Download Combined Magnetic Resonance Imaging and Spectroscopic

JOURNAL OF MAGNETIC RESONANCE IMAGING 16:451– 463 (2002)
Invited Review
Combined Magnetic Resonance Imaging and
Spectroscopic Imaging Approach to Molecular
Imaging of Prostate Cancer
John Kurhanewicz, PhD,* Mark G. Swanson, PhD, Sarah J. Nelson, PhD, and
Daniel B. Vigneron, PhD
Key Words: prostate cancer; citrate; choline; polyamines;
magnetic resonance spectroscopic imaging (MRSI); magnetic
resonance imaging (MRI); HR-MAS; prostate specific antigen
(PSA); hormone deprivation therapy; radiation therapy
J. Magn. Reson. Imaging 2002;16:451– 463.
© 2002 Wiley-Liss, Inc.
Magnetic resonance spectroscopic imaging (MRSI) provides
a noninvasive method of detecting small molecular markers (historically the metabolites choline and citrate) within
the cytosol and extracellular spaces of the prostate, and is
performed in conjunction with high-resolution anatomic
imaging. Recent studies in pre-prostatectomy patients
have indicated that the metabolic information provided by
MRSI combined with the anatomical information provided
by MRI can significantly improve the assessment of cancer
location and extent within the prostate, extracapsular
spread, and cancer aggressiveness. Additionally, pre- and
post-therapy studies have demonstrated the potential of
MRI/MRSI to provide a direct measure of the presence and
spatial extent of prostate cancer after therapy, a measure of
the time course of response, and information concerning
the mechanism of therapeutic response. In addition to detecting metabolic biomarkers of disease behavior and therapeutic response, MRI/MRSI guidance can improve tissue
selection for ex vivo analysis. High-resolution magic angle
spinning (1H HR-MAS) spectroscopy provides a full chemical analysis of MRI/MRSI-targeted tissues prior to pathologic and immunohistochemical analyses of the same tissue. Preliminary 1H HR-MAS spectroscopy studies have
already identified unique spectral patterns for healthy
glandular and stromal tissues and prostate cancer, determined the composition of the composite in vivo choline
peak, and identified the polyamine spermine as a new metabolic marker of prostate cancer. The addition of imaging
sequences that provide other functional information within
the same exam (dynamic contrast uptake imaging and diffusion-weighted imaging) have also demonstrated the potential to further increase the accuracy of prostate cancer
detection and characterization.
Magnetic Resonance Science Center, Department of Radiology, University of California–San Francisco, San Francisco, California
Contract grant sponsor: NIH; Contract grant numbers: R33-CA32610;
R01-CA79980; R01-CA59897; R29-CA64667; F32-CA84774; Contract
grant sponsor: American Cancer Society; Contract grant number:
RPG96-146-03-CCE; Contract grant sponsor: CaPCURE Foundation.
*Address reprint requests to: J.K., Magnetic Resonance Science Center,
1 Irving Street, AC109, Department of Radiology, Box 1290, University
of California–San Francisco, San Francisco, CA. 94143-1290.
E-mail: [email protected]
Received 23 April 2002; Accepted 4 June 2002.
DOI 10.1002/jmri.10172
Published online in Wiley InterScience (www.interscience.wiley.com).
© 2002 Wiley-Liss, Inc.
THE AMERICAN CANCER SOCIETY estimates that
189,000 males will be newly diagnosed with prostate
cancer in the United States in 2002, making it the most
commonly diagnosed noncutaneous cancer among
American men, with an incidence similar to that of
breast cancer (an estimated 203,500 cases) in women
(1). Due to increased prostate cancer screening using
serum prostate-specific antigen (PSA) and transrectal
ultrasound (TRUS) guided biopsy, thousands of prostate cancer patients are being identified at an earlier
and potentially treatable stage (2). However, the decision on how to manage prostate cancer once detected
still poses a great dilemma for both patients and their
clinicians. The dilemma stems from the fact that prostate cancers demonstrate a tremendous range in biologic malignancy, and are treated with a broad spectrum of approaches from “watchful waiting” and
hormone deprivation therapy to aggressive surgical, radiation, and cryosurgical therapies (3,4). Prostate cancer is one of the few cancers that can grow so slowly that
they never threaten the lives of some patients, but at
present this cannot be predicted in individual patients
with current prognostic markers (5– 8). However, if the
cancer does metastasize there is currently no cure and
the cancer becomes lethal, leading to an estimated
30,200 deaths in the United States in 2002 (1). A number of clinical (digital rectal exam (DRE)), pathologic
(histologic grade from biopsy, and number and percentage of positive biopsies) (9), and biochemical parameters in serum (PSA, PAP) (10 –13) and in tissue (MIB-1,
bcl-2, p53, CD34) (14 –19) can aid in assessing the
extent and aggressiveness of the disease. However,
these are often inaccurate or inadequate, particularly
when used alone in individual patients. Additionally,
with early detection, there has also been increased interest in focal “disease-targeted” therapies, including
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Figure 1. Comparison of axial endorectal coil/pelvic phased array FSE prostate images (a) before and (b) after analytic
correction for the reception profiles of the endorectal and pelvic phased array coils. In the corrected image, the high signal
intensity close to the endorectal coil has been removed, allowing for improved visualization of prostate cancer (low T2 signal
intensity, white arrows) compared to adjacent healthy prostate peripheral zone (high T2 signal intensity). Additionally, important
anatomical features such as the prostatic capsule and the step-off angle in the prostatic capsule on the left side of the image (b)
identifying extracapsular spread (black arrow) can be more clearly visualized.
interstitial brachytherapy, intensity-modulated radiotherapy, and focal cryosurgery, which can potentially
reduce treatment-related morbidity and allow patients
to maintain their quality of life (20). These therapies
require an improved knowledge of the location and spatial extent of the disease within the gland. Finally, the
long natural history of prostate cancer and the increasingly younger age of patients at the time of detection
underscores the need for shorter-term endpoints than
survival in order to reduce the duration of therapeutic
trials and the number of patients required (21,22).
New discoveries in the molecular and cellular biology
of prostate cancer present opportunities for the development of noninvasive imaging modalities that could
improve the characterization of prostate cancers in individual patients prior to and after therapy. The use of
a combination of magnetic resonance imaging (MRI)
and magnetic resonance spectroscopic imaging (MRSI)
represents an exciting new approach that is currently
being investigated. Conventional MRI of the prostate
relies on abnormal signal intensities that result from
morphologic changes within the prostate to define the
presence and extent of cancer (23). Unfortunately, the
morphologic changes observed by MRI often do not accurately reflect the presence and spatial extent of active
tumor (23). The addition of metabolic information provided by MRSI complements the morphologic information provided by high-resolution MRI, and improves the
discrimination of cancer from surrounding healthy tissue and necrosis (24). A combined MRI/MRSI exam can
be performed in less than 1 hour using a standard
clinical 1.5 Tesla MR scanner and the same coils used
for MRI. A commercial package has recently been released and will be clinically tested in an upcoming multicenter trial. Since this molecular imaging technique
will soon be more globally available to clinicians, it is
timely to review what is already known about the utility
of combined MRI/MRSI, and describe how it might be
improved and used in the future.
MORPHOLOGIC IDENTIFICATION OF PROSTATE
CANCER—MRI
High-spatial-resolution endorectal-coil T2-weighted
images provide an excellent depiction of prostatic zonal
anatomy, prostate cancer, and surrounding soft tissues
in untreated patients (Fig. 1) (25,26). On T2-weighted
MRI, regions of prostate cancer demonstrate decreased
signal intensity relative to normal peripheral zone tissue due to increased cell density and a loss of the
prostatic ducts (Fig. 1) (23,26). Currently, the prostate
is best imaged using an endorectal coil combined with
four external coils (pelvic phased array) (26). The use of
the body coil for excitation and an endorectal coil/pelvic phased array coil system for signal reception allows
for the acquisition of high-spatial-resolution images of
the prostate as well as coverage to the bifurcation for
assessment of pelvic lymph node and bone metastases
within the same exam. The endorectal coil provides a
⬃10-fold increase in the signal-to-noise ratio (SNR) over
the pelvic phased coil, thereby allowing for the acquisition of both high-resolution images and spectroscopic
data from the prostate. However, the inhomogeneous
reception profiles of the surface coils employed must be
Combined MRI/MRSI of Prostate Cancer
taken into account when interpreting the data. If uncorrected, images exhibit very high intensity close to
the coil and lower intensity further into the prostate
(Fig. 1A). Even with windowing and leveling, it is difficult to interpret such images. One way to address this
problem is to analytically correct the images for the
reception profile of the endorectal coil, thereby eliminating near-field high signal intensity artifacts and producing images in which prostatic zonal anatomy and
pathology can be more easily visualized (Fig. 1B) (24).
Knowledge of the spread of cancer outside the prostate is critical for determining whether focal, systemic,
or a combination of both therapies is required. The use
of T2-weighted fast spin echo imaging (27) and a pelvic
phased-array incorporating an endorectal coil can
markedly improve the evaluation of extracapsular extension (ECE: accuracy ⫽ 81%; sensitivity ⫽ 84%; and
specificity ⫽ 80%) and seminal vesicle invasion (SVI:
accuracy ⫽ 96%; sensitivity ⫽ 83%; and specificity ⫽
98%), thereby improving the staging of prostatic cancer
(26). However, the detection of extracapsular extension
by MRI is becoming more difficult since men are being
diagnosed at earlier stages of disease, and because the
microscopic spread of cancer through the prostatic capsule cannot be directly seen on MR images (23). Additionally, there still remains great variability in the reported staging accuracy of endorectal/phased array
MRI between individual readers. One recent study reported an overall staging accuracy of 93% and 56% for
two different readers within the same study (28). Although inter-reader variability can be due to differences
in reader experience and subjectivity, the addition of
objective metabolic criteria provided by MRSI has been
demonstrated to decrease this inter-reader variability
(29).
In addition to staging, the assessment of prostate
cancer location and extent is becoming increasingly
important due to the emergence of disease-targeted
therapies such as interstitial brachytherapy, intensitymodulated radiotherapy, and cryosurgery. Studies
evaluating clinical data (DRE, PSA, and PSA density),
systematic biopsy, TRUS, and MRI alone have so far
shown disappointing results for tumor localization
within the prostate (30 –33). High-resolution endorectal/pelvic phased array MRI has demonstrated good
sensitivity (78%) but low specificity (55%) in tumor location due to a large number of false-positives (26).
These false-positives can be attributed to factors other
than cancer, including post-biopsy hemorrhage, prostatitis, and therapeutic effects, which cause low signal
intensity on T2-weighted images similar to that of prostate cancer (33,34). The addition of highly cancer-specific metabolic information to the sensitivity of MRI has
resulted in a significant improvement in the overall
accuracy of cancer localization to a sextant of the prostate (35).
METABOLIC IDENTIFICATION OF PROSTATE
CANCER—MRSI
As with MRI, MRSI uses a strong magnetic field and
radiowaves to noninvasively obtain metabolic information (spectra) based on the relative concentrations of
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endogenous chemicals (metabolites) that exist in the
cytosol of the cell and in extracellular ducts. With prostate MRSI, the large tissue water and lipid signals must
be suppressed in order to detect the prostatic metabolites citrate, choline, creatine, and polyamines that are
present in much lower concentrations (36 –39). The
technology required for the robust acquisition of MRSI
data from the prostate has just become available and
requires very accurate volume selection (36,37) and
efficient outer volume suppression (38). The resonances for citrate, choline, creatine, and polyamines
occur at distinct frequencies or positions in the spectrum, although the peaks for choline, creatine, and
polyamines overlap at 1.5T (Fig. 2D and E). The areas
under these resonances are related to the concentration of the respective metabolites, and changes in these
concentrations can be used to identify cancer with high
specificity (39). Specifically, in spectra taken from regions of prostate cancer (Fig. 2D), citrate and polyamines are significantly reduced or absent, while choline is elevated relative to spectra taken from
surrounding healthy peripheral zone tissue (Fig. 2E).
MRSI produces arrays of contiguous volumes (0.24 –
0.34 cc voxels) that can map the entire prostate, and
because MRSI and MRI are acquired within the same
exam, the data sets are already in alignment and can be
directly overlaid (Figs. 2–7) (39). In this way, areas of
anatomic abnormality (decreased signal intensity on
T2-weighted images) can be correlated with the corresponding area of metabolic abnormality (increased choline, and decreased citrate and polyamines). It is the
concordance of MRI and multiple metabolic changes
observed by MRSI that leads to the most confident identification of cancer (35,40). Additionally, since threedimensional, volume MRI and MRSI data are collected,
the data can be viewed in any plane (axial, coronal, or
sagittal) (Fig. 3), and the position of spectroscopic voxels can be retrospectively changed to better examine a
region of abnormality on MRI after the data is acquired
(Fig. 4). This method of interactive analysis will be the
way that MRI/MRSI data is used in the future and
should reduce interpretative errors associated with the
overlap of normal and cancerous tissues.
One of the strengths of prostate spectroscopy is that
many of the biochemical mechanisms that result in the
observed metabolic changes are now known and correlate with stage of carcinogenesis and response to therapy. Healthy prostate epithelial cells possess the
unique ability to synthesize and secrete enormous
quantities of citrate (41). The decrease in citrate with
prostate cancer is due to changes in both cellular function (41,42) and the organization of the tissue, resulting
in a loss of its characteristic ductal morphology (43,44).
Biochemically, the loss of citrate in prostate cancer is
intimately linked with changes in zinc levels that are
extraordinarily high in healthy prostate epithelial cells
(45,46). In healthy prostatic epithelial cells, the presence of high levels of zinc inhibits the enzyme aconitase,
thereby preventing the oxidation of citrate in the Krebs
cycle. Consequently, high levels of citrate are observed
in the MRSI spectra of healthy glandular prostate tissues. Zinc levels are dramatically reduced in prostate
cancer, and the malignant epithelial cells demonstrate
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Figure 2. a: A representative reception-profile corrected T2-weighted FSE axial image taken from a volume data set demonstrating a large tumor in the right midgland to base (same patient as in Fig. 1). The selected volume for spectroscopy (bold white
box) and a portion of the 16 ⫻ 8 ⫻ 8 spectral phase-encode grid from one of eight axial spectroscopic slices is shown overlaid (fine
white line) on (b) the T2-weighted image with (c) the corresponding 0.3 cm3 proton spectral array. Spectra in (d, red box) regions
of cancer demonstrate dramatically elevated choline, and a reduction or absence of citrate and polyamines relative to (e, green
box) regions of healthy peripheral zone tissue. In this fashion, metabolic abnormalities can be correlated with anatomic
abnormalities from throughout the prostate. The strength of the combined MRI/MRSI exam is demonstrated when changes in
all three metabolic markers (choline, polyamines, and citrate) and imaging findings are concordant for cancer. The focus of
future studies will be to increase the number of metabolic markers and to better understand the cause of these changes through
correlation with earlier protein and genetic changes.
a diminished capacity for net citrate production and
secretion (45,46). There exists strong evidence that the
loss of the capability to retain high levels of zinc is an
important factor in the development and progression of
malignant prostate cells (45,46). It is also believed that
the transformation of prostate epithelial cells to citrateoxidizing cells, which increases energy production capability, is essential to the process of malignancy and
metastasis (47).
As in other human cancers, the elevation of the choline peak in prostate cancer is associated with changes
in cell membrane synthesis and degradation that occur
with the evolution and progression of cancer (48,49).
Phosphatidylcholine is the most abundant phospholipid in biological membranes, and together with other
phospholipids, such as phosphatidylethanolamine and
neutral lipids, it forms the characteristic bilayer struc-
ture of cells and regulates membrane integrity and
function (50,51). High-resolution 31P and 1H NMR studies of surgical prostate cancer tissue extracts have
demonstrated that many of the compounds involved in
phosphatidylcholine and phosphatidylethanolamine
synthesis and hydrolysis (choline, phosphocholine,
glycerophosphocholine, ethanolamine, phosphoethanolamine, and glycerophosphoethanolamine) contribute to the magnitude of the in vivo “choline” resonance
(52–56). There is also evidence that changes in the cytosolic levels of these phospholipid metabolites correlate with cellular proliferation (57– 60) and cellular differentiation (61– 63). Additionally, changes in epithelial
cell density can also contribute to the observed increase
in the “in vivo” choline resonance in prostate cancer,
since densely packed malignant epithelial cells replace
the normal ductal morphology, forming prostate cancer
Combined MRI/MRSI of Prostate Cancer
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Figure 3. a: Coronal T2-weighted FSE image of the same prostate cancer patient shown in Fig. 2. b: Coronal image with overlying
spectroscopic selected volume (bold white box) and phase-encode grid (fine white line) taken from a portion of the 3-D array of
spectra and (c) corresponding 0.3-cm3 proton spectra. The coronal slice is taken at the level of the peripheral zone, and
MRI/MRSI (red arrows and outlined grid) are concordant for a large volume of tumor involving all of the right peripheral zone
from apex to base and extending into the right seminal vesicles (black arrows). The metabolic pattern in the region of cancer is
characteristic of a high Gleason score.
nodules that are often palpable by digital rectal examination (44). In more recent high-resolution NMR studies of human prostate cell extracts, strong evidence was
provided associating elevated phosphocholine and glycerophosphocholine in prostate cancer with altered
phospholipid metabolism and not simply to increased
cell density, doubling time, or other nonspecific effects
(64).
Another strength of prostate spectroscopy is that
multiple metabolic changes occur within the same voxels that indicate the presence of cancer. Historically,
two metabolic markers (choline and citrate) have been
relied upon for the metabolic detection of prostate cancer (65). However, high-resolution NMR studies of ex
vivo prostatic tissues have identified several new metabolic markers for prostate cancer, including polyamines, myo-inositol, scyllo-inositol, and taurine
(53,55,56,66 –70). Of these the most promising are the
polyamines, which appear very elevated in spectra of
healthy prostatic peripheral zone tissues and predominantly glandular benign prostatic hyperplasia (BPH),
and dramatically reduced in prostate cancer (67,70).
Similar to changes in choline-containing compounds,
changes in cellular polyamine levels have been associated with cellular differentiation and proliferation
(71,72). Moreover, it has recently been demonstrated
that the loss of polyamines in regions of cancer can be
detected by MRSI as an improvement in the resolution
of the choline and creatine peaks (Fig. 2D) (73). Studies
are under way to determine how the addition of this
metabolic change further improves the detection and
characterization of prostate cancer.
CURRENT CLINICAL FINDINGS
Over the past decade, thousands of prostate cancer
patients have received combined MRI/MRSI exams.
Many of these patients subsequently underwent radical
prostatectomy, thereby providing a “gold standard”
(i.e., step-section histopathology of the resected gland)
for determination of the utility and accuracy of combined MRI/MRSI in the assessment of prostate cancer.
The following studies in pre-prostatectomy patients
provide compelling evidence of the clinical potential of
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Figure 4. a: A T2-weighted weighted axial image and corresponding spectral array from the apex of a patient who had an
elevated PSA (6.0 ng/ml) but negative prior biopsy. A small focus of low T2 signal intensity in the left peripheral zone indicated
cancer. The MRSI spectral array was not optimally aligned with the peripheral zone and the MRI abnormality was split between
two voxels, yielding a borderline metabolic abnormality. b: During postprocessing the spectral array was shifted downward such
that the MRI abnormality was centered in a spectroscopic voxel (red box) yielding a clear-cut metabolic abnormality
(choline⫹creatine)/citrate peak area ratio greater then 3 SDs above normal values. A subsequent TRUS-guided biopsy confirmed
the presence of cancer.
combined MRI/MRSI for the improved characterization
of prostate cancer in individual patients.
Improved Prostate Cancer Staging Using
Combined MRI/MRSI
MRI alone has good accuracy in detecting seminal vesicle invasion (96%; Fig. 3) (26). However, the assessment of cancer spread through the prostatic capsule is
more difficult (81% accuracy) (26) and is becoming even
harder to assess as fewer men demonstrate gross cancer spread (directly visible on MRI) due to earlier cancer
detection. In a recent study of 53 patients with earlystage prostate cancer, tumor volume estimates based
on MRSI findings were combined with high-specificity
MRI criteria (74) in order to assess the ability of combined MRI/MRSI to predict extracapsular cancer
spread. This study was based on prior histopathologic
studies that demonstrated that tumor volume was a
significant predictor of extracapsular extension (ECE)
of prostate cancer (75,76). It was found that tumor
volume per lobe estimated by MRSI was significantly
(P ⬍ 0.01) higher in patients with ECE (2.14 ⫾ 2.3 cm3)
than in patients without ECE (0.98 ⫾ 1.1 cm3) (29).
Moreover the addition of an MRSI estimate of tumor
volume to high-specificity MRI findings for ECE (74)
improved the diagnostic accuracy and decreased the
inter-observer variability of MRI in the diagnosis of extracapsular extension of prostate cancer (Fig. 2) (29). In
a recent study of 37 patients prior to radical prostatectomy, it was demonstrated that the addition of MRSI to
MRI increases the overall accuracy of prostate cancer
tumor volume measurement, although measurement
variability still limits consistent quantitative tumor volume estimation, particularly for small tumors (⬍0.5
cm3) (77).
Improved Intraglandular Cancer Localization
Using Combined MRI/MRSI
It has been demonstrated that the high specificity of
MRSI to metabolically identify cancer can also be used
to improve the ability of MRI to identify the location and
extent of cancer within the prostate (35). A study of 53
Combined MRI/MRSI of Prostate Cancer
457
Figure 5. a: A representative reception profile corrected T2-weighted MR image taken from the midgland of a 55-year-old
prostate cancer patient with a current PSA of 0.6 ng/ml who had received intensity-modulated radiation therapy in June 2000.
A portion of the 16 ⫻ 8 ⫻ 8 spectral phase-encode grid from one of eight axial slices is shown overlaid on (a) the T2-weighted
image with (b) the corresponding 0.3 cm3 proton spectral array. The presence of cancer in the left lateral aspect of the prostate
(right side of image) was subsequently confirmed by ultrasound-guided biopsies.
biopsy-proven prostate cancer patients prior to radical
prostatectomy and step-section pathologic examination
demonstrated a significant improvement in cancer localization to a prostatic sextant (left and right— base,
midgland, and apex) using combined MRI/MRSI vs.
MRI alone (35). A combined positive result from both
MRI and MRSI indicated the presence of tumor with
high specificity (91%), while high sensitivity (95%) was
attained when either test alone indicated the presence
of cancer (Figs. 2– 5) (35). In another recent study it was
found that the addition of a positive sextant biopsy
finding to concordant MRI/3D MRSI findings further
increased the specificity (98%) of cancer localization to
a prostatic sextant, whereas high sensitivity (94%) was
again obtained when any of the tests alone were positive
for cancer. Both of these studies used only the (choline ⫹ creatine)/citrate ratio to metabolically detect
prostate cancer. The addition of other metabolic ratios
(choline/creatine, citrate/normal citrate) as well as the
addition of new metabolic markers, such as polyamines, offers the possibility of further increasing the
accuracy of the metabolic assessment of cancer within
the prostate.
Assessment of Prostate Cancer Aggressiveness
MRSI information may also provide new insights into
tumor aggressiveness, which may lead to improved risk
assessment for patients with prostate cancer (24). In a
preliminary MRI/MRSI study of 26 biopsy-proven prostate cancer patients prior to radical prostatectomy,
spectroscopic voxels were shifted in postprocessing to
be within a region of cancer as defined by step-section
pathology and T2-weighted MRI. Spectra obtained from
these voxels demonstrated a linear correlation between
the magnitude of the decrease of citrate and the elevation of choline with the pathologic Gleason score. The
magnitude of the elevation of choline was the most
significant predictor of the Gleason score, with choline
being significantly (P ⬍ 0.0001) higher in high grade
(Gleason 7 ⫹ 8) vs. moderate grade (Gleason 5 ⫹ 6)
cancers (78).
CURRENT CLINICAL APPLICATIONS
In untreated patients, the improved intraglandular
cancer localization, staging, and assessment of cancer
aggressiveness provided by combined MRI/MRSI are
currently being used in two main ways. The primary
reason for patient referral for MRI/MRSI has been for
improved therapeutic selection. A representative example of MRI/MRSI having an impact on therapeutic selection is provided by a patient who was considering
“watchful waiting.” This patient had a PSA of 4.7 ng/ml
(7.5% free PSA) and two of six biopsy cores positive for
Gleason (3 ⫹ 3) and (3 ⫹ 4) prostate cancer in the right
lobe (Figs. 1–3). Based upon just these clinical and
pathologic findings, watchful waiting appeared to be a
plausible option. However, MRI/MRSI findings were
concordant for a large volume of abnormality involving
almost the entire right peripheral zone (left side of image) from apex to base (Fig. 3). The metabolic abnormality consisted of an almost complete loss of citrate
and polyamines, and a very elevated choline-to-creatine
ratio (Cho:Cr ⫽ 5 to 10), and corresponded to a region of
low signal intensity on T2-weighted MRI. Based on the
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Kurhanewicz et al.
Figure 6. a: T2-weighted image and corresponding 0.3-cm3 spectral array from a 77-year-old patient with bilateral Gleason 3⫹4
cancer after 1 year of combined (Lupron and Casodex) hormone deprivation therapy. PSA was 0.4 ng/ml at the time of the
MRI/MRSI scan. b: A corresponding T2-weighted image and spectral array from the same patient 1 year after cessation of
hormone deprivation therapy. Metabolism and PSA (4.5 ng/ml) have significantly recovered, and bilateral recurrent cancer is
identified by MRSI.
large volume of aggressive-appearing cancer on MRSI
and capsular irregularity on MRI, extracapsular extension of cancer was predicted (Fig. 2). There was also
MRI evidence of seminal vesicle invasion (Fig. 3). Based
on these findings it was decided that the patient should
receive a combination of hormone deprivation and external beam radiation therapy as soon as possible.
Another important group of patients being referred
for an MRI/MRSI exam prior to therapy is comprised of
men who have elevated or rising PSA levels but negative
TRUS-guided biopsies. These patients tend to have very
enlarged central glands due to BPH, which present
sampling problems for TRUS-guided biopsies, or they
have cancers in locations that are difficult to biopsy,
such as the apex (79). In a preliminary study it was
found that MRI/MRSI targeting of cancer in these patients can significantly increase the positive yield of
subsequent TRUS-guided biopsies (80). An example of
such a patient is shown in Fig. 4. The patient had a PSA
of 6.0 ng/ml at the time of the scan, which was up from
a PSA of 3.8 ng/ml 1 year prior to the scan, and had a
prior negative biopsy. A very small region of clear-cut
metabolic abnormality corresponding to a small focus
of low T2-weighted MRI signal was observed in the left
lateral aspect of the apex abutting the prostatic capsule. A subsequent TRUS-guided biopsy confirmed
prostate cancer (Gleason score ⫽ 3 ⫹ 3, 10% of core) in
this region. A study is currently under way to determine
the value of MRI/MRSI targeting of cancer, compared to
a second systematic TRUS-guided biopsy without MRI/
MRSI targeting, in a large cohort of patients with prior
negative biopsies.
Growing numbers of patients receiving MRI/MRSI
are referred for suspected local cancer recurrence after
Combined MRI/MRSI of Prostate Cancer
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Figure 7. a T2-weighted MRI image and b: in vivo MRSI spectrum concordant for the presence of prostate cancer at the right
base (left side of image). c Ex vivo 1H HR-MAS spectrum. d H&E stain, and e MIB-1 immunohistochemical stain of a single piece
of prostate cancer tissue (Gleason 3 ⫹ 3) resected from this region.
various therapies (hormonal deprivation therapy, radiation therapy, cryosurgery, and radical prostatectomy).
Recurrent cancer is typically suspected in these patients due to a detectable or rising PSA. However, the
use of PSA testing to monitor therapeutic efficacy is not
ideal, since PSA is not specific for prostate cancer. Additionally, it can take 1–2 years or more for PSA levels to
reach nadir values following radiation therapy (both
external beam and brachytherapy) (81,82). Further, the
interpretation of PSA data is more complicated for patients undergoing therapies, such as hormone deprivation therapy, that have a direct effect on the production
of PSA. Conventional imaging methods, including
TRUS, computed tomography (CT) and MRI, often cannot distinguish healthy from malignant tissue following
therapy because of therapy-induced changes in tissue
structure (83,84). The only definitive way to determine
whether residual or recurrent tissue is malignant is the
histologic analysis of random biopsies, which are subject to sampling errors and are more difficult to pathologically interpret after therapy.
Studies have indicated that MRI/MRSI can discriminate residual or recurrent prostate cancer from normal
and necrotic tissue after cryosurgery (39,85,86). In a
study of 25 patients before and after cryosurgery, histologically confirmed necrotic tissue (N ⫽ 432 voxels)
demonstrated a loss of all observable prostatic metabolites, while the (choline ⫹ creatine)/citrate ratio in
regions of histologically confirmed benign prostatic hyperplasia (0.61 ⫾ 0.21, N ⫽ 52 voxels) and cancer (2.4 ⫾
1.0, N ⫽ 65 voxels) after cryosurgery were not significantly different from those observed prior to therapy,
but were significantly different from each other. These
initial studies suggested that MRSI could discriminate
successful therapy (complete loss of prostatic metabolites) from residual disease. Subsequent studies have
indicated that MRSI can also detect residual disease
after unsuccessful hormone deprivation therapy
(87,88) and radiation therapy (89). Figure 5 shows an
example of a patient with biopsy-proven cancer in the
left lobe, who had a PSA of 0.6 ng/ml at the time of the
MRI/MRSI exam, which was almost 3 years after intensity modulated radiation therapy was administered.
Consistent with effective radiation therapy, many spectroscopic voxels (left side of image) demonstrate a complete loss of all prostate metabolites (metabolic atrophy). However, on the right side of the image, several
spectroscopic voxels demonstrate abnormal prostatic
metabolism ((choline ⫹ creatine)/citrate ⬎ 3 SD above
normal values). This region of abnormal metabolism
was later confirmed by biopsy to be residual cancer.
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In addition to the potential of MRI/MRSI to provide a
direct measure of the presence and spatial extent of
prostate cancer after therapy, there is evidence that
MRI/MRSI can provide a measure of the time course of
response and information concerning the mechanism
of therapeutic response (88). For example, prostatic
citrate production and secretion have been shown to be
regulated by testosterone and prolactin (42), and an
early dramatic reduction of citrate after initiation of
complete hormonal blockade has been observed by
MRSI (88). Additionally, there is a time-dependent loss
of all prostatic metabolites in both regions of cancer and
healthy tissue following the initiation of hormone deprivation therapy (88). This finding is consistent with the
increased frequency of tissue atrophy that occurs with
increasing duration of hormone deprivation therapy,
and is considered to be a indicator of effective therapy
(90). An example of the morphologic and metabolic consequences of long-term (12 months) complete hormone
deprivation therapy (Lupron and Casodex) in a prostate
cancer patient is shown in Fig. 6A. On MRI, the entire
peripheral zone demonstrates diffuse low signal intensity, making identification of zonal anatomy and pathology very difficult. On MRSI, there was a complete
loss of signals from all prostatic metabolites (metabolic
atrophy).
Moreover, recent studies of patients on intermittent
hormone deprivation therapy have demonstrated that
the time course of metabolic recovery after cessation of
therapy can also be monitored by MRI/MRSI. As shown
in Fig. 6B, which is the same patient as shown in Fig.
6A 1 year after cessation of hormone deprivation therapy, significant recovery of prostatic zonal anatomy on
MRI and a recovery of metabolism on MRSI were observed. Additionally, recovery of bilateral metabolic abnormalities consistent with biopsy findings prior to
therapy was observed. Studies are currently under way
to investigate the accuracy of MRI/MRSI in assessing
the presence and spatial extent of prostate cancer after
these therapies (87); the prognostic value of the time
course to metabolic atrophy; the duration of undetectable metabolism; and the rate of metabolic recovery,
particularly of cancer. The detection of residual cancer
at an early stage following treatment, and the ability to
monitor the time course of therapeutic response would
allow earlier intervention with additional therapy and
provide a more quantitative assessment of therapeutic
efficacy.
FUTURE DIRECTIONS
The studies described above provide compelling evidence that the addition of MRI/MRSI data to PSA and
biopsy data can improve the characterization of prostate cancer in individual patients prior to therapy and
provide information about its response to therapy.
However, as promising as this may seem, there are
currently only a few academic medical centers worldwide that have experience with this new technology. In
the next stage, MRI/MRSI must be implemented and
validated at multiple institutions, and large-scale patient studies must be performed to determine the true
clinical value of MRI/MRSI for the improved manage-
Kurhanewicz et al.
ment of prostate cancer patients. There is also a clinical
need to further improve the sensitivity and specificity of
prostate cancer detection and characterization, particularly for small tumors and early-stage disease.
There are several new applications of MRI/MRSI that
are currently under investigation. One area of great
potential is the use of MRI/MRSI for improved radiation
treatment planning. The motivation for MRI/MRSI
treatment planning is that non-contrast CT overestimates the volume of the prostate as compared to MRI,
and is inadequate for identifying the complex anatomy
of the prostate (91). MR images obtained using a pelvic
phased array and endorectal coil provide improved definition of the prostate, its complex zonal anatomy, and
important surrounding structures. The integration of
this information into the treatment plan has the potential to reduce the dose delivered to anatomic structures
close to the prostate (i.e., the rectum, bladder, and
neurovascular bundles) and hence decrease the incidence of damage to normal tissue. MRI, MRSI, and
biopsy results can also be used to define the distribution of dominant intraprostatic lesions (DILs) within the
prostate (79). Two recent studies indicated the potential
of MRI/MRSI data in combination with CT to optimize
radiation dose selectively to regions of prostate cancer
using either intensity modulated radiotherapy (IMRT)
(92) or brachytherapy (93).
Another area of recent work is the use of MRI/MRSI
to improve tissue selection for ex vivo spectroscopic
analysis. Previous ex vivo high-resolution nuclear magnetic resonance (NMR) studies of human prostate tissues have involved relatively blind tissue sampling and
required laborious tissue extraction procedures. In a
preliminary study, prostate cancer was identified in 25
out of 25 samples targeted using presurgical MRI/MRSI
data (69). This study indicates that MRI/MRSI guidance can significantly improve the quality of tissue
samples used for biomarker discovery. Tissue extraction was previously necessary because the motional
restriction of the molecules in the intact tissue results
in extreme spectral broadness under normal spinning
conditions. Two major drawbacks of tissue extraction
are that 1) the tissue is completely destroyed, preventing any subsequent histopathologic analysis; and 2)
labile metabolites can be lost during the extraction process. Solid-state “magic angle spinning” (MAS) NMR
techniques have existed for decades; however, they
have only recently been applied to intact tissues
(94,95). By spinning the sample at a fast rate (ⱖ2 kHz)
and a specific angle (␪ ⫽ 54.7°), MAS dramatically reduces chemical shift anisotropy and dipole-dipole interactions such that solution-like spectra with narrow
linewidths can be obtained. Since HR-MAS spectroscopy is nondestructive, samples can subsequently undergo histopathologic, immunohistochemical, genetic,
or other analyses, thereby providing the previously
missing link between the pathologic, biochemical, and
metabolic assessment of prostate cancer. As shown in
Fig. 7, elevation of the composite in vivo choline resonance is due to significant increases in phosphocholine, glycerophosphocholine, and choline. Additionally,
dramatic reductions in citrate and polyamines have
been observed in cancer as compared to normal periph-
Combined MRI/MRSI of Prostate Cancer
eral zone tissues. Ongoing studies are aimed at identifying new metabolic markers of prostate cancer and
correlating metabolic patterns with specific tissue
types, as well as markers for cellular proliferation (MIB1), apoptosis (p53), and angiogenesis (53,55,56,66 –70).
Future studies are required to determine whether metabolic changes can be correlated with specific protein or
genetic changes. Additionally, continuing improvements in MR technology, such as higher magnetic field
clinical scanners (3–7 Tesla), will allow the exploitation
of new metabolic markers in patients, and will also
allow the acquisition of MRI/MRSI with higher spatial
resolution, and the visualization of even finer anatomic
and metabolic details.
The addition of other types of imaging sequences that
provide additional functional information within the
same exam should further increase confidence in prostate cancer detection and characterization. The enhancement of prostate cancer during the first pass of
contrast with fast dynamic imaging can provide valuable information concerning prostate cancer microvascularity and angiogenesis (96 –101). Regions of prostate
cancer, particularly high-grade tumors, have been
characterized by early and rapidly accelerating enhancement and faster rates of wash-out compared to
surrounding tissues.
Additionally, several recent studies (102,103) have
demonstrated the feasibility of performing single-shot
echo-planar imaging (EPI)-based diffusion-weighted
imaging of the prostate, and the potential of this technique to identify cancer in the peripheral zone based on
a significant reduction in the apparent diffusion coefficient (ADC). Another recent study (104) has demonstrated that a single-shot Fast Spin Echo/Rapid Acquisition with Relaxation Enhancement (FSE/RARE)
diffusion tensor imaging sequence could produce images superior in quality to EPI sequences, and that both
the ADC and anisotropy were observed to be significantly different for biopsy-confirmed cancer as compared to the normal peripheral zone (104). Future studies will need to address the incremental value of these
new functional parameters when added to an MRI/
MRSI patient exam.
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