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STATE OF THE ART
PROSTATE MR
IMAGING
STATE OF THE ART PROSTATE
MR IMAGING
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DYNAMIC CONTRAST-ENHANCED MRI
(DCE-MRI)
LYMPHOTROPIC SUPERPARAMAGNETIC
NANOPARTICLES ENHANCED MRI
MR SPECTROSCOPIC IMAGING (MRSI)
ENDORECTAL COIL FOR
HIGH-RESOLUTION
ANATOMIC ANALYSIS
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PROSTATE GLAND
PROSTATE CAPSULE
SEMINAL VESICLES
NEUROVASCULAR BUNDLES
DENONVILLIER’S FASCIA
PARARECTAL LYMPH NODES
BLOOD FROM RECENT
BIOPSY
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COMPLICATES INTERPRETATION OF MR
ANATOMIC IMAGING
COMPLICATES INTERPRETATION OF
MRSI
COMPLICATES INTERPRETATION OF
DCE-MRI
PELVIC MRI
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LYMPH NODE ANALYSIS
VASCULAR DISEASE
OTHER MASSES
DYNAMIC CONTRASTENHANCED MRI
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Anatomic imaging provides only one index of
biologic activity
Some therapies, such as antiangiogenic and
vaccines therapies, are expected to be cytostatic
and thus may not produce “objective” responses
in tumor size
DYNAMIC CONTRASTENHANCED MRI
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DCE-MRI -- acquisition of serial MR images
before, during, and after the administration of
an IV contrast agent
Resulting signal intensity measurements of the
tumor reflect a composite of tumor perfusion,
vessel permeability, and the volume of the
extravascular-extracellular space
DCE-MRI, in conjunction with traditional MRI,
provides functional and detailed morphologic
information in the same study
DYNAMIC CONTRASTENHANCED MRI
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DCE-MRI has been employed for tumor
detection, characterization, staging, and therapy
monitoring
Cancers demonstrate typical enhancement
kinetics; rapid and high amplitude wash-in
followed by a relatively rapid wash-out. This
pattern can be used to distinguish malignant
masses from benign lesions or normal tissue,
which enhance slowly and washout slowly
DYNAMIC CONTRASTENHANCED MRI -- FALSE
POSITIVES AND NEGATIVES
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Microscopic disease may still be present even
when DCE-MRI shows no evidence of tumor
Some malignant processes can mimic benign
contrast kinetics, and some benign processes
(e.g., inflammation) can mimic malignant
contrast kinetics
It is thus important to have histopathologic
correlation at the initial study to determine the
particular contrast kinetics of a tumor
DYNAMIC CONTRASTENHANCED MRI
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Monitoring of cancer therapy is another
important role of DCE-MRI
DCE-MRI provides direct and early evidence of
a therapeutic effect by demonstrating changes in
the enhancement curves (slower initial
enhancement, decreased amplitude, slower
wash-out)
Failure of particular areas of the tumor to
respond to therapy implies the presence of
resistant clones
DYNAMIC CONTRASTENHANCED MRI
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Tumors with higher initial permeability often
respond better to chemotherapy than tumors
with lower permeabilities, as it is possible to
deliver more cytotoxic therapy to these lesions
More permeable tissues may be better
oxygenated and therefore initially more
radiosensitive
Changes on DCE-MRI may be non-predictive;
the therapy may induce physiologic changes in
the tumor without affecting patient survival
DYNAMIC CONTRASTENHANCED MRI
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Angiogenesis is now considered one of the
major events that must occur if a tumor is to
grow beyond several millimeters in diameter
If tumors are to grow beyond this size, they
must induce surrounding vessels to create neovessels, i.e., angiogenesis
DYNAMIC CONTRASTENHANCED MRI
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Angiogenic inhibitors reduce both the number
of vessels (especially nonfunctional vessels) and
their permeability on DCE-MRI
Some therapies, such as antivascular endothelial
growth factor antibody, are specifically directed
against a growth factor, VEGF, and are thought
to regulate vascular maturation, and thus
permeability
Such changes are predicted to occur early after
treatment
DYNAMIC CONTRASTENHANCED MRI
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More conventional therapies can also be
monitored with DCE-MRI because vessel loss is
a final common pathway for many therapies
Cytotoxic chemotherapy and vaccine
immunotherapy result in changes in
enhancement kinetics within a tumor
DYNAMIC CONTRASTENHANCED MRI
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Therapeutic radiation can also be monitored
because decreased vascularity is anticipated with
successful treatment early after therapy
A form of angiogenesis induced by radiation
fibrosis may be seen months after initial therapy,
leading to paradoxical increases in vessel
permeability
Local therapies, such as cryotherapy and
radiofrequency ablation, can also be monitored
with DCE-MRI
DYNAMIC CONTRASTENHANCED MRI
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Prostate gland is particularly difficult to evaluate
Heterogeneous gland with its central regions
prone to hyperplastic changes and tumors, both
of which display a range of angiogenesis
The peripheral zone is normally relatively
hypovascular
Low grade tumors also tend to be relatively
hypovascular and thus are difficult to detect
against the background of normal contrast
enhancement
DYNAMIC CONTRASTENHANCED MRI
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Nonetheless, contrast-enhanced MRI using
rapid bolus techniques have been reported to be
more sensitive to tumors and are a useful
adjunct to T2-weighted scans in tumor
localization and staging.
LYMPHOTROPIC
SUPERPARAMAGNETIC
NANOPARTICLES ENHANCED MRI
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NANOPARTICLES WITH IRON OXIDE
CORE ARE SLOWLY EXTRAVASATED
FROM THE VASCULAR SPACE INTO THE
INTERSTITIAL SPACE
TRANSPORTED TO LYMPH NODES VIA
LYMPHATICS
LYMPHOTROPIC
SUPERPARAMAGNETIC
NANOPARTICLES ENHANCED MRI
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NANOPARTICLES INTERNALIZED BY
MACROPHAGES IN LYMPH NODES
INTRACELLULAR IRON-CONTAINING
NANOPARTICLES CAUSE CHANGES IN
MAGNETIC PROPERTIES DETECTABLE
BY MR IMAGING
LYMPHOTROPIC
SUPERPARAMAGNETIC
NANOPARTICLES ENHANCED MRI
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MRI PERFORMED BEFORE AND 24
HOURS AFTER IV ADMINISTRATION OF
THE NANOPARTICLES
NODAL INFILTRATION BY TUMOR
CAUSES LESS MAGNETIC
SUSCEPTIBILITY CHANGE
LYMPHOTROPIC
SUPERPARAMAGNETIC
NANOPARTICLES ENHANCED MRI
Sensitivity Specificity Accuracy
PPV
NPV
Per Patient
100%
95.7%
97.5%
94.7%
100%
Per Individual
Lymph Node
90.5%
97.8%
97.3%
95%
97.8%
LN Short Axis 95.4%
5-10 mm
99.3%
98.9%
95.4%
99.3%
LN Short Axis 41.1%
< 5 mm
98.1%
90.4%
77.7%
91.3%
N ENGL J MED 2003; 348:2491-2499
COMBINED ANATOMIC AND
METABOLIC IMAGING OF
PROSTATE CANCER -- MRI/3D
MRSI
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MRSI PROVIDES A NON-INVASIVE
METHOD OF DETECTING SMALL
METABOLITES WITHIN THE CYTOSOL
OR IN THE EXTRACELLULAR SPACES OF
THE PROSTATE GLAND
PERFORMED IN CONJUNCTION WITH
HIGH RESOLUTION ANATOMIC
IMAGING
COMBINED ANATOMIC AND
METABOLIC IMAGING OF
PROSTATE CANCER -- MRI/3D
MRSI
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INITIAL HUMAN STUDIES HAVE FOCUSED ON
MRI/MRSI ON 1.5 T SYSTEMS
VALUE OF THIS COMBINED APPROACH HAS
BEEN SHOWN IN THE LITERATURE
WHILE ALREADY VALUABLE, COMBINED
MRI/MRSI IS STILL IN ITS INFANCY.
DRAMATIC IMPROVEMENTS IN SPATIAL
RESOLUTION, CHEMICAL SPECIFICITY, AND
BIOLOGIC INFORMATION ARE POSSIBLE
RADIOLOGIC TESTS FOR
PROSTATE CANCER?
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LOCAL STAGING (FOR EXAMPLE, EXTRACAPSULAR
EXTENSION OR SEMINAL VESICLE INVASION) BY
TRUS AND MRI IS FELT TO BE IMPORTANT -DETERMINES WHETHER THE PATIENT GETS
CURATIVE LOCAL THERAPY OR PALLIATIVE
SYSTEMIC THERAPY
LOCATION AND EXTENT OF CANCER WITHIN THE
PROSTATE GLAND IS BECOMING INCREASINGLY
IMPORTANT DUE TO THE EMERGENCE OF FOCAL
PROSTATE CANCER THERAPIES, AND FOR THE
SELECTION AND RISK STRATIFICATION OF PATIENTS
IN CLINICAL TRIALS
MRI Methods
tumor
•
Multi-planar high-resolution T2 weighted images are acquired through the
prostate and surrounding structures in order to assess the location,
spatial extent, and spread of prostate cancer.
•
T1 weighted images are acquired through the prostate gland and pelvis in
order to assess for the presence of post-biopsy hemorrhage within the
prostate gland and metastases to pelvic bones and lymph nodes.
MRI Staging of Prostate Cancer

MRI alone has good
accuracy in detecting
seminal vesicle invasion
(96%).
 Assessment of spread
through the capsule is
more difficult (accuracy 81%), and is getting
harder with fewer men
demonstrating gross
ECE at diagnosis.
Tumor
Tumor
extracapsular
extension
extracapsular
extension
Radiology 1994;193:703-709
MRI Lacks Specificity for Localizing
Cancer within the Prostate;
3D-MRSI Adds Specificity
High Resolution MRI has demonstrated good sensitivity
(79%) but low specificity (55%) in determining tumor
location due to a large number of false positives.
Tumor ?
Citrate
Cho+Cr
Clearly Tumor
Cho
Cr
Radiology 1994;193:703-709
MRSI: Metabolic Identification of Prostate Cancer
Prostate Cancer
–
Increased Choline - cellular
proliferation, cell density, phospholipid
composition and metabolism
–
Decreased Citrate - unique zinc and
citrate metabolism and changes in
ductal morphology
–
Decreased Polyamines - least
understood, possibly related to
proliferation and secretory function
Citrate
Polyamines
Choline
Polyamines
Creatine
Creatine
Choline
Citrate
PPM
3.0
2.5
Cancer
2.0
PPM
3.0
2.5
Healthy
2.0
Interpretation of Combined MRI/MRSI Data
The output of the MRI/MRSI exam are
arrays of 0.3cc spectra and
corresponding high resolution anatomic
images.
The interpretation of the data requires a
knowledge of what constitutes a
useable spectra, how spectra change
with zonal anatomy and age, and other
complicating factors such as postbiopsy hemorrhage, and contamination
from surrounding tissues.
The strength of the exam is when there
is concordance of the anatomic and
metabolic information.
Portion of the 3-D MRSI spectral array
Contamination from Different Tissues Within the
Prostate
creatine
Choline Citrate
Prostate Cancer
A voxel containing both healthy glandular tissue and cancer may
look like this: elevated choline to creatine but normal levels of
citrate
Complications to the Interpretation of Prostate Spectra
Post-biopsy
artifact
T1 WI
At the time of this
previous study, biopsy
hemorrhage was
observed in 28% of
patients studied
biopsy artifact
biopsy artifact
T2 WI
Choline
T2 WI
Cancer
Creatine
Creatine
Choline
Normal Pz
Citrate
Citrate
Radiology 1998;206:785-790
Appearance of Spectra In Regions of Hemorrhage
Patients have demonstrated both metabolic atrophy and changes in their
metabolite levels in regions of extensive hemorrhage, particularly early after
biopsy
3 weeks
after
biopsy
tumor
atrophy
atrophy atrophy
Cho +Cr
citrate
+PA
tumor
tumor
Hemorrhage
Induced Changes in Healthy Tissue
A
T1 weighted MRI
CC/C=0.81
Choline
4 weeks
after biopsy
Citrate
CC/C=0.22
12 weeks
after biopsy
By requiring elevated choline be
present when there is hemorrhage
can reduce over-calling cancer
Choline
5.0
4.0
3.5
3.0
Citrate
2.5
2.0 PPM
Li, ISMRM 2002
MRI/MRSI : Data Summary
Up to 1024 spectra per study - Need for summary images
MRSC/UCSF - Proton MRS Study
1
1
1
3
3
5
4
1
2
3 3
4
5
1
2
4
4 4
3
3
2
5
5
3
3
4 5
4
5
1
4
5
3 3
3
5
4
5 5
3
3
1
1
2
Overlaid
Choline/Citrate
image
3
4
5 3
4
5
5
5 5
3
4
5 3
5 5
1=Def Nor
2=Prob Nor
3=Equivocal
4=Prob Abnor
5=Def Abnor
A=Atrophy
U=Unusable
B=Biopsy Art
Cancer
Normal
Overlaid
Citrate
Choline
Images
Assessment of Cancer Aggressiveness (Grade)
Ratio
Grade 5
(2+3)
Cho+Cr/Cit
8
Citrate
Cho/Norm Cho
Grade 6
(3+3)
Cit/norm. cit
6
4
Grade 7
(3+4)
Choline
2
0
Grade 8
(4+4)
5
6
7
Gleason Score
8
Neoplasia 2000;2(1-2) 166-169
STAGING PREDICTION OF ECE
ROC Analysis (187 patients)
Sensitivity
1
0.75
0.5
MRI/MRSI
TRUS
0.25
Biopsy
0
0
0.25
0.5
1 - Specificity
0.75
1
Localization of Cancer to a Sextant of the
Prostate by MRI/MRSI
MRI/MRSI data can be combined to provide both high
specificity or sensitivity in localizing cancer to a
prostatic sextant depending on the clinical question.
 A specificity of up to 91% was obtained when both MRI and
MRSI were positive for cancer. Add positive sextant biopsy
results - 98%.
 A sensitivity of 95% was obtained when MRI or MRSI
were positive for cancer. With the addition of positive
sextant biopsy, the sensitivity remains high at 94%.
 A significant (P<0.05) improvement in overall accuracy
(≈ 80%) over MRI and biopsy alone.
Journal Urology 2000, 164(2) 400-404; Radiology 1999; 213:473-480
MRI/MRSI: Current Clinical Uses
• Therapeutic Selection - individualized therapy
(≈ 60% of patients)
• Cancer Diagnosis - men with rising PSA but
negative biopsies (≈ 10% of patients)
• Therapeutic Monitoring (≈ 30% of patients)
– Early identification of failure
–Time course of response
Individualized Therapeutic Selection
• MRI/MRSI
C
concordant for
a large volume
of aggressive
cancer with
spread outside
the capsule and
seminal vesicle
invasion
Cho
Cr
•Brachytherapy
alone not
appropriate
Clinical Application: MR Targeted, TRUS-Guided
Biopsies
5
5
5
5
5
The sensitivity of TRUS guided biopsy is
reduced in large prostates and when the
cancer is located in difficult locations such
MRI/MRSI positive
MR targeted TRUS guided biopsy as the apex of the gland or in the anterior
positive
or lateral aspects of the gland
PSA - 12 ng/ml
Two prior negative biopsies
Journal Urology 2000, 164(2) 400-404
Monitoring Therapy: Radiation Therapy
•
The addition of the metabolic information provided by MRSI becomes
even more important after therapy since the contrast between healthy
tissue and cancer is reduced on MRI
•
There is a homogeneous reduction of T2 signal throughout the
prostate gland after radiation therapy causing a loss in the ability to
visualize both prostatic zonal anatomy and cancer
seeds
Tumor
Pre-Therapy
Post-Therapy
MRSI has Demonstrated the Ability to Identify Cancer
Metabolically after Therapy
choline
Creatine
Choline
ppm3.5 3.0 2.5 2.0 1.5
Atrophy or Necrosis
citrate
creatine
citrate
ppm3.5 3.0 2.5 2.0 1.5
ppm3.5 3.0 2.5 2.0 1.5
Benign Tissue
Cancer
Radiology 1996; 200:489-96
Successful Therapy: Complete Metabolic Atrophy
Pre-therapy
Cho
Post-therapy
Citrate
Residual
Water
Metabolic Atrophy = undetectable levels of
all metabolites
Unsuccessful External Beam Radiation Therapy
Cancer
Cancer
Atrophy
Cancer
A T2-weighted MR image and spectral array taken from the midgland of a 55-yearold prostate cancer patient with a current PSA of 0.6 ng/ml who had IMRT in June of
2000. Note the metabolic atrophy consistent with effective therapy in the right side of
the gland, and residual metabolism on the left side of the gland. The presence of
cancer in the left lateral aspect of the prostate gland was subsequently confirmed by
ultrasound guided biopsies.
Unsuccessful Hormone Deprivation Therapy
21 months of combined hormone
deprivation therapy - PSA - 0.4
Biopsy proven residual/recurrent
cancer
Choline
Cr
Metabolic
Atrophy
Time Course of Metabolic Response to Brachytherapy
red = abnormal metabolism
PreTherapy
55 weeks
107 wks
Time-Course of Metabolic Recovery After Cessation of Therapy
1 year after
cessation of
Therapy
77 year old
patient
Gleason
3+4
PSA - 4.5
ng/ml
1 year of
combined
Lupron and
Casodex
PSA at time
of scan - 0.4
ng/ml
Significant
morphologic
and
metabolic
recovery
Metabolic Atrophy
Cho
Citrate
CONCLUSIONS
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MRI/MRSI HAS BEEN ESTABLISHED AS A
POWERFUL IMAGING TECHNIQUE FOR
PRE- AND POST-TREATMENT ANALYSIS
GREAT PROMISE FOR LYMPHOTROPIC
SUPERPARAMAGNETIC
NANOPARTICLES TO ASSESS LYMPH
NODE METASTASES
DCE-MRI IS RELATIVELY NEW IN THE
EVALUATION OF PROSTATE CANCER,
AND ITS CLINICAL UTILITY IS YET TO
BE DETERMINED