Case 1

Update on
Brain Tumor Imaging
Soonmee Cha, M.D.

Case 3

Case 2

T1-post

Perfusion

Cor & Axial T1-post

T2

Case 3

Case 4

T1-post

FLAIR

DWI

ADC

Case 5

Goals of this lecture

44-year-old woman w/breast CA

1. Review advances in MR imaging

Diffusion-weighted imaging
Proton MR spectroscopy
Perfusion-weighted imaging

T1-post

2. Discuss clinical application of

advanced MR imaging in brain
tumor patients
3. Present strengths & limitations of
advanced MR imaging methods

CBV map

Transition in Brain Tumor Therapy

Glioblastoma Multiforme (GBM)

1. Shift in Cancer Therapy

Nonspecific anti-DNA therapy to
molecularly/genetically targeted therapy
Who should be treated with what?

2. Critical need for optimal endpoints for

clinical trials
3. How to measure therapy response?
4. How to predict clinical outcome?

Most common, rapidly fatal, primary

brain tumor of adults
Extreme histologic/molecular/genetic
heterogeneity
Minimal improvement in survival despite
combo of aggressive therapy
Several biologically targeted therapy in
clinical trials

SEER 1973-1996
HISTOLOGY

Glioblastoma

ICDO
Code(s)
9440-9442

No. of
Cases

Two Year
Obs.

Five Year

Rel.

Obs.

Ten Year

Rel.

Obs.

Rel.

11,703

8.3

8.7

2.9

3.4

1.7

2.3

Astrocytoma, NOS

9400

6,611

44.5

45.8

32.8

35.5

24.3

28.9

Pilocytic astrocytoma

9421

676

91.0

91.4

86.8

87.6

82.9

84.3

Diffuse astrocytoma

9410, 9420

577

61.6

62.8

44.8

47.0

33.0

36.8

Anplastic astrocytoma

9401, 9411

1,695

44.3

45.5

28.2

30.2

19.6

22.8

9450

1,183

78.0

79.1

61.8

64.3

42.9

47.0

Oligodendroglioma
Anaplastic oligodendroglioma

9461, 9460

128

57.0

58.5

38.2

40.8

23.7

26.9

Ependymoma/
anaplastic ependymoma

9391-9393

874

77.1

77.9

63.9

65.6

52.9

56.2

Glioma, malignant, NOS

9380

2,063

32.5

34.1

24.2

27.2

17.9

23.0

Mixed glioma

9382

540

72.8

73.7

55.9

57.7

37.6

40.5

Embryonal/primitive/medulloblasto
ma

8963, 9443,
9470-9473,
9502-9503

1,046

68.7

69.0

51.2

51.5

42.3

43.0

Neuroepithelial

9381, 9423,
9430

219

49.1

50.3

38.1

40.3

28.6

32.5

Malignant neuronal/glial,
neuronal and mixed

8680, 9364,
9490-9491,
9500, 95059506

148

63.8

64.2

51.2

51.9

48.0

49.2

35.7

24.7

27.2

18.5

22.9

TOTAL: All brain and other CNSb

80009989

29,371

34.4

http://www.cbtrus.org/2001/table2001_12.htm

Median survival ~ 14 months

Molecularly targeted therapy of GBM

Monoclonal antibodies

Challenges & Opportunities

1. Who should be treated with what?
Molecular sub-classification of brain
tumors

Anti-EGFR (Iressa, OSI-774, Tarceva)

Targeting signaling pathways

Anti-PDGFR (Gleevec)
Rapamycin/CCI-779
IL13-PE38QQR

2. How to measure if the drug is working?

Imaging based biomarkers as
endpoints for clinical trials

Targeting angiogenesis & invasion

Avastin

Immunotherapy

Anatomic Imaging is the backbone of brain

tumor detection & characterization

FLAIR

T1-post

2-D Structural MR Imaging

SWI
Janine Lupo

3-D Structural MR Imaging

3-D Structural MR Imaging

Current Problems with Anatomic Imaging

Contrast enhancement is nonspecific!

GBM

Abscess

TB

Highly sensitive but nonspecific

Cannot reliably differentiate tumor and
treatment effects
Unable to guide specific targeted
therapy
Cannot assess early therapy failure &
predict clinical outcome
XRT
necrosis

Demyelinating
lesion

Glioblastoma Multiforme

T1-post

Imaging has to do a better job in.

Characterizing brain tumor biology
Guiding therapy
Assessing therapeutic response
Detecting early treatment failure
Distinguishing tumor progression &
treatment effects
Predicting clinical outcome

3 different male patients in mid-50s with GBM

s/p Surgery + XRT + Temodar
3 different clinical outcomes WHY?

Stable 3 years
after surgery

Died w/in 12 mo
due to distant
recurrence

Died w/in 6 mo
due to local
recurrence

Advances in MR Imaging
Diffusion-weighted imaging
Perfusion-weighted imaging
Proton MR Spectroscopy
Transition from
Anatomy Physiology Biology

Infiltration

Hypoxia

Angiogenesis

Key biologic hallmarks of GBM

1. Infiltration/invasion

2. Hypoxia/Necrosis

Lactate
MRS

3. Angiogenesis

Diffusion

Perfusion

Advanced MR Imaging

Advanced MR Imaging

Diffusion-weighted imaging
Proton MR Spectroscopy
Perfusion-weighted imaging

Diffusion-weighted imaging
Proton MR Spectroscopy
Perfusion-weighted imaging

Diffusion-weighted Imaging (DWI)

ADC &
Glioma
Grade

II

III
H+ in CSF
H+ in WM
H+ in Infarct

Acute
PCA
Infarct

IV

Postoperative Brain Tumor

Postoperative Diffusion Abnormality

Pre-op

Immed post-op

Pre-op

DWI

2-month F/U

Immed post-op

ADC

4-month F/U

1-mo post-op

4-mo post-op

Recurrence?

Tumor?

T1-post

Abscess

DWI

FLAIR

No change in reduced diffusion for 3 mos on

antibiotics

Infected Metastasis

ADC

T1-post

FLAIR

DWI

ADC

Limitations: DWI

Temporal Lobe Hematoma

EPI related distortion & susceptibility

artifact
Blood products can mimic pathologic
reduced diffusion

T1-pre

Diffusion

1H

Advanced MR Imaging
Diffusion-weighted imaging
Proton MR Spectroscopy
Perfusion-weighted imaging

ADC

MRSI Metabolites @ 1.5 Tesla

Shift
(ppm)

Biologic correlate

Surrogate marker

NAA

2.01

Neuronal marker

Tumor infiltration
Edema

Cr

3.03

Energetic

Cho

3.19

Membrane turnover

Tumor proliferation

Lac

1.31

Anaerobic
metabolism

Hypoxia;
radioresistance

Lip

0.9-1.2

Necrosis

Rapid tissue
destruction

Choroid Plexus Papilloma

Proton MR Spectroscopy (1H MRS)

Choline
Lipid/Lactate

Normal
Cho

Cr

NAA

High Choline
No NAA

Fibrillary Astrocytomas

Fibrillary Astrocytomas

Grade II

Grade III

Grade IV
Grade II

Grade IV

Lactate: Poor prognostic marker?

Anaplastic Astrocytoma

3D Lac-edited MRS
3D MRSI
(TE=144
ms)
Lactate

Grade III

Lac
Cho

Cr

NAA

Single voxel (TE=288 ms)

9/02

9/02

3/03

10/03

Pre-op

postop

6-mo F/U

12-mo F/U

Grade III Glioma

Limitations: Proton MRS

EPI related distortion & susceptibility
artifact
Incomplete water suppression
Lipid contamination
Limited size of PRESS box

MRS Artifacts:
Incomplete water
suppression

MRS Artifacts:

Advanced MR Imaging

Lipid Contamination

Diffusion-weighted imaging
Proton MR Spectroscopy
Perfusion-weighted imaging

T1-SPGR

Steady-state

vs

T2*

Spin echo (T2) EPI

(0.3mmol/kg)

Gradient echo (T2*) EPI

(0.1mmol/kg)

First-pass

DCS Perfusion MR Imaging

Perfusion MR Imaging
Dynamic contrast-enhanced
Susceptibility-weighted
(DCS) Imaging

What it is NOT
Absolute measure of tissue perfusion
(ml/100gm tissue/min)

What it is
Relative measure of blood volume
Gross estimation of intravascular [Gd-DTPA]

What it could BE
Surrogate marker of tumor angiogenesis
Predictor of outcome
Potential endpoint for anti-angiogenesis Rx

T1 Effect of Gd-DTPA

Quantification of Perfusion from Bolus MRI

Principles of tracer kinetics for
nondiffusable tracers (Zierler 1962; Axel
1980)
Assumes that in the presence of an intact
BBB, the contrast material remains
intravascular

T2* Effect of Gd-DTPA

DSC Perfusion MRI Protocol

TR=1250 ms
TE=54 ms
Flip angle=35
FOV=26cm
Matrix=128x128
No. slice=7-8
Slice thickness= 2.5-4.5mm (0-1gap)

1600

Signal Intensity

1400
1200
1000
800
600
400
200
0
0

10

20

30

40

50

60

Time

T2* signal
intensity
1000

R2*= -ln S(t)/S(0)

TE

GBM
[Gd-DTPA]
0.02

800

0.015

600
0.01
400
0.005

200
0

0
0

20 time/sec 40

60

Blood volume

Permeability

T2*-weighted susceptibility signal time curve

DSC pMRI derived variables:

baseline

bolus

1.Relative cerebral blood volume

(rCBV)

recirculation
Peak
height

2.Peak height (PH)

b x 100
a

Percent
signal
recovery

3.Abnormal recovery (aRec)

DSC Perfusion MRI:

Clinical Applications

Astrocytoma progression

Glioma grading (astrocytomas

only)
Image-guided biopsy
Primary vs Secondary brain
tumor
Tumor vs Treatment effect
Tumor-mimicking lesions

Survival

Grade II
5-10yrs

Grade III
2-3 yrs

Grade IV
9-12 mos

Malignant Differentiation of Astrocytoma

Grade II

Grade II

Grade III

Grade IV

Grade III

Grade IV

DSC Perfusion MRI based glioma

grading should be limited to
astrocytomas only

Low-grade
T1

T2

Low-grade oligodendrogliomas
& oligoastrocytomas may show
high rCBV
High-grade

T1

T2

Low-grade oligodendroglioma

Grade II Gliomas

Glioblastoma Multiforme
rCBV
lesion

contrast
enhancing
lesion

Biopsy
directed to
the max rCBV

T1-post

DSA

rCBV map
F. Crawford

rCBV map & selection of biopsy spots

Image-guided tissue collection protocol

Image-Guided Stereotactic
Biopsy : 2-4 biopsies

Biopsy spot

Biopsy is placed in a 50 ml centrifuge tube

containing 70% ethanol that is subsequently
labeled. The ethanol is replaced with zinc
formalin outside of the O.R.

Research software provided by GE, Milwaukee, WI.

Histopathological Methods:
Proliferative Index

Imaging-Histopathology
H&E

MIB-1

Factor VIII
H&E

Perfusion MRI guided tumor

biopsy

GBM vs MET

3 vascular morphology in GBM

1. Delicate vessels
2. Simple hyperplasia
3. Glomeruloid

MIB-1

Both are highly malignant but

treated differently
Anatomic imaging can appear
similar but usually multiple lesions in
MET
Up to 30% of MET can be present as
a single brain mass
Preoperative differentiation critical
for proper management

GBM vs MET

GBM vs MET

Both can be highly vascular

MET capillaries resemble those
of primary systemic cancer
NO blood-brain barrier
MET capillaries are much more
leaky than those of GBM

GBM vs MET

Tumor capillaries: GBM vs MET

Integrity of Blood-brain Barrier (BBB)

GBM

rCBV
PH

RBC
Endothelial
cell

Met

Continuous
basement
membrane

PSR

Astrocytic foot
process
Tight junction

PH: Peak height

PSR: Percent signal recovery

T2* signal intensity time curve: Met vs GBM

Tumor

1600

Signal Intensity

1400
1200
1000
800
600
400
200
0

Lung CA metastasis

10

20

30

40

50

60

Time

Tumor

Signal Intensity

1000
900

GBM

800
700
600
500
400
300
200
100
0
0

10

20

30
Time

40

50

60

Janine Lupo

Tumor vs Treatment Effects

Met

Glioma

Delayed Radiation Necrosis

3-month follow up
Radiation Necrosis

T2

Post-contrast T1

rCBV

Tumor

Radiation Necrosis

Recurrent
tumor vs
Recurrent tumor

Lipid peaks only

Treatment effect

treatment
effect?

MS plaque

Tumor-mimicking lesions of
the brain

GBM

Tumor?

Tumefactive Demyelinating Lesion

Post Contrast T1

FLAIR

Color Overlay

T2

Tumefactive Demyelinating Lesion

T2

T1-post

Dynamic T2*
perfusion

T1-pre

T1-post

Tumefactive Demyelinating Lesion

Meningioma Embolization

High-grade Glioma
CBV

MTT

Perfusion
Assessment
Dynamics

A. Martin, PhD

Meningioma Pre- & Post-embolization

CBV

MTT
Pre (IV)

Post (IA)

Post (IV)

Pre
IV
(20 cc @ 4cc/s)

Post L-ECA Embolization

IA (L-ECA)
IA (L-CCA)
(15 cc of 10% Gd @ 3cc/s)

(5 cc of 10% Gd @ 1cc/s)

IV
(20 cc @ 4cc/s)

Limitation: DSC Perfusion MRI

Susceptibility artifacts
Near brain-bone-air interface
yAnterior & middle cranial fossa
Metal, blood products, Ca++
Nyquist ghost artifact

T1 (Gd)

T1 effect
6 mm

4 mm
Flip angle=30

Flip angle=90

Susceptibility Artifact
(Hemorrhagic Metastasis)

Pre-contrast

Nyquist ghost

During bolus

Case 1

Case 2

Delayed Radiation Necrosis

Toxoplasmosis Encephalitis

Cor & Axial T1-post

T1-post

Perfusion

Case 3
GBM

TOXO

T2

Delayed Radiation Necrosis

Case 3: Radiation Necrosis

Case 4: No change in reduced diffusion for 3 mos

on antibiotics

Infected Metastasis

T1-post

FLAIR

DWI

ADC

Lipid peaks only

Summary

Case 5: 44-year-old woman w/breast CA

Dx: Neurocysticercosis

Review of advanced MR imaging methods for brain

tumor imaging
DWI
Proton MRS
Perfusion MRI

Clinical application of advanced MRI

Improved detection & characterization of tumors

before, during, & after therapy
Biomarkers of tumor biology
Endpoints for clinical trials
Work in progress
Predictors of outcome

T1-post

CBV map

Pitfalls & limitations

Acknowledgement
Grants
NIH NINDS K23
NIH NCI (Brain Tumor SPORE)
NIH NCI (PBTC)
Accelerate Brain Cancer Cure

Thank you

Any questions or comments to

soonmee.cha@radiology.ucsf.edu