The Journal of International Medical Research 2011; 39:

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1 The Journal of International Medical Research 2011; 39: Evaluation of Diffusion-weighted Magnetic Resonance Imaging and Contrast-enhanced Harmonic Ultrasonography in Detection and Location of Prostate Transition-zone Cancer R WANG 1 *, J-J CHEN 2 *, Y-C ZHOU 1, M-M HUANG 1, X-R ZHANG 3 AND H-D MIAO 4 1 Department of Ultrasound in Medicine, The 6th People s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; 2 Department of Children s Care and Health, Shanghai Children s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; 3 Department of Urology, The 6th People s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; 4 Department of Radiology, Huashan Hospital Affiliated to Fudan University, Shanghai, China This retrospective study was designed to evaluate the value of contrast-enhanced harmonic ultrasonography (CEHU), diffusion-weighted magnetic resonance imaging (DW-MRI) and CEHU plus DW- MRI for the diagnosis of prostate transitionzone (TZ) cancer. In total, 31 TZ cancers in 28 patients and 25 peripheral zone (PZ) cancers in 21 patients without a TZ cancer were evaluated. All patients underwent DW-MRI and CEHU followed by radical prostatectomy. Predictors for the diagnosis of prostate cancer were evaluated in three protocols (CEHU, DW-MRI, CEHU plus DW- MRI). Statistical analysis of the differences between these protocols and receiver operating characteristic (ROC) curve analysis were carried out. CEHU plus DW- MRI had a significantly higher sensitivity, accuracy and negative-predictive value (90.3%, 73.2% and 81.3%, respectively) for TZ cancer than either method alone. The area under the ROC curve values were 0.659, and for CEHU, DW-MRI, and CEHU plus DW-MRI, respectively. In conclusion, CEHU plus DW-MRI might be a useful protocol for the detection and location of TZ cancer. KEY WORDS: PROSTATE CANCER; DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING; CONTRAST-ENHANCED HARMONIC ULTRASONOGRAPHY; TRANSITION ZONE Introduction Prostate cancer is one of the most frequently *R Wang and J-J Chen are joint first authors. diagnosed malignancies in males and is the second leading cause of cancer-specific death. 1 It is a major health concern as its incidence has risen dramatically over the 256

2 past two decades, due to the fact that most Western countries have ageing populations, with increasing life expectancy. 1,2 The number of new cases of prostate cancer in the USA in 2005 was estimated at , with deaths. 2 In China, although accurate epidemiological data for the entire country are not currently available, prostate cancer detection rates in developed areas have increased dramatically in recent years, due to widespread screening. 3 Combining serum prostate-specific antigen (PSA) levels with a digital rectal examination is a widely used screening tool for prostate cancer. 4 6 Pathological features are determined by undertaking a transrectal ultrasound (TRUS)-guided prostate biopsy, and these are used for a clinical diagnosis and to inform the choice of any subsequent treatment such as radiotherapy, chemotherapy and/or prostatectomy. 4 8 The sextant biopsy method only locates cancers in the peripheral zone (PZ) of the prostate, whereas it has been reported that 24% of prostate cancers originate in the transition zone (TZ). 9 TZ cancers are clinically important because they are more frequently confined to the organ, despite producing higher serum PSA levels and larger tumour volumes than PZ cancers Although a few studies have advised the addition of a TZ biopsy to the sextant biopsy, the number of cores has to be increased dramatically because the TZ is larger than the PZ, and this could result in a higher rate of complications or adverse events. 13,14 Unfortunately, neither TRUS, computed tomography (CT), nor magnetic resonance imaging (MRI) are reliable for the detection of TZ cancer because it is difficult to differentiate the lesion from surrounding tissue using these routine imaging techniques. 15,16 Thus, a reliable imaging technique to guide targeted biopsy sampling in the TZ of the prostate would be extremely useful. Several studies have reported that contrast-enhanced harmonic ultrasonography (CEHU) and diffusion-weighted MRI (DW- MRI) are valuable tools for detecting prostate cancers, including those in both the PZ and TZ. 4,17 28 The utility of these two methods for the detection of TZ cancer has not yet been well evaluated. Moreover, whether CEHU plus DW-MRI could improve the detection and location of TZ cancers remains unknown. Thus, the purpose of the present study was to evaluate the clinical value of CEHU, DW-MRI and CEHU plus DW-MRI in the diagnosis of prostate TZ cancer. Patients and methods PATIENTS The study population consisted of patients attending the Department of Urology at The 6th People s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China, between March 2008 and February 2010, who had undergone DW-MRI and CEHU followed by a radical prostatectomy. The study included patients with TZ cancers (study group) and patients with PZ cancers without TZ cancers, as confirmed by stepsection pathological maps (control group). All patients underwent MRI and ultrasonography before the prostate biopsy. For all patients, the period from imaging examination to radical prostatectomy ranged from 1 to 4 weeks (median 2 weeks). Gleason scores were also calculated to evaluate each patient s prognosis (2, best prognosis; 10, worst prognosis). The study was approved by the Joint Committee of Ethics of the School of Medicine, Shanghai Jiao Tong University. All the patients providing samples for this study were required to give their written informed consent. 257

3 IMAGING PROTOCOLS Ultrasonography A radiologist with 10 years experience (R.W.) performed all the ultrasonography examinations, including TRUS and CEHU, using a Technos MPX DU8 (Esaote, Genoa, Italy) ultrasonography system equipped with an EC end-fire probe. All patients were examined in the left lateral decubitus position. Grey-scale imaging was performed with a probe frequency of 7.0 MHz and a dynamic range of 80 db. For colour Doppler ultrasonography, the probe frequency was 6.0 MHz, the colour Doppler gain was adjusted to maximize the signal but eliminate colour noise from prostate tissue, and the colour Doppler window was set to include the entire gland. After the baseline ultrasonography, a CEHU was performed with a probe frequency of 8.0 MHz, a dynamic range of 81 db and a mechanical index of For CEHU, two planes were scanned for each patient: one being the transverse plane of maximal width; the other being the transverse plane of the sonographic abnormality, or the most hypervascular plane on colour Doppler imaging, for patients with no suspicion of prostate cancer on baseline ultrasonography. The entire examination was saved in a Digital Imaging and Communications in Medicine format and transmitted to a workstation for further analysis. Contrast-enhanced imaging was performed during the injection of a sulphur hexafluoride microbubble (SonoVue, Bracco, Italy) at a concentration of 8 µl/ml. A volume of 2.4 ml of contrast agent was administered for each contrast plane. In addition, a total volume of 4.8 ml of contrast agent was administered to each patient for two contrast planes. The contrast agent was administered as a bolus via an antecubital vein in the right arm. Immediately after contrast injection, 5 ml of 0.9% sodium chloride was injected to clear the intravenous cannula. Enhancement patterns of the lesions were observed and calculated. The peak intensity of the enhancement within the lesion was subjectively categorized into four groups: (i) no enhancement; (ii) increased; (iii) equal; or (iv) decreased enhancement, compared with adjacent normal tissue. The time-toenhancement, time-to-peak (TTP) intensity and peak intensity (PI) of the lesions and their adjacent normal tissue were objectively measured with Qontrast time intensity analysis software (Esaote). The time intensity curve was reconstructed and the curve characteristics were described using the following haemodynamic indices: arrival time (AT), which was the time when the signal had grown by 20% (measured in s); TTP, which indicated the moment of maximum enhancement (in s); PI; and area under the curve (AUC). To decrease interpatient variability, the normal tissue immediately adjacent to each nodule was used as the reference tissue and the relative time-to-enhancement, TTP and PI were calculated by subtracting the parameters in the normal tissue from those measured in the nodules. The suspicion of carcinoma included the presence of an echotexture abnormality or contour deformity on greyscale images, consisting of an increased or asymmetric flow pattern on Doppler images and substantial or heterogeneous enhancement on post-contrast images. MRI All scans were performed on a 3T MRI scanner (Magnetom Trio; Siemens AG, Erlangen, Germany) using an eight-channel phased-array body coil for signal reception. The entire prostate gland and seminal vesicles were imaged in axial, sagittal and coronal slices using a T2-weighted (T2W) 258

4 turbo spin-echo (TSE) sequence with a repetition time (TR) of 5160 ms, echo time (TE) of 96 ms, echo train length of 13 and three averages. Axial T1-weighted (T1W) TSE imaging was performed with a TR of 700 ms, TE of 12 ms, an echo train length of 3 and one average. These conventional MRIs were each obtained with a 3-mm slice thickness, 0.45-mm slice gap, 200-mm field of view (FOV), and a matrix of For the T2W sequence, a parallel imaging reduction factor of 2 was used, giving an acquisition time of 3 min 59 s for each slice orientation. For the T1W sequence, the acquisition time was 2 min 51 s. Axial DW images were obtained using a single-shot echoplanar imaging sequence with a TR of 2100 ms, TE of 72 ms, flip angle of 90, b-factors of 0, 300 and 600 s/mm 2, seven averages, 5-mm slice thickness, 1.5-mm slice gap, 230-mm FOV, matrix, and a parallel imaging reduction factor of 2. The voxel size was 2.18 mm 2.18 mm 5.0 mm, equalling mm 3. Following the acquisition of b = 0 s/mm 2 images, motion-probing gradients in three orthogonal orientations were applied sequentially. The scan time was 1 min 57 s. Apparent diffusion coefficient (ADC) maps were calculated automatically from the DW images acquired at the three b-factors. All image-interpretation sessions were performed on a workstation and the ADC maps were simultaneously displayed to the readers for DW-MRI. The ADC values were calculated from two DW-MRI scans acquired with b = 0 and b = 1000 s/mm 2. A lesion in the TZ or the PZ with abnormally intense surrounding tissue on DW-MRI and low ADC values was regarded as being a cancer (scale 5). A confidence level for the probability of malignancy (1, definitely absent; 2, probably absent; 3, undetermined; 4, probably present; 5, definitely present) in both the zones was recorded by a radiologist with at least 15 years experience. For sensitivity and specificity calculations, levels 1 through 3 were treated as meaning malignancy absent, and levels 4 and 5 were treated as meaning malignancy present. EVALUATION OF IMAGING PROTOCOLS Three image-interpretation protocols were analysed: protocol A (CEHU), protocol B (DW-MRI), and protocol C (CEHU plus DW- MRI). The basis of positive findings for protocols A or B have been described in detail above. The findings of protocol C were considered as positive when any of the protocol A or B findings were positive. The sensitivity, specificity, accuracy, positivepredictive value (PPV) and negativepredictive value (NPV) were evaluated for all three protocols. STATISTICAL ANALYSES Statistical analyses were carried out using the SPSS statistical package, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows. Sensitivity, specificity, PPV, NPV and accuracy for each protocol were calculated. The statistical analysis of differences between each protocol was carried out using the McNemar test. Receiver operating characteristic (ROC) curve analysis and 95% confidence intervals (CI) were calculated using the maximum likelihood estimation. A P-value < 0.05 was considered to be statistically significant. Results Forty-nine patients underwent DW-MRI and CEHU followed by a radical prostatectomy. The study included 31 TZ cancers in 28 patients with at least one tumour (tumour size > 10 mm) located predominantly in the TZ (i.e. > 50% of the tumour was located within the TZ). The patients with TZ tumours 259

5 ranged from 57 to 81 years of age (mean age, 68 years). The control group consisted of 25 PZ cancers in 21 patients without a TZ cancer. The patients with PZ tumours ranged from 62 to 86 years of age (mean age, 70 years). There were no significant differences in the characteristics of patients in the TZ and control (PZ) groups (data not shown). The 56 cancers from the 49 patients with prostate adenocarcinoma had Gleason scores ranging from 6 to 8. Gleason score analysis of the 31 TZ cancers showed 13 lesions had a Gleason score of 6, 14 lesions had a score of 7 and four lesions had a score of 8. Representative DW-MRI and CEHU images and a photograph of the tumour from a 69-year old patient with a TZ cancer of the prostate are shown in Fig.1. The sensitivity, specificity, accuracy, PPV and NPV for each protocol for TZ and PZ cancer diagnosis are shown in Table 1. With regard to the diagnosis of TZ cancers, there was a significant difference between protocol C (CEHU plus DW-MRI) and the other two protocols according to the McNemar test (P A*C = 0.021; P B*C = 0.001), but there was no significant difference between protocols A and B. Protocol C improved the sensitivity, accuracy and NPV more than protocols A (CEHU) and B (DW-MRI), but the specificity decreased. With regard to the diagnosis of PZ tumours, there was no significant difference between the three protocols according to the McNemar test. In the ROC curve analysis for TZ cancer, the area under the ROC curve (Az) values were (95% CI 0.513, 0.804), (95% CI 0.535, 0.822) and (95% CI 0.570, 0.853) for protocols A, B and C, respectively (Fig. 2). Discussion The management of prostate cancer is challenging because this disease has variable clinical and pathological findings. There is a growing demand for further individualization of treatment plans, which necessitates the accurate characterization of the location and extent of the prostate tumour. Both DW-MRI and CEHU have been rapidly promoted as diagnostic techniques for prostate cancer, in recent years. DW-MRI, which was developed in acute-stroke cases, has acquired new applications in detecting malignancies throughout the body since the ADC value was demonstrated to be significantly correlated with the cellular density of tissue Studies have demonstrated significant differences in the ADC value between malignant and nonmalignant prostate tissue A decrease in prostate ADC values with the development of cancer may be attributed to the proliferation of tightly packed cellular elements, with little space for mucus or fluid storage These studies concluded that prostate cancer can cause restricted diffusion relative to that of normal tissue, resulting in an increased signal for malignant lesions on DW-MRI and decreased pixel values on ADC maps Thus, DW-MRI has been applied in the detection and localization of prostate cancer. Prostate cancer tends to have increased vascularity compared with healthy prostatic tissue due to the formation of new vessels or an increase in the capacity of existing vessels Microbubble contrast agents provide a practical solution to the problem of imaging microvasculature in the prostate Contrast-enhanced ultrasonography, which is useful in assessing microvessel density, has shown potential value in the detection and localization of prostate cancer, and studies have suggested that contrast-enhanced ultra sonography is more sensitive than conventional systematic biopsy for the detection of clinically significant prostate cancer About 75 85% of prostate cancers arise 260

6 A B C FIGURE 1: (A) Diffusion-weighted magnetic resonance imaging and (B) contrastenhanced harmonic ultrasonography in a 69-year old patient with prostate cancer who underwent prostatectomy showed a suspect lesion in the left transition zone (TZ) (arrows). (C) Arrow indicates TZ cancer in the prostatectomy specimen (adenocarcinoma, Gleason score = 7) 261

7 TABLE 1: Sensitivity, specificity, accuracy, positive-predictive values (PPV) and negative-predictive values (NPV) for diagnostic protocols A, B and C in transition-zone (TZ) cancer and peripheral zone (PZ) cancer groups, in a study investigating the value of contrastenhanced harmonic ultrasonography (CEHU) and diffusion-weighted magnetic resonance imaging (DW-MRI) for prostate cancer diagnosis TZ cancer group (%) PZ cancer group (%) Protocol Sensitivity Specificity Accuracy PPV NPV Sensitivity Specificity Accuracy PPV NPV A B C a Protocol A, CEHU; protocol B, DW-MRI; protocol C, CEHU plus DW-MRI. a Statistically significant difference between protocol C and the other two protocols in the TZ cancer group according to the McNemar test (PA*C = 0.021; P B*C = 0.001). in the PZ of the gland. 42 Several studies have shown that both CEHU and DW-MRI provide important information that may help to improve the diagnostic capability of the traditional T2W imaging and TRUS methods for detecting prostate cancer in the PZ. 4,16 28 However, these studies have focused exclusively on prostate PZ cancers 4,16 28 and it has been shown that the TZ harbours cancer in up to 25% of radical prostatectomy specimens. 8,9,43 54 Cancers located in the TZ show some pathological and clinical features that are different compared with those of cancers located in the PZ. 46,47 With digital rectal examination, TZ cancers are more difficult to detect than PZ cancers because they are located anteriorly and are far from the rectum. 8,48,49 In fact, most TZ cancers are found incidentally, in transurethral prostateresection specimens. 9,50 It is important to distinguish TZ cancers accurately, with imaging to guide biopsy, to plan diseasetargeting therapies and avoid positive anterior surgical margins at radical prostatectomy. 48,51 54 Some researchers have applied CEHU or DW-MRI in the detection of TZ cancer, 4,15 28,33 36 but there has been no comparison of the two methods, or an evaluation of the efficacy of these two methods being used in combination. It was considered appropriate, therefore, to determine whether the use of CEHU, DW- MRI or CEHU plus DW-MRI could help to improve the detection and location of prostate TZ cancers. The present study retrospectively evaluated 49 patients undergoing radical prostatectomy: these patients had 31 TZ and 25 PZ cancers. The latter group of patients with PZ cancers formed the control group. For TZ cancer diagnosis, the sensitivity, specificity, accuracy, PPV and NPV of CEHU were 61.3%, 64.0%, 62.5%, 67.9% and 57.1% respectively, and for DW-MRI were 262

8 Sensitivity Protocol A B C Specificity FIGURE 2: Receiver operating characteristic (ROC) curves for three protocols: protocol A, contrast-enhanced harmonic ultrasonography (CEHU); protocol B, diffusionweighted magnetic resonance imaging (DW-MRI); protocol C, CEHU plus DW-MRI 64.5%, 68.0%, 66.1%, 71.4% and 60.7%, respectively; these findings were similar to those of other published studies. 16,36 When the two methods were compared, the sensitivity, specificity, accuracy, PPV and NPV of DW-MRI for TZ cancer diagnosis were not statistically significantly higher than those of CEHU. The sensitivity, accuracy and NPV were improved when DW-MRI was combined with CEHU for TZ cancer diagnosis. This implies that the possibility of a missed diagnosis for TZ cancer is decreased when DW-MRI is added to CEHU, which would be very useful for locating the target for biopsy in the TZ and improving the efficiency of TRUS-guided needle biopsy in the TZ, especially for patients who need to receive a repeat prostate puncture because of prior negative systematic biopsy findings. The DW-MRI plus CEHU combination was also valuable in excluding negative cases, as shown by the higher NPV. At the same time, more falsepositive cases would be found with DW-MRI plus CEHU, because of its lower specificity (52.0%). Consequently, it would be necessary for a patient with positive findings on DW- MRI plus CEHU to receive a further pathological examination. There was a significant difference between the DW-MRI plus CEHU combination and CEHU or DW-MRI alone for TZ cancer diagnosis according to the McNemar test, whereas there was no significant difference between the three protocols for PZ cancer diagnosis according to the McNemar test. The Az values for protocol C were higher than the other two protocols in the ROC curve analysis for TZ cancer (Fig. 2), which suggested that DW-MRI plus CEHU might be more valuable in the diagnosis of prostate TZ cancer. The sensitivity, specificity, accuracy, PPV and NPV of all of the three protocols were higher in the control (PZ) group than in 263

9 the TZ group, which might be related to the different clinical features of TZ cancer compared with PZ cancer (for example, the TZ cancer was more difficult to detect than the PZ cancer no matter which protocol was used). There were some limitations to the present study. First, the sample size used was small; secondly, the study did not use endorectal coils, thereby providing a spatial resolution that was inferior compared with MRI using endorectal coils. Thus, future studies should include a larger number of cases and MRI examinations with a higher spatial resolution. In conclusion, adding DW-MRI to CEHU increased the sensitivity, accuracy and NPV of the diagnosis of prostate TZ cancer. This protocol may, therefore, be a potentially useful option in the detection and location of prostate TZ cancer. Acknowledgements We thank Mr Xing Zhu MSc (Department of Biostatistics, School of Medicine, Shanghai Jiao Tong University, Shanghai, China) for his help with the statistical analysis and the nurses of the Department of Ultrasound in Medicine (The 6th People s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China) for their invaluable help in performing this study. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 28 August 2010 Accepted subject to revision 6 September 2010 Revised accepted 19 November 2010 Copyright 2011 Field House Publishing LLP References 1 Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, CA Cancer J Clin 2001; 51: Jemal A, Murray T, Ward E, et al: Cancer statistics, CA Cancer J Clin 2005; 55: Shao C-X, Xiang Y-B, Liu Z-W, et al: The analysis of the relative survival for urological cancer in urban Shanghai. Chin J Clin Oncol 2005; 32: Halpern EJ, Strup SE: Using gray-scale and color and power Doppler sonography to detect prostatic cancer. AJR Am J Roentgenol 2000; 174: Hodge KK, McNeal JE, Terris MK, et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142: Damiano R, Autorino R, Perdona S, et al: Are extended biopsies really necessary to improve prostate cancer detection? Prostate Cancer Prostatic Dis 2003; 6: Bourdin S, Karam G, Clemain P, et al: Clinical experience with leuprorelin acetate before radiotherapy for prostatic cancer. J Int Med Res 1990; 18(suppl 1): Eskew LA, Bare RL, McCullough DL: Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997; 157: McNeal JE, Redwine EA, Freiha FS, et al: Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988; 12: Noguchi M, Stamey TA, Neal JE, et al: An analysis of 148 consecutive transition zone cancers: clinical and histological characteristics. J Urol 2000; 163: Sakai I, Harada K, Kurahashi T, et al: Analysis of differences in clinicopathological features between prostate cancers located in the transition and peripheral zones. Int J Urol 2006; 13: Augustin H, Hammerer PG, Blonski J, et al: Zonal location of prostate cancer: significance for disease-free survival after radical prostatectomy? Urology 2003; 62: Yunkai Z, Yaqing C, Ren W, et al: Are transition zone biopsies necessary in transrectal ultrasound-guided transperineal prostate biopsy protocol? Results of a Chinese population-based study. Clin Imaging 2010: 34: Stewart CS, Leibovich BC, Weaver AL, et al: Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies. J Urol 2001; 166: Rabbani F, Sullivan LD: Transition zone 264

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