Traditionally, the diagnosis of prostate cancer is established with a biopsy based on an elevated PSA (generally greater than 4.0), with a subsequent need to assess the extent of disease prior to qualifying for a treatment. Clinical assessment of the extent of prostate cancer (PC) is often difficult because of the prostate’s relatively small size and the complex and often inaccessible anatomy deep within the pelvis. Traditionally, the extent of PC has been evaluated by digital rectal examination (DRE) in combination with PSA, the total number of positive biopsy cores and/or the percentage of the individual cores positive for PC. Imaging has not played a significant role in determining the extent of disease as it was dependent on relatively insensitive and non-specific testing including CAT Scan, PET Scan or Prostascint Scan. Increased awareness of limitations of traditional methods for diagnosis and staging of PC has encouraged the development and application of new imaging modalities for its assessment including 3 T MRSI (magnetic resonance spectroscopy imaging). Modifications in traditional non-invasive imaging techniques, such as micro-bubbles with transrectal ultrasound of the prostate (TRUSP) have been developed to aid in this evaluation; however a predictive response is absent limiting their clinical utility. Even when combined with other clinical tools they often cannot consistently provide all the information needed by physicians.
Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRI-S) examinations are techniques that are FDA-approved, while the clinical utility of MRI in assessing PC has been well studied.(1-8,28) MRI-S has been integrated into an MRI staging exam at centers of excellence like the Diagnostic Center for Disease™ in Sarasota, UCSF and Memorial Sloan Kettering. The combined metabolic and anatomic data has proven more accurate than MRI alone in identifying the location and spatial extent of the cancer within the prostate (9) as well as determining whether it has spread beyond the gland.(10) Additionally, recent studies have indicated that MRI-S may provide an assessment of cancer aggression and can detect residual or recurrent cancer after therapy.(4,11-14) This review will focus on the combined use of MRI and MRI-S for the assessment of PC.
MRI emerged in the1980s as an outgrowth of the use of nuclear magnetic resonance to study the structure of chemical compounds. It quickly became the best imaging technique to assess problems associated with soft tissues. MRI uses a strong magnetic field and radio frequency (RF) waves to non-invasively obtain morphologic pictures (images) based on tissue water. It has the following advantages over other radiological techniques used for PC diagnosis:
Within the same exam, endorectal MRI can also be used to assess the possibility of PC spread to lymph nodes and bones within the pelvis as well as capsular breach. Additional advantages of MRI and Spectroscopy are the following:
Recently, there has been a dramatic improvement in MRI assessment of PC. The latest endorectal MRI studies have demonstrated staging accuracies consistently between 75% and 90% (5,10,16) that are higher than staging accuracies reported using TRUS.(17) This increased accuracy has been the result both of improved MRI technology and of greater experience in interpreting MRI-S of the prostate.
One important technical improvement is the use of multiple coils to image the prostate. Currently the prostate is imaged using an endorectal coil and a combination of external coils.(18) This approach provides both the sensitivity to acquire high resolution images of the prostate and the ability to image the entire pelvis. The use of the endorectal coil provides the necessary sensitivity to focus on the prostate and to acquire the MRI-S data, while the pelvic phased array coil allows a large enough field-of-view (FOV) to assess pelvic lymph nodes and pelvic bones for metastatic disease.
Variability in image quality due to image intensity dramatically decreases with distance from the surface coil with subsequent difficulties in interpretation thereby presenting a potential problem. To correct for this, the MR research team at UCSF developed computer post-processing software to create uniform images that greatly improve image interpretation.(11,19) The improvement in image quality can be clearly seen in the anatomic image through the middle of the prostate of a patient with cancer (as shown on the right side of the prostate in the image. Figure (1).
|Figure 1. Comparison of axial endorectal coil/pelvic phased array FSE prostate images A (prior to) and B (after) performing an analytic correction for the reception profiles of the endorectal and pelvic phased array coils. The slight (10°) tilt in the placement of the endorectal coil hindered the ability to identify the low signal intensity cancer in the right peripheral zone of the uncorrected image.|
In the corrected image, the high signal intensity close to the endorectal coil has been removed allowing for improved visualization of the PC (low T2 signal intensity on the right side, short arrow on the visual left) and the prostatic capsule (thin dark line encompassing the prostate, arrows on the left side of the prostate or visual right).
After the high (bright) signal intensity close to the endorectal coil (Figure 1A) has been corrected for, the anatomy of the prostate as well as the tumor process can be more clearly visualized. The cancer can now be identified as a region of low (dark) signal intensity in the peripheral zone of the prostate as indicated by the arrow on the right in Figure 1B. The correction also improves visualization of the prostatic capsule (Figure 1B, left side), which is critical to an assessment of cancer spread beyond the prostate capsule.
Additionally, increased experience in interpreting endorectal coil MR images(7) provides a better understanding of the morphologic criteria used to diagnose extra-prostatic disease that has also improved the performance of endorectal MRI.(16) This improvement in the performance of endorectal MRI should continue in the future as the UCSF image correction becomes available to other sites like the Diagnostic Center for Disease™ and as radiologists gain additional experience concerning what morphologic and metabolic findings are most predictive of early cancer spread. Increased experience should result in improved guidelines for those patients most likely to benefit most from an MRI exam, and should allow integration of MRI and Spectroscopy sequences with other radiological and clinical findings. Sequences that are defining an improved diagnosis include a concordance of Dynamic Contrast Enhancement (DCE) adapted to CAD Stream analysis, Spectroscopy, T1-Weighted images and T2-Weighted images
The graphic reporting of MR findings in an objectified format will need to become routine in order to avoid ambiguities due to the English language. This commits the reader to evaluate all aspects of the MRI and MRI-S that may have clinical relevance. An example of a proposed format for such objectified reporting is shown below:
While the staging accuracy of MRI has recently improved, the assessment of location and extent of PC within the prostate still remains unsettled. Studies evaluating clinical data, systematic biopsy, TRUS, and MRI have shown inconsistent results for tumor localization within the prostate.(6,8,20,21) The problem lies in (1) the lack of specificity that TRUS and MRI alone have in identifying cancer and (2) the sampling error associated with systematic blind biopsies. Spectroscopy, however, has demonstrated high specificity in identifying cancer using 3 Tesla technology.
Expanding the Effectiveness of MRI by Including MRI-S
Figure 2. Fifty-Eight year old man with pathologic stage pT3a PC, Gleason score (GS) 5. Corrected T2- weighted axial MR image through the mid-prostate was obtained using an endorectal coil. A 0.24 cc spectrum obtained from the area of imaging abnormality (1) demonstrates elevated choline at 3.2 ppm, creatine at 3.0 ppm, and reduced citrate at 2.6 ppm; this is a pattern consistent with cancer. MR spectra obtained from the left side of the image (2) demonstrate a normal spectral pattern with citrate dominant and no abnormal elevation in choline.
The recent development and use of MR spectroscopic imaging (MRI-S) expands the diagnostic assessment of PC beyond the morphologic information provided by MRI. (12,13,22) As with MRI, MRI-S uses a strong magnetic field and radio waves to non-invasively obtain metabolic images (spectra) based on the relative concentrations of cellular bio-chemicals (choline, creatine, citrate).
With MRI-S, one observes specific resonances (peaks) for citrate, choline and creatine from contiguous small volumes of tissue throughout the gland. The peaks for these different bio-chemicals occur at distinct frequencies or positions in the MRI-S spectrum (Figure 2, plots 1 and 2). The area under these peaks is related to the concentration of these metabolites, and changes in these concentrations can be used to identify cancer. Figure 2 shows cancer in the low signal intensity region labeled by box 1 (right side of prostate) versus the normal peripheral zone high signal intensity labeled by box 2 (left side of prostate). These are two 0.24 cc volumes (a cube 6.5 mm on a side) pulled out of the entire MRI-S array of volume (that consists of hundreds of tissue volume regions within the total prostate).
In a study of 85 PC patients who had combined MRI/MRI-S evaluation prior to radical prostatectomy, significantly higher choline levels, and significantly lower citrate levels were observed in regions of cancer as compared to BPH and normal prostatic tissues. The ratio of these metabolites (creatine+choline ÷ citrate) in regions of cancer had minimal overlap when compared to normal prostate tissue or BPH values (high specificity).(22) This study indicated that MRI-Spectroscopy could provide the degree of specificity for identifying cancer within the prostate that was lacking with MRI alone.
Recent studies have, in fact, demonstrated that an improved assessment of the presence and spatial extent of cancer within the prostate (9), as well as its spread outside the gland (16) can be obtained by combining the information from MRI and MRI-S (See Figure 3).
Figure 3. PC can be more accurately identified based on a concordant decrease in signal intensity demonstrated on the MRI image (A) and metabolic abnormality detected by MRI-S (B). Image B shows a region of abnormal metabolism (in red) overlaid on the corresponding T2 weighted MR image. The region of abnormal metabolism in red corresponded with the area of decreased T2 signal intensity (image A) allowing for the identification of cancer with increased confidence. The region of cancer can be viewed volumetrically in multiple planes as seen from selected axial images taken from the apex (C), mid-gland (D), and base (E) of the prostate. Normally, 30-40 axial images are acquired contiguously through the prostate. By stepping through these high-resolution axial images, the radiologist or MRI-S trained Urologist can assess the spread of cancer through the capsule as seen in images D and E.
34 patients with a mean age of 60 and a mean PSA of 8.0 ng/ml were studied by Futterer et al. Reading the dynamic images (dynamic contrast enhancement) in conjunction with the T2-weighted images resulted in accuracies of 81-91% for the localization of tumors with a volume of .5 cubic centimeters or greater. The specificity was highest using the ‘washout’ phase of the metabolic activity. Dynamic contrast enhancement is a key concordant component to the interpretation for prostate cancer in all patients noting prostate cancer (28)
In a study of 62 patients undergoing MRI/MRI-S evaluation prior to RP, with step section histopathology, it was demonstrated that PC could be localized to a sextant of the prostate (i.e. [left/right] apex, mid-gland and base) with a specificity of up to 91% when both MRI and MRI-S were positive for cancer and a sensitivity of up to 95% when either MRI or MRI-S were positive for cancer (See Table 1) (9).
|(a) Sensitivity = True Positives ÷ (True Positives + False Negatives)
(b) Specificity = True Negatives ÷ (True Negatives + False Positives)
Figure 4. This graph demonstrates the trade-off between sensitivity and specificity when using MRI/MRI-S to predict ECE. A perfect test (100% sensitive and 100% specific) would be a straight line up the vertical axis. The area under the curve (Az) represents the overall accuracy of the test. It can be clearly seen that combining MRI and MRI-S increases the accuracy (increased area under the ROC curve) of predicting early ECE.
A high sensitivity study is associated with only a few patients being told they do not have PC when in fact they do have PC (false negative results are minimal, therefore the sensitivity is high). A high specificity study is associated with only a few patients being told they do have PC when in fact they do not have PC (false positive results are minimal, therefore the specificity is high).
It has also been demonstrated that assessment of cancer spread outside the prostate can be significantly improved by combining MRI findings that are predictive of cancer spread (based on studies of patients who received surgery after MRI/MRI-S) with an estimate of the spatial extent of metabolic abnormality provided by MRI-S.(16) In a study of 53 patients who received an MRI and MRI-S exam prior to surgery, it was demonstrated that the addition of MRI-S information increased the accuracy (from 0.77 to 0.83) in predicting early cancer spread outside the prostate (See Figure 4).
Metabolic information can also provide new insights into tumor aggressiveness, which may lead to improved risk assessment of patients with PC. An MRI/MRI-S study of 26 biopsy-proven PC patients was performed prior to RP and a step-section pathologic examination was recently reported. It demonstrated a correlation between the magnitude of the decrease in citrate and the elevation of choline with cancer aggressiveness as reflected in the Gleason Score (See Figure 5).(11) When comparing higher GS (> 6 or 7-10) to a lower GS (≤ 6) cancers, a statistically significant (P< 0.0001) difference in (cancer choline)/(normal choline) ratios was observed. There was also a significant (P< 0.05) correlation between the elevation of choline and (creatine + choline) ÷ citrate ratio and reduction in citrate correlating to Gleason Score.
Figure 5 shows aggressive PC (bottom image left side) and nonaggressive PC (upper image left side). The cancerous area can be visualized as a region of lower signal intensity on the left side of the image, while the corresponding spectra are shown to the visual right. In not very aggressive cancer (GS 5 top left), Citrate was reduced but Choline was not elevated. Conversely, in aggressive cancer (GS 8, bottom left), Citrate was absent and Choline was very elevated.
(Cho = Choline, Cr = Creatine and Cit = Citrate)
While the Gleason Score (represented by a cancerous tissue sample) still remains the standard for confirming the presence of PC and predicting biologic behavior, the potential of MRI-S to provide similar information is now available at the Diagnostic Center for Disease™ and other advanced 3 T centers. The obvious advantage precludes the issue of needle tracking. Due to the great heterogeneity of prostate cancers as well as biopsy sampling errors, cancers are often inaccurately graded or not detected during standard randomized biopsy sessions. In these cases, 3D-MRI-S might be valuable in providing an additional assessment of cellular function and organization, non-invasively and throughout the gland.
MRI-S will probably have its greatest impact on the assessment of PC therapy and on the selection of additional therapy. After therapy, the ability to detect the presence and spatial extent of cancer by MRI alone is reduced due to the morphologic changes induced by the therapy (See Figure 6). However, studies have indicated that residual or recurrent PC can be metabolically discriminated from normal and necrotic tissue after therapy. Basically, the pattern of elevated choline and reduced citrate observed in regions of cancer prior to therapy are also seen in areas of persistent or recurrent PC after therapy.(4,12,13)
Figure 6 illustrates recurrent cancer after brachytherapy. The axial images shown represent one 3-mm section through the prostate (before and after therapy) selected from a contiguous series of 32 images through the prostate. The regions colored in red are areas determined to be abnormal by MRI-S. These regions had (creatine + choline) ÷ citrate peak area ratios that were more than three standard deviations greater than healthy values. Radiation seeds can be seen as very dark spots in the peripheral zone of the prostate in the bottom image. Although cancer was dramatically reduced after brachytherapy, a region of residual abnormal metabolism consistent with cancer is seen on the left side of the imaged prostate. This area also corresponded to a region of low radiation dose. This information allows for earlier intervention with additional therapy.
Note: Both Images are mirrored images. The reddish area is on the left side.In some cases, such as after androgen deprivation therapy (ADT), the treatment directly affects one of the metabolites. For example, prostatic citrate production and secretion have been shown to be regulated by the hormones testosterone and prolactin (23, 24), and we have observed an early dramatic reduction of citrate after initiation of combined ADT.(11)
Additionally, there is a time-dependent loss of all prostatic metabolites in regions of both cancer and healthy tissue following the initiation of ADT.(11) This finding is consistent with the increased frequency of tissue atrophy that occurs as the duration of ADT increases.(25) These findings indicate the potential of MRI/3D-MRI-S to provide a measure of the time course of response and information concerning the mechanism of therapeutic response.(11) The improved assessment of therapeutic response provided by combined MRI/MRI-S should allow for earlier intervention in patients with recurrent disease.
The determination of the accuracy of combined MRI/3D-MRI-S for detecting residual cancer after therapy is more difficult than it is prior to therapy due to the lack of a gold standard (pathology of the surgically removed prostate) and the long natural history of PC. Therefore, large-scale outcome studies are required to determine if MRI/3D-MRI-S can morphologically and metabolically assess the early efficacy of therapy. These studies are currently underway. If successful, MRI/MRI-S should again allow for earlier intervention in patients with recurrent cancer after therapy and shorten clinical trials of PC therapy by providing surrogate endpoints of therapeutic success.
The combined MRI/MRI-S PC-staging exam has gone from a research model to a clinical exam based on the exceptional and enduring work at UCSF. This practice has been implemented at the Diagnostic Center for Disease™.
MRI-S data is factored into clinical MRI reports generated independently by our Radiologists and Urologists at the Diagnostic Center for Disease™. These reports summarize the location and extent of disease within the prostate, evidence to support organ confinement or the spread of cancer through the capsule, any involvement of nearby tissues including nerves, blood vessels and seminal vesicles as well as any cancer extension to the lymph nodes and bones within the pelvis. Additionally, the report may provide a prostate volume (by MRI) and PSA density if a recent PSA is given. Currently however, the report does not provide a cancer volume but rather a quadrant(s) of involvement. The ability of MRI/MRI-S to provide an estimate of cancer volume is currently under investigation. Additionally, Spectroscopy is being evaluated as a comparative to Gleason Score.
PC patients have opted for an MRI/MRI-S exam prior to therapy for a number of reasons. Some of the more common reasons are listed below:
Figure 7. On the right side are two representative axial MRI/MRI-S images (cancer in red) taken prior to (top) and after Brachytherapy (bottom). On the visual left side is an axial CT image taken through the same prostate, with overlaid MRI/MRI-S information (white lines). Oncologists currently use CT images to plan radiation therapy (red lines represent a contour map of radiation dose). CT is very good at visualizing bones within the human body, but does not visualize soft tissues such as the prostate very well.(26) Moreover, CT cannot accurately detect cancer within the prostate. The superior anatomic detail provided by high resolution MRI (using an Endorectal coil) can be used to better define the prostate (traced in white on the CT image) and surrounding radiation-sensitive tissues for improved radiation treatment planning. The combination of MRI and MRI-S can also better define the location and extent of cancer within the prostate (hash-marked area on CT image) thereby allowing radiation oncologists to give these regions increased doses of radiation while minimizing radiation to surrounding tissue.
A growing number of patients with suspected cancer recurrence after therapy are getting an MRI/MRI-S restaging exam as well as many patients who need to know the disease they had treated is indeed gone. Examples of usage include patients entering our diagnostic world through various treatment pathways include:
Acknowledgement given to the Prostate Cancer MRI-MRIS Group at the University of California, San Francisco for their Research and Development enabling the promulgation of this timely article