumors typically affect younger patients .

9. Secondary brain tumors
 Cerebral metastasis is common complication in patients with systemic
cancers
 Tumors most metastasize to the brain are : lung ,breast and melanoma .
 Median survival rate is less than one year .

10. Treatment and outcome

11. Treatment and outcome
 High-Grade Gliomas: Rapid and fatal , median survival of 1 y.
 Treated by surgical resection followed by chemotherapy and post
surgical radiotherapy .
 these tumors recur and patients should be followed clinically for
neurologic symptoms and through neuroimaging with MRI.
 A rapidly enlarging, enhancing lesion on MRI with or without clinical
symptoms usually establishes diagnosis of progressing tumor

12.  Low grade glioma :
 mainly in children and young adults .
 Grow slowly and malignant transformation is very rare .
 Treated mainly with surgical resection only !
 Chemotherapy and radiotherapy are preserved for un unrespectable
tumors .

13.  Secondary brain tumors (metastatic ):
 Traditionally these patients are treated with whole brain irradiation.
 Surgery persevered in patients with solitary lesions associated with a
significant mass effect.

14. Imaging modalities

15. Imaging modalities
MRI :
 The clinical gold standard, MRI, provides excellent anatomical details.
 Standard T1- and T2-weighted MRI is highly sensitive in determining the
size and location of brain tumors .
 Most high grade tumors such as glioblastoma lead to disruption of the
blood–brain barrier (BBB) – show enhancement due to the leakage of
contrast media .

16.  Low-grade tumors usually show no or minimal enhancement .
 A high-grade glioma normally presents as an irregular hypodense lesion
on
T1-weighted MRI, with various degrees of contrast enhancement and
edema.

17. Imaging modalities
Limitation of MRI :
 Low sensitivity in distinguishing neoplastic disease from vascular or
inflammatory process .
 Clinically challenging to revaluate treatment response or assessing
recurrence .

18. Imaging modalities
CT
MR spectroscopy .
Nuclear studies.

19. Blood brain barrier

21. Blood brain barrier
 BBB plays an important role in controlling the substance that are allowed
to pass to the brain.
 Many tracer can reach the brain tumors only once the tumors caused a
disruption of BBB, (high grade gliomas ,brain metastasis ).
 BBB disruption can be easily detected on contrast enhanced MRI and CT.
 BBB disruption can be caused also by infection and ischemia .
 Efforts have been invested into the developing of new tracers that don’t
depend on BBB disruption (FDG and labelled AA)

22. Nuclear medicine imaging modalities
1. SPECT tracers.
2. PET tracers .

23. SPECT tracers
 K+ analogue : 201 TI –chloride.
 Technetium -99m-labeled compounds : MIBI , Tetrofosmine .
 Radioiodineted amino acid:
1. Tyrosine derivatives IMT (L3,I 123, Iod-9 methyltyrosine).
2. Phenyl alanine derivatives (P, I 123,Ido-L phenyl alanine) .

24. SPECT tracers
Thallium-201(201Tl) :
 single-photon emission computed tomography (SPECT) has been used
for the assessment of the biologic activity of primary and recurrent
intracranial neoplasms .
 not an ideal radiopharmaceutical for SPECT imaging due to its low-
energy gamma emission and the poor photon flux .

25. SPECT tracers
 The uptake of 201Tl to myocardial and tumor cells is related to Na+–K+
ATPase activity and cell membrane potential.
 Perfusion to malignant tissue appears important for delivery purposes.
 Tumors with poor perfusion, especially if necrotic, appear to take up less
than the same type of tumors with little or no necrosis.

26. SPECT tracers
 Thallium-201(201Tl):
 It accumulates within viable tumor tissue, less within normal or
inflammatory tissues and least in necrotic or non-active tissues.
 The normal, physiological uptake are the choroid plexus of the lateral
ventricles, lacrimal glands, salivary glands, thyroid, myocardium, liver,
spleen, bowels, kidneys, and testes.
 TI 201 :will not pass through an intact blood-brain- barrier (BBB).
 Uptake in brain tumors is also likely dependent on the activity of
sodium-potassium ATPase pump .

27.  accumulates in residual or recurrent tumor in proportion to the malignant
grade .
 Benign brain tumors such as meningiomas and pituitary adenomas can
also accumulate thallium.
 Sites of radiation necrosis and post-surgical change have minimal or
negative uptake.
 It better than MRI and CT in differentiating between recurrence and
therapy response .

28. Technetium-99m-labeled compounds
 They are more suitable for SPECT imaging because they have the 140
keV gamma-ray energy and high photon flux.
 mechanism of cellular accumulation of 99mTc-MIBI most likely involves
passive diffusion across mitochondrial membranes in response to
transmembrane potentials.

29. Technetium-99m-labeled compounds
 99mTc- compounds uptake was seen only in scalp, in the choroid plexus and
pituitary gland, but not in normal cerebral parenchyma.
 Tumor uptake of 99mTc-compounds is high in high grade glioma , low grade
glioma will show no uptake !

30. 99mTc-TF SPECT and Gd-enhanced MR images in patients with oligodendroglioma (grade II) and glioblastoma multiforme
(grade IV).

31. PET tracers

32. PET-tracers:
1. Glucose metabolism :F18-FDG.
2. Radiolabeled amino acid
 Tyrosine analogue :F18-FET, C11-methionine.
 Phenylalanine derivatives : 3,4,dihydroxy-6-F18-fluoro-L-phenylalanine
(FDOPA)
3. Others
 Thymidine analogue :F18-FLT.
 F18 Fluoromisonidazole.
 Ga 68-DOTA-TOC.

33. PET CT tracers (F18-FDG)
 F-FDG PET Imaging of brain tumors with 18F-FDG was the first oncologic
application of PET .
 18F-FDG is actively transported across the BBB into the cell, where it is
phosphorylated.
 18F-FDG uptake is generally high in high-grade tumors.
 Good prognostic value :
High uptake in a previously known low-grade tumor establishes the
diagnosis of anaplastic transformation .

35. PET CT tracers (F18-FDG)
Limitations of F18-FDG:
 Because of the high rate of physiologic glucose metabolism in normal
brain tissue, detection of tumors with normal FDG uptake such as low-
grade tumors and recurrent high-grade tumors, is difficult.
 18F-FDG uptake in low-grade tumors is usually similar to that in normal
white matter.
 high-grade tumors may have uptake that is only similar to or slightly
above that in white matter.

36. How to improve the sensitivity of F18-FDG PET
1. Co-Registration with MRI.
2. Obtain delayed Images .

37. PET-CT tracers (Radiolabeled amino acid)
 Best tracer for imaging because of high uptake in tumor tissue and low
uptake in normal brain tissue .
 The best-studied amino acid tracer is 11C-methionine
 Because of the short half-life of 11C (20 min), 18F-labeled aromatic amino
acid analogs have been developed for tumor imaging .
 Tumor uptake of O-(2-18F-fluoroethyl)-L-tyrosine (FET) and 3,4-
dihydroxy6-18F-fluoro-L-phenylalanine (FDOPA) has been reported to
be similar to that of 11C-methionine .

38. PET-CT tracers (Radiolabeled amino acid)
Mechanism of uptake:
 Amino acids are transported into the cell via carrier mediated processes .
 Amino acid transport is generally increased in malignant transformation .
 Not incorporated into protein .
 FET: stable in vivo ,not taken by inflammatory cell as C11 methionine

39. PET-CT tracers (Radiolabeled amino acid)
 Amino acid transport is increased in tumor cells regardless of the phase
of the cell cycle, and this upregulation of transport does not depend on
breakdown of the BBB, but may be enhanced by, a breakdown in the
BBB .

40. PET-CT tracers (Radiolabeled amino acid)
18F-FDOPA
 Used in diagnose Parkinson disease.
 18F-FDOPA was more sensitive than 18F-FDG in identifying brain
tumors.
 18F-FDOPA may help to detect low-grade and recurrent tumors with
greater sensitivity than 18F-FDG.

41. PET-CT tracers (Radiolabeled amino acid)
 18F-FDOPA demonstrated excellent visualization of high and low-grade
tumors and was more sensitive and specific than 18F-FDG for evaluating
recurrent tumors.
 Limitations:
1. Metabolic degradation in vivo.
2. Uptake in striatum .

43. Other PET tracers
F 18-FLT PET
 The thymidine analog 39-deoxy-39-18F-fluorothymidine (FLT) PET was
developed as a noninvasive method to evaluate tumor cell proliferation
 Uptake of 18F-FLT correlates with thymidine kinase-1 activity, an enzyme
expressed during the DNA synthesis phase of the cell .

44. Other PET tracers
 Phosphorylation of 18F FLT intracellularly by thymidine kinase-1 results in
trapping of the negatively charged 18F-FLT monophosphate.
 FLT cant cross intact BBB !

46. Other PET tracers
 18 F-Fluoromisonidazole
 nitroimidazole derivative that has been developed as a PET agent to
image hypoxia
 Metabolites of 18 F-fluoromisonidazole are trapped exclusively in hypoxic
cells.
 Hypoxia is associated with tumor progression and resistance to
radiotherapy.

47. Other PET tracers
 18 F-Fluoromisonidazole uptake was found in high grade gliomas but
not in low-grade gliomas.
 18 F-fluoromisonidazole may have a role in directing and monitoring
targeted hypoxic therapy.

48. Other PET tracers
 Ga68 -DOTA-TOC
 The somatostatin analog was investigated in meningiomas, because they
show high expression of the somatostatin receptor subtype 2.
 In contrast to 18F-FDG, 68Ga-DOTA-TOC showed a high meningioma-
to-background ratio .

50. Clinical applications

51. Clinical applications of nuclear brain imaging
1. Evaluation of disease status.
2. Evaluation of recurrent tumors .
3. Guidance of diagnosis and therapy .

52. Evaluation of disease status :( radiation
necrosis)
Radiotherapy produces necrosis which associated with clinical symptoms
and it can become difficult to differentiate necrosis from recurrent viable
tumor .

53. Evaluation of disease status :(radiation
necrosis)
 Radiation necrosis is difficult to differentiate from tumor growth on MRI .
 F-FDG PET had a sensitivity of 81%–86% and a specificity of 40%– 94%
for distinguishing between radiation necrosis and tumor .
 FDG may show focal hypometabolism in area of necrosis.

54. Evaluation of disease status
 FDG PET has some limitations in evaluating disease status .
 Lesions most of the times showed activity that slightly higher than the
background.
 FDG- not a good tracer for evaluating recurrence !.

55. Evaluation of disease status
 amino acid tracers appear more sensitive than 18F-FDG PET in visualizing
tumor, they also have potentially better diagnostic performance than
18F-FDG PET in evaluating radiation necrosis.
 the degree of amino acid uptake in radiation necrosis lesions is not well
known.

56.  11C-Methionine has been available for 2 decades, but few studies have
been published on its performance in differentiating radiation necrosis
from brain tumor recurrence .
 a study of 21 patients with brain metastases treated by stereotactic
radiosurgery, 11C-methionine correctly identified 7of 9 recurrences and
10of 12radiation injuries.

57.  F18 -FET is promising for differentiating radiation necrosis from tumor
recurrence as necrosis wouldn’t show any uptake .

58. Evaluation of Recurrent Tumors
 High 18F-FDG uptake in a previously diagnosed low-grade glioma with
low 18F-FDG uptake is diagnostic of anaplastic transformation.
 increase in 18F-FDG uptake is strongly prognostic.
 18F-FDG PET performs generally well in identifying growing high-grade
gliomas.
 18F-FDG PET is generally not sensitive in identifying recurrent low grade
tumors without anaplastic transformation.

60. Evaluation of Recurrent Tumors
 Amino acid uptake has been shown to be increased relative to normal
brain tissue in most low- and high-grade tumors, and radiolabeled
amino acids might therefore be preferable for evaluating recurrent .
 18F-FET was able to distinguish between recurrent tumor and therapy-
induced benign changes with 100% accuracy.

61.  expression of amino acid transporters is upregulated in tumor tissue but
not in tissues affected by posttreatment changes.
 increased amino acid uptake can be increased in tissue after therapy ?
treatment-induced disruption of the blood–brain barrier.

62.  The best differentiation between benign posttreatment changes and
recurrent tumor was found at a threshold of 2.3 for the absolute maximum
SUV.
 When a threshold of 2.3 was used for the maximum SUV, the specificity of
18F-FET PET was 92.9% and the sensitivity was 100%. The sensitivity of
MRI was 93.5% and the specificity was 50%.
 18F-FET PET can differentiate between posttreatment changes and tumor
recurrence and to avoid both under- and overtreatment.

63. A 30-y-old man who had undergone initial surgery, radiation therapy,and
intra lesional radioimmunotherapy for anaplastic astrocytoma. Biopsy proven
recurrent tumor (WHO grade IV) occurred 20 mo after initial diagnosis.

65. Is grading possible with PET tracers?
 Increased FDG uptake in well known low grade gliomas indicates
anaplastic differentiation.
 Most studies have shown that gliomas of different grades overlaps in
their degree of amino acid uptake .
 Grading can be possible using dynamic F18-FET PET as the tracer
exhibits differences in the time activity curve depending on the grade.

67. PET guidance for diagnosis and therapy
 MRI guided stereotactic biopsy are not always yield a valid diagnosis or
tumor grading, because some regions of the no enhancing tumors may
be high-grade.
 11C-methionine and 18F-FET provides a more sensitive results and they
are tracers of choice for single tracer PET-guided neurosurgical
procedures on gliomas.
 MRI yielded a sensitivity of 96% for the detection of tumor tissue but a
specificity of 53%.

68. PET guidance for diagnosis and therapy
 Combined use of MRI and 18F-FET PET yielded a sensitivity of 93% and a
specificity of 94%.
 The diagnostic accuracy in distinguishing neoplastic from non
neoplastic tissue could be increased from 68% with the use of MRI alone to
97% with the use of MRI with 18F-FET PET and MRI spectroscopy.

69. Grade III astrocytoma :MRI vs F18-FET

70. a 37-year-old woman with a glioblastoma multiforme in the left insular and
temporal regions, who was treated with chemotherapy in 2-week cycles

71. Glioblastoma pretreated by surgery and radiochemotherapy. T1 weighted
MRI after application
of Gd-DTPA (A) and T2-weighted MRI (B) are ambiguous. (C) 18F-FET PET

72. Pitfalls of SPECT and PET tracers

73. Pitfalls of SPECT and PET tracers

75. SUMMARY
 broad range of tracers has been evaluated for clinical use in the
diagnosis of brain tumors with PET or SPECT.
 Amino acid tracers, including 11C-METhionine, 18F-FET, and 18F- FDOPA,
provide better sensitivity and distinction from normal tissue for gliomas,
including most low-grade tumors.

76. Summary
 Recently, the use of 18F-FLT has been investigated among this type of
tracers because its uptake also reflects tumor proliferation rates, which
are of particular interest in the monitoring of chemo- and radiotherapy.
 The distinction between RT-induced necrosis and recurrent tumor is a
persistent challenge in the management of brain tumors.

77. References
 Brain Tumors Karl Herholz, MD,* Karl-Josef Langen, MD,† Christiaan Schiepers, MD, PhD,‡ and James M. Mountz, MD, PhD§
 Imaging Proliferation in Brain Tumors with 18F-FLT PET: Comparison with 18F-FDG Wei Chen, MD, PhD1; Timothy Cloughesy, MD2; Nirav Kamdar, BS1;
Nagichettiar Satyamurthy, PhD1; Marvin Bergsneider, MD3; Linda Liau, MD, PhD3; Paul Mischel, MD4; Johannes Czernin, MD1; Michael E. Phelps, PhD1; and
Daniel H.S. Silverman, MD, PhD1
 18F-FDOPA PET Imaging of Brain Tumors: Comparison Study with 18F-FDG PET and Evaluation of Diagnostic Accuracy Wei Chen1,2, Daniel H.S. Silverman1,
Sibylle Delaloye1, Johannes Czernin1, Nirav Kamdar1, Whitney Pope3, Nagichettiar Satyamurthy1, Christiaan Schiepers1, and Timothy Cloughesy4
 Clinical Applications of PET in Brain Tumors* Wei Chen
 Brain tumor imaging with 99mTc-tetrofosmin: comparison with 201Tl, 99mTc-MIBI, and 18F-fluorodeoxyglucose Joon Young Choi1, Sang Eun Kim1, Hyung Jin
Shin2, Byung-Tae Kim1 and Jong Hyun Kim2 1Department of Nuclear Medicine, 2Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea
 68Ga-Labeled Peptides in Tumor Imaging Helmut R. Maecke, PhD1; Michael Hofmann, MD2; and Uwe Haberkorn, MD3 1Division of Radiological Chemistry,
Department of Radiology, University Hospital Basel, Basel, Switzerland; 2Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany; and
3Department of Nuclear Medicine, University of Heidelberg and Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg,
Germany
 DELAYED FDG-PET/CT IMAGES IN PATIENTSWITH BRAIN TUMORS - IMPACT ON VISUAL ANDSEMIQUANTITATIVE ASSESSMENT Pavel H. Bochev1, Aneliya
Klisarova1, Ara Kaprelyan2, Borislav Chaushev1, ZhivkaDancheva1 1Department of Nuclear Medicine and Radiotherapy, “St. Marina” UniversityHospital, Varna,
Bulgaria 2Department of Neurology, “St. Marina” University Hospital, Varna, Bulgaria

78. References
 Diagnostic Accuracy of 11C-Methionine PET for Differentiation of Recurrent Brain Tumors from Radiation Necrosis After Radiotherapy Yuzo Terakawa1, Naohiro Tsuyuguchi1, Yoshiyasu Iwai2,
Kazuhiro Yamanaka2, Shigeaki Higashiyama3,Toshihiro Takami1, and Kenji Ohata1
 Comparison of F-18 FDG and C-11 Methionine PET/CT for the Evaluation of Recurrent Primary Brain TumorsMadhavi Tripathi, MD, DNB,* Rajnish Sharma, DRM, DNB,* Raunak Varshney, PhD,†
Abhinav Jaimini, DRM,* Jyotika Jain, MD,‡ Maria M. D. Souza, MD,* Jaspriya Bal, DRM,* Santosh Pandey, BSc,* Nitin Kumar, MSc,† Anil K. Mishra, PhD,† and Anupam Mondal, DRM, DNB*