Update onBrain Tumor Imaging

Soonmee Cha, M.D.

Case 1

Cor & Axial T1-post Perfusion

T2

Case 2

T1-post

Case 3

Case 3 Case 4

T1-post ADCDWIFLAIR

T1-post CBV map

Case 5

44-year-old woman w/breast CAGoals of this lecture

1. Review advances in MR imagingDiffusion-weighted imagingProton MR spectroscopyPerfusion-weighted imaging

2. Discuss clinical application of advanced MR imaging in brain tumor patients

3. Present strengths & limitations of advanced MR imaging methods

Transition in Brain Tumor Therapy1. Shift in Cancer Therapy

Nonspecific anti-DNA therapy to molecularly/genetically targeted therapyWho 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?

Glioblastoma Multiforme (GBM)Most common, rapidly fatal, primary brain tumor of adultsExtreme histologic/molecular/genetic heterogeneityMinimal improvement in survival despite combo of aggressive therapySeveral biologically targeted therapy in clinical trials

22.918.527.224.735.734.429,3718000-9989TOTAL: All brain and other CNSb

49.248.051.951.264.263.81488680, 9364, 9490-9491,

9500, 9505-9506

Malignant neuronal/glial, neuronal and mixed

32.528.640.338.150.349.12199381, 9423, 9430Neuroepithelial

43.042.351.551.269.068.71,0468963, 9443, 9470-9473, 9502-9503

Embryonal/primitive/medulloblastoma

40.537.657.755.973.772.85409382Mixed glioma

23.017.927.224.234.132.52,0639380Glioma, malignant, NOS

56.252.965.663.977.977.18749391-9393Ependymoma/anaplastic ependymoma

26.923.740.838.258.557.01289461, 9460Anaplastic oligodendroglioma

47.042.964.361.879.178.01,1839450Oligodendroglioma

22.819.630.228.245.544.31,6959401, 9411Anplastic astrocytoma

36.833.047.044.862.861.65779410, 9420Diffuse astrocytoma

84.382.987.686.891.491.06769421Pilocytic astrocytoma

28.924.335.532.845.844.56,6119400Astrocytoma, NOS

2.31.73.42.98.78.311,7039440-9442GlioblastomaRel.Obs.Rel.Obs.Rel.Obs.

Ten YearFive YearTwo YearNo. of Cases

ICDO Code(s)HISTOLOGY

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

SEER 1973-1996

Median survival ~ 14 months

Molecularly targeted therapy of GBMMonoclonal antibodies

Anti-EGFR (Iressa, OSI-774, Tarceva)Targeting signaling pathways

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

Targeting angiogenesis & invasionAvastin

Immunotherapy

Challenges & Opportunities1. Who should be treated with what?

Molecular sub-classification of brain tumors

2. How to measure if the drug is working?Imaging based biomarkers as endpoints for clinical trials

Anatomic Imaging is the backbone of brain tumor detection & characterization

FLAIR T1-post SWIJanine Lupo

2-D Structural MR Imaging

3-D Structural MR Imaging3-D Structural MR Imaging

Highly sensitive but nonspecificCannot reliably differentiate tumor and treatment effectsUnable to guide specific targeted therapyCannot assess early therapy failure & predict clinical outcome

Current Problems with Anatomic ImagingContrast enhancement is nonspecific!Contrast enhancement is nonspecific!

GBM Abscess TB

Demyelinatinglesion

XRT necrosis

Glioblastoma Multiforme

T1-post

3 different male patients in mid-50s with GBMs/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

Imaging has to do a better job in….Characterizing brain tumor biologyGuiding therapyAssessing therapeutic responseDetecting early treatment failureDistinguishing tumor progression & treatment effectsPredicting clinical outcome

Advances in MR Imaging

Diffusion-weighted imagingPerfusion-weighted imaging

Proton MR Spectroscopy

Transition from

Anatomy Physiology Biology

Key biologic hallmarks of GBM

1. Infiltration/invasion

2. Hypoxia/Necrosis

3. Angiogenesis

AngiogenesisAngiogenesisInfiltrationInfiltration HypoxiaHypoxia

Diffusion Perfusion

LactateMRS

Advanced MR Imaging

Diffusion-weighted imagingProton MR Spectroscopy

Perfusion-weighted imaging

Advanced MR Imaging

DiffusionDiffusion--weighted imagingweighted imagingProton MR Spectroscopy

Perfusion-weighted imaging

Diffusion-weighted Imaging (DWI)

Acute PCA

Infarct

H+ in CSF

H+ in Infarct

H+ in WM

ADC & GliomaGrade

II

III

IV

Postoperative Diffusion AbnormalityPre-op Immed post-op

DWI ADC

2-month F/U 4-month F/U

Recurrence?

Postoperative Brain TumorPre-op Immed post-op

4-mo post-op

1-mo post-op

Tumor?

T1-post FLAIR

DWI

ADC

Abscess

T1-post ADCDWIFLAIR

No change in reduced diffusion for 3 mos on antibiotics…

Infected Metastasis

Limitations: DWIEPI related distortion & susceptibility artifactBlood products can mimic pathologic reduced diffusion

Temporal Lobe Hematoma

ADCDiffusionT1-pre

Advanced MR Imaging

Diffusion-weighted imagingProton MR SpectroscopyProton MR Spectroscopy

Perfusion-weighted imaging

1H MRSI Metabolites @ 1.5 Tesla

Rapid tissue destruction

Necrosis0.9-1.2Lip

Hypoxia; radioresistance

Anaerobic metabolism

1.31Lac

Tumor proliferationMembrane turnover3.19Cho

?Energetic3.03Cr

Tumor infiltrationEdema

Neuronal marker2.01NAA

Surrogate markerBiologic correlateShift (ppm)

Proton MR Spectroscopy (1H MRS)Lipid/Lactate

NAACho Cr

Choline

Normal

Choroid Plexus Papilloma

High Choline

No NAA

Grade IV

Fibrillary Astrocytomas

Grade IIIGrade II

Fibrillary Astrocytomas

Grade IVGrade IIIGrade II

Grade III Glioma

3D MRSI (TE=144 ms)

3D Lac-edited MRS

Single voxel (TE=288 ms)

Lac

Cho

NAACr

Lactate

Lactate: Poor prognostic marker?Anaplastic Astrocytoma

9/02Pre-op

9/02postop

3/036-mo F/U

10/0312-mo F/U

Limitations: Proton MRSEPI related distortion & susceptibility artifactIncomplete water suppressionLipid contaminationLimited size of PRESS box

MRS Artifacts:

Incomplete water suppression

MRS Artifacts:

Lipid Contamination

Advanced MR Imaging

Diffusion-weighted imagingProton MR Spectroscopy

PerfusionPerfusion--weighted imagingweighted imaging

T1-SPGR vs T2*

Steady-state First-pass

Spin echo (T2) EPI(0.3mmol/kg)

Gradient echo (T2*) EPI(0.1mmol/kg)

Perfusion MR ImagingDynamic contrast-enhanced

Susceptibility-weighted (DCS) Imaging

DCS Perfusion MR ImagingWhat it is NOT

Absolute measure of tissue perfusion (ml/100gm tissue/min)

What it isRelative measure of blood volumeGross estimation of intravascular [Gd-DTPA]

What it could BESurrogate marker of tumor angiogenesisPredictor of outcomePotential endpoint for anti-angiogenesis Rx

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

T1 Effect of Gd-DTPA

T2* Effect of Gd-DTPA

0

200

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1200

1400

1600

0 10 20 30 40 50 60

Time

Sig

nal I

nten

sity

DSC Perfusion MRI ProtocolTR=1250 msTE=54 msFlip angle=35°FOV=26cmMatrix=128x128No. slice=7-8Slice thickness= 2.5-4.5mm (0-1gap)

0

200

400

600

800

1000

0 20 40 60

0

0.005

0.01

0.015

0.02

T2* signal intensity [Gd-DTPA]

time/sec

ΔR2*= -ln S(t)/S(0)

TE

Blood volume Permeability

GBM

DSC DSC pMRIpMRI derived variables:derived variables:

1.Relative cerebral blood volume (rCBV)

2.Peak height (PH)

3.Abnormal recovery (aRec)

baseline bolus

recirculation

T2*-weighted susceptibility signal time curve

ab

b x 100a

Peak height

Percent signal

recovery

DSC Perfusion MRI: Clinical Applications

Glioma grading (astrocytomasonly)Image-guided biopsyPrimary vs Secondary brain tumorTumor vs Treatment effectTumor-mimicking lesions

Astrocytoma progression

Grade IVGrade IIIGrade II9-12 mos2-3 yrs5-10yrsSurvival

Malignant Differentiation of Astrocytoma

Grade II Grade IVGrade III

Grade II Grade IVGrade III

Low-grade

High-grade

T1T1

T1T1 T2T2

T2T2

DSC Perfusion MRI based gliomagrading should be limited to

astrocytomas only

Low-grade oligodendrogliomas& oligoastrocytomas may show high rCBV

Grade II Gliomas

Low-grade oligodendroglioma

Glioblastoma Multiforme

T1-post DSA rCBV map

contrast enhancing lesion

rCBVlesion

Biopsy directed to

the max rCBV

F. Crawford

rCBV map & selection of biopsy spots

Biopsy spot

Research software provided by GE, Milwaukee, WI.

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.

Image-guided tissue collection protocol

Image-Guided StereotacticBiopsy : 2-4 biopsies

Imaging-Histopathology

MIB-1

H&E

Factor VIII

Histopathological Methods: Proliferative Index

H&E MIB-1

Perfusion MRI guided tumor biopsy

3 vascular morphology in GBM

1. Delicate vessels

2. Simple hyperplasia

3. Glomeruloid

1 2 3

GBM vs METBoth are highly malignant but treated differentlyAnatomic imaging can appear similar but usually multiple lesions in METUp to 30% of MET can be present as a single brain massPreoperative differentiation critical for proper management

GBM vs MET GBM vs METBoth can be highly vascularMET capillaries resemble those of primary systemic cancer NO blood-brain barrierMET capillaries are much more leaky than those of GBM

RBC

Endothelial cell

Continuous basement membrane

Astrocytic foot process

Tight junction

Tumor capillaries: GBM vs MET

Integrity of Blood-brain Barrier (BBB)

GBM vs MET

GBM

Met

rCBV

PH

PSR

PH: Peak height

PSR: Percent signal recovery Janine Lupo

T2* signal intensity time curve: Met vs GBM

0100200300400500600700800900

1000

0 10 20 30 40 50 60

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Sign

al In

tens

ity

0

200

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1000

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Time

Sign

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Lung CA metastasis

GBM

Tumor

Tumor

Met Glioma

Tumor vs Treatment Effects

T2 Post-contrast T1 rCBV

Delayed Radiation Necrosis 3-month follow upRadiation Necrosis

Tumor

Lipid peaks only

Radiation Necrosis Recurrent tumor vs

treatment effect?Recurrent tumor

Treatment effect

Tumor-mimicking lesions of the brain

MS plaque

GBM

Tumefactive Demyelinating Lesion

Post Contrast T1 FLAIR Color Overlay

T1-pre

Tumor?

T2 T1-post

Tumefactive Demyelinating Lesion

T2 T1-post Dynamic T2* perfusion

Tumefactive Demyelinating Lesion

High-grade Glioma Meningioma Embolization

Perfusion Assessment

CBV

MTT

Dynamics

Pre Post L-ECA EmbolizationIV

(20 cc @ 4cc/s)IV

(20 cc @ 4cc/s)IA (L-CCA)

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

(5 cc of 10% Gd @ 1cc/s)A. Martin, PhD

Meningioma Pre- & Post-embolization

Pre (IV) Post (IA) Post (IV)

CBV

MTT

T1 (Gd)

Limitation: DSC Perfusion MRI

Susceptibility artifactsNear brain-bone-air interface

Anterior & middle cranial fossaMetal, blood products, Ca++

Nyquist ghost artifact

6 mm

4 mm

T1 effect

Flip angle=90ºFlip angle=30º

Susceptibility Artifact (Hemorrhagic Metastasis)

Pre-contrast During bolus

Nyquist ghost

Case 1

Cor & Axial T1-post Perfusion

Delayed Radiation Necrosis

T2

Toxoplasmosis Encephalitis

T1-post

Case 2

GBM

TOXO

Case 3 Delayed Radiation Necrosis

Lipid peaks only

Case 3: Radiation Necrosis

T1-post ADCDWIFLAIR

Case 4: No change in reduced diffusion for 3 moson antibiotics…

Infected Metastasis

Dx: Neurocysticercosis

T1-post CBV map

Case 5: 44-year-old woman w/breast CA SummaryReview of advanced MR imaging methods for brain tumor imaging

DWIProton MRSPerfusion MRI

Clinical application of advanced MRIImproved detection & characterization of tumors before, during, & after therapyBiomarkers of tumor biologyEndpoints for clinical trialsPredictors of outcome

Pitfalls & limitations

Work in progress

Acknowledgement

GrantsGrantsNIH 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