Advances in Ultrasound for the Detection of Prostate Cancer

Transcription

1 Ultrasound Quarterly Vol. 18, No. 2, pp Lippincott Williams & Wilkins, Inc., Philadelphia Advances in Ultrasound for the Detection of Prostate Cancer Ferdinand Frauscher, M.D.,* Andrea Klauser, M.D., and Ethan J. Halpern, M.D. *Radiologist and Professor of Radiology, Department of Radiology, Jefferson Prostate Diagnostic Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. and Radiologist, Department of Radiology II, University Hospital Innsbruck, Innsbruck, Austria Summary: The introduction of ultrasound (US) microbubble contrast agents has dramatically expanded the possibilities for US detection of prostate cancer. Recent advances in US technology have increased the value of US contrast agents. Many newer US techniques, which are quite sensitive for detection of microbubbles, are yet to be explored for prostate applications. A critical evaluation of the current status of transrectal US imaging for the detection of prostate cancer and background information for US contrast agents and imaging techniques are presented. Early results have demonstrated the feasibility of US contrast agents to enhance US imaging of prostatic disease. The application of US contrast agents for the detection and clinical staging of prostate cancer is promising. Future clinical trials are needed to determine whether the promise of contrast-enhanced US of the prostate will evolve into widespread clinical application. Key Words: Ultrasound Doppler studies Ultrasound contrast agents Prostate Diseases. Objectives: After reading this article and completing the posttest, the reader should be able to: Describe a standardized gray-scale and color Doppler imaging method for the evaluation of the prostate. Describe the normal and abnormal gray-scale and color Doppler imaging characteristics of the prostate. Describe the potential use of ultrasound contrast agents for detection of prostate cancer. Identify the role of new imaging techniques (i.e., contrast-enhanced color Doppler imaging, gray-scale harmonic imaging, intermittent imaging) to direct targeted biopsies performed in patients with suspected prostate cancer. Prostate cancer is currently the most commonly diagnosed visceral malignancy in men. In the United States, prostate cancer was estimated to account for approximately 198,100 new cases and 31,500 deaths among men in One decade ago, prostatic acid phosphatase, digital rectal examination, and subsequent manual biopsy were the only The authors have disclosed that they have no significant relationships with or financial interests in any commercial companies pertaining to this educational activity. Address correspondence and reprint requests to Ferdinand Frauscher, M.D., Department of Radiology, Jefferson Prostate Diagnostic Center, Thomas Jefferson University, Main Building, 7 th Floor, 132 South 10 th Street, Philadelphia, PA Ferdinand.Frauscher@uibk.ac.at. tools available for detection of prostate malignancy. The advents of prostate-specific antigen (PSA) assessment and transrectal ultrasound (US) imaging have revolutionized prostate cancer detection. 2 Combined with the current worldwide increase in prostate cancer awareness, newer screening methods have resulted in a great increase in prostate cancer detection. 3 Unfortunately, the increased detection rate of prostate cancer is associated with increased costs and morbidity among the increasing number of patients subjected to prostate biopsy. Because approximately one-fourth to one-third of patients who undergo biopsy have cancer, we estimate that more than 600,000 prostate biopsies are performed annually in the United States. Complications of prostate biopsy include hematuria, hematospermia, rectal bleeding, urinary retention, and urinary tract infection. 4 Although the quality of US machinery has improved remarkable over the course of the past decade, the positive predictive value of transrectal gray-scale US for prostate cancer has remained low. The chance of a hypoechoic lesion proving malignant after evaluation with directed biopsy varies between 17% and 57%. 4 9 Furthermore, the sensitivity and specificity of transrectal US is limited by inability to detect isoechoic tumors and by the often heterogeneous appearance of the prostate. 4 These difficulties have prompted research to improve the diagnostic accuracy of tests for prostate cancer detection and staging. One such area of 135

2 136 F. FRAUSCHER ET AL. interest is the application of Doppler and contrast-enhanced US techniques. COLOR DOPPLER IMAGING Color Doppler Ultrasound Color Doppler US is easily adapted for evaluation of vascularity within the prostate and in surrounding structures The reasoning behind application of color Doppler US for evaluation of tumor and neovascularity is straightforward. Cancer typically grows more rapidly than does normal tissue Tissue that replicates at faster rates of growth requires increased blood supply. The blood flow to malignant tissue is increased as compared with normal tissue and benign conditions. Color Doppler US of malignant tissue may demonstrate an increased number of visualized vessels, an increase in the size and irregularity of the vessels, and an increased flow rate. 22 These findings suggest that color Doppler US may have the potential to diagnose prostate cancer. Early results with Doppler US have suggested that up to 85% of men with prostate cancers greater than 5 mm in size have visibly increased Doppler flow in the area of tumor involvement. 10 Furthermore, Doppler imaging has the potential to identify areas of hypervascularity in patients with isoechoic and hyperechoic lesions, which are more difficult to identify. Doppler sensitivity for slow flow in small vessels is increased at higher frequencies of insonation. Most studies of color Doppler imaging of the prostate published in the past 5 years use frequencies in the range of 5 to 7.5 MHz. 23,24 Commercially available transrectal US probes now provide increased flow sensitivity with Doppler frequencies up to 9 MHz. In a recent study, we evaluated high-frequency Doppler for detection of prostate cancer. Furthermore, we evaluated the impact of patient position on increased Doppler flow in healthy volunteers. Each volunteer showed increased Doppler flow in the left base and mid gland when the subject was in the left lateral decubitus position. Flow was increased on the right side with the patient in the right lateral decubitus position. In supine position, a more symmetric flow pattern (Fig. 1) was demonstrated. Our results for Doppler detection of cancer (performed in left lateral decubitus position) demonstrated that the positive yield of directed biopsy was not better than the yield of sextant biopsy. Therefore, we recommend prostate biopsies using high-frequency Doppler in supine position. 25 Unfortunately, our own further studies suggest that the targeted biopsy in the supine position with color Doppler US will still miss a few cancers. Thus, color Dopplertargeted biopsy is not sufficiently sensitive to replace the standard systematic biopsy approach. Power Doppler Ultrasound Power Doppler US, an amplitude-based technique for the detection of flow, is more sensitive to slow flow and is less angle-dependent than is color Doppler US. This newer technique has been less commonly applied to the assessment of prostate tumor vascularity. 26 However, early studies have suggested that power Doppler US may be useful in detection of prostate cancer. In a recent study, we assessed the value of gray-scale, color, and power Doppler US for detection of prostatic cancer. We investigated 251 patients before biopsy. Each biopsy site was prospectively scored for gray-scale and Doppler abnormalities. Cancer was detected in 211 biopsy sites of 85 patients. Among patients with at least one positive biopsy result for cancer, foci of increased power Doppler flow were 4.7-times more likely to contain cancer than were adjacent tissues without flow. We concluded that power Doppler may be useful for targeted biopsies when the number of biopsy passes must be limited, 27 but there is no substantial advantage of power Doppler over color Doppler US. With current technology, neither color Doppler US nor power Doppler US provides sufficient sensitivity to preclude biopsy. 28 CONTRAST-ENHANCED ULTRASOUND IMAGING TECHNIQUES Recently developed microbubble US contrast agents improve the detection of low-volume blood flow by increasing the signal-to-noise ratio between blood and surrounding tissues Microbubbles have finite lifetimes in vivo that are highly dependent on bubble construction. Bubbles can be free or encapsulated in soft or hard shells. Thus, the duration of enhancement after injection lasts from a few seconds to more than 60 minutes, depending on the bubble type. The striking features associated with cancer neovessels include higher microvessel density and changes in vascular patterns (radiating into the tumor from the margins), tortuosity, and frequency of interconnections between adjacent vessels that produce a basket or network pattern with knots of intersections. 32 Intravascular contrast agents allow a more complete delineation of the neovascular anatomy by enhancing the signal strength from small vessels. Furthermore, these agents provide an entirely new opportunity to time the transit of an injected bolus. Unlike radiographic contrast media, which diffuse into the tissue and thus may obscure smaller vessels, microbubble echo-enhancing agents are confined to the vascular lumen where they persist until they dissolve. Contrast-Enhanced Doppler Imaging Between October 1997 and July 1998, 72 patients recruited from our PSA screening program were investigated to asses the value of a US contrast agent (Levovist; Schering, Berlin, Germany) for color Doppler imaging of the prostate. Forty patients had confirmed prostate cancer, 28 patients had benign prostatic hyperplasia, and four patients had prostatitis. To quantify the results obtained on color

3 ADVANCES IN US FOR DETECTING PROSTATE CANCER 137 FIG. 1. High-frequency color Doppler US of the prostate in a healthy subject. Transverse high-frequency color Doppler US scan operating at a frequency of 9 MHz shows symmetric, radial, intraprostatic vascular flow pattern. Doppler US, patients were categorized according to the degree of vascularization (Table 1). Among 40 patients with histologic evidence of prostate cancer, cancer was detected in 21 by means of contrast-enhanced color Doppler US (Fig. 2). Enhanced US yielded false-positive results in nine patients, whereas true-negative findings were obtained in 23 patients. In terms of distinguishing prostate cancer from benign lesions, contrast-enhanced US demonstrated a sensitivity of 53%, a specificity of 72%, and a positive predictive value of 70%. Unenhanced color Doppler US revealed a sensitivity of 37%, a specificity of 71%, and a positive predictive value of 48%. Additional resistive index measurements did not improve prostate cancer detection rate. Based on these findings, we concluded that contrast-enhanced color Doppler FIG. 2. Contrast-enhanced color Doppler US in a patient with prostate cancer. Sagittal contrast-enhanced color Doppler US scan reveals a hypervascular area with a peak systolic velocity of 50 cm/s in the right peripheral zone, which has proven to be prostate cancer. US significantly improved the detection of prostate cancer (p < 0.001) and may be useful for targeted biopsies. 33 Similar results were reported by Bree et al., 34 who used contrast-enhanced color Doppler to increase the diagnostic yield in a group of 17 patients with normal gray-scale transrectal ultrasonography results and increased PSA values. Correlation of biopsy sites with color Doppler US abnormalities revealed a sensitivity of 54%, a specificity of 78%, a positive predictive value of 61%, and a negative predictive FIG. 3. Gray-scale US and contrast-enhanced color Doppler US in a patient with prostate cancer. A. Transverse gray-scale US demonstrates an enlarged gland without a focal abnormality suspicious for cancer. B. Contrast-enhanced color Doppler US shows hypervascular area on the right side. Two positive biopsy core results were obtained only from that area.

4 138 F. FRAUSCHER ET AL. TABLE 1. Degree of vascularization G0 G1 G2 G3 G4 Criteria for grading tumor vascularity by color Doppler imaging CDI finding Prostate normally vascularized; PSV <0.3 m/s Hypervascularized areas ( 1); PSV <0.3 m/s Hypervascularized areas ( 1); PSV >0.3 m/s detected in 1 vessel Hypervascularized areas ( 1); PSV >0.3 m/s detected in 2 4 vessels Hypervascularized areas ( 1); PSV >0.3 m/s detected in 5 vessels PSV peak systolic velocity. PSV measurement was performed in hypervascularized areas only. Vessel count is related to one hypervascularized area only. Patients in groups G0, 1, and 2 had benign tumors, and patients in groups G3 and 4 were considered as having malignant tumors. value of 72% for the detection of prostate cancer. Three of their patients with a positive contrast-enhanced biopsy result had negative, transrectal ultrasonography, random biopsy results during the previous year. In a more recent study, we compared contrast-enhanced color Doppler-targeted biopsy with systematic conventional US-guided biopsy for the detection of prostate cancer. We investigated 84 consecutive men, recruited from a PSA screening program (serum total PSA 1.25 ng/ml and free/total PSA < 18%). Two independent investigators evaluated each subject. One investigator used contrastenhanced color Doppler with a Sequoia 512 unit (Acuson Corp., Mountain View, CA, U.S.A.) fitted with an end-fire probe operating at a Doppler frequency of 9 MHz. Targeted biopsies ( 5) were performed into hypervascular regions during intravenous infusion of Levovist (Schering, Berlin, Germany). A concentration of 300 mg/ml at an infusion rate of 1 ml/min to a maximum dose of 5 g was used. Afterwards, a second investigator performed 10 systematic biopsies of the prostate guided by conventional US (Combison 530MT unit; Kretztechnik AG, Zipf, Austria). Prostate cancer was detected in 24 of 84 patients (29%), with a mean total PSA of 3.7 ng/ml. Prostate cancer was detected in 23 of 84 patients (27%) with contrast-enhanced targeted biopsy. In 17 of 84 patients (20%), prostate cancer was detected with systematic biopsy. The contrast-enhanced technique detected cancer in seven patients (8%) with a negative systematic biopsy result (Figs. 3A,B), whereas the systematic biopsy detected cancer in only one subject. That subject s cancer was missed by contrast-enhanced targeted biopsy. The by-patient patient analysis demonstrates a significant improvement in the detection of prostate cancer for the contrast-enhanced targeted biopsy (McNemar s test: p 0.034). Furthermore, the odds ratio for detection of cancer by targeted biopsy versus systematic biopsy was 4.3 (p < 0.001). Our preliminary results suggest that this technique may allow for a cost-effective, limited, targeted biopsy approach. 35 Bogers et al. 36 evaluated contrast-enhanced threedimensional imaging of prostate vasculature with power Doppler. Three-dimensional power Doppler images were obtained before and after intravenous administration of 2.5 g Levovist (Schering). Subsequently, random and/or directed transrectal ultrasonography-guided biopsies were performed. Prostate vasculature was judged with respect to symmetry and vessel distribution. Eighteen patients with a suspicion of prostate cancer were included in the study. Prostate cancer was detected in 13 patients. Vascular anatomy was judged to be abnormal in unenhanced images in six cases, of which five proved to be malignant. Enhanced images were considered suspicious for malignancy in 12 patients, including one with benign pathology and 11 with malignant biopsy results. Sensitivity of enhanced images was 85% (specificity 80%) compared with 38% for unenhanced images (specificity 80%) and 77% for conventional gray-scale transrectal ultrasonography (specificity 60%). Among six patients who showed no B-mode abnormalities, vascular patterns were judged to be abnormal in four, of which three were malignant. Based on these findings, they concluded that contrast-enhanced threedimensional power Doppler angiography is feasible in patients with suspicion of prostate cancer who are scheduled for prostate biopsies. A more recent analyses by the same group suggested that the most suitable diagnostic predictor for prostate cancer was a combination of three-dimensional contrast-enhanced power Doppler US and PSA levels. 37 Contrast-Enhanced Harmonic Imaging A new approach to contrast-enhanced imaging of the prostate is Ensemble contrast imaging (Siemens Ultrasound, Issaquah, WA, U.S.A.). Ensemble contrast imaging uses phase-inversion technology to exploit the nonlinear behavior of the bubbles to differentiate blood-flow echoes from background tissue. Ensemble contrast imaging provides excellent contrast and spatial resolution. Albrecht et al. 38 demonstrated this method in 39 human subjects. The B-mode enhancement of vessels and organ parenchyma were seen in all subjects. Enhancement occurred from both flowing and stationary microbubbles. Flow-independent enhancement of tissue represents a major advance in contrast-enhanced US with many potential applications, particularly in tumor imaging. In a preliminary study of 26 subjects, we investigated the value of contrast-enhanced US to depict vascularity in the prostate. Continuous gray-scale imaging and intermittent gray-scale imaging were performed at the fundamental frequency. Phase-inversion gray-scale imaging was available for the final few subjects in the study. Sonographic findings were correlated with sextant biopsy results. After the administration of contrast material, gray-scale and Doppler images revealed visible enhancement (p < 0.05). Using intermittent imaging, we found focal enhancement in two

5 ADVANCES IN US FOR DETECTING PROSTATE CANCER 139 FIG. 4. Gray-scale, color, and power Doppler imaging and contrastenhanced harmonic imaging in a patient with prostate cancer. A. Transverse gray-scale US demonstrates no focal abnormality suspicious for cancer. B. Unenhanced color Doppler US shows no focal area of hypervascularity. C. Unenhanced power Doppler US shows subtle increased flow on the right base. D. Enhanced color Doppler US shows hypervascular area at the right base. E. Enhanced power Doppler US again shows hypervascular area at the right base. F. Ensemble contrast image in continuous mode shows subtle increased enhancement at the right base. G. Ensemble contrast image using intermittent imaging with an interscan delay of 2.0 seconds shows bright enhancing area at the right base.

6 140 F. FRAUSCHER ET AL. isoechoic tumors that were not visible on baseline images (Figs. 4A G). No definite focal area of enhancement was identified in any patient without cancer. We concluded that gray-scale and Doppler enhancement of the prostate can be seen on sonographic images after the administration of an intravenous contrast agent and that contrast-enhanced intermittent US of the prostate may be useful for the selective enhancement of malignant prostatic tissue. 39 We have recently completed a prospective study of contrast-enhanced transrectal US in 60 patients who underwent sextant biopsy of the prostate. All examinations were performed with the Sonoline Elegra (Siemens, Issaquah, WA, U.S.A.) using Ensemble contrast imaging. Each subject was evaluated with conventional gray-scale, harmonic grayscale, and power Doppler US before contrast infusion. The evaluation was repeated during intravenous infusion of Definity (DuPont Pharmaceuticals, Billerica, MA, U.S.A.). Gray-scale imaging was performed in continuous mode and with intermittent imaging using interscan delay times of 0.5 seconds, 1.0 second, 2.0 seconds, and 5.0 seconds. Each biopsy result was scored prospectively as benign or malignant on baseline imaging and again during contrastenhanced transrectal US. Prostate cancer was present in 37 biopsy sites from 20 subjects. Baseline imaging demonstrated cancer in 14 sites from 11 subjects. Contrastenhanced transrectal US showed cancer in 24 sites from 15 subjects (Figs. 5A C). Each of the five subjects whose prostate cancer was not detected by contrast-enhanced transrectal US had only a single positive biopsy core with a Gleason score of 6 or less. The improvement in sensitivity from 38% (baseline) to 65% (contrast-enhanced) was significant (p < 0.004). Specificity was not significantly different at baseline (83%) or during contrast-enhanced imaging (80%). Our results suggest that contrast-enhanced transrectal US may improve sensitivity for prostate cancer detection without substantial loss of specificity. 40 In another study, we correlated contrast-enhanced US detection of prostate cancer with pathology results from whole mount slides of radical prostatectomy specimens. Our purpose was to correlate contrast enhancement with foci of malignancy or other pathologic processes in the prostate. Transrectal US was performed in 12 subjects with cancer of the prostate before radical prostatectomy. Each gland was evaluated with conventional gray-scale and wideband har- FIG. 5. Contrast-enhanced harmonic imaging in a patient with prostate cancer. A. Transverse gray-scale US demonstrates no focal abnormality suspicious for cancer. B. Ensemble contrast image in continuous mode shows subtle increased enhancement at the right base (one arrow) after contrast administration. Enhancement was also seen on the left side (three arrows). C. Ensemble contrast image using intermittent imaging with an interscan delay of 1.0 second shows bright enhancing area at the right base. One positive biopsy core was obtained only from that area (two arrows).

7 ADVANCES IN US FOR DETECTING PROSTATE CANCER 141 monic imaging at baseline and again during intravenous infusion of a microbubble contrast agent (Sonazoid; Nycomed Amersham, Oslo, Norway). Focal areas of contrast enhancement were identified prospectively in the transverse plane and at the base, mid gland, and apex. Correlation was performed with pathologic interpretation of whole mount prostatectomy specimens. We found 31 foci of prostate cancer on surgical pathology, with multiple foci of cancer in 11 of the 12 glands. Baseline US detected three of 10 inner gland cancers and five of 21 outer gland cancers. Diffuse inner gland enhancement was identified in all patients during US contrast agent infusion. Contrast-enhanced imaging demonstrated an additional five cancer foci in the outer gland (p 0.025). Seven additional sites of focal contrast enhancement were identified. Five of these sites corresponded to foci of hyperplasia. Two sites were falsepositive with no pathologic abnormality. Increased flow was not demonstrated posteriorly in the midline, even when tumor was present diminished contrast-enhancement in this area may be related to probe pressure. In summary, contrast-enhanced US of the prostate can improve sensitivity for detection of cancers in the outer gland, but it will also demonstrate focal enhancement in areas of benign hyperplasia. Although most enhancing foci correspond to sites of malignancy, only half of all cancer foci were detected by contrast enhancement. Based on these results, we believe that contrast-enhanced US may be useful for repeat biopsy in patients with an increased PSA and negative sextant biopsy results. 41 FUTURE INNOVATIONS The increased blood flow detected with contrastenhanced US is consistent with the observation that prostate cancer has a two-fold increase in microvessel density as compared with benign prostatic tissue. 28 Quantification of microvessel density provides a unique indicator of pathologic stage and progression in prostatic cancer. Although the detection of prostate cancer with contrastenhanced transrectal US may be improved relative to baseline transrectal US, substantial uncertainty remains in the interpretation of contrast-enhanced transrectal US images. 40 Future studies of transrectal contrast-enhanced US of the prostate should investigate new techniques to optimize the signal from US contrast agents and to maximize the difference in signal between benign and malignant prostatic tissues. As seen from our images, prostate cancer often demonstrates enhancement, but the level of enhancement may not be much greater than that of normal parenchyma. Greater enhancement may be obtained with the bolus administration of contrast agents. New imaging techniques may be developed to decrease bubble destruction during imaging. Newer microbubble agents that resonate at higher frequencies may provide better signal because the prostate is generally evaluated with a frequency in the range of 5.0 to 7.5 MHz. Alternatively, harmonic imaging at lower frequencies or with subharmonics may be helpful with current contrast agents. 42,43 Quantification of color Doppler US information is generally based on a classification or subjective estimation by the examiner. 44 These approaches are highly subjective. Cosgrove et al. 45 presented a system for objective evaluation, thus introducing a method of color pixel and vessel counting. However, this manual method is cumbersome and does not distinguish pixels with different flow velocities. Flow velocity has been shown to be helpful in the differentiation of benign and malignant lesions in continuous-wave and duplex US studies. Huber et al. 46 adapted a computerized method for the evaluation of color Doppler US images to quantify color pixels in a selected region of interest. This method evaluates local flow velocities by using a microbubble-based US contrast agent, and it allows additional assessment of enhancement kinetics. 46 After microbubble contrast agent injection, breast carcinomas and benign lesions behave differently in degree, onset, and duration of Doppler US enhancement. Therefore, timeintensity curves may be useful as another objective measure to differentiate benign from malignant prostatic tissue. In summary, promising preliminary results have been obtained for the application of US contrast agents to detect and stage prostate cancer. Technical improvements in US equipment will allow better detection of smaller, low-flow vessels (i.e., tumor vessels). Three-dimensional technologies may allow improved detection of areas of flow asymmetry. Computerized quantification of enhancement will provide an objective grading system. Future clinical trials are essential to determine whether the promise of contrastenhanced transrectal US evolves into a practical clinical application. REFERENCES 1. Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics CA Cancer J Clin 2001;51: Carter HB, Coffey DS. The prostate: an increasing medical problem. Prostate 1990;16: Scardino PT, Weaver R, Hudson MA. Early detection of prostate cancer. Hum Pathol 1992;23: Rifkin MD. Ultrasound of the prostate. New York: Lippincott-Raven; Rifkin MD. Prostate cancer: the diagnostic dilemma and the place of imaging in detection and staging. World J Urol 1998;16: Bartsch G, Egender G, Hubscher H, et al. Sonometrics of the prostate. 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