Magnetic Resonance Anatomic and Spectroscopic Imaging of Prostate Cancer – Current Status

John Kurhanewicz, Christopher K. Sotto and Fergus Coakley
Department of Radiology, University of California San Francisco
Edited from PCRI Insights November, 2006 vol. 9 no. 4

Magnetic Resonance Imaging (MRI)

Development of Magnetic Resonance Imaging (MRI) as a clinically useful technique for the assessment of prostate cancer has been a major focus at the University of California San Francisco and other medical universities since the mid-1980s.11-15 MR images, especially high spatial-resolution endorectal coil MR images, provide an excellent depiction of prostatic anatomy with regions of healthy prostate tissue demonstrating higher signal intensity than prostate cancer (Figure 1).11-15 This reduction in MR image signal intensity is due to a loss of the normal glandular (ductal) morphology in regions of prostate cancer. However, other benign pathologies (e.g. inflammation, stromal BPH) and therapy also cause a loss of ductal morphology and low signal intensity on MRI.16 Additionally, infiltrating prostate cancer may not cause a reduction in normal glandular morphology and therefore will not be hypointense on MRI.16 Due to these confounding factors, MRI alone has demonstrated good (78%) sensitivity (few false negatives) but poor (55%) specificity (many false positives) in detecting cancer in the prostate.17

Figure 1. Consecutive 3 mm axial reception-profile corrected T2 weighted FSE images from the seminal vesicles through the apex of the prostate. We observe a large volume of hypointensity in the left lobe extending from the base to the apex of the prostate (red arrows).The black arrows indicate suspected extracapsular extension.

The role of MRI in prostate cancer has chiefly been the staging, or assessing the extent of disease, rather than the primary diagnosis of cancer. MRI alone has been shown to have good accuracy in detecting seminal vesicle invasion (96%).17 The assessment of cancer spread through the prostatic capsule (extracapsular extension, or ECE) is more difficult (accuracy - 81%).17 Cancer spread is becoming even harder to assess now as fewer men demonstrate gross cancer spread (directly visible on MRI) due to earlier cancer detection. At 1.5 Tesla (T) MRI, it has been demonstrated that anatomical features on MRI, such as bulging of the prostate, obliteration of the rectoprostatic angle, and asymmetry of the neurovascular bundle, could predict ECE, with a high specificity (up to 95%) but with low sensitivity (38%).18

Magnetic Resonance Spectroscopic Imaging (MRSI)

Performed in conjunction with high-resolution anatomic imaging (MRI), Magnetic Resonance Spectroscopic Imaging (MRSI) provides a non-invasive method of detecting small molecular markers (choline containing metabolites, polyamines and citrate) within the cytosol and extracellular spaces of the prostate. On MRSI spectra, the resonances for choline, creatine, polyamines and citrate occur at distinct frequencies (approximately 3.2, 3.0, 3.1 and 2.6 ppm, respectively) or positions in the spectrum, despite the fact that the peaks for choline, creatine and polyamines overlap in regions of healthy prostate tissue due to the presence of high levels of the polyamine spermine in healthy glandular prostate tissue (Figure 2C). The areas under these signals are related to the concentration of the respective metabolites, and changes in these concentrations can be used to identify cancer with high specificity.3,19 Especially, in spectra taken from regions of prostate cancer (Figure 2D), citrate and polyamines are significantly reduced or absent, while choline is elevated relative to spectra taken from surrounding healthy peripheral zone tissue (Figure 2C). The morphologic and biochemical causes of these metabolic changes are fairly well understood and have been discussed in a recent review article.20

Figure 2. (A) The reception-profile corrected T2 weighted FSE axial image taken from the volume data set shown in Figure 1 demonstrates a large region of hypointensity in the right midgland (red arrows) with suspected ECE (black arrow).The selected volume for spectroscopy (bold white box) and a portion of the 16x8x8 spectral phase encode grid overlaid (fine white line) on the T2 weighted image (B) corresponds to the 0.3 cm3 proton spectral array (E).Spectra in regions of cancer (D, red box) demonstrate dramatically elevated choline, an absence of citrate and polyamines relative to regions of healthy peripheral zone tissue (C). In this fashion, metabolic abnormalities can be correlated with anatomic abnormalities from throughout the prostate. The strength of the combined MRI/MRSI exam is when changes in all three metabolic markers (choline, polyamines and citrate) and imaging findings are concordant for cancer.

MRSI produces arrays of contiguous spectra from 0.34 cc volumes that can map the entire prostate (Figure 2E); because MRSI and MRI are acquired within the same exam, the data sets are already in alignment and can be directly overlaid (Figures 2B and 2E). 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). The concordance of abnormal MRI/MRSI findings yields the best overall accuracy in detecting and localizing cancer within the prostate.20

Combined MRI/MRSI – Current Clinical Findings

There are several commercial packages that now allow the acquisition of MRI/MRSI on a clinical 1.5T scanner, utilizing the commercially available MEDRAD (MedRad, Inc. - Pittsburgh, PA) endorectal coil combined with a pelvic or torso phased array. Increasing numbers of studies are currently being performed around the world with the release of commercial MRI/MRSI packages. Many of these studies have involved patients who subsequently underwent radical prostatectomies, thereby providing a step-section histopathology of the resected gland for determining the utility and accuracy of combined MRI/1H MRSI in the assessment of prostate cancer in individual patients.

MRI/MRSI – Detection and Intraglandular Cancer Localization

In clinical practice, reliable detection and localization of often small regions of prostate cancer is of increasing therapeutic importance due to the emergence of “active surveillance” and focal ablative therapy such as interstitial brachytherapy, intensity-modulated radiotherapy (IMRT), high-intensity focused ultrasound (HIFU) and cryosurgery.21 Such focal treatments hold out the promise of substantially reducing the morbidity associated with treating the entire prostate, whether by surgery or radiation. In addition, tumor localization has been related to the risk of post-prostatectomy tumor recurrence, with a higher risk when surgical margins are positive at the base than at the apex.19 It has been demonstrated that the high specificity of MRSI to metabolically identify cancer can be used to improve the ability of MRI to identify the location and extent of cancer within the prostate.1,3,19,22-24

A study of 53 biopsy-proven prostate cancer patients performed prior to radical prostatectomy and step-section pathologic examination demonstrated a significant improvement in cancer localization to a prostatic sextant biopsy (left and right x base, midgland, and apex) using combined MRI/MRSI versus MRI alone. A combined positive result from both MRI and MRSI detected the presence of tumor with high specificity (91%) while high sensitivity (95%) was attained when either test alone indicated the presence of cancer.3 In another study, it was found that the addition of a positive sextant biopsy finding to concordant MRI/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.19

However, more recent studies in early-stage prostate cancer patients have indicated that combined 1.5 MRI/MRSI does poorly at detecting and localizing small low-grade tumors.10,22,24 One recent study demonstrated that overall sensitivity of MR spectroscopic imaging was 56% for tumor detection, increasing from 44% in lesions with a Gleason score of 3 + 3 to 89% in lesions with Gleason score greater than or equal to 4 + 4.10

The inability to detect small low-grade tumors by MRSI (with its relatively coarse spatial resolution of 1.5T MRSI (0.34 cc, ~7mm on a side) is primarily due to the partial voluming of surrounding benign tissue in spectroscopic volumes containing cancer.

MRI/MRSI – Tumor Volume Estimation

In pathology, interest has focused on tumor volume as an important independent parameter of tumor biology. Several investigators have suggested tumor volume is the “missing link” in understanding the natural history of prostate cancer. They hypothesize prostate cancer begins as a small well-differentiated tumor that becomes larger and less differentiated over time.25 The finding that larger tumors are more likely to be of an advanced stage supports this hypothesis. In a study of 104 patients with prostate cancer, the percentage of patients with extracapsular extension ranged from 31% in those with a tumor volume less than 4 ml to 48% in those with a tumor volume greater than 12 ml.26 This view is also supported by a study of 379 patients in which multivariate analysis showed tumor volume, but not pathologic stage or baseline PSA level, was independently predictive of post-prostatectomy disease recurrence.27 This suggests that measurement of prostate cancer tumor volume may provide information on prognosis that is independent of direct morphologic assessment of extracapsular extension. This has important implications for the potential prognostic role of imaging in prostate cancer, since: “it is beyond the capability of any current imaging study to detect microscopic local tumor extension”.28

We recently investigated the estimation of prostate cancer tumor volume by endorectal MRI and MRSI in 37 patients who were scanned prior to radical prostatectomy.24 Two independent readers recorded the peripheral-zone tumor nodule location and volume, both by planimetry on MRI and by recording the number of abnormal voxels (elements of volume picture) on MRSI. Results were analyzed using step-section histopathologic tumor localization and volume measurement as the standard of reference. The mean volume of all peripheral zone tumor nodules (n = 51) was 0.79 cm³ (range, 0.02 to 3.70). Readers detected 20 (65%) and 23 (74%) of the 31 peripheral zone tumor nodules greater than 0.5 cm³. For these nodules, tumor volume measurements by MRI, MRSI, and combined MRI and MRSI were all positively correlated with histopathologic volume (Pearson's correlation coefficients of 0.49, 0.59, and 0.55, respectively), but only measurements by MRSI and combined MRI/MRSI reached statistical significance (p < 0.05). The findings suggest 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 (under 0.5 cm³).

MRI/MRSI – Extra-Capsular Extension

Two studies have suggested that the addition of MRI/MRSI data to other clinical data can improve prostate cancer staging. In one study of 53 patients with early stage prostate cancer, tumor volume estimates based on MRSI findings were combined with high specificity MRI criteria7 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.29,30

It was found that tumor volume per lobe estimated by MRSI was significantly (p<0.01) higher in patients with ECE than in patients without ECE. Moreover the addition of an MRSI estimate of tumor volume to high specificity MRI findings for ECE18 improved the diagnostic accuracy and decreased the inter-observer variability of MRI in the diagnosis of extracapsular extension of prostate cancer.7 In another study of 383 prostate cancer patients, 1.5T MRI/MRSI data were added to a staging nomogram for predicting organ-confined PC in order to assess its incremental value. MR findings were of significant incremental value (p = .02) to the nomogram in the overall study population. The contribution of MR findings were significant in all risk groups but were greatest in the intermediate- and high-risk groups (p < .01 for both).

MRI/MRSI – PC Aggressiveness

Early biochemical studies have indicated that citrate levels in prostatic adenocarcinomas are grade-dependent, with citrate levels being low in well-differentiated, low-grade prostatic cancer and effectively absent in poorly differentiated high-grade prostatic cancer.31,32 More recent ex vivo proton spectroscopy studies of intact human prostate tissues have demonstrated higher levels of choline containing metabolites in prostate cancers having higher Gleason grades.33,34 In two in vivo MRI/MRSI studies of prostate cancer patients, a correlation between the choline and creatine to citrate ratio and Gleason score was also observed.10,35

Current Clinical Applications
Staging Newly Diagnosed Patients

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 the MRI/MRSI prostate staging exam at UCSF has historically been to combine the anatomic and metabolic information with clinical data (serum PSA, #, % and grade of cancer positive TRUS-guided biopsies) during weekly clinical tumor boards in order to improve therapeutic selection for individual patients. A representative example where MRI/MRSI had a significant impact on therapeutic selection is given in the following patient case study.

Case Study

A 52-year old man interested in “active surveillance” presented with a PSA of 7.9 ng/nL and biopsy- proven prostate cancer (10% of Gleason 3+3 cancer in one out of 12 cores) in the left midgland. As is common practice at UCSF, the patient was seen by both a urologist and a radiation oncologist. He was subsequently referred for a high-spatial resolution MRI/MRSI exam to confirm the extent of disease observed at biopsy in order to help assess the best course of action. The patient had no prior prostate cancer treatment at the time of his prostate MRI/MRSI.

On T2 weighted MR images, prostate cancer appears as regions of decreased signal intensity as compared to surrounding regions of healthy peripheral zone tissue (Figure 1, red arrows). In this patient, the MRI/MRSI findings were concordant, indicating a large region of T2 hypointensity (Figures 1 and 2A, red arrows) and associated abnormal spectroscopic voxels (significantly elevated choline and reduced polyamine and citrate (Figures 2D and 2E, red outline) in the peripheral zone of the left base and midgland of the prostate. Additionally, there was a mild bulge of the prostate and irregularity prostatic capsule in the left midgland to base (black arrows, Figures 1 and 2A) that was deemed suspicious for extracapsular extension. However, there was no evidence of seminal vesicle invasion or pelvic lymphadenopathy within the pelvis. Based on these findings, it was clear that aggressive therapy would be necessary. The patient subsequently underwent high-dose-rate (HDR) brachytherapy combined with 22 sessions of external beam radiation therapy, and neoadjuvant androgen deprivation therapy.

Another important group of patients being referred for an MRI/MRSI exam prior to therapy consists 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. Alternatively, they may have cancers in difficult-to-biopsy locations such as the apex or in the lateral or anterior locations within the prostate.36 A recent publication has demonstrated that MRI/MRSI can improve the identification of regions of cancer for targeting of TRUS guided biopsies in patients who had prior negative TRUS biopsies.37

Monitoring Patients after Therapy

Growing numbers of patients receiving an MRI/MRSI are referred for suspected an MRI/MRSI are referred for suspected local cancer recurrence after 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, and it can take two years or more for PSA levels to reach a nadir following radiation therapy (either external beam or brachytherapy).38,39 Furthermore, 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, CT, and MRI, often cannot distinguish healthy from malignant tissue following therapy due to therapy-induced changes in tissue structure.40,41 The only definitive way to determine if residual or recurrent tissue is malignant is the histological analysis of random biopsies, which are subject to sampling errors and are more difficult to pathologically interpret after therapy.

After therapy, the spectroscopic criteria used to identify residual/recurrent prostate cancer need to be adjusted due to a time-dependent loss of prostate metabolites following therapy. For example, prostatic citrate production and secretion have been shown to be regulated by hormones,42 and an early dramatic reduction of citrate and polyamines after initiation of complete hormonal blockade has been observed by MRSI.43 There was slower loss of choline and creatine with increasing duration of hormone deprivation therapy.43 This loss of prostatic metabolites correlates with the presence of tissue atrophy and is considered to be an indicator of effective therapy.43 Similar time-dependent reductions in prostate metabolites also occurred after radiation therapy.44,45

Studies have also demonstrated the ability of MRI/MRSI to discriminate residual or recurrent prostate cancer from residual benign tissue and atrophic/necrotic tissue after cryosurgery,46-48 hormone deprivation therapy43,49 and radiation therapy.44,50 These studies have relied on elevated choline to creatine as a metabolic marker for prostate cancer since polyamines and citrate tend to disappear early after therapy in both residual healthy and malignant tissues. Figure 3 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 MRI/MRSI exam which was three years after intensity-modulated radiation therapy. Consistent with effective radiation therapy, many spectroscopic voxels (left side of image) demonstrated a complete loss of all prostate metabolites (metabolic atrophy). However, residual metabolic abnormalities (choline to creatine = 1.5) persisted in the left lobe of the prostate and this region was later confirmed as residual cancer by a TRUS-guided biopsy. A recent MRI/MRSI study of 21 prostate cancer patients with biochemical failure after external beam radiation therapy demonstrated that the presence of three or more voxels having a choline/creatine = 1.5 in a hemiprostate showed a sensitivity and specificity of 87% and 72%, respectively, for the diagnosis of local cancer recurrence. 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.

Figure 3. Post-therapy MRI/MRSI data. Axial T2-weighted MR prostate images are shown on the left for a 60-year-old man with a rising prostatic specific antigen level three years after intensity modulated external beam radiation therapy for prostate cancer. As is typical for post-therapy MRI, the gland is uniformly hyperintense, and no clear tumor foci were observed. A grid overlaid on the top image corresponds to the proton spectral array shown on the right. This MR spectroscopic imaging demonstrates several suspicious voxels with elevated choline peaks (arrows) relative to creatine (choline/creatine ratio greater than 1.5) in the left side of the gland. Subsequent transrectal ultrasound-guided biopsy confirmed the presence of locally recurrent prostate cancer in the left gland.

The Imaging Protocol – What a Patient Needs to Know

MR imaging is performed on a 1.5T whole-body MR scanner (Signa; GE Medical Systems - Milwaukee, WI). The MRI/MRSI exam will involve the patient lying on his back inside a magnet, which is about one yard in diameter and three yards long. Prior to the exam, the patient will be sent a package of information that explains the procedures including the use of the endorectal coil and how to prepare for the exam. Preparation involves performing a Fleet enema 1-3 hours prior to the exam and eating a light diet the evening prior to or day of the exam. It is also recommended that the patient avoid coffee or tea as this may increase the frequency of urination causing some discomfort of lying still during the exam. Therefore, the MR data quality is optimized when the patient is properly prepared and fully informed of the procedures involved.

Once the patient has changed into the proper hospital attire, he will be instructed to lie down on the MRI table and turn on his side with his back to the nurse. The nurse will complete a brief digital rectal examination to assess the area for safe probe insertion and then insert the endorectal coil, which is lubricated with KY gel. The patient will then turn onto his back, which is the final position, and the external coils will be placed by the MR technologist. A body coil is used for signal excitation, and a combination of (1) a BPX-15 MEDRAD disposable endorectal coil injected with a perfluorocarbon liquid and (2) a pelvic phased-array coil (GE Medical Systems - Milwaukee, WI) is used for signal reception. The patient will be given earphones or earplugs to block out the noise from the scanner and moved into the MRI tube. There is a communication set-up between the control room and the patient so that dialogue can occur during the exam.

Once scanning is initiated, a preliminary sagittal localizer will be acquired to ensure the endorectal coil is positioned correctly. Axial spin-echo T1 weighted images are then obtained to assess metastases to the pelvic lymph nodes and bone. The T1-weighted images are also used to assess the presence of post-biopsy hemorrhage within the prostate that would complicate the interpretation of both MRI and MRSI data.51-53 Thin-section, high-spatial-resolution axial and coronal T2-weighted fast-spin-echo images of the prostate and seminal vesicles are also acquired to determine the location and extent of prostate cancer within the prostate and to assess for extracapsular spread.18 After review of the axial T2-weighted images, a MR spectroscopic imaging volume is selected to cover the prostate; this requires a few minutes before scanning starts again. In this fashion, regions of abnormal metabolism can be directly mapped to regions of abnormal morphology.

The collection of the spectroscopic data takes ~ 17 minutes because of the low concentration of the metabolites that are being measured. All MR images will be post-processed to compensate for the reception profile of the endorectal and pelvic-phased array coils. The total examination time is one hour, including coil placement and patient positioning. In order to obtain the best images and data possible, the patient needs to remain motionless and relaxed during the entire examination. If the patient is claustrophobic, his referring physician can prescribe sedatives to be taken 30 minutes prior the exam or as directed by his doctor.

Summary

Combining high resolution anatomic (MRI) and metabolic (MRSI) imaging data with other clinical data has proven useful in selecting the most appropriate therapy for individual patients and in determining the effectiveness of therapy. With growing numbers of imaging centers having access to MRI/MRSI technology, there will be increasing amounts of published information about the utility of MRI/MRSI in a variety of patient situations. As with any new technology, there is a learning curve to acquiring and interpreting MRI/MRSI data, and the most accurate results will come from sites with the most experience. There is also a great deal of on-going research to improve the accuracy of MRI/MRSI of prostate cancer. The use of higher magnetic field scanners (3T versus 1.5T) has allowed higher spatial resolution MRSI data (0.16 cc versus 0.3 cc) to be acquired, thereby increasing the sensitivity of MRSI to smaller cancers.54-56 Additionally, many sites are investigating the addition of other types of functional information that can improve the accuracy of prostate MRI/MRSI yet be acquired within the same one hour magnetic resonance imaging exam. These include measuring changes in tissue microstructure using diffusion weighted MRI57-61 and changes in tissue vascularity using dynamic contrast imaging62-66 that occur with the evolution and progression of prostate cancer. Most likely, the most accurate detection and characterization of prostate cancer in individual patients will occur by combining all of these techniques into a single imaging exam. 

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