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Original Research |
1 Joint Department of Medical Imaging, Princess Margaret Hospital, University
Health Network and Mount Sinai Hospital, University of Toronto, 610 University
Ave., Toronto, ON M5G 2M9, Canada.
2 Department of Pathology and Laboratory Medicine, Princess Margaret Hospital,
University Health Network, University of Toronto, ON, Canada.
3 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
University of Toronto, ON, Canada.
4 Department of Biostatistics, Princess Margaret Hospital, University Health
Network, University of Toronto, ON, Canada.
5 Department of Surgical Oncology, Princess Margaret Hospital, University Health
Network, University of Toronto, ON, Canada.
Received September 28, 2006;
accepted after revision March 28, 2007.
Address correspondence to M. A. Haider.
Abstract
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SUBJECTS AND METHODS. T2-weighted imaging and DWI (b value = 600
s/mm2) were performed in 49 patients before radical prostatectomy
using an endorectal coil at 1.5 T in this prospective trial. The peripheral
zone of the prostate was divided into sextants and the transition zone into
left and right halves. T2 images alone and then T2 images combined with
apparent diffusion coefficient (ADC) maps (T2 + DWI) were scored for the
likelihood of tumor and were compared with whole-mount histology results.
Fixed window and level settings were used to display the ADC maps. Only tumors
with an area of more than 0.13 cm2 (> 4 mm diameter) and a
Gleason score of 
6 were considered significant. The area under the
receiver operating characteristic curve (Az) was used to
assess accuracy.
RESULTS. In the peripheral zone, the Az value was significantly higher (p = 0.004) for T2 plus DWI (Az = 0.89) than for T2 imaging alone (Az = 0.81). Performance was poorer in the transition zone for both T2 plus DWI (Az = 0.78) and T2 (Az = 0.79). For the whole prostate, sensitivity was significantly higher (p < 0.001) with T2 plus DWI (81% [120/149]) than with T2 imaging alone (54% [81/149]), with T2 plus DWI showing only a slight loss in specificity compared with T2 imaging alone (84% [204/243] vs 91% [222/243], respectively).
CONCLUSION. Combined T2 and DWI MRI is better than T2 imaging alone
in the detection of significant cancer (Gleason score 6 and diameter >
4 mm) within the peripheral zone of the prostate.
Keywords: diffusion-weighted imaging • MRI technique • oncologic imaging • prostate cancer • radiologic-pathologic correlation • T2-weighted imaging
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Studies have shown the added value of T2-weighted MRI and proton spectroscopy (MR spectroscopy) in localizing prostate cancer compared with endorectal sonographically guided biopsy and digital rectal examination, which are the traditional methods of determining prostate cancer location [2, 3]. T2-weighted imaging has been shown to provide some localization information in this setting, with previously reported sensitivities and specificities of 67-81% and 46-69%, respectively. MR spectroscopy has shown promise in prostate cancer localization with a sensitivity of 73% and a specificity of 80%; however, in these studies up to 26% of the sextants were inadequately evaluated by spectroscopy and were eliminated from the analysis [3, 4]. This has motivated investigation into other MRI methods for prostate cancer detection. Diffusion-weighted imaging (DWI) is an MRI method typically used in neuroradiology. From DWI parametric maps, apparent diffusion coefficients (ADCs) can be calculated. Recently, a number of investigators have reported the potential usefulness of DWI for detecting prostate cancer because it shows a lower ADC than a normal peripheral zone [2, 5-7].
The purpose of this study was to compare the accuracy of T2-weighted MRI alone and T2 combined with DWI for the localization of prostate cancer.
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MRI Protocol
Axial and coronal T2-weighted images and axial diffusion-weighted images
were obtained. All examinations were performed using a 1.5-T MRI system
(EchoSpeed, Excite, or Excite HD; GE Healthcare) and a 4-channel phased-array
surface coil coupled to an endorectal coil. Imaging parameters for the T2
images were TR range/TE, 4,800-5,650/96; echo-train length, 16; bandwidth,
20.83 kHz; field of view, 14 cm; slice thickness, 3 mm; gap, 0 mm; number of
excitations, 3; no phase wrap; phase-encoding direction, left to right; and
matrix, 256-320 x 256. Next, an axial echo-planar DWI pulse sequence (b
value = 600 s/mm2) with the same slice locations as the T2 sequence
was performed using the following parameters: TR/TE, 4,000/73; bandwidth, 167
kHz; field of view, 14 cm; slice thickness, 3 mm; number of excitations, 8;
matrix, 128 x 256; 3 acquisitions with 8 slices per acquisition; ramp
sampling; and optimized TE options. The time required to acquire the DWI image
set was 8 minutes.
Image Analysis and Interpretation
ADC maps were generated using in-house software developed using IDL
(version 6.0, ITT Visual Information Solutions). These maps were converted to
8-bit gray-scale images with a window width of 1,650 x 10-6
mm2/s and a window level of 1,675 x 10-6
mm2/s and were displayed using ImageJ software (U.S. National
Institutes of Health). With this method, regions of low ADC were darker than
regions of high ADC, with areas less than or equal to 850 x
10-6 mm2/s being black. By using a fixed window width
and level, we were able to take advantage of the quantitative nature of ADC
mapping. T2-weighted images were reviewed on a workstation (eFilm, version
2.1, Merge eMed).
The peripheral zone of the prostate was divided into base, mid, and apex and left and right halves, thus yielding six regions. The central gland comprising the transition zone was divided into left and right halves. The base was defined as the region extending from the most superior margin of the prostate to the widest transverse diameter of the prostate. The mid gland was defined as the region between the widest transverse diameter and the orifices of the ejaculatory ducts at the verumontanum. The apex was defined as the region inferior to the mid gland.
All images were reviewed by a single radiologist with 11 years of experience interpreting body MRI and 6 years of experience interpreting prostate MRI. The T2 images were reviewed first. The ADC maps were subsequently reviewed in conjunction with the T2 images. The observer assigned a score to each zone using the following 5-point scale: 0, definitely no cancer; 1, probably no cancer; 2, possible cancer; 3, probable cancer; and 4, definite cancer. The criteria for these scores in the peripheral zone and in the transition zone of the prostate are listed in Table 2. The observer was blinded to the pathology results.
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Pathology
After fixation in buffered formalin, prostatectomy specimens were inked
with three different colors of stain to identify the left, right, and anterior
sides of the specimen. After removal of the apex and the bladder neck
resection margins, the prostate was sectioned axially to match the MRI plane
of section at regular intervals of 4 mm or less, yielding serial slices of
tissue. A ruler was used to ensure no single slice was more than 4 mm in
thickness. These slices were sectioned into two halves (left and right) or
four quarters (anterior and posterior, left and right) to fit on a standard
slide. On each slide, a pathologist outlined the region of cancer and assigned
a Gleason score. The slides were then digitized and reconstructed into
whole-mount sections using Photoshop (Adobe Systems) at 300 dpi. From these
digitized slides, each tumor region was traced by the pathologist to obtain a
cross-sectional area using ImageJ software. The pathologist was blinded to the
MRI results.
For the purposes of radiologic-pathologic correlation, a region was considered positive for cancer if it contained tumor with a cross-sectional area that was greater than 0.1 cm2 on the fixed specimen with a Gleason score of 6 or higher. Assuming an ellipsoid shape of the tumor and accounting for tissue shrinkage after fixation and processing (linear factor = 1.14) [8], this would be equivalent to a geometric mean diameter of 4 mm and an area of 0.13 cm2. In cases in which a sextant contained more than one tumor, the largest one was used. The radiologist reviewed the pathologic specimens in conjunction with the MR images to spatially match tumors in each zone. This was done 6 weeks after completion of MR image review. Each pathologic slice was visually matched to a corresponding MR image on the basis of the location of the ejaculatory ducts, diameter of the prostate, and approximate distance from the base or apex. To be considered a match, a tumor not only had to be in the same region from superior to inferior in the prostate but also had to lie in the same anterior or posterior half of the prostate.
Statistical Analysis
Receiver operating characteristic (ROC) curves were estimated separately
for each region of the prostate using maximum likelihood and assuming
bivariate normal data using ROCKIT software (version 0.9.1-Beta, CE Metz,
University of Chicago) [9]. The
combined area under the ROC curve (Az) was obtained by
averaging the areas under the ROC curves for each region. This was done for
the ratings of T2 imaging alone and for the combined T2 plus DWI ratings over
all eight regions, just the peripheral zone (six regions), and just the
transition zone (two regions). The jackknife method was used to estimate the
variances of the Az derived from multiple regions of the
prostate and to compare the correlated Az between the T2
imaging alone and T2 plus DWI assessments
[10]. For visual display, the
ROC curves obtained from the pooled data were plotted. Sensitivity,
specificity, and positive and negative predictive values were calculated by
choosing a threshold score of 3 or greater to indicate cancer. To account for
any correlations due to multiple regions being assessed for each patient,
generalized estimating equation models were used to calculate the
corresponding variances and 95% CIs and to test for differences between
methods [11].
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The Az value was significantly higher (p = 0.006) for T2 plus DWI (Az = 0.87) than for T2 imaging alone (Az = 0.80) when evaluating the entire prostate. This was particularly true in the peripheral zone, where the Az value was 0.89 for T2 plus DWI and 0.81 for T2 (p = 0.004) (Figs. 1A and 1B). Performance was poorer in the transition zone for both T2 plus DWI (Az = 0.78) and T2 (Az = 0.79) methods. T2 plus DWI did not improve tumor localization compared with T2 imaging alone in the transition zone (p = 0.90) (Fig. 1C). For cancers anywhere in the prostate, using a threshold score of 3 or greater to indicate cancer, sensitivity was significantly higher for T2 plus DWI than for T2 imaging alone without overlap of the CIs (81% [120/149]; 95% CI, 74-86% vs 54% [81/149]; 95% CI, 44-65%, respectively; p < 0.001), and specificity was maintained above 80% (Figs. 2A, 2B, 2C and 3A, 3B, 3C and Table 3). The negative predictive value was also significantly higher for T2 plus DWI versus T2 imaging alone (88% [204/233]; 95% CI, 82-92% vs 77% [222/290]; 95% CI, 69-82 %, respectively; p < 0.001) (Table 3). DWI added little to the detection of cancer in the transition zone with low sensitivities for T2 imaging alone (36% [8/22]; 95% CI, 16-63%) and for T2 plus DWI (41% [9/22]; 95% CI, 19-67%).
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mechanism by which DWI adds diagnostic accuracy to T2 imaging is uncertain. T2 signal loss in the peripheral zone may be related to a number of causes, including cancer, inflammation, fibrosis, and hemorrhage [12-14]. It is possible that the ADC value is more drastically altered by cancer than it is by factors such as hemorrhage, inflammation, or fibrosis. The cause of lower ADC values in prostate cancer may be related to the many tightly packed glandular elements found in cancers that locally replace the fluid-containing peripheral zone ducts. This could result in a local drop in the ADC value. The different natures of ADC and T2-weighted tissue contrast in the prostate are supported by at least one prior study showing no significant correlation between quantitative T2 measurement and ADC values in the prostate [15].
Another reason for the improved performance of DWI may be the quantitation of ADC, which theoretically eliminates the effect of T2 signal variations as well as receiver gain and coil intensity profiles from the image, thereby allowing fixed window levels for assessment. Prior studies have shown ADC values to be lower in prostate cancer, ranging from 1,100 to 1,340 x 10-6 mm2/s with b values of 300-1,000 mm2/s compared with normal peripheral zone values of 1,610-1,680 x 10-6 mm2/s [5, 6, 15]. The window and level settings chosen to display the ADC images in this study are consistent with settings that allow cancer to be distinguished from normal peripheral zone. Non-quantitative T2 imaging relies on visual assessment of relative signal changes between the tumor and normal peripheral zone and of the morphologic appearance of areas of low signal for the diagnosis, which may be more subjective and may affect test performance.
Other methods of cancer detection in the prostate include MR spectroscopy and dynamic contrast-enhanced MRI, with many of the published articles in the literature focusing on staging. MR spectroscopy has shown promise in prostate cancer localization, with a sensitivity of 73% and a specificity of 80% [3, 4]; however, in those studies, up to 26% of the sextants were inadequately evaluated by spectroscopy and were eliminated from the analysis. Localization studies with dynamic contrast-enhanced MRI have shown a sensitivity and specificity of 73% and 77%, respectively, using a 3-T MRI system [16]. In contrast to these methods, DWI has the advantages of not requiring IV contrast material and of being simple to process. Moreover, DWI requires less time to acquire than proton spectroscopy and less technologist training to perform.
DWI has some limitations. In this study, an echoplanar imaging-based pulse sequence was used. This sequence can be affected by magnetic susceptibility, resulting in spatial distortion and signal loss. Alternative DWI methods based on line scan diffusion [17] or on the addition of parallel imaging can help reduce distortion and may help further improve diagnostic accuracy.
MRI detection of prostate cancer is dependent on the size of the tumor.
Tumor size is related to the risk of extracapsular spread
[18], relapse after radical
prostatectomy [19], and PSA
progression [20]; and the
larger the tumor, the higher the risk of treatment failure. Prior studies have
shown that 89% of tumors less than 0.5 cm3 (1 cm in diameter) are a
Gleason score of 
6 [21].
Such tumors are likely indolent
[20,
22]. This suggests that the
tumor size cutoff used in our study of 4 mm is sufficient to detect
significant cancers in a large proportion of patients.
This study has limitations. Interobserver variability was not assessed. Our standard T2 interpretation results are consistent with those of prior studies. A standardized interpretation scheme was also used for both the T2 imaging alone and the T2 plus DWI data sets (Table 2). We also used fixed window level settings for ADC map display, which should have added robustness to the interpretation, to take advantage of the quantitative nature of DWI. There was a bias toward patients with established cancer in this study because all patients had cancer proven on prior biopsy and were proceeding to radical prostatectomy. Thus, the population of patients with small tumors or with elevated PSA values resulting from inflammation or other causes may not have been fully represented. Finally, precise radiologic-pathologic correlations are made difficult by tissue deformation, difficulty in precise matching of slicing angles to the plane of imaging, and deformation of the prostate at the time of MRI by the endorectal coil. We attempted to minimize errors in this study through careful radiologic-pathologic correlation and matching size and internal structures such as the ejaculatory ducts.
Our results suggest a potential role for DWI in providing localization before sonographically guided biopsy in patients with persistently elevated PSA values and prior negative biopsy results. Further investigation of this patient group is required to determine whether DWI can help improve the detection of prostate cancer in these patients.
In conclusion, T2 plus DWI MRI is significantly better than T2-weighted
imaging alone in the detection of significant cancer (Gleason score 6 and
diameter > 4 mm) within the peripheral zone of the prostate.
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