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Genitourinary Imaging |
1 From the Departments of Radiology (E.J.H.) and Urology (L.G.G.), Jefferson Prostate Diagnostic Center, Thomas Jefferson University, 132 S 10th St, Philadelphia, PA 19107-5244; and DuPont Pharmaceuticals, Billerica, Mass (M.R.). Received June 23, 2000; revision requested July 27; revision received August 18; accepted September 14. Address correspondence to E.J.H. (e-mail: ethan.halpern@mail.tju.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Sixty subjects were examined with conventional gray-scale, harmonic gray-scale, and power Doppler sonography. Evaluation was repeated during intravenous infusion of contrast agent. Gray-scale imaging was performed in continuous mode and with intermittent imaging by using interscan delay times of 0.5, 1.0, 2.0, and 5.0 seconds. Sextant biopsy sites were scored prospectively as benign or malignant at baseline imaging and again during enhanced transrectal sonography.
RESULTS: Prostate cancer was present in 37 biopsy sites from 20 subjects. Baseline imaging demonstrated prostate cancer in 14 sites in 11 subjects. Enhanced transrectal sonography depicted prostate cancer in 24 sites in 15 subjects. Each of the five subjects in whom prostate cancer was missed had only a single biopsy core with positive findings (Gleason score 
6). In three of these five subjects, prostate cancer made up less than 10% of the core. The improvement in sensitivity from 38% (14 of 37 malignant foci) at baseline to 65% (24 of 37 malignant foci) with contrast enhancement was significant (P < .004, McNemar 
2 test). Specificity was similar at baseline (267 [83%] of 323 malignant foci) and during enhanced transrectal sonography (257 [80%] of 323 malignant foci). Clustered receiver operating characteristic analysis demonstrated significant improvement in diagnostic accuracy during enhanced transrectal sonography (P = .027).
CONCLUSION: Enhanced transrectal sonography improves sensitivity for the detection of malignant foci within the prostate without substantial loss of specificity. Low-volume tumors with a Gleason score of 6 or less may not be detected with enhanced transrectal sonography.
Index terms: Prostate, US, 844.12984, 844.12988, 844.12989 • Prostate neoplasms, 844.32 • Ultrasound (US), contrast media, 844.12988 • Ultrasound (US), harmonic study, 844.12989 • Ultrasound (US), power Doppler studies, 844.12984
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A sextant biopsy of the prostate consists of the acquisition of six biopsy cores distributed throughout the prostate. Among patients with an elevated PSA level and a negative initial sextant biopsy finding, repeat biopsy demonstrates the presence of malignancy in approximately 20%–30% (3–6). Authors of recent articles (7–10) have recommended that the number of biopsy cores should be increased to reduce the false-negative rate of sextant biopsy. A patient with an elevated PSA level and repeated negative biopsy findings may undergo a saturation biopsy procedure under anesthesia, with numerous biopsy cores obtained to identify a cancer. In terms of monetary costs, this large number of prostate biopsies is associated with expenditures both for the procedure itself and for the pathologic assessment of biopsy cores. Furthermore, each biopsy procedure and each additional biopsy core is associated with a small incremental risk of hemorrhage and infection (11).
An accurate, noninvasive diagnostic imaging examination of the prostate could be used to limit the number of men without cancer subjected to biopsy and to target selected sites in men with the disease. Accurate, noninvasive image-guided biopsy will be cost-effective if it can be used to identify clinically important cancers in the prostate and direct a limited, targeted biopsy procedure of those malignancies. Unfortunately, conventional ultrasonography (US), which is used to guide biopsy of the prostate, is not sufficiently accurate for targeted biopsy, even with the addition of Doppler evaluation (12). An earlier study (13) at our institution demonstrated selective enhancement of tumor foci within the prostate during the administration of a US contrast agent. Intermittent imaging was used to slow the US frame rate and improve gray-scale enhancement of the neovasculature associated with prostate cancer. The present study was performed as a prospective blinded protocol to assess the detection of prostate cancer with contrast material–enhanced transrectal sonography.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sonographic examination was performed with the Sonoline Elegra system (Siemens Medical Systems, Issaquah, Wash) by using software version 5.0, which provides wideband harmonic pulse inversion imaging with the EC6.5 transrectal probe. Gray-scale imaging was first performed in both transverse and sagittal planes at the fundamental frequency and then was repeated in the wideband harmonic mode by using default settings optimized for contrast-enhanced harmonic imaging. Four additional transverse harmonic imaging passes were performed in intermittent imaging mode with interscan delay times of 0.5, 1.0, 2.0, and 5.0 seconds. A final transverse imaging pass was performed for power Doppler imaging. The intermittent imaging mode on our system controls the frame rate by setting a fixed interval between the transmit pulses for each frame. A longer interscan delay will allow more contrast material to traverse into the microvasculature in the imaging plane.
The mechanical index was initially set to 0.3 for most patients. However, the examiner was allowed to change the mechanical index to optimize visualization of contrast enhancement. Gray-scale gain was adjusted for baseline imaging and was not altered after contrast material injection. Power Doppler gain was adjusted at baseline to maximize signal but eliminate clutter noise from the prostate. The entire imaging sequence was performed at baseline and was repeated during infusion of contrast material (enhanced transrectal sonography). Power gain was reduced after contrast material injection to eliminate blooming. The entire examination was recorded on S-VHS videotape.
The US contrast agent used in this study (Definity; DuPont Pharmaceuticals, Billerica, Mass) was a sterile nonpyrogenic suspension of liposome-encapsulated perfluoropropane microbubbles. The contrast agent is composed of a blend of three phospholipids contained in a matrix of sodium chloride, propylene glycol, and glycerin in water. The contrast agent is supplied in a vial that contains the phospholipids and perfluouropropane gas. The microbubble agent is supplied in a standard-size vial and is prepared by shaking the vial with the aid of a shaking device (Vialmix; ESPE, Seefeld, Germany). Two vials of the agent were prepared immediately prior to its infusion and were diluted into a 50-mL bag of normal saline, yielding a concentration of 49.4 µL/mL. The entire contents of this bag were infused at an initial rate of 4 mL/min.
Sextant biopsy was performed after completion of the imaging protocol. When there was no visible abnormality, standard sextant biopsy was performed with three samples from each side of the gland at the base, midgland, and apex. Biopsy specimens were directed preferentially to the lateral portion of the gland to sample outer gland material. When an abnormality was present either at baseline or during contrast material infusion, the biopsy specimen from the corresponding sextant was directed toward the visualized abnormality. The site of each biopsy specimen was evaluated and rated during the procedure at baseline and again during contrast material infusion by the examining physician (E.J.H.).
A six-point rating scale was used to classify each site in terms of the likelihood of malignancy. Each biopsy site was scored as follows: 6, malignant definite; 5, malignant possible; 4, malignant indeterminate; 3, benign indeterminate; 2, benign possible; or 1, benign definite. The baseline score was a subjective impression based on gray-scale and Doppler US findings. Gray-scale considerations included the presence of an echotexture abnormality or a contour deformity. Power Doppler images were evaluated for the presence of increased flow. The postcontrast score of each biopsy site was based on baseline findings, as well as the level of visualized enhancement during contrast material infusion. When baseline gray-scale findings and postinfusion enhancement were discordant, the degree of contrast enhancement was weighted more strongly in determining the postcontrast score. Baseline scores were assigned prior to contrast material infusion. Postcontrast scores were assigned prior to biopsy. All complications of the procedure and physical complaints by the patient were recorded.
Pathologic evaluation of the biopsy cores was the reference standard for calculation of sensitivity and specificity. Each biopsy core was evaluated by a pathologist for the presence of cancer. A Gleason score was recorded for each positive biopsy core finding. Sensitivity and specificity of baseline sonography and enhanced sonography were computed both for biopsy site and for patient. The six-point US grading scheme was divided into two equal halves for this calculation. Scores of 1–3 were classified as benign, while scores of 4–6 were classified as malignant. The comparison of results from baseline and enhanced US requires a paired analysis, which was performed with a McNemar 2 test for symmetry by using STATA 6.0 software (Stata; College Station, Tex). Receiver operating characteristic (ROC) analysis of the biopsy site ratings was complicated by the lack of independence among the six observations within each prostate. This analysis was handled with a nonparametric technique for clustered ROC analysis (14).
Theoretically, there should be a correlation between the degree of contrast enhancement as a marker for tumor neovascularity and the Gleason grade. The "nptrend" command in the software (Stata) was applied to all positive biopsy core findings to test for trend in the confidence of diagnosis as a function of the Gleason score. Nptrend performs a nonparametric test for trend across ordered groups and is an extension of the Wilcoxon rank sum test. For the purposes of this test statistic, biopsy cores were ordered in the following sequence of ordered groups: microfoci of tumor too small for grading, microfoci of tumor with a single Gleason pattern of 3 or less, tumor cores with a Gleason score of 5, those with a Gleason score of 6, those with a Gleason score of 7, and those with a Gleason score of 8. To better evaluate the magnitude of the relationship between confidence of diagnosis and the Gleason score, a nonparametric correlation coefficient, Spearman 
, was computed.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One subject complained of a mild headache after infusion of the contrast agent. Two subjects complained of back pain during the infusion. The back pain in both subjects subsided several minutes after the infusion was stopped. In one subject with severe lower back pain, the infusion was terminated before the acquisition of Doppler data. All of the remaining subjects completed the entire imaging protocol. One subject experienced hematuria and urinary retention after the biopsy procedure and needed placement of a Foley catheter that remained in place for 3 days. There were no other complications.
Both gray-scale and Doppler enhancement sonograms were evaluated at baseline and during contrast material infusion. With baseline evaluation, gray-scale sonograms depicted suspicious foci. Additional suspicious foci were depicted on the basis of an increased Doppler flow superimposed on a normal gray-scale pattern. With enhanced transrectal sonography, all suspicious foci were demonstrated at gray-scale imaging either as a hypoechoic focus prior to contrast material administration or as focal enhanced areas during the infusion.
Two examples of tumor detected with enhanced transrectal sonography are presented to illustrate the sonographic appearance of malignant foci with enhanced transrectal sonography. In the first example, a hypoechoic focus appreciated at baseline (Fig 1a) was associated with focal enhancement during contrast material infusion (Fig 1b, 1c). In the second example, no abnormality was appreciated at baseline imaging (Fig 2a), but a focus of asymmetric enhancement was identified with enhanced transrectal sonography and was suggestive of malignancy (Fig 2b). In general, enhancement of the prostate was best with continuous imaging or with intermittent imaging with an interscan delay time of 0.5 seconds. Visualizaion of contrast enhancement was substantially better with a mechanical index of 0.3 or lower. Higher levels of the mechanical index resulted in poor visualization of contrast enhancement, particularly with continuous imaging and short interscan delay times. In many subjects, visualization of contrast enhancement was improved by decreasing the mechanical index to 0.1 or 0.2.
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2 test for symmetry, 8.33), while the difference in specificity was not significant (P = .239; McNemar 2 test for symmetry, 1.39). Those biopsy cores with positive findings that were missed on prospective interpretation of enhanced transrectal sonograms included two cores with a Gleason score of 7, seven cores with a Gleason score of 6, and four cores with tumor microfoci.
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was computed as 0.15 for correlation between baseline confidence ratings and the Gleason score (P = .36). Spearman was computed as 0.33 for correlation between confidence ratings during contrast material infusion and the Gleason score (P = .049).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Optimal enhanced transrectal sonographic scanning parameters used in the present study were different from those identified in our prior work (13). Optimal tumor enhancement in our previous preliminary study was obtained with an interscan delay time of 2.0 seconds. In the current study, optimal enhancement was obtained with continuous imaging or an interscan delay of 0.5 seconds. The optimal mechanical index in our prior study was approximately 0.7–0.8. By using an updated version of the same US system, the optimal mechanical index in the present study was at or below 0.3. Some of the difference could be related to the use of a different contrast agent. The imaging technique was also different in the two studies; the previous study was performed with fundamental imaging, while the present study involved the use of a wideband harmonic pulse-inversion mode. Finally, some of the difference could be related to upgrading of the software on the system.
Authors of several preliminary articles have described the application of enhanced imaging to the evaluation of the prostate. A dose-response relationship was demonstrated (16) for Doppler enhancement of the prostate with one agent. Authors of two articles (17,18) have suggested that enhanced color flow US may be associated with the presence of prostate cancer. The authors of another article (19) suggested that color flow US might be used to monitor progress of therapy for prostate cancer. Author of a recent article (20) of three-dimensional power imaging with contrast material administration suggested that enhanced power Doppler evaluation provides increased sensitivity for the presence of prostate cancer. In none of these studies were pathologic data from individual biopsy sites correlated with contrast material enhancement in a prospective fashion.
Our own preliminary data (13) demonstrated little diagnostic advantage for enhanced Doppler evaluation, but they did suggest that enhanced gray-scale imaging might demonstrate the location of prostatic malignancies. Although Doppler enhancement was present in every subject examined in the present study, Doppler findings did not alter the diagnosis as demonstrated with gray-scale imaging. Gray-scale imaging of contrast enhancement offers several theoretic advantages over Doppler evaluation. Gray scale provides better spatial and temporal resolution. Intermittent imaging with gray scale can be performed with short interscan delays. Perhaps most important, destruction of microbubbles is minimized with gray-scale imaging. Finally, the commercial introduction of harmonic imaging techniques has dramatically improved the visualization of contrast material with gray-scale imaging.
Will enhanced transrectal sonography with targeted biopsy of the prostate provide a cost-effective alternative to the current standard of care? The cost-effectiveness analysis consists of two parts. First, we must determine whether the technique can be used to identify clinically important cancers, and second, we must demonstrate a reduction in costs.
The clinical importance of a cancer in the prostate correlates with tumor grade, stage, volume, and microvascular density. Published articles (21,22) based on the Connecticut tumor registry demonstrated no loss of life expectancy in conservatively treated men with Gleason scores of 2–4, and demonstrated only a modest risk of death with Gleason scores of 5–6. In a prospective study (23) of 642 patients in Sweden, it was concluded that patients with localized prostate cancer have a favorable outlook, with watchful waiting, and that an aggressive approach in all patients with early disease would entail substantial overtreatment. Results of an analyses (24) of prostate cancer volumes suggest that tumors with a volume of less than 0.5 mL are unlikely to be clinically important. Study findings of microvessel density within the prostate demonstrate a clear association of increased microvessel density with the presence of cancer (25), metastases (26), the stage of disease (27–29), and disease-specific survival (30,31). Quantitative assessment of microvascular density may actually provide important data to guide therapeutic decision making (32).
In the 20 subjects with cancer in the current study, tumor was identified prospectively with enhanced transrectal sonography in 15. The 15 cancers that were detected were of generally higher grade than the five cancers that were missed. Furthermore, each of the five subjects whose tumors were missed had no more than one biopsy core with positive findings. Although the results of sextant needle biopsy cannot be used to predict the precise stage or volume of tumor in a particular individual, our results (33) suggest that enhanced transrectal sonography does preferentially depict larger and higher-grade lesions. Furthermore, it is possible that directed sextant biopsy in this enhanced series revealed additional lesions that might have gone undetected with standard sextant biopsy. On the basis of these considerations, we suggest that the sensitivity of enhanced transrectal sonographic targeted biopsy is equal to or greater than that of standard sextant biopsy for clinically important lesions.
The direct medical costs associated with the procedure include a single US and biopsy charge (hospital charge, $2,490; Pennsylvania Medicare reimbursement for diagnostic prostate US, Health Care Common Procedure Coding System [HCPCS] code 76872, $103.70; US guidance for needle biopsy, HCPCS code 76942, $102.55; needle biopsy, HCPCS code 55700, $89.55 [34]), as well as an additional pathologic examination charge for the interpretation of findings in each biopsy core (hospital charge, $194; Pennsylvania medicare reimbursement for HCPCS code 88305, $81.37 [34]).
As demonstrated in Table 1, targeted biopsy of those sites with positive enhanced transrectal sonographic findings would have resulted in 90 biopsy cores instead of 360, resulting in a reduction of pathologic interpretation costs by 75%. The data in Table 2 suggest that targeted biopsy of patients with positive enhanced transrectal sonographic findings would have resulted in biopsy of 35 patients in our study population of 60, resulting in a reduction in diagnostic US and biopsy charges by 42%. Although the cost of US contrast agents has not been established, it seems likely that enhanced transrectal sonography with limited, targeted biopsy will result in cost savings. Furthermore, limiting the number of biopsy procedures would undoubtedly reduce complications. As an interesting aside, there will be an economic disincentive for the physician who performs the biopsy, since enhanced transrectal sonography will reduce the number of reimbursable biopsy procedures.
On the basis of the results of this small prospective trial, it seems likely that enhanced transrectal sonography of the prostate with targeted biopsy will be cost-effective relative to standard sextant biopsy. However, several constraints of our study design limit the generalizability of this conclusion. The sample size of 60 subjects yielded only 20 patients with cancer. To confirm that clinically important cancers are identified, it would be best to have a larger sample size with 5–10-year follow-up of negative US findings. Furthermore, a single imager in a single center examined all of the subjects in the current study. If these results are to be of value to the wider medical community, they must be reproduced in a larger trial at multiple centers.
The use of US to select the biopsy sites introduced an element of work-up bias into the study (35,36). This form of bias was unavoidable since we wished to sample areas of sonographic abnormality to determine the importance of these US findings. However, two features of our study design minimize the effect of this work-up bias. The requirement for sextant biopsy in all subjects ensured that there were many biopsy sites without US abnormalities. Furthermore, since biopsy was directed to any focus of abnormality seen either at baseline or after contrast material administration, a similar bias was introduced for both pre- and postcontrast imaging.
The study design is further limited by the use of biopsy cores for pathologic correlation. Although each biopsy site was correlated with imaging findings, we cannot be certain that the biopsy needle passed through each visible sonographic abnormality. A sampling error of a few millimeters can result in a false-negative biopsy finding that is interpreted as a false-positive finding with enhanced transrectal sonography. Similarly, we cannot be certain that all of the cancers were identified, since none of the patients with negative biopsy results underwent pathologic examination of the remaining prostate tissue. Thus, we may have underestimated the false-negative rate of enhanced transrectal sonography. Nonetheless, our study design does provide a prospective evaluation of enhanced transrectal sonography relative to the current standard for the diagnosis of prostate cancer. Thus, comparison of enhanced transrectal sonographic findings with biopsy data is a reasonable way to measure cost-effectiveness of targeted biopsy on the basis of enhanced transrectal sonography.
One final limitation is the issue of inner gland tumors. Sextant biopsy cores were obtained from only the outer gland. Nonetheless, since the vast majority of prostate cancers are in the outer gland and since sextant biopsy of the outer gland is the standard of care, it was reasonable to direct this initial study at the detection of outer gland cancers. Inner gland cancers will be more difficult to detect because they are often superimposed on changes of benign prostatic hyperplasia.
Although the detection of prostate cancer with enhanced transrectal sonography is improved relative to baseline transrectal sonography, substantial uncertainty remains in the interpretation of enhanced transrectal sonograms. As demonstrated in Table 3, 59 of 360 biopsy sites were rated prospectively as indeterminate on enhanced transrectal sonograms. Future studies of enhanced transrectal sonography should be conducted to investigate new techniques to maximize the difference in signal between benign and malignant tissues.
Greater enhancement may be obtained with bolus administration of contrast material. New imaging techniques may reduce bubble destruction. Newer bubble agents that resonate at higher imaging frequencies may provide better signal, since the prostate is generally evaluated at 6–7 MHz. Alternatively, harmonic imaging at lower frequencies or with subharmonics may be useful with current contrast agents (37,38). Time-intensity curves may provide an objective measure to demonstrate the more rapid enhancement of tumor relative to normal parenchyma. Three-dimensional presentation and other postprocessing image enhancements may increase the conspicuity of cancers. In the final analysis, a simplified protocol will be needed with clear enhancement of malignant foci if enhanced transrectal sonography is to be generally applicable in screening for prostate cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: HCPCS = Health Care Common Procedure Coding System, PSA = prostate-specific antigen, ROC = receiver operating characteristic
Author contributions: Guarantor of integrity of entire study, E.J.H.; study concepts, E.J.H., M.R., L.G.G.; study design, E.J.H., M.R.; literature research, E.J.H.; clinical studies, E.J.H.; data acquisition, E.J.H., L.G.G.; data analysis/interpretation, E.J.H.; statistical analysis, E.J.H.; manuscript preparation and editing, E.J.H.; manuscript definition of intellectual content, E.J.H., M.R.; manuscript revision/review and final version approval, E.J.H., M.R., L.G.G.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and with contrast-enhanced US (
). ROC area for the detection of prostate cancer is significantly greater with contrast-enhanced US.