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Genitourinary Imaging |
1 From the Department of Radiology (E.K., M.A.B.) and the Radiology Fellowship Program (H.M.F., M.B.), Boston University School of Medicine, 88 E Newton St, Boston, MA 02118. Received July 5, 2000; revision requested August 16; final revision received March 29, 2001; accepted March 29. Address correspondence to E.K. (e-mail: ewa.kuligowska@bmc.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Between 1995 and 1999, 544 patients with elevated PSA levels and/or abnormal digital rectal examination underwent transrectal US-guided sextant biopsy and targeted biopsy of US abnormalities. Sensitivity, specificity, and accuracy of gray-scale US, color Doppler US, targeted biopsy, and PSA and excess PSA were calculated.
RESULTS: Gray-scale US depicted 78 (41.1%) of 190 cancers, whereas color Doppler US depicted 30 (15.8%) additional cancers. Targeted biopsy was used to detect 108 (56.8%) cancers, whereas sextant biopsy was used to detect 82 (43.2%) additional cancers. Although US-visible cancers had a higher Gleason grade than did cancers discovered at sextant biopsy (P < .05), 25 of the 66 cancers identified with sextant biopsy alone were Gleason grade 6 or higher. Color Doppler US–depicted hypervascularity correlated with biologically aggressive tumors. Excess PSA was normal in 58 (30.5%) cancers, with an accuracy of 67.3%, resulting in better prediction of prostate tumors than with serum PSA level alone.
CONCLUSION: Gray-scale transrectal US, even coupled with color Doppler US, is inadequate for prostate carcinoma screening; therefore, targeted biopsy should always be accompanied by complete sextant biopsy sampling.
Index terms: Genitourinary system, abnormalities, 844.32 • Prostate, biopsy, 844.1261, 844.12985 • Prostate, US, 844.12983, 844.12985, 844.12989
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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DRE, transrectal US, and PSA measurement are limited as screening tests because of insufficient sensitivity, specificity, and cost-effectiveness (2–4). Prostate cancer, hyperplasia, and prostate inflammation result in elevated serum PSA levels to different extents. This lack of specificity of serum PSA measurement for screening has led to a search for the correct combination of the results of PSA, transrectal US, and DRE to improve specificity without a reduction in sensitivity (5–7). Lee and Littrup (7) developed the concept of a predicted PSA value based on the individual prostate volume estimation from transrectal US. The predicted PSA value is then compared with the measured serum PSA level to generate a value for excess PSA level (6–8). The often significant contribution of prostatic hyperplasia to the elevated PSA level is thus taken into account (9–11). Although transrectal US is recognized as the method of choice for biopsy guidance, its low positive predictive value (PPV) in diagnosing malignancy has consistently been a weakness (12,13).
Color Doppler US has been shown to be an important adjunct to conventional gray-scale transrectal US, improving the accuracy of cancer detection, especially for isoechoic cancers (14–19). It has also been suggested that color Doppler US is important for recognition of tumors with higher Gleason grades (20–28). Despite extensive evaluation of all methods currently available for diagnosing prostate cancer at an early and potentially curable stage, no single test or procedure has, to our knowledge, emerged as the most efficacious.
The purpose of this study was to retrospectively evaluate the accuracy of serum PSA, calculated excess PSA, and transrectal US (gray-scale and color Doppler) as predictors for prostate carcinoma and to assess color Doppler US depiction of tumor vascularity as a predictor of higher-grade Gleason scores, which may reflect more aggressive tumors. We also compared targeted with random sextant transrectal US–guided biopsy in identifying prostate cancer and attempted to determine whether the cancers identified with targeted biopsy differed in biologic activity from those found with random sextant biopsy in terms of their Gleason scores.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Imaging Technique
The entire transrectal US examination was performed by one of three experienced radiologists (E.K., M.A.B., or H.M.F.) using a broad-bandwidth 5–9-MHz dedicated endorectal probe (Advanced Technology Laboratories, Bothell, Wash). Transrectal US included imaging in transverse and sagittal planes by using both gray-scale and color Doppler US. Gray-scale imaging was performed first, followed by color Doppler US. The color window sector width was increased to include the entire transverse width of the gland. To optimize detection of low-velocity flow, the pulse repetition frequency was set to 800 Hz, with a wall filter of 50 Hz. The prostate volume was determined with the prolate ellipsoid formula: length x width x height x 0.52 (6,7). Length was recorded as the greatest dimension in the sagittal plane; height, as the greatest diameter perpendicular to length; and width, as the greatest diameter in the transverse plane. The predicted PSA level was defined as the transrectal US volume x 0.12, and excess PSA was defined as the serum PSA level minus the predicted PSA level (6,7).
Gray-scale US findings were recorded as either normal or abnormal. Abnormal results were considered focal hypoechoic, focal hyperechoic, focal isoechoic but border-deforming lesions, or nonfocal poorly defined areas of alteration in gray-scale appearance. Color Doppler US findings were considered abnormal when either a focal area of increased vascularity was seen or asymmetry in color between the two sides of the prostate was defined. Color Doppler US results were recorded as either normal or abnormal; no attempt was made to grade the amount of vascularity. The type and sextant locations of all abnormalities at gray-scale and color Doppler US were recorded in a computer database immediately after transrectal US by the radiologist who had performed the procedure. This was done prior to availability of the pathology reports. The radiologist was therefore blinded to the pathologic findings, although the results of DRE, PSA level measurement, and excess PSA were available at the conclusion of the imaging examination.
Biopsy Technique
All biopsies were performed by the same radiologist (E.K., M.A.B., or H.M.F.) who performed transrectal US. Prior to biopsy, the risks and benefits of the biopsy procedure, as well as alternative methods of diagnosis, were explained to the patient to obtain informed written consent. Patients who did not consent to biopsy were excluded from the study. Biopsy was performed with an 18-gauge needle (ASAP; Meditech, Watertown, Mass) with transrectal US guidance toward any suspicious area (Fig 1) followed by systematic sextant biopsy of the entire gland. When transrectal US did not depict an abnormality, only sextant biopsy was performed.
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Data Analysis
We performed a retrospective review of prostate data from our computer database, which contained the transrectal US findings and pathology reports. The gray-scale and color Doppler US findings were correlated with the results of pathologic examination from the 6,528 core biopsy specimens. Data analysis rules were applied in the following order: A true-positive gray-scale transrectal US finding was defined as at least one gray-scale abnormality in the same location as a core biopsy containing malignancy. If additional core biopsy specimens in the same patient were positive, even in areas of normal gray-scale US findings, the findings were still considered true-positive. A true-negative gray-scale US finding was defined as the absence of any gray-scale abnormality and the absence of malignancy on all biopsy specimens. A false-negative finding was defined as the absence of a gray-scale abnormality in the same location as a biopsy finding positive for cancer. A false-positive finding was defined as a gray-scale abnormality at imaging, with a normal biopsy specimen from that location. Identical rules were applied for color Doppler US. For PSA level or excess PSA, analysis was performed for the overall gland. A true-positive finding was defined as an abnormal PSA level or excess PSA with at least one core specimen positive for malignancy.
The sensitivity, specificity, PPV, negative predictive value (NPV), and accuracy of gray-scale and color Doppler US, targeted biopsy, PSA level, and excess PSA were calculated on the basis of the data analysis rules presented previously. Statistical significance was calculated with the 
2 test, with P < .05 considered to indicate a significant difference. To determine which screening method or combination of methods best depicted the prostate cancer, multiple logistic regression was used to examine the independent effects of each screening method. We first fit a complete model with all interaction terms between the three screening methods and used backward stepwise elimination to remove nonsignificant interaction terms. All main effects were included in our final model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Gray-scale US findings were abnormal in 147 patients; the examination enabled correct identification of 78 (41.1%) of the 190 cancers but had false-positive findings in 69 cases. Gray-scale US yielded true-negative findings in 285 (85.3%) of 334 patients but did not include 112 (59%) of the 190 cancers. Use of gray-scale US alone resulted in a sensitivity of 41%, a specificity of 81%, a PPV of 52.7%, an NPV of 72%, and an accuracy of 67%.
Color Doppler US resulted in abnormal findings in 201 patients and correct identification of 82 (43.2%) of the 190 cancers but false-positive findings in 119 (59.2%) of 201. Color Doppler US produced true-negative findings in 235 (66.4%) patients but did not enable identification of 108 (56.8%) of the 190 cancers. Color Doppler US alone had a sensitivity of 43.2%, a specificity of 66.4%, a PPV of 40.8%, an NPV of 68.5%, and an accuracy of 58.3%. Tumors with a Gleason score of 7 or higher were also significantly more likely to be positive than negative at color Doppler US (P < .05) (Fig 3).
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Combining excess PSA with gray-scale US and/or color Doppler US abnormality resulted in correct identification of 155 (81.6%) of the 190 cancers but resulted in false-positive findings in 200 cases; although it was correctly negative in 154, it still resulted in 35 (18%) missed cancers. This produced a sensitivity of 81.6%, a specificity of 43.5%, a PPV of 43.7%, an NPV of 81.5%, and an accuracy of 56.8%. Seven of the 30 cancers that were missed by combining the three parameters also had Gleason scores of 6 or more. An analysis of the relative sensitivity and specificity of the various techniques used for prostate cancer detection in this study can be summarized in a receiver operating characteristic plot (Fig 8), as well as in tabular form (Table 3).
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There were no fatalities, serious complications, or major postbiopsy hemorrhage in any of the 544 patients. One (0.2%) patient who did not comply with the prophylactic antibiotic regimen was hospitalized because of septicemia.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In the current study, gray-scale US depicted 41% of the cancers, with a PPV of 52.7%. More than half (57%) the prostate cancers were sonographically occult and were missed at gray-scale and color Doppler US. A number of studies (11,12,14,16,27,28) have produced similar data, with PPVs of 0%–60%. Many macroscopic cancers are not readily visible at gray-scale US, and their conspicuity may be obscured by multiple factors (28–31).
Color Doppler US is a convenient and integral adjunct to gray-scale US. Our prospective study established that color Doppler US improved the identification of malignancy in an additional 30 patients but decreased specificity. When color Doppler US was added to transrectal gray-scale US findings, the sensitivity for prostate cancer increased from 41.0% to 56.8%, but the PPV decreased from 52.7% to 44.0% because of the low specificity of color Doppler US. Our results with color Doppler US are similar to those in other studies (14,15,16,27) that demonstrated an improvement in the detection of prostate cancer by an additional 10%–20%. Our data support the association of increased vascularity at color Doppler US with higher Gleason scores (P < .05). Transrectal color Doppler US improved the detection of higher-grade prostate cancer and also depicted hypervascularity, which appears to be a marker for more aggressive tumors.
An elevated PSA level greater than 4.0 ng/mL had a PPV of 37.7%, with a high sensitivity of 92.1% but a low specificity for cancer of 18.4%. Excess PSA (PSA > predicted PSA) improved the PPV to 52.4% and the specificity to 66.1% but decreased sensitivity to 69.5%. One limitation of this analysis is that an elevated PSA level was an entry criterion for the study, leading to a referral bias.
When all factors predictive of prostate cancer (ie, gray-scale and color Doppler US findings and excess PSA) were combined, sensitivity improved to 81.6%; specificity, to 43.5%; and PPV, to 43.7%. The combination still cannot reliably exclude prostate cancer with a false-negative rate of 15.8%, and biopsy is thus still required. In our study, if biopsy had been performed only on lesions visible at gray-scale and/or color Doppler US, only 108 patients with cancer would have been identified, and 82 (43%) of the 190 patients with cancer would have been missed. Therefore, targeted biopsy of US-visible lesions alone results in missing almost half of all cancers. On the basis of our findings, we believe that sextant biopsy coupled with targeting according to transrectal US and color Doppler US findings is the single best method at present for detection of prostate tumor.
Pathologic analysis of most sextant biopsy samples reveals benign findings. It is therefore important to determine first whether the extra biopsy procedures increase patient morbidity, and second, whether sextant biopsy reveals clinically important cancers. Complications were rare, and there was an extremely low morbidity rate with no fatalities. There is clearly some added discomfort associated with multiple biopsy procedures, but there was no significant bleeding complication in any of 544 patients. There was one (0.18%) hospital admission for septicemia in a patient who had not fully complied with the antibiotic regimen.
Sextant biopsy alone likely results in some missed lesions that would have been identified and targeted with US (31). Although cancers with Gleason scores greater than 7 were more likely to be visible at US and identified with the targeted rather than with the sextant biopsy technique (P < .001), a substantial number of occult cancers identified at sextant biopsy alone had Gleason scores greater than 6 (n = 25). Therefore, in our study, sextant biopsy also increased the yield of clinically important cancer (Gleason score > 6).
We attempted to determine whether serum or excess PSA levels could be used to reduce the number of patients who undergo biopsy that yields only benign specimens. If sextant biopsy had been performed only in patients with serum PSA levels greater than 4.0 ng/mL, 461 of 544 patients would have undergone biopsy. This would have eliminated 80 biopsy procedures but would have missed 15 (8%) of the 190 cancers. If sextant biopsy had been performed only in patients with a excess PSA level greater than 0 ng/mL, this threshold would have obviated 292 biopsy procedures but missed 58 (31%) of the 190 cancers. If sextant biopsy was performed only when any of the combinations of gray-scale US, color Doppler US, or excess PSA were positive, 355 of 544 patients would have undergone biopsy, obviating 184 biopsy procedures but missing 35 (18%) of the 190 cancers, including seven cancers with a Gleason score of six or more.
There are several limitations of this study. The data were analyzed on a per-patient basis, since this approach most closely reproduces the clinical use of the technique. Therefore, a true-positive result was recorded for patients in whom a single cancer was present in the same location as a gray-scale or color Doppler US-depicted abnormality. If additional core biopsy specimens in the same patient were positive even in areas of normal gray-scale imaging findings, the case was still considered as having a true-positive finding. This may have falsely elevated the sensitivity of transrectal US. Because the bias is toward a higher sensitivity for transrectal US, this is unlikely to have altered the conclusion that transrectal US is not sufficiently sensitive for screening.
In conclusion, all patients with abnormal DRE findings or PSA levels who are referred for transrectal US should undergo sextant biopsy regardless of the gray-scale US or color Doppler US findings. This is due to the relatively low sensitivity of transrectal US for lesion detection. However, when a lesion is seen at transrectal US, targeted biopsy should be performed, since the specificity of a transrectal US abnormality is sufficiently high to justify the additional effort of imaging-guided biopsy. In addition, cancers with a Gleason score of 7 or more were more likely to be visible at US and to undergo biopsy with the targeted rather than the sextant method. However, targeted biopsy of lesions visible at US alone misses almost half of all cancers.
Sextant biopsy results in a dramatic increase in the sensitivity of sampling for prostate cancer, and a substantial number of cancers occult at US have Gleason scores greater than 6. Sextant biopsy is safe and should be mandatory in all patients with abnormal DRE results or elevated PSA levels, regardless of transrectal US findings. The primary value of transrectal US is to guide the systematic sampling of normal prostate parenchyma and abnormal prostate parenchyma. The results of this study show that gray-scale transrectal US, even coupled with color Doppler US, is not an adequate screening method for prostate carcinoma; therefore, targeted biopsy should always be accompanied by complete sampling of the gland with sextant biopsy.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, E.K., M.A.B.; study concepts, E.K., M.A.B.; study design, E.K., M.A.B., H.M.F.; literature research, E.K.; clinical studies, E.K., M.A.B., H.M.F.; data acquisition, E.K., M.A.B., H.M.F.; data analysis, M.A.B., M.B., H.M.F.; statistical analysis, M.A.B., H.M.F.; manuscript preparation, E.K., M.A.B.; definition of intellectual content, M.A.B.; manuscript editing and review, all authors; manuscript final version approval, E.K., M.A.B.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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